WO2003090732A1 - Lxr modulators for the treatment of cardiovascular diseases - Google Patents

Abstract

The present invention relates to methods for treatment of certain diseases or conditions mediated by liver X receptor (LXR) by the administration of a composition containing as an active ingredient a compound according to Formula I. In particular, the invention relates to methods for treatment of cardiovascular diseases and atherosclerosis through the administration of a compound which modulates LXR activity.

Description

LXR MODULATORS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES

FIELD OF THE INVENTION

The present invention relates to methods for treatment of certain diseases or conditions mediated by Liver X Receptor (LXR) by the administration of a composition containing as an active ingredient a compound according to Formula I. In particular, the invention relates to methods for treatment of cardiovascular diseases and atherosclerosis through the administration of a compound which modulates LXR activity.

BACKGROUND

Liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate the expression of cytochrome P450 7A (CYP7A1), and thus the metabolism of several important lipids, including cholesterol and bile acids. LXRs were first identified as orphan members of the nuclear receptor superfamily (Song et al., Proc. Natl. Acad. Sci. 191 :10809-10813 (1994). Willy et al., Genes Dev. 9:1033-1045 (1995)). The identification of a specific class of oxidized derivatives of cholesterol (oxysterol) as ligands for the LXRs, in combination with the description of an LXR response element in the promoter of the rat cholesterol 7α-hydroxylase genes, suggested that LXRs play an important role in the regulation of cholesterol homeostasis. Additional support for this role came from the analysis of LXRα-deficient mice (LXRα-/-), which uncovered the dysregulation of the CYP7A1 gene and several other important lipid-associated genes (Peet et al., Curr. Opin. Genet Dev. 8: 571-575 (1998)). Studies utilizing these animals confirmed the essential function of LXRα as a major sensor of dietary cholesterol and an activator of the bile acid synthetic pathway in mice. LXRα is expressed most highly in the liver and to a lesser extent in the kidney, small intestine, spleen and adrenal gland. On the contrary, LXRβ is ubiquitously expressed. Naturally occurring or synthetic oxysterols such as 22(R)- hydroxycholesterol, 24(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol are believed to be transcriptional activators of LXRα and β. These oxysterols exist at concentrations that activate LXRs in tissues (e.g. liver, brain and placenta) where both cholesterol metabolism and LXR expression are high. In human monocyte-derived macrophages by cholesterol loading, it was demonstrated a dose-dependent induction of ABCA1 and ABCG1 genes, suggesting that 27-hydroxycholesterol is an endogenous ligand for LXRs (Fu et al., J. Biol. Chem. 276:38378-38387(2001 )).

LXRs bind to the ATP binding cassette transporter-1 (ABCA1 ) gene promoter and increases expression of the gene to result in increased ABCA1 protein. ABCA1 is a membrane bound transport protein which is involved in the regulation of cholesterol efflux from extrahepatic cells onto nascent HDL particles. Humans with mutations in the gene ABCA1 have low levels of high density lipoprotein (HDL) and a concomitant increased risk of cardiovascular diseases such as atherosclerosis, myocardial infarction and ischemic stroke (Brooks-Wilson et al, Nat. Genet. 22: 336-345 (1999), Bodzioch et al., Nat. Genet. 22: 347-351 (1999); and Rust et al., Nat Genet. 22: 352-355 (1999)). LXRα and β agonists were demonstrated to increase ABCA1 gene expression which resulted in increased HDL cholesterol, and decreased absorption of cholesterol and thereby decreased the risk of cardiovascular diseases (Sparrow et al., J. Biol. Chem. 277:10021-10027 (2002).

LXRs signaling pathways play a central role in the control of macrophage cholesterol efflux through the coordinate regulation of ABCA1 and ABCG1 and surface constituent of plasma lipoprotein apolipoprotein E (apoE) gene expression. Recently, it was demonstrated that LXR/RXR heterodimers regulate apoE transcription directly, through interaction with a conserved LXR response element present in both ME.1 and ME.2. The ability of oxysterol and synthetic ligands to regulate apoE expression in adipose tissue and peritoneal macrophages is reduced in LXRα-/- or LXRβ-/- mice and abolished in double knockouts.

LXRs also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein-1c (SREBP-1c) gene (Tobin, et al., J. Biol. Chem. 277:10691-10697 (2002). In rodent liver and hepatoma cells, transcription of the SREBP-1c gene is stimulated by naturally occurring oxysterols, like 24(S),25-expoxycholesterol and 22(R)-hydroxycholesterol, that bind to LXRα and β. LXRs are also activated by T0901317, a synthetic nonsteroidal compound. The level of SREBP-1c mRNA declined dramatically when cultured rat hepatoma cells were treated with inhibitors of 3-hydroxy-3- methylglutaryl coenzyme reductase, which block the synthesis of endogenous LXR ligands. This inhibition was reversed when the cells were incubated with either T0901317 or mevalonate, the product of the reductase reaction. These data indicated that basal transcription of the SREBP-1c gene requires an endogenous sterol that activates LXRs (Laffitte et al., Proc. Natl. Acad. Sci. 98: 507-512 (2001 )).

Accordingly, compounds which function as LXR modulators would be useful in methods of increasing ABCA1 , SREBP-1c, and apoE expression, increasing HDL cholesterol and treating LXR mediated diseases or conditions such as hypercholesterolemia and cardiovascular diseases.

SUMMARY OF THE INVENTION The present invention related to compounds of the following general structure (I):

(0 their prodrugs and pharmaceutically acceptable salts, wherein Ri, R₂, A, m, X, Y, and Z are as defined below. Other aspects of this invention will become apparent as the description of this invention continues. Hence, the foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description of the invention that follows is not intended to be exhaustive or to limit the invention to the precise details disclosed. It has been chosen and described to best explain the details of the invention to others skilled in the art.

The present invention related to the compounds of the following general structure (I):

(I) wherein

R-i is independently chosen from halo, haloalkyl, hydroxy, thiol, substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substituted amino, CrC₆ alkyl and C-_t- C₆ alkoxy, and when R-i is hydroxy, C-i-Cβ alkoxy, thiol, substituted thiol, amino, substituted amino, or C C₆ alkyl, such radical may be combined with

R₂ to form a ring of 5-7 members when R-i is ortho to R₂;

R₂ is selected from NR₃C(S)NR₄R₅, NR₃C(=NR₃)NR₄R₅, NR₃C(=NCN)NR₄R₅,

NR₃C(=CHN0₂)NR₄R₅, NR₃P(0)R₄R₅, NR₃P(0)(OR₄)(OR₅), NR₃P(0)(OR₄)(NR₅), NR₃P(0)(NR₄)(NR₅), NR₃C(=NR₃)R₆, COR₆,

R₆C(OH)R₇, CR₈=NOR₄, CR₈=NR₃, CR₈=NNR₄R₅, SOR₇, S0₂R_7,

P(0)(OR₄)(OR₅), P(0)(R₄)(R₅), P(0)(OR₄)(OR₅), P(0)(NR₃)(OR₄),

P(0)(NR₄)(NR₅), a 3-7 membered ring containing from zero to three heteroatoms selected from O, N, or S, which may be substituted by Rg, R-io, R-_I-_{I ,} R-ι₂ or Rι₃, or may be combined with R-i to form a ring of 5-7 members when Ri is ortho to R₂;

R₃ is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R₄ or R₅; R is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R₅ or R₃;

R₅ is hydrogen, alkyl, aryl, or heterocyclyl, acyl or may form a ring of 5-7 members with R₃ or R₄; Rβ and R may be equal or different and are selected from hydrogen, alkyl, aryl, or heterocylcyl; R₈ is hydrogen, alkyl, aryl, heterocylcyl, amino or substituted amino; R₉, R1₀, R11 and Rι₂ may be equal or different and are selected from hydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid, ester, amide, halo, hydroxyl, amino, substituted amino, alkoxy, acyl, ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl; R-ι₃ is hydrogen, alkyl, aryl, heterocyclyl, acyl, ester, sulfonyl, ureido, or guanadinyl; A is O, S, or NR₃; m is from zero to four;

X is H, CF₂Z, or CF₃, or together with Y forms a double bond when A is O; Y is hydrogen, or together with X forms a double bond when A is O; Z is F, Br, CI, l or CF_3; their prodrugs and pharmaceutically acceptable salts. The enantiomers, diasteromers, or tautomers of the compound (I) are also encompassed in the present invention.

Preferably, the compounds of this invention have the following general structures (la and lb):

(la) (lb)

wherein R**, R₂, A, m, X, Y, and Z are as defined above. More preferred compounds are depicted in the following general structures (lc and Id):

(lc) (Id) wherein R₂ is as defined above and R-i is hydrogen, halo, hydroxyl, or cyano group. DEFINITIONS As used herein, "alkyl" means a cyclic, branched, or straight chain chemical group containing only carbon and hydrogen, such as methyl, pentyl, and adamantyl. Alkyl groups can either be unsubstituted or substituted with one or more substituents, e.g., halogen, alkoxy, acyloxy, amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl, heteroaryl, or other functionality that may be suitably blocked, if necessary for purposes of the invention, with a protecting group. Alkyl groups can be saturated or unsaturated (e.g., containing -C=C- or -C≡C- subunits), at one or several positions. Typically, alkyl groups will comprise 1 to 12 carbon atoms, preferably 1 to 10, and more preferably 1 to 8 carbon atoms or cyclic groups containing three to eight carbons. As used herein, "lower alkyl" means a subset of alkyl, and thus is a hydrocarbon substituent, which is linear, cyclic or branched. Preferred lower alkyls are of 1 to about 6 carbons, and may be branched or linear, and may include cyclic substituents, either as part or all of their structure. Examples of lower alkyl include butyl, propyl, isopropyl, ethyl, and methyl. Likewise, radicals using the terminology "lower" refer to radicals preferably with 1 to about 6 carbons in the alkyl portion of the radical.

As used herein, "amido" means a H-CON- or alkyl-CON-, aryl-CON- or heterocyclyl-CON group wherein the alkyl, aryl or heterocyclyl group is as herein described. As used herein, "aryl" means a substituted or unsubstituted aromatic radical having a single-ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can be optionally unsubstituted or substituted with amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and other substituents, and which may or may not include one or more heteroatoms. Preferred carbocyclic aryl is phenyl. The term "heteroaryl" is clearly contemplated in the term "aryl". Preferably where the term aryl represents a heterocycle, it is referred to as "heteroaryl", and has one or more heteroatom(s). Preferred are monocyclic heterocycles of 5 or 6 members. Hence preferred heteroaryl is a monovalent unsaturated aromatic group having a single ring and having at least one hetero atom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with amino, cyano, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, aryl, halo, mercapto, oxo (hence forming a carbonyl.) and other substituents. Examples of heteroaryl include thienyl, pyrridyl, furyl, oxazolyl, oxadiazolyl, pyrollyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl and others.

In this definition it is clearly contemplated that substitution on the aryl ring is within the scope of this invention. Where substitution occurs, the radical is called substituted aryl. Preferably one to three, more preferably one or two, and most preferably one substituent occur on the aryl ring. Preferred substitution patterns in five membered rings are substituted in the 2 position relative to the connection to the claimed molecule. Though many substituents will be useful, preferred substituents include those commonly found in aryl compounds, such as alkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkyl, mercapto and the like.

As used herein, "amide" includes both RNR'CO- (in the case of R = alkyl, alkaminocarbonyl-) and RCONR'- (in the case of R = alkyl, alkyl carbonylamino-). As used herein, the term "ester" includes both ROCO- (in the case of R = alkyl, alkoxycarbonyl-) and RCOO- (in the case of R = alkyl, alkylcarbonyloxy-). As used herein, "acyl" means an H-CO- or alkyl-CO-, aryl-CO- or heterocyclyl-CO- group wherein the alkyl, aryl or heterocyclcyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary alkyl acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl, butanoyl and palmitoyl.

As used herein, "halo" is a chloro, bromo, fluoro or iodo atom radical. Chloro, bromo and fluoro are preferred halides. The term "halo" also contemplates terms sometimes referred to as "halogen", or "halide".

As used herein, "haloalkyl" means a hydrocarbon substituent, which is linear or branched or cyclic alkyl, alkenyl or alkynyl substiuted with chloro, bromo, fluoro or iodo atom(s). Most preferred of these are fluoroalkyls, wherein one or more of the hydrogen atoms have been substituted by fluoro. Preferred haloalkyls are of 1 to about 5 carbons in length, More preferred haloalkyls are 1 to about 4 carbons, and most preferred are 1 to 3 carbons in length. The skilled artisan will recognize then that as used herein, "haloalkylene" means a diradical variant of haloalkyl, such diradicals may act as spacers between radicals, other atoms, or between the parent ring and another functional group. For example, the linker CHF-CHF is a haloakylene diradical.

As used herein, "heterocyclyl" means heterocyclic radicals, which are saturated or unsaturated. These may be substituted or unsubstituted, and are attached to other via any available valence, preferably any available carbon or nitrogen. More preferred heterocycles are of 5 or 6 members. In six membered non-aromatic monocyclic heterocycles, the heteroatom(s) are selected from one up to three of O, N or S, and wherein when the heterocycle is five membered and non-aromatic, preferably it has one or two heteroatoms selected from O, N, or S.

As used herein, "substituted amino" means an amino radical which is substituted by one or two alkyl, aryl, or heterocyclyl groups, wherein the alkyl, aryl or heterocyclyl are defined as above.

As used herein, "substituted thiol" means RS- group wherein R is an alkyl, an aryl, or a heterocyclyl group, wherein the alkyl, aryl or heterocyclyl are defined as above. As used herein, "sulfonyl" means an alkylS0₂, arylS0₂ or heterocyclyl-

S0₂ group wherein the alkyl, aryl or heterocyclyl are defined as above. As used herein, "sulfamido" means an alkyl-N-S(0)₂N-, aryl-NS(0)₂N- or heterocyclyl-NS(0)₂N- group wherein the alkyl, aryl or heterocyclcyl group is as herein described.

As used herein, "sulfonamido" means an alkyl-S(0)₂N-, aryl-S(0)₂N- or heterocyclyl- S(0)₂N- group wherein the alkyl, aryl or heterocyclcyl group is as herein described.

As used herein, "ureido" means an alkyl-NCON-, aryl-NCON- or heterocyclyl-NCON- group wherein the alkyl, aryl or heterocyclcyl group is as herein described A used herein, a "radical" may form a ring with another radical as described herein. When such radicals are combined, the skilled artisan will understand that there are no unsatisfied valences in such a case, but that specific substitutions, for example a bond for a hydrogen, is made. Hence certain radicals can be described as forming rings together. The skilled artisan will recognize that such rings can and are readily formed by routine chemical reactions, and it is within the purview of the skilled artisan to both envision such rings and the methods of their formations. Preferred are rings having from 3-7 members, more preferably 5 or 6 members. As used herein the term "ring" or "rings" when formed by the combination of two radicals refers to heterocyclic or carbocyclic radicals, and such radicals may be saturated, unsaturated, or aromatic. For example, preferred heterocyclic ring systems include heterocyclic rings, such as morpholinyl, piperdinyl, imidazolyl, pyrrolidinyl, and pyridinyl.

The skilled artisan will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be fairly represented by other chemical structures, even when kinetically, the artisan recognizes that such structures are only a very small portion of a sample of such compound(s). Such compounds are clearly contemplated within the scope of this invention, though such resonance forms or tautomers are not represented herein. For example,

the above substructures clearly represent the same radical and reference to either clearly contemplates the other. In addition, the following compounds may represent prodrugs when R can be removed by biological processes in situ:

Compounds and compositions herein also specifically contemplate pharmaceutically acceptable salts, whether cationic or anionic. A "pharmaceutically-acceptable salt" is an anionic salt formed at any acidic (e.g., carboxyl) group, or a cationic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 1 1 , 1987 (incorporated by reference herein). Preferred counter-ions of salts formable at acidic groups can include cations of salts, such as the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred salts formable at basic sites include anions such as the halides (such as chloride salts). Of course, the skilled artisan is aware that a great number and variation of salts may be used, and examples exist in the literature of either organic or inorganic salts useful in this manner.

It is also clearly contemplated that compounds of the invention can be provided as biohydrolyzable prodrugs, as they are understood in the art. "Prodrug", as used herein is any compound wherein when it is exposed to the biological processes in an organism, is hydrolyzed, metabolized, derivatized or the like, to yield an active substance having the desired activity. The skilled artisan will recognize that prodrugs may or may not have any activity as prodrugs. It is the intent that the prodrugs described herein have no deleterious effect on the subject to be treated when dosed in safe and effective amounts. These include for example, biohydrolyzable amides and esters. A "biohydrolyzable amide" is an amide compound which does not essentially interfere with the activity of the compound, or that is readily converted in vivo by a cell, tissue, or human, mammal, or animal subject to yield an active compound of the invention. A "biohydrolyzable ester" refers to an ester compound of the invention that does not interfere with the activity of these compounds or that is readily converted by an animal to yield an active formula (I) compound. Such biohydrolyzable prodrugs are understood by the skilled artisan and are embodied in regulatory guidelines.

Inasmuch as the compounds of the invention may contain optical centers, "optical isomer", "stereoisomer", "enantiomer," "diastereomer," as referred to herein have the standard art recognized meanings (cf. Hawleys Condensed Chemical Dictionary, 1 1th Ed.) and are included in the compounds claimed, whether as racemates, or their optical isomers, stereoisomers, enantiomers, diastereomers.

As used herein "cardiovascular diseases" include arrhthymia, atrial fibrillation, congestive heart failure, coronary artery disease, hypertension, myocardial infarction, stroke, ventricular fibrillation, among others, particularly cardiovascular ischemia such as angina pectoris and those conditions mediated by LXR.

COMPOSITIONS

The compositions of the present invention comprise: (a) a safe and therapeutically effective amount of a LXR activating compound (I), prodrug or pharmaceutical salt thereof; and (b) a pharmaceutically-acceptable carrier.

As discussed above, numerous diseases can be mediated by LXR related therapy. Thus, the compounds of this invention are useful in therapy with regard to conditions involving this LXR activity.

Accordingly, the compounds of this invention can therefore be formulated into pharmaceutical compositions for use in prophylaxis, management and treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

A "safe and therapeutically effective amount" of a compound of the present invention is an amount that is effective, to modulate LXR activity, in a subject, a tissue, or a cell, and preferably in an animal, more preferably in a mammal, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio, when used in the manner of this invention. The specific "safe and therapeutically effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the compound therein, and the dosage regimen desired for the composition.

In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated. Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, the preferred pharmaceutically- acceptable carrier is sterile, physiological saline, with blood-compatible suspending agent, the pH of which has been adjusted to about 7.4. In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition. The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. (The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day, and are expected to be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.) These compositions preferably contain from about 5 mg (milligrams), more preferably from about 10 mg to about 1000 mg, more preferably to about 500 mg, most preferably to about 300 mg, of the selected compound. The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, nasal, rectal, topical (including transdermal), ocular, intracereberally, intravenous, intramuscular, or parenteral administration. (The skilled artisan will appreciate that oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies.) Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981 ); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976). Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the compound. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591 , tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above. Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

Compositions of the subject invention may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

The compositions of this invention can also be administered topically to a subject, e.g., by the direct application or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1 %, and preferably from about 1 % to about 5%, of the compound. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the compound. The carrier may include pharmaceutically-acceptable emollient, emulsifiers, thickening agents, solvents and the like. METHODS OF ADMINISTRATION

The compounds and compositions of this invention can be administered topically or systemically. Systemic application includes any method of introducing compound into the tissues of the body, e.g., intra-articular, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual administration, inhalation, rectal, or oral administration. The compounds of the present invention are preferably administered orally.

The specific dosage of the compound to be administered, as well as the duration of treatment is to be individualised by the treating clinicians. Typically, for a human adult (weighing approximately 70 kilograms), from about 5 mg, preferably from about 10 mg to about 3000 mg, more preferably to about 1000 mg, more preferably to about 300 mg, of the selected compound is administered per day. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors listed above. In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication. For example, in the treatment of cardiovascular diseases, it is clearly contemplated that the invention may be used in conjunction with beta-blockers, calcium antagonists, ACE inhibitors, diuretics, angiotensin receptor inhibitors, or known cardiovascular drugs or therapies. Hence, in this example, novel compounds or compositions of this invention are useful when dosed together with another active and can be combined in a single dosage form or composition.

The compositions can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

PREPARATION OF COMPOUNDS OF THE INVENTION

The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the claimed compounds.

It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry and the like.

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 2^nd Ed., John Wiley & Sons (1991 ).

The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure.

Scheme 1

VII VI

As shown in Scheme 1 , aniline derivative II, which either is commercially available or prepared easily via literature procedure, was converted into its corresponding N-substituted phenylhexafluoroisopropanol aniline derivatives III. The latter were transformed into the corresponding urea IV, which is subsequently converted into the targeted molecule thioureas (V). Thioureas V could be also prepared directly from compound III via thiocarbamoyl chloride intermediate followed by the reaction with primary or secondary amines. When treated with cyanide or phosphoryl chloride, the aniline compound III gave the corresponding guanidines or phosphonamides respectively, under reaction conditions depicted in the above scheme.

Scheme 2

XI XII XIII

Similarly, reaction of Λ/-phenylaminoaldehyde diethyl acetal (VIII), which was prepared from Λ/-phenylacetaldehyde diethyl acetal according to Scheme 1 , was reacted wtih thioisocyantes to afford its corresponding thiourea acetals intermediate (IX). Cyclization of the intermediate into thioimidazolone (X) was achieved following the conventional Λ/-acyliminium cyclization reaction under acidic condition. On the other hand, aminoalcohol derivatives (XI) were converted into substituted thioimidazolones (XIII) through reaction with thioisocyantes followed by oxidation (e.g. Dess-Martin oxidation) and acid treatment (Scheme 2). Scheme 3

XVIII XVII

Non-cyclic or cyclic derivatives including ketones (XV), oximes (XVI), hydrazone/carbazide (XX), alcohols (XIX) and isoxazoles/isoxazolines/isoxazolidines (XVII, XVIII), were prepared via a common ketone/aldehyde intermediate (XV), which was prepared from the

Weinreb amide XIV. Thus, reaction of ketones or aldehydes (XV) with hydroxylamine or alkoxylamine afforded the corresponding oximes (XVI).

Subsequent 1 ,3-dipolar reaction of aldoxime (XVI, R₃ = R₄ =H) with olefines or acetylenes gave rise to Δ2-isoxazoline or isoxazole derivatives (XVII). Similarly, aldehyde intermediate (XV) was converted into isoxazolidine (XVIII) upon treatment with Λ/-substituted hydroxylamine and dienophiles (olefines or acetylenes). On the other hand, treatment of intermediate (XV) with organdithium or Grignard reagents resulted in a secondary or tertiary alcohol derivative (XIX). Or, the ketone intermediate XV could be converted into hydrazones (XX) via the reaction with hydrazines.

Scheme 4

Scheme 4 summarizes the preparation of isoxazole related compounds. Thus, 2-hydroxyhexafluoroisoproyl-bromobenzene (XXI) was converted into the corresponding boronic acid (ester), which underwent Suzuki coupling with halogenated isoxazole compounds to provide XXIII or XXIV. Further modification led to compound XXV to XXIX as shown in Scheme 4. Scheme 5

XXX XXXI

XXXII

R₄R₅NCOCI R₅S0₂CI

R₄COCI

XXXIII XXXIV XXXV

A = O or NR₁₃

An alternative synthetic route for preparing this type of isoxazole and pyrazole compounds are shown in Scheme 5. Tolyl-hexafluoro-2- hydroxyisopropanol XXX was first monobrominated to the corresponding benzyl bromide intermediate which was subsequently reacted with potassium cyanide to give rise to the benzyl nitrile compound XXXI. Reaction of the nitrile compound with ester in the presense of strong bases such as LDA to furnish the b- ketonitrile which upon treatment with hydroxylamine or substituted hydrazine gave the aminoisoxazole or aminopyrazole (XXXII) in good yields. Manipulation of the amino group led to the desired derivatives such as amides, ureas, sulfonamides and thioureas.

XXXVIII XXXIX

The corresponding isoxazoline derivatives were prepared according to the procedure described in Scheme 6. Buchwald-Hartwig reaction of bromobenzene derivative XXI with ketone in the presence of appropriate Pd catalyst and ligands provided the ketone intermediate XXXVI. Alkylation of the ketone product with halides or equivalent furnished the alkylated product XXXVII. The later could also be prepared directly from the starting material XXI using Buchwald-Hartwig conditions. On the other hand, aldol reaction of the ketone with aldehyde would provide the intermediate XXXVIII, which upon treatment with hydroxylamine gave the desired isoxazoline products XXXIX.

Scheme 7

XIII XXXIX XXXX Scheme 7 described a synthesis of imidazole compounds. Ugi four component reaction of benzoic acid derivative XIII with isocyanide, amine and α- ketoaldehyde gave rise to a β-ketoamide intermediate XXXIX. The later underwent cyclization to give the desired imidazole compounds XXXX in the presence of ammonium acetate.

Scheme 8

XXXXIV

dation

Scheme 8 described an example for preparation of opening chain compounds such as XXXXII or pyrazole/pyrizoline compounds. Thus the aldehyde XV was converted into halohydrazone such as chlorohydrazone XXXXI, which reacted with amine to give the open chain product XXXXII or to give pyrazoline compound XXXXII when it reacted with an olefin. The pyrazoline compounds could be oxidized into their corresponding pyrazoles XXXXV under oxidative conditions.

Scheme 9

XXXXVII

Phosphorus-containing compounds such as XXXXVI and XXXXVII were prepared from the brominated precursor XXI. Coupling of bromobenzene derivative with phosphite in the presence of NiCI₂ gave rise to the phosphorate derivative XXXXVI. In the presence of palladium catalyst, the coupling of bromobenzene derivative with phosphonate provided the phosphorus compound XXXXVII.

22.. 5500%% aaqq.. HHCCII

XXXXVIII 3. Fe/ HOAc XXXXIX

FF₃ ^NaH' ^THF

LI

Lll LIN

As shown in Scheme 10, trifluormethylketone derivatives were prepared from a commercially available nitrobenzoate XXXXVIII. Reaction of the nitrobenzoate with trifluoromethyl trimethyl silane provided the desired trifluormethyl ketone functionality. After reduction of the nitro group, the resulting aniline XXXXIX was converted into amide derivative L under the conventional conditions. Alkylation of anilide L was conducted in an indirect fashion. Thus, trifluoromethyl ketone functionality in L was reduced into its corresponding trifluoromethyl alcohol Lll with NaBH₄. Subsequent alkylation with R₄X in the presence of NaH afforded the alkylated anilide Lll. Oxidation of the alcohol intermediate gave the desired trifluoromethyl ketone product Llll.

BIOLOGICAL ACTIVITY In Vitro LXRa and β activity assay:

The assay for gene expression (apoE, ABCA1 , and SREBP-1c) are performed following the literature procedures (Sparrow et al., J. Biol. Chem. 277:10021- 10027(2002); Laffitte et al., Proc. Natl. Acad. Sci., 98:507-512(2001 ); Repa et al., Genes Dev. 14:2819-2830(2000)). LXR modulator refers to compounds which achieve at least 50% activation or inhibition of LXR relative to 24(S)25- epoxycholesterol, the positive control, or which stimulate the expression of the responsive genes, such as ABCA1 genes, in a cell system.

To determine the effectiveness of representative compounds of the present invention as LXR modulators, THP-1 cells were maintained in suspension for passage and growth in PRMI 1640 (Invitrogen) containing 10% FBS (Irvine Scientific, Santa Ana, CA), 100 units/ml penicillin/1 OOug/ml streptomycin (Irvine Scientific), 1 mM sodium pyruvate (Invitrogen) and 55 uM β- mercaptoethanol (Sigma). Passaging was performed every 3-4 days at a 1 :4 dilution. For experiments, 1X106 cells/well were plated in 6-well plates in media supplemented with 100 ng/ml phorbol 12-myristate-13-acetate (PMA, Sigma) to induce differentiation. Cells were maintained in this media for 5-days prior to treatment with LXR agonists. Generally, the culture media was replaced with media containing vehicle (DMSO or ethanol) or 1-10 uM drugs at 0 h. THP-1 cells were dosed a second time at 24 h and then harvested for RNA isolation 24 h later.

Total RNA samples were diluted to 100 ug/ml and treated with 40 units/ml RNA-free Dnase I (Ambion, Austin, TX) for 30 min at 37°C followed by inactivation at 75oC for 5 min. Samples were quantitated by spectrophotometry or with the RiboGreen assay (Molecular Probes, Eugee, OR) and diluted to a concentration of 10ng/ul. Samples were assayed in duplicate 25-ul reactions using 35ng of RNA/reaction with PerkinElmer chemistry on an ABI Prism 7700 (Applied Biosystems). Gene specific primers were used at 7.5 or 22.5 pmd/reaction and optimized for each gene examined, and the gene-specific fluorescently tagged probe was used at 5 pmol/reaction. In this system, the probe is degraded by Taq polymerase during the amplification phase, releasing the fluorescent tag from its quenched state; amplification data is expressed as the number of PCR cycles required to elevate the fluorescence signal beyond a threshold intensity level. Fold induction values were calculated by subtracting the mean threshold cycle number for each treatment group from the mean threshold cycle number of the vehicle group and raising 2 to the power of this difference. As shown in Table A, LXR modulating activity was determined from the magnitude of gene expression induction as compared to a control (DMSO). Compounds showing significant induction of the ABCA1 gene in a THP-1 cell system, as compared to the control (DMSO), demonstrates that the compounds of the present invention are useful LXR modulators for increasing ABCA1 expression, increasing HDL cholesterol and treating LXR mediated diseases or conditions such as hypercholesterolemia and cardiovascular diseases.

Table A. Gene Expression Induction

EXAMPLES To further illustrate this invention, the following examples are included.

The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.

¹H nuclear magnetic resonance spectra (NMR) is measured in CDCI₃ or other indicated solvents on a Varian NMR spectrometer (Unity Plus 400, 400 MHz for ¹H) unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak multiplicities are denoted as follows, s, singlet; d, doublet; t, triplet; m, multiplet.

The following abbreviations have the indicated meanings:

Ac = acetyl Allyl = CH₂=CH₂-CH₂-

Bn = benzyl

CDI = carbonyl diimidazole

CH₂CI₂ = dichloromethane

DIBAL= diisobutylaluminum hydride DMAP = 4-(dimethylamino)-pyridine

DMF= N,N-dimethylformamide

DMSO = dimethylsulfoxide

EDCI or EDAC = 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloric acid ESIMS = electron spray mass spectrometry

Et₃N = triethylamine

EtOAc = ethyl acetate

HMTA = hexamethylenetetramine

Lawesson's reagent = 2,4-bis(4-methoxyphenyl)-1 ,3,2,4- dithiadiphosphetane-2,4-disulfide

LDA = lithium diisopropylamide

LHMDS = lithium bis(trimethylsilyl)amide

MgS0₄ = magnesium sulfate

NaHC0₃ = sodium bicarbonate Na₂C0₃ = sodium carbonate

NaH = sodium hydride

NBS = N-bromosuccinimide

NCS = N-chlorosuccinimide

NH CI= ammonium chloride Ph = phenyl

Py, or Pyr = pyridinyl r.t.= room temperature

TFA = trifluoroacetic acid THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = trimethylsilyl

Tf₂0 = triflic anhydride Vinyl= CH₂=CH-

Alkyl group abbreviations

Me = methyl

Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl t-Bu = tertiary butyl s-Bu = secondary butyl c-Hex = cyclohexyl

Example 1

Preparation of morpholine-4-carbothioic acid [4-(2,2,2-trifluoro-1-hydroxy-1- thfluoromethyl-ethyl)-phenyl]-(4-trifluoromethyl-benzyl)-amide

Step l

To the solution of 2-(4-Amino-phenyl)-1 ,1 ,1 ,3,3,3-hexafluoro-propan-2-ol (200 mg, 0.77 mmol) and 4-morpholin carbonyl chloride (180 μL, 1.54 mmol) in pyridine (2 mL), is added DMAP (20 mg) at room temperature. After being heated at 90°C for 2 hrs, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with saturated CuS0 solution, 0.1 N HCI solution, saturated NaHC0₃ solution and brine, then dried over anhydrous Na₂S0 . The solvent is removed under reduced pressure and the residue is purified by preparative TLC (Hexane:EtOAc, 2:1 ) to afford the urea intermediate as white solid (120 mg, 42%). ¹H NMR δ 3.45 (t, 4H), 3.74 (t, 4H), 4.92 (b, 1H), 6.46 (s, 2H), 7.36 (d, 2H), 7.61 (d, 2H); ESIMS: m/z 370.8 (M+H).

Step 2

To the solution of the urea intermediate (185 mg, 0.5 mmol) in DMF (5 mL), is added sodium hydride (100 mg, 2.5 mmol) at room temperature. The suspension is stirred for an additional 10 mins before being heated at 90°C for 2 hrs. The reaction mixture is diluted with ethyl acetate. The organic phase is washed with water and dried over anhydrous Na₂S0 . The solvent is removed under reduced pressure and the residue is purified by preparative TLC (CH₂CI₂:MeCN, 10:1 ) to afford the alkylated intermediate as yellow oil (120 mg, 45%). ¹H NMR 53.21 (t, 4H), 3.51 (t, 4H), 4.91 (s, 2H), 5.12 (b, 1 H), 7.11 (d, 2H), 7.39 (d, 2H), 7.55 (d, 2H), 7,64 (d, 2H); ESIMS: m/z 528.8 (M-H).

Step 3

The alkylated intermediate (110 mg, 0.207 mmol) and Lawesson's reagent (320 mg, 0.832 mmol) are mixed in toluene (3 mL) and the reaction mixture is heated at 120 °C for 6 hrs. The organic solvent is removed under reduced pressure and the residue is purified by preparative TLC (CH₂CI₂:MeCN, 20:1 ) to afford the title compound as white foam (24 mg, 21%). ¹H NMR 53.52 (t, 4H), 3.66 (t, 4H), 4.94 (b, 1 H), 5.48 (s, 2H), 7.09 (d, 2H), 7.46 (d, 2H), 7.58 (d, 2H), 7,68 (d, 2H); ESIMS: m/z 544.5 (M-H).

Example 2

Preparation of N-(4-cyanobutyl)-N-{4-[2,2,2-thfluoro-1 -hydroxy-1 -(trifluoromethyl) ethyl] phenyl}morpholine-4-carbothioamide

Step l

To the solution of 2-(4-Amino-phenyl)-1 ,1 ,1 ,3,3,3-hexafluoro-propan-2-ol (200 mg, 0.77 mmol) and 4-morpholin carbonyl chloride (180 μL, 1.54 mmol) in pyridine (2 mL), is added DMAP (20 mg) at room temperature. After being heated at 90°C for 2 hrs, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with saturated CuS0₄ solution, 0.1 N HCI solution, saturated NaHC0₃ solution and brine, then dried over anhydrous Na₂S0₄. The solvent is removed under reduced pressure and the residue is purified by preparative TLC (Hexane:EtOAc, 2:1 ) to afford the urea intermediate as white solid (120 mg, 42%). ¹H NMR 5 3.45 (t, 4H), 3.74 (t, 4H), 4.92 (b, 1H), 6.46 (s, 2H), 7.36 (d, 2H), 7.61 (d, 2H); ESIMS: m/z 370.8 (M+H).

Step 2

To the solution of the urea intermediate (110 mg, 0.3 mmol) in DMF (2 mL), is added sodium hydride (36 mg, 3 mmol) at room temperature. The suspension is stirred for an additional 10 mins before 5-bromovaleronitrile (42 μL, 0.4 mmol) was added. After being heated at 90°C for 2 hrs, the reaction mixture is diluted with ethyl acetate. The organic phase is washed with water and dried over anhydrous Na₂S0₄. The solvent is removed under reduced pressure and the residue is purified by preparative TLC (CH₂CI :MeCN, 10:1 ) to afford the alkylated intermediate as yellow oil (34 mg, 25%). ¹H NMR 1.65 (m, 4H), 2.31 (t, 2H), 3.10 (t, 4H), 3.40 (t, 4H), 3.63 (t, 2H), 4.98 (s, 1 H), 5.12 (b, 1 H), 7.09 (d, 2H), 7.65 (d, 2H); ESIMS: m/z 450.8 (M-H).

Step 3

The alkylated intermediate (30 mg, 0.066 mmol) and Lawesson's reagent (107 mg, 0.266 mmol) are mixed in toluene (2 mL) and the reaction mixture is heated at 120 °C for 6 hrs. The organic solvent is removed under reduced pressure and the residue is purified by preparative TLC (CH₂CI₂:MeCN, 20:1 ) to afford the title compound as white foam (21 mg, 68%). ¹H NMR 51.73 (m, 2H), 1.86 (m, 2H), 2.4(t, 2H), 3.48 (t, 4H), 3.56 (t, 4H), 4.14(t, 2H), 4.23 (b, 1 H), 7.11 (d, 2H), 7.72 (d, 2H); ESIMS: m/z 467.9 (M-H). Example 3

Preparation of 1 -butyl-3,3-dimethyl-1 -[4-(2,2,2-trifluoro-1 -hydroxy-1 ^■ trifluoromethyl-ethyl)-phenyl]-thiourea

2-(4-Butylamino-phenyl)-1 ,1 ,1 ,3,3,3-hexafluoro-propan-2-ol and dimethylthio- carbamoyl chloride are mixed together in a sealed vial and heated at 150°C for 10 min in a microwave. The reaction mixture is dissolved in dichloromethane and purified over preparative TLC (Acetonitrile: CH₂CI₂= 2:98) to give the title compound. ¹HNMR (CD₃OD) 5 0.95(t, 3H), 1.38(m, 2H), 1.65(m, 2H), 2.99 (s, 6H), 4.05(t, 2H), 4.90(s, 1 H), 7.04(d, 2H), and 7.68(d, 2H); ESIMS m/z 401 (M-H).

Example 4

Preparation of butyl {4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]phenyl} amino) (diethylamino)methaniminium chloride

Aluminum chloride (81 mg, 0.603 mmol) is added to chlorobenzene (5 mL) containing diethylcyanamide (75 μL). The reaction mixture is stirred at r.t.under argon for 5 min before adding Λ/-butyl-4[2,2,2-trifluoro-1 -hydroxy-1 - (trifluoromethyl) ethyljbenzenaminium chloride (200 mg; 0.57 mmol). The light yellow solution is heated at 140°C for 3 days. The reaction mixture is evaporated and then directly purified by preparative TLC (MeOH:CHCI₃ 15:85) to afford the title compound as colorless solid (120 mg, 46.9%). m.p. 217.1-219.2°C (dec). ¹H NMR 50.84 (m, 9H), 1.17 (m, 2H), 1.55 (m, 2H), 3.17 (m, 4H), 3.71 (t, 2H), 7.03 (d, 2H), 7.68 (d, 2H); ESIMS: m/z 414 (M+H).

Example 5

Table 1. The following compounds are prepared in accordance with the procedure described as in the above examples

Example 6

Preparation of 1 -(4-{2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl)phenyl}-butan-1 - one

Step l

A few drops of DMF are added to a solution of benzoic acid (5 g, 17.4 mmol) and oxalyl chloride (10 mL, 20 mmol) in dichlormethane at 0°C. The reaction mixture is stirred at room temperature for 14 hours. The solvents are removed under reduced pressure to afford the acyl chloride.

Step 2 The acyl chloride obtained above in acetone (25 mL) is added to a solution of Λ/,0-dimethyl hydroxyamine ( 20 mmol) in saturated Na₂C0₃ (25 mL) at room temperature. The reaction mixture is stirred at the temperature for 16 hours and acidified with concentrated HCI. The organic solvent is removed under reduced pressure and the aqueous layer is extracted with EtOAc. The combined organic extract is washed with 1 N HCI, saturated NaHC0₃ and brine and dried over MgS0₄. After removal the solvent, the Λ/-methoxymethyl amide (Weinreb amide) is obtained in pure form (5.8 g).

Step 3 n-Propylmagnesium bromide (3 mL) is added to a solution of the Weinreb amide intermediate obtained above (662 mg, 2 mmol) in THF (6 mL) at 0°C under an argon atmosphere. The reaction mixture is stirred at 0°C for 30 minutes and then at the room temperature for 4 hours. The reaction mixture is poured into ice cold 1 N HCI and extracted with EtOAc. The combined organic solvent is washed with saturated NaHC0₃, brine and dried over MgS0₄. The solvent is removed under reduced pressure to afford the title compound (620.7 mg). ¹H NMR 51.00 (t, 3H), 1.78 (qt, 2H), 2.95 (t, 2H), 7.80 (d, 2H), 8.00 (d, 2H); ESIMS: tπ/z 313 (M-H).

Example 7 Preparation of 1-{4-[2,2,2-trifluoro-1 -hydroxy-1 -

(trifluoromethyl)ethyl]phenyl}butan-1 -one oxime

1-(4-{2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl)phenyl}-butan-1 -one (47 mg; cf. Example 6) and hydroxyamine (52 mg) are mixed in EtOH (2 mL). The mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is purified by preparative TLC to afford the title compound (20.5 mg). ¹H NMR (CD₃OD) 50.98 (t, 3H), 1.46 (qt, 2H), 2.78 (t, 2H), 7.70 (m, 4H); ESIMS: m/z 330 (M+H).

Example 8

Table 2. The following ketone and oxime compounds are prepared in accordance with the procedure as described in the above examples.

Example 9

Preparation of 1 ,1 ,1 ,3,3,3-hexafluoro-2-(4-{1-[(2-furylmethyl)amino]butyl}phenyl) propan-2-ol

1 -(4-{2,2,2-Trifluoro-1 -hydroxy-1 -trifluoromethyl)phenyl}-butan-1 -one (237 mg, 0.75 mmol, cf. Example 6) and furfuryl amine (0.08 mL) in MeOH (3 mL) are treated with solid NaBH₃CN (94 mg, 1.5 mmol) followed by HOAc (0.1 mL) at room temperature. The reaction mixture is stirred overnight. The solvent is removed and the residue is re-dissolved in EtOAc. The organic layer is washed with 1 N HCI, saturated NaHC0₃ and brine and dried over MgS0₄. The desired product (33.7 mg) is obtained after purification by preparative TLC (acetonithle:CH₂CI₂, 3:97). ¹H NMR 50.80 (t, 3H), 1.20 (m, 2H), 1.71 (m. 2H), 3.60 (d, 2H), 3.62 (m, 1 H), 6.08(d, 1 H), 6.30 (d, 1 H), 7.34 (s, H), 7.41 (d, 2H), 7.70 (d, 2H); ESIMS: m/z 396 (M+H).

Example 10

Preparation of methyl-3-{4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl )ethyl] phenyl}-4,5-dihydroisoxazole-5-carboxylate

Step l

DIBAL (12 mL, 1 M in Toluene) is added dropwise to a solution of the Weinreb amide (1.66 g, 5 mmol, Example 6, Step 2) in THF (15 mL) at -78°C under argon atmosphere. The reaction mixture is stirred at the temperature for 2 hours. The reaction mixture is poured into 1 N HCI and extracted with EtOAc three times. The combined organic solvent is washed with saturated NaHC0₃, brine and dried over MgS0₄. The organic solvent is removed under reduced pressure to afford the benzaldehyde intermediate as colorless solid (1.27 g).

Step 2

The benzaldehyde intermediate (1.0 g) and hydroxyamine hydrochloric acid (1.27 g) are mixed in MeOH (8 mL). The reaction mixture is stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc. The combined organic solvent is washed with brine and dried MgS0 . Removal of solvent affords the oxime intermediate (1.1 g).

Step 3

NBS (208 mg) is added to a solution of oxime intermediate (225 mg) obtained above in DMF (1 mL) at room temperature. After stirring for 1 hour, methyl acrylate (0.14 mL) is added followed by Et₃N (0.22 mL). The reaction mixture is stirred for 12 hours and diluted with EtOAc. The organic layer is washed with 1 N HCI, saturated NaHC0₃, brine and dried over MgS0 . The residue after removal of the solvent is purified by preparative TLC (CH₂CI₂:MECN, 95:5) to afford the title compound (119 mg). ¹H NMR 53.62 (dd, 2H), 3.80 (s, 3H), 4.48 (bs, 1 H), 5.20 (dd, 1 H), 7.75 (m, 4H); ESIMS: m/z 370 (M-H).

Example 11

Preparation of 3-{4-[2,2,2-Trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]phenyl}-4, 5- dihydro-isoxazole-5-carboxylic acid

To a solution of methyl ester (90 mg, 0.24 mmol) prepared in the above example in methanol was added NaOH aq. (1.0 M, 0.2 ml) at room temperature. The mixture was then heated reflux for 3 hrs and poured into water. The solution was extracted with ethyl acetate and the organic layer was washed with brine and dried over MgS04. The solvent was evaporated off and the residue was subjected to preparative TLC (AcOEt : methanol=10:1 ) to give the title compound (55 mg, 63%). ¹H NMR 5 3.51 (dd, 1 H), 3.64 (dd, 1 H), 5.00 (dd, 1 H), 7.98 (s, 4H).

Example 12 Preparation of 1 ,1-dimethylethyl Λ/-[(3-{4-[2,2,2-trifluoro-1 -hydroxy-1 - (trifluoromethyl) ethyl] phenyl}-4,5-dihydroisoxazol-5-yl)carbonyl]-beta-alaninate

To a solution of the acid (18 mg, 0.05 mmol) in DMF (1 ml) prepared in the above example were added H-beta-Ala-OtBu HCI salt (11 mg, 0.75 mmol), BOP (44 mg, 0.1 mmol) and Λ/-methyl morpholine (20 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 12 hrs and then, water was added. The solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over MgS04. The solvent was evaporated off and the residue was subjected to preparative TLC (Hexane:AcOEt=2:1 ) to give the title compound (15 mg, 61%). ¹H NMR 5 1.39 (s, 9H), 2.45 (m, 2H), 3.35-3.51 (m, 2H), 3.60 (dd, 1 H), 3.75 (dd, 1 H), 5.15 (dd, 1 H), 7.80 (s, 4H); ESIMS: m/z 483 (M-H).

Example 13

Preparation of ethyl 5-methyl-3-{4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl) ethyl] phenyl}isoxazole-4-carboxylate

To a solution of oxime intermediate (50 mg, 0.17 mmol, cf. Example 10, Step 2) in DMF (1.5 ml) was added NBS (46 mg, 0.26 mmol) at 0 C and the mixture was stirred for 3 hrs. To the solution were added ethyl acetoacetate (34 mg, 0.26 mmol) and sodium ethoxide ethanol solution (80 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred for 12hrs and diluted with ethyl acetate. The organic layer was washed with water and brine and dried over MgS04. The solvent was evaporated off and the residue was purified by preparative TLC (CHCI₃:MeOH=50:1 ) to give the title compound ( 18 mg, 26%). ¹H NMR 5 1.09 (t, 3H), 2.75 (s, 3H), 3.75 (b, 1 H), 4.21 (q, 2H), 7.70 (d, 2H), 7.79 (d, 2H); ESIMS: m/z 396 (M-H).

Example 14

Table 3. The following compounds are prepared in accordance with the procedure described in the above examples.

Example 15

Preparation of 3-{4-[2,2,2-trifluoro-1 -hydroxy-1 -

(trifluoromethyl)ethyl]phenyl}heptan-3-ol

Propylmagnesium bromide (1 mL) is added to the solution of 1-(4-{2,2,2-trifluoro- 1 -hydroxy-1 -trifluoromethyl)phenyl}-butan-1 -one (170 mg, Example 6) in THF (2 mL) at 0°C under argon atmosphere. The reaction mixture is stirred at room temperature for 12 hours and poured into ice cold 1 N HCI and extracted with EtOAc three times. The combined organic solvent is washed with saturated NaHC0₃, brine and dried over MgS0₄. The residue after removal of the solvent is purified by preparative TLC to afford the title compound (99.4mg). ¹H NMR 50.82 (t, 6H), 1.02 (m, 2H), 1.25 (m, 2H), 1.80 (m, 4H), 3.41 (s, 1 H), 7.42 (d, 2H), 7.62 (d, 2H). ESIMS: m/z 357 (M-H).

Example 16

Preparation of 2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-1 ,1 ,1 ,3,3,3-hexafluoro- propan-2-ol

Step l 2-(4-bromophenyl)-1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol (723 mg, 2.24 mmol), bis(pinacolato) diborane (625 mg, 2.46 mmol) and KOAc (659 mg, 6.72 mmol) are mixed in DMF (15 mL). The suspension is deoxygenated by nitrogen flow before Pd(dppf)CI₂ (60 mg) is added. After been heated at 90°C for 30 mins under nitrogen atmosphere, the reaction mixture is partitioned between EtOAc and water. The organic layer is dried over Na₂S0₄ and condensed under reduced pressure. The residue is subjected to flash column chromatography (Hexane:EtOAc, 5:1 ) to afford the arylboronate intermediate as white solid (650 mg, 78%). ¹H NMR (CDCI₃) 5 1.33 (s, 1 H), 3.88 (s, 1 H), 7.70 (d, 2H), 7.87 (d, 2H); ESIMS: m/z 369.9 (M).

Step 2

The arylboronate intermediate (50 mg, 0.135 mmol), 4-bromo-3,5-dimethyl isoxazole (33 mg, 0.189 mmol) and saturated NaHC0₃ solution (2 mL) are mixed in THF (5 mL). The suspension is deoxygenated by nitrogen flow before Pd(dppf)CI₂ (10 mg) is added. After been heated at 70°C for 7 hrs under nitrogen atmosphere, the reaction mixture is partitioned between EtOAc and water. The organic layer is dried over Na₂S0₄ and condensed under reduced pressure. The residue is subjected to flash column chromatography (Hexane:Acetone, 5:1 ) to afford the title compound as white solid (18 mg, 39%). ¹H NMR (CD₃OD) δ 2.27 (s, 3H), 2.42 (s, 3H), 7.45 (d, 2H), 7.82 (d, 2H); ESIMS: m/z 337.8 (M-H).

Example 17

Preparation of N- (5-methyl-4-{4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl) ethyl] phenyl} isoxazol-3-yl)-N'-phenylurea

Step l

1 ,1-Dimethylethyl 5-methyl-4-{4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl) ethyljphenyl} isoxazol-3-ylcarbamate (40 mg, 0.09 mmol) prepared according to the above example, is treated with 50% TFA in CH2CI2 (2 mL) at room temperature. The reaction mixture is stirred for another 1 h and condensed under reduced pressure. The residue is purified by preparative TLC (Hexane:Acetone, 1 :1) to afford the amine intermediate as white solid (24 mg, 78%). ¹HNMR (CD₃OD) 5 2.32 (s, 3H), 7.49 (d, 2H), 7.82 (d, 2H); ESIMS: m/z 338.9 (M-H).

Step 2

The solution of the amine intermediate (45mg, 0.13mmol) and phenyl isocyanate (34 μL, O.δmmol) in pyridine (2 mL) is stirred at 90°C under nitrogen atmosphere for 4 hrs. The reaction mixture is diluted with EtOAc, washed with saturated CuS0₄ solution and brine, dried over Na₂S0₄ and condensed under reduced pressure. The residue is purified by preparative TLC (CH₂CI₂:Methanol, 20:1 ) to afford the title compound as white solid (38 mg, 63%). ¹H NMR (CD₃OD) 5 2.38 (s, 3H), 7.02 (t, 1 H), 7.25 (t, 2H), 7.38 (d, 2H), 7.50 (d, 2H), 7.86 (d, 2H); ESIMS: m/z 457.9 (M-H).

Example 18

Preparation of ethyl (2E)-3-(5-methyl-4-{4-[2,2,2-trifluoro-1 -hydroxy-1 - (trifluoromethyl) ethyl] phenyl}isoxazol-3-yl)prop-2-enoate

Step l

Ethyl 5-methyl-4-{4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]phenyl} isoxazole-3-carboxylate ( 1.9 g, 4.78 mmol) prepared according to example 16 is dissolved in methanol (20 mL) and treated with the solution of NaOH (1.0 g, 23.9 mmol) in water (10 mL) at room temperature. The reaction mixture is stirred for another 1 h, then diluted with water and extracted with EtOAc. The aqueous phase was acidified with 1 N HCI solution to PH 2 and extracted with EtOAc. The organic layer is dried over Na₂S0₄. Removal of the solvent under reduced pressure affords the acid intermediate as white solid (1.56 g, 89%). ¹HNMR (CD₃OD) 5 2.44 (s, 3H), 4.91 (s, 1 H), 7.45 (d, 2H), 7.77 (d, 2H); ESIMS: tτ?/z 324.0 (M-COOH).

Step 2 To the solution of the acid intermediate (150 mg, 0.406 mmol) in THF (2 mL) is added 1 M solution of oxalyl chloride in CH₂CI₂ (812 μL) under nitrogen atmosphere, and followed by 4 drops of DMF. The reaction mixture is stirred at room temperature for 1 h. After removal of the solvent under reduced pressure, the residue is dissolved in THF (1 mL) and added the solution of N,0- dimethylhydroxylamine hydrochloride (80 mg, 0.812 mmol) and triethyl amine (113 μL, 0.812 mmol) in THF (1 mL). The reaction mixture is stirred at room temperature for 2 hrs before being quenched with 1 N HCI solution. EtOAc is used to extract, and the organic layer is washed with 1 N HCI, sat. NaHC0₃ and brine, then dried over Na₂S0 . After removal of solvent under reduced pressure, the residue is purified by preparative TLC (hexane: EtOAc, 3:1 ) to afford the Weinreb amide intermediate as white solid (45 mg, 27%). ¹HNMR (CDCI₃) 5 2.48 (s, 3H), 3.22 (s, 3H), 3.57 (s, 3H), 4.69 (b, 1 H), 7.33 (d, 2H), 7.68 (d, 2H); ESIMS: m/z 413.0 (M+H).

Step 3

The suspension of LiALH (14 mg, 0.335 mmol) in THF (0.5 mL) is charged with the solution of the Weinreb amide intermediate in THF (1 mL) at --40^oC under nitrogen atmosphere. The cooling bath is removed after the addition and the reaction mixture is allowed to warm up to room temperature in 2 hrs. After quenching with 0.1 N HCI solution, the suspension is extracted with EtOAc, washed with 1 N HCI solution, saturated NaHC0₃ solution and brine, then dried over Na₂S0₄. After removal of solvent under reduced pressure, the residue is purified by preparative TLC (hexane:EtOAc, 2:1 ) to afford the aldehyde intermediate as yellow oil (33 mg, 56%). ¹HNMR (CDCI₃) 5 2.51 (s, 3H), 4.61 (b, 1 H), 7.41 (d, 2H), 7.78 (d, 2H), 10.17 (s, 1 H); ESIMS: m/z 324.0 (M-CHO). Step 4

The aldehyde intermediate (13 mg, 0.037 mmol) and (carbethoxy methylene)triphenylphosphorane (14 mg, 0.04 mmol) are mixed in toluene (1 mL). The reaction mixture is stirred at 90 °C for 3 hrs before condensed under reduced pressure. The residue is purified by preparative TLC (hexane:Acetone, 2:1 ) to afford the title compound as white solid (13 mg, 81%). ¹HNMR (CD₃OD) 5 1.17 (t, 3H), 2.36 (s, 3H), 4.11 (q, 2H), 6.36 (d, 1 H), 7.34 (d, 2H), 7.37 (d, 2H), 7.79 (d, 2H); ESIMS: m/z 421.8 (M-H).

Example 19

Preparation of N-{3-Phenyl-4-[4-(2,2,2-trifluoro-1 -hydroxy-1 -trifluoromethyl- ethyl)-phenyl]-isoxazol-5-yl}-isobutyramide

Step l

1 M of LHDMS in THF (10.6ml 10.6mmol) is added to the solution of 4- hexafluoro-2-hydroxyisopropyl phenyl acetonitrile in THF at room temperature under argon atmosphere. The reaction mixture is stirred at room temperature under argon atmosphere for 30 minutes before adding methyl benzoate (527μl 4.24mmol). Then the solution is allowed to stir for 8 hours. H₂0 is poured to the reaction mixture, and the solution is washed with EtOAc. The aqueous layer is acidified by 1 N HCI and extracted with EtOAc. This organic layer is then washed with brine and dried over MgS0₄. Concentration and purification by preparative TLC afford the intermediate 3-Oxo-2-[4-(2,2,2-trifluoro-1 -hydroxy-1 - trifluoromethyl-ethyl)-phenyl]-butyronitrile. Step 2

The above intermediate( 560.8mg 1.45mmol) and hydroxyamine hydrochloric acid (201 mg 2.9mmol) are mixed in 2.5ml pyridine. The reaction mixture is stirred at 80°C for 12 hours. The reaction mixture is diluted with EtOAc and washed with Sat. NaHC0₃, H₂0 and brine and dried over MgS0₄. Concentration and purification by preparative TLC afford the 2-[4-(5-Amino-3-phenyl-isoxazol-4- yl)-phenyl]-1 ,1 ,1 ,3,3,3-hexafluoro-propan-2-ol (260mg 45%).

Step 3 Sodium hydride (18mg 0.45mmol) is added to the solution of 2-[4-(5-Amino-3- phenyl-isoxazol-4-yl)-phenyl]-1 ,1 ,1 ,3,3,3-hexafluoro-propan-2-ol in DMF at 0°C under argon atmosphere. The reaction mixture is stirred at room temperature under argon atmosphere for 30 minutes before adding isobutyryl chloride (23.8ul, 0.23mmol). The solution is allowed to stir for 8 hours and diluted with EtOAc. The organic layer is washed with H₂0 brine and dried over MgS04. Concentration and purification by preparative TLC afford the title compound. ¹HNMR 1.11 (s, 3H), 1.12 (s, 3H), 2.60 (m, 1 H), 7.26 (d, 2H), 7.4 (m, 5H), 7.72 (d, 2H); ESIMS: m/z 471 (M-H).

Example 20

Table 4. The following compounds are prepared in accordance with the procedure described in the above example

Example 22

Preparation of Λ/-butyl-4-phenyl-1 -propyl-2-{4-[2,2,2-trifluoro-1 -hydroxy-1 ^■

(trifluoromethyl) ethyl]phenyl}-1 H-imidazole-5-carboxamide

Step l

To a solution of 4-(2-Hydorxy-hexafluoroisopropyl)-benzoic acid (100 mg, 0.35 mmol) and phenylglyoxal hydrate (46 mg, 0.35 mmol) in methanol (1.5 ml) was added propylamine (20 mg, 0.35 mmol) at room temperature. After being stirred for 5 mins, butyl isocyanide (83 mg, 0.35 mmol) was added to the mixture at room temperature. The resultant mixture was stirred for 12 hrs at the same temperature and acidified with 0.1 N HCI solution. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine and dried over MgS04. The solvent was evaporated off under reduced pressure. The residue (165 mg) was used for the next step without further purification.

Step 2 The residue obtained (54 mg) was dissolved in acetic acid (1 ml) and ammonium acetate (77 mg, 1 mmol) was added. The reaction mixture was stirred under reflux condition for 3 hrs. After being diluted with water, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over MgS04. The solvent was evaporated off under reduced pressure. The residue was purified by preparative TLC (Hexane: EtOAc, 2:1 ) to afford the title compound (24 mg, 46%). ¹H NMR 5 0.79 (t, 3H), 0.83 (t, 3H), 1.09 (m, 2H), 1.34 (m, 2H), 1.70 (m, 2H), 3.28 (m, 2H), 4.28 (m, 2H), 5.72 (t, 1 H), 6.34 (b, 1 H), 7.35-7.47 (m, 3H), 7.55 (d, 2H), 7.62 (d, 2H), 7.75 (m, 2H); ESIMS: m/z 528 (M+H).

Example 23

Table 5. The following compounds are prepared in accordance with the procedure described in the above examples.

Example 24

Preparation of 1 -Methyl-3-{4-[2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]phenyl}-1 H- pyrazole-4-carbonitrile.

Step 1

To a solution of 4-[2,2,2-thfluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]benzaldehyde (200 mg, 0.735 mmol) in benzene (1.5 mL) is added a solution of methylhydrazine (51 mg, 1.1 mmol) in benzene (1 mL) at room temperature under nitrogen. The mixture is stirred under reflux conditions for 2 h. The mixture is allowed to cool to room temperature and then dried over MgS0 . The solvent is removed under reduced pressure to afford the product methyl hydrazone (145 mg, 66%) which is used in the next step without purification. ¹H NMR (CDCI₃) 5 2.96 (s, 3H), 3.79 (b, 1 H), 7.47 (s, 1 H), 7.58 (d, 2H), 7.67 (d, 2H).

Step 2

Dimethyl sulfide (90 mg, 1.45 mmol) is added to a solution of N- chlorosuccinimide (107 mg, 0.805 mmol) in CH₂CI₂ (5.5 mL) at 0°C. The mixture is stirred at 0°C for 5 minutes, then cooled to -70°C. To the solution is added dropwise a solution of methyl hydrazone (145 mg, 0.483 mmol) from above in CH₂CI₂ (1 mL). The mixture is stirred for 4.5 h, gradually allowing the temperature to warm to 0°C. The reaction is quenched with cold water and extracted with CH₂CI₂. The organic layer is washed with water and brine, then dried over MgS0 . The solvent is removed under reduced pressure to afford the hydrazonoyl chloride intermediate (115 mg, 71 %) which is used in the next step without purification. ¹HNMR (CDCI₃) 5 3.18 (s, 3H), 7.69 (d, 2H), 7.75 (s, 1 H), 7.86 (d, 2H). Step 3

To a solution of hydrazonoyl chloride intermediate (115 mg, 0.344 mmol) from above in CHCI₃ (3 mL) is added fumaronitrile (27 mg, 0.344 mmol), followed by Et₃N (35 mg, 0.344 mmol) at room temperature. The mixture is stirred under reflux conditions overnight. After cooling to r.t., the reaction is diluted with CHCI₃, washed with water, and dried over MgS0₄. The solvent is removed under reduced pressure and the residue is purified by preparative TLC (Hexane: EtOAc, 3:1 ) to afford the title compound as a light yellow solid (25 mg, 21 %). ¹H NMR (DMSO) 5 3.93 (s, 3H), 7.80 (d, 2H), 7.95 (d, 2H), 8.62 (s, 1 H), 8.83 (b, 1 H); ESIMS: m/z 348 (M-H).

Example 25

Preparation of A/,A/-1 -trimethyl-3-{4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl) ethyl] phenyl}-4,5-dihydro-1 H-pyrazole-5-carboxamide.

Step l

To a mixture of hydrazonoyl chloride intermediate (204 mg, 0.610 mmol) (as obtained in Step 2 of Example 24 above) and Λ/,Λ/-dimethylacrylamide (61 mg, 0.610 mmol) in CHCI₃ is added Et₃N (62 mg, 0.610 mmol). The reaction mixture is stirred at room temperature for 5 days. The solvent is removed under reduced pressure, and the residue is dissolved in EtOAc, washed with water, and dried over MgS0 . The solvent is removed under reduced pressure and the residue is purified by preparative TLC (hexane:EtOAc, 2:1 ) to afford the title compound as a white solid (29 mg, 12%). ¹HNMR (DMSO-d₆) 5 2.83 (s, 3H), 2.85 (s, 3H), 2.99 (dd, 1 H), 3.04 (s, 3H), 3.45 (dd, 1 H), 4.28 (t, 1 H), 7.65 (m, 4H), 8.71 (s, 1 H); ESIMS: m/z 396 (M-H).

Example 26 Preparation of Λ/,Λ/-bis(1-methylethyl)-Λ/'-phenyl-4-[2,2,2-trifluoro-1 -hydroxy-1 - (trifluoro-methyl)ethyl]benzenecarbohydrazonamide.

Step l

To a solution of 4-[2,2,2-trifluoro-1 -hydroxy-1 -(trifluoromethyl)ethyl]benzaldehyde (500 mg, 1.84 mmol) in benzene (3 mL) is added phenylhydrazine (200 mg, 1.84 mmol) at room temperature. The mixture is stirred at r.t. for 4 h. The solvent is removed under reduced pressure to afford the product phenyl hydrazone (656 mg, 99%) which is used in the next step without purification. ¹H NMR (CDCI₃) 5 3.62 (b, 1 H), 6.88 (t, 1 H), 7.10 (d, 2H), 7.28 (t, 2H), 7.34 (s, 1 H), 7.70 (m, 4H).

Step 2

Dimethyl sulfide (338 mg, 5.43 mmol) is added to a solution of N- chlorosuccinimide (404 mg, 3.02 mmol) in CH₂CI₂ (21 mL) at 0°C. The mixture is stirred at 0°C for 5 minutes, then cooled to -70°C. To the solution is added dropwise a solution of phenyl hydrazone (656 mg, 1.81 mmol) from above in CH₂CI₂ (3 mL). The mixture is stirred for 2 h, gradually allowing the temperature to warm to 0°C. The reaction is quenched with cold water and extracted with CH₂CI₂. The organic layer is washed with water and brine, then dried over MgS0₄. The solvent is removed under reduced pressure to afford the hydrazonoyl chloride intermediate (387 mg, 54%) which is used in the next step without purification. ¹H NMR (CDCI₃) 5 3.60 (b, 1 H), 6.88 (t, 1 H), 7.17 (d, 2H), 7.32 (t, 2H), 7.74 (d, 2H), 8.00 (d, 2H), 8.10 (s, 1 H); ESIMS: m/z 395 (M-H). Step 3

A solution of hydrazonoyl chloride intermediate (100 mg, 0.252 mmol) in 1 ,4- dioxane (1.5 mL) is added dropwise to diisopropylamine (7.5 mL) at 0°C over a period of 20 h. The mixture is stirred at room temperature for an additional 3.5 h. Solvents are removed under reduced pressure, and the residue is dissolved in EtOAc, washed with water and brine, and dried over MgS0 . Solvent is removed under reduced pressure, and the residue is purified by preparative HPLC to afford the title compound as a light yellow solid (26 mg, 22%). ¹H NMR (DMSO) 5 1.17 (d, 7H), 1.55 (d, 5H), 3.52 (m, 1.2H), 4.29 (m, 0.8H), 6.73 (d, 2H), 6.80 (t, 1 H), 7.16 (t, 2H), 7.68 (d, 2H), 7.76 (d, 2H), 8.28 (b, 1 H), 8.91 (b, 1 H); ESIMS: m/z 462 (M+H).

Example 27

Preparation of diethyl 4-[2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl] phenyl amido phosphate

To a solution of 2-(4-aminophenyl)-1 ,1 ,1 ,3,3,3)-hexafluoroisopropan-2-ol (777.4 mg, 3 mmol), DMAP (146.4 mg, 1.2 mmol) , Et₃N ( 0.5 ml, 3.6 mmol) and CH₂CI₂ (15 mL) was added diethyl chlorophoshate (520 mL, 3.3 mmol). The reaction mixture was stirred at room temperature for 72hrs and then refluxed for another 24 hrs. The solvent was removed and EtOAc was added. The solution was washed with water. After removal of solvent, the residue was purified by a short Ion Exchange column (Dowex-50u, ethanol)) to afford the title compound as a white solid (859 mg, 72.4%). ¹HNMR (DMSO-d₆) 51.20 (t, 6H), 3.89 (m, 4H), 7.08 (d, 2H), 7.46 (d, 2H), 8.24 (d, 2H), 8.43 (br, 1 H); ESIMS: m/z 394 (M-H). Example 28

Preparation of diethyl ethyl {4-[2,2,2-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl] phenyl} amidophosphate

The compound was prepared in accordance with the procedure described in the above example. Yield: 8.5%; ¹H NMR 51.25 (d, t, 6H), 1.45 (t, 3H), 3.64-3.73 (m, 2H), 3.95-4.04 (m, 2H), 4.04-4.12 (m, 2H), 7.29 (d, 2H ), 7.61 (d, 2H ); ESIMS: m/z 422 (M-H).

Example 29

Preparation of diethyl 4-[2,2,2-trifluoro-1-hydro(trifluoromethyl)ethyl]phenyl phosphonate

The mixture of 2-(4-bromophenyl)-1 ,1 ,1 ,3,3,3)-hexafluoroisopropan-2-ol (162 mg, 0.5 mmol), triethyl phosphite (154 μL, 0.9 mmol), anhydrous nickel chloride (13 mg, 0.1 mmol) and 3 ml diglyme was degassed for 15 minutes by argon. The reaction mixture was heated at 150 °C under argon for 5 hrs. After cooling, EtOAc was added and solution was washed with water, brine and dried over MgS0 _. The solvents were removed under reduced pressure and residue was purified by preparative TLC ( MeOH: CHCI₃ 10:90) to afford the title compound as colorless oil (72.1 mg, 38 %). ¹HNMR 51.31 (t, 6H), 4.10 (m, 4H), 5.90 (br, 1 H), 7.69 (dd, 2H ), 7.79 (dd, 2H ); ESIMS: m/z 381 (M+H). Example 30

Preparation of 2-phenoxy-Λ/-[4-(trifluoroacetyl)phenyl]acetamide

Step l Methyl 4-nitrobenzoate (4.0 g, 22.0 mmol) is dissolved in anhydrous CH₂CI₂ (80 mL) under Argon atmosphere. The solution is then cooled to -78°C. (Trifluoromethyl) thmethylsilane (4.08 mL, 27.6 mmol) is added to the solution followed by solid tetrabutylammoniumfluoride (560 μL, 0.56 mmol). The light pink solution is then allowed to slowly warm to r.t. and stir for 20 h. The orange solution is washed with water, brine, dried over MgS0 and evaporated under reduced pressure. The crude TMS ether is then dissolved in acetone (60 mL) before adding 8 M HCI (30 mL) and trifluoroacetic acid (2 mL). The yellow solution is washed with water, saturated NaHC0₃, brine, dried over MgS0 and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (Hexane:CHCI₃, 1 :9, CHCI₃, Methanol:CHCI₃, 3.5:96.5) to afford the title compound as yellow solid (3.05 g, 63.0%). ¹H NMR 57.78 (d, 2H), 8.20 (d, 2H); ESIMS: m/z 220 (M+H).

Step 2 4-Nitro-2',2',2',-trifluoroacetophenone (3.05 g, 13.9 mmol), glacial acetic acid (30 mL, 500 mmol), and Iron powder (4.7 g, 83 mmol) are added to 95% ethanol (63 mL). The mixture is then heated reflux for 17 h. The brown mixture is then filtered through Celite and evaporated under reduced pressure. The residue is co-evaporated twice with toluene to remove any remaining acetic acid. The brown solid is mixed with chloroform and filtered through a pad of silica gel to remove polar impurities, to afford the title compound as yellow solid (2.08 g, 79.1 %). ¹H NMR 54.45 (bs, 2H), 6.67 (d, 2H) 7.90 (d, 2H); ESIMS: m/z 190 (M+H). Step 3

4-Amino-2',2',2',-trifluoroacetophenone (595 mg, 3.15 mmol) and poly(4- vinylpyridine) (720 mg, 6.3 mmol) are mixed in anhydrous CH₂CI₂ (20 mL). Phenoxyacetyl chloride (450 μL, 3.26 mmol) is added to the suspension and the reaction mixture is stirred at r.t. for 24 hrs. The mixture is filtered and the organic solvent is removed under reduced pressure. The yellow solid is purified by preparative TLC (100% CHCI₃) to afford the title compound as colorless solid (705 mg, 69.2%). ¹H NMR 54.62 (s, 2H), 6.97 (d, 2H), 7.07 (t, 1 H), 7.34 (t, 2H), 7.79 (d, 2H), 8.06 (d, 2H), 8.59 (bs, 1 H); ESIMS: m/z 324 (M+H).

Example 31

Table 6. The following compounds are prepared in accordance with the procedure described in the above example.

All references described herein are hereby incorporated by reference, for example, all patents, patent applications cited are incorporated herein by reference.

Modification of the preceding embodiments is within the scope of the skilled artisan in formulation, given the guidance of the specification in light of the state of the art. While particular embodiments of this invention have been described, it will be apparent to those skilled in the art that various changes and modifications of this invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention. Hence, the foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. Indeed, various modifications of the above-described makes for carrying out the invention which are obvious to those skilled in the fields of molecular biology, chemistry, medicine, pharmaceutics, or related fields are intended to be within the scope of the following claims.

Claims

We claim:

1. A method for modulating Liver X Receptor (LXR) which comprises the administration of a therapeutically effective amount of a composition selected from the group consisting of compounds of the following formula (I):

(I) wherein

R-i is independently chosen from halo, haloalkyl, hydroxy, thiol, substituted thiol, sulfonyl, sulfinyl, nitro, cyano, amino, substituted amino, C Cβ alkyl and C C₆ alkoxy, and when R-* is hydroxy, CrC₆ alkoxy, thiol, substituted thiol, amino, substituted amino, or C*ι-C₆ alkyl, such radical may be combined with

R₂ to form a ring of 5-7 members when R-i is ortho to R₂;

R₂ is selected from NR₃C(S)NR₄R₅, NR₃C(=NR₃)NR₄R₅, NR₃C(=NCN)NR₄R₅,

NR₃C(=CHN0₂)NR₄R₅, NR₃P(0)R₄R₅, NR₃P(0)(OR₄)(OR₅), NR₃P(0)(OR₄)(NR₅), NR₃P(0)(NR₄)(NR₅), NR₃C(=NR₃)R6, COR₆,

R₆C(OH)R₇, CR₈=NOR₄, CR₈=NR₃, CR₈=NNR₄R₅, SOR₇, S0₂R₇,

P(0)(OR₄)(OR₅), P(0)(R₄)(R₅), P(0)(OR₄)(OR₅), P(0)(NR₃)(OR₄),

P(0)(NR )(NR₅), a 3-7 membered ring containing from zero to three heteroatoms selected from O, N, or S, which may be substituted by R₉, R-ι₀, R-i-i_, R*ι₂ or Rι₃, or may be combined with R-i to form a ring of 5-7 members when R-i is ortho to R₂;

R₃ is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R or R₅; R is hydrogen, alkyl, aryl, heterocyclyl, acyl, or may form a ring of 5-7 members with R₅ or R₃;

R₅ is hydrogen, alkyl, aryl, or heterocyclyl, acyl or may form a ring of 5-7 members with R₃ or R ; R₆ and R₇ may be equal or different and are selected from hydrogen, alkyl, aryl, or heterocylcyl; R₈ is hydrogen, alkyl, aryl, heterocylcyl, amino or substituted amino; R₉, R-io_, Rii and Rι₂ may be equal or different and are selected from hydrogen, alkyl, aryl, heterocyclyl, nitro, cyano, carboxylic acid, ester, amide, halo, hydroxyl, amino, substituted amino, alkoxy, acyl, ureido, sulfonamido, sulfamido, sulfonyl, sulfinyl, or guanadinyl; R-ι₃ is hydrogen, alkyl, aryl, heterocyclyl, acyl, ester, sulfonyl, ureido, or guanadinyl; A is O, S, or NR₃; m is from zero to four;

X is H, CF₂Z, or CF₃ or together with Y forms a double bond when A is O; Y is hydrogen, or together with X forms a double bond when A is O; Z is F, Br, CI, I or CF_3; and enantiomers, diasteromers, or tautomers of the compound (I), as well as their prodrugs and pharmaceutically acceptable salts.

2. A method according to claim 1 comprising the administration of a composition containing compounds I having the following structural formula (1a) or (1 b):

(la) (lb)

3. A method according to claim 1 comprising the administration of a composition containing compounds I having the following structural formula (Ic and Id):

(Ic) (Id) wherein R₂ is as defined above and R*ι is a hydrogen, halo, hydroxyl, or cyano group.

A method according to claim 3 comprising the administration of a composition containing a compound selected from the group consisting of:

Morpholine-4-carbothioic acid (4-cyano-butyl)-[4-(2,2,2-trifluoro-1 - hydroxy-1 -trifluoromethyl-ethyl)-phenyl]-amide, and

5-{(Morpholine-4-carbothioyl)-[4-(2,2,2-trifluoro-1 -hydroxy-1 - trifluoromethyl-ethyl)-phenyl]-amino}-pentanoic acid methyl ester.