Biomarkers for Age-Related Macular Degeneration

Abstract

Provided herein are biomarkers and diagnostic methods useful for diagnosing age-related macular degeneration. Also provided herein are treatments for diseases including age-related macular degeneration.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 191,739, filed May 21, 2021, the entirety of which is incorporated herein by reference. [Background technology]

[0002] There is a need in the medical field for effective risk assessment, diagnosis, and treatment of diseases and disorders associated with retinol binding protein 4 (RBP4), such as age-related macular degeneration (AMD). Summary of the Invention

[0003] Provided herein is a biomarker that can be used to assess the presence of age-related macular degeneration (AMD) in an individual or assess the risk of developing AMD.Also provided herein is an assay for measuring the biomarker provided herein.Further provided herein is a method for treating AMD by administering treatment.

[0004] Provided herein is a method for treating age-related macular degeneration in an individual in need thereof, comprising: (a) determining by assay a level of retinol binding protein 4 (RBP4) in a sample from the individual; and (b) administering a treatment to reduce the level of RBP4 in the individual if the sample has at least a threshold level of RBP4, the threshold being at least 25 μg / ml, thereby treating age-related macular degeneration in the individual. Further provided herein is a method, wherein the threshold level of RBP4 is 35 μg / ml. Further provided herein is a method, wherein the threshold level of RBP4 is 25-100 μg / ml. Further provided herein is a method, wherein the assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatographic assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. Further provided herein is a method, wherein the antibody assay comprises an ELISA. Further provided herein is a method further comprising: c) determining the level of vitamin A in a sample from the individual by a second assay; and d) administering a treatment to reduce the level of vitamin A in the individual if the sample has at least a threshold level of vitamin A, the threshold level of vitamin A being at least 150 ng / mL. Further provided herein is a method wherein the threshold level of vitamin A is about 225 ng / mL or about 390 ng / mL. Further provided herein is a method wherein the threshold level of vitamin A is 150-500 ng / mL. Further provided herein is a method wherein the second assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatographic assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. Further provided herein is a method wherein the sample comprises a blood sample. Further provided herein is a method wherein the level is measured from plasma or serum derived from the blood sample.Further provided herein is a method that provides a recommendation to re-evaluate the individual for macular degeneration after a period of time if the level falls below the RBP4 threshold. Further provided herein is a method that provides a recommendation to re-evaluate the individual for macular degeneration after a period of time if the level falls below the RBP4 threshold. Further provided herein is a method that provides a pharmaceutical composition that includes an RBP4 inhibitor or a compound that reduces the individual's blood RBP4 concentration. Further provided herein is a pharmaceutical composition that includes an RBP4 inhibitor or a compound that reduces the individual's blood RBP4 concentration.

[0005] [ka] or a pharma- ceutically acceptable salt thereof, wherein R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF, or C-C alkyl, where R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 At least two of the are other than H, and R A 6 is H, OH, or a halogen, and A A The structure:

[0006] [ka] wherein α, β, χ, and δ are each independently absent or present and, when present, each is a bond; X is C or N; Z1 is N; and Z2 is N or NR A 9 where R A 9 is H, C1-C4 alkyl, or oxetane; B Ais a substituted or unsubstituted 5-, 6-, or 7-membered ring structure. Further provided herein is a method wherein the compound has the structure:

[0007] [ka] Further provided herein is a method, wherein the compound has the structure:

[0008] [ka] Further provided herein is a method for preparing a pharmaceutical composition comprising administering to a patient a compound of formula (II):

[0009] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A B is an optionally further substituted benzene; R B 1 is an optionally substituted branched C3-C6 alkyl group; X B 1 is O, S, SO, SO2, or NH, and X B 2 is a bond or a C1-C3 alkylene group, and ring B B is azetidine or piperidine, and X B 3 is CO or SO2, R B 2is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, a cyano group, a nitro group, an acyl group, or a halogen atom. Further disclosed herein is a compound, wherein the compound is 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutyric acid, 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, 2-{[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]carbonyl}pyridine, 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutyric acid, {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, The method further provides a pharmaceutical composition comprising a compound of formula (III):

[0010] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A C is a benzene ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) halogen atoms and (b) C alkyl groups, and ring B Cis a piperazine ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms; R C (1) optionally substituted C1-C 10 (2) an optionally substituted C-C 14 (2) an optionally substituted aryl group, (3) an optionally substituted 5- or 6-membered aromatic heterocyclic group, (4) an optionally substituted amino group, (5) an optionally substituted carboxy group, or (6) an optionally substituted carbamoyl group. Further provided herein is a method, wherein the compound is N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycine, 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid, [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetic acid, 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione, [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid, or a pharma- ceutically acceptable salt thereof. Further provided herein is a method, wherein the pharmaceutical composition is a compound of formula (IV):

[0011] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A D is a 5-membered non-aromatic heterocycle optionally further substituted with one oxo group, and ring B D is a benzene ring optionally further substituted with 1 to 4 substituents; X Dis O, CHO, OCH, CH, (CH), S, CHS, SCH, S(O), CHS(O), S(O)CH, S(O), CHS(O), or S(O)CH. Further provided herein is a method wherein the compound is ({(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetic acid, ({1-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid, 3-{(2R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}propanoic acid, or a pharma- ceutically acceptable salt thereof. Further provided herein is a pharmaceutical composition comprising a compound of formula (V):

[0012] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A E is a pyrazole ring, a pyridine ring, an oxazole ring, an imidazole ring, or a pyrimidine ring; X E is S, optionally substituted alkylene, or O; R E is a hydrogen atom or a C1-C6 alkyl group. Further provided herein is a method, wherein the compound is ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetic acid, ethyl ((6-(3,5-bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetic acid, ((6-(3,5-bis(trifluoromethyl)-phenyl)pyridin-3-yl)sulfanyl)acetic acid, or 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid.

[0013] Provided herein is a method for treating age-related macular degeneration in an individual in need thereof, comprising: determining a level of vitamin A in a sample from the individual by an assay; and administering a treatment to reduce the individual's level of vitamin A or the level of RBP4 if the sample has at least a threshold level of vitamin A, the threshold being at least 150 ng / ml, thereby treating age-related macular degeneration in the individual. Further provided herein is a method, wherein the threshold level of vitamin A is about 225 ng / mL or about 390 ng / mL. Further provided herein is a method, wherein the threshold level of vitamin A is 150-500 ng / mL. Further provided herein is a method, wherein the assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatographic assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. Further provided herein is a method, wherein the chromatographic assay comprises high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC), or liquid chromatography / mass spectrometry (LC-MS). Further provided herein is a method, wherein the sample comprises a blood sample. Further provided herein is a method, wherein the level is measured from plasma or serum derived from the blood sample. Further provided herein is a method, wherein if the level is below a vitamin A threshold, a recommendation is provided to re-evaluate the individual for macular degeneration after a period of time. Further provided herein is a method, wherein the treatment comprises a pharmaceutical composition comprising an RBP4 inhibitor or a compound that reduces the individual's blood RBP4 concentration.

[0014] Provided herein is a method for assessing the likelihood, severity, or diagnosis of age-related macular degeneration in an individual, comprising one or more of the following steps: a) determining whether the level of retinol binding protein 4 (RBP4) in a sample from the individual is above a threshold value for RBP4 by an assay; b) determining the age and medical history of the individual; and c) assessing the likelihood, severity, or diagnosis of age-related macular degeneration based on the level of RBP4, and optionally based on the age and / or medical history of the individual, wherein the threshold level of RBP4 is at least 25 μg / ml. Further provided herein is a method wherein the threshold is 35 μg / ml. Further provided herein is a method wherein the threshold is 25-100 μg / ml. Further provided herein is a method wherein the method further comprises performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry. Further provided herein is a method wherein the method further comprises classifying the stage of age-related macular degeneration. Further provided herein is a method, wherein the step of classifying comprises using AREDS categories. Further provided herein is a method, wherein the assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatographic assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. Further provided herein is a method, wherein the antibody assay comprises an ELISA. Further provided herein is a method, wherein the sample comprises a blood sample. Further provided herein is a method, wherein the level is measured from plasma or serum derived from the blood sample. Further provided herein is a method, wherein the step of assessing the likelihood of developing macular degeneration comprises generating a risk score. Further provided herein is a method, wherein if the risk score is above a threshold, a pharmaceutical composition for treating macular degeneration is administered. Further provided herein is a method, wherein the step of selecting a dose of the pharmaceutical composition based on the level of RBP4 is further provided.Further provided herein are methods that, if the risk score falls below a threshold, provide a recommendation to re-evaluate the individual for macular degeneration after a period of time.

[0015] Provided herein is a method for treating age-related macular degeneration in an individual in need thereof, comprising: a) determining the presence or absence of one or more genomic variants by assay, wherein the one or more genomic variants comprise at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555 or rs1801574; b) using the presence or absence of one or more genomic variants to calculate the risk score of age-related macular degeneration; and c) administering a treatment for treating age-related macular degeneration in the individual.Further provided herein is a method, wherein the one or more genomic variants comprise at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555 or rs1801574. Further provided herein is a method for determining whether one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs754765164, rs2 Further provided herein is a method comprising at least five of the following: rs01602424, rs564661476, rs4147831, rs6657239, rs2297632, rs1801555, rs1762114, rs55860151, rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281. Further provided herein is a method comprising determining the age or medical history of the individual. Further provided herein is a method comprising determining the level of retinol binding protein 4 (RBP4) in a sample from the individual. Further provided herein is a method wherein the treatment comprises administering a pharmaceutical composition to the individual. Further provided herein is a method wherein the pharmaceutical composition comprises an RBP4 inhibitor or a compound that reduces the blood RBP4 concentration of the individual. Further provided herein is a method wherein the pharmaceutical composition comprises a compound represented by formula (I):

[0016] [ka] or a pharma- ceutically acceptable salt thereof, wherein R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF, or C-C alkyl, where R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 At least two of the are other than H, and R A 6 is H, OH, or a halogen, and A A The structure:

[0017] [ka] wherein α, β, χ, and δ are each independently absent or present and, when present, each is a bond; X is C or N; Z1 is N; and Z2 is N or NR A 9 where R A 9 is H, C1-C4 alkyl, or oxetane; B A is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure. Further provided herein is a pharmaceutical composition comprising a compound having the structure:

[0018] [ka] or a pharma- ceutically acceptable salt thereof. Further provided herein is a pharmaceutical composition comprising a compound having the structure:

[0019] [ka] or a pharma- ceutically acceptable salt thereof.

[0020] Provided herein is a method for assessing the likelihood of age-related macular degeneration in an individual in need thereof, comprising: a) extracting a protein fraction from a blood sample obtained from the individual; b) extracting a nucleic acid fraction from the blood sample; c) determining a level of retinol binding protein 4 (RBP4) from the protein fraction by a first assay; d) determining an allele frequency of one or more genomic variants from nucleic acids in the nucleic acid fraction by a second assay, wherein the one or more genomic variants comprise at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574; and e) assessing the likelihood of age-related macular degeneration based on the level of RBP4 and the allele frequency of the one or more genomic variants. Further provided herein is a method, wherein the first assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. Further provided herein is a method, wherein the antibody assay comprises an ELISA. Further provided herein is a method, wherein the level is measured from the plasma or serum derived from a blood sample. Further provided herein is a method, wherein the one or more genomic variants comprise at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.Further provided herein is a method for determining whether one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs754765164, rs2 The method further comprises at least five of the following: rs1602424, rs564661476, rs4147831, rs6657239, rs2297632, rs1801555, rs1762114, rs55860151, rs1800549, rs3112831, rs4147830, rs2297634, or rs4847281. The method further comprises determining the age or medical history of the individual. The method further comprises performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry. The method further comprises classifying the progression of age-related macular degeneration. The method further comprises the classifying comprises using AREDS categories. Further provided herein is a method, wherein assessing the likelihood of age-related macular degeneration comprises generating a risk score.

[0021] Provided herein is a method for treating age-related macular degeneration in an individual in need thereof, comprising: a) providing the level of retinol binding protein 4 (RBP4), the level being determined by assaying a protein fraction of a sample from the individual; b) providing the allele frequency of one or more genomic variants, the allele frequency being determined by assaying a nucleic acid fraction of a sample from the individual, the one or more genomic variants comprising at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574; and c) administering treatment based on the assessment of the level of RBP4 and the allele frequency of one or more genomic variants.Further provided herein is a method, the sample comprising a blood sample.Further provided herein is a method, the level being measured from the plasma or serum derived from the blood sample. Further provided herein is a method, wherein the assay is an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatographic assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. Further provided herein is a method, wherein the antibody assay comprises an ELISA. Further provided herein is a method, wherein the evaluation comprises a diagnosis of age-related macular degeneration. Further provided herein is a method, wherein the evaluation further comprises an analysis of at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry. Further provided herein is a method, wherein the evaluation further comprises an analysis of the individual's age or medical history. Further provided herein is a method, wherein the one or more genomic variants include at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.Further provided herein is a method for determining whether one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs754765164, rs2 rs4147830, rs2297634, or rs4847281. Further provided herein is a method, wherein the treatment comprises administering a pharmaceutical composition to the individual. Further provided herein is a method, wherein the pharmaceutical composition comprises an RBP4 inhibitor or a compound that reduces the blood RBP4 concentration of the individual. Further provided herein is a method, wherein the pharmaceutical composition comprises a compound represented by formula (I):

[0022] [ka] or a pharma- ceutically acceptable salt thereof, wherein R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF, or C-C alkyl, where R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 At least two of the are other than H, and R A 6 is H, OH, or a halogen, and A A The structure:

[0023] [ka] wherein α, β, χ, and δ are each independently absent or present and, when present, each is a bond; X is C or N; Z1 is N; and Z2 is N or NR A 9 where R A 9 is H, C1-C4 alkyl, or oxetane; B A is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure. Further provided herein is a pharmaceutical composition comprising a compound having the structure:

[0024] [ka] or a pharma- ceutically acceptable salt thereof. Further provided herein is a pharmaceutical composition comprising a compound having the structure:

[0025] [ka] or a pharma- ceutically acceptable salt thereof. Further provided herein is a pharmaceutical composition comprising a compound having formula (II):

[0026] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A B is an optionally further substituted benzene; R B 1 is an optionally substituted branched C3-C6 alkyl group; X B 1 is O, S, SO, SO2, or NH, and X B 2 is a bond or a C1-C3 alkylene group, and ring B B is azetidine or piperidine, and X B 3is CO or SO2, R B 2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, a cyano group, a nitro group, an acyl group, or a halogen atom. Further disclosed herein is a compound, wherein the compound is 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutyric acid, 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, 2-{[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]carbonyl}pyridine, 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutyric acid, {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, The method further provides a pharmaceutical composition comprising a compound of formula (III):

[0027] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A C is a benzene ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) halogen atoms and (b) C alkyl groups, and ring B Cis a piperazine ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms; R C (1) optionally substituted C1-C 10 (2) an optionally substituted C-C 14 (2) an optionally substituted aryl group, (3) an optionally substituted 5- or 6-membered aromatic heterocyclic group, (4) an optionally substituted amino group, (5) an optionally substituted carboxy group, or (6) an optionally substituted carbamoyl group. Further provided herein is a method, wherein the compound is N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycine, 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid, [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetic acid, 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione, [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid, or a pharma- ceutically acceptable salt thereof. Further provided herein is a method, wherein the pharmaceutical composition is a compound of formula (IV):

[0028] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A D is a 5-membered non-aromatic heterocycle optionally further substituted with one oxo group, and ring B D is a benzene ring optionally further substituted with 1 to 4 substituents; X Dis O, CHO, OCH, CH, (CH), S, CHS, SCH, S(O), CHS(O), S(O)CH, S(O), CHS(O), or S(O)CH. Further provided herein is a method wherein the compound is ({(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetic acid, ({1-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid, 3-{(2R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}propanoic acid, or a pharma- ceutically acceptable salt thereof. Further provided herein is a pharmaceutical composition comprising a compound of formula (V):

[0029] [ka] or a pharma- ceutically acceptable salt thereof, wherein ring A E is a pyrazole ring, a pyridine ring, an oxazole ring, an imidazole ring, or a pyrimidine ring; X E is S, optionally substituted alkylene, or O; R E is a hydrogen atom or a C1-C6 alkyl group. Further provided herein is a method, wherein the compound is ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetic acid, ethyl ((6-(3,5-bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetic acid, ((6-(3,5-bis(trifluoromethyl)-phenyl)pyridin-3-yl)sulfanyl)acetic acid, or 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid.

[0030] Citation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. [Brief description of the drawings]

[0031] The novel features of the invention are set forth with particularity in the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings.

[0032] [Figure 1] Figure 1 shows box plots of plasma retinol binding protein 4 (RBP4) levels in healthy controls and different Age-Related Eye Disease Study (AREDS) categories. Plasma RBP4 mean ± SD (μg / ml) is 29.4 ± 7.1 (control), 32.1 ± 6.6 (AREDS2), 37.3 ± 8.8 (AREDS3), and 36.1 ± 7.8 (AREDS4). *P<0.05. **P<0.01. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "the cell" includes one or more cells (or cells) and equivalents thereof known to those of skill 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 therein are intended to be included. The term "about," when referring to a number or numerical range, means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and thus, in some cases, the number or numerical range varies by 1% to 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that embodiments, e.g., any composition of matter, composition, method, or process consisting of the substances described herein, "consist of" or "consist essentially of" the described features, in certain other embodiments.

[0034] definition As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings specified below.

[0035] "Amino" refers to the -NH2 radical.

[0036] "Cyano" refers to the -CN radical.

[0037] "Nitro" refers to the -NO2 radical.

[0038] "Oxa" refers to the radical --O--.

[0039] "Oxo" refers to the =O radical.

[0040] "Thioxo" refers to the =S radical.

[0041] "Imino" refers to the =NH radical.

[0042] "Oximo" refers to the =N-OH radical.

[0043] "Hydrazino" refers to the =N-NH2 radical.

[0044] "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 includes 1 to 13 carbon atoms (e.g., C-C 13 In certain embodiments, the alkyl comprises 1-8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises 1-5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises 1-4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises 1-3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises 1-2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises 5-15 carbon atoms (e.g., C5-C6 alkyl). 15In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group comprises 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 (tent-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group may be selected from 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 )C(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 (where t is 1 or 2), optionally replaced by one or more of 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).

[0045] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0046] "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 in the specification, an alkenyl group may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... 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 )C(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 (where 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).

[0047] "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, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specified in the specification, an alkynyl group may include 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 )C(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 (where t is 1 or 2), optionally replaced by one or more of 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).

[0048] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain, or through any two carbons within the chain. In certain embodiments, the alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene comprises 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene comprises 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified in the specification, the alkylene chain may include 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 )C(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 (where 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).

[0049] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and has 2 to 12 carbon atoms. The alkenylene chain is attached to the rest of the molecule 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 otherwise stated in the specification, an alkenylene chain may include 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 )C(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 (where 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).

[0050] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists solely of carbon and hydrogen, contains at least one carbon-carbon triple bond, and has 2 to 12 carbon atoms. The alkynylene chain is attached to the rest of the molecule 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, the alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless otherwise stated in the specification, the alkynylene chain may include 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 )C(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 (where 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).

[0051] "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 aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon of 5 to 18 carbon atoms, where 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 otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include aryl radicals that are optionally substituted with one or more substituents, where the one or more substituents are independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R 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), and each R a are 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, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0052] "Aralkyl" is a group of the formula -Rc -aryl radical, R c is an alkylene chain as defined above, e.g., methylene or ethylene. 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.

[0053] "Aralkenyl" is a group of the formula -R d -aryl radical, 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.

[0054] "Aralkynyl" refers to a group of the formula -R e -aryl radical, R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the alkynylene radical is optionally substituted as defined above for an alkynylene chain.

[0055] "Aralkoxy" is a group of the formula -O-R c - refers to a radical bonded through an oxygen atom of an aryl, R c is an alkylene chain as defined above, e.g., methylene or ethylene. 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.

[0056] "Carbocyclyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting exclusively 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 remainder of the molecule by a single bond. A carbocyclyl is saturated (i.e., contains only single C-C bonds) 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 intended to include carbocyclyl radicals optionally substituted by one or more substituents, the one or more substituents being independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -Rb -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), and each R aare 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, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0057] A "carbocyclylalkyl" is a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0058] "Carbocyclylalkynyl" refers to a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0059] "Carbocyclylalkoxy" is Rc is an alkylene chain as defined above, c - refers to a radical attached through the oxygen atom of a carbocyclyl. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0060] As used herein, a "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:

[0061] [ka] These include, but are not limited to, the following:

[0062] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0063] "Fluoroalkyl" refers to an alkyl radical, as defined above, which is substituted with one or more fluoro radicals, as defined above, such as, for example, 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.

[0064] "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 remainder 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 otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl radicals, as defined above, optionally substituted by one or more substituents, said one or more substituents being 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 , -Rb -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), and each R aare 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, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0065] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above that contains 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.

[0066] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above that contains 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- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0067] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclyl radical, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen atom of the heterocyclyl is optionally attached to the alkyl radical. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0068] "Heterocyclylalkoxy" is R c is an alkylene chain as defined above, c -refers to a radical attached via the oxygen atom of a heterocyclyl. If the heterocyclyl is a nitrogen-containing heterocyclyl, the nitrogen atom of the heterocyclyl is optionally attached to the alkyl radical. 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.

[0069] "Heteroaryl" refers to a radical derived from a 3-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where 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 the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. 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 yl), 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]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, the term "heteroaryl" is intended to include heteroaryl radicals as defined above, optionally substituted by one or more substituents, said one or more substituents being 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), and each R a are 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, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0070] "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.

[0071] "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.

[0072] "Heteroarylalkyl" refers to a group of the formula -R c - refers to the heteroaryl radical, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the nitrogen atom of the heteroaryl is optionally attached to the alkyl radical. 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.

[0073] "Heteroarylalkoxy" refers to R c is an alkylene chain as defined above, c -refers to a radical attached through the oxygen atom of a heteroaryl. If the heteroaryl is a nitrogen-containing heteroaryl, the nitrogen atom of the heteroaryl is optionally attached to the alkyl radical. 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.

[0074] 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 the compounds described herein contain an alkene double bond, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans), unless otherwise specified. Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to the 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.

[0075] "Tautomer" refers to a molecule that can undergo proton transfer from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. 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 the following:

[0076] [ka]

[0077] In some embodiments, the compounds disclosed herein are used in various isotopic enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, and therefore increase the duration of action of pharmaceutical agents.

[0078] Unless otherwise stated, structures depicted herein are 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.

[0079] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C) may be labeled with an isotope. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125All isotopic substitutions 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.

[0080] In certain embodiments, the compounds disclosed herein are 2 Substituted with H atom 1 Having some or all of the H atoms. Methods for synthesizing compounds containing deuterium are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0081] Deuterium substituted compounds are synthesized using a variety of methods such as those described in Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 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.

[0082] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to effect the synthesis of compounds containing deuterium. Many deuterium-containing reagents and building blocks are commercially available from chemical companies such as Aldrich Chemical Co.

[0083] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer deuterium-substituted carbon atoms to reaction substrates under nucleophilic substitution reaction conditions. By way of example only, the use of CD3I is shown in the following reaction scheme.

[0084] [ka]

[0085] Deuterium transfer reagents, such as lithium aluminum deuteride (LiAlD4), are used to transfer deuterium to reaction substrates under reducing conditions. By way of example only, the use of LiAlD4 is shown in the reaction scheme below.

[0086] [ka]

[0087] Deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon bonds and effect reductive displacement of aryl carbon-halogen bonds, as shown, by way of example only, in the reaction scheme below.

[0088] [ka]

[0089] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and are non-exchangeable. 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by the synthesis method in which deuterated synthetic building blocks are used as starting materials.

[0090] "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 all pharmaceutically suitable salt forms.Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0091] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, such as, 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. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those of ordinary skill in the art.

[0092] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali, alkaline earth metals, or organic amines. Salts 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 from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and base 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.

[0093] As used herein, "treatment of" or "treating" or "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to eradication or amelioration of the underlying disease being treated. Similarly, therapeutic benefit is achieved by eradication or reduction of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient still suffers from the underlying disease. For prophylactic benefit, the composition is administered in some embodiments to a patient who is at risk of developing a particular disease or who reports one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0094] "Prodrug" is intended to refer to a compound that, in some embodiments, is converted under physiological conditions or by solvolysis to a biologically active compound as described herein. Thus, the term "prodrug" refers to a pharma- ceutically acceptable precursor of a biologically active compound. Prodrugs are usually inactive when administered to a subject, but are converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often have the advantage 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)).

[0095] 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, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0096] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein are prepared by modifying functional groups present in the active compound in a manner such that the functional group modification is cleaved in vivo to the parent active compound by routine manipulation. Prodrugs include compounds bonded to any group that cleaves a hydroxy, amino, or mercapto group to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate derivatives of alcohol or amine functional groups in the active compound, and the like.

[0097] Markers of age-related macular degeneration Provided herein are methods for diagnosing or assessing the risk of developing age-related macular degeneration in an individual, and methods for treating an individual, as well as biomarkers associated with such diagnosis or risk assessment. Age-related macular degeneration (AMD) is a common eye disease and is 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 required for clear central vision. As AMD progresses, a common symptom is a blurred area near the center of vision. Over time, the blurred area may become larger, resulting in a blank spot in the subject's central vision.

[0098] Retinol-binding protein 4 levels predict AMD In some embodiments, provided herein is a method for diagnosing or assessing the risk of developing age-related macular degeneration (AMD) in an individual in need thereof, comprising determining the level of retinol binding protein 4 (RBP4) in a sample from the individual by assay.In some embodiments, the diagnosing or risk assessment step involves a treatment step, such as administering a treatment to reduce the level of RBP4 in the individual, thereby treating or preventing AMD in the individual.In some embodiments, if the level of RBP4 in the sample is above a threshold value (e.g., 25 μg / mL), a treatment is administered.In some embodiments, if the level of RBP4 in the sample is above a threshold value (e.g., 25 μg / mL), an individual is diagnosed or assessed as being at risk of developing AMD.

[0099] In another aspect, the present specification provides a method for evaluating the likelihood of age-related macular degeneration in an individual, comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from an individual is above a threshold value of RBP4; and evaluating the likelihood of developing macular degeneration based on the level of RBP4.In some embodiments, the method also includes determining the age and / or medical history of the individual.Therefore, in some embodiments, the step of evaluating the likelihood of developing macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0100] In another aspect, the present disclosure provides a method for assessing the severity of age-related macular degeneration in an individual, comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from an individual is greater than a threshold value for RBP4; and assessing the severity of macular degeneration based on the level of RBP4.In some embodiments, the method also comprises determining the age and / or medical history of the individual.Therefore, in some embodiments, assessing the severity of macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0101] In another aspect, the present disclosure provides a method for assessing the diagnosis of age-related macular degeneration in an individual, comprising: determining by assay that the level of retinol-binding protein 4 (RBP4) in a sample from an individual is above a threshold value for RBP4; and assessing the diagnosis of macular degeneration based on the level of RBP4.In some embodiments, the method also comprises determining the age and / or medical history of the individual.Therefore, in some embodiments, assessing the diagnosis of macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0102] In another aspect, the present disclosure provides a method for evaluating a dosage regimen in an individual with age-related macular degeneration, comprising: determining by assay that the level of retinol binding protein 4 (RBP4) in a sample from the individual is above a threshold value for RBP4; and evaluating the diagnosis of macular degeneration based on the level of RBP4.In some embodiments, the method also includes determining the age and / or medical history of the individual.Therefore, in some embodiments, the step of evaluating a dosage regimen in an individual with macular degeneration is based on the level of RBP4, age, and medical history of the individual.

[0103] In some embodiments, the threshold level of RBP4 is at least 25 μg / mL. In some embodiments, the threshold level of RBP4 is at least 30 μg / mL. In some embodiments, the threshold level of RBP4 is at least 35 μg / mL. In some embodiments, the threshold level is about 25 μg / mL to about 100 μg / mL. In some embodiments, the threshold value is about 25 μg / mL to about 30 μg / mL, about 25 μg / mL to about 35 μg / mL, about 25 μg / mL to about 40 μg / mL, about 25 μg / mL to about 50 μg / mL, about μg / mL to about μg / mL, about μg / mL to about μg / mL, about μg / mL to about 80 μg / mL, about 25 μg / mL to about 90 μg / mL, about 25 μg / mL to about 100 μg / mL, about 30 μg / mL to about 35 μg / mL, about 30 μg / mL to about 40 μg / mL, about 30 μg / mL to about 50 μg / mL , about 30 μg / mL to about 60 μg / mL, about 30 μg / mL to about 70 μg / mL, about 30 μg / mL to about 80 μg / mL, about 30 μg / mL to about 90 μg / mL, about 30 μg / mL to about 100 μg / mL, about 35 μg / mL to about 40 μg / mL, about 35 μg / mL to about 50 μg / mL, about 35 μg / mL to about 60 μg / mL, about 35 μg / mL to about 70 μg / mL, about 35 μg / mL to about 80 μg / mL, about 35 μg / mL to about 90 μg / mL, or about 35 μg / mL to about 100 μg / mL. In some embodiments, the threshold is about 25 μg / mL, about 30 μg / mL, or about 35 μg / mL. In some embodiments, the threshold is at least about 25 μg / mL, about 30 μg / mL, or about 35 μg / mL, in some embodiments, the threshold is at most about 30 μg / mL, about 35 μg / mL, about 40 μg / mL, about 50 μg / mL, about 60 μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, or about 100 μg / mL.

[0104] In some embodiments, the threshold may vary based on various characteristics of the individual, including, but not limited to, demographics, sex, age, medical history, previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease, including non-alcoholic fatty liver disease.

[0105] In some embodiments, a diagnosis of AMD is made when the level of RBP4 is above a threshold. In some embodiments, a risk score is calculated when the level of RBP4 is above a threshold.

[0106] In some embodiments, a treatment is administered when the level of RBP4 is above a threshold. In some embodiments, the treatment is administered to reduce the level of RBP4. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor may be any of the RBP4 inhibitors provided herein.

[0107] In some embodiments, if the level of RBP4 falls below a threshold, further steps may be taken or recommended. Measurements below such thresholds may still indicate that the individual has some risk of developing AMD in the future, and therefore further monitoring may be recommended or further testing may be required to confirm or complete the diagnosis of AMD.

[0108] Further, in some embodiments, the method comprises assessing the likelihood of developing AMD based on the level of RBP4. In some embodiments, assessing the likelihood of developing AMD comprises generating a risk score. In some embodiments, if the risk score is above a threshold, treatment for AMD is administered (e.g., treatment with an RBP4 inhibitor). In some embodiments, the risk score reflects the probability that an individual will develop AMD at some point in the future based on the measurements provided herein.

[0109] In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time (e.g., when a risk score for developing AMD is calculated, or when the level of RBP4 falls below a threshold but other indicators of possible development of AMD are present). In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time if the level or risk score falls below a threshold. The period of time may be any suitable period of time. In some embodiments, the period of time is from about 1 month to about 24 months. In some embodiments, the period is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the period is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months, In some embodiments, the period is up to about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months.

[0110] A recommendation to reassess may include reassessing the individual's RBP4 levels or performing any of the other tests or evaluations for AMD provided herein, such as performing further testing after a period of time, including, but not limited to, a follow-up visit with a physician for a physical eye examination.

[0111] In some embodiments, the level of RBP4 in an individual is assessed by an assay. Any suitable assay for measuring the level of RBP4 can be used (e.g., antibody assay, mass spectrometry-based assay (e.g., LC / MS), liquid chromatography assay (e.g., HPLC, UPLC), etc.). In some embodiments, the assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatography assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the assay comprises an antibody assay. In some embodiments, the antibody assay comprises an enzyme-linked immunosorbent assay (ELISA).

[0112] In some embodiments, the sample comprises a blood sample from the individual. The blood sample may be further processed, such as to remove impurities or to leave serum and / or plasma. In some embodiments, the sample is a plasma sample or a serum sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the levels are measured from plasma or serum derived from the blood sample. In some embodiments, the levels are measured from plasma derived from the blood sample. In some embodiments, the levels are measured from serum derived from the blood sample.

[0113] In some embodiments, the determination of AMD diagnosis, risk assessment of developing AMD, and / or treatment decision is based on further considerations in addition to the level of RBP4. In some embodiments, the determination is based on the age and / or medical history of the individual. In some embodiments, the determination is based at least in part on the age of the individual. In some embodiments, the determination is based at least in part on the medical history of the individual. In some embodiments, the medical history of the individual can include information such as previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease including non-alcoholic fatty liver disease. In some embodiments, the determination is based at least in part on the level of vitamin A of the individual (e.g., in the blood sample of the individual).

[0114] Additionally, the methods provided herein may further include any of the additional tests or diagnostic methods provided herein for assessing the presence of AMD in an individual, including measuring the presence or absence of any of the genomic variants provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the methods further include performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0115] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification may be based on the level of RBP4 measured as provided herein or in conjunction with other methods provided herein, such as by classifying using the Age-Related Eye Disease Study (AREDS) classification.

[0116] Vitamin A Levels Predict AMD In some embodiments, provided herein is a method for diagnosing or assessing the risk of developing age-related macular degeneration (AMD) in an individual in need thereof, comprising determining the level of vitamin A in a sample from the individual by assay.In some embodiments, the diagnosing or risk assessment step involves a treatment step, such as administering a treatment to reduce the level of vitamin A or RBP4 in the individual, thereby treating or preventing AMD in the individual.In some embodiments, if the level of vitamin A in the sample is above a threshold value (e.g., 150ng / mL), a treatment is administered.In some embodiments, if the level of vitamin A in the sample is above a threshold value (e.g., 150ng / mL), an individual is diagnosed or assessed as being at risk of developing AMD.

[0117] In another aspect, the present disclosure provides a method for assessing the likelihood of age-related macular degeneration in an individual, comprising: determining by assay that the level of vitamin A in a sample from the individual is above a vitamin A threshold; and assessing the likelihood of developing macular degeneration based on the level of vitamin A. In some embodiments, the method also includes determining the age and / or medical history of the individual. Thus, in some embodiments, assessing the likelihood of developing macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0118] In another aspect, provided herein is a method for assessing the severity of age-related macular degeneration in an individual, comprising: determining by assay that the level of vitamin A in a sample from the individual is above a vitamin A threshold; and assessing the severity of macular degeneration based on the level of vitamin A. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, assessing the severity of macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0119] In another aspect, provided herein is a method for assessing the diagnosis of age-related macular degeneration in an individual, comprising: determining by assay that the level of vitamin A in a sample from the individual is above a vitamin A threshold; and assessing the diagnosis of macular degeneration based on the level of vitamin A. In some embodiments, the method also comprises determining the age and / or medical history of the individual. Thus, in some embodiments, assessing the diagnosis of macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0120] In another aspect, provided herein is a method for evaluating a dosage regimen in an individual with age-related macular degeneration, comprising: determining by assay that the level of vitamin A in a sample from the individual is above a vitamin A threshold; and evaluating the diagnosis of macular degeneration based on the level of vitamin A. In some embodiments, the method also includes determining the age and / or medical history of the individual. Thus, in some embodiments, evaluating a dosage regimen in an individual with macular degeneration is based on the vitamin A level, age, and medical history of the individual.

[0121] In some embodiments, the threshold level of vitamin A is at least about 150 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 175 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 200 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 220 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 221 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 222 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 223 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 224 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 225 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 250 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 300 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 350 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 390 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 391 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 392 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 393 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 394 ng / mL. In some embodiments, the threshold level of vitamin A is at least about 395 ng / mL. In some embodiments, the threshold level of vitamin A is about 150 ng / mL to about 500 ng / mL.In some embodiments, the threshold level of vitamin A is about 150 ng / mL to about 175 ng / mL, about 150 ng / mL to about 200 ng / mL, about 150 ng / mL to about 225 ng / mL, about 150 ng / mL to about 250 ng / mL, about 150 ng / mL to about 300 ng / mL, about 150 ng / mL to about 350 ng / mL, about 150 ng / mL to about 400 ng / mL, about 150 ng / mL to about 450 ng / mL, about 150 ng / mL to about 500 ng / mL, about 175 ng / mL to about 2 ... mL ~ about 225ng / mL, about 175ng / mL - about 250ng / mL, about 175ng / mL - about 300ng / mL, about 175ng / mL - about 350ng / mL, about 175ng / mL - about 400ng / mL, about 175ng / mL - about 450ng / mL, about 17 5ng / mL to about 500ng / mL, about 200ng / mL to about 225ng / mL, about 200ng / mL to about 250ng / mL, about 200ng / mL to about 300ng / mL, about 200ng / mL to about 350ng / mL, about 200ng / mL to about 400ng / mL, Approximately 200ng / mL to approximately 450ng / mL, approximately 200ng / mL to approximately 500ng / mL, approximately 225ng / mL to approximately 250ng / mL, approximately 225ng / mL to approximately 300ng / mL, approximately 225ng / mL to approximately 350ng / mL, approximately 225ng / mL to approximately 400ng / mL, about 225ng / mL to about 450ng / mL, about 225ng / mL to about 500ng / mL, about 250ng / mL to about 300ng / mL, about 250ng / mL to about 350ng / mL, about 250ng / mL to about 400ng / mL, about 250ng / mL to about 45 0 ng / mL, about 250 ng / mL to about 500 ng / mL, about 300 ng / mL to about 350 ng / mL, about 300 ng / mL to about 400 ng / mL, about 300 ng / mL to about 450 ng / mL, about 300 ng / mL to about 500 ng / mL, about 350 ng / mL to about 400 ng / mL, about 350 ng / mL to about 450 ng / mL, about 350 ng / mL to about 500 ng / mL, about 400 ng / mL to about 450 ng / mL, about 400 ng / mL to about 500 ng / mL, or about 450 ng / mL to about 500 ng / mL.In some embodiments, the threshold level of vitamin A is about 150ng / mL, about 175ng / mL, about 200ng / mL, about 225ng / mL, about 250ng / mL, about 300ng / mL, about 350ng / mL, about 400ng / mL, about 450ng / mL, or about 500ng / mL. In some embodiments, the threshold level of vitamin A is at least about 150ng / mL, about 175ng / mL, about 200ng / mL, about 225ng / mL, about 250ng / mL, about 300ng / mL, about 350ng / mL, about 400ng / mL, or about 450ng / mL. In some embodiments, the threshold level of vitamin A is up to about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, or about 500 ng / mL.

[0122] In some embodiments, the threshold may vary based on various characteristics of the individual, including, but not limited to, demographics, sex, age, medical history, previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease, including non-alcoholic fatty liver disease.

[0123] In some embodiments, the threshold level of vitamin A depends on the age of the individual. In some embodiments, the threshold level of vitamin A is lower for adolescents (e.g., individuals between the ages of 12-17) than for adults (e.g., individuals aged 18 and over). In some embodiments, the threshold level of vitamin A for adolescents is at least about 150 ng / mL, at least about 175 ng / mL, at least about 200 ng / mL, at least about 210 ng / mL, at least about 220 ng / mL, at least about 221 ng / mL, at least about 222 ng / mL, at least about 223 ng / mL, at least about 224 ng / mL, at least about 225 ng / mL, at least about 230 ng / mL, or at least about 250 ng / mL. In some embodiments, the threshold level of vitamin A in an adult is at least about 300 ng / mL, at least about 325 ng / mL, at least about 350 ng / mL, at least about 375 ng / mL, at least about 380 ng / mL, at least about 385 ng / mL, at least about 390 ng / mL, at least about 391 ng / mL, at least about 392 ng / mL, at least about 393 ng / mL, at least about 394 ng / mL, at least about 395 ng / mL, or at least about 400 ng / mL.

[0124] In some embodiments, a diagnosis of AMD is made if the level of vitamin A is above a threshold. In some embodiments, a risk score is calculated if the level of vitamin A is above a threshold.

[0125] In some embodiments, if the level of vitamin A is above a threshold, a treatment is administered. In some embodiments, a treatment is administered to reduce the level of vitamin A. In some embodiments, a treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, a treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, a pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor may be any of the RBP4 inhibitors provided herein.

[0126] In some embodiments, further steps may be taken or recommended if the vitamin A level falls below a threshold. Measurements below such thresholds may still indicate that the individual has some risk of developing AMD in the future, and therefore further monitoring may be recommended or further testing may be required to confirm or complete the diagnosis of AMD.

[0127] Further, in some embodiments, the method comprises evaluating the likelihood of developing AMD based on the level of vitamin A. In some embodiments, evaluating the likelihood of developing AMD comprises generating a risk score. In some embodiments, if the risk score is above a threshold, treatment for AMD is administered (e.g., treatment with an RBP4 inhibitor). In some embodiments, the risk score reflects the probability that an individual will develop AMD at some point in the future based on the measurements provided herein.

[0128] In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time (e.g., when a risk score for developing AMD is calculated, or when vitamin A levels are below a threshold but other indicators of possible development of AMD are present). In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time if the levels or risk score are below a threshold. The period of time may be any suitable period of time. In some embodiments, the period of time is from about 1 month to about 24 months. In some embodiments, the period is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the period is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months, In some embodiments, the period is up to about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months.

[0129] Recommendations to reassess may include reassessing the individual's vitamin A levels or performing any of the other tests or evaluations for AMD provided herein, such as performing further testing after a period of time, including, but not limited to, a follow-up visit with a physician for a physical eye exam.

[0130] In some embodiments, the individual's vitamin A level is assessed by an assay. Any suitable assay for measuring vitamin A levels can be used (e.g., antibody assay, mass spectrometry-based assay (e.g., LC / MS), liquid chromatography assay (e.g., HPLC, UPLC), etc.). In some embodiments, the assay comprises an antibody assay, an electrophoretic assay, an immunoassay, a radioimmunoassay, a chromatographic assay, a mass spectrometry assay, a microarray-based detection assay, a polymerase chain reaction assay, a sequencing assay, an immunohistochemistry assay, or any combination thereof. In some embodiments, the assay comprises an antibody assay. In some embodiments, the antibody assay comprises an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the assay is a chromatographic assay. In some embodiments, the assay comprises high performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC), or liquid chromatography / mass spectrometry (LC-MS).

[0131] In some embodiments, the sample comprises a blood sample from the individual. The blood sample may be further processed, such as to remove impurities or to leave serum and / or plasma. In some embodiments, the sample is a plasma sample or a serum sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the levels are measured from plasma or serum derived from the blood sample. In some embodiments, the levels are measured from plasma derived from the blood sample. In some embodiments, the levels are measured from serum derived from the blood sample.

[0132] In some embodiments, the determination of AMD diagnosis, risk assessment of developing AMD, and / or treatment decision is based on additional considerations in addition to vitamin A level. In some embodiments, the determination is based on the individual's age and / or medical history. In some embodiments, the determination is based at least in part on the individual's age. In some embodiments, the determination is based at least in part on the individual's medical history. In some embodiments, the individual's medical history can include information such as previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease including non-alcoholic fatty liver disease. In some embodiments, the determination is based at least in part on the individual's level of RBP4 (e.g., in the individual's blood sample).

[0133] Additionally, the methods provided herein may further include any of the additional tests or diagnostic methods provided herein for assessing the presence of AMD in an individual, including measuring the presence or absence of any of the genomic variants provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the methods further include performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0134] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification may be based on the level of RBP4 measured as provided herein or in conjunction with other methods provided herein, such as by classifying using the Age-Related Eye Disease Study (AREDS) classification.

[0135] Genomic variants that predict AMD Also provided herein are genomic variants that indicate an individual's propensity to develop AMD. In some embodiments, the genomic variants comprise a single nucleotide polymorphism (SNP) in the gene encoding ATP-binding cassette subfamily A member 4 (ABCA4) of the individual. ABCA4 is a protein encoded by the ABCA4 gene in humans and other eukaryotes. The ABCA4 protein is expressed almost exclusively in the retina and is associated with Stargardt's disease and other eye diseases, including but not limited to fundus flavimaculatus, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Attenuated activity of ABCA4 is linked to the excessive accumulation of toxic retinoids and lipofuscin. Such mutations are detected, in some cases, by sequencing the subject's DNA or RNA. In some embodiments, the genomic variants provided herein, alone or in combination with other factors, predict the likelihood that a subject will develop AMD. Genomic variants herein may include SNPs that are missense SNPs, intronic SNPs, synonymous SNPs, or any other type of SNP.An individual may include one or more of the SNPs provided herein, either in the same allele or in different alleles.Examples of such genomic variants and SNPs can be found in Table A below.

[0136] [Table 1]

[0137] In some aspects, methods are provided herein for assessing whether an individual has AMD, is likely to develop AMD, and in some cases, methods are provided herein for treating or preventing AMD. In some embodiments, the method comprises determining the presence or absence of one or more genomic variants by assay. In some embodiments, the one or more genomic variants comprise at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the method comprises calculating a risk score for age-related macular degeneration using the presence or absence of one or more genomic variants. In some embodiments, the method comprises diagnosing age-related macular degeneration using the presence or absence of one or more genomic variants. In some embodiments, the method further comprises administering a therapy for treating age-related macular degeneration in the individual. In some embodiments, the method further comprises administering a therapy for preventing age-related macular degeneration in the individual.

[0138] In some embodiments, the method comprises determining the presence or absence of one or more genomic variants by assay.In some embodiments, the one or more genomic variants comprise at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.In some embodiments, the one or more genomic variants comprise at least two of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least three of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least five of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include at least six of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574. In some embodiments, the one or more genomic variants include each of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.

[0139] In some embodiments, the one or more genomic variants comprise rs4147863. In some embodiments, the one or more genomic variants comprise rs2275029. In some embodiments, the one or more genomic variants comprise rs1800739. In some embodiments, the one or more genomic variants comprise rs4147857. In some embodiments, the one or more genomic variants comprise rs4147856. In some embodiments, the one or more genomic variants comprise rs1801555. In some embodiments, the one or more genomic variants comprise rs1801574.

[0140] In some embodiments, the one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 rs4147830, rs2297634, or rs4847281. In some embodiments, the one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs7547651 rs4147830, rs2297634, or rs4847281. In some embodiments, the one or more genomic variants include at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 genomic variants.

[0141] In some embodiments, the one or more genomic variants comprise at least one genomic variant from Table A. In some embodiments, the one or more genomic variants comprise at least five genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least seven genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least ten genomic variants from Table A. The one or more genomic variants comprise at least fifteen genomic variants from Table A. In some embodiments, the one or more genomic variants comprise at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty genomic variants from Table A.

[0142] In some embodiments, detecting the presence or absence of one or more genomic variants further comprises determining the allele frequency of one or more genomic variants in the individual. In some embodiments, the one or more genomic variants are present in a single copy of the gene in the individual. In some embodiments, the one or more genomic variants are present in multiple copies of the gene in the individual.

[0143] In some embodiments, determining the presence or absence of one or more genomic variants comprises performing an assay on genetic material from an individual.In some cases, genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known to those skilled in the art.In some embodiments, genetic material is obtained from the blood, serum, or plasma of an individual.

[0144] In some embodiments, the method of detecting the presence or absence or level of a genomic variant in a sample obtained from an individual comprises detecting a nucleic acid sequence. In some cases, such as when detecting complementary DNA (cDNA) of an mRNA transcript, the nucleic acid sequence comprises deoxyribonucleic acid (DNA). In some cases, the nucleic acid sequence comprises a denatured DNA molecule or a fragment thereof. In some cases, the nucleic acid sequence comprises DNA selected from genomic DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some cases, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denatured double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some cases, the nucleic acid sequence comprises ribonucleic acid (RNA). In some cases, the nucleic acid sequence comprises fragmented RNA. In some cases, the nucleic acid sequence comprises partially degraded RNA.

[0145] In some embodiments, disclosed herein are genomic variants detected by subjecting a sample obtained from a subject to a nucleic acid-based detection assay. In some cases, the nucleic acid-based detection assay includes quantitative polymerase chain reaction (qPCR), gel electrophoresis (including, for example, Northern blot or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technology includes next-generation sequencing. In some embodiments, the method includes a hybridization assay, such as fluorogenic qPCR (e.g., TaqMan™, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, pyronin Y, DAPI, acridine orange, Blue View, or phycoerythrin), which includes a nucleic acid amplification reaction using a specific primer pair and hybridization of an amplified nucleic acid probe that includes a detectable moiety or molecule specific to the target nucleic acid sequence. In some cases, the number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some cases, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some cases, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some examples, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. In the TaqMan™ method, the probe may be a hydrolysis probe that includes a fluorophore and a quencher, and is hydrolyzed by a DNA polymerase when hybridized to a target nucleic acid.In some cases, the presence of the target nucleic acid is determined if the number of amplification cycles that reach the threshold is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some cases, hybridization may occur at standard hybridization temperatures, for example, from about 35° C. to about 65° C., in a standard PCR buffer.

[0146] Further exemplary nucleic acid-based detection assays include the use of nucleic acid probes conjugated or otherwise immobilized to beads, multi-well plates, or other substrates, where the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some cases, the nucleic acid probes are specific to one or more gene products (of the PRSs) described herein. In some cases, the biomarker-specific nucleic acid probes include a nucleic acid probe sequence that is sufficiently complementary to the polynucleotide sequence of the biomarker. In some cases, the biomarkers include a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probes may be full-length cDNAs or portions thereof, such as oligonucleotides that are at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize to the target nucleic acid sequence under standard hybridization conditions. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example, by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane such as nitrocellulose. In some embodiments, the probe is immobilized on a solid surface, for example, an Affymetrix gene chip array, and contacted with the target nucleic acid sequence.

[0147] In some embodiments, the term "probe", when referring to a nucleic acid, refers to any nucleic acid molecule that can selectively bind to a specifically intended target nucleic acid sequence. In some cases, the probe is specifically designed to be labeled with, for example, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags known in the art. In some cases, the fluorescent label comprises a fluorophore. In some cases, the fluorophore is an aromatic or heteroaromatic compound. In some cases, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxaazole, indole, benzoindole, oxazole, thiazole, benzothiazole, cyanine, carbocyanine, salicylate, anthranilate, xanthene dye, coumarin. Exemplary xanthene dyes include, for example, fluorescein dyes and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to, 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N;N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include naphthylamine dyes with amino groups at the alpha or beta positions. For example, naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonic acid, 1-anilino-8-naphthalenesulfonic acid, and 2-p-toluidinyl-6-naphthalenesulfonic acid, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).Exemplary coumarins include, for example, 3-phenyl-7-isocyanatocoumarin, acridines such as 9-isothiocyanatoacridine and acridine orange, N-(p-(2-benzoxazolyl)phenyl)maleimides such as indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxazolidine, and the like. Cyanines such as carbocyanine (CyA), 1H,5H,11H,15H-xanthen[2,3,4-ij:5,6,7-i'j']diquinolizin-18-ium, 9-[2(or 4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfanyl]-4(or 2)-sulfophenyl]-2,3,6,7,12,13,16,17-octahydro-inner salt (TR or Texas Red), or BODIPY™ dyes. In some cases, the probe contains FAM as the dye label.

[0148] In some embodiments, detecting one or more genomic variants comprises sequencing the genetic material obtained from a sample from the subject. Sequencing can be performed using any suitable sequencing technique, including, but not limited to, single molecule real-time (SMRT) sequencing, polony sequencing, ligation sequencing, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or synthetic sequencing. Sequencing methods also include modern sequencing techniques such as next generation sequencing, e.g., Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next generation sequencing includes high throughput sequencing methods. Additional sequencing methods available to those skilled in the art may be used.

[0149] In some embodiments, when a genomic variant provided herein is identified in an individual, a treatment is administered. In some embodiments, the treatment is administered to reduce the level of RBP4 in the individual. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor may be any of the RBP4 inhibitors provided herein.

[0150] Additionally, the methods provided herein may further include any of the additional tests or diagnostic methods provided herein for assessing the presence of AMD in an individual, including measuring the level of RBP4 and comparing it to a threshold value as provided herein, measuring the level of vitamin A and comparing it to a threshold value as provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the method further includes performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0151] In some embodiments, the method also includes determining the age and medical history of the individual. Thus, in some embodiments, assessing the likelihood of developing macular degeneration is based on the presence of one or more genomic variants, the age and medical history of the individual.

[0152] In some embodiments, the determination of AMD diagnosis, risk assessment of developing AMD, or treatment decision is based on additional considerations in addition to the presence or absence of one or more genomic variants. In some embodiments, the determination is based on the age and / or medical history of the individual. In some embodiments, the determination is based at least in part on the age of the individual. In some embodiments, the determination is based at least in part on the medical history of the individual. In some embodiments, the medical history of the individual can include information such as previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease including non-alcoholic fatty liver disease.

[0153] In some embodiments, identifying one or more genomic variants provided herein in an individual does not necessarily require immediate intervention with a treatment, but may prompt the attending physician to recommend increased monitoring for the onset of AMD or associated symptoms indicative of the onset of AMD. In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time. In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time if the level or risk score falls below a threshold. The period of time may be any suitable period of time. In some embodiments, the period of time is about 1 month to about 24 months. In some embodiments, the period is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the period is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months. In some embodiments, the period is up to about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. The period may also be longer, such as at least about 2 years, at least about 3 years, at least about 5 years, at least about 10 years, or more. In some embodiments, it may be recommended to periodically monitor the individual for the development of AMD.

[0154] A recommendation to re-evaluate may include performing further testing after a period of time, including, but not limited to, assessing the individual's levels of RBP4 or performing any of the other tests or evaluations for AMD provided herein, such as a follow-up visit with a physician for a physical eye examination.

[0155] Additionally, the methods provided herein may further include any of the additional tests or diagnostic methods provided herein for assessing the presence of AMD in an individual, including measuring the level of RBP4 and comparing it to a threshold value as provided herein, measuring the level of vitamin A and comparing it to a threshold value as provided herein, or any other measurement that can be used to diagnose AMD. In some embodiments, the method further includes performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0156] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification may be based on the level of RBP4 measured as provided herein or in conjunction with other methods provided herein, such as by classifying using the Age-Related Eye Disease Study (AREDS) classification.

[0157] RBP4 levels / vitamin A levels and genomic variants in combination predict AMD The biomarker levels (e.g., blood levels of RBP4 and / or vitamin A) and genomic variants (e.g., ABCA4 variants) provided herein may also be probed simultaneously to provide a diagnosis, risk score, and recommendations for treatment of AMD in an individual. In some embodiments, this combination approach results in a more reliable diagnosis or risk score than either method alone. In some embodiments, this allows a specific diagnosis or risk assessment of AMD without more invasive physical examination of the eye, since a diagnosis or risk score can be calculated from a single sample (e.g., a blood sample) from an individual.

[0158] In one aspect, provided herein is a method for assessing the likelihood of age-related macular degeneration in an individual in need thereof, comprising: obtaining a blood sample from the individual; extracting a protein fraction from the blood sample; extracting a nucleic acid fraction from the blood sample; determining the level of retinol binding protein 4 (RBP4) and / or the level of vitamin A from the protein fraction by a first assay; determining the allele frequency of one or more genomic variants from the nucleic acid in the nucleic acid fraction by a second assay; and assessing the likelihood of age-related macular degeneration based on the level of RBP4 and / or the level of vitamin A and the allele frequency of the one or more genomic variants. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.

[0159] In one aspect, provided herein is a method for treating age-related macular degeneration in an individual in need thereof, comprising: a) providing a level of retinol binding protein 4 (RBP4) and / or a level of vitamin A, wherein the level is determined by an assay of a protein fraction of a sample from the individual; b) providing an allele frequency of one or more genomic variants, wherein the allele frequency is determined by an assay performed on a nucleic acid fraction of a sample from the individual; and c) administering a treatment based on the assessment of the level of RBP4 and / or the level of vitamin A and the allele frequency of one or more genomic variants. In some embodiments, the one or more genomic variants include at least one of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, or rs1801574.

[0160] In some embodiments, the level of RBP4 is compared with the threshold value of RBP4 as provided elsewhere herein.Any of the threshold values ​​of RBP4 provided herein may be used in diagnostic methods / assessment protocols in conjunction with the detection of genomic variants.Furthermore, any of the methods or assays used to determine the level of RBP4 in a sample provided herein are equally applicable to the method of diagnosing AMD, assessing the risk of developing AMD, or determining the treatment of AMD based on the combination of genomic variants and RBP4 levels.

[0161] In some embodiments, the methods herein provide for the detection of the presence or absence of one or more genomic variants.The evaluation of any combination or any number of genomic variants provided herein can be used in conjunction with the information provided by the level of RBP4 in diagnosing, risk assessment, or treating AMD as provided herein.

[0162] In embodiments where both RBP4 levels and genomic variants are measured, the steps of measuring RBP4 levels by an assay and determining the presence or absence (or allele frequency) of one or more genomic variants by a second assay are performed on multiple samples from the individual. In some embodiments, the assay and the second assay are performed on the same sample. In some embodiments, the assay and the second assay are performed on multiple different samples from the individual. The multiple samples need not be taken from the individual at the same time, and need not be of the same type. In some embodiments, the assay and the second assay are performed on the same sample from the individual. In some embodiments, the assay and the second assay are performed on two separate samples from the individual. In some embodiments, the two separate samples are the same type of sample (e.g., a blood sample). In some embodiments, the two separate samples are different types of samples (e.g., a blood sample and a urine sample). In some embodiments, the two separate samples are two blood samples. The two separate samples do not need to be taken from the individual at the same time. In some embodiments, the two separate samples are taken from the individual at the same time. In some embodiments, the two separate samples are taken at different times, hi some embodiments, the two separate samples are taken at most about 1 day, at most about 2 days, at most about 3 days, at most about 1 week, at most about 2 weeks, at most about 1 month, at most about 2 months, at most about 3 months, or at most about 6 months apart.

[0163] As provided herein, the method based on the measurement of RBP4 level or the presence or absence of genomic variants may further include further testing or diagnostic methods to confirm the presence of AMD in an individual, so is the method utilizing both RBP4 level and the presence or absence of genomic variants. In some embodiments, the diagnosis, risk assessment, or treatment decision is further based on further criteria, such as the subject's age and medical history. In some embodiments, the determination is based on the individual's age and / or medical history. In some embodiments, the determination is based at least in part on the individual's age. In some embodiments, the determination is based at least in part on the individual's medical history. In some embodiments, the individual's medical history can include information such as previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease, including non-alcoholic fatty liver disease.

[0164] In addition, the methods provided herein may further include any of the additional tests or diagnostic methods provided herein for assessing the presence of AMD in an individual. In some embodiments, the method further includes performing at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry.

[0165] In some embodiments, the method further comprises classifying the progression of age-related macular degeneration. Classification may be based on the level of RBP4 measured as provided herein or in conjunction with other methods provided herein, such as by classifying using the Age-Related Eye Disease Study (AREDS) classification.

[0166] In some embodiments, the risk score reflects the probability that an individual will develop AMD at some point in the future based on the measurements provided herein.

[0167] In some embodiments, identification of one or more genomic variants provided herein in an individual and measurement of levels or RBP4 may not necessarily require immediate intervention with treatment, but may prompt the attending physician to recommend increased monitoring for the onset of AMD or associated symptoms indicative of the onset of AMD. In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time. In some embodiments, the method includes providing a recommendation to reassess the individual for AMD after a period of time if the levels or risk score are below a threshold. The period of time may be any suitable period of time. In some embodiments, the period of time is about 1 month to about 24 months. In some embodiments, the period is about 1 month to about 3 months, about 1 month to about 6 months, about 1 month to about 9 months, about 1 month to about 12 months, about 1 month to about 18 months, about 1 month to about 24 months, about 3 months to about 6 months, about 3 months to about 9 months, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 6 months to about 9 months, about 6 months to about 12 months, about 6 months to about 18 months, about 6 months to about 24 months, about 9 months to about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 12 months to about 18 months, about 12 months to about 24 months, or about 18 months to about 24 months. In some embodiments, the period is about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. In some embodiments, the period is at least about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, or about 18 months. In some embodiments, the period is up to about 3 months, about 6 months, about 9 months, about 12 months, about 18 months, or about 24 months. The period may also be longer, such as at least about 2 years, at least about 3 years, at least about 5 years, at least about 10 years, or more. In some embodiments, it may be recommended to periodically monitor the individual for the development of AMD.

[0168] A recommendation to re-evaluate may include performing further testing after a period of time, including, but not limited to, assessing the individual's levels of RBP4 or performing any of the other tests or evaluations for AMD provided herein, such as a follow-up visit with a physician for a physical eye examination.

[0169] In some embodiments, when a genomic variant provided herein is identified in an individual, a treatment is administered. In some embodiments, the treatment is administered to reduce the level of RBP4 in the individual. In some embodiments, the treatment comprises administering a pharmaceutical composition to the individual. In some embodiments, the treatment comprises administering a pharmaceutical compound to the individual. In some embodiments, the pharmaceutical composition comprises an RBP4 inhibitor. The RBP4 inhibitor may be any of the RBP4 inhibitors provided herein.

[0170] Further considerations for predicting or diagnosing AMD In some embodiments, the determination of AMD diagnosis, the assessment of risk of developing AMD, or the decision of treatment is based on the measurement of the subject's RBP4 level and / or the determination of the presence or absence of genomic variants provided herein, and further tests that can be optionally performed.Therefore, the method provided herein may further provide further tests that are used in conjunction with the biomarkers provided herein that indicate AMD.

[0171] The methods provided herein may further include further tests used to assess the presence of AMD or the risk of developing AMD in an individual. A variety of such further tests and diagnostics are known in the art, including color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, and microperimetry.

[0172] In some embodiments, the methods provided herein further comprise analysis of at least one of color fundus photography, fundus autofluorescence, spectral domain optical coherence tomography, or microperimetry. In some embodiments, the methods further comprise analysis of color fundus photography. In some embodiments, the methods further comprise analysis of fundus autofluorescence. In some embodiments, the methods further comprise spectral domain optical coherence tomography. In some embodiments, the methods further comprise microperimetry. In some embodiments, the diagnosis of AMD, the assessment of the risk of developing AMD, or the decision to treat AMD is based at least in part on one of these assessments.

[0173] Additionally, the methods provided herein may also include determining the age or medical history of the individual. In some embodiments, the determination is based at least in part on the age of the individual. In some embodiments, the determination is based at least in part on the medical history of the individual. In some embodiments, the medical history of the individual may include information such as a previous diagnosis of eye disease, body mass index (BMI), height, weight, obesity, hyperlipidemia, hyperglycemia, hypertension, diabetes mellitus, cardiovascular disease, or systemic disease including non-alcoholic fatty liver disease.

[0174] In some embodiments, the methods herein include classifying the progression of AMD. In some embodiments, the classification is based on Age-Related Eye Disease Study Research G. The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials. 1999;20(6):573-600) (AREDS). AREDS categories include category 1 (defined as a few (1-15) small (<63 μm) drusen or no drusen and no pigmentary changes), category 2 (early AMD characterized by many small drusen and a few medium-sized (63-124 μm) drusen in one or both eyes and / or pigmentary changes), category 3 (intermediate AMD characterized by widespread medium-sized (20 soft or 65 hard with no soft) drusen in one or both eyes, one large (>125 μm) drusen, and / or geographic atrophy not involving the macula), and category 4 (advanced unilateral AMD consisting of advanced nonexudative AMD with geographic atrophy involving the macula in one eye or exudative AMD with choroidal neovascularization).

[0175] RBP4 inhibitors and compounds that reduce RBP4 in the blood In some embodiments, provided herein are RBP4 inhibitor compounds, compounds that reduce blood RBP4 levels, and pharmaceutical compositions that include the compounds. In some embodiments, the compounds are RBP4 inhibitors. In some embodiments, the compounds reduce blood RBP4 levels. The compounds and compositions are useful for inhibiting RBP4 and treating various disorders, including age-related macular degeneration. In some embodiments, upon diagnosis of AMD using the methods provided herein, or upon assessment that an individual is at risk for developing AMD, the individual is administered a treatment that includes an RBP4 inhibitor compound, such as those provided herein. Examples of RBP4 inhibitor compounds can be found in U.S. Patent Application Publication No. 2010 / 0292206, International Publication No. 2010 / 119992, U.S. Patent Application Publication No. 2011 / 0251187, U.S. Patent Application Publication No. 2018 / 0237404, U.S. Patent No. 10,273,243, U.S. Patent No. 8,980,924, U.S. Patent No. 9,637,450, U.S. Patent No. 9,944,644, U.S. Patent No. 9,938,291, U.S. Patent No. 10,072,016, and International Publication No. 2018 / 232154, each of which is incorporated by reference.

[0176] Some embodiments provided herein include a compound represented by formula (I):

[0177] [ka] or a pharma- ceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof for use in treating age-related macular degeneration, the RBP4 inhibitor having the structure: During the ceremony, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5each independently represents halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkyl, -COR A 7 , -CON(R A 7 )2, optionally substituted (C0-C4 alkylene)-CN, optionally substituted (C0-C4 alkylene)-OR A 7 , optionally substituted (C0-C4 alkylene)-N(R A 7 )2, optionally substituted (C0-C4 alkylene)N(R A 8 )-COR A 7 , optionally substituted (C0-C4 alkylene)-SO2N(R A 7 )2, optionally substituted (C0-C4 alkylene)-SO2R A 7 , optionally substituted (C0-C4 alkylene)N(R A 8 )-SO2N(R A 7 )2, or optionally substituted (C0-C4 alkylene)N(R A 8 )-SO2R A 7 and R A 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 A 11 groups taken together with the nitrogen to which they are attached form an optionally substituted N-heterocyclyl; RA 8 are each independently selected from H or optionally substituted alkyl; R A 6 is -H, -OH, optionally substituted alkyl, or halogen; p is 0, 1, 2, 3, 4, or 5; A A The structure:

[0178] [ka] having During the ceremony, each of α, β, χ, and δ is 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 A 9 and R A 9 is H, optionally substituted alkyl, or oxetane; B A is a substituted or unsubstituted 5-, 6-, or 7-membered fused ring structure.

[0179] In certain embodiments, the compound of formula (I) has the structure:

[0180] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5are each independently H, halogen, CF, or C-C alkyl, where R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 At least two of are other than H, R A 6 is H, OH, or a halogen; A A The structure:

[0181] [ka] having During the ceremony, each of α, β, χ, and δ is independently absent or present and, when present, each is a bond; X is C or N; Z1 is N; Z2 is N or NR A 9 and R A 9 is H, C1-C4 alkyl, or oxetane; B A is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

[0182] In some embodiments, the compound of formula (I) is 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. In certain embodiments, the compound of formula (I) is 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)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(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-(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-(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-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;1-(3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethane-1- (4-(3-fluoro-2,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)phenyl) (4-(2-chloro-3-fluorophenyl)piperidin-1-yl)(5-(methylsulfanyl)-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-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;3-(4-(3,5-difluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile (6-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-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-(methylsulfanyl)-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-dihydro Fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-3-methylbutan-1-one;1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)propan-1-one;1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-2-methylpropan-1-one 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carbonitrile;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4- (3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-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-(cyclopropyl (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)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)piperidin-1-yl)methanone; (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-yl)(6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;Methyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3 ,5-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile;Methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl) Methanone;(6-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(2-chloro-5-fluorophenyl)piperidin-1-yl)(4,5,6,7- Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;Imidazo[1,2-a]pyridin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5 H-Pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;(5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-N-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide;(4-(3-fluoro-2-(trifluoromethyl)phenyl) )piperidin-1-yl)(5-(methylsulfanyl)-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[4,3-c]pyridin-3-yl)methanone )methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3,5-bis(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[ 3,4-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;1-(3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-1,4,5 ,7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;1-(3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;1-(3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;1-(3-(4-(3,5-bis(trifluoromethyl)phenyl)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-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;(5-(cyclopropylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Methyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonitrile; 1-(3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;tert-Butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate;tert-Butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 3-(4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate;tert-Butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate;tert-Butyl 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 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-(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-; 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-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)-1,4,6,7-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)piperidin-1-yl)methanone;(1,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3 -yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1,4,5,7-tetrahydropyrano[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-Ethyl-N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxamide;(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl) (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 1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine-1-yl)methanone (6-fluoro-1-(oxetan-3-yl)-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-ethyl-6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-fluoro-1-isopropyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-fluoro-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one;(5-fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-methyl-4,5,6,7-tetrahydro- 1H-Pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(5-F (5-((chloromethyl)sulfanyl)-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;(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;( 4-Fluoro-4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone;1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-1-one;(1-ethyl-5-fluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Fluoro-1-methyl-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one;6-Methyl-3-(4-(2- (Trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-c]pyridin-5-one;5-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[4,3-c]pyridin-6-one;(5,5-dioxide-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)meth Non;(1-Methyl-5-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-Methyl-6-(methylsulfanyl)-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; 2-Methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one;2,2-Dimethyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-1-one;(5-(isopropylsulfanyl)-4,5,6,7-tetrahydro- 1H-Pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(isobutylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(ethylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1H-indazole-5-carbonitrile;(7-chloro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5,6-difluoro-1H-indazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(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) 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-(methylsulfanyl)-4,5,6,7-tetrahydro-1 H-Pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-ethyl-6-(methylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(1-methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidine ... 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)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide )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-(isopropylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2- (Trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(ethylsulfanyl)-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)- 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)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-butylsulfanyl)-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-(isobutylsulfanyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;3-methyl-1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl )butan-1-one;(6-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6- Ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(tert-butylsulfanyl)-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-(oxetane -3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-ethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;1- (3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-3-methylbutan-1-one;1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-2-methylpropan-1-one;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-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-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carbonitrile;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(3,3,3-trifluoropropyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(5-benzoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Methyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate;(4-(; 3,4-Difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-( Pyrrolidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-isonicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-nicotinoyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole -3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(piperazine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)methanone;1-(3-(4-(3,4-difluoro (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-(methylsulfanyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-methyl-5-(methylsulfanyl)-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;(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-Trifluoromethylphenyl Fluoro-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-(isobutylsulfanyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(isopropylsulfanyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(ethylsulfanyl)-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-(Methylsulfanyl)-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]pyrazole-5( 1H)-yl)ethan-1-one;(5-(tert-butylsulfanyl)-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)piperidin-1-yl)methanone; 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)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)piperidin-1-yl)methanone;(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;tert-Butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate; tert-Butyl 3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate;(5,5-dioxido-4,6,7,8-tetrahydro-1H-thiepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4,6,7,8-tetrahydro-1H-oxepino[4,3-c]pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;N-Methyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide;(5-(2,2,2-trifluoroethyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(tert-butylsulfanyl)-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-(ISOBUTYLSULFANYL)-1,4,5,6,7,8-HEXAHYDROPYRAZOLO[4,3-C]AZEPINE-3-YL)(4-(2-(TRIFLUOROMETHYL)PHENYL)PIPERIDIN-1-YL)METHANONE;3-METHYL-1-(3-(4-(2-(TRIFLUOROMETHYL)PHENYL)PIPERIDINE-1-CARBONYL)-4,6,7,8-TETRAHYDROPYRAZOLO[4,3-C]AZEPINE-5(1H)-YL)BUTANE-1-ONE;(5-ISOBUTYL-1,4,5,6,7,8-HEXAHYDROPYRAZOLO[4,3-C]AZEPINE -3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(5-(isopropylsulfanyl)-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-(methylsulfanyl)-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-(ethylsulfanyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (5-ethyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(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)piperidine-1-yl)methanone;(5-(methylsulfanyl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepin-3-yl)(4-(2-(trifluoromethyl) 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-(methylsulfanyl)-1,4,5,6,7,8-hexahydropyrazo N,N-dimethyl-3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxamide;(1-Methyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine-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-Trifluoropyrazolo[4,3-c]azepin-5(1H)-yl Fluoro-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) (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)piperidin-1-yl)methanone;(6-chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl) Methanone;(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(6-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone;6-Methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylic acid;Methyl 6-Methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)pyrimidine-4-carboxylate;N-(cyclopropylsulfanyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;N-(phenylsulfanyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;N-(methylsulfanyl)-2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide 3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid;3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid;2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzoic acid;4-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid;2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid;3-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)benzoic acid;4-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)benzamide;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,7-dihydroisothiazolo[5,4-c]pyridine-6( 5H)-yl)ethan-1-one;(4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisoxazolo[4,5-c]pyridine-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]thiazo benzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;benzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;1-(3-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydroisothiazolo[4,5-c]pyridin-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-(te rt-Butyl)phenyl)piperidine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxylate;rac-tert-butyl(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-dioxidetetrahydrothiophene-2-yl) rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,3R)-3-hydroxypyrrolidin-2-yl)methanone;rac-(4-(2-(tert-butyl)phenyl)piperidin-1-yl)((2R,4R)-4-hydroxypyrrolidin-2-yl)methanone;rac-(R)-1-(2-(4-(2-(tert-butyl)phenyl)piperidine-1-carbonyl)pyrrolidin-1-yl)ethan-1-one;(6-bromo-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trimethylphenyl)pyridin-2-yl)ethane-1-one (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; (1H-Pyrrolo[3,2-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Imidazo[1,2-b]pyridazin-6-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Pyrrolo[2,3-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Pyrrolo[3,2-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (6-morpholino-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1-methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;( 5-Methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Fluoro-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-Imidazo[4,5-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-Methyl-1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (1H-indol-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-pyrrolo[3,2-b]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-pyrrolo[2,3-c]pyridin-2-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-pyrazol-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(1H-1,2,3-triazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;Pyrazin-2-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-methoxypyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(6-methylpyridazin-3-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone;(4-methyl-1,2,3-thiadiazol-5-yl)(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone )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.

[0183] Some embodiments provided herein include a compound represented by formula (II):

[0184] [ka] or a pharma- ceutical acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof for use in treating age-related macular degeneration, During the ceremony, Ring A B is an optionally further substituted benzene; R B 1 is an optionally substituted branched C3-6 alkyl group; X B 1 is O, S, SO, SO2, or NH; X B 2 is a bond or a C1-C3 alkylene group, Ring B B is azetidine, pyrrolidine, or piperidine; X B 3 is CO or SO2, R B 2 is a substituent.

[0185] In some embodiments, the compound of Formula (II) has the structure:

[0186] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Ring A B is an optionally further substituted benzene; R B 1 is an optionally substituted branched C3-C6 alkyl group; X B 1 is O, S, SO, SO2, or NH; X B 2 is a bond or a C1-C3 alkylene group, Ring B B is azetidine or piperidine, X B 3 is CO or SO2, R B 2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, a cyano group, a nitro group, an acyl group, or a halogen atom.

[0187] In some embodiments, the compound of formula (II) is 4-(3-(2-tert-butylphenoxy)azetidin-1-yl)-4-oxobutyric acid, 3-{3-[(2-tert-butyl-4-fluorophenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, 2-{[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]carbonyl}pyridine, 4-[3-(2-tert-butyl-4-chlorophenoxy)azetidin-1-yl]-4-oxobutyric acid, {3-[(2-tert-butyl-4-chlorophenoxy)methyl]azetidin-1-yl}

[0036] In one embodiment, the acetaminophenic acid is selected from the group consisting of {3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, {3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}(oxo)acetic acid, 3-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}-3-oxopropanoic acid, {4-[(2-tert-butyl-4-chlorophenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, [4-(2-tert-butylphenoxy)piperidin-1-yl](oxo)acetic acid, or {4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}(oxo)acetic acid, or a pharma- ceutically acceptable salt thereof.

[0188] Some embodiments provided herein include a compound represented by formula (III):

[0189] [ka] or a pharma- ceutical acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof for use in treating age-related macular degeneration, During the ceremony, Ring A C is an optionally further substituted benzene ring; Ring B C is an optionally further substituted piperazine ring; R C is a substituent.

[0190] In some embodiments, the compound of Formula (III) has the structure:

[0191] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Ring A C is a benzene ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) halogen atoms and (b) C1-6 alkyl groups; Ring B C is a piperazine ring optionally substituted with 1 to 3 substituents selected from the group consisting of (a) a halogen atom, (b) a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (c) a C1-C6 alkoxy group optionally substituted with 1 to 3 halogen atoms; R C (1) optionally substituted C1-C 10 (2) an optionally substituted C-C 14 (3) an optionally substituted 5- or 6-membered aromatic heterocyclic group; (4) an optionally substituted amino group; (5) an optionally substituted carboxy group; or (6) an optionally substituted carbamoyl group.

[0192] In some embodiments, the compound of formula (III) is N-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}glycine, 3-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoic acid, [4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl](oxo)acetic acid, 5-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}imidazolidine-2,4-dione, [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}isoxazol-3-yl)oxy]acetic acid, or a pharma- ceutically acceptable salt thereof.

[0193] Some embodiments provided herein include a compound represented by formula (IV):

[0194] [ka] or a pharma- ceutical acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof for use in treating age-related macular degeneration, During the ceremony, Ring A D is a 5-membered non-aromatic heterocycle optionally further substituted by one substituent; Ring B D is an optionally further substituted benzene ring; X D is a bond, O, CH2O, OCH2, CH2, (CH2)2, S, CH2S, SCH2, S(O), CH2S(O), S(O)CH2, S(O)2, CH2S(O)2, or S(O)2CH2.

[0195] In some embodiments, the compound of formula (IV) has the structure:

[0196] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Ring A D is a 5-membered non-aromatic heterocycle optionally further substituted with one oxo group; Ring B D is a benzene ring optionally further substituted with 1 to 4 substituents; X D is O, CH2O, OCH2, CH2, (CH2)2, S, CH2S, SCH2, S(O), CH2S(O), S(O)CH2, S(O)2, CH2S(O)2, or S(O)2CH2.

[0197] In some embodiments, the compound of formula (IV) is ({(3S)-1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}oxy)acetic acid, ({1-[4-chloro-3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid, 3-{(2R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]tetrahydrofuran-2-yl}propanoic acid, or a pharma- ceutically acceptable salt thereof.

[0198] Some embodiments provided herein include a compound represented by formula (V):

[0199] [ka] or a pharma- ceutical acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof for use in treating age-related macular degeneration, During the ceremony, Ring A E is an optionally further substituted monocyclic nitrogen-containing aromatic heterocycle; X E is CH2 or O, R E is a hydrogen atom or a C1-6 alkyl group.

[0200] In some embodiments, the compound of Formula (V) has the structure:

[0201] [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony, Ring A E is a pyrazole ring, a pyridine ring, an oxazole ring, an imidazole ring, or a pyrimidine ring, X E is S, optionally substituted alkylene, or O; R Eis a hydrogen atom or a C1-C6 alkyl group.

[0202] In some embodiments, the compound of formula (V) is ((4-(3,5-bis(trifluoromethyl)phenyl)-1,3-oxazol-2-yl)sulfanyl)acetic acid, ethyl ((6-(3,5-bis(trifluoromethyl)phenyl)-pyridin-3-yl)sulfanyl)acetic acid, ((6-(3,5-bis(trifluoromethyl)-phenyl)pyridin-3-yl)sulfanyl)acetic acid, or 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)butanoic acid.

[0203] In some embodiments, the RBP4 inhibitor is an RBP4 inhibitor presented in Table B.

[0204] [Table 2-1]

[0205] [Table 2-2]

[0206] [Table 2-3]

[0207] [Table 2-4]

[0208] Preparation of compounds The compounds used in the chemical reactions described herein are made by organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature."Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0209] Suitable reference books and articles 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, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions", 2nd Ed., WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers detailing the synthesis of reactants useful for the preparation of the compounds described herein or referencing articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC“Comprehensive Organic Transformations: A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure”4th Edition(1992)John Wiley & Sons, ISBN:0-471-60180-2;Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN:3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN:0-471-93022-9;Solomons,TWG“Organic Chemistry”7th Edition(2000)John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 8 volumes of “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X; 55 volumes of “Organic Reactions” (1942-2000) John Wiley & Sons; and 73 volumes of “Chemistry of Functional Groups” John Wiley & Sons.

[0210] Alternatively, certain similar reactants are identified by indexes of known chemical products prepared by the Chemical Abstract Service of the American Chemical Society, available at most public and university libraries and via online data services (for more information, contact the American Chemical Society in Washington, DC). Chemical products that are known but not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. Criteria for the preparation and selection of pharmaceutical salts of the heterocyclic RBP4 inhibitor compounds described herein can be found in PHStahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0211] Retinol-binding protein 4 (RBP4) Retinol-binding protein 4 (RBP4), the only retinol transporter in blood, is secreted from fat cells and liver. Reducing the level of RBP4 can reduce the accumulation of lipofuscin, which leads to vision loss in diseases such as age-related macular degeneration or dry (atrophic) age-related macular degeneration. In some cases, reducing RBP4 reduces the accumulation of lipofuscin in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, thus slowing or stopping vision loss due to excess accumulation of lipofuscin in the retina. In some embodiments, the compounds and formulations described herein reduce serum or plasma RBP4, thus slowing or stopping vision loss due to age-related macular degeneration.

[0212] In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0213] In some embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0214] In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0215] In some embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, after 12 hours of administration of the RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, after 12 hours of administration of the RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 80% from baseline. In some embodiments, after 12 hours of administration of the RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 85% from baseline.

[0216] In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 20% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 25% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 30% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 40% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 50% from baseline. In other embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 65% from baseline. In certain embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 80% from baseline. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 85% from baseline.

[0217] In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL. In other embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL. In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL. In certain embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL. In some embodiments, after 48 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL.

[0218] In some embodiments, after 36 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL. In other embodiments, after 36 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL. In some embodiments, after 36 hours of administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL. In certain embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 36 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0219] In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL. In other embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL. In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL. In certain embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 10 mg / dL. In some embodiments, 24 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 15 mg / dL.

[0220] In some embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL. In other embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL. In some embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL. In certain embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 12 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0221] In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 1 mg / dL. In other embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 2 mg / dL. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, the serum or plasma level of RBP4 is reduced by at least 5 mg / dL. In certain embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 10 mg / dL. In some embodiments, 6 hours after administration of an RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer, serum or plasma levels of RBP4 are reduced by at least 15 mg / dL.

[0222] Treatment In some embodiments, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate a disease associated with alterations in the RBP4 pathway, such as age-related macular degeneration. In some cases, the compounds disclosed herein, when administered to a subject in need thereof, are used to treat or ameliorate the effects of a disease associated with alterations in the RBP4 pathway, such as age-related macular degeneration.

[0223] 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 needed for sharp, central vision. As AMD progresses, a common symptom is a blurry area near the center of vision. Over time, the blurry area can get larger, causing a blank spot in an object's central vision.

[0224] Some embodiments provided herein describe the use of the RBP4 inhibitor described herein for treating AMD in a subject in need thereof. In some embodiments, the RBP4 inhibitor inhibits AMD. In certain embodiments, the RBP4 inhibitor prevents the onset of AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor reduces the onset of AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor alleviates the subject of AMD. In certain embodiments, the RBP4 inhibitor causes regression, reversal, or improvement of AMD. In certain embodiments, the RBP4 inhibitor reduces the number, frequency, duration, or severity of clinical symptoms of AMD.

[0225] In some embodiments, RBP4 inhibitor is used prophylactically.In certain embodiments, RBP4 inhibitor is used to prevent or reduce the risk of developing AMD.In certain embodiments, RBP4 inhibitor prevents the clinical symptoms of AMD from developing in subjects who may have a predisposition to AMD but have not yet experienced or shown symptoms of AMD.

[0226] Dry (atrophic) age-related macular degeneration Approximately 85%-90% of cases of macular degeneration are of the "dry" (atrophic) type. It is estimated that 62.9 million individuals worldwide have this form of AMD, of which 8 million are Americans. Due to increases in life expectancy and current demographics, this number is expected to triple by 2020. Currently, there are no FDA-approved treatments for dry AMD. Due to the lack of treatments and high prevalence, drug development for dry AMD is crucial. Clinically, atrophic AMD represents a slowly progressive neurodegenerative disease in which specialized neurons (rod and cone photoreceptors) die in the central site of the retina called the macula. Histopathological and clinical imaging studies show that photoreceptor degeneration in dry AMD is caused by abnormalities in the retinal pigment epithelium (RPE), which is located beneath the photoreceptors and provides critical metabolic support to the cells of these light-sensing neurons. Experimental and clinical data indicate that excessive accumulation of cytotoxic autofluorescent lipid-protein retinoid aggregates (lipofuscin) in the RPE is the primary trigger of dry AMD. The major cytotoxic component of RPE lipofuscin is the pyridinium bisretinoid A2E. Further 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) begins in photoreceptor cells in a nonenzymatic manner and can be considered as a by-product of a properly functioning visual cycle.

[0227] Some embodiments provided herein describe the use of the RBP4 inhibitor described herein for treating dry (atrophic) AMD in a subject in need thereof. In some embodiments, the RBP4 inhibitor inhibits dry (atrophic) AMD. In certain embodiments, the RBP4 inhibitor prevents the development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor reduces the development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the RBP4 inhibitor alleviates the subject of dry (atrophic) AMD. In certain embodiments, the RBP4 inhibitor causes regression, reversal, or improvement of dry (atrophic) AMD. In certain embodiments, the RBP4 inhibitor reduces the number, frequency, duration, or severity of clinical symptoms of dry (atrophic) AMD.

[0228] In some embodiments, RBP4 inhibitor is used prophylactically.In certain embodiments, RBP4 inhibitor is used to prevent or reduce the risk of developing dry (atrophic) AMD.In certain embodiments, RBP4 inhibitor prevents the clinical symptoms of dry (atrophic) AMD from developing in subjects who may have a predisposition to dry (atrophic) AMD but have not yet experienced or shown symptoms of dry (atrophic) AMD.

[0229] Pharmaceutical Compositions In some embodiments, the RBP4 inhibitor compounds described herein are administered as pure chemicals. In other embodiments, the RBP4 inhibitor compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st The compositions are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the chosen route of administration and standard pharmaceutical practice, as described in U.S. Pat. No. 6,313,311 (Ed. Mack Pub. Co., Easton, PA (2005)).

[0230] Provided herein is a pharmaceutical composition comprising at least one RBP4 inhibitor compound, or its stereoisomer, pharma-ceutically acceptable salt or N-oxide, together with one or more pharma-ceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is not deleterious to the recipient of the composition (i.e., subject or patient).

[0231] One embodiment provides a pharmaceutical composition comprising an RBP4 inhibitor, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration, which comprises a compound provided herein and one or more pharma- ceutically acceptable excipients or carriers.

[0232] In certain embodiments, the RBP4 inhibitor compound is substantially pure, in that it contains 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 produced in one or more of the steps of the synthetic method.

[0233] Suitable dosage forms for oral administration include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 st See Ed. Mack Pub. Co., Easton, PA (2005).

[0234] In some embodiments, the pharmaceutical compositions provided herein are formulated for oral administration in the form of a tablet, capsule, powder, or liquid. In some embodiments, the tablet comprises a solid carrier or adjuvant. Liquid pharmaceutical compositions typically comprise a liquid carrier, such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic petroleum. In some embodiments, saline solution, dextrose or other saccharide solution, or glycols are optionally included. In some embodiments, the capsule comprises a solid carrier, such as gelatin.

[0235] In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration, which comprises the compound provided herein and one or more pharma- ceutically acceptable excipients or carriers.When the pharmaceutical composition is formulated for intravenous, cutaneous, or subcutaneous injection, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity, and stability.Those skilled in the art can fully prepare appropriate solutions using isotonic vehicles such as, for example, sodium chloride injection, Ringer's injection, or lactated gel injection.In some embodiments, preservatives, stabilizers, buffers, antioxidants, and / or other additives are included.

[0236] In yet another embodiment, the pharmaceutical composition is provided in a dosage form for topical administration, which comprises a compound provided herein and one or more pharma- ceutically acceptable excipients or carriers.

[0237] Methods of Administration and Treatment Regimens The dosage of the compositions comprising at least one RBP4 inhibitor compound described herein will vary depending on the patient's condition, ie, stage of the disease, general health, age, and other factors.

[0238] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the suitable duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dose and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome), or a reduction in the severity of symptoms. The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body type, weight, or blood volume.

[0239] In one embodiment, the compounds described herein or pharma- ceutically acceptable salts thereof are used in the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from the administration of any one of the disclosed compounds. A method for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof.

[0240] In some embodiments, compositions comprising the compounds described herein are administered for preventive and / or therapeutic treatment. In some therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0241] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or at risk of a particular disease, disorder, or condition. Such amounts are defined as "prophylactically effective amounts or dosages." In this use, the exact amount will vary depending on the patient's health, weight, and the like. When used in patients, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing the compounds described herein or a pharma- ceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition.

[0242] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, to ameliorate or otherwise inhibit or limit the symptoms of the patient's disease or disorder.

[0243] Oral doses are typically in the range of about 1.0 mg to about 1000 mg, one to four or more times per day. In general, however, doses used for adult treatment are typically in the range of 0.01 mg to 5000 mg per day. In one aspect, dosages used for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., two, three, four or more subdoses per day.

[0244] In one embodiment, a suitable daily dosage for the compounds described herein or a pharma- ceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage or effective amount of the active ingredient in the dosage form will be less than or greater than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dose will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0245] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, depending on the symptoms, is reduced to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, patients require intermittent treatment on a long-term basis upon recurrence of symptoms.

[0246] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determining LD50 and ED50. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or a therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within a range of blood concentrations that includes the ED50 of minimal toxicity. In certain embodiments, the daily dosage range and / or unit dose varies within this range depending on the dosage form used and the route of administration utilized.

[0247] In any of the above aspects, in further embodiments, an effective amount of the compound described herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered locally to a mammal, and / or (f) administered non-systemically or locally to a mammal. In some embodiments, the RBP4 inhibitor, its pharma- ceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered orally or parenterally to a subject in need thereof. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration. In some embodiments, the RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered orally or intravenously to a subject in need thereof. In some embodiments, the RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered orally to a subject in need thereof. In some embodiments, the RBP4 inhibitor, its pharmaceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer is administered intravenously to a subject in need thereof.

[0248] In any of the above aspects, there are further embodiments comprising a single administration of an effective amount of the compound, where (i) the compound is administered once a day, or (ii) the compound is administered to the mammal multiple times throughout the day, for example, two, three, four or more times a day. In some embodiments, the RBP4 inhibitor compounds described herein are administered daily, every other day, every other day for three days a week, every two weeks, every three weeks, every four weeks, every five weeks, every third day, every fourth day, every fifth day, every sixth day, every week, every other week, three times a week, four times a week, five times a week, six times a week, once a month, twice a month, three times a month, once every two months, once every three months, once every four months, once every five months, or once every six months. In some embodiments, the RBP4 inhibitor compounds described herein, or a pharma- ceutically acceptable salt, solvate, polymorph, prodrug, metabolite, N-oxide, stereoisomer or isomer thereof, are administered daily.

[0249] In any of the foregoing aspects, there are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently, such as in a single dose; (ii) the multiple doses are spaced apart by every 3 hours; (iii) the multiple doses are spaced apart by every 6 hours; (iv) the compound is administered to the mammal every 8 hours; (v) the compound is administered to the mammal every 12 hours; or (vi) the compound is administered to the mammal every 24 hours.

[0250] In certain embodiments where the patient's condition improves, the dose of the drug being administered is temporarily reduced or temporarily stopped for a period of time (e.g., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, such as, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday is, by way of example only, 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In further or alternative embodiments, the method includes a drug holiday, where administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 to 7 days. In one embodiment, the length of the drug holiday is 7 days. In one embodiment, the length of the drug holiday is 14 days. In one embodiment, the length of the drug holiday is 28 days. EXAMPLES

[0251] Example 1: Biomarker analysis in age-related macular degeneration Design: Healthy and AMD subjects were recruited for the study. For the AMD group, inclusion criteria were subjects over 50 years of age with a diagnosis of AMD in the primary eye as defined by the Age-Related Eye Disease Study (AREDS) study group. For the healthy group, subjects over 50 years of age without ocular disease and with a best corrected visual acuity (BCVA) of 20 letters according to the Early Treatment Diabetic Retinopathy Study (ETDRS) were included. Subjects with active hepatitis, chronic kidney disease, or pregnant women were excluded from the study. From medical records, demographic data, age, height, weight and body mass index (BMI), obesity (waist / hip ratio >0.90 in men and >0.85 in women, or BMI >30 kg / m2), hyperlipidemia (triglyceride level >150 mg / dl, or high-density lipoprotein cholesterol <35 mg / dl in men and <39 mg / dl in women), metabolic syndrome, prediabetic state, diabetes mellitus, hypertension (blood pressure >140 / 90 mmHg), cardiovascular disease, and systemic diseases including nonalcoholic fatty liver disease and steatohepatitis were collected. All participants signed informed consent. The study protocol was approved by the review board of the Chang Gung Medical Foundation (No. 201701197B0), and the study was conducted in accordance with the Declaration of Helsinki.

[0252] Grading of AMD severity. Age at AMD diagnosis was collected from medical records, and AMD disease duration was calculated as the time between diagnosis and study enrollment. Color fundus photography (nonmyd 8s; Kowa Co., Nagoya, Japan), fundus autofluorescence (Spectralis HRA2; Heidelberg Engineering, Heidelberg, Germany), and spectral domain optical coherence tomography (Spectralis HRA2; Heidelberg Engineering) were used to grade AMD severity according to the AREDS definition. Images were classified by experienced ophthalmologists (K.-JC, W.-CW, Y.-SH, H.-DC) and reviewed by a senior ophthalmologist (C.-CL) at Chang Gung Memorial Hospital, Linkou. Briefly, AREDS category 1 (C1) is defined as a small number (1–15) of small (<63 μm) drusen or no drusen and no pigmentary changes. AREDS category 2 (C2, early AMD) is characterized by numerous small and few medium-sized (63–124 μm) drusen in one or both eyes and / or pigmentary changes. AREDS category 3 (C3, intermediate AMD) is characterized by widespread medium-sized (20 soft or 65 hard with no soft) drusen, one large (>125 μm) drusen, and / or geographic atrophy not involving the macula in one or both eyes. AREDS category 4 (C4, advanced unilateral AMD) consists of advanced nonexudative disease with geographic atrophy involving the macula in one eye or exudative disease with choroidal neovascularization.

[0253] Measurement of plasma RBP4. Peripheral venous blood was collected from study subjects. Samples were divided into buffy coat and plasma and stored in a -80°C freezer until analysis. Plasma RBP4 concentrations were measured using a commercially available enzyme-linked immunosorbent assay kit (R&D System, USA). The assay was validated at multiple concentration points, including the maximum and minimum detection levels of the assay, using commercially available human RBP4 recombinant protein (R&D System) and serum samples from healthy subjects. The detection range of the assay was 0.224-100 ng / ml, and the intra-assay and inter-assay coefficients of variation for RBP4 validation were 5.25% and 4.54%, respectively.

[0254] Analysis of ABCA4 variants. DNA material was isolated from buffy coat samples using a QIAamp DNA mini kit (QIAGEN, The Netherlands). Next-generation sequencing of DNA samples was performed on a MiniSeq with an AmpliSeq custom panel designed by Illumina (Illumina, USA). Sequence data were analyzed and variant calling was performed using BaseSpace (Illumina). Sequence alignment was performed against the reference genome GRCh37 / hg19 using BWA (0.7.13) and analyzed using samtools (1.3) and Picard (2.1.1). Variant calling was performed using gatk (1.6). To curate information based on existing studies, population databases dbSNP and ClinVar were consulted, and allele frequencies were obtained from the gnomAD and TOPMed databases. In silico algorithms, including PolyPhen-2, PANTHER, and Condel, were used to predict the functional effects of unreported variants. Quantitative trait association modeling was performed using PLINK (1.90).

[0255] Statistical analysis. Differences in clinical variables between the four groups were evaluated using χ for categorical variables. 2Analysis was performed with the ANOVA test or the Kruskal-Wallis test for continuous variables. Direct comparisons between groups were performed using Student's t test. Simple linear regression and logistic regression were used for continuous and categorical variables, respectively. Associations between severity grade, RBP4, age, and other variables of interest were analyzed using Spearman rank correlation. Odds ratios (ORs) were calculated using the median unbiased estimator. All statistical analyses were performed using R (3.6.0) and RStudio (1.1.442; RStudio Inc, USA) and confirmed using SAS software (version, SAS Institute Inc., USA). The significance level was set at 0.05. Details of the analysis of ABCA4 are described in the previous section.

[0256] Cohort characteristics. A total of 67 subjects, including 20 healthy subjects and 47 AMD (AREDS C2, C3, and C4) subjects, were recruited from March 2018 to May 2019 at the Department of Ophthalmology, Linkou Medical Center, Chang Gung Memorial Hospital, Taiwan. Table 1 shows the demographic and clinical characteristics of the study cohort. Because of the difficulty in enrolling age-matched subjects, subjects in the healthy group were significantly younger than the three AMD groups. Metabolic syndrome was more prevalent in the AMD group compared with the healthy group. AREDS C3 and AREDS C4 subjects had significantly higher RBP4 levels (37.3 ± 8.8 and 36.1 ± 7.8 μg / ml, respectively) than those of healthy controls (29.4 ± 7.1 μg / ml; P = 0.003 and P = 0.002, respectively) (Figure 1). RBP4 levels in AREDS C2 subjects (32.1 ± 6.6 μg / ml) were not significantly lower than those in AREDS C3 and C4 subjects, and AREDS C2 subjects exhibited smaller and less extensive drusen compared to subjects with more severe AMD severity.

[0257] [Table 3]

[0258] Association between RBP4 and severe AMD. Correlations between variables including age, plasma RBP4 levels, BMI, and age at AMD diagnosis and AMD severity were analyzed using Spearman rank correlation (Table 2). AMD severity was most significantly associated with age (ρ = 0.68; P < 0.0001), followed by plasma RBP4 levels (ρ = 0.36; P = 0.001), and age at AMD diagnosis (ρ = -0.43; P < 0.0001). Age was also significantly correlated with RBP4 levels (ρ = 0.44; P < 0.001).

[0259] [Table 4]

[0260] Univariate logistic regression was performed on the variables significantly associated with AMD severity, namely age, plasma RBP4 levels, and age at AMD diagnosis. Only age (P<0.001) and RBP4 levels (P=0.017) remained significantly associated with AMD severity, whereas age at AMD diagnosis was no longer significant (P=0.057).

[0261] We investigated plasma RBP4 levels between the study cohort median (32.69 μg / ml) and the disease group median (35.96 μg / ml) to identify the plasma RBP4 level threshold that best differentiates AMD severity. Three logistic regression models were constructed using plasma RBP4 levels of 33 μg / ml, 34 μg / ml, and 35 μg / ml as cutoff values, respectively. When healthy controls were used as reference, a plasma RBP4 level of 35 μg / ml (P=0.001) could be used to better predict subjects with AREDS C4 than using 33 μg / ml (P=0.01) or 34 μg / ml (P=0.04). Subjects with RBP4 levels higher than 35 μg / ml had significantly higher odds of being present in AREDS C3 and AREDS C4 (OR 10.3 and 6.9, respectively) (Table 3). Odds ratios for each AREDS category when plasma RBP4 levels were >35 μg / ml.

[0262] [Table 5]

[0263] Furthermore, we combined healthy controls and AREDS C2 subjects into a no / mild AMD group, and AREDS C3 and C4 subjects into a severe AMD group, and analyzed the OR for severe AMD using an RBP4 level of 35 μg / ml as a cutoff. The results demonstrated that subjects with RBP4 levels higher than 35 μg / ml were more likely to have severe AMD, with an OR of 6.06 (95% CI = 2.0 to 18.4; P = 0.001), when the no / mild AMD group was used as the reference group.

[0264] Table 4 shows the results of the univariate and multivariate logistic regression models. The odds of having severe AMD, unadjusted for age, was 1.26 (95% CI = 1.13 to 1.40) and increased by 11.6% for each 1 μg / ml increase in plasma RBP4 level. Nevertheless, the odds of having severe AMD were significant only for age (OR = 1.24; 95% CI = 1.12 to 1.39) and not for plasma RBP4 level (OR = 1.04; 95% CI = 0.95 to 1.14).

[0265] [Table 6]

[0266] Association of ABCA4 mutations with AMD severity and RBP4 levels. To identify associations between mutations and AMD disease status, only AMD subjects were sequenced to detect genetic mutations in ABCA4. A total of 31 variants were identified in AMD subjects, including four missense mutations, one intronic splice acceptor variant, and one 3-prime UTR variant (Table 5). The majority of variants (18 / 31) are consistent with previous publications. Many of these variants were found only in severe forms of AMD. Twenty-four variants occurred at higher allele frequencies in the AMD cohort compared to the allele frequencies reported in the GnomAD and TOPMed databases. For example, the missense mutation rs1800549 was found in 8 of 47 AMD patients, which is higher than the overall allele frequency of 0.34%. Furthermore, in 16 subjects, seven variants (i.e., rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, rs1801574) were found to be associated with having higher RBP4 levels than subjects without these variants (37.8 ± 7.7 vs. 32.4 ± 7.9 μg / ml; P = 0.026).

[0267] [Table 7-1]

[0268] [Table 7-2]

[0269] Description: Age-related macular degeneration (AMD) is one of the most common eye diseases in the middle-aged population and is characterized by the presence of lipofuscin in the retinal pigment epithelium (RPE) layer. Upon photoexcitation, all-trans-retinaldehyde bound to rhodopsin is released to form N-retinylidenephosphatidylethanolamine (A2PE). A2PE is normally processed and reduced to all-trans-retinol for reuse in another photoconversion reaction in healthy individuals. However, A2PE gradually accumulates with age, and A2PE forms A2E, a component of lipofuscin that induces cytotoxicity to photoreceptors and RPE cells. To avoid the toxicity of A2E, potential therapeutic approaches include reducing A2E formation and accumulation by modulating the visual cycle. One approach is to directly inhibit visual cycle proteins. Alternatively, the formation of A2E can also be regulated by reducing the retinol supply to the retina, which can be achieved by inhibiting RBP4, the main transporter protein for retinol.

[0270] RBP4 is a 21 kDa protein with a single binding site for retinol. RBP4 is produced primarily in the liver to deliver retinol to peripheral tissues. Most of the previous studies on RBP4 have been in the field of metabolic syndrome and cardiovascular disease. A study of acute ischemic stroke found that stroke patients had significantly higher serum RBP4 levels compared to normal controls (28.9 vs. 23.7 μg / ml). Another 10-year study of 352 children showed that children with persistent metabolic syndrome had significantly higher baseline RBP4 levels (42.1 μg / ml) than those without any signs of metabolic syndrome (32.7 μg / ml). Furthermore, in this study, baseline RBP4 predicted hyperglycemia, elevated triglycerides, elevated blood pressure, and insulin resistance. Furthermore, our study cohort showed similar trends consistent with these results, with only 15% of healthy controls having metabolic syndrome and low plasma RBP4 levels (29.4 μg / ml) compared to a higher proportion of AMD patients (43%-64%) with metabolic syndrome and high plasma RBP4 levels (32-37.3 μg / ml).

[0271] Except for the association of RBP4 with systemic diseases, we did not explore the relationship between RBP4 and eye diseases to a great extent. In our study, we analyzed RBP4 and AMD and found a positive association between plasma RBP4 levels and AMD severity. We also established a cutoff concentration of plasma RBP4 of 35 μg / ml, which was significantly associated with higher odds of severe AMD. However, there was a significant age difference between the AMD and control groups due to the difficulty in recruiting age-matched healthy controls. As a result, the correlation between RBP4 and AMD was overshadowed by the strong correlation between age and AMD severity. Nevertheless, our results still showed a positive trend between RBP4 and AMD, suggesting the possibility of using plasma RBP4 levels to assess the risk of severe AMD and the possibility of using anti-RBP4 therapy in managing AMD.

[0272] Several RBP4 inhibitors have been proposed for the treatment of AMD and Stargardt disease (STGD), a juvenile maculopathy that shares a similar pathology with AMD. This theory was tested in a transgenic rodent model carrying an ABCA4 mutation that recapitulates the phenotype of lipofuscin accumulation and subsequent retinal dystrophy. Treating this mouse model with an RBP4 inhibitor effectively reduced bisretinoid synthesis by 50% compared to untreated mice, and partially restored the expression of complement component 3, complement factor D, complement factor H, and C-reactive protein compared to wild-type mice. As bisretinoids are one of the lipofuscin components that contain A2E, and the complement system and inflammation are both associated with AMD, this mouse model demonstrated a potential role for ABCA4 mutations in exacerbating retinal degeneration.

[0273] A clinical trial used another RBP4 inhibitor, namely fenretinide, to treat patients with non-neovascular AMD. In this two-year randomized controlled trial, 246 AMD patients with only geographic atrophy were treated with 100 mg or 300 mg of fenretinide or a placebo. The results showed that the incidence of choroidal neovascularization was reduced in treated patients, especially in the high-dose group. Furthermore, in patients who achieved RBP4 levels below 1 μM (approximately 20 μg / ml) after treatment with fenretinide, lower serum RBP4 levels correlated with a slower rate of progression of geographic atrophy. Due to an insufficient number of subjects who achieved serum RBP4 levels below 1 μM, the entire cohort did not show a statistically significant slowing in the rate of growth of geographic atrophy, but further clinical trials targeting RBP4 are ongoing.

[0274] In this study, genetic profiling of ABCA4 revealed six variants associated with RBP4 levels above 35 μg / ml in AMD subjects, especially in the AREDS C3 and C4 groups. The results suggest that there may be a genetic contribution to elevated RBP4 levels in patients with more severe AMD. There were two subjects who carried all six variants but were only diagnosed with less severe AMD (AREDS C2). Both of these subjects were newly diagnosed with AMD and had high RBP4 levels (34.3 μg / ml and 43.5 μg / ml). These two patients are likely to develop more severe AMD in the future and are suggested to be followed up closely.

[0275] To our knowledge, this is the first study to investigate plasma RBP4 levels in AMD subjects and the correlation between RBP4 levels and ABCA4 variants. A plasma RBP4 threshold of 35 μg / ml was significantly associated with severe AMD and may have a genetic basis. Results from this pilot study suggest that RBP4 has a role in AMD and may potentially serve as a biomarker or therapeutic target, especially when combined with ABCA4 gene profiling.

[0276] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in implementing the present invention. The following claims define the scope of the present invention, and it is intended that methods and structures within the scope of these claims, and their equivalents, be covered thereby.

Claims

1. A composition comprising an RBP4 inhibitor for use in treating age-related macular degeneration in an individual in need thereof, wherein the individual has been assessed for a plasma or serum level of retinol binding protein 4 (RBP4) of at least 25 μg / ml.

2. The composition described in claim 1, wherein the plasma or serum level of RBP4 is at least 35 μg / ml.

3. The composition of claim 1, wherein the individual has been assessed to have a plasma or serum level of vitamin A of at least 150 ng / mL.

4. The composition described in claim 4, wherein the individual has been assessed to have a plasma or serum level of vitamin A of at least about 225 ng / mL or at least about 390 ng / mL.

5. The RBP4 inhibitor of claim 4, wherein the RBP4 inhibitor has formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl, where two or more of R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are other than H; R A 6 is H, OH, or halogen; A A has the structure: 【Chemistry 2】 having During the ceremony, each of α, β, χ, and δ is independently absent or present and, when present, each is a bond; X is C or N; Z 1 is N; Z 2 is N or NR A 9 ; where R A 9 is H, C 1 -C 4 alkyl, or oxetane; 10. The composition of claim 1, wherein BA is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

6. The compound of claim 1, wherein the compound has the structure: 【Chemistry 3】 The composition of claim 5 having the formula:

7. The compound of claim 1, wherein the compound has the structure: 【Chemistry 4】 The composition of claim 5 having the formula:

8. A composition comprising an RBP4 inhibitor for use in treating age-related macular degeneration in an individual in need of such treatment, wherein the individual has been identified as having one or more genomic variants selected from rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, and rs1801574.

9. The composition of claim 8, wherein the one or more genomic variants include at least four of rs4147863, rs2275029, rs1800739, rs4147857, rs4147856, rs1801555, and rs1801574.

10. The one or more genomic variants are rs3747961, rs6666652, rs1800717, rs763108716, rs185601596, rs17110761, rs61748519, rs1801359, rs145766145, rs76258939, rs200551567, rs754765164, rs2016024 10. The composition of claim 8, further comprising at least five of the following: rs1801555, rs1762114, rs55860151, rs1800549, rs3112831, rs4147830, rs2297634, and rs4847281.

11. The RBP4 inhibitor of claim 1, wherein the RBP4 inhibitor has formula (I): 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, During the ceremony, R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are each independently H, halogen, CF 3 , or C 1 -C 4 alkyl, where two or more of R A 1 , R A 2 , R A 3 , R A 4 , and R A 5 are other than H; R A 6 is H, OH, or halogen; A A has the structure: 【Chemistry 6】 having During the ceremony, each of α, β, χ, and δ is independently absent or present and, when present, each is a bond; X is C or N; Z 1 is N; Z 2 is N or NR A 9 ; R A 9 is H, C 1 -C 4 alkyl, or oxetane; 9. The composition of claim 8, wherein BA is a substituted or unsubstituted 5-, 6-, or 7-membered ring structure.

12. The RBP4 inhibitor has the structure: 【Chemistry 7】 9. The composition of claim 8, which is a compound having the formula:

13. The RBP4 inhibitor having the structure: 【Chemistry 8】 9. The composition of claim 8, which is a compound having the formula:

14. The composition of claim 8, wherein the individual has been assessed as having a plasma or serum level of retinol binding protein 4 (RBP4) of at least 25 μg / ml.

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