Tablet formulations of RBP4 inhibitors and methods of use

Abstract

Provided herein are heterocyclic derivative compounds, and tablet pharmaceutical compositions comprising the compounds, that are useful for treating retinol binding protein (RBP4)-associated diseases, such as macular degeneration.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 282,540, filed November 23, 2021, which is incorporated herein by reference in its entirety. [Background technology]

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

[0003] Provided herein are formulations for reducing serum or plasma levels of RBP4.

[0004] Provided herein is a tablet pharmaceutical composition comprising: (i) Formula (I)

[0005] [ka] a compound of the formula (I) or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, During the ceremony, R 1 are each independently halogen, haloalkyl, or alkyl; R 2 is -H, -OH, or a halogen; p is 0, 1, 2, 3, 4, or 5; A is as follows:

[0006] [ka] having the structure During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane; B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure, a compound, a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof; (ii) at least one excipient comprising one or more of a disintegrant, a dispersion polymer, a diluent, a glidant, and a lubricant. Further provided herein is a pharmaceutical composition, wherein A is

[0007] [ka] having the structure During the ceremony, n is 0, 1, or 2; α, β, χ, δ, ε, and Φ are each independently absent or present, and when present, each is a bond; Z1 is S, O, or N; Z2 is S, O, N or NR 3 and where R 3 is H, C1-C4 alkyl, or oxetane; X is C, Each occurrence of Y1, Y2, Y3, and Y4 independently 4 , C(R 5 )2, NR 6 , O, N, SO2, or -(C=O)-, where 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 10alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C 10 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C 10 alkyl), -CN, or -CF; R 5 is H, or C1-C 10 is alkyl, R 6 is H, C1-C 10 Alkyl, C3-C6 cycloalkyl, -(C1-C 10 alkylene)CF3, -(C1-C 10 alkylene)OCH3, -(C1-C 10 Alkylene)-halogen, -SO2(C1-C 10 alkyl), -SO2(C1-C 10 alkylene)-CF3, -SO2(C1-C 10 alkylene)OCH3, -SO2(C1-C 10 alkylene)-halogen, -C(O)(C1-C 10 alkyl), -C(O)(C1-C 10 alkylene)CF3, -C(O)(C1-C 10 alkylene)OCH3, -C(O)(C1-C 10 alkylene)-halogen, -C(O)NH(C1-C 10 alkyl), -C(O)N(C1-C 10 alkyl)2, -(C1-C 10 Further provided herein is a pharmaceutical composition, wherein A is:

[0008] [ka] having the structure During the ceremony, n is 0, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y3 are each CH2 or C(CH3)2; Y2 is O, SO2, or NR 6 and R 6 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, -C(O)(C

[0013] Further provided herein is a pharmaceutical composition wherein the compound of formula (I) is:

[0009] [ka] or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. Further provided herein are pharmaceutical compositions in which the compound of formula (I) is effective for lowering RBP4 levels in a dosage form of about 1 to about 200 mg or about 5 to about 25 mg. Further provided herein are pharmaceutical compositions in which the compound of formula (I) is micronized crystals. Further provided herein are pharmaceutical compositions in which the compound of formula (I) is a polymorph that exhibits an X-ray powder diffraction pattern with at least three characteristic peaks occurring at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 0.5 degrees 2-theta). Further provided herein are pharmaceutical compositions in which the compound of formula (I) is amorphous. Also provided herein are pharmaceutical compositions in which at least one excipient comprises a disintegrant. Also provided herein are pharmaceutical compositions in which the disintegrant is selected from the group consisting of agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, and combinations thereof. Also provided herein are pharmaceutical compositions in which the disintegrant comprises CCNa, MCC, crospovidone, tapioca starch, or a combination thereof. Also provided herein are pharmaceutical compositions in which the disintegrant is present in an amount of about 0.01-99%, 1-50%, or 2-20% by weight of the pharmaceutical composition. Further provided herein is a pharmaceutical composition, wherein CCNa or MCC is about 0.75% or 3% by weight of the pharmaceutical composition. Further provided herein is a pharmaceutical composition, wherein at least one excipient comprises a dispersion polymer.Further provided herein are pharmaceutical compositions in which the dispersion polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof. Further provided herein are pharmaceutical compositions in which the compound of Formula (I) is amorphous and / or molecularly dispersed in the dispersion polymer. Further provided herein are pharmaceutical compositions in which the dispersion polymer comprises HPC, HPMC, or both. Further provided herein are pharmaceutical compositions in which the dispersion polymer comprises HPMC, HPMC-AS, PVP, or combinations thereof. Further provided herein are pharmaceutical compositions in which the dispersion polymer is present in an amount of about 0.01-99%, 1-50%, or 2-20% by weight of the pharmaceutical composition. Further provided herein are pharmaceutical compositions in which HPC or HPMC is present in an amount of about 6% by weight of the pharmaceutical composition. Further provided herein are pharmaceutical compositions in which HPMC, HPMC-AS, or PVP is present in an amount of about 10% or 20% by weight of the pharmaceutical composition. Further provided herein are pharmaceutical compositions in which at least one excipient comprises about 0.75% by weight of CCNa, MCC, crospovidone, or tapioca starch and about 6% by weight of HPC. Further provided herein are pharmaceutical compositions in which at least one excipient comprises about 0.75% by weight of CCNa, MCC, crospovidone, or tapioca starch and about 10% by weight of HPMC. Further provided herein is a pharmaceutical composition, wherein the at least one excipient comprises about 0.75% CCNa, MCC, crospovidone, or tapioca starch by weight of the pharmaceutical composition, and about 20% HPMC by weight of the pharmaceutical composition.Further, it is provided herein that the compound of formula (I) is:

[0010] [ka] or a pharmaceutically acceptable salt, crystalline solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. Also provided herein are pharmaceutical compositions wherein at least one excipient comprises a diluent, binder, anti-adherent, filler, sweetener, wetting agent, glidant, lubricant, or surfactant, or a combination thereof. Also provided herein are pharmaceutical compositions wherein the compound of Formula (I) is not formulated for delayed release. Also provided herein are pharmaceutical compositions wherein at least one excipient is not formulated for delayed release. Also provided herein are pharmaceutical compositions further comprising an outer coating. Also provided herein are pharmaceutical compositions wherein the outer coating is about 0.01-99%, 1-50%, or 2-20% by weight of the pharmaceutical composition. Also provided herein are pharmaceutical compositions wherein the outer coating does not cause delayed release of the compound of Formula (I) and / or at least one excipient. Further provided herein are pharmaceutical compositions in which the diluent comprises MCC, lactose monohydrate (LMH), or both. Further provided herein are pharmaceutical compositions in which the binder comprises MCC, HPC, or both. Further provided herein are pharmaceutical compositions in which the flow aid comprises colloidal silicon dioxide (CSD), magnesium stearate, or both. Further provided herein are pharmaceutical compositions in which the glidant comprises CSD. Further provided herein are pharmaceutical compositions in which the lubricant comprises magnesium stearate. Further provided herein are pharmaceutical compositions in which at least one excipient comprises one or more of MCC, LMH, HPC, CCNa, CSD, and magnesium stearate. Further provided herein are pharmaceutical compositions in which at least one excipient comprises two or more of MCC, LMH, HPC, CCNa, CSD, and magnesium stearate. Further provided herein are pharmaceutical compositions in which the diluent functions as a binder and / or disintegrant. Further provided herein are pharmaceutical compositions wherein the fluidization aid functions as a glidant or lubricant.Further provided herein is a pharmaceutical composition having a dry weight of about 0.1 mg to about 400 mg. Further provided herein is a pharmaceutical composition in which the compound of formula (I) is present in an amount of about 1 to 99.99%, about 10 to 80%, or about 20 to 60% by weight of the pharmaceutical composition. Further provided herein is a pharmaceutical composition comprising 1 to 10% by weight of the compound of formula (I). Further provided herein is a pharmaceutical composition comprising 0.1 to 1.5% by weight of CCNa. Further provided herein is a pharmaceutical composition comprising 1 to 10% by weight of HPC. Further provided herein is a pharmaceutical composition comprising 15 to 60% by weight of MCC. Further provided herein is a pharmaceutical composition comprising 15 to 60% by weight of LMH. Further provided herein is a pharmaceutical composition comprising 0.1 to 2% by weight of magnesium stearate. Further provided herein are pharmaceutical compositions that, when stored at other atmospheric conditions, do not exhibit a significant loss of chemical stability, deterioration, and / or degradation after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years at 25° C. Further provided herein are pharmaceutical compositions that, when stored at other atmospheric conditions, do not exhibit a significant loss of chemical stability, deterioration, and / or degradation of the compound of Formula (I), its pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer, or at least one excipient, after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years at 25° C. Further provided herein are pharmaceutical compositions that do not exhibit a significant loss of chemical stability, deterioration, and / or decomposition after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, or 1 year at 40°C when stored at other atmospheric conditions.Further provided herein are pharmaceutical compositions that, when stored at other atmospheric conditions, do not exhibit significant loss of chemical stability, deterioration, and / or decomposition of the compound of Formula (I), its pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer, or at least one excipient after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, or 1 year at 40° C. Further provided herein are pharmaceutical compositions in which at least about 5%, 10%, 25%, 50%, 75%, 80%, 90%, 95%, or 100% by weight of the pharmaceutical composition separates or dissolves after about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 1 hour when placed in an aqueous medium at about pH 7 at 25° C. Also provided herein are pharmaceutical compositions in which at least about 5%, 10%, 25%, 50%, 75%, 80%, 90%, 95%, or 100% of the weight of the pharmaceutical composition separates or dissolves after about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 1 hour when placed in simulated gastric fluid at 37°C. Also provided herein are pharmaceutical compositions in which the aqueous medium comprises water. Also provided herein are pharmaceutical compositions in which the aqueous medium comprises water and the pharmaceutical composition is placed in a USP Type II Apparatus at 50 rpm in 900 mL of simulated gastric fluid at 37°C. Also provided herein are pharmaceutical compositions in which at least one excipient accounts for about 0.01-99%, 1-50%, or 2-20% of the weight of the pharmaceutical composition.

[0011] Provided herein is a method for treating an ocular disease, comprising administering a therapeutically effective amount of a pharmaceutical composition described herein to a subject in need of treatment for the ocular disease. Also provided herein is a pharmaceutical composition, wherein the ocular disease is a disease characterized by excessive lipofuscin accumulation in the retina. Also provided herein is a pharmaceutical composition, wherein the disease characterized by excessive lipofuscin accumulation includes age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt disease), Best disease, adult vitelliform maculopathy, geographic atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene-associated retinal disease.

[0012] Provided herein are methods for reducing serum or plasma levels of RBP4 in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. Also provided herein are pharmaceutical compositions, wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg to about 400 mg of a compound of Formula (I). Also provided herein are pharmaceutical compositions, wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.5 mg to about 50 mg of a compound of Formula (I). Also provided herein are pharmaceutical compositions, wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg of a compound of Formula (I). Also provided herein are pharmaceutical compositions, wherein the therapeutically effective amount of the pharmaceutical composition comprises about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, or about 400 mg of a compound of Formula (I). Also provided herein are pharmaceutical compositions, wherein the pharmaceutical composition is administered once, twice, three times, or four times daily. Further provided herein is a pharmaceutical composition that is administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, every week, every other week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. Further provided herein is a pharmaceutical composition that is administered once a day. Further provided herein is a pharmaceutical composition that is administered orally. Further provided herein is a pharmaceutical composition that reduces the subject's serum RBP4 concentration or plasma RBP4 concentration to less than 1 μM after treatment.Further provided herein is a method for making a tablet pharmaceutical composition, comprising the steps of: (i) simultaneously sieving a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, a disintegrant, a dispersion polymer, two diluents, a glidant, and a lubricant through a 30 mesh screen; (ii) charging the sieved materials from step (i) into a blender and blending for a first period of time; (iii) removing the blended materials from step (ii) and sieving them through a 30 mesh screen; and (iv) blending the sieved materials from step (iii) into a blender. (v) simultaneously sieving the glidant and lubricant through a 60 mesh screen and lubricating the mixed material of step (iv) in the blender for a third period of time, (vi) granulating the lubricated material of step (v) by roller compaction, (vii) sieving the lubricant through a 60 mesh screen and lubricating with the granulated material of step (vi) for a fourth period of time, and (viii) compressing the material of step (vii) into a tablet pharmaceutical composition. Further provided herein is a method further comprising packaging the produced tablet pharmaceutical composition in a bottle. Further provided herein is a method wherein the disintegrant comprises agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, or combinations thereof.Further provided herein is a method in which the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or a combination thereof. Further provided herein is a method in which the diluent comprises CCNa, HPC, MCC, LMH, CSD, magnesium stearate, or a combination thereof. Further provided herein is a method in which the glidant comprises colloidal silicon dioxide, talc, corn starch, metal silicate, higher fatty acid metal salt, metal oxide, alkaline earth metal salt, metal hydroxide, or a combination thereof. Further provided herein is a method wherein the lubricant comprises 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. Further provided herein is a method wherein the mixing in step (ii) is performed at 15 rpm for 15 minutes. Further provided herein is a method wherein the mixing in step (iv) is performed at 15 rpm for 15 minutes. Further provided herein is a method wherein the mixing in step (v) is performed at 15 rpm for 5 minutes. Further provided herein is a method wherein the mixing in step (vii) is performed at 15 rpm for 5 minutes. Further provided herein is a method wherein step (vi) is performed at a roll pressure of about 2 to about 5 MPa, a roll gap of about 0.3 to about 4 mm, a roll speed of about 3 to about 7 rpm, and / or a feed screw speed of about 18 to about 81 rpm.Further provided herein is a method in which step (vi) is carried out at a roll pressure of about 3 MPa, a roll gap of about 2 mm, a roll speed of about 4 rpm, and / or a feed screw speed of about 20 rpm. Further provided herein is a method in which step (viii) is carried out using a circular punch of about 6.0 mm at a rotation speed of about 20 to about 30 rpm, a thickness scale of about 1.0 to about 3.5 mm, a fill depth scale of about 3.0 to about 10.0 mm, and / or a main compression force of about 3.0 to about 10.0 kN. Further provided herein is a method in which step (viii) is carried out at a rotation speed of about 30 rpm, a thickness scale of about 2.0 mm, a fill depth scale of about 6.0 mm, and / or a main compression force of about 7.0 kN. Further provided herein is a method in which the bulk density of the lubricated material in step (vi) is about 0.45 to about 0.6 g / ml. Further provided herein is a method wherein the bulk density of the lubricated material in step (vi) is about 0.5 g / ml. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method is about 92.5 to about 107.5 mg. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method is about 100 mg. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method comprises a thickness of about 2.7 to about 3.3 mm. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method comprises a thickness of about 3.0 mm. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method comprises a hardness of about 45 to about 95 N. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method comprises a hardness of about 70 N. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to this method comprises a friability of about 1.0 wt% or less. Further provided herein is a method wherein the tablet pharmaceutical composition produced according to the method has a disintegration time of 15 minutes or less. Further provided herein is a method wherein at least one of the two diluents functions as a binder and / or a disintegrant. Further provided herein is a method wherein the glidant functions as a fluidization aid.Further provided herein is a method wherein a lubricant functions as a fluidization aid. Further provided herein is a method wherein at least one of the blenders used in steps (ii), (iv), and (v) is an approximately 100 L bin blender. Further provided herein is a method wherein the packaging step is performed using approximately 45 ml HDPE bottles, and the HDPE bottles contain the 30 tablets of the tablet pharmaceutical composition produced. Further provided herein is a method further comprising, after step (iv), obtaining samples of about 98.5 to about 295.5 mg of the blended material from each of about 10 locations in the blender. Further provided herein is a method wherein the samples are about 197 mg. Further provided herein is a method wherein the obtaining step is performed such that all individual assays are within the mean ± 10% (absolute value) and RSD %, and the NMT is about 5%. Further provided herein is a method further comprising, after step (v), testing the BD and / or TD of the material lubricated in step (v) so that the resulting density is about 0.5 g / ml or about 0.45 to about 0.6 g / ml. Further provided herein is a method wherein the lubricant used in step (v) is intragranular. Further provided herein is a method wherein the lubricant used in step (vii) is extragranular. Further provided herein is a method wherein the disintegrant is selected from the group consisting of agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, and combinations thereof.Further provided herein is a method wherein the dispersion polymer is selected from the group comprising hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, and combinations thereof. Further provided herein is a method wherein the compound of formula (I) is

[0013] [ka] or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. Also provided herein are methods in which each of the disintegrant, dispersion polymer, two diluents, glidant, and lubricant is about 0.01-99%, 1-50%, or 2-20% by weight of the tablet pharmaceutical composition. Also provided herein are methods in which the compound of Formula (I) is about 1-99.99%, about 10-80%, or about 20-60% by weight of the tablet pharmaceutical composition. Also provided herein are methods in which the dry weight of the tablet pharmaceutical composition is about 0.1 mg to about 400 mg.

[0014] Provided herein is a method for reducing serum or plasma levels of RBP4 in a subject, comprising:

[0015] [ka] or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, and at least one excipient, wherein the pharmaceutical composition is administered in an amount of about 5 mg, and the pharmaceutical composition is administered daily, wherein the subject's serum or plasma level of RBP4 is reduced to less than 1 μM.

[0016] Provided herein is a pharmaceutical composition comprising any one of Formulas 1-140 in Tables 31-38. Provided herein is a method of reducing the serum or plasma concentration of RBP4 in a subject, comprising administering to the subject a tablet of a pharmaceutical composition described herein.

[0017] Provided herein are methods for treating age-related macular degeneration, dry (atrophic) age-related macular degeneration, early-onset macular degeneration (Stargardt's disease), Best's disease, adult vitelliform maculopathy, geographic atrophy, Stargardt's macular dystrophy, diabetic retinopathy, or an ABCA4 gene-associated retinal disease in a subject, the method comprising administering to the subject a tablet of the pharmaceutical composition provided herein.

[0018] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. [Brief explanation of the drawings]

[0019] The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0020] [Figure 1]Pharmacokinetic profiles of five different tablet and capsule API-in-Capsule formulations of the compound of Formula (I). The Y-axis displays the concentration of the compound of Formula (I) (ng / mL, 1-1000 in log intervals), and the X-axis displays time (hours, 0-24 in 4-hour intervals). Legend: Period 1: Capsule API (black diamond), Period 2: 3% CCNa (white square), Period 3: 0.75% CCNa (black circle), Period 4: 0.75% CCNa + 6% HPC (white triangle), Period 5: 0.75% CCNa + 10% HPMC (X), Period 6: 0.75% CCNa + 20% HPMC (white circle). [Figure 2] Pharmacodynamic profiles of five tablet and capsule drug substance formulations of the compound of Formula (I) are shown. The Y-axis displays the mean RBP4 concentration (ng / mL, 1-25,000 in 5,000-unit intervals), and the X-axis displays time (hours, 0-24 in 4-hour intervals). Legend: Phase 1: API in Cupsule (black diamonds), Phase 2: 3% CCNa (white squares), Phase 3: 0.75% CCNa (black circles), Phase 4: 0.75% CCNa + 6% HPC (white triangles), Phase 5: 0.75% CCNa + 10% HPMC (crosses), Phase 6: 0.75% CCNa + 20% HPMC (white circles). [Figure 3] Figure 1 shows serum RBP4 reduction for five tablet and capsule drug substance formulations of the compound of Formula (I). The Y-axis displays mean RBP4 levels (%, 0-100 in 10% intervals), and the X-axis displays time (hours, 0-24 in 4-hour intervals). Legend: Phase 1: API in cupsule (black diamonds), Phase 2: 3% CCNa (white squares), Phase 3: 0.75% CCNa (black circles), Phase 4: 0.75% CCNa + 6% HPC (white triangles), Phase 5: 0.75% CCNa + 10% HPMC (X), Phase 6: 0.75% CCNa + 20% HPMC (white circles). DETAILED DESCRIPTION OF THE INVENTION

[0021] 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, a reference to "an agent" includes a plurality of such agents; a reference to "the cell" includes a 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 formulas, all combinations and subcombinations of ranges and specific embodiments within the ranges are intended to be included. The term "about," when referring to a numerical value or numerical range, means that the stated numerical value or numerical range is approximate within experimental error (or within statistical experimental error), and thus the numerical value or numerical range, as the case may be, varies by 1% to 15% of the stated numerical value or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, such as any composition of matter, composition, method, or process described herein, from "consisting of" or "consisting essentially of" the described features.

[0022] definition The following terms, as used in this specification and the appended claims, have the meanings indicated below, unless specified to the contrary.

[0023] "Amino" refers to the -NH2 radical.

[0024] "Cyano" refers to the -CN radical.

[0025] "Nitro" refers to the -NO2 radical.

[0026] "Oxa" refers to the -O- radical.

[0027] "Oxo" refers to the =O radical.

[0028] "Thioxo" refers to the =S radical.

[0029] "Imino" refers to the =NH radical.

[0030] "Oximo" refers to the =N-OH radical.

[0031] "Hydrazino" refers to the =N-NH2 radical.

[0032] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (e.g., C-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified specifically in the specification, an alkyl group may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0033] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0034] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specified specifically in the specification, an alkenyl group may contain the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-R a , -N(Ra )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0035] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specified specifically in the specification, an alkynyl group may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0036] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, that connects the rest of the molecule to a radical group, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through a single carbon in the alkylene chain or any two carbons within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene contains 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene contains 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene contains 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless otherwise specified specifically in the specification, an alkylene chain may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0037] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms, that connects the rest of the molecule to a radical group. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, an alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2), optionally replaced by one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0038] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms, connecting the rest of the molecule to a radical group. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, the alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, an alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, an alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a)2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0039] "Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic, delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include an aryl radical that is optionally substituted by one or more substituents, the substituents being independently 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 , -Rb -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0040] "Aralkyl" is a group of the formula -R c -refers to an aryl radical, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0041] "Aralkenyl" refers to a group of the formula -R d -refers to an aryl radical, where R d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0042] "Aralkynyl" refers to a group of the formula -R e -refers to an aryl radical, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0043] "Aralkoxy" is a group of the formula -OR c -refers to a radical attached through an oxygen atom of an aryl, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0044] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals optionally substituted by one or more substituents, which substituents are independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a, -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0045] A "carbocyclylalkyl" is a group of the formula -R c -refers to a carbocyclyl radical, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0046] "Carbocyclylalkynyl" refers to a group of the formula -R c -refers to a carbocyclyl radical, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0047] "Carbocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached through the oxygen atom of a carbocyclyl, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0048] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include:

[0049] [ka] These include, but are not limited to:

[0050] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0051] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0052] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in this specification, the term "heterocyclyl" is meant to include heterocyclyl radicals, as defined above, optionally substituted by one or more substituents, including alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-Ra , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0053] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0054] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0055] "Heterocyclylalkyl" refers to a group of the formula -R c - refers to the heterocyclyl radical, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0056] "Heterocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a heterocyclyl, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0057] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one of the rings is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]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-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, Pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] Pyrimidinyl, 6,7,8,9-tetrahydro-5H-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]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified specifically in this specification, the term "heteroaryl" is intended to include heteroaryl radicals as defined above, optionally substituted by one or more substituents, where the substituents are alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a ,-R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -Rb -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and R b are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0058] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0059] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0060] "Heteroarylalkyl" refers to R c is an alkylene chain as defined above, c - refers to a radical of heteroaryl. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0061] "Heteroarylalkoxy" refers to R c is an alkylene chain as defined above, c -refers to a radical bonded through the oxygen atom of a heteroaryl. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0062] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as racemic and optically pure forms thereof, and all tautomeric forms, are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0063] "Tautomer" refers to a molecule that is capable of transferring a proton from one atom of the molecule to another atom of the same molecule. The compounds presented herein, in certain embodiments, exist as tautomers. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on various factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0064] [ka] Examples include:

[0065] In some embodiments, the compounds disclosed herein are used in various enriched isotopic forms, for example: 2 H, 3 H, 11 C. 13 C, and / or 14C content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can increase the duration of action of a drug by improving metabolic stability and / or efficacy.

[0066] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0067] The compounds of the present disclosure may optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 It may be labeled with an isotope such as 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, 81Br, 125 All isotopic substitutions at I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0068] In certain embodiments, the compounds disclosed herein comprise: 2 exchanged with H atoms 1 Some or all of the H atoms are present. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthesis methods:

[0069] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in Dean, Dennis C., Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110pp; George W., Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates Tetrahedron, 1989,45(21),6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981,64(1-2),9-32.

[0070] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to synthesize deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0071] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be utilized to deliver a deuterium-substituted carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I can be seen, by way of example only, in the following reaction scheme:

[0072] [ka]

[0073] As exemplified below. Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are utilized to deliver deuterium to reaction substrates under reducing conditions. The use of LiAlD4 is illustrated, by way of example only, in the following reaction scheme:

[0074] [ka] As exemplified below.

[0075] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds, and by way of example only, the following reaction scheme:

[0076] [ka]

[0077] It is used to perform reductive substitution of aryl carbon-halogen bonds, as exemplified by:

[0078] 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 include five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and are non-exchangeable. 1 In one embodiment, the level of deuterium incorporation is determined by the synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0079] Throughout the specification, examples, and claims, various 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 the weight ratio of each component.

[0080] " Pharmaceutically acceptable salt " includes both acid addition salt and base addition salt.The pharmaceutically acceptable salt of any one of the heterocyclic RBP4 inhibitor compounds described herein is intended to include any pharmaceutically suitable salt form.Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salt and pharmaceutically acceptable base addition salt.

[0081] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, which salts are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Additionally, salts of amino acids such as arginate, gluconate, galacturonate, and the like are contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, 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 those skilled in the art.

[0082] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, which salts are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0083] As used herein, "treatment," "treating," "palliating," or "ameliorating" are used interchangeably. These terms refer to an approach to obtaining a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Furthermore, therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that the patient observes improvement despite still suffering from the underlying disease. With regard to prophylactic benefit, in some embodiments, the composition is administered to a patient who is at risk of developing the disease or who reports one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0084] In some embodiments, "prodrug" refers to a compound that is converted into a biologically active compound described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. Prodrugs are generally inactive when administered to a subject, but are converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)).

[0085] A discussion of prodrugs is provided in Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0086] The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when the prodrug is administered to a mammalian subject. As described herein, prodrugs of active compounds are prepared by modifying functional groups present in the active compound such that the modifications are cleaved to the parent active compound, either in routine manipulation or in vivo. Prodrugs include compounds that are bonded to any group such that a hydroxyl, amino, or mercapto group is cleaved to form a free hydroxyl, amino, or mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compound.

[0087] X-ray powder diffraction (XRPD) peaks are described throughout this specification and claims. XRPD peak values ​​in this application refer to those obtained using a copper source with a wavelength of 1.5406 angstroms, unless otherwise specified.

[0088] As used herein, "Compound 1" or "CMPD-1" refers to Compound No. 1 shown in Table 1. Compound 1 is

[0089] [ka] Compound 1 has the structure: Compound 1 is also referred to by the full chemical name 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one.

[0090] RBP4 inhibitor compounds In some embodiments, the present disclosure provides RBP4 inhibitor compounds and pharmaceutical compositions comprising these compounds.The subject compounds and compositions inhibit RBP4 and are useful for treating eye diseases or disorders such as age-related macular degeneration, dry (atrophic) age-related macular degeneration, early-onset macular degeneration (Stargardt's disease), Best's disease, adult vitelliform maculopathy, geographic atrophy, Stargardt's macular dystrophy, diabetic retinopathy or ABCA4 gene-related retinal disease.

[0091] Some embodiments provided herein include a compound of formula (I) for use in the treatment of a metabolic disease or disorder.

[0092] [ka] or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure: During the ceremony, R 1 are each independently selected from halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, -COR 7 , -CON(R 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene)N(R 8 )-COR 7, optionally substituted (C0-C4 alkylene)-SON(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7 , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 and R 7 are each independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, or two R 11 groups taken together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; R 8 are each independently selected from H or optionally substituted alkyl; R 2 is —H, —OH, optionally substituted alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A is as follows:

[0093] [ka] having the structure During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3is H, optionally substituted alkyl, or oxetane; B describes a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, which is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0094] Some embodiments provided herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 each independently represents a halogen, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 3-10 Heterocycloalkyl, -COR 7 , -CON(R 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene)N(R 8 )-COR 7 , optionally substituted (C0-C4 alkylene)-SON(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7 , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 and R 7 are each independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Carbocyclyl, optionally substituted C3-10 Carbocyclylalkyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 2-10 heterocyclylalkyl, or two R 11 groups, together with the nitrogen to which they are attached, optionally substituted C 2-6 forming an N-heterocyclyl, R 8 are each independently H or optionally substituted C 1-6 alkyl, R 2 is -H, -OH, optionally substituted C 1-6 alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A is as follows:

[0095] [ka] having the structure During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, optionally substituted C 1-6 alkyl, or oxetane; B describes a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, which is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0096] Certain embodiments provided herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclyl, C 3-10 Heterocycloalkyl, -COR 7 , -CON(R 7 )2, (C 0- (C4 alkylene)-CN, (C0-C4 alkylene)-OR 7 , C0-C4 alkylene)-N(R 7 )2, (C0-C4 alkylene)N(R 8 )-COR 7 , (C0-C4 alkylene)-SON(R 7 )2, (C0-C4 alkylene)-SO2R 7 , (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or (C0-C4 alkylene)N(R 8 )-SO2R 7 and R 7 are independently H, C 1-6 Alkyl, C3-6 carbocyclyl, C 3-10 Carbocyclylalkyl, C 2-6 Heterocyclyl, C 2-10 heterocyclylalkyl, or two R 11 The groups, together with the nitrogen to which they are attached, form C 2-6 forming an N-heterocyclyl, R 8 are each independently H or C 1-6 alkyl, R 2 -H, -OH, C 1-6 alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A is as follows:

[0097] [ka] having the structure During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C 1-6 alkyl, or oxetane; B describes a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, which is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0098] Some embodiments provided herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 are each independently halogen, haloalkyl, or alkyl; R 2 is -H, -OH, or a halogen; p is 0, 1, 2, 3, 4, or 5; A is as follows:

[0099] [ka] having the structure During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3is H, C1-C4 alkyl, or oxetane; B describes a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, which is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0100] Certain embodiments provided herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof: During the ceremony, R 1 are independently Br, Cl, F, and C 1-6 Fluoroalkyl, or C 1-6 is alkyl, R 2 is -H, -OH, Br, Cl, or F, p is 0, 1, 2, 3, 4, or 5; A is as follows:

[0101] [ka] having the structure During the ceremony, α, β, χ, and δ are each independently absent or present, and when present, each is a bond; X is C, Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane; B describes a compound, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, which is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure.

[0102] For any and all embodiments of formula (I), the substituents are selected from among a subset of the listed options.

[0103] In some embodiments, R 1 each independently represents a halogen, an optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 3-10 Heterocycloalkyl, -COR 7 , -CON(R 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR 7 , optionally substituted (C0-C4 alkylene)-N(R 7 )2, optionally substituted (C0-C4 alkylene)N(R 8 )-COR 7 , optionally substituted (C0-C4 alkylene)-SON(R 7 )2, optionally substituted (C0-C4 alkylene)-SO2R 7 , optionally substituted (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or optionally substituted (C0-C4 alkylene)N(R 8 )-SO2R 7 In certain embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclyl, C 3-10 Heterocycloalkyl, -COR 7 , -CON(R 7 )2, (C0-C4 alkylene)-CN, (C0-C4 alkylene)-OR 7 , (C0-C4 alkylene)-N(R 7 )2, (C0-C4 alkylene)N(R 8 )-COR 7, (C0-C4 alkylene)-SON(R 7 )2, (C0-C4 alkylene)-SO2R 7 , (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or (C0-C4 alkylene)N(R 8 )-SO2R 7 In some embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -COR 7 , -CON(R 7 )2, (C0-C4 alkylene)-CN, (C0-C4 alkylene)-OR 7 , or (C0-C4 alkylene)-N(R 7 )2. In other embodiments, R 1 are each independently (C0-C4 alkylene)N(R 8 )-COR 7 , (C0-C4 alkylene)-SON(R 7 )2, (C0-C4 alkylene)-SO2R 7 , (C0-C4 alkylene)N(R 8 )-SO2N(R 7 )2, or (C0-C4 alkylene)N(R 8 )-SO2R 7 In some embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -COR 7 , -CON(R 7 )2, -CN, (C0-C4 alkylene)-OR 7 , or (C0-C4 alkylene)-N(R 7 )2. In some embodiments, R 1 are each independently a halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -CN. In certain embodiments, R 1 are independently F, Br, Cl, and C 1-6 Haloalkyl, or C 1-6In specific embodiments, R 1 are each independently F or CF3.

[0104] In some embodiments, R 7 are each independently H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Carbocyclyl, optionally substituted C 3-10 Carbocyclylalkyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 2-10 heterocyclylalkyl, or two R 11 groups, together with the nitrogen to which they are attached, optionally substituted C 2-6 In some embodiments, R 7 are independently H, C 1-6 Alkyl, C 3-6 Carbocyclyl, C 3-10 Carbocyclylalkyl, C 2-6 Heterocyclyl, C 2-10 heterocyclylalkyl, or two R 11 The groups, together with the nitrogen to which they are attached, form C 2-6 In some embodiments, R 7 are independently H, C 1-6 Alkyl, or C 3-6 In certain embodiments, two R 11 groups, together with the nitrogen to which they are attached, optionally substituted C 2-6 In some embodiments, R 7 are each independently H or C 1-6 In some embodiments, R 7 are H or Me, respectively.

[0105] In some embodiments, R 8 are independently H, C 1-6 Alkyl, or C1-6 In some embodiments, R is selected from haloalkyl. 8 are each independently H or C 1-6 In some embodiments, R 8 are each independently selected from H or Me. In some embodiments, R 8 are H, respectively.

[0106] 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.

[0107] In some embodiments, R 2 is —H, —OH, optionally substituted alkyl, or halogen. In some embodiments, R 2 is —H, —OH, alkyl, haloalkyl, or halogen. 2 -H, -OH, C 1-6 Alkyl, C 1-6 haloalkyl, or halogen. In some embodiments, R 2 is —H, —OH, Me, CF, or halogen. 2 is —H, —OH, Me, CF, Cl, or F. In some embodiments, R 2 is —H, —OH, Me, CF, or F. In some embodiments, R 2 is —H, —OH, or halogen. In some embodiments, R2 is —H, —OH, or F. In some embodiments, R 2 is —H. In some embodiments, R 2 is —OH. In some embodiments, R 2 is F. In some embodiments, R 2 is Cl.

[0108] In some embodiments, when α is present, Z1 is O or S, Z2 is N, X is C, χ is present, and β and δ are absent. In other embodiments, when α is absent, Z1 is N and Z2 is NR 3 and X is C, β and δ are present, and χ is absent. In certain embodiments, when α is absent, Z1 is N, Z2 is O or S, X is C, β and δ are present, and χ is absent.

[0109] In some embodiments, A is

[0110] [ka] having the structure During the ceremony, n is 0, 1, or 2; α, β, χ, δ, ε, and Φ are each independently absent or present, and when present, each is a bond; Z1 is S, O, or N; Z2 is S, O, N, or NR 3 and where R 3 is H, C1-C4 alkyl, or oxetane; X is C, Each occurrence of Y1, Y2, Y3, and Y4 independently 4 , C(R 5 )2, NR 6 , O, N, SO2, or -(C=O)-, where R 4 H, halogen, C1-C 10 Alkyl, C1-C10 Cycloalkyl, -O(C1-C 10 alkyl), -C(O)OH, -C(O)O(C1-C 10 alkyl), -C(O)NH2, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -NHC(O)NH(C1-C 10 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C 10 alkyl), -CN, or -CF; R 5 is H or C1-C 10 is alkyl, R 6 is H, C1-C 10 Alkyl, C3-C6 cycloalkyl, -(C1-C 10 alkylene)CF3, -(C1-C 10 alkylene)OCH3, -(C1-C 10 Alkylene)-halogen, -SO2(C1-C 10 alkyl), -SO2(C1-C 10 alkylene)-CF3, -SO2(C1-C 10 alkylene)OCH3, -SO2(C1-C 10 alkylene)-halogen, -C(O)(C1-C 10 alkyl), -C(O)(C1-C 10 alkylene)CF3, -C(O)(C1-C 10 alkylene)OCH3, -C(O)(C1-C 10 alkylene)-halogen, -C(O)NH(C1-C 10 alkyl), -C(O)N(C1-C 10 alkyl)2, -(C1-C 10 alkylene)C(O)OH, —C(O)NH2, or oxetane.

[0111] In some embodiments, when α is present, Z1 is O or S, Z2 is N, X is C, χ is present, and β and δ are absent. In other embodiments, when α is absent, Z1 is N, Z2 is N, X is C, β and δ are present, and χ is absent. In particular embodiments, when α is absent, Z1 is N, Z2 is O or S, X is C, β and δ are present, and χ is absent. In further or additional embodiments, when ε and φ are each present, n=1, and each of Y1, Y2, Y3, and Y4 is independently -CR 4 - or N. In other embodiments, when ε and φ are each absent, n=0, 1, or 2, and each occurrence of Y, Y, Y, and Y is independently C(R 5 )2, NR 6 , O, or SO2.

[0112] In some embodiments, β and δ are present. In some embodiments, α, χ, ε, and φ are absent. In some embodiments, Z1 is N. In some embodiments, Z2 is O, S, or NR 3 where R 3 is H, C1-C4 alkyl, or oxetane. In some embodiments, X is C. In certain embodiments, β and δ are present, α, χ, ε, and φ are absent, Z1 is N, and Z2 is O, S, or NR 3 and R 3 is H, C1-C4 alkyl, or oxetane, and X is C.

[0113] In some embodiments, β, δ, ε, and φ are present. In some embodiments, α and χ are absent. In some embodiments, Z1 is N. In some embodiments, Z2 is O or NR3, where R 3 is H, C1-C4 alkyl, or oxetane. In some embodiments, X is C. In certain embodiments, β, δ, ε, and φ are present, α, and χ are absent, Z1 is N, Z2 is O or NR3, and R 3is H, C1-C4 alkyl, or oxetane, and X is C.

[0114] In some embodiments, A is

[0115] [ka] having the structure During the ceremony, n is 0, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y4 are each CH2 or C(CH3)2; Y2 is O, SO2, or NR 6 and R 6 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0116] In some embodiments, A is

[0117] [ka] having the structure n is 1, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y4 are CH2 or C(CH3)2; Y2 and Y3 are CH2 or C(CH3)2, O, SO2, or NR 6 and R 6 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0118] In some embodiments, A is

[0119] [ka] having the structure n is 2, R 3 is H, C1-C4 alkyl, or oxetane; Y1 and Y4 are CH2 or C(CH3)2; Y2 and Y3 are CH2 or C(CH3)2, O, SO2, or NR 6 and R 6is H, C1-C4 alkyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)CF3, -(C1-C4 alkylene)OCH3, -(C1-C4 alkylene)-halogen, -SO2(C1-C4 alkyl), -SO2(C1-C4 alkylene)CF3, -SO2(C1-C4 alkylene)OCH3, -SO2(C1-C4 alkylene)-halogen, - C(O)(C1-C4 alkyl), -C(O)(C1-C4 alkylene)CF3, -C(O)(C1-C4 alkylene)OCH3, -C(O)(C1-C4 alkylene)-halogen, -C(O)NH(C1-C4 alkyl), -C(O)N(C1-C4 alkyl)2, -(C1-C4 alkylene)C(O)OH, -C(O)NH2, or oxetane.

[0120] In some embodiments, A is

[0121] [ka] It has the following structure.

[0122] In other embodiments, A is

[0123] [ka] It has the following structure.

[0124] In certain embodiments, A is

[0125] [ka] It has the following structure.

[0126] In certain embodiments, A is

[0127] [ka] It has the following structure.

[0128] In certain embodiments, A is

[0129] [ka] It has the following structure.

[0130] In certain embodiments, A is

[0131] [ka] It has the following structure.

[0132] In some embodiments, R 6 is H, C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C6 alkylene)CF3, -(C1-C6 alkylene)OCH3, -(C1-C6 alkylene)-halogen, -SO2-C1-C6 alkyl, -SO2(C1-C6 alkylene)-CF3, -SO2(C1-C6 alkylene)OCH3, -SO2(C1-C6 alkylene)-halogen, - In some embodiments, R is C(O)(C-C alkyl), -C(O)(C-C alkylene)CF, -C(O)(C-C alkylene)OCH, -C(O)(C-C alkylene)-halogen, -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -(C-C alkylene)C(O)OH, -C(O)NH, or oxetane. 6 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)(C-C alkyl), —C(O)(C-C alkylene)CF, —C(O)(C-C alkylene)OCH, —C(O)(C-C alkylene)-halogen, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —(C-C alkylene)C(O)OH, —C(O)NH, or oxetane. In some embodiments, R6 is —C(O)(C1-C6 alkyl). In some embodiments, R 6 is H, C1-C4 alkyl, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, t-Bu, -CH2OCH3, -CH2CF3, -CH2Cl, -CH2F, -CH2CH2OCH3, -CH2CH2CF3, -CH2CH2Cl, -CH2CH2F,

[0133] [ka] , -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2(t-Bu), -SO2CH2OCH3 , -SO2CH2CF3, -SO2CH2Cl, -SO2CH2F, -SO2CH2CH2OCH3, -SO2CH2CH2CF3, -SO2CH2CH2Cl, -SO2CH2CH2F,

[0134] [ka] , C(O)CH3, C(O)CH2CH3, -C(O)CH2CH2CH3, -C(O)CH(CH3)2, -C(O)CH2CH(CH3)2, -C(O)t-Bu, -C(O)CH2OCH3, - C(O)CH2CF3, -C(O)CH2Cl, -C(O)CH2F, -C(O)CH2CH2OCH3, -C(O)CH2CH2CF3, -C(O)CH2CH2Cl, -C(O)CH2CH2F,

[0135] [ka] In some embodiments, R 6 is —C(O)(C1-C6 alkyl). In some embodiments, R 6 is H, C1-C4 alkyl 、-CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, t-Bu, -CH2OCH3, -CH2CF3, -CH2Cl, -CH2F, -CH2CH2OCH3, -CH2CH2CF3, -CH2CH2Cl, -CH2CH2F, or

[0136] [ka] In other embodiments, R 6 -SO2CH3, -SO2CH2CH3, -SO2CH2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2(t-Bu), -SO2CH2OCH3, -SO2CH2CF3, -SO2CH2Cl, -SO2CH2F, -SO2CH2CH2OCH3, -SO2CH2CH2CF3, -SO2CH2CH2Cl, -SO2CH2CH2F, or

[0137] [ka] 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,

[0138] [ka] is.

[0139] In some embodiments, A is

[0140] [ka] having the structure During the ceremony, Each occurrence of Y1, Y2, Y3, and Y4 independently 4 , or N During the ceremony, 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), -CN, or -CF.

[0141] 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.

[0142] In certain embodiments, A is

[0143] [ka] It has the following structure.

[0144] 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-C10 alkyl), -NHC(O)N(C1-C4 alkyl)2, -SO2NH(C1-C 10 alkyl), -SO2N(C1-C l0 alkyl), -CN, or -CF. In some embodiments, R 3 is H, halogen, C-C alkyl, C-C cycloalkyl, -O(C-C alkyl), -C(O)OH, -C(O)O(C-C alkyl), -C(O)NH, -C(O)NH(C-C alkyl), -C(O)N(C-C alkyl), -NHC(O)NH(C-C alkyl), -NHC(O)N(C-C alkyl), -SONH(C-C alkyl), -SON(C-C alkyl), -CN, or -CF. In some embodiments, 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.

[0145] In some embodiments, the heterocyclic compounds of Formula (I) are presented in Table 1.

[0146] [Table 1-1]

[0147] [Table 1-2]

[0148] [Table 1-3]

[0149] [Table 1-4]

[0150]

Table 1-5

[0151]

Table 1-6

[0152]

Table 1-7

[0153] In certain embodiments, the heterocyclic compound of Formula (I) is selected from the group consisting of 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, (4-(3-fluoro-2,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(4-fluoro-2-(trifluoromethyl)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- (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-6-yl)ethan-1-one, ... [3,4-c]pyridin-3-yl)methanone, (4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(6-( Oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, methyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4 ,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-neopentyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, ( 4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4 ,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-neopentyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, methyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4, 5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, 1-(3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3,5-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)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-3-methylbutan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-methylpropan-1-one, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-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-(oxetan-3-yl)- 4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetic acid, (4-(3,4-difluoro -2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-methyl-4,5,6, ,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, methyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,5-difluoro-2- (trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile, methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile H-pyrazolo[4,3-c]pyridine-5-carboxylate, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-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-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)- (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[3,4-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-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-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(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[4,3-c]pyridin-3-yl)methanone -pyrazolo[3,4-c]pyridin-3-yl)methanone, 1-(3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, (5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone Hydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, methyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3- c]pyridine-5-carbonitrile, 1-(3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, tert-butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)- tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(5-fluoro- 2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H -pyrazolo[3,4-c]pyridine-6-carboxylate tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(3,5-bis(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-chloro-5 -fluorophenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-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-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, tert-Butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, (6,6-dimethyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6,6-dioxide-1,4,5,7-tetrahydrothiopyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone (1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-ethyl-N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[ 3,4-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine ... -yl)methanone, (1-ethyl-6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, (5-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-(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)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethane-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, Lysin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone, 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (1-ethyl-5-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)- 6-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one, 5-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one, (5,5-dioxide- 1,4,6,7-Tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-6-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(1-ethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, (5-(methoxymethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(methoxymethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, (5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)butan-1-one, 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-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)butan-1-one, ]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)piperidine-1-carbonyl)-1H-indazole-5-carbonitrile, (7-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5,6-difluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(2-methoxyphenyl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, (5-(tert-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(, 2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- Carboxamide, N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (5-bromo-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl) -1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate, (5-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) Methanone, (7-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-pyrazolo[4,3-b]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methoxy-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-ethyl-5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 1-( 1-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one, N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide, N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7- Tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide, (1-methyl-5,5-dioxide-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(2-(trifluoromethyl)phenyl)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)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, (6-(isopropylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6 -(Ethylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, 2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H- Pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one, (1H-indazol-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-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(tert-butylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one, (6-(tert-butyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(isobutylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, Ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(tert-butylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H- Pyrazolo[4,3-c]pyridine-5-carboxylate, (4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(1-methyl-1H-indazol-3-yl)methanone, 1-(3-(4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one, 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-4,6-Dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-neopentyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (5-(cyclopropylmethyl)-1 ,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazo 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-methylpropan-1-one, (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)piperidine-1-yl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-methylpropan-1-one (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (5-benzoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5( 1H)-carboxylate, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole, -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 ... (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[ 3,4-c]pyrazol-3-yl)methanone, 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, (5,5-dioxide-4,6-dihydro-1H-thieno[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4,6-dihydro-1H-furo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (1-ethyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, (5-(2-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)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, (5-(oxetan-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(isobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine -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, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3 ,4-c]pyrazole-5(1H)-carboxylate, (5-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(methylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, (5-(tert-butylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(tert-butyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isobutyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol- 3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isopropyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbo 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)ethan-1-one, 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)butan-1-one, 2-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)propan-1-one, N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxamide, (5-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-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)piperidine-1-yl)methanone (1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate, tert-butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone, (1,4,5,6-tetrahydropyrrolo[3,4-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)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate, (5,5-dioxide-4,6,7,8-tetrahydro-1H-oxepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4,6,7,8-tetrahydro-1H-oxepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone N-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide, (5-(2,2,2-trifluoroethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(tert-butylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2,2-dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (5-(tert-butyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(isobutyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone, 3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)butan-1-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)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (1-ethyl-5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one, (5-(methoxymethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-methyl-1,4,5,6,7,8-Hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-isopropyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(ethylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (5-ethyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-(methylsulfonyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one, (1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)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 N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide, (5-(2-methoxyethyl) -1,4,5,6,7,8-Hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-methoxy-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)ethan-1-one, 3,3,3-trifluoro-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepin-5(1H)-yl)propan-1-one, (5-(oxetan-3-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, tert-butyl 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate, (6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl) (4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-fluoroimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-Methoxyimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-Methylimidazo[1,2-b]pyridazin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-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)piperidine-1-yl)methanone (6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (1H-imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone, 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylic acid, methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4 -carboxylate, N-(cyclopropylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, N-(phenylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, N-(methylsulfonyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide, 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide Methyl)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-dihydroisothiazolo[5,4-c]pyridin-6(5H)-yl)ethan-1-one, (4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone,7-Tetrahydroisothiazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisoxazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisoxazolo[5,4-c]pyridin-6(5H)-yl ) ethan-1-one, (4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)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 phenyl)piperidin-1-yl)methanone, 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisothiazolo[4,5-c]pyridin-5(4H)-yl)ethan-1-one, benzo[d]oxazol-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (3-methyloxetan-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, oxetan-3-yl(4-(2- (trifluoromethyl)phenyl)piperidin-1-yl)methanone, 2-(2-hydroxyphenyl)-1-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethan-1-one, (4-(2-(tert-butyl)phenyl)piperidin-1-yl)(tetrahydrothiophen-2-yl)methanone, rac-tert-butyl (2R,3R)-2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylate, (2R,4R)-2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxylate 2-(2-oxo-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)ethyl)phenylsulfamate, (4-(2-(tert-butyl)phenyl)piperidin-1-yl)(1,1-dioxidetetrahydrothiophen-2-yl)methanone, rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,3R)-3-hydroxypyrrolidine-1-carboxylate 4-(2-(tert-butyl)phenyl)piperidine-1-yl)methanone, rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,4R)-4-hydroxypyrrolidin-2-yl)methanone, rac-(R)-1-(2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)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, (5-fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (5-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, (6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone, 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, (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-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, (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 (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) (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) (6-chloropyridazin-3-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.

[0154] Preparation of compounds The compounds used in the chemical reactions described herein are made 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" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancarshire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0155] Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; "Organic Functional Group Preparations," by S.R. Sandler et al., 2nd ed., Academic Press, New York, 1983; "Modern Synthetic Reactions," by H.O. House, 2nd ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972; "Heterocyclic Chemistry," by Gilchrist, 2nd ed., John Wiley & Sons, New York, 1992; and "Advanced Organic Chemistry: Reactions, Mechanism and Structure," by J. March, 4th ed., Wiley Interscience, New York, 1992. Additional suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing their preparation include, for example, "Organic Synthesis: Concepts, Methods, Starting Materials" by Fuhrhop, J. and Penzlin G., Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; "Organic Chemistry, An Intermediate Text" by Hoffman, RV (1996) Oxford University Press, ISBN 0-19-509618-5; "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Larock, RC, Second Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4;"Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2, "Modern Carbonyl Chemistry" by Otera, J. (editor) (2000) Wiley-VCH, ISBN: 3-527-29871-1, "Patai's 1992 Guide to the Chemistry of Functional Groups" by Patai, S. (1992) Interscience ISBN: 0-471-93022-9, "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, "Intermediate Organic Chemistry" by Stowell, JC "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 in total, "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes in total, and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes in total.

[0156] Alternatively, specific and similar reactants can be identified through an index of known chemicals and reactants prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, as well as through online databases (for more information, contact the American Chemical Society, Washington, D.C.). Chemicals that are known but not commercially available in catalogs are optionally prepared by specialized chemical synthesis facilities, where many of the standard chemical supply facilities (e.g., those listed above) offer specialized synthesis services. For the preparation and selection of pharmaceutical salts of the monocyclic RBP4 inhibitor compounds described herein, see "Handbook of Pharmaceutical Salts" by P.H. Stahl & C.G. Wermuth, Verlag Helvetica Chimica Acta, Zurich 2002.

[0157] Retinol-binding protein 4 (RBP4) Retinol-binding protein 4 (RBP4), the only retinol transporter in the blood, is secreted by adipocytes and the liver. Reducing RBP4 levels can reduce lipofuscin accumulation, which leads to vision loss in diseases such as age-related macular degeneration, dry (atrophic) age-related macular degeneration, early-onset macular degeneration (Stargardt disease), Best disease, adult vitelliform maculopathy, geographic atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene-associated retinal disease. In some cases, reducing RBP4 reduces lipofuscin accumulation in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, thereby delaying or preventing vision loss caused by excessive lipofuscin accumulation in the retina.

[0158] In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0159] In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0160] In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0161] In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0162] In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 20% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 25% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 30% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 40% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 50% from baseline. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 65% from baseline. In certain embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0163] In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 48 ​​hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0164] In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0165] In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0166] In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0167] In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 1 mg / dL. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 2 mg / dL. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 5 mg / dL. In certain embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0168] In some embodiments, after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1 μM. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1 μM. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1 μM. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 μM. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 μM.

[0169] In some embodiments, after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1.5 μM. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1.5 μM. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1.5 μM. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 μM. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 μM.

[0170] In some embodiments, after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 2 μM. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 2 μM. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 2 μM. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 μM. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 μM.

[0171] In some embodiments, after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1 μM. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1 mM. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1 mM. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 mM. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1 mM.

[0172] In some embodiments, after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1.5 mM. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1.5 mM. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 1.5 mM. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 mM. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 1.5 mM.

[0173] In some embodiments, after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 2 mM. In other embodiments, 6 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 2 mM. In some embodiments, 12 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, the serum or plasma level of RBP4 is reduced to less than 2 mM. In certain embodiments, 24 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 mM. In some embodiments, 36 hours after administration of a compound of Formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, serum or plasma levels of RBP4 are reduced to less than 2 mM.

[0174] Treatment method In some embodiments, the compounds disclosed herein are used to treat or ameliorate diseases associated with alterations in the RBP4 pathway when administered to a subject in need of such treatment. In some cases, the compounds disclosed herein are used to treat or ameliorate the effects of diseases associated with alterations in the RBP4 pathway when administered to a subject in need of such treatment. Examples of diseases associated with alterations in RBP4 include ocular diseases. In some cases, the ocular diseases are characterized by excessive lipofuscin accumulation in the retina. In some cases, the compounds disclosed herein are used to treat or ameliorate ocular diseases when administered to a subject in need of such treatment. Examples of ocular diseases include age-related macular degeneration, dry (atrophic) age-related macular degeneration, juvenile macular degeneration (Stargardt disease), Best disease, adult vitelliform maculopathy, geographic atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene-related retinal diseases.

[0175] Age-related macular degeneration Age-related macular degeneration (AMD) is a common eye disease and the leading cause of vision loss in people over the age of 50. AMD damages the macula, a tiny spot near the center of the retina and a part of the eye necessary for sharp, central vision. As AMD progresses, blurring of the area near the center of the field of vision is a common symptom. Over time, the blurred area grows larger, and the subject may develop a blank spot in their central vision.

[0176] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat AMD in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits AMD. In certain embodiments, the compound of Formula (I) prevents the onset of AMD or its clinical symptoms. In certain embodiments, the compound of Formula (I) reduces the onset of AMD or its clinical symptoms. In certain embodiments, the compound of Formula (I) alleviates a subject with AMD. In certain embodiments, the compound of Formula (I) causes regression, reversal, or improvement of AMD. In certain embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of AMD.

[0177] 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 developing AMD.In certain embodiments, the compound of formula (I) prevents the clinical symptoms of AMD from developing in the subject who may have a predisposition to AMD but has not yet developed or shown the symptoms of AMD.

[0178] Dry (atrophic) age-related macular degeneration Approximately 85% to 90% of cases of macular degeneration are "dry" (atrophic) forms. An estimated 62.9 million people worldwide suffer from this form of AMD, 8 million of whom are Americans. Due to increased life expectancy and current demographic trends, this number is expected to triple by 2020. Currently, there are no FDA-approved treatments for dry AMD. Given the lack of treatment and high prevalence, drug development for dry AMD is crucial. Clinically, atrophic AMD is a slowly progressive neurodegenerative disorder characterized by the death of specialized nerve cells (rod and cone photoreceptors) in the central region of the retina, known as the macula. Histopathological and clinical imaging studies have shown that photoreceptor degeneration in dry AMD is caused by abnormalities in the retinal pigment epithelium (RPE), which lies beneath the photoreceptors and provides critical metabolic support to light-sensing nerve cells. Experimental and clinical data indicate that excessive accumulation of cytotoxic autofluorescent lipid-protein-retinoid aggregates (lipofuscin) in the RPE is a major trigger of dry AMD. The primary cytotoxic component of RPE lipofuscin is the pyridinium bisretinoid A2E. Other cytotoxic bisretinoids are isoA2E, atRAL di-PE, and A2-DHP-PE. The formation of A2E and other lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridine-phosphatidylethanolamine) and atRAL di-PE (all-trans-retinal dimer-phosphatidylethanolamine), is nonenzymatic and can be considered a by-product of a properly functioning visual cycle that begins in photoreceptor cells.

[0179] Some embodiments provided herein describe the use of a compound of formula (I) described herein to treat dry (atrophic) AMD in a subject in need thereof. In some embodiments, the compound of formula (I) inhibits dry (atrophic) AMD. In certain embodiments, the compound of formula (I) prevents the onset of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the compound of formula (I) reduces the onset of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the compound of formula (I) alleviates a subject's dry (atrophic) AMD. In certain embodiments, the compound of formula (I) causes regression, reversal, or improvement of dry (atrophic) AMD. In certain embodiments, the compound of formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of dry (atrophic) AMD.

[0180] 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 developing dry (atrophic) AMD.In certain embodiments, the compound of formula (I) prevents the clinical symptoms of dry (atrophic) AMD from developing in the subject who may have a predisposition to dry (atrophic) AMD but has not yet developed or shown the symptoms of dry (atrophic) AMD.

[0181] Juvenile macular degeneration (Stargardt disease) Stargardt disease (STGD) is a hereditary early-onset macular degeneration (ADD). STGD is characterized by dramatic accumulation of lipofuscin in the retina. STGD is associated with defects in the ABCA4 gene. Overproduction of lipofuscin bisretinoid is thought to be the only biochemical trigger for monogenic STGD, caused by recessive mutations in the ABCA4 gene. Symptoms include wavy vision, blind spots, blurred vision, loss of depth perception, glare sensitivity, color vision impairment, and difficulty adapting to dim light. Symptoms typically begin before the age of 20.

[0182] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat STGD in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits STGD. In certain embodiments, the compound of Formula (I) prevents the onset of STGD or its clinical symptoms. In certain embodiments, the compound of Formula (I) reduces the onset of STGD or its clinical symptoms. In certain embodiments, the compound of Formula (I) alleviates a subject with STGD. In certain embodiments, the compound of Formula (I) causes regression, reversal, or improvement of STGD. In certain embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of STGD.

[0183] In some embodiments, the compound of formula (I) is used prophylactically. In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing STGD. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of STGD from developing in subjects who may have a predisposition to STGD but have not yet developed or exhibited symptoms of STGD.

[0184] Best Disease Vitelliform dystrophy, or Best disease, is an inherited retinal dystrophy involving the retinal pigment epithelium (RPE), resulting in a characteristic bilateral yellow, "egg-yellow" appearance of the macula. The disease tends to present in childhood or early adulthood. Best disease is caused by mutations in the BEST1 gene, which encodes the transmembrane protein bestrophin 1. This mutation leads to the accumulation of lipofuscin between the outer retina and the RPE.

[0185] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat Best disease in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits Best disease. In certain embodiments, a compound of Formula (I) prevents the onset of Best disease or its clinical symptoms. In certain embodiments, a compound of Formula (I) reduces the onset of Best disease or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates a subject with Best disease. In certain embodiments, a compound of Formula (I) causes regression, reversal, or improvement of Best disease. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of Best disease.

[0186] In some embodiments, the compound of Formula (I) is used prophylactically. In certain embodiments, the compound of Formula (I) is used to prevent or reduce the risk of developing Best's disease. In certain embodiments, the compound of Formula (I) prevents the development of clinical symptoms of Best's disease in subjects who may be predisposed to Best's disease but have not yet developed or exhibited symptoms of Best's disease.

[0187] Geographic atrophy Geographic atrophy is a chronic, progressive degeneration of the macula that is sometimes considered part of late-stage age-related macular degeneration (AMD). The disease causes a central scotoma and permanent vision loss. The disease is characterized by focal, well-defined atrophy of the outer retinal tissues, the retinal pigment epithelium, and the choriocapillaris.

[0188] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat geographic atrophy in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits geographic atrophy. In certain embodiments, the compound of Formula (I) prevents the onset of geographic atrophy or its clinical symptoms. In certain embodiments, the compound of Formula (I) reduces the onset of geographic atrophy or its clinical symptoms. In certain embodiments, the compound of Formula (I) alleviates geographic atrophy in a subject. In certain embodiments, the compound of Formula (I) causes regression, reversal, or improvement of geographic atrophy. In certain embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of geographic atrophy.

[0189] In some embodiments, the compound of formula (I) is used prophylactically. In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing geographic atrophy. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of geographic atrophy from developing in subjects who may have a predisposition to geographic atrophy but have not yet developed or exhibited symptoms of geographic atrophy.

[0190] Adult vitelliform maculopathy Adult vitelliform maculopathy is an eye disorder that can cause progressive vision loss. The disease causes lipofuscin accumulation in the cells underlying the macula. The disease typically appears after age 40. The disease can be caused by mutations in the RDS and VMD2 genes.

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

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

[0193] Stargardt-like macular dystrophy Stargardt-like macular dystrophy has similar symptoms and signs to Stargardt disease, but typically begins later in childhood. Stargardt-like macular dystrophy is associated with mutations in the EVOVL4 gene.

[0194] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat Stargardt-like macular dystrophy in a subject in need thereof. In some embodiments, a compound of Formula (I) inhibits Stargardt-like macular dystrophy. In certain embodiments, a compound of Formula (I) prevents the onset of Stargardt-like macular dystrophy or its clinical symptoms. In certain embodiments, a compound of Formula (I) reduces the onset of Stargardt-like macular dystrophy or its clinical symptoms. In certain embodiments, a compound of Formula (I) alleviates a subject with Stargardt-like macular dystrophy. In certain embodiments, a compound of Formula (I) causes regression, reversal, or improvement of Stargardt-like macular dystrophy. In certain embodiments, a compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of Stargardt-like macular dystrophy.

[0195] In some embodiments, the compound of formula (I) is used prophylactically. In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing Stargardt-like macular dystrophy. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of Stargardt-like macular dystrophy from developing in subjects who may have a predisposition to Stargardt-like macular dystrophy but have not yet developed or exhibited symptoms of Stargardt-like macular dystrophy.

[0196] diabetic retinopathy Diabetic retinopathy is a complication of diabetes that affects the eyes. It can be caused by damage to blood vessels in the light-sensitive tissue at the back of the eye and can ultimately lead to blindness. Diabetic retinopathy can occur when new blood vessels in the retina fail to grow. Diabetic retinopathy can also develop when blood vessels are damaged and blocked, allowing abnormal new blood vessels to grow in the retina.

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

[0198] In some embodiments, the compound of formula (I) is used prophylactically. In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing diabetic retinopathy. In certain embodiments, the compound of formula (I) prevents the development of clinical symptoms of diabetic retinopathy in subjects who may have a predisposition to diabetic retinopathy but have not yet developed or exhibited symptoms of diabetic retinopathy.

[0199] ABCA4 gene-related retinal disease ATP-binding cassette, subfamily A, member 4 (ABCA4) is a protein encoded by the ABCA4 gene in humans and other eukaryotes. The ABCA4 protein is expressed almost exclusively in the retina and is associated with Stargardt disease and other ocular diseases, including, but not limited to, fundus flava, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Decreased ABCA4 activity is associated with excessive accumulation of toxic retinoids and lipofuscin. Such mutations can be detected by sequencing the subject's DNA or RNA.

[0200] Some embodiments provided herein describe the use of a compound of Formula (I) described herein to treat an ABCA4 gene-associated retinal disease in a subject in need thereof. In some embodiments, the compound of Formula (I) inhibits the ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) prevents the onset of an ABCA4 gene-associated retinal disease or its clinical symptoms. In certain embodiments, the compound of Formula (I) reduces the onset of an ABCA4 gene-associated retinal disease or its clinical symptoms. In certain embodiments, the compound of Formula (I) alleviates a subject's ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) causes regression, reversal, or improvement of the ABCA4 gene-associated retinal disease. In certain embodiments, the compound of Formula (I) reduces the number, frequency, duration, or severity of clinical symptoms of the ABCA4 gene-associated retinal disease.

[0201] In some embodiments, the compound of formula (I) is used prophylactically. In certain embodiments, the compound of formula (I) is used to prevent or reduce the risk of developing ABCA4 gene-associated retinal disease. In certain embodiments, the compound of formula (I) prevents the clinical symptoms of ABCA4 gene-associated retinal disease from developing in subjects who may have a predisposition to ABCA4 gene-associated retinal disease but have not yet developed or exhibited symptoms of ABCA4 gene-associated retinal disease.

[0202] Pharmaceutical Composition In certain embodiments, the compounds of formula (I) described herein can be used in combination with other compounds described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 2001). stThe compositions may be combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected in accordance with the chosen route of administration and standard pharmaceutical practice, as described in Ed. Mack Pub. Co., Easton, PA (2005).

[0203] Provided herein is a pharmaceutical composition comprising at least one heterocyclic RBP4 inhibitor compound, or its pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and not deleterious to the recipient (i.e., subject or patient) of the composition.

[0204] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, and at least one excipient. In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, which comprises a compound provided herein and one or more pharmaceutically acceptable excipients or carriers.

[0205] In certain embodiments, the pharmaceutical compositions disclosed herein may be in the form of tablets, pills, granules, capsules, or variations thereof. In certain embodiments, tablet pharmaceutical compositions are disclosed herein. In certain embodiments, the tablet pharmaceutical composition may comprise a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the compound of formula (I) in the tablet pharmaceutical composition may comprise a compound of formula (I) disclosed herein. In certain embodiments, the tablet pharmaceutical composition may comprise at least one excipient.

[0206] Although embodiments of the present disclosure may describe limitations, amounts, percentages, properties, compositions, processes, and / or methods related to tablet pharmaceutical compositions, they are not intended to limit the scope of the present disclosure. Those skilled in the art will understand that limitations, amounts, percentages, properties, compositions, processes, and / or methods related to tablet pharmaceutical compositions may also be applied to pharmaceutical compositions in other forms, such as pill pharmaceutical compositions, granule pharmaceutical compositions, capsule pharmaceutical compositions, or variations thereof.

[0207] In certain embodiments, the heterocyclic RBP4 inhibitor compounds as described by Formula (I) are substantially pure, containing, for example, less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as unreacted intermediates or synthetic by-products resulting from one or more of the steps of the synthetic method.

[0208] Suitable dosage forms include, for example, tablets, pills, granules, or capsules of hard or soft gelatin, methylcellulose, or other suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 2012) st See Ed. Mack Pub. Co., Easton, PA (2005).

[0209] In some embodiments, the pharmaceutical compositions provided herein are formulated for oral administration in the form of tablets, pills, granules, or capsules. In some embodiments, the pharmaceutical formulation is formulated as a tablet. In some embodiments, the pharmaceutical formulation is formulated as a capsule. In some embodiments, the tablet comprises a solid carrier or adjuvant. In some embodiments, saline, dextrose or other saccharide solution, or glycol is optionally included. In some embodiments, the capsule consists of a solid carrier such as gelatin.

[0210] In another embodiment, a pharmaceutical composition is provided in a dosage form for parenteral administration, which includes a compound provided herein and one or more pharmaceutically acceptable excipients or carriers, which in some embodiments include preservatives, stabilizers, buffers, antioxidants, and / or other additives.

[0211] composition In certain embodiments, a tablet pharmaceutical composition is disclosed herein. In certain embodiments, the tablet pharmaceutical composition may comprise a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof. In certain embodiments, the compound of formula (I) in the tablet pharmaceutical composition may comprise a compound of formula (I) disclosed herein. In certain embodiments, the tablet pharmaceutical composition may comprise at least one excipient.

[0212] In certain embodiments, the tablet pharmaceutical composition contains a compound of Formula (I) in an amount of from about 1 to about 200 mg, e.g., about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg , 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg , 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115 mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 133mg, 134mg, 135mg, 13 6mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 1 57mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg,Dosage forms of 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or about 200 mg, or any amount therebetween, may be effective in reducing RBP4 concentrations.

[0213] In certain embodiments, the compound of formula (I) in the tablet pharmaceutical composition is present in an amount of from about 2 to about 100 mg, e.g., 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 2 0.5mg, 21mg, 21.5mg, 22mg, 22.5mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg, 28mg, 28.5mg, 29mg, 29.5mg, 30mg, 30.5m g, 31mg, 31.5mg, 32mg, 32.5mg, 33mg, 33.5mg, 34mg, 34.5mg, 35mg, 35.5mg, 36mg, 36.5mg, 37mg, 37.5mg, 38mg, 38.5mg, 39mg, 39.5mg, 40mg, 40.5mg, 41m g, 41.5mg, 42mg, 42.5mg, 43mg, 43.5mg, 44mg, 44.5mg, 45mg, 45.5mg, 46mg, 46.5mg, 47mg, 47.5mg, 48mg, 48.5mg, 49mg, 49.5mg, 50mg, 50.5mg, 51mg, 51 .5mg, 52mg, 52.5mg, 53mg, 53.5mg, 54mg, 54.5mg, 55mg, 55.5mg, 56mg, 56.5mg, 57mg, 57.5mg, 58mg, 58.5mg, 59mg, 59.5mg, 60mg, 60.5mg, 61mg, 61.5mg , 62mg, 62.5mg, 63mg, 63.5mg, 64mg, 64.5mg, 65mg, 65.5mg, 66mg, 66.5mg, 67mg, 67.5mg, 68mg, 68.5mg, 69mg, 69.5mg, 70mg, 70.5mg, 71mg, 71.5mg, 72m g, 72.5mg, 73mg, 73.5mg, 74mg, 74.5mg, 75mg, 75.5mg, 76mg, 76.5mg, 77mg, 77.5mg, 78mg, 78.5mg, 79mg, 79.5mg, 80mg, 80.5mg, 81mg, 81.5mg, 82mg, 82.Dosage forms of 5 mg, 83 mg, 83.5 mg, 84 mg, 84.5 mg, 85 mg, 85.5 mg, 86 mg, 86.5 mg, 87 mg, 87.5 mg, 88 mg, 88.5 mg, 89 mg, 89.5 mg, 90 mg, 90.5 mg, 91 mg, 91.5 mg, 92 mg, 92.5 mg, 93 mg, 93.5 mg, 94 mg, 94.5 mg, 95 mg, 95.5 mg, 96 mg, 96.5 mg, 97 mg, 97.5 mg, 98 mg, 98.5 mg, 99 mg, 99.5 mg, or 100 mg, or any amount therebetween, may be effective in reducing RBP4 concentrations.

[0214] In certain embodiments, the tablet pharmaceutical composition contains a compound of Formula (I) in an amount of from about 1 to about 50 mg, e.g., about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.2 mg, 5.4 mg, 5.6 mg, 5.8 mg, 6 mg, 6.2 mg, 6.4 mg, 6.6 mg, 6.8 mg, 7 mg, 7.2 mg, 7.4 mg, 7.6 mg, 7.8 mg, 8 mg, 8.2 mg, 8.4 mg, 8.6 mg, 8.8 mg, 9 mg, 9.2 mg, 9.4 mg, 9.6 mg, 9.8 mg, 10 mg , 10.2mg, 10.4mg, 10.6mg, 10.8mg, 11mg, 11.2mg, 11.4mg, 11.6mg, 11.8mg, 12mg, 12.2mg, 12.4mg, 12.6mg, 12.8mg, 13mg, 13.2mg, 13.4mg, 13.6mg, 13.8 mg, 14mg, 14.2mg, 14.4mg, 14.6mg, 14.8mg, 15mg, 15.2mg, 15.4mg, 15.6mg, 15.8mg, 16mg, 16.2mg, 16.4mg, 16.6mg, 16.8mg, 17mg, 17.2mg, 17.4mg, 17.6 mg, 17.8mg, 18mg, 18.2mg, 18.4mg, 18.6mg, 18.8mg, 19mg, 19.2mg, 19.4mg, 19.6mg, 19.8mg, 20mg, 20.2mg, 20.4mg, 20.6mg, 20.8mg, 21mg, 21.2mg, 21.4 mg, 21.6mg, 21.8mg, 22mg, 22.2mg, 22.4mg, 22.6mg, 22.8mg, 23mg, 23.2mg, 23.4mg, 23.6mg, 23.8mg, 24mg, 24.2mg, 24.4mg, 24.6mg, 24.8mg, 25mg, 25.2 29 mg, 29.2mg, 29.4mg, 29.6mg, 29.8mg, 30mg, 30.2mg, 30.4mg, 30.6mg, 30.8mg, 31mg, 31.2mg, 31.4mg, 31.6mg, 31.8mg, 32mg, 32.2mg, 32.4mg, 32.6mg, 32.8mg, 33mg, 33.2mg, 33.4mg, 33.6mg, 33.8mg, 34mg, 34.2mg, 34.4mg, 34.6mg, 34.8mg, 35mg, 35 .2mg, 35.4mg, 35.6mg, 35.8mg, 36mg, 36.2mg, 36.4mg, 36.6mg, 36.8mg, 37mg, 37.2mg, 37.4mg , 37.6mg, 37.8mg, 38mg, 38.2mg, 38.4mg, 38.6mg, 38.8mg, 39mg, 39.2mg, 39.4mg, 39.6mg, 39. 8mg, 40mg, 40.2mg, 40.4mg, 40.6mg, 40.8mg, 41mg, 41.2mg, 41.4mg, 41.6mg, 41.8mg, 42mg, 42. Dosage forms of 2 mg, 42.4 mg, 42.6 mg, 42.8 mg, 43 mg, 43.2 mg, 43.4 mg, 43.6 mg, 43.8 mg, 44 mg, 44.2 mg, 44.4 mg, 44.6 mg, 44.8 mg, 45 mg, 45.2 mg, 45.4 mg, 45.6 mg, 45.8 mg, 46 mg, 46.2 mg, 46.4 mg, 46.6 mg, 46.8 mg, 47 mg, 47.2 mg, 47.4 mg, 47.6 mg, 47.8 mg, 48 mg, 48.2 mg, 48.4 mg, 48.6 mg, 48.8 mg, 49 mg, 49.2 mg, 49.4 mg, 49.6 mg, 49.8 mg, or 50 mg, or any amount therebetween, may be effective in reducing RBP4 concentrations. .

[0215] In certain embodiments, the tablet pharmaceutical composition contains a compound of Formula (I) in an amount of from about 1 to about 25 mg, e.g., about 1 mg, 1.2 mg, 1.4 mg, 1.5 mg, 1.7 mg, 2 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.7 mg, 2.9 mg, 3.0 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.7 mg, 3.9 mg, 4.0 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5 mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, 10mg, 10.1mg, 10.2mg, 10.3mg, 10.4mg, 10.5mg, 10.6mg, 10.7mg, 10.8mg, 10.9mg, 11mg, 11.1mg, 11.2mg, 11.3mg, 11.4mg, 11.5mg, 11.6mg, 11.7mg, 11.8mg, 11.9mg, 12mg, 12.1mg, 12.2mg, 12.3mg, 12. 4mg, 12.5mg, 12.6mg, 12.7mg, 12.8mg, 12.9mg, 13mg, 13.1mg, 13.2mg, 13.3mg, 13.4mg, 13.5mg, 13.6mg, 13.7mg, 13.8mg, 13.9mg, 14mg, 14.1mg, 14.2mg , 14.3mg, 14.4mg, 14.5mg, 14.6mg, 14.7mg, 14.8mg, 14.9mg, 15mg, 15.1mg, 15.2mg, 15.3mg, 15.4mg, 15.5mg, 15.6mg, 15.7mg, 15.8mg, 15.9mg, 16mg, 16 .1mg, 16.2mg, 16.3mg, 16.4mg, 16.5mg, 16.6mg, 16.7mg, 16.8mg, 16.9mg, 17mg, 17.1mg, 17.2mg, 17.3mg, 17.4mg, 17.5mg, 17.6mg, 17.7mg, 17.8mg, 17.9mg, 18mg, 18.1mg, 18.2mg, 18.3mg, 18.4mg, 18.5mg, 18.6mg, 18.7mg, 18.8mg, 18.9mg, 19mg, 19.1mg, 19.2mg, 19.3mg, 19.4mg, 19.5mg, 19.6mg, 19.7mg, 19.8mg, 19.9mg, 20mg, 20.1mg, 20.2mg, 20.3mg, 20.4mg, 20.5mg, 20.6mg, 20.7mg, 20.8mg, 20.9mg, 21mg, 21.1mg, 21.2mg, 21.3mg, 21.4mg, 21.5mg, 21.6mg, 21.7mg, 21.8 Dosage forms of 21.9 mg, 22 mg, 22.1 mg, 22.2 mg, 22.3 mg, 22.4 mg, 22.5 mg, 22.6 mg, 22.7 mg, 22.8 mg, 22.9 mg, 23 mg, 23.1 mg, 23.2 mg, 23.3 mg, 23.4 mg, 23.5 mg, 23.6 mg, 23.7 mg, 23.8 mg, 23.9 mg, 24 mg, 24.1 mg, 24.2 mg, 24.3 mg, 24.4 mg, 24.5 mg, 24.6 mg, 24.7 mg, 24.8 mg, 24.9 mg, or 25 mg, or any amount therebetween, may be effective in reducing RBP4 concentrations.

[0216] In certain embodiments, the compound of formula (I) in the tablet pharmaceutical composition disclosed herein may be micronized crystals. In certain embodiments, the compound of formula (I) in the tablet pharmaceutical composition disclosed herein may be a polymorph that exhibits an X-ray powder diffraction pattern with at least three characteristic peaks occurring at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / -0.5 degrees 2-theta). In certain embodiments, the compound of formula (I) in the tablet pharmaceutical composition disclosed herein may be amorphous.

[0217] In certain embodiments, at least one excipient of the tablet pharmaceutical composition disclosed herein may include a disintegrant. In embodiments, the disintegrant may be selected from the group including agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, and combinations thereof. In embodiments, the disintegrant may include CCNa, MCC, or both.

[0218] In embodiments, the disintegrant in the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32% ,0.33%,0.34%,0.35%,0.36%,0.37%,0.38%,0.39%,0.40%,0.41%,0.42%,0.43%,0.44%,0.45%,0.46%,0.47%,0.48%,0.49%,0.50%,0.51%,0.52%,0.5 3%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0. 74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50% ,2.60%,2.70%,2.80%,2.90%,3.00%,3.10%,3.20%,3.30%,3.40%,3.50%,3.60%,3.70%,3.80%,3.90%,4.00%,4.10%,4.20%,4.30%,4.40%,4.50%,4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11. 00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00%, 43.00%, 44.00%, 45.00%, 46.00%, 47.00%, 48.00%, 49.00%, 50.00%, 51.00%, 52.00%, 53.00%, 54.00%, 55.00%, 56.00%, 57.00%, 58.00%, 59.00%, 60.00%, 61.00%, 62.00%, 63.00%, 64.00%, 65.00%, 66.00%, 67.00%, 68.00%, 69.00%, 70. 00%, 71.00%, 72.00%, 73.00%, 74.00%, 75.00%, 76.00%, 77.00%, 78.00%, 79.00%, 80.00%, 81.00%, 82.00%, 83.00%, 84.00%, 85.00%, 86.00%, 87.00%, 88.00%, 89.00%, 90.00%, 91.00%, 92.00%, 93.00%, 94.00%, 95.00%, 96.00%, 97.00%, 98.00%, or 99.The various percentages listed above are applicable to agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, and combinations thereof.

[0219] In embodiments, the disintegrant in the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% ~approximately 70%, approximately 0.01% to approximately 80%, approximately 0.01% to approximately 90%, approximately 0.01% to approximately 99%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 4%, approximately 0.1% to approximately 5%, approximately 0.1% to approximately 6%, approximately 0.1% to approximately 7%, approximately 0.1% to approximately 8%, approximately 0.1% to approximately 9%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 20%, approximately 0.1% to approximately 30%, approximately 0.1% to approximately 40%, approximately 0.1% to approximately 50%, approximately 0.1% to approximately 60%, approximately 0.1% to approximately 70%, approximately 0.1% to approximately 80%, approximately 0.1% to approximately 90%, approximately 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% ~ about 99%, about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 5% to about 99%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 9 9%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, About 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, and about 90% to about 99%. The various ranges listed above are applicable to agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, and combinations thereof.

[0220] In embodiments, the disintegrant of the tablet pharmaceutical composition disclosed herein may comprise CCNa. In embodiments, CCNa may be about 0.75% by weight of the tablet pharmaceutical composition. In embodiments, CCNa may be about 3% by weight of the tablet pharmaceutical composition. In embodiments, CCNa may be about any other percentage by weight of the tablet pharmaceutical composition disclosed herein.

[0221] In certain embodiments, at least one excipient of the tablet pharmaceutical composition disclosed herein may comprise a dispersion polymer. In embodiments, the dispersion polymer may comprise hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethylcellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or a combination thereof. In certain embodiments, the compound of formula (I) of the tablet pharmaceutical composition disclosed herein may be amorphous and molecularly dispersed in the dispersion polymer. In embodiments, the dispersion polymer may comprise HPC. In embodiments, the dispersion polymer may comprise HPMC.

[0222] In embodiments, the dispersion polymer of the tablet pharmaceutical composition disclosed herein is from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0 .53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94% ,0.95%,0.96%,0.97%,0.98%,0.99%,1.00%,1.10%,1.20%,1.30%,1.40%,1.50%,1.60%,1.70%,1.80%,1.90%,2.00%,2.10%,2.20%,2.30%,2.40%,2.50 %, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90%, 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11. 00%, 12.00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00%, 43.00%, 44.00%, 45.00%, 46.00%, 47.00%, 48.00%, 49.00%, 50.00%, 51.00%, 52.00%, 53.00%, 54.00%, 55.00%, 56.00%, 57.00%, 58.00%, 59.00%, 60.00%, 61.00%, 62.00%, 63.00%, 64.00%, 65.00%, 66.00%, 67.00%, 68.00%, 69.00%, 70. 00%, 71.00%, 72.00%, 73.00%, 74.00%, 75.00%, 76.00%, 77.00%, 78.00%, 79.00%, 80.00%, 81.00%, 82.00%, 83.00%, 84.00%, 85.00%, 86.00%, 87.00%, 88.00%, 89.00%, 90.00%, 91.00%, 92.00%, 93.00%, 94.00%, 95.00%, 96.00%, 97.00%, 98.00%, or 99.The percentages listed above may be 0.0000%, 1.0000%, or any percentage therebetween. The various percentages listed above are applicable to hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or combinations thereof.

[0223] In embodiments, the dispersion polymer of the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% to about 70%, from about 0.01% ~ about 80%, about 0.01% to about 90%, about 0.01% to about 99%, about 0.1% to about 1%, 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 0.1% to about 6%, about 0.1% to about 7%, about 0.1% to about 8%, about 0.1% to about 9%, about 0.1% ~ about 10%, about 0.1% to about 20%, about 0.1% to about 30%, about 0.1% to about 40%, about 0.1% to about 50%, about 0.1% to about 60%, about 0.1% to about 70%, about 0.1% to about 80%, about 0.1% to about 90%, about 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1 % to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to about 99%, about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 5% to about 99%, Approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99%, approximately 20% to approximately 30%, approximately 20% to approximately 40%, approximately 20% to approximately 50%, approximately 20% to Approximately 60%, approximately 20% to approximately 70%, approximately 20% to approximately 80%, approximately 20% to approximately 90%, approximately 20% to approximately 99%, approximately 30% to approximately 40%, approximately 30% to approximately 50%, approximately 30% to approximately 60%, approximately 30% to approximately 70%, approximately 30% to approximately 80%, approximately 30% to approximately 90%, approximately 30% to approximately 99%, approximately 40% to approximately 50%,It may be about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. The various ranges listed above are applicable to hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol-polyvinyl acetate copolymer, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone (PVP), polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer, or combinations thereof.

[0224] In certain embodiments, the dispersion polymer may comprise HPC. In embodiments, HPC may be about 6% by weight of a tablet pharmaceutical composition disclosed herein. In certain embodiments, the dispersion polymer may comprise HPMC. In certain embodiments, HPMC may be about 10% by weight of a tablet pharmaceutical composition disclosed herein. In certain embodiments, HPMC may be about 20% by weight of a tablet pharmaceutical composition disclosed herein. In certain embodiments, at least one excipient may comprise both about 0.75% CCNa and about 6% HPC by weight of a tablet pharmaceutical composition disclosed herein. In certain embodiments, at least one excipient may comprise both about 0.75% CCNa and about 10% HPMC by weight of a tablet pharmaceutical composition disclosed herein. In certain embodiments, at least one excipient may comprise both about 0.75% CCNa and about 20% HPMC by weight of a tablet pharmaceutical composition disclosed herein.

[0225] In certain embodiments, the dispersion polymer may comprise PVP. In certain embodiments, HPMC may comprise about 10% by weight of the tablet pharmaceutical composition disclosed herein. In certain embodiments, PVP may comprise about 20% by weight of the tablet pharmaceutical composition disclosed herein. In certain embodiments, at least one excipient may comprise both about 0.75% CCNa and about 6% PVP by weight of the tablet pharmaceutical composition disclosed herein. In certain embodiments, at least one excipient may comprise both about 0.75% CCNa and about 10% PVP by weight of the tablet pharmaceutical composition disclosed herein. In certain embodiments, at least one excipient may comprise both about 0.75% CCNa and about 20% PVP by weight of the tablet pharmaceutical composition disclosed herein.

[0226] In certain embodiments, the at least one excipient may comprise a disintegrant, dispersion polymer, diluent, binder, fluidization aid, filler, sweetener, wetting agent, glidant, lubricant, or surfactant, or any combination thereof. In certain embodiments, the diluent may comprise microcrystalline cellulose (MCC), lactose monohydrate (LMH), or both. In embodiments, the binder may comprise MCC, HPC, or both. In certain embodiments, the fluidization aid may comprise colloidal silicon dioxide (CSD), magnesium stearate, or both. In certain embodiments, the glidant may comprise CSD. In certain embodiments, the lubricant may comprise magnesium stearate. In certain embodiments, the lubricant may be intragranular or extragranular. In certain embodiments, the at least one excipient may comprise MCC, LMH, HPC, CCNa, CSD, and magnesium stearate. In certain embodiments, the diluent may function as a binder and / or disintegrant. In certain embodiments, MCC may function as a binder and / or disintegrant. In certain embodiments, a fluidization aid may function as a glidant or a lubricant. In certain embodiments, CSD may function as a glidant. In certain embodiments, magnesium stearate may function as a lubricant. In certain embodiments, the compound of formula (I) of the tablet pharmaceutical composition may not be formulated for delayed release. In certain embodiments, at least one of the at least one excipient may not be formulated for delayed release. In certain embodiments, each of the at least one excipient may not be formulated for delayed release.

[0227] In embodiments, the diluent in the tablet pharmaceutical compositions disclosed herein is from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32% ,0.33%,0.34%,0.35%,0.36%,0.37%,0.38%,0.39%,0.40%,0.41%,0.42%,0.43%,0.44%,0.45%,0.46%,0.47%,0.48%,0.49%,0.50%,0.51%,0.52%,0.5 3%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0. 74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50% ,2.60%,2.70%,2.80%,2.90%,3.00%,3.10%,3.20%,3.30%,3.40%,3.50%,3.60%,3.70%,3.80%,3.90%,4.00%,4.10%,4.20%,4.30%,4.40%,4.50%,4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11.00%, 12. 00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00% ,43.00%,44.00%,45.00%,46.00%,47.00%,48.00%,49.00%,50.00%,51.00%,52.00%,53.00%,54.00%,55.00%,56.00%,57.00%,58.00%,59.00%,60.00%,61.00%,62.00%,63.00%,64.00%,65.00%,66.00%,67.00%,68.00%,69.00%,70.00%,71.00%,72.00%,73 The percentage may be 0.00%, 74.00%, 75.00%, 76.00%, 77.00%, 78.00%, 79.00%, 80.00%, 81.00%, 82.00%, 83.00%, 84.00%, 85.00%, 86.00%, 87.00%, 88.00%, 89.00%, 90.00%, 91.00%, 92.00%, 93.00%, 94.00%, 95.00%, 96.00%, 97.00%, 98.00%, or 99.00%, or any percentage therebetween. The various percentages listed above may be applicable to microcrystalline cellulose (MCC), lactose monohydrate (LMH), or both. In embodiments, the diluent may comprise about 43.25% MCC by weight of the tablet pharmaceutical composition. In embodiments, the diluent may comprise about 43.In an embodiment, the diluent may comprise about 43.25% MCC by weight of the tablet pharmaceutical composition and about 43.50% LMH by weight of the tablet pharmaceutical composition.

[0228] In embodiments, the diluent in the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% ~approximately 70%, approximately 0.01% to approximately 80%, approximately 0.01% to approximately 90%, approximately 0.01% to approximately 99%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 4%, approximately 0.1% to approximately 5%, approximately 0.1% to approximately 6%, approximately 0.1% to approximately 7%, approximately 0.1% to approximately 8%, approximately 0.1% to approximately 9%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 20%, approximately 0.1% to approximately 30%, approximately 0.1% to approximately 40%, approximately 0.1% to approximately 50%, approximately 0.1% to approximately 60%, approximately 0.1% to approximately 70%, approximately 0.1% to approximately 80%, approximately 0.1% to approximately 90%, approximately 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to Approximately 99%, approximately 5% to approximately 10%, approximately 5% to approximately 20%, approximately 5% to approximately 30%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 5% to approximately 60%, approximately 5% to approximately 70%, approximately 5% to approximately 80%, approximately 5% to approximately 90%, approximately 5% to approximately 99%, approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99 %, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about The ranges may be 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. The various ranges listed above may be applicable to microcrystalline cellulose (MCC), lactose monohydrate (LMH), or both.

[0229] In embodiments, the binder of the tablet pharmaceutical composition disclosed herein is from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32% ,0.33%,0.34%,0.35%,0.36%,0.37%,0.38%,0.39%,0.40%,0.41%,0.42%,0.43%,0.44%,0.45%,0.46%,0.47%,0.48%,0.49%,0.50%,0.51%,0.52%,0.5 3%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0. 74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50% ,2.60%,2.70%,2.80%,2.90%,3.00%,3.10%,3.20%,3.30%,3.40%,3.50%,3.60%,3.70%,3.80%,3.90%,4.00%,4.10%,4.20%,4.30%,4.40%,4.50%,4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11.00%, 12. 00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00% ,43.00%,44.00%,45.00%,46.00%,47.00%,48.00%,49.00%,50.00%,51.00%,52.00%,53.00%,54.00%,55.00%,56.00%,57.00%,58.00%,59.00%,60.00%,61.00%,62.00%,63.00%,64.00%,65.00%,66.00%,67.00%,68.00%,69.00%,70.00%,71.00%,72.00%,73 The binder may comprise about 43.25% MCC by weight of the tablet pharmaceutical composition. In embodiments, the binder may comprise about 6% HPC by weight of the tablet pharmaceutical composition. In embodiments, the binder may comprise about 43% HPC by weight of the tablet pharmaceutical composition.The tablet pharmaceutical composition may contain 25% MCC and about 6% HPC by weight.

[0230] In embodiments, the binder of the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% ~approximately 70%, approximately 0.01% to approximately 80%, approximately 0.01% to approximately 90%, approximately 0.01% to approximately 99%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 4%, approximately 0.1% to approximately 5%, approximately 0.1% to approximately 6%, approximately 0.1% to approximately 7%, approximately 0.1% to approximately 8%, approximately 0.1% to approximately 9%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 20%, approximately 0.1% to approximately 30%, approximately 0.1% to approximately 40%, approximately 0.1% to approximately 50%, approximately 0.1% to approximately 60%, approximately 0.1% to approximately 70%, approximately 0.1% to approximately 80%, approximately 0.1% to approximately 90%, approximately 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to Approximately 99%, approximately 5% to approximately 10%, approximately 5% to approximately 20%, approximately 5% to approximately 30%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 5% to approximately 60%, approximately 5% to approximately 70%, approximately 5% to approximately 80%, approximately 5% to approximately 90%, approximately 5% to approximately 99%, approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99 %, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about The ranges may be 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. The various ranges listed above may be applicable to MCC, HPC, or both.

[0231] In embodiments, the fluidization aid of the tablet pharmaceutical compositions disclosed herein may comprise from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78 2%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0. 53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94% ,0.95%,0.96%,0.97%,0.98%,0.99%,1.00%,1.10%,1.20%,1.30%,1.40%,1.50%,1.60%,1.70%,1.80%,1.90%,2.00%,2.10%,2.20%,2.30%,2.40%,2.50 %, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90%, 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11.00%, 12. 00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00% ,43.00%,44.00%,45.00%,46.00%,47.00%,48.00%,49.00%,50.00%,51.00%,52.00%,53.00%,54.00%,55.00%,56.00%,57.00%,58.00%,59.00%,60.00%,61.00%,62.00%,63.00%,64.00%,65.00%,66.00%,67.00%,68.00%,69.00%,70.00%,71.00%,72.00%,73 The percentage of CSD may be 0.00%, 74.00%, 75.00%, 76.00%, 77.00%, 78.00%, 79.00%, 80.00%, 81.00%, 82.00%, 83.00%, 84.00%, 85.00%, 86.00%, 87.00%, 88.00%, 89.00%, 90.00%, 91.00%, 92.00%, 93.00%, 94.00%, 95.00%, 96.00%, 97.00%, 98.00%, or 99.00%, or any percentage therebetween. The various percentages listed above are applicable to CSD, magnesium stearate, or both. In embodiments, the fluidization aid may comprise about 0.5% CSD by weight of the tablet pharmaceutical composition. In embodiments, the fluidization aid is present in an amount of about 1.In embodiments, the flow aid may comprise about 0.5% CSD by weight of the tablet pharmaceutical composition and about 1.0% magnesium stearate by weight of the tablet pharmaceutical composition.

[0232] In embodiments, the fluidization aid of the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% to about 100%, from about 0.01% to about 150%, from about 0.01% to about 160%, from about 0.01% to about 170%, from about 0.01% to about 180%, from about 0.01% to about 200%, from about 0.01% to about 250%, from about 0.01% to about 260%, from about 0.01% to about 280%, from about 0.01% to about 300%, from about 0.01% to about 350%, from about 0.01% to about 360%, from about 0.01% to about 370%, from about 0.01% to about 380%, from about 0.01% to about 400%, from about 0.01% to about 450%, from about 0.01% to about 490%, from about 0.01% to about 50 % to about 70%, about 0.01% to about 80%, about 0.01% to about 90%, about 0.01% to about 99%, about 0.1% to about 1%, 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 0.1% to about 6%, about 0.1% to about 7%, about 0.1% to about 8%, about 0.1% to about 9%, about 0.1% to about 10%, about 0.1% to about 20%, about 0.1% to about 30%, about 0.1% to about 40%, about 0.1% to about 50%, about 0.1% to about 60%, about 0.1% to about 70%, about 0.1% to about 80%, about 0.1% to about 90%, about 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to Approximately 99%, approximately 5% to approximately 10%, approximately 5% to approximately 20%, approximately 5% to approximately 30%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 5% to approximately 60%, approximately 5% to approximately 70%, approximately 5% to approximately 80%, approximately 5% to approximately 90%, approximately 5% to approximately 99%, approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99 %, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about The ranges may be 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. The various ranges listed above may be applicable to CSD, magnesium stearate, or both.

[0233] In embodiments, the glidant in the tablet pharmaceutical compositions disclosed herein is from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 2%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0. 53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94% ,0.95%,0.96%,0.97%,0.98%,0.99%,1.00%,1.10%,1.20%,1.30%,1.40%,1.50%,1.60%,1.70%,1.80%,1.90%,2.00%,2.10%,2.20%,2.30%,2.40%,2.50 %, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90%, 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11.00%, 12. 00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00% ,43.00%,44.00%,45.00%,46.00%,47.00%,48.00%,49.00%,50.00%,51.00%,52.00%,53.00%,54.00%,55.00%,56.00%,57.00%,58.00%,59.00%,60.00%,61.00%,62.00%,63.00%,64.00%,65.00%,66.00%,67.00%,68.00%,69.00%,70.00%,71.00%,72.00%,73 The glidant may comprise 0.00%, 74.00%, 75.00%, 76.00%, 77.00%, 78.00%, 79.00%, 80.00%, 81.00%, 82.00%, 83.00%, 84.00%, 85.00%, 86.00%, 87.00%, 88.00%, 89.00%, 90.00%, 91.00%, 92.00%, 93.00%, 94.00%, 95.00%, 96.00%, 97.00%, 98.00%, or 99.00%, or any percentage therebetween. The various percentages listed above are applicable to the CSD. In embodiments, the glidant may comprise about 0.5% of the CSD by weight of the tablet pharmaceutical composition.

[0234] In embodiments, the glidant in the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% to about 70%, from about 0.01% to about 80%, from about 0.01% to about 90%, from about 0.01% to about 100%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% to about 10 ... % to about 70%, about 0.01% to about 80%, about 0.01% to about 90%, about 0.01% to about 99%, about 0.1% to about 1%, 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 0.1% to about 6%, about 0.1% to about 7%, about 0.1% to about 8%, about 0.1% to about 9%, about 0.1% to about 10%, about 0.1% to about 20%, about 0.1% to about 30%, about 0.1% to about 40%, about 0.1% to about 50%, about 0.1% to about 60%, about 0.1% to about 70%, about 0.1% to about 80%, about 0.1% to about 90%, about 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to Approximately 99%, approximately 5% to approximately 10%, approximately 5% to approximately 20%, approximately 5% to approximately 30%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 5% to approximately 60%, approximately 5% to approximately 70%, approximately 5% to approximately 80%, approximately 5% to approximately 90%, approximately 5% to approximately 99%, approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99 %, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about The ranges may be 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, and about 90% to about 99%. The various ranges listed above are applicable to CSD.

[0235] In embodiments, the lubricant in the tablet pharmaceutical compositions disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32% ,0.33%,0.34%,0.35%,0.36%,0.37%,0.38%,0.39%,0.40%,0.41%,0.42%,0.43%,0.44%,0.45%,0.46%,0.47%,0.48%,0.49%,0.50%,0.51%,0.52%,0.5 3%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0. 74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50% ,2.60%,2.70%,2.80%,2.90%,3.00%,3.10%,3.20%,3.30%,3.40%,3.50%,3.60%,3.70%,3.80%,3.90%,4.00%,4.10%,4.20%,4.30%,4.40%,4.50%,4.6 0%, 4.70%, 4.80%, 4.90%, 5.00%, 5.10%, 5.20%, 5.30%, 5.40%, 5.50%, 5.60%, 5.70%, 5.80%, 5.90%, 6.00%, 6.10%, 6.20%, 6.30%, 6.40%, 6.50%, 6.60%, 6.70%, 6.80%, 6.90%, 7.00%, 7.10%, 7.20%, 7.30%, 7.40%, 7.50%, 7.60%, 7.70%, 7.80%, 7.90%, 8.00%, 8.10%, 8.20%, 8.30%, 8.40%, 8.50%, 8.60%, 8.70%, 8.80%, 8.90%, 9.00%, 9.10%, 9.20%, 9.30%, 9.40%, 9.50%, 9.60%, 9.70%, 9.80%, 9.90%, 10.00%, 11.00%, 12. 00%, 13.00%, 14.00%, 15.00%, 16.00%, 17.00%, 18.00%, 19.00%, 20.00%, 21.00%, 22.00%, 23.00%, 24.00%, 25.00%, 26.00%, 27.00%, 28.00%, 29.00%, 30.00%, 31.00%, 32.00%, 33.00%, 34.00%, 35.00%, 36.00%, 37.00%, 38.00%, 39.00%, 40.00%, 41.00%, 42.00% ,43.00%,44.00%,45.00%,46.00%,47.00%,48.00%,49.00%,50.00%,51.00%,52.00%,53.00%,54.00%,55.00%,56.00%,57.00%,58.00%,59.00%,60.00%,61.00%,62.00%,63.00%,64.00%,65.00%,66.00%,67.00%,68.00%,69.00%,70.00%,71.00%,72.00%,73 The lubricant may be 0.00%, 74.00%, 75.00%, 76.00%, 77.00%, 78.00%, 79.00%, 80.00%, 81.00%, 82.00%, 83.00%, 84.00%, 85.00%, 86.00%, 87.00%, 88.00%, 89.00%, 90.00%, 91.00%, 92.00%, 93.00%, 94.00%, 95.00%, 96.00%, 97.00%, 98.00%, or 99.00%, or any percentage therebetween. The various percentages listed above are applicable to magnesium stearate. In embodiments, the lubricant may comprise about 1.0% magnesium stearate by weight of the tablet pharmaceutical composition.

[0236] In embodiments, the lubricant in the tablet pharmaceutical composition disclosed herein comprises from about 0.01% to about 99% by weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, from about 0.01% ~approximately 70%, approximately 0.01% to approximately 80%, approximately 0.01% to approximately 90%, approximately 0.01% to approximately 99%, approximately 0.1% to approximately 1%, approximately 0.1% to approximately 2%, approximately 0.1% to approximately 3%, approximately 0.1% to approximately 4%, approximately 0.1% to approximately 5%, approximately 0.1% to approximately 6%, approximately 0.1% to approximately 7%, approximately 0.1% to approximately 8%, approximately 0.1% to approximately 9%, approximately 0.1% to approximately 10%, approximately 0.1% to approximately 20%, approximately 0.1% to approximately 30%, approximately 0.1% to approximately 40%, approximately 0.1% to approximately 50%, approximately 0.1% to approximately 60%, approximately 0.1% to approximately 70%, approximately 0.1% to approximately 80%, approximately 0.1% to approximately 90%, approximately 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to Approximately 99%, approximately 5% to approximately 10%, approximately 5% to approximately 20%, approximately 5% to approximately 30%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 5% to approximately 60%, approximately 5% to approximately 70%, approximately 5% to approximately 80%, approximately 5% to approximately 90%, approximately 5% to approximately 99%, approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99 %, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about The ranges may be 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, and about 90% to about 99%. The various ranges listed above are applicable to magnesium stearate.

[0237] In certain embodiments, the tablet pharmaceutical compositions disclosed herein may include an outer coating. In embodiments, the outer coating of the tablet pharmaceutical compositions disclosed herein comprises from about 0.01% to about 99% of the weight of the tablet pharmaceutical composition, e.g., from about 0.01% to about 1%, from about 0.01% to about 2%, from about 0.01% to about 3%, from about 0.01% to about 4%, from about 0.01% to about 5%, from about 0.01% to about 6%, from about 0.01% to about 7%, from about 0.01% to about 8%, from about 0.01% to about 9%, from about 0.01% to about 10%, from about 0.01% to about 20%, from about 0.01% to about 30%, from about 0.01% to about 40%, from about 0.01% to about 50%, from about 0.01% to about 60%, or from about 0.01% to about 10%. 0.01% to about 70%, about 0.01% to about 80%, about 0.01% to about 90%, about 0.01% to about 99%, about 0.1% to about 1%, 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 0.1% to about 6%, about 0.1% to about 7%, about 0.1% to about 8%, about 0.1% to about 9%, about 0.1% to about 10%, about 0.1% to about 20%, about 0.1% to about 30%, about 0.1% to about 40%, about 0.1% to about 50%, about 0.1% to about 60%, about 0.1% to about 70%, about 0.1% to about 80%, about 0.1% to about 90%, about 0.1% to about 99%, about 1% to about 10%, about 1% to about 20%, about 1% to about 30%, about 1% to about 40%, about 1% to about 50%, about 1% to about 60%, about 1% to about 70%, about 1% to about 80%, about 1% to about 90%, about 1% to about 99%, about 2% to about 10%, about 2% to about 20%, about 2% to about 30%, about 2% to about 40%, about 2% to about 50%, about 2% to about 60%, about 2% to about 70%, about 2% to about 80%, about 2% to about 90%, about 2% to Approximately 99%, approximately 5% to approximately 10%, approximately 5% to approximately 20%, approximately 5% to approximately 30%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 5% to approximately 60%, approximately 5% to approximately 70%, approximately 5% to approximately 80%, approximately 5% to approximately 90%, approximately 5% to approximately 99%, approximately 10% to approximately 20%, approximately 10% to approximately 30%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99 %, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 20% to about 99%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 30% to about 99%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about The release rate may be 40% to about 80%, about 40% to about 90%, about 40% to about 99%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 80% to about 90%, about 80% to about 99%, or about 90% to about 99%. In embodiments, the outer coating of the tablet pharmaceutical composition may not cause a delayed release of the compound of Formula (I) and / or at least one excipient.

[0238] In certain embodiments, the dry weight of the tablet pharmaceutical compositions disclosed herein is from about 0.1 mg to about 400 mg, e.g., about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg. g, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5 .6mg, 5.7mg, 5.8mg, 5.9mg, 6mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7m g, 7.8mg, 7.9mg, 8mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9 .9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg,84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 102mg, 104mg, 106mg, 108mg, 110mg, 112mg, 1 14mg, 116mg, 118mg, 120mg, 122mg, 124mg, 126mg, 128mg, 130mg, 132mg, 134mg, 136mg, 138mg, 140mg, 142mg, 144mg, 146mg, 148mg, 150mg, 152mg, 154mg , 156mg, 158mg, 160mg, 162mg, 164mg, 166mg, 168mg, 170mg, 172mg, 174mg, 176mg, 178mg, 180mg, 182mg, 184mg, 186mg, 188mg, 190mg, 192mg, 194mg, 196 mg, 198mg, 200mg, 202mg, 204mg, 206mg, 208mg, 210mg, 212mg, 214mg, 216mg, 218mg, 220mg, 222mg, 224mg, 226mg, 228mg, 230mg, 232mg, 234mg, 236mg, 2 38mg, 240mg, 242mg, 244mg, 246mg, 248mg, 250mg, 252mg, 254mg, 256mg, 258mg, 260mg, 262mg, 264mg, 266mg, 268mg, 270mg, 272mg, 274mg, 276mg, 278m g, 280mg, 282mg, 284mg, 286mg, 288mg, 290mg, 292mg, 294mg, 296mg, 298mg, 300mg, 302mg, 304mg, 306mg, 308mg, 310mg, 312mg, 314mg, 316mg, 318mg, 32 0mg, 322mg, 324mg, 326mg, 328mg, 330mg, 332mg, 334mg, 336mg, 338mg, 340mg, 342mg, 344mg, 346mg, 348mg, 350mg, 352mg, 354mg, 356mg, 358mg, 360mg, 362mg, 364mg, 366mg, 368mg, 370mg, 372mg, 374mg, 376mg, 378mg, 380mg, 382mg, 384mg, 386mg, 388mg, 390mg, 392mg, 394mg, 396mg, 398mg, or 400mg,Or it can be any amount therebetween.

[0239] In an embodiment, the compound of formula (I) comprises from about 1% to about 99.99% by weight of the tablet pharmaceutical composition, e.g., from about 1% to about 10%, from about 1% to about 20%, from about 1% to about 30%, from about 1% to about 40%, from about 1% to about 50%, from about 1% to about 60%, from about 1% to about 70%, from about 1% to about 80%, from about 1% to about 90%, from about 1% to about 99%, from about 1% to about 99.99%, from about 10% to about 20%, from about 10% to about 30%, from about 10% to about 40%, from about 10% to about 50%, 0%, approximately 10% to approximately 60%, approximately 10% to approximately 70%, approximately 10% to approximately 80%, approximately 10% to approximately 90%, approximately 10% to approximately 99%, approximately 10% to approximately 99.99%, approximately 20% to approximately 30%, approximately 20% to approximately 40%, approximately 20% to approximately 50%, approximately 20% to approximately 60%, approximately 20% to approximately 70%, approximately 20% to approximately 80%, approximately 20% to approximately 90%, approximately 20% to approximately 99%, approximately 20% to approximately 99.99%, approximately 30% to approximately 40%, approximately 30% to approximately 50%, approximately 30% to Approximately 60%, approximately 30% to approximately 70%, approximately 30% to approximately 80%, approximately 30% to approximately 90%, approximately 30% to approximately 99%, approximately 30% to approximately 99.99%, approximately 40% to approximately 50%, approximately 40% to approximately 60%, approximately 40% to approximately 70%, approximately 40% to approximately 80%, approximately 40% to approximately 90%, approximately 40% to approximately 99%, approximately 40% to approximately 99.99%, approximately 50% to approximately 60%, approximately 50% to approximately 70%, approximately 50% to approximately 80%, approximately 50% to approximately 90%, approximately 50% to approximately 99%, approximately 5 It can be 0% to about 99.99%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 99%, about 60% to about 99.99%, about 70% to about 80%, about 70% to about 90%, about 70% to about 99%, about 70% to about 99.99%, about 80% to about 90%, about 80% to about 90%, about 80% to about 99.99%, about 90% to about 99%, about 90% to about 99.99%, or about 99% to about 99.99%.

[0240] In certain embodiments, the tablet pharmaceutical compositions disclosed herein, when stored at about 25°C and other atmospheric conditions, may not exhibit oxidation, loss of chemical stability, significant deterioration, and / or decomposition after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years, or any period therebetween. In certain embodiments, storage conditions for the tablet pharmaceutical compositions may include relative humidity. In certain embodiments, storage conditions for the tablet pharmaceutical compositions may include relative humidity of about 60% or about 75%.

[0241] In certain embodiments, the tablet pharmaceutical compositions disclosed herein, when stored at about 25°C and other atmospheric conditions, may not exhibit significant degradation, loss of chemical stability, decomposition, and / or oxidation of the compound of Formula (I), its pharmaceutically acceptable salts, crystals, solvates, polymorphs, prodrugs, metabolites, N-oxides, stereoisomers, or isomers after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years, or any period therebetween. In certain embodiments, storage conditions for the tablet pharmaceutical composition may include a relative humidity of about 60% or about 75%.

[0242] In certain embodiments, the tablet pharmaceutical compositions disclosed herein, when stored at about 40°C and other atmospheric conditions, may not exhibit oxidation, loss of chemical stability, significant deterioration, and / or decomposition after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, or 1 year, 2 years, or 3 years, or any period therebetween. In certain embodiments, the storage conditions for the tablet pharmaceutical compositions may include relative humidity. In certain embodiments, the storage conditions for the tablet pharmaceutical compositions may include a relative humidity of about 60% or about 75%. Storage of tablet pharmaceutical compositions at temperatures above room temperature is used to approximate longer-term tablet storage, as higher temperatures may promote tablet instability and / or accelerate undesired chemical reactions.

[0243] In certain embodiments, the tablet pharmaceutical compositions disclosed herein, when stored at about 40°C and other atmospheric conditions, may not exhibit significant degradation, loss of chemical stability, decomposition, and / or oxidation of the compound of Formula (I), its pharmaceutically acceptable salts, crystals, solvates, polymorphs, prodrugs, metabolites, N-oxides, stereoisomers, or isomers after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years, or any period therebetween. In certain embodiments, storage conditions for the tablet pharmaceutical compositions may include relative humidity. In certain embodiments, storage conditions for the tablet pharmaceutical compositions may include a relative humidity of about 60% or about 75%. Storage of the tablet pharmaceutical compositions at temperatures above room temperature is used to approximate longer-term tablet storage, as higher temperatures may promote tablet instability and / or accelerate unwanted chemical reactions.

[0244] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89. 50%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 5 minutes when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0245] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 10 minutes when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0246] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 20 minutes when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0247] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 30 minutes when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0248] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 40 minutes when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0249] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 50 minutes when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0250] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 1 hour when placed in an aqueous medium at about pH 7 and 25°C. In certain embodiments, the aqueous medium may include water.

[0251] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 5 minutes in simulated gastric fluid at 37°C, e.g., 900 mL of simulated gastric fluid at 37°C, 50 rpm in a USP Type II Apparatus.

[0252] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 10 minutes in simulated gastric fluid at 37°C, e.g., 900 mL of simulated gastric fluid at 37°C, 50 rpm in a USP Type II Apparatus.

[0253] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 20 minutes in simulated gastric fluid at 37°C, e.g., in 900 mL of simulated gastric fluid at 37°C, at 50 rpm in a USP Type II Apparatus.

[0254] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 30 minutes in simulated gastric fluid at 37°C, e.g., in 900 mL of simulated gastric fluid at 37°C, at 50 rpm in a USP Type II Apparatus.

[0255] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 40 minutes in simulated gastric fluid at 37°C, e.g., 900 mL of simulated gastric fluid at 37°C, 50 rpm in a USP Type II Apparatus.

[0256] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50%, 42.00%, 42.50%, 43.00%, 43.50%, 44.00%, 44.50%, 45.00%, 45.50%, 46.00%, 46.50%, 47.00%, 47.50% ,48.00%,48.50%,49.00%,49.50%,50.00%,50.50%,51.00%,51.50%,52.00%,52.50%,53.00%,53.50%,54.00%,54.50%,55.00%,55.50%,56.00%,56.50 %, 57.00%, 57.50%, 58.00%, 58.50%, 59.00%, 59.50%, 60.00%, 60.50%, 61.00%, 61.50%, 62.00%, 62.50%, 63.00%, 63.50%, 64.00%, 64.50%, 65.00%, 65.5 0%, 66.00%, 66.50%, 67.00%, 67.50%, 68.00%, 68.50%, 69.00%, 69.50%, 70.00%, 70.50%, 71.00%, 71.50%, 72.00%, 72.50%, 73.00%, 73.50%, 74.00%, 74.50%, 75.00%, 75.50%, 76.00%, 76.50%, 77.00%, 77.50%, 78.00%, 78.50%, 79.00%, 79.50%, 80.00%, 80.50%, 81.00%, 81.50%, 82.00%, 82.50%, 83.00%, 83.50%, 84.00%, 84.50%, 85.00%, 85.50%, 86.00%, 86.50%, 87.00%, 87.50%, 88.00%, 88.50%, 89.00%, 89.5 0%, 90.00%, 90.50%, 91.00%, 91.50%, 92.00%, 92.50%, 93.00%, 93.50%, 94.00%, 94.50%, 95.00%, 95.50%, 96.00%, 96.50%, 97.00%, 97.50%, 98.00%, 98.50%, 99.00%, 99.50%, or about 100.00%, or any amount therebetween, separated or dissolved after about 50 minutes in simulated gastric fluid at 37°C, e.g., 900 mL of simulated gastric fluid at 37°C, 50 rpm in a USP Type II Apparatus.

[0257] In certain embodiments, at least about 5%, 5.50%, 6.00%, 6.50%, 7.00%, 7.50%, 8.00%, 8.50%, 9.00%, 9.50%, 10.00%, 10.50%, 11.00%, 11.50%, 12.00%, 12.50%, 13.00%, 13.50%, 14.00%, 14.50%, 15.00%, 15.50%, 16.00%, 16.50%, 17.00%, 17.50%, 18.00%, 18.50%, 19.00%, 19.50%, 20.00%, 20.50%, 21.00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 30.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37.50%, 38.00%, 38.50%, 39.00%, 39.50%, 40.00%, 40.50%, 41.00%, 41.50 .00%, 21.50%, 22.00%, 22.50%, 23.00%, 23.50%, 24.00%, 24.50%, 25.00%, 25.50%, 26.00%, 26.50%, 27.00%, 27.50%, 28.00%, 28.50%, 29.00%, 29.50%, 3 0.00%, 30.50%, 31.00%, 31.50%, 32.00%, 32.50%, 33.00%, 33.50%, 34.00%, 34.50%, 35.00%, 35.50%, 36.00%, 36.50%, 37.00%, 37...

Claims

1. A tablet pharmaceutical composition, comprising: (i) Below 【Chemistry 1】 or a pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer thereof, having the structure: (ii) at least one excipient comprising one or more of a disintegrant, a dispersion polymer, a diluent, a glidant, and a lubricant.

2. The tablet pharmaceutical composition of claim 1, wherein the compound of formula (I) is effective in reducing RBP4 levels in a dosage form of about 1 to about 200 mg or about 5 to about 25 mg.

3. The tablet pharmaceutical composition of claim 1, wherein the compound of formula (I) is a micronized crystal.

4. The tablet pharmaceutical composition of claim 1, wherein the compound of formula (I) is a polymorph that exhibits an X-ray powder diffraction pattern having at least three characteristic peaks occurring at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0 degrees 2-theta (+ / - 0.5 degrees 2-theta).

5. The tablet pharmaceutical composition of claim 1, wherein the at least one excipient comprises a disintegrant.

6. The tablet pharmaceutical composition of claim 5, wherein the disintegrant is selected from the group consisting of agar, algin, calcium carbonate, carboxymethylcellulose, cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, clay, croscarmellose sodium (CCNa), crospovidone, gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose (MCC), polacrilin potassium, sodium alginate, sodium starch glycolate, corn starch, potato starch, tapioca starch, and combinations thereof.

7. The tablet pharmaceutical composition of claim 5, wherein the disintegrant comprises CCNa, MCC, crospovidone, tapioca starch, or a combination thereof.

8. The tablet pharmaceutical composition of claim 7, wherein the CCNa or the MCC is about 0.75% or 3% by weight of the tablet pharmaceutical composition.

9. The tablet pharmaceutical composition of claim 1, wherein the at least one excipient comprises a dispersion polymer.

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

11. The tablet pharmaceutical composition of claim 9, wherein the dispersion polymer comprises HPC, HPMC, or both.

12. The tablet pharmaceutical composition of claim 9, wherein the dispersion polymer is about 0.01-99%, 1-50%, or 2-20% by weight of the tablet pharmaceutical composition.

13. The tablet pharmaceutical composition of claim 11, wherein the HPC or HPMC is about 6% by weight of the tablet pharmaceutical composition.

14. The tablet pharmaceutical composition of claim 1, wherein the at least one excipient comprises about 0.75% of CCNa, MCC, crospovidone, or tapioca starch by weight of the tablet pharmaceutical composition, and about 6% of HPC by weight of the tablet pharmaceutical composition.

15. The tablet pharmaceutical composition of claim 1, wherein the at least one excipient comprises about 0.75% by weight of the tablet pharmaceutical composition of CCNa, MCC, crospovidone, or tapioca starch, and about 10% by weight of the tablet pharmaceutical composition of HPMC.

16. The tablet pharmaceutical composition of claim 1, wherein the at least one excipient comprises about 0.75% by weight of the tablet pharmaceutical composition of CCNa, MCC, crospovidone, or tapioca starch, and about 20% by weight of the tablet pharmaceutical composition of HPMC.

17. The tablet pharmaceutical composition of claim 1, wherein the at least one excipient comprises a diluent, binder, flow aid, filler, sweetener, wetting agent, glidant, lubricant, or surfactant, or any combination thereof.

18. The tablet pharmaceutical composition of claim 17, wherein the diluent comprises MCC, lactose monohydrate (LMH), or both.

19. The tablet pharmaceutical composition of claim 17, wherein the fluidization aid comprises colloidal silicon dioxide (CSD), magnesium stearate, or both.

20. The tablet pharmaceutical composition of claim 17, wherein the at least one excipient comprises two or more of MCC, LMH, HPC, CCNa, CSD, and magnesium stearate.

21. The tablet pharmaceutical composition of claim 1, wherein the dry weight of the tablet pharmaceutical composition is from about 0.1 mg to about 400 mg.

22. The tablet pharmaceutical composition of claim 1, wherein the compound of formula (I) is about 1-99.99%, about 10-80%, or about 20-60% by weight of the tablet pharmaceutical composition.

23. The tablet pharmaceutical composition of claim 1, wherein the tablet pharmaceutical composition does not exhibit a significant loss of chemical stability, deterioration, and / or decomposition after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years at 25°C when stored under other atmospheric conditions.

24. The tablet pharmaceutical composition of claim 1, wherein the tablet pharmaceutical composition does not exhibit a significant loss of chemical stability, deterioration, and / or decomposition of the compound of Formula (I), its pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer, or the at least one excipient after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, 1 year, 2 years, or 3 years at 25°C when stored under other atmospheric conditions.

25. The tablet pharmaceutical composition of claim 1, wherein the tablet pharmaceutical composition does not exhibit a significant loss of chemical stability, deterioration, and / or decomposition after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, or 1 year at 40°C when stored under other atmospheric conditions.

26. The tablet pharmaceutical composition of claim 1, wherein the tablet pharmaceutical composition does not exhibit a significant loss of chemical stability, deterioration, and / or decomposition of the compound of Formula (I), its pharmaceutically acceptable salt, crystal, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer, or isomer, or the at least one excipient after about 1 week, 2 weeks, 3 weeks, 4 weeks, 10 weeks, 20 weeks, 30 weeks, 40 weeks, or 1 year at 40°C when stored under other atmospheric conditions.

27. The tablet pharmaceutical composition of claim 1, wherein at least about 5%, 10%, 25%, 50%, 75%, 80%, 90%, 95%, or 100% of the tablet pharmaceutical composition by weight separates or dissolves after about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 1 hour when placed in an aqueous medium at about pH 7 and 25°C.

28. The tablet pharmaceutical composition of claim 1, wherein at least about 5%, 10%, 25%, 50%, 75%, 80%, 90%, 95%, or 100% of the tablet pharmaceutical composition by weight separates or dissolves after about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 1 hour when placed in simulated gastric fluid at 37°C.

29. The tablet pharmaceutical composition of claim 1 for use in treating an ophthalmic disease in a subject in need thereof.

30. The tablet pharmaceutical composition of claim 29, wherein the eye disease is a disease characterized by excessive lipofuscin accumulation in the retina.

31. The tablet pharmaceutical composition of claim 30, wherein the disease characterized by excessive lipofuscin accumulation comprises age-related macular degeneration, dry (atrophic) age-related macular degeneration, early-onset macular degeneration (Stargardt disease), Best disease, adult vitelliform maculopathy, geographic atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or ABCA4 gene-associated retinal disease.

32. A pharmaceutical composition comprising any one of formulas 1 to 140 in Tables 31 to 38.

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