ZA200303967B

ZA200303967B - ABCA-1 elevating compounds.

Info

Publication number: ZA200303967B
Application number: ZA200303967A
Authority: ZA
Inventors: Michael Campbell; Prahba N Ibrahim; Jeff A Zablocki; Richard M Lawn
Original assignee: Therapeutics Inc
Priority date: 2000-12-07
Filing date: 2003-05-22
Publication date: 2004-05-10
Also published as: ZA200304436B

Description

ABCA-1 ELEVATING COMPOUNDS

This application claims priority to U.S. Provisional Application Serial Nos. ) 60/251916 filed on December 7, 2000 and 60/313274 filed on August 17, 2001. . j Field of the Invention

The present invention relates to compounds useful for raising cellular ABCA-1 production in mammals, and to methods of using such compounds in the treatment of coronary artery diseases. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

Background of the Invention

Cholesterol is essential for the growth and viability of higher organisms. Itis a lipid that modulates the fluidity of eukaryotic membranes, and is the precursor to steroid hormones such as progesterone, testosterone, and the like. Cholesterol can be obtained from the diet, or synthesized internally in the liver and the intestines. Cholesterol is transported in body fluids to specific targets by lipoproteins, which are classified according to increasing density. For example, low density lipoprotein cholesterol (LDL) is responsible for transport of cholesterol to and from the liver and to peripheral tissue cells, where LDL receptors bind LDL, and mediate its entry into the cell.

Although cholesterol is essential to many biological processes in mammals, elevated serum levels of LDL cholesterol are undesirable, in that they are known to contribute to the formation of atherosclerotic plaques in arteries throughout the body, which may lead, for example, to the development of coronary artery diseases.

Conversely, elevated levels of high density lipoprotein cholesterol (HDL-C) have been found, based upon human clinical data, and animal model systems, to protect against development of coronary diseases.

In general, excess cholesterol is removed from the body by a pathway involving : high density lipoproteins (HDLs). Cholesterol is “effluxed” from cells by one of two processes - either by passive transfer to mature HDL, or an active transfer to ’ apolipoprotein A-1. The latter process is mediated by a protein known as ATP binding cassette transporter 1 (ABC-1, or alternatively referenced as ABCA-1). In the latter process, lipid-poor HDL precursors acquire phospholipid and cholesterol, which leads to increased plasma levels of mature HDL particles. HDL cholesterol is eventually ) transported to the liver in a process known as “reverse cholesterol transport”, where it is 5. either recycled or excreted as bile.

One method of treatment aimed at reducing the risk of formation of atherosclerotic plaques in arteries relates to decreasing plasma lipid levels. Such a method includes diet changes, and/or treatment with drugs such as derivatives of fibric acid (clofibrate, gemfibrozil, and fenofibrate), nicotinic acid, and HMG-CoA reductase 10 inhibitors, such as mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, and lovastatin, which reduce plasma LDL cholesterol levels by either inhibiting the intracellular synthesis of cholesterol or inhibiting the uptake via LDL receptors. In _ addition, bile acid-binding resins, such as cholestyrine, colestipol and probucol decrease the level of LDL-cholesterol by reducing intestinal uptake and increasing the catabolism 15 of LDL-cholesterol in the liver.

It is desired to provide alternative therapies aimed at reducing the risk of formation of atherosclerotic plaques in arteries, especially in individuals deficient in the removal of cholesterol from artery walls via the HDL pathway. Given that HDL levels - are generally related to the expression of ABCA-1, one method of increasing HDL levels 20 would be to increase the expression of ABCA-1. Accordingly, it is desired to provide compounds that are potent stimulators of the expression of ABCA-1 in mammals, thus increasing cholesterol efflux and raising HDL cholesterol levels in blood, This would be useful for the treatment of various disease states characterized by low HDL levels, in particular coronary artery disease. 25 It has also been shown that a combination of a drug that decreases LDL cholesterol levels and a drug that increases HDL cholesterol is beneficial; see, for example, Arterioscler., Thromn., Vasc. Biol. (2001), 21(8), 1320-1326, by Marian C.

Cheung et al. Accordingly, it is also desired to provide a combination of 2 compound ) that stimulates the expression of ABCA-1 with a compound that lowers LDL cholesterol ) 30 levels. -

It should be noted it has also been shown that raising ABCA-1 production in macrophages locally reduces cholesterol deposition in coronary arteries without significantly raising plasma HDL cholesterol. In this instance, raising ABCA-1 expression is beneficial even in the absence of increased HDL cholesterol. . 5 | .

SUMMARY OF THE INVENTION

+ Itis an object of this invention to provide compounds that elevate cellular expression of the ABC-1 gene, thus increasing the level of high density lipoprotein 10 cholesterol (HDL-C) in plasma and lowering lipid levels in a mammal. Accordingly, in a first aspect, the invention relates to compounds of Formula I: ;

Rr2 NHAR'

SOY

R4 X—Y. 7 ls

RY -

R®

Formula I wherein:

R! is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally 15 substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

A is a covalent bond, C(X)-, or Cx! )-NH-, where X' is oxygen or sulfur,

RZR*>R*and R’are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halo, or optionally substituted cycloalkyl; 20 Xs oxygen, sulfur, -C(XY-, or -NH-;

Y is optionally substituted lower alkylene when X is oxygen or sulfur; or » Y is -NH- when X is -C(X")-; or

Y is -C(X')- when X is -NH-; ) with the proviso that X and Y cannot both be -NH-;

R°, R’,R% and R’ are independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted ' heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or 5s Rand R’,orR’andR®, orR®and R’, or R® and R'°, taken together with the carbon atoms to which they are attached form 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or an aromatic or non-aromatic carbocyclic moiety, all of which are optionally substituted by halo, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl.

In a second aspect, the invention relates to a method for using the compounds of

Formula I in the treatment of a disease or condition in a mammal that can be usefully treated with a compound that elevates serum levels of HDL cholesterol, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease, and diabetes.

In a third aspect, the invention relates to a method for using the compounds of

Formula I in the treatment of a disease or condition in a mammal that can be usefully treated with a compound that promotes cholesterol efflux from cells, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease, and diabetes. : :

In a fourth aspect, the invention relates to a method for using the compounds of ~ Formula I in the treatment of a disease or condition characterized by low HDL-C in a : | mammal that can be usefully treated with a compound that elevates serum levels of HDL-

C, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, diseases of the artery, in particular coronary artery disease, and diabetes.

A fifth aspect of this invention relates to pharmaceutical formulations, comprising a therapeutically effective amount of a compound of Formula I and at least one * pharmaceutically acceptable excipient.

A sixth aspect of this invention relates to methods of preparing the compounds of } Formulal .

Definitions and General Parameters

The term “alkyl” refers to a monoradical branched or unbranched saturated ’ hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, 2- ’ methylbutyl, n-hexyl,n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to: 1) an alkyl group as defined above, having from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, : alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, : carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- aryl,-SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO,-heteroaryl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O),R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2; or 2) an alkyl group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and -NR,-, where R, is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O).R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2; or . 3) an alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms. This term is exemplified by groups * such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1 to 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1-5 atoms as defined for substituted ’ alkyl, or a lower alkyl group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbon atoms. This term is exemplified by groups such as : methylene (-CH,-), ethylene (-CH,CHs;-), the propylene isomers (e.g., -CH,CH,CH,- and-CH(CH;)CH-) and the like.

The term “lower alkylene” refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1 to 6 carbon atoms.

The term*‘substituted alkylene” refers to: - (1) an alkylene group as defined above having from 1 to 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, - aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO- heteroaryl, -SO,-alkyl, SO,-aryl and -SO,-heteroaryl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —-S(O).R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or (2) analkylene group as defined above that is interrupted by 1-5 atoms or groups independently chosen from oxygen, sulfur and NR,-, where R, is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide ’ and sulfonyl; or (3) an alkylene group as defined above that has both from 1 to 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples 6 i of substituted alkylenes are chloromethylene (-CH(CI)-), aminoethylene (-

CH(NH,)CH,-), methylaminoethylene (-CH(NHMe)CH;-), 2-carboxypropylene isomers(-CH,CH(CO,H)CH;-), ethoxyethyl (-CH,CH,0-CH;CHy-), ethylmethylaminoethyl (-CH,CH,N(CH;)CH,CH,-),1-ethoxy-2-(2-ethoxy- } 5 ethoxy)ethane (-CH,CH;0-CH,;CH,-OCH,CH,-OCH,CH,-), and the like.

The term “aralkyl” refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. “Optionally substituted aralkyl” refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4- methoxyphenyl)propyl, and the like. :

The term “alkoxy” refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy groups are optionally substituted alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

The term “alkylthio” refers to the group R-S-, where R is as defined for alkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more : . preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and ~ having 1-6, preferably 1, double bond (vinyl). -Preferred alkenyl groups include ethenyl or vinyl (-CH=CHy), 1-propylene or allyl (-CH,CH=CH,), isopropylene (-C(CH;)=CH,), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached . to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from 2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as defined above having . 30 from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,

acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO-aryl,-SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO»-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —=S(O).R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (-C=CH), propargyl (or prop-1-yn-3-yl, -CH,C=CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group : consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamine, nitro, -SO- alkyl, -SO-aryl,-SO-heteroaryl, -SO»-alkyl, SO,-aryl and -SO,-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CFs, amino, substituted amino, cyano, or -S(O).R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or2.

The term “aminocarbonyl” refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are

Joined to form a heterocyclic group (e.g., morpholino) . All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF, amino, substituted amino, } © 30 cyano, or —S(O),R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “acylamino” refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF, amino, substituted amino, cyano, or —S(O)4R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “acyloxy” refers to the groups —O(0)C-alkyl, —O(O)C-cycloalkyl, — O(O)C-aryl, -O(O)C-heteroaryl, and ~O(O)C-heterocyclyl. All substituents may be _ optionally further substituted by alkyl, alkoxy, halogen, CFs, amino, substituted amino, cyano, or —~S(O),R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “aryl” refers to an aromatic.carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy; cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SOs-alkyl, SOz-aryl and -SO,-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —-S(O).R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O- wherein the aryl group is as | : defined above, and includes optionally substituted aryl groups as also defined above. The term “arylthio” refers to the group R-S-, where R is as defined for aryl.

The term “amino” refers to the group -NH,. -

The term “substituted amino” refers to the group -NRR where each R is . independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, : carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl, All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O),R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “carboxyalkyl” refers to the groups -C(0)O-alkyl, -C(0)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O),R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example indan, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-

SO-heteroaryl, -SO,-alkyl, SO,-aryl and -SO,-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CFs, amino, substituted amino, cyano, or ~S(O),R, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2.

The term “non-aromatic carbocycle” as used herein refers to a 5 or 6 membered carbocyclic group consisting of carbon and hydrogen comprising 0-2 double bonds.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “acyl” denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

The term “heteroaryl” refers to an aromatic group (i.e., unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. © Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SOs-alkyl, SO,-aryl and -SO;-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O)aR, in which R is alkyl, aryl, or heteroaryl and nis 0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl). Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogen containing heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O-.

The term “heterocyclyl” refers to a monoradical saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclic substituent, : such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,

heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -S0O;-alkyl, SO,-aryl and -SO,-heteroaryl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O)R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.

The term “thiol” refers to the group -SH.

The term “substituted alkylthio” refers to the group —S-substituted alkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.

The term “sulfoxide” refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl. “Substituted sulfoxide” refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

The term “sulfone” refers to a group -S(O);R, in which R is alkyl, aryl, or heteroaryl. “Substituted sulfone” refers to a group -S(O)zR, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

The term “keto” refers to a group —C(O)-. The term “thiocarbonyl” refers to a group —C(S)-. The term “carboxy” refers to a group —C(0)-OH. “Optional” or “optionally” means that the subsequently described event or circumstance may ‘or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

The term “compound of Formula I” is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically : acceptable esters, and prodrugs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2" stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(£)" is used to designate a racemic mixture where appropriate. : "Diastereoisomers"” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line.

The term “therapeutically effective amount” refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

The term “coronary artery disease” means a chronic disease in which there is a “hardening” (atherosclerois) of the coronary arteries.

The term “atherosclerosis” refers to a form of arteriosclerosis in which deposits of yellowish plaques containing cholesterol, lipoid material , and lipophages are formed within the intima and innner media of large and medium-sized arteries.

The term “treatment” or “treating” means any treatment of a disease in a mammal,

including: (1) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii)relieving the disease, that is, causing the regression of clinical symptoms.

In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds of Formula I, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, triatkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diary] amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the ’ amino nitrogen, form a heterocyclic or heteroaryl group.

Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)

amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N- alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N- ’ ethylpiperidine, and the like.

Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.

The disclosure contains the following definition; “R®and R’, orR” and R? orR® and R® orR’and RI! taken together with the carbon atom to which they are attached form 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or an aromatic or non- “10 aromatic carbocyclic moiety. Thus, a compound of Formula I in which R® and R” taken together with the carbon atoms to which they are attached may form a 6 membered heterocyclyl as shown below:

R: NHAR! oo .

R X—Y. tl

R¥® R

R

Other such moieties include, but are not limited to: . 0 J & & & @

OC OC

S 0} 15 .

Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I: 3 NHAR! ¢ x —Y y R¥ RS Rr Formula I Wherein: R! is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; A is a covalent bond, cxh-, or -C(X")-NH-, where X! is oxygen or sulfur, R%R’, R*and R® are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halo, or optionally substituted cycloalkyl; X is oxygen, sulfur, -C(X")-, or -NH-; Y is optionally substituted lower alkylene when X is oxygen or sulfur; or Y is -NH- when X is -C(X')-; or Yis -cXYH- when X is -NH-; with the proviso that X and Y cannot both be -NH-; RR’, R?, and R® are independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or Réand R’, or R” and R®, or R® and R’, or R® and R'? taken together with the carbon atoms to which they are attached form 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or an aromatic or non-aromatic carbocyclic moiety, all 45 AMENDED SHEET g of which are optionally substituted by halo, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl; for use in the treatment of a disease state in a mammal that is alleviable by treatment with an agent capable of increasing ABCA-1 expression.

2. The compound of claim 1, wherein X is oxygen and Y is methylene.

3. The compound of claim 2, wherein R2 R?, RY, R® R®and Rare hydrogen.

4. The compound of claim 3, wherein R® and R’ taken together with the carbon atoms to which they are attached form a 6 membered heterocyclyl.

5. The compound of claim 4, wherein heterocyclyl is optionally substituted 1,3 dioxane.

6. The compound of claim 5, wherein A is a covalent bond, R! is hydrogen, and R’ is : chloro, namely 2-[(6-chloro-2H,4H-benzo[e] 1,2-dioxin-8-y)methoxy]-phenylamine.

7. The compound of claim 5, wherein A is -C(X")- and R'is optionally substituted alkyl.

8. The compound of claim 7, wherein X' is oxygen, R' is trichloromethyl, and R” is chloro, namely, 2,2,2-trichloro-N- {2-[6-chloro(2H,4H,-benzole] 1,3-dioxin-8-yl) methoxy]phenyl} acetamide.

9. The compound of claim 7, wherein X' is oxygen, R' is methyl, and R’ is chloro, namely N-{ 2-[6-chloro(2H,4H,-benzol[e] 1,3-dioxin-8-yl)methoxy]phenyl} acetamide.

10. The compound of claim 7, wherein X1 is oxygen, Rl is dimethylpropyl, and R9 is chloro, namely, N- {2-[6-chloro(2H,4H,-benzo[e]1,3 -dioxin-8-yl)methoxy]phenyl} -2,2- dimethylpropanamide. 46 AMENDED SHEET

11. The compound of claim 1, wherein X is sulfur and Y is methylene.

12. The compound of claim 1 1, wherein R?, R’, RY, R>, R® and R" are hydrogen.

13. The compound of claim 12, wherein Rand R taken together with the carbon atoms to which they are attached form a 6 membered heterocyclyl.

14. The compound of claim 13, wherein heterocyclyl is optionally substituted 1,3 dioxane.

15. The compound of claim 14, wherein A is a covalent bond, R'is hydrogen, and R® is chloro, namely 2-[(6-chloro-2H,4H-benzo[e] 1,3-dioxin-8-yl)methylthio]phenylamine.

16. The compound of claim 14, wherein A is a covalent bond, R! is hydrogen, and R® is fluoro, namely 2-[(6-fluoro-2H,4H-benzol[e] 1 ,3-dioxin-8-yDmethylthio]phenylamine.

17. The compound of claim 14, wherein A is -C(X')and R'is optionally substituted alkyl.

18. The compound of claim 17, wherein X ! is oxygen, R'is methyl, and R’ is chloro, namely N- {2-[6-chloro(2H,4H,-benzole] 1,3-dioxin-8-yl)methylthio] phenyl} acetamide.

19. The compound of claim 17, wherein X' is oxygen, R'is dimethylpropyl, and Ris chloro, namely. N- {2-[6-chloro(2H,4H-benzo[€]1,3-dioxin-8-ylmethylthiolphenyl-2,2- dimethylpropanamide.

20. The compound of claim 17, wherein X'is oxygen, R!is trichloromethyl, and R’is chloro, namely 2,2,2-trichloro-N- {2-[6-chloro(2H,4H-benzo]e] 1,3-dioxin-8- yl)methylthio]phenyl} acetamide.

21. The compound of claim 1, wherein X is carbonyl and Y is -NH-. 47 AMENDED SHEET

22. The compound of claim 21, wherein A is a covalent bond and R! is hydrogen.

23. The compound of claim 22, wherein R% R®, R*, R’, R®, R’and R'° are hydrogen.

24. The compound of claim 22, wherein R® and R” taken together with the phenyl group to which they are attached form naphthyl-1-yl, namely 2 aminophenyl-N- napthylcarboxamide

25. The compound of claim 22, wherein R® and R” taken together with the phenyl group to which they are attached form 1,2,3,4-tetrahdronaphthyl-5-yl, namely 2(2 aminophenyl)-N-(5 16,7,8-tetrahydronapthyl)carboxamide.

26. The compound of claim 22, wherein R®and R” taken together with the phenyl group to which they are attached form 5-quinolyl, namely (2 aminopheny!)-N-(5- quinolyl)carboxamide.

27. The compound of claim 22, wherein R® and R’taken together with the phenyl group to which they are attached form 5-isoquinolyl, namely (2 aminophenyl)-N-(5- : isoquinolyl)carboxamide.

28. The compound of claim 21, wherein A is —C(X")-and R'is substituted alkyl.

29. The compound of claim 28, wherein R2, R®, R*, R°, R% R’, R%and R™® are hydrogen.

30. The compound of claim 29, wherein X' is oxygen and R' is trichloromethyl, . namely 2,2,2-trichloro-N-[2-[(N. -naphthylcarbamoyl)phenyljacetamide.

31. The compound of claim 29, wherein Ris 1,1,1,3,3,3-hexafluoro-2-phenylpropan- 2-ol namely 2 (2-aminopheny1)-N- {4-[2,2,-trifluoro-1 -hydroxy-1- (trifluoromethyl)ethyl]phenyl} carboxamide. 48 AMENDED SHEET

32. A compound of Formula I that elevates serum levels of HDL cholesterol for use in } treating a disease or condition in a mammal.

33. The compound of claim 32, wherein the disease state or condition is coronary artery disease or atherosclerosis.

34. A compound of Formula I for use in treating a disease or condition in a mammal related to low HDL cholesterol levels,

35. The compound of claim 34, wherein the disease state or condition is coronary artery disease or atherosclerosis.

36. A compound of Formula I for use in treating a disease or condition in a mammal that can be usefully treated with a compound that promotes cholesterol efflux from cells.

37. The compound of claim 36, wherein the disease state or condition is coronary artery disease or atherosclerosis,

38. A compound of Formula I and a compound that lowers LDL cholesterol for use in treating a condition related to coronary artery disease in a mammal that can be usefully treated with a combination of a compound that elevates serum levels of HDI. cholesterol and a compound that lowers LDL cholesterol.

39. The compound of claim 37, wherein the LDL cholesterol lowering compound is chosen from clofibrate, gemfibrozil, and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyrine, colestipol and probucol.

40. A compound of Formula I: 49 AMENDED SHEET

Ftd $ R X wee Ys 7 R® Re R? Formula I wherein: Ris hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; A is a covalent bond, C(X")-, or -C(X')-NH-, where X! is oxygen or sulfur, R%L R® R* and Rare independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halo, or optionally substituted cycloalkyl; X is oxygen, sulfur, -C(X")-, or -NH-; Y is optionally substituted lower alkylene when X is oxygen or sulfur; or Y is -NH- when X is -C(X")-; or Y is -C(X')- when X is -NH-; with the proviso that X and Y cannot both be -NH-; RS R, R® and R%are independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or R® and R, or R’ and RS, or Rand rR’, or R’and RC taken together with the carbon atoms to which they are attached form 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or an aromatic or non-aromatic carbocyclic moiety, all of which are optionally substituted by halo, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl.

41. The compound of claim 40, wherein X is oxygen and Y is methylene. 50 AMENDED SHEET

42. The compound of claim 41, wherein R?, R®, RY, R® ,R®and R'® are hydrogen.

43. The compound of claim 42, wherein R® and R taken together with the carbon atoms to which they are attached form a 6 membered heterocyclyl.

44. The compound of claim 43, wherein heterocyclyl is optionally substituted 1,3 dioxane.

45. The compound of claim 44, wherein A is a covalent bond, R! is hydrogen, and R’ is chloro, namely 2-[(6-chloro-2H,4H-benzo[e] 1,2-dioxin-8-yl)methoxy]- phenylamine.

46. The compound of claim 44, wherein A is -C(X')- and R! is optionally substituted alkyl.

47. The compound of claim 46, wherein X' is oxygen, R' is trichloromethyl, and R’ is chloro, namely, 2,2,2-trichloro-N- {2-[6-chloro(2H,4H,-benzo[e]1,3-dioxin-8- yl)methoxy]phenyl} acetamide.

48. The compound of claim 46, wherein X' is oxygen, R'is methyl, and Ris chloro, namely N-{2-[6-chloro(2H,4H,-benzo[e]1 ,3-dioxin-8-yl)methoxy]phenyl } acetamide.

49. The compound of claim 46, wherein X' is oxygen, R! is dimethylpropyl, and R’ is chloro, namely, N-{2-[6-chloro(2H,4H,-benzo[e] 1,3-dioxin-8-yl)methoxy]phenyl} - 2,2-dimethylpropanamide.

50. The compound of claim 40, wherein X is sulfur and Y is methylene.

51. The compound of claim 50, wherein R?, R®, R*, R®, R® and R'° are hydrogen.

52. The compound of claim 51, wherein R® and R taken together with the carbon 51 AMENDED SHEET atoms to which they are attached form a 6 membered heterocyclyl.

53. The compound of claim 52, wherein heterocyclyl is optionally substituted 1,3 dioxane.

54. The compound of claim 53, wherein A is a covalent bond, R' is hydrogen, and R’ is chloro, namely 2-[(6-chloro-2H,4H-benzo[e] 1,3-dioxin-8- ylmethylthio]phenylamine.

55. The compound of claim 54, wherein A is a covalent bond, R' is hydrogen, and R’ is fluoro, namely 2-[(6-fluoro-2H,4H-benzo[e]1,3-dioxin-8- yDmethylthio]phenylamine.

56. The compound of claim 53, wherein A is -C(X")and R'is optionally substituted alkyl.

57. The compound of claim 56, wherein X' is oxygen, R! is methyl, and R’ is chloro, namely N-{2- [6-chloro(2H,4H,-benzo[e] 1 »3-dioxin-8-yl)methylthio]phenyl} acetamide.

58. The compound of claim 56, wherein X' is oxygen, R' is dimethylpropyl, and R’ is chloro, namely. N- {2-[6-chloro(2H,4H-benzo[e]1,3-dioxin-8-yl)methylthio]phenyl- 2,2-dimethylpropanamide.

59. The compound of claim 56, wherein X' is oxygen, R' is trichloromethyl, and R® is chloro, namely 2,2,2-trichloro-N- {2-[6-chloro(2H,4H-benzo[e] 1,3-dioxin-8-yl) methylthio]phenyl} acetamide.

60. The compound of claim 40, wherein X is carbonyl and Y is -NH-.

61. The compound of claim 60, wherein A is a covalent bond and R! is hydrogen.

62. The compound of claim 61, wherein R% R}, RY RY ,R®, Rand R"° are hydrogen.

52 . AMENDED SHEET

63. The compound of claim 62, wherein R® and R” taken together with the phenyl group to which they are attached form naphthyl-1-yl, namely 2 aminophenyl-N- napthylcarboxamide.

64. The compound of claim 63, wherein R® and R taken together with the phenyl group to which they are attached form 1,2,3,4-tetrahdronaphthyl-5 -yl, namely 2 (2 aminophenyl)-N-(5,6,7,8-tetrahydronapthyl)carboxamide.

65. The compound of claim 63, wherein R® and R” taken together with the phenyl group to which they are attached form 5-quinolyl, namely (2 aminophenyl)-N-(5- quinolyl)carboxamide.

66. The compound of claim 63, wherein R® and R taken together with the phenyl group to which they are attached form 5-isoquinolyl, namely (2 aminophenyl)-N-(5- isoquinolyl)carboxamide.

67. The compound of claim 60, wherein A is —C(X')- and R! is substituted alkyl.

68. The compound of claim 67, wherein R?, R? , RY, rR’ RS, R’, R9 and R'° are hydrogen.

69. The compound of claim 68, wherein X' is oxygen and R' is trichloromethyl, namely 2,22 -trichloro-N-[2-[(N-naphthylcarbamoyl)phenyl]acetamide.

70. The compound of claim 69, wherein R®is 1,1,1,3,3,3-hexafluoro-2- phenylpropan-2-ol namely 2 (2-aminophenyl)-N- {4-[2,2,-trifluoro- 1 -hydroxy- 1- (trifluoromethyl)ethyl]phenyl} carboxamide.

71. A pharmaceutical composition comprising at least one pharmaceutically : acceptable excipient and a therapeutically effective amount of a compound of claim 40. 53 AMENDED SHEET

72. Use of a compound of Formula I:

fH NHAR' R —Y.

Y

R* RS - R’ Formula I

Wherein:

R'is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;

A is a covalent bond, C(X')-, or -C(X")-NH-, where X' is oxygen or sulfur,

R%R’, R*and R’ are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halo, or optionally substituted cycloalkyl;

X is oxygen, sulfur, -c(xh-, or -NH-;

Y is optionally substituted lower alkylene when X is oxygen or sulfur; or

Y is -NH- when X is -C(X")-; or

Y is -C(X')- when X is -NH-;

with the proviso that X and Y cannot both be -NH-;

R®, R’, R®, and R’ are independently hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; or

RS and R’, orR’ and RE, or R® and R’ or R? and R' taken together with the carbon atoms to which they are attached form 5 or 6 membered heterocyclyl, heteroaryl, cycloalkyl, or an aromatic or non-aromatic carbocyclic moiety, all of which are optionally substituted by halo, alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl;

in the manufacture of a medicament for the treatment of a disease state in a mammal that

54 AMENDED SHEET is alleviable by treatment with an agent capable of increasing ABCA-1 expression.

73. Use of claim 72, wherein X is oxygen and Y is methylene.

74. Use of claim 73, wherein R? R®, RY, R’, R®and Rare hydrogen.

75. Use of claim 74, wherein R® and R” taken together with the carbon atoms to which they are attached form a 6 membered heterocyclyl.

76. Use of claim 75, wherein heterocyclyl is optionally substituted 1,3 dioxane.

77. Use of claim 76, wherein A is a covalent bond, R! is hydrogen, and R’ is chloro, namely 2-[(6-chloro-2H,4H-benzo[e] 1,2-dioxin-8-yI)methoxy] -phenylamine.

78. Use of claim 76, wherein A is -C(X')- and R' is optionally substituted alkyl.

79. Use of claim 78, wherein X' is oxygen, R! is trichloromethyl, and R’ is chloro, namely, 2,2,2-trichloro-N-{2-[6-chloro(2H,4H,-benzo[e] 1 ,3-dioxin-8-yl) methoxy]phenyl}acetamide.

80. Use of claim 78, wherein X' is oxygen, R' is methyl, and R? is chloro, namely N-{2-[6-chloro(2H,4H,-benzo[e]1,3-dioxin-8-yl)methoxy]phenyl} acetamide.

81. Useof claim 78, wherein X1 is oxygen, R1 is dimethylpropyl, and R9 is chloro, namely, N-{2-[6-chloro(2H,4H,-benzo[e]1 ,3-dioxin-8-yl)methoxy]phenyl}-2,2- dimethylpropanamide. :

82. Use of claim 72, wherein X is sulfur and Y is methylene.

83. Use of claim 82, wherein R% R%, R*, R®, R® and R'’ are hydrogen.

84. Use of claim 83, wherein R® and R” taken together with the carbon atoms to ! 55 AMENDED SHEET which they are attached form a 6 membered heterocyclyl.

85. Use of claim 84, wherein heterocyclyl is optionally substituted 1,3 dioxane.

86. Use of claim 85, wherein A is a covalent bond, R'is hydrogen, and R’ is chloro, namely 2-[(6-chloro-2H,4H-benzo[e]1,3-dioxin-8-yl)methylthio]phenylamine.

87. Use of claim 85, wherein A is a covalent bond, R' is hydrogen, and R’is fluoro, namely 2-[(6-fluoro-2H,4H-benzo[e]1,3-dioxin-8-yI)methylthio]phenylamine.

88. Use of claim 85, wherein A is -C(X') and R! is optionally substituted alkyl.

89. Use of claim 88, wherein X ! is oxygen, R'is methyl, and R® is chloro, namely N- {2-[6-chloro(2H,4H,-benzo[e]1,3-dioxin-8-yl)methylthio]phenyl} acetamide.

90. Use of claim 88, wherein X' is oxygen, R'is dimethylpropyl, and R’ is chloro, namely. N-{2-[6-chloro(2H,4H-benzo[e] 1,3-dioxin-8-yl)methylthio]phenyl-2,2- dimethylpropanamide.

91. Use of claim 88, wherein X' is oxygen, R'is trichloromethyl, and R%s chloro, namely 2,2,2-trichloro-N- {2-{6-chloro(2H,4H-benzo[e] 1,3-dioxin-8- yl)methylthio]phenyl} acetamide.

92. Use of claim 72, wherein X is carbonyl and Y is -NH-.

93. Use of claim 92, wherein A is a covalent bond and R' is hydrogen.

94, Use of claim 93, wherein R?, R3 R* R’, Rr}, R’and R" are hydrogen.

95. Use of claim 93, wherein R® and R taken together with the phenyl group to which they are attached form naphthyi-1-yl, namely 2 aminophenyl-N- napthylcarboxamide. 56 AMENDED SHEET

96. Use of claim 93, wherein R® and R’ taken together with the phenyl group to which they are attached form 1,2,3,4-tetrahdronaphthyl-5-yl, namely 2(2 aminophenyl)- N-(5,6,7,8-tetrahydronapthyl)carboxamide.

97. Use of claim 93, wherein R®and R taken together with the phenyl group to which they are attached form 5-quinolyl, namely (2 aminophenyl)-N-(5- quinolyl)carboxamide.

98. Use of claim 93, wherein R® and R” taken together with the phenyl group to which they are attached form 5-isoquinolyl, namely (2 aminophenyl)-N-(5- isoquinolyl)carboxamide.

99. Use of claim 92, wherein A is —C(X')- and R! is substituted alkyl.

100. Use of claim 99, wherein R%, R3 LR R®, RS, R’,R°and R'® are hydrogen.

101. Use of claim 100, wherein X'is oxygen and R! is trichloromethyl, namely 2,2,2- trichloro-N-[2-[(N-naphthylcarbamoyl)phenyl]acetamide.

102. Use of claim 100, wherein R®is 1,1,1,3,3,3-hexafluoro-2-phenylpropan-2-ol namely 2 (2-aminophenyl)-N- {4-[2,2,-trifluoro-1-hydroxy-1- (trifluoromethyl)ethyl]phenyl} carboxamide.

103. Use of a compound of Formula I in the manufacture of a medicament for the treatment of a disease or condition in a mammal that can be usefully treated with a compound that elevates serum levels of HDL cholesterol.

104. Use of claim 103, wherein the disease state or condition is coronary artery disease or atherosclerosis.

105. Use of a compound of Formula I in the manufacture of a medicament for treating 57 AMENDED SHEET a disease or condition in a mammal related to low HDL cholesterol levels.

106. Use of claim 105, wherein the disease state or condition is coronary artery disease or atherosclerosis.

107. Use of a compound of Formula I in the manufacture of a medicament for treating a disease or condition in a mammal that can be usefully treated with a compound that promotes cholesterol efflux from cells.

108. Use of claim 107, wherein the disease state or condition is coronary artery disease or atherosclerosis.

109. Use of a compound of Formula I and a compound that lowers LDL cholesterol in the manufacture of a medicament for treating a condition related to coronary artery disease in a mammal that can be usefully treated with a combination of a compound that elevates serum levels of HDL cholesterol and a compound that lowers LDL cholesterol.

110. Use of claim 109, wherein the LDL cholesterol lowering compound is chosen from clofibrate, gemfibrozil, and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholestyrine, colestipol and probucol.

111. A compound of any of claims 1, 32, 34, 36, or 38, substantially as herein described and exemplified.

112. A compound of claim 40, substantially as herein described and exemplified.

113. A pharmaceutical composition of claim 71 substantially as herein described and exemplified.

114. Use of any of claims 72, 103, 105, 107 or 109, substantially as herein described and exemplified. 58 AMENDED SHEET