The present disclosure provides non-naturally occurring polyphenol compounds that upregulate the expression of Apolipoprotein A-I (ApoA-I). The disclosed compositions and methods can be used for treatment and prevention of cardiovascular disease and related disease states, including cholesterol or l
The present disclosure provides non-naturally occurring polyphenol compounds that upregulate the expression of Apolipoprotein A-I (ApoA-I). The disclosed compositions and methods can be used for treatment and prevention of cardiovascular disease and related disease states, including cholesterol or lipid related disorders, such as, e.g., atherosclerosis.
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1. A compound of Formula I: wherein X is O;Y is CO;R1, R3, R4, R5, R6, R8, and R9 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,
1. A compound of Formula I: wherein X is O;Y is CO;R1, R3, R4, R5, R6, R8, and R9 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R2 is selected from alkoxy, aryloxy, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R7 is selected from aryloxy, alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R10 is selected from aryloxy, alkenyl, alkyl, alkynyl, amide, amino, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;at least one W is N;Z1 and Z3 are each a single bond; andZ2 is a double bond;and pharmaceutically acceptable salts thereof. 2. A compound of Formula VII: wherein: R1, R2, R3, R5, R6, R3, R9, and R10 are each independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R7 is selected from aryloxy, alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, ortwo adjacent substituents selected from R1, R2, R3, R5, R6, R7, R8, R9, and R10 are connected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;and pharmaceutically acceptable salts thereof. 3. A compound that is 2-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 1, where R7 is hydroxyl. 5. A compound according to claim 1, wherein at least one W in the A ring is N. 6. A compound according to claim 1, wherein R5, R6, R8, R9 and R10 are each hydrogen. 7. A compound according to claim 1, wherein at least one W in the B ring is N. 8. A compound according to claim 1, wherein the W in the C ring is selected from N and NR10, where R10 is hydrogen or methyl. 9. A compound according to claim 1, wherein R8 is halogen. 10. A compound according to claim 1, wherein at least one of R1, R2, R3 and R4 is alkoxy. 11. A compound selected from 2-(5-Methoxy-pyridin-2-yl)-chromen-4-one;2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one;2-(6-Hydroxy-pyridin-3-yl)-chromen-4-one;5,7-Dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one;5,7-Dihydroxy-2-(4-hydroxy-phenyl)-quinolin-4-one;2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one;2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(4-Hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one;2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one;2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one;4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile;2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one;2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(4-Hyd roxy-phenyl)-pyrano[2,3-c]pyridin-4-one;2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one;3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one;3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1(2H)-one;2-Fluoro-4-(5-methoxy-1-(methylamino)-isoquinolin-3-yl)phenol;6-Naphthalen-2-yl-pyridin-3-ol;4-Isoquinolin-3-yl-phenol;4-(1,6-Naphthyridin-7-yl)phenol;2-(4-Hydroxy-phenyl)-[1,4]naphthoquinone;2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one;6-Naphthalen-2-yl-pyridin-3-ol;2-(4-Ethoxycarbonyloxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid ethyl ester;4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate;4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate;4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate;5,7-Difluoro-2-(4-hydroxy-phenyl)-chromen-4-one;2-(3,5-Difluoro-4-hydroxyphenyl)chromen-4-one;2-(4-Hydroxy-3,5-dimethylphenyl)chromen-4-one;2-(4-Methoxy-phenyl)-thiochromen-4-one;2-(4-Hydroxy-phenyl)-thiochromen-4-one;2-(4-Hydroxyphenyl)-3-methyl-4H-chromen-4-one;4-(6-Bromo-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate;1-(2-Nitro-4-methoxy-phenyl)-chromen-4-one;2-(4-Hydroxy-2-nitrophenyl)chromen-4-one;2-(2-Amino-4-methoxy-phenyl)-chromen-4-one;2-(2-Amino-4-hydroxy-phenyl)-chromen-4-one;N-[5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]acetamide;6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one;2-(2-Fluoro-4-hydroxyphenyl)chromen-4-one;2-(4-Hydroxyphenyl)-8-nitro-4H-chromen-4-one;2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one;2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one;2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-one;2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile;2-(4-Methoxy-phenyl)-chromen-4-one;2-(3-Fluoro-4-hydroxyphenyl)chromen-4-one;2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid;6-Hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one;6-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one;8-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;2-(4-Hydroxy-phenyl)-chromen-4-one;7-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;5-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;5,7-Dihydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;5,7-Dihydroxy-2-phenyl-chromen-4-one;5-Hydroxy-2-phenyl-chromen-4-one;2-(4-Acetoxy-phenyl)-thiochromen-4-one;2-(4-Acetoxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one;2-(4-Hydroxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one;2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile;3-(Hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one;2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one;4-Naphthalen-2-yl-phenol;3-(4-Hydroxyphenyl)-naphthalene-1-ol;4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate;4-(Benzo[b][1,4]dioxin-2-yl)phenol;4-(4H-Chromen-2-yl)-phenol;Nicotinic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester;Acetic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester;2-Amino-5-guanidino-pentanoic acid 4-(4-oxo-4H-chromen-2-yl)phenyl ester; and2-(4-(Nicotinoyloxy)phenyl)-4-oxo-4H-chromene-5,7-diyl dinicotinate, and pharmaceutically acceptable salts thereof. 12. A pharmaceutical composition comprising a compound according to claim 1, 2, or 11, and a pharmaceutically acceptable carrier.
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