BACKGROUND OF THE INVENTION Field of the Invention

[0001] Aspects of the present invention relate to compounds of Formulae 1 and 2. This invention further relates to the chemical synthesis and the pharmaceutical and/or medical use of such compounds in the treatment of conditions involving cancer, inflammation, cellular differentiation and proliferation, wound healing, metabolism of lipids and carbohydrates, obesity, diabetes, or energy homoeostasis. Description of the Related Art

[0002] Over the last decade instances of metabolic diseases such as hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, diabetes, and obesity have become increasingly prevalent. Rather strong correlations exist between dietary habits and the onset of these disorders. Type 2 or non-insulin dependent diabetes (NIDD) is a metabolic disease characterized by Resistance to insulin. Patients who suffer from this syndrom often develop various other chronic diseases such as neuropathy, cardiovascular complications and retinopathy. There is now irrefutable evidence that modulation of a group of nuclear hormone receptors, called peroxisome proliferator- activated receptors (PPARs), can help regulate hyperglycemia in NIDD patients. More recently, PPARs have also been indicated in the process of wound healing. Furthermore, they stimulate cellular migration and differentiation and promote survival of keratinocytes after an injury. The PPAR family is composed of three tissue specific subtypes: PP ARa, PPARδ and PPARγ. Once bound to a ligand, these receptors are activated and heterodimerize with another nuclear receptor known as Retinoid X Receptor (RXR), resulting in gene expression.

[0003] The PPARs were initially recognized for their ability to regulate energy balance, with PP ARa being involved in beta-oxidation pathways, and PPARγ in the differentiation of fat cells. PP ARa also acts as a mediator by which a number of drugs cause hepatic peroxisome proliferation. PPARδ is the most universally expressed of the three. The PPARs are expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by numerous compounds including synthetic drugs, such as the

thiazolidinediones, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low-density lipoproteins.

[0004] Current PPAR activators that are marketed as oral drugs (e.g. Troglitazone, Pioglitazone, and Rosiglitazone) are highly selective PPARγ ligands. Although quite effective at reducing insulin resistance, there are risks associated with these therapies and there have been reports of liver toxicity and other clinical complications in NIDD patients who take these drugs. The aforementioned modulators of PPARs bear a thiazolidinedione group in a specific position of the molecule. Research in this field indicates that removal of this group can drastically reduce the potency of these modulators. This is in part due to a unique interaction between the thiazolidinedione moiety and some amino acids in the binding pocket of the receptors. There are however, other amino acid residues in the binding pocket of these receptors that can interact with the modulators. None of the modulators of PPARs described to date take advantage of these critical interactions. Another drawback of the current state of the art is the limited aqueous solubility of certain PPAR modulators. There exists therefore a need to improve upon the prior art in order to enhance the clinical profile of such therapeutics. Such improvements may be carried out by introducing specially designed functional groups at specific positions on the molecular backbone of the modulator. The novel compounds of this invention address these issues and display enhanced in vitro profiles when compared to compounds of the prior art.

Summary of the Invention

[0005] Disclosed herein are compounds of Formulae 1 and 2:

Formula 1 Formula 2

[0006] Also disclosed herein are pharmaceutical compositions comprising a compound of Formula 1 or a compound of Formula 2, or a mixture thereof.

[0007] Further, disclosued herein are methods of eliciting, modulating and/or regulating selective gene expression by cellular receptors in cells or tissues and providing

control over cellular growth, proliferation and differentiation processes regulated by certain hormones or vitamins, such as for example all-trans-retinoic acid, 13-cis-retinoic acid, 9- cis-retinoic acid, vitamin D, thyroid hormone and the like, comprising contacting cells or tissues with a compound of Formula 1 or a compound of Formula 2.

[0008] In addition, disclosed herein are methods of treating a mammalian subject having, suspected of having, or being prone to a disease or condition involving cancer, cellular differentiation and proliferation, wound healing, metabolism of lipids and carbohydrates, obesity, atherosclerosis, arteriosclorosis, intermittent claudication, cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary heart disease, heart insufficiency, cataracts, diabetes, type 1 diabetes, type 2 diabetes, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, metabolic syndrom X, cystic fibrosis related diabetes, polycistic ovarian syndrom, gestational diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, hypertension, essential hypertension, acute hypertensive emergency, hypertriglyceridemia, insulin resistance, myocardial ischemia, tissue ischemia, energy homoeostasis, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, inflammatory or immune disease, rheumatoid arthritis, asthma, acute coronary syndrome, angia pectoris, unstable angia, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non- Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, inflammatory bowel disease, irritable bowel syndrome, chronic obstructive pulmonary disease, or psoriasis, by administering a therapeutically or prophylactically effective amount of a compound of Formula 1 or a compound of Formula 2.

Brief Description of the Drawings

[0009] Figure 1 is a graph depicting the data for the comparison between the compound of Example 6 () and rosiglitazone (A) in the in- vitro activation of PPAR-γ.

[0010] Figure 2 is a graph depicting the data for the comparison between the compound of Example 10 (o) and rosiglitazone ( A) in the in-vitro activation of PPAR-γ.

[0011] Figure 3 is a graph depicting the data for the comparison between the compound of Example 15 (o) and rosiglitazone ( A) in the in-vitro activation of PPAR-γ.

[0012] Figure 4 is a graph depicting the data for the comparison between the compound of Example 22 (o) and rosiglitazone (A) in the in-vitro activation of PPAR-γ.

[0013] Figure 5 is a graph depicting the data for the comparison between the compound of Example 30 (o) and rosiglitazone (A) in the in-vitro activation of PPAR-γ.

[0014] Figure 6 is a graph depicting the data for the comparison between the compound of Example 32 (o) and rosiglitazone (A) in the in-vitro activation of PPAR-γ.

Detailed Description of the Invention

[0015] Certain PPAR modulators are known in the art. Some of these modulators have the following formulae:

[0016] These PPAR modulators are all based on a common thiazolidinedione heterocyclic component. In contrast, aspects of the present invention disclosed herein describe a novel approach to designing and synthesizing new analogs of these PPAR modulators through chemical modifications and derivations of the thiazolidinedione heterocyclic component. Suitable modifications of the thiazolidinedione heterocyclic component could generate safe, efficacious PPAR modulators.

[0017] Thus, in one aspect, there are provided herein compounds having the structural Formulae 1 or 2:

Formula 1 Formula 2 where a) Xi and X ₂ are independently selected from the group consisting of O, S, and

NH. b) Y is Ci-io substituted or unsubstituted alkyl, c) Ri is selected from the group consisting of compounds having formulae A ₁ , A ₂ , A ₃ , -CO ₂ R ₅ , and -CONR ₆ R ₇ ,

where

Z is selected from the group consisting of C _2-8 alkyl, and C _2-8 substituted alkyl;

R ₅ , R ₆ , R ₇ , Rn and Ri ₂ are independently selected from the group consisting of hydrogen, alkyl, and aryl; or R ₆ and R ₇ taken together with the nitrogen to which they are attached may form an unsubstituted or optionally substituted saturated or unsaturated cyclic system containing 3 to 10 carbon atoms;

R ₈ is selected from the group consisting of -OH, alkyloxy, aryloxy, alkylcarboxy, arylcarboxy, -SH, alkylthio, arylthio, -NH ₂ , alkylamino, arylamino, N-aryl-N-alkylaminό, -NHNH ₂ , alkylhydrazino, arylhydrazino, N-aryl-N-alkylhydrazino, -NHORn, -0(P=O)(ORn)(ORi ₂ ), -OCH ₂ O(P=O)(ORn)(ORi ₂ ), and -OSO ₃ Rn;

R ₉ and Rio are independently selected from the group consisting of -OH, alkyloxy, aryloxy, -NH ₂ , alkylamino, arylamino, N-aryl-N-alkylamino, -NHNH ₂ , alkylhydrazino, arylhydrazino, N-aryl-N-alkylhydrazino, -NHORn, alkyl, and aryl; and "**" represents the point of attachment of Y to Ri;

d) R ₂ and R ₃ are independently selected from the group consisting of hydrogen, halogen and alkyl; e) R ₄ is selected from the group consisting Of B ₁ , B ₂ , B3, B ₄ , B5, B ₆ , B ₇ , B ₈ , B ₉ , B ₁₀ , B ₁₁ , B ₁₂ , Bi ₃ , and B ₁₄

B ₁₃ B ₁₄ where m and n are independently O, 1 or 2;

X ₃ and X ₄ are independently selected from the group consisting of O, S, NH, and alkylamino;

R ₁₃ is substituted or unsubstituted alkyl;

R ₁₄ is selected from the group consisting of substituted heteroaryl, unsubstituted heteroaryl, substituted aryl, and unsubstituted aryl;

R _1S and R ₁₆ are independently selected from the group consisting of hydrogen, halogen, substituted alkyl, unsubstituted alkyl, substituted alkyloxy, and unsubstituted alkyloxy, or R ₁₅ and R ₁₆ may be linked together to form a substituted or unsubstituted 3- to

6-membered cycloalkyl or 5- to 6-membered cycloalkenyl ring, where said substituents are selected from the group consisting of hydroxy, halogen, and alkyl;

Ri ₇ and R] ₈ are independently selected from the group consisting of hydrogen, halogen, -NO ₂ , -CN, -S(O) ₂ OR ₅ , -COR ₅ , -CO ₂ R ₅ , -CONR ₆ R ₇ , substituted alkyl, unsubstituted alkyl, substituted alkyloxy, unsubstituted alkyloxy, substituted alkylthio, unsubstituted alkylthio, substituted alkylamino, and unsubstituted alkylamino;

Ri ₉ is selected from the group consisting of alkyl, alkyloxy, alkylthio, aryl, and heteroaryl;

R _2O is selected from the group consisting of alkyl, aryl, heteroaryl, and adamantyl, or RiQ and R ₂₀ may be linked together to form a substituted or unsubstituted 5- or 6- membered cycloalkyl or cycloalkenyl ring, where said substituents are selected from the group consisting of hydroxy, C=O, halogen, and alkyl, and where 1 or 2 of the carbon atoms on said 5- or 6-membered cycloalkyl or cycloalkenyl ring may be optionally replaced by W, where W is selected from the group consisting of O, S, N, NH, alkylamino, and arylamino, or a pharmaceutically acceptable salt, or prodrug thereof, with the proviso that If R ₄ is B ₃ , then X ₂ cannot be O or NH.

[0018] In certain embodiments, Xi is sulfur. In some embodiments, X ₂ is sulfur.

[0019] In further embodiments, Y is an unsubstituted Ci _-5 alkyl. In some of these embodiments, Y is selected from the group consisting of methylene, ethylene, propylene, n-butylene, pentylene, 1-methylpropylene, 2-methylpropylene, 1- methylbutylene, and 2-methylbutylene. In other embodiments, Y is methylene, ethylene, or propylene.

[0020] In some embodiments Ri is -CO ₂ R ₅ . In some of these embodiments, R ₅ is selected from the group consisting of hydrogen and unsubstituted Ci _-5 alkyl. In certain of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, pentyl, 1-methylpropyl, 2-methylpropyl, 1-methylbutyl, and 2-methylbutyl. In further embodiments, R ₅ is hydrogen. In yet further embodiments, R ₅ is ethyl. In other embodiments still, R ₅ is 2-methylpropyl.

[0021] In some embodiments, R ₂ is selected from the group consisting of hydrogen and unsubstituted Ci _-5 alkyl. In some of these embodiments, the alkyl is selected

from the group consisting of methylene, ethylene, propylene, n-butylene, pentylene, 1- methylpropylene, 2-methylpropylene, 1 -methylbutylene, and 2-methylbutylene. In further embodiments, R ₂ is hydrogen.

[0022] In some embodiments, R ₃ is selected from the group consisting of hydrogen and unsubstituted Ci _-5 alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, pentyl, 1 -methylpropyl, 2- methylpropyl, 1-methylbutyl, and 2-methylbutyl. In further embodiments, R ₃ is hydrogen.

[0023] In some embodiments, X ₃ is oxygen, while in other embodiments, X ₃ is NH.

[0024] In some embodiments, X ₄ is sulfur.

[0025] In further embodiments, Ri ₃ is an unsubstituted Ci _-5 alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, and pentyl. In certain embodiments, Ri ₃ is methyl.

[0026] Embodiments of the present invention include those in which Ri ₄ is a substituted or unsubstituted aryl or heteroaryl. In addition, in some of the embodiments Ri ₄ is selected from the group consisting of

[0027] In certain embodiments, Ri ₅ and Ri ₆ taken together along with the carbon atom to which they are attached form a substituted or unsubstituted 3- to

6-membered cycloalkyl or 5- to 6-membered cycloalkenyl ring. In some of these embodiments, Ri ₅ and Ri ₆ taken together along with the carbon atom to which they are attached form a substituted or unsubstituted 3- to 6-membered cycloalkyl ring. In further embodiments, Ri ₅ and Ri ₆ taken together along with the carbon atom to which they are attached form a 3-membered cycloalkyl ring.

[0028] In some embodiments, Rj ₇ is selected from the group consisting of hydrogen, halogen, alkyloxy, and perhaloalkyloxy. In some of these embodiments, the alkyl of the alkyloxy and the perhaloalkyloxy are each independently selected from the group consisting of methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, and pentyl. In certain embodiments, Rn is selected from the group consisting of hydrogen, fluoro, methoxy, and trifluoromethoxy.

[0029] In some embodiments, Ri ₈ is selected from the group consisting of substituted alkyl, unsubstituted alkyl, substituted alkyloxy, and unsubstituted alkyloxy. In some of these embodiments, the alkyl and the alkyl of the alkyloxy are each independently selected from the group consisting of methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, and pentyl. In certain embodiments, Rj ₈ is methyl.

[0030] In some embodiments, Ri ₉ and R ₂₀ taken together along with the carbon atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered cycloalkyl or cycloalkenyl ring. In certain embodiments, R ₁₉ and R ₂₀ taken together along

with the carbon atoms to which the are attached form

[0031] In another aspect, the present invention relates to a compound selected from the group consisting of Ci, C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , Ci ₀ , Cn, Ci ₂ , Ci ₃ , Ci ₄ , Ci ₅ , C ₁₆ , C ₁₇ , C ₁₈ , Ci ₉ , C _2O , C _2I , C ₂₂ , C ₂₃ , C ₂₄ , C ₂₅ , C ₂₆ , C ₂₇ , C ₂₈ , C ₂₉ , C ₃ 0, C31, C ₃₂ , C ₃₃ , C ₃₄ , C ₃₅ , C ₃₆ , C ₃₇ , C ₃₈ , C ₃₉ , C4 ₀ , C ₄ 1, C ₄₂ , C ₄₃ , and C ₄₄ wherein X ₁ , X ₂ , Y and Ri are as described above:

C ₂₂

C ₄₄

or a pharmaceutically acceptable salt, or prodrug thereof.

[0032] In a further aspect, the present invention relates to a compound selected from the group consisting Of D ₁ , D ₂ , D ₃ , D ₄ , D ₅ , D ₆ , D ₇ , D ₈ , D ₉ , D ₁₀ , Dn, D ₁₂ , D ₁₃ , D ₁₄ , D ₁₅ , D ₁₆ , D ₁₇ , Di ₈ , Di ₉ , D ₂ O, D _2I , D ₂₂ , D ₂₃ , D ₂₄ , D ₂₅ , D ₂₆ , D ₂₇ , D ₂₈ , D ₂₉ , D ₃₀ , D ₃₁ , and D ₃₂

or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

[0033] In certain embodiments, X ₁ is not sulfur, hi some embodiments, X ₂ is not sulfur, or oxygen.

[0034] In further embodiments, Y is not an unsubstituted C _1-5 alkyl. hi some embodiments, Y is not methylene, ethylene, propylene, n-butylene, pentylene, 1- methylpropylene, 2-methylpropylene, 1-methylbutylene, or 2-methylbutylene.

[0035] In some embodiments Ri is not -CO ₂ R ₅ . In some embodiments, R ₅ is not hydrogen or unsubstituted Ci _-5 alkyl. In certain embodiments, the alkyl is not methyl, ethyl, propyl, n-butyl, pentyl, 1-methylpropyl, 2-methylpropyl, 1-methylbutyl, or 2-

methylbutyl. In further embodiments, R ₅ is not hydrogen. In yet other embodiments, R ₅ is not ethyl. In still other embodiments, R ₅ is not 2-methylpropyl.

[0036] In some embodiments, R ₂ is not hydrogen or unsubstituted Ci _-5 alkyl. In some embodiments, the alkyl is not methyl, ethyl, propyl, n-butyl, pentyl, 1 -methylpropyl, 2-methylpropyl, 1 -methylbutyl, or 2 -methylbutyl. In further embodiments, R ₂ is not hydrogen.

[0037] In some embodiments, R ₃ is not hydrogen or unsubstituted Ci _-5 alkyl. In some embodiments, the alkyl is not methyl, ethyl, propyl, n-butyl, pentyl, 1 -methylpropyl, 2-methylpropyl, 1 -methylbutyl, or 2-methylbutyl. In further embodiments, R ₃ is not hydrogen.

[0038] In some embodiments, X ₃ is not oxygen. In some embodiments, X ₃ is not NH. In some embodiments, X ₄ is not sulfur.

[0039] In some embodiments, Ri ₃ is not unsubstituted Ci _-5 alkyl. In some embodiments, the alkyl is not methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, or pentyl. In certain embodiments, R] ₃ is not methyl.

[0040] In some embodiments, Ri ₄ is not a substituted or unsubstituted aryl or heteroaryl. hi some embodiments, Ri ₄ is not one of the following:

[0041] In certain embodiments, R ₄₅ and Ri ₆ taken together along with the carbon atom to which they are attached do not form a substituted or unsubstituted 3- to 6-membered cycloalkyl or 5- to 6-membered cycloalkenyl ring. In some embodiments, R ₁₅ and Ri ₆ taken together along with the carbon atom to which they are attached do not form a substituted or unsubstituted 3- to 6-membered cycloalkyl ring. In further embodiments, Ri ₅ and Ri ₆ taken together along with the carbon atom to which they are attached do not form a 3-membered cycloalkyl ring.

[0042] In some embodiments, Rn is not hydrogen, halogen, alkyloxy, or perhaloalkyloxy. In some embodiments, the alkyl of the alkyloxy or the perhaloalkyloxy is not methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, or pentyl. In certain embodiments, Rn is not hydrogen, fluoro, methoxy, or trifluoromethoxy.

[0043] In some embodiments, Ri ₈ is not substituted alkyl, unsubstituted alkyl, substituted alkyloxy, or unsubstituted alkyloxy. In some embodiments, the alkyl or the alkyl of the alkyloxy is not methyl, ethyl, propyl, n-butyl, sec-butyl, tert-butyl, and pentyl. In certain embodiments, Ri ₈ is not methyl.

[0044] In some embodiments, R ₁₉ and R ₂₀ taken together along with the carbon atoms to which they are attached do not form a substituted or unsubstituted 5- or 6- membered cycloalkyl or cycloalkenyl ring. In certain embodiments, R19 and R ₂₀ taken

together along with the carbon atoms to which the are attached do not form

[0045] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted," it is meant that the substitutent is a group that may be substituted with one or more group(s) individually and independently selected from the group consisting of cycloalkyl, aryl, heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found

in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated by reference herein in its entirety.

[0046] The compounds according to this invention may occur as a mixture of tautomers. The term "tautomer" or "tautomerism" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples include keto-enol tautomers, such as acetone/propen-2-ol and the like, ring-chain tautomers, such as glucose/ 2,3,4,5,6-pentahydroxy-hexanal and the like. The compounds described herein may have one or more tautomers and therefore include various isomers. All such isomeric forms of these compounds are expressly included in the present invention. The following example of tautomerism is provided for reference:

[0047] The compounds according to this invention may contain one or more asymmetric carbon atoms and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures or individual diastereomers. The term "stereoisomer" refers to a chemical compound having the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light. However, some pure stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation. The compounds described herein may have one or more asymmetrical carbon atoms and therefore include various stereoisomers. AU such isomeric forms of these compounds are expressly included in the present invention.

[0048] Each stereogenic carbon may be of R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned. When chiral centers are found in the derivatives of this invention, it is to be understood that this invention encompasses all possible stereoisomers.

[0049] The terms "optically pure compound" or "optically pure isomer" refers to a single stereoisomer of a chiral compound regardless of the configuration of the said compound.

[0050] The term "substantially homogeneous" refers to collections of molecules wherein at least 80%, preferably at least about 90% and more preferably at least about 95% of the molecules are a single compound or a single stereoisomer thereof.

[0051] As used herein, the term "attached" signifies a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art.

[0052] The terms "optional" or "optionally" refer to occurrence or non- occurence of the subsequently described event or circumstance, and that the description includes instances where said event or circumstance occurs and instances where it does not. In such context, the sentence "optionally substituted alkyl group" means that the alkyl group may or may not be substituted and the description includes both a substituted and an unsubstituted alkyl group.

[0053] The term "effective amount" of a compound refers a non-toxic but sufficient amount of the compound that provides a desired effect. This amount may vary from subject to subject, depending on the species, age, and physical condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. A suitable effective amount may be determined by one of ordinary skill in the art.

[0054] The term "pharmaceutically acceptable" refers to a compound, additive or composition that is not biologically or otherwise undesirable. For example, the additive or composition may be administered to a subject along with a compound of the invention without causing any undesirable biological effects or interacting in an undesirable manner with any of the other components of the pharmaceutical composition in which it is contained.

[0055] The term "pharmaceutically acceptable salts" includes hydrochloric salt, hydrobromic salt, hydroiodic salt, hydrofluoric salt, sulfuric salt, citric salt, maleic salt, acetic salt, lactic salt, nicotinic salt, succinic salt, oxalic salt, phosphoric salt, malonic salt, salicylic salt, phenylacetic salt, stearic salt, pyridine salt, ammonium salt, piperazine salt, diethylamine salt, nicotinamide salt, formic salt, urea salt, sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, lithium salt, cinnamic salt, methylamino salt, methanesulfonic salt, picric salt, tartaric salt, triethylamino salt, dimethylamino salt, tris(hydroxymethyl)aminomethane salt and the like. Additional pharmaceutically acceptable salts are known to those of skill in the art.

[0056] When used in conjunction with a compound of this invention, the terms "elicit", "eliciting," "modulator", "modulate", "modulating", "regulator", "regulate" or "regulating" selective gene expression refer to a compound that can act as an activator, an agonist, a pan-agonist or an antagonist of gene expression by a particular receptor, such as for example a Retinoid X Receptor, a peroxisome proliferator-activated receptor (PPAR), and the like.

[0057] The terms "therapeutic agent" and "chemotherapeutic agent", refer to a compound or compounds and pharmaceutically acceptable compositions thereof that are administered to mammalian subjects as prophylactic or remedy in the treatment of a disease or medical condition. Such compounds may be administered to the subject via oral formulation, transdermal formulation or by injection.

[0058] The term "subject" refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans.

[0059] The term "therapeutically effective amount" is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0060] The terms "treating," "treatment," "therapeutic," or "therapy" do not necessarily mean total loss of nociception. Any alleviation of any undesired signs or symptoms of a disease, such as cancer, cellular differentiation and proliferation, wound

healing, metabolism of lipids and carbohydrates, obesity, atherosclerosis, arteriosclorosis, intermittent claudication, cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary heart disease, heart insufficiency, cataracts, diabetes, type 1 diabetes, type 2 diabetes, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, metabolic syndrom X, cystic fibrosis related diabetes, polycistic ovarian syndrom, gestational diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, hypertension, essential hypertension, acute hypertensive emergency, hypertriglyceridemia, insulin resistance, myocardial ischemia, tissue ischemia, energy homoeostasis, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, inflammatory or immune disease, rheumatoid arthritis, asthma, acute coronary syndrome, angia pectoris, unstable angia, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non-Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, inflammatory bowel disease, irritable bowel syndrome, chronic obstructive pulmonary disease, or psoriasis, or a subset of these conditions, to any extent can be considered treatment or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well being or appearance.

[0061] The term "Lewis acid" refers to a molecule that can accept an unshared pair of electrons and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "Lewis acid" includes but is not limited to: boron trifluoride, boron trifluoride etherate, boron trifluoride tetrahydrofuran complex, boron trifluoride tert- butyl-methyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride dihydrate, boron trifluoride di-acetic acid complex, boron trifluoride dimethyl sulfide complex, boron trichloride, boron trichloride dimethyl sulfide complex, boron tribromide, boron tribromide dimethyl sulfide complex, boron triiodide, triimethoxyborane, triethoxyborane, trimethylaluminum, triethylaluminum, aluminum trichloride, aluminum trichloride tetrahydrofuran complex, aluminum tribromide, titanium tetrachloride, titanium tetrabromide, titanium iodide, titanium tetraethoxide, titanium tetraisopropoxide, scandium (III) trifluoromethanesulfonate, yttrium (III) trifluoromethanesulfonate, ytterbium (III)

trifluoromethanesulfonate, lanthanum (III) trifluoromethanesulfonate, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, zinc (II) trifluoromethanesulfonate, zinc (II) sulfate, magnesium sulfate, lithium perchlorate, copper (II) trifluoromethanesulfonate, copper (II) tetrafluoroborate and the like. Certain Lewis acids may have optically pure ligands attached to the electron acceptor atom, as set forth in Corey, E. J. Angewandte Chemie, International Edition (2002), 41(10), 1650-1667; Aspinall, H. C. Chemical Reviews (Washington, DC, United States) (2002), 102(6), 1807-1850; Groger, H. Chemistry-A European Journal (2001), 7(24), 5246-5251; Davies, H. M. L. Chemtracts (2001), 14(11), 642-645; Wan, Y. Chemtracts (2001), 14(11), 610-615; Kim, Y. H. Accounts of Chemical Research (2001), 34(12), 955-962; Seebach, D. Angewandte Chemie, International Edition (2001), 40(1), 92-138; Blaser, H. U. Applied Catalysis, A: General (2001), 221(1-2), 119- 143; Yet, L. Angewandte Chemie, International Edition (2001), 40(5), 875-877; Jorgensen, K. A. Angewandte Chemie, International Edition (2000), 39(20), 3558-3588; Dias, L. C. Current Organic Chemistry (2000), 4(3), 305-342; Spindler, F. Enantiomer (1999), 4(6), 557-568; Fodor, K. Enantiomer (1999), 4(6), 497-511; Shimizu, K. D.; Comprehensive Asymmetric Catalysis I-III (1999), 3, 1389-1399; Kagan, H. B. Comprehensive Asymmetric Catalysis I-III (1999), 1, 9-30; Mikami, K. Lewis Acid Reagents (1999), 93- 136 and all references cited therein. Such Lewis acids may be used by one of ordinary skill and knowledge in the art to produce optically pure compounds from achiral starting materials.

[0062] The term "acylating agent" refers to a molecule that can transfer an alkylcarbonyl, substituted alkylcarbonyl or aryl carbonyl group to another molecule. The definition of "acylating agent" includes but is not limited to ethyl acetate, vinyl acetate, vinyl propionate, vinyl butyrate, isopropenyl acetate, 1-ethoxyvinyl acetate, trichloroethyl butyrate, trifiuoro ethyl butyrate, trifluoroethyl laureate, S-ethyl thiooctanoate, biacetyl monooxime acetate, acetic anhydride, acetyl chloride, succinic anhydride, diketene, diallyl carbonate, carbonic acid but-3-enyl ester cyanomethyl ester, amino acid and the like.

[0063] The term "nucleophile" or "nucleophilic reagent" refers to a negatively charged or neutral molecule that has an unshared pair of electrons and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "nucleophile" includes but is not limited to: water, alkylhydroxy, alkoxy anion, arylhydroxy, aryloxy anion, alkylthiol, alkylthio anion, arylthiol, arylthio anion, ammonia, alkylamine,

arylamine, alkylamine anion, arylamine anion, hydrazine, alkyl hydrazine, arylhydrazine, alkylcarbonyl hydrazine, arylcarbonyl hydrazine, hydrazine anion, alkyl hydrazine anion, arylhydrazine anion, alkylcarbonyl hydrazine anion, arylcarbonyl hydrazine anion, cyanide, azide, hydride, alkyl anion, aryl anion and the like.

[0064] The term "electrophile" or "electrophilic reagent" refers to a positively charged or neutral molecule that has an open valence shell and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "electrophile" includes but is not limited to: hydronium, acylium, lewis acids, such as for example, boron trifluoride and the like, halogens, such as for example Br ₂ and the like, carbocations, such as for example tert-butyl cation and the like, diazomethane, trimethylsilyldiazomethane, alkyl halides, such as for example methyl iodide, benzyl bromide and the like, alkyl triflates, such as for example methyl triflate and the like, alkyl sulfonates, such as for example ethyl toluenesulfonate, butyl methanesulfonate and the like, acyl halides, such as for example acetyl chloride, benzoyl bromide and the like, acid anhydrides, such as for example acetic anhydride, succinic anhydride, maleic anhydride and the like, isocyanates, such as for example methyl isocyanate, phenylisocyanate and the like, chloroformates, such as for example methyl chloroformate, ethyl chloroformate, benzyl chloroformate and the like, sulfonyl halides, such as for example methanesulfonyl chloride, p-tolunesulfonyl chloride and the like, silyl halides, such as for example trimethylsilyl chloride, tertbutyldimethyl silyll chloride and the like, phosphoryl halide such as for example dimethyl chlorophosphate and the like, alpha-beta-unsaturated carbonyl compounds such as for example acrolein, methyl vinyl ketone, cinnamaldehyde and the like.

[0065] The term "leaving group" (LG) refers to any atom (or group of atoms) that is stable in its anion or neutral form after it has been displaced by a nucleophile and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "leaving group" includes but is not limited to: water, methanol, ethanol, chloride, bromide, iodide, methanesulfonate, tolylsulfonate, trifluoromethanesulfonate, acetate, trichloro acetate, benzoate and the like.

[0066] The term "oxidant" refers to any reagent that will increase the oxidation state of a carbon atom in the starting material by either adding an oxygen atom to this carbon or removing an electron from this carbon and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "oxidant" includes but is not

limited to: osmium tetroxide, ruthenium tetroxide, ruthenium trichloride, potassium permanganate, meta-chloroperbenzoic acid, hydrogen peroxide, dimethyl dioxirane and the like.

[0067] The term "metal ligand" refers to a molecule that has an unshared pair of electrons and can coordinate to a metal atom and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "metal ligand" includes but is not limited to: water, alkoxy anion, alkylthio anion, ammonia, trialkylamine, triarylamine, trialkylphosphine, triarylphosphine, cyanide, azide and the like.

[0068] The term "reducing reagent" refers to any reagent that will decrease the oxidation state of a carbon atom in the starting material by either adding a hydrogen atom to this carbon or adding an electron to this carbon and as such would be obvious to one of ordinary skill and knowledge in the art. The definition of "reducing reagent" includes but is not limited to: borane-dimethyl sulfide complex, 9-borabicyclo[3.3.1.]nonane (9-BBN), catechol borane, lithium borohydride, sodium borohydride, sodium borohydride-methanol complex, potassium borohydride, sodium hydroxyborohydride, lithium triethylborohydride, lithium n-butylborohydride, sodium cyanoborohydride, calcium (II) borohydride, lithium aluminum hydride, diisobutylaluminum hydride, n-butyl-diisobutylaluminum hydride, sodium bis-methoxyethoxyaluminum hydride, triethoxysilane, diethoxymethylsilane, lithium hydride, lithium, sodium, hydrogen Ni/B, and the like. Certain acidic and Lewis acidic reagents enhance the activity of reducing reagents. Examples of such acidic reagents include: acetic acid, methanesulfonic acid, hydrochloric acid, and the like. Examples of such Lewis acidic reagents include: trimethoxyborane, triethoxyborane, aluminum trichloride, lithium chloride, vanadium trichloride, dicyclopentadienyl titanium dichloride, cesium fluoride, potassium fluoride, zinc (II) chloride, zinc (II) bromide, zinc (II) iodide, and the like.

[0069] The term "coupling reagent" refers to any reagent that will activate the carbonyl of a carboxylic acid and facilitate the formation of an ester or amide bond. The definition of "coupling reagent" includes but is not limited to: acetyl chloride, ethyl chloroformate, dicyclohexylcarbodiimide (DCC), diisopropyl carbodiiimide (DIC), 1-ethyl- 3-(3-dimethylaminopropyl) carbodiimide (EDCI), N-hydroxybenzotriazole (HOBT), N- hydroxysuccinimide (HOSu), 4-nitrophenol, pentafluorophenol, 2-(lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetrafluorob orate (TBTU), O-benzotriazole-N,N,N'N'-

tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris- pyrrolidinophosphonium hexafluorophosphate, bromo-trispyrrolidino- phosphonium hexafluorophosphate, 2-(5-norbornene-2,3-dicarboximido)-l,l,3,3-tetramethyluroniu m tetrafluoroborate (TNTU), O-(N-succinimidyl)- 1 , 1 ,3 ,3 -tetramethyluronium tetrafluorob orate (TSTU), tetramethylfluoroformamidinium hexafluorophosphate and the like.

[0070] The term "removable protecting group" or "protecting group" refers to any group which when bound to a functionality, such as the oxygen atom of a hydroxyl or carboxyl group or the nitrogen atom of an amino group, prevents reactions from occurring at these functional groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the functional group. The particular removable protecting group employed is not critical.

[0071] The definition of "hydroxyl protecting group" includes but is not limited to: a) Methyl, tert-butyl, allyl, propargyl, p-chlorophenyl, p-methoxyphenyl, p- nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, methoxymefhyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxy-benzyloxymethyl, p-nitrobenzyloxymethyl, o- nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, tert-butoxymethyl, 4- pentenyloxymethyl, tert-butyldimethylsiloxymethyl, thexyldimethylsiloxymethyl, tert- butyldiphenylsiloxymefhyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, 1-ethoxyethyl, 1- (2-chloroethoxy)ethyl, l-[2-(trimethylsilyl)ethoxy]ethyl, 1 -methyl- 1-ethoxyethyl, 1- methyl- 1 -benzyloxy ethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 1 -methyl- 1 -phenoxyethyl, 2,2,2-trichloroethyl, l-dianisyl-2,2,2-trichloroethyl, l,l,l,3,3,3-hexafiuoro-2- phenylisopropyl, 2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylselenyl)ethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydropyranyl S,S-dioxide, 1 -[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl, 1 -(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1 ,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and the like;

b) Benzyl, 2-nitrobenzyl, 2-trifluoromethylbenzyl, 4-methoxybenzyl, A- nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-phenylbenzyl, A- acylaminobenzyl, 4-azidobenzyl, 4-(methylsulfmyl)benzyl, 2,4-dimethoxybenzyl, 4-azido- 3-chlorobenzyl, 3,4-dimethoxybenzyl, 2,6-dichlorobenzyl, 2,6-difluorobenzyl, 1- pyrenylmethyl, diphenylmethyl, 4,4'-dinitrobenzhydryl, 5-benzosuberyl, triphenylmethyl (Trityl), α-naphthyldiphenylmethyl, (4-Methoxyphenyl)-diphenyl-methyl, di-(p- methoxyphenyl)-phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)- phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"- tris(levulinoyloxyphenyl)methyl, 4,4'-dimethoxy-3"-[N-(imidazolylmethyl)]trityl, 4,4'- dimethoxy-3"-[N-(imidazolylethyl)carbamoyl]trityl, 1 , 1 -bis(4-methoxyphenyl)-l '- pyrenylmethyl, 4-(17-tetrabenzo[a,c,g,I]fluorenylmethyl)-4,4'-dimethoxytrit yl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl and the like; c) Trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like; d) -C(O)R ₂₀ , where R ₂₀ is selected from the group consisting of alkyl, substituted alkyl, aryl and more specifically R ₂₀ = hydrogen, methyl, ethyl, tert-butyl, adamantyl, crotyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, methoxymethyl, triphenylmethoxymethyl, phenoxymethyl, 4-chlorophenoxymethyl, phenylmethyl, diphenylmethyl, 4-methoxycrotyl, 3-phenylpropyl, 4-pentenyl, 4-oxopentyl, 4,4-(ethylenedithio)pentyl, 5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]- A- oxopentyl, phenyl, 4-methylphenyl, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, A- methoxyphenyl, 4-phenylphenyl, 2,4,6-trimethylphenyl, α-naphthyl, benzoyl and the like; e) -C(O)OR ₂₀ , where R ₂₀ is selected from the group consisting of alkyl, substituted alkyl, aryl and more specifically R ₂₀ = methyl, methoxymethyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloromethyl, l,l-dimethyl-2,2,2-trichloroethyl, 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, isobutyl, tert-Butyl, vinyl, allyl, A- nitrophenyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-(methylthiomethoxy) ethyl, 2-dansenyl ethyl, 2-(A- nitrophenyl)ethyl, 2-(2,4-dinitrophenyl) ethyl, 2-cyano-l-phenylethyl, thiobenzyl, 4-ethoxy-

1-naphthyl and the like. Other examples of hydroxyl protecting groups are given in Greene and Wutts, above.

[0072] The definition of "amino protecting group" includes but is not limited to: a) 2-methylthio ethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2- (l,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 1- methyl-l-(triphenylphosphonio)ethyl, l,l-dimethyl-2-cyanoethyl, 2-dansylethyl, 2-(4- nitrophenyl) ethyl, 4-phenylacetoxybenzyl, 4-azidobenzyl, 4-azidomethoxybenzyl, m- chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2- (trifluoromethyl)-6-chromonytmethyl, m-nitrophenyl, 3.5-dimethoxybenzyl, 1-methyl-l- (3,5-dimethoxyphenyl)ethyl, o-nitrobenzyl, α-methylnitropiperonyl, 3,4-dimethoxy-6- nitrobenzyl, N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl. N-2-nitro-4-methoxybenzenesulfenyl, N- triphenylmethylsulfenyl, N- 1 -(2,2,2-trifluoro- 1 , 1 -diphenyl)ethylsulfenyl, N-3-nitro-2- pyridinesulfenyl, N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4- methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzene-sulfonyl, N-2,6-dimethyl-4- methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5.6-tetramethyl-4- methoxybenzenesulfonyl and the like; b) -C(O)OR ₂₀ , where R ₂₀ is selected from the group consisting of alkyl, substituted alkyl, aryl and more specifically R ₂₀ = methyl, ethyl, 9-fluorenylmethyl, 9-(2- sulfo)fluorenylmethyl. 9-(2,7-dibromo)fluorenylmethyl, 17- tetrabenzo[a,c,g,i]fluorenylmethyl. 2-chloro-3-indenylmethyl, benz[f|inden-3-ylmethyl, 2,7-di-t-butyl-[9-(l 0, 10-dioxo- 10,10,10,10-tetrahydrothloxanthyl)]methyl, 1,1- dioxobenzo[b]thiophene-2-ylmethyl, 2,2,2-trichloroethyl, 2-trirnethylsilylethyl, 2- phenyl ethyl, l-(l-adamantyl)-l -methyl ethyl, 2-chloroethyl, l.l-dimethyl-2-haloethyl, 1,1- dimethyl-2,2-dibromoethyl, 1 , 1 -dimethyl-2,2,2-trichloroethyl, 1 -methyl- 1 -(4- biphenylyl)ethyl, l-(3,5-di-tert-butylphenyl)-l-methylethyl, 2-(2'-pyridyl)ethyl, 2-(4'- pyridyl) ethyl, 2,2-bis(4'-nitrophenyl)ethyl, N-(2-pivaloylamino)-l,l-dimethylethyl, 2-[(2- nitrophenyl)dithio]-l-phenylethyl, tert-butyl, 1-adamantyl, 2-adamantyl, Vinyl, allyl, 1- lsopropylallyl, cinnamyl. 4-nitrocinnamyl, 3-(3 ^/ -pyridyl)prop-2-enyl, 8-quinolyl, N- Hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl. p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfmylbenzyl, 9-anthrylmethyl, diphenylmethyl, tert-amyl, S-benzyl thiocarbamate, butynyl, p-cyanobenzyl, cyclobutyl,

cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-(N,N'-dimethylcarboxamido)benzyl, 1 ,1 -dimethyl-3-(N,N'- dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-lodoethyl, isobomyl, isobutyl, isonicotinyl, p-(p'-methoxyphenylazo)benzyl, 1- methylcyclobutyl, 1 -methylcyclohexyl, 1 -methyl- 1 -cyclopropylmethyl, 1 -methyl- 1 -(p- phenylazo phenyl) ethyl, 1 -methyl- 1 -phenyl ethyl, 1 -methyl- 1 -4 '-pyridylethyl, phenyl, p- (phenylazo)benzyl, 2,4,6-tri-methylphenyl, 4-(trimethylammonium)benzyl, 2,4,6- trimethylbenzyl and the like. Other examples of amino protecting groups are given in Greene and Wutts, above.

[0073] The definition of "carboxyl protecting group" includes but is not limited to:

2-N-(morpholino)ethyl, choline, methyl, methoxyethyl, 9-Fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, cyanomethyl, acetol, p- bromophenacyl. α-methylphenacyl, p-methoxyphenacyl, desyl, carboxamidomethyl, p- azobenzenecarboxamido-methyl, N-phthalimidomethyl, (methoxyethoxy)ethyl, 2,2,2- trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 4-chlorobutyl, 5- chloropentyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, l,3-dithianyl-2-methyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2 -pyridyl)ethyl, 2-(p- methoxyphenyl) ethyl, 2-(diphenylphosphino)ethyl, 1 -methyl- 1 -phenyl ethyl, 2-(4-acetyl-2- nitrophenyl) ethyl, 2-cyanoethyl, heptyl, tert-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, 2,4-dimethyl-3-pentyl, cyclopentyl, cyclohexyl, allyl, methallyl, 2-methylbut-3-en-2-yl, 3- methylbut-2-(prenyl), 3-buten-l-yl, 4-(trimethylsilyl)-2-buten-l-yl, cinnamyl, α- methylcinnamyl, propargyl, phenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl, 2,6-di-tert- butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl, pentafluorophenyl, benzyl, triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9- anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl. 5-dibenzosuberyl, 1-pyrenylmethyl, 2- (trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o- nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2.6-dimethoxybenzyl, 4- (methylsulfmyl)benzyl, 4-Sulfobenzyl, 4-azidomethoxybenzyl, 4-{a/-[l-(4,4-dimethyl-2,6- dioxocyclohexylidene) -3 -methylbutyl] amino} benzyl, piperonyl, 4-picolyl, trimethylsilyl,

triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, di-tert- butylmethylsilyl, triisopropylsilyl and the like. Other examples of carboxyl protecting groups are given in Greene and Wutts, above.

[0074] The definition of "thiol protecting group" includes but is not limited to: a) Alkyl, benzyl, 4-methoxybenzyl, 2-hydroxybenzyl, 4-hydroxybenzyl, 2- acetoxybenzyl, 4-acetoxybenzyl, 4-nitrobenzyl, 2,4,6-trimethylbenzyl, 2,4,6- trimethoxybenzyl, 4-picolyl, 2-quinolinylmethyl, 2-picolyl n-oxido, 9-anthrylmethyl, 9- fluorenylmethyl, xanthenyl, ferrocenylmethyl and the like; b) Diphenylmethyl, bis(4-methoxyphenyl)methyl, 5-dibenzosuberyl, triphenylmethyl, diphenyl-4-pyridylmethyl, phenyl, 2,4-dinitrophenyl, tert-butyl, 1- adamantyl and the like; c) Methoxymethyl, isobutoxymethyl, benzyloxymethyl, 2-tetrahydropyranyl, benzylthiomethyl, phenylthiomethyl, acetamidomethyl, trimethylacetamidomethyl, benzamidomethyl, allyloxycarbonylaminomethyl, phenylacetamidomethyl, phthalimidomethyl, acetyl, carboxy-, cyanomethyl and the like; d) (2-nitro-l-phenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-(4'-pyridyl)ethyl, 2- cyanoethyl, 2-(trimethylsilyl)ethyl, 2,2-bis(carboethoxy)ethyl, l-(3-nitrophenyl)-2-benzoyl- ethyl, 2-phenylsulfonyl ethyl, l-(4-methylphenylsulfonyl)-2-methylpro4-2-yl and the like; e) Trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl and the like; f) Benzoyl, trifluoroacetyl, N-[[(4-biphenylyl)isopropoxy]carbonyl]-N-methyl- γ-aminothiobutyrate, N-(t-butoxycarbonyl)-N-methyl-γ-aminothiobutyrate and the like; g) 2,2,2-Trichloroethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, A- methoxybenzyloxycarbonyl and the like; h) N-(Ethylamino)carbonyl, N-(methoxymethylamino)carbonyl and the like; i) Ethylthio, tert-butylthio, phenylthio, substituted phenylthio and the like; j) (Dimethylphosphino)thioyl, (diphenylphosphino)thioyl and the like; k) Sulfonate, alkyloxycarbonylthio, benzyloxycarbonylthio, 3-nitro-2- pyridinethio and the like;

1) Tricarbonyl[l,2,3,4,5-η]-2,4-cyclohexadien-l-yl]-iron(l+) and the like. Other examples of thiol protecting groups are given in Greene and Wutts, above.

[0075] The term "Amino acid" refers to any of the naturally occurring amino acids, as well as synthetic analogs and derivatives thereof. Alpha-Amino acids comprise a carbon atom to which is bonded an amino group, a carboxy group, a hydrogen atom, and a distinctive group referred to as a "side chain". The side chains of naturally occurring amino acids are well known in the art and include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), arylalkyl (e.g., as in phenylalanine), substituted arylalkyl (e.g., as in tyrosine), hetero arylalkyl (e.g., as in tryptophan, histidine) and the like. One of skill in the art will appreciate that the term "amino acid" can also include beta-, gamma-, delta-, omega- amino acids, and the like. Unnatural amino acids are also known in the art, as set forth in, Natchus, M. G. Organic Synthesis: Theory and Applications (2001), 5, 89-196; Ager, D. J. Current Opinion in Drug Discovery & Development (2001), 4(6), 800; Reginato, G. Recent Research Developments in Organic Chemistry (2000), 4(Pt. 1), 351- 359; Dougherty, D. A. Current Opinion in Chemical Biology (2000), 4(6), 645-652; Lesley, S. A. Drugs and the Pharmaceutical Sciences (2000), 101(Peptide and Protein Drug Analysis), 191-205; Pojitkov, A. E. Journal of Molecular Catalysis B: Enzymatic (2000), 10(1-3), 47-55; Ager, D. J. Speciality Chemicals (1999), 19(1), 10-12, and all references cited therein. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as alpha, alpha-disubstituted amino acids and other unconventional amino acids may also be suitable components for compounds of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, 3- methylhistidine, 5-hydroxylysine, and other similar amino acids and imino acids (e.g., A- hydroxyproline) .

[0076] The term "N-protected amino acid" refers to any amino acid which has a protecting group bound to the nitrogen of the amino functionality. This protecting group prevents reactions from occurring at the amino functional group and can be removed by conventional chemical or enzymatic steps to reestablish the amino functional group. The particular protecting group employed is not critical.

[0077] The term "O-protected amino acid" refers to any amino acid which has a protecting group bound to the oxygen of the carboxyl functionality. This protecting group prevents reactions from occurring at the carboxyl functional group and can be removed by conventional chemical or enzymatic steps to reestablish the carboxyl functional group. The particular protecting group employed is not critical.

[0078] The term "Prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, "Drug Latentiation" in Jucker, ed. Progress in Drug Research 4:221-294 (1962); Morozowich et al., "Application of Physical Organic Principles to Prodrug Design" in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APHA Acad. Pharm. Sci. (1977); Bioreversible Carriers in Drug in Drug Design, Theory and Application, E. B. Roche, ed., APHA Acad. Pharm. Sci. (1987); Design of Prodrugs, H. Bundgaard, Elsevier (1985); Wang et al. "Prodrug approaches to the improved delivery of peptide drug" in Curr. Pharm. Design. 5(4):265-287 (1999); Pauletti et al. (1997) Improvement in peptide bioavailability: Peptidomimetics and Prodrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al. (1998) "The Use of Esters as Prodrugs for Oral Delivery of .beta.-Lactam antibiotics," Pharm. Biotech. l l,:345-365; Gaignault et al. (1996) "Designing Prodrugs and Bioprecursors I. Carrier Prodrugs," Pract. Med. Chem. 671-696; Asgharnejad, "Improving Oral Drug Transport", in Transport Processes in Pharmaceutical Systems, G. L. Amidon, P. I. Lee and E. M. Topp, Eds., Marcell Dekker, p. 185-218 (2000); Balant et al., "Prodrugs for the improvement of drug absorption via different routes of administration", Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53 (1990); Balimane and Sinko, "Involvement of multiple transporters in the oral absorption of nucleoside analogues", Adv. Drug Delivery Rev., 39(1-3): 183-209 (1999); Browne, "Fosphenytoin (Cerebyx)", Clin. Neuropharmacol. 20(1): 1-12 (1997); Bundgaard, "Bioreversible derivatization of drugs— principle and applicability to improve the therapeutic effects of drugs", Arch. Pharm. Chemi 86(1): 1-39 (1979); Bundgaard H. "Improved drug delivery by the prodrug approach", Controlled Drug

Delivery 17: 179-96 (1987); Bundgaard H. "Prodrugs as a means to improve the delivery of peptide drugs", Adv. Drug Delivery Rev. 8(1): 1-38 (1992); Fleisher et al. "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Adv. Drug Delivery Rev. 19(2): 115-130 (1996); Fleisher et al. "Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting", Methods Enzymol. 112 (Drug Enzyme Targeting, Pt. A): 360-81, (1985); Farquhar D, et al., "Biologically Reversible Phosphate-Protective Groups", J. Pharm. Sci., 72(3): 324-325 (1983); Freeman S, et al., "Bioreversible Protection for the Phospho Group: Chemical Stability and Bioactivation of Di(4-acetoxy-benzyi) Methylphosphonate with Carboxyesterase," J. Chem. Soc, Chem. Commun., 875-877 (1991); Friis and Bundgaard, "Prodrugs of phosphates and phosphonates: Novel lipophilic alpha-acyloxyalkyl ester derivatives of phosphate- or phosphonate containing drugs masking the negative charges of these groups", Eur. J. Pharm. Sci. 4: 49-59 (1996); Gangwar et al., "Pro-drug, molecular structure and percutaneous delivery", Des. Biopharm. Prop. Prodrugs Analogs, [Symp.] Meeting Date 1976, 409-21. (1977); Nathwani and Wood, "Penicillins: a current review of their clinical pharmacology and therapeutic use", Drugs 45(6): 866-94 (1993); Sinhababu and Thakker, "Prodrugs of anticancer agents", Adv. Drug Delivery Rev. 19(2): 241-273 (1996); Stella et al., "Prodrugs. Do they have advantages in clinical practice?", Drugs 29(5): 455-73 (1985); Tan et al. "Development and optimization of anti-HIV nucleoside analogs and prodrugs: A review of their cellular pharmacology, structure- activity relationships and pharmacokinetics", Adv. Drug Delivery Rev. 39(1-3): 117-151 (1999); Taylor, "Improved passive oral drug delivery via prodrugs", Adv. Drug Delivery Rev., 19(2): 131-148 (1996); Valentino and Borchardt, "Prodrug strategies to enhance the intestinal absorption of peptides", Drug Discovery Today 2(4): 148-155 (1997); Wiebe and Knaus, "Concepts for the design of anti-HIV nucleoside prodrugs for treating cephalic HIV infection", Adv. Drug Delivery Rev.: 39(l-3):63-80 (1999); Waller et al., "Prodrugs", Br. J. Clin. Pharmac. 28: 497-507 (1989).

[0079] The term "halogen", "halide" or "halo" includes fluorine, chlorine, bromine, and iodine.

[0080] The terms "alkyl" and "substituted alkyl" are interchangeable and include substituted and unsubstituted Ci-Cio straight chain saturated aliphatic hydrocarbon groups, substituted and unsubstituted C ₂ -Ci _O straight chain unsaturated aliphatic

hydrocarbon groups, substituted and unsubstituted C ₄ -C10 branched saturated aliphatic hydrocarbon groups, substituted and unsubstituted C ₄ -C ₁₀ branched unsaturated aliphatic hydrocarbon groups, substituted and unsubstituted C ₃ -C ₈ cyclic saturated aliphatic hydrocarbon groups, substituted and unsubstituted C ₅ -C ₈ cyclic unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "alkyl" shall include but is not limited to: methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (^-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, adamantyl, norbornyl and the like. Alkyl substituents are independently selected from the group consisting of halogen, -OH, -SH, -NH ₂ , -CN, -NO ₂ , =0, -CH ₂ , trihalomethyl, carbamoyl, arylCo-i _O alkyl, heteroarylCo-ioalkyl, Ci-^alkyloxy, arylCo-i ₀ alkyloxy, C _{1- l} oalkylthio, arylCo-ioalkylthio, Ci-ioalkylamino, arylCo-i ₀ alkylamino, N-aryl-N-C _{0- l} oalkylamino, Q-ioalkylcarbonyl, arylCo-ioalkylcarbonyl, Ci.ioalkylcarboxy, arylCo- _l oalkylcarboxy, Ci-ioalkylcarbonylamino, arylCQ.iQalkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, hydroxypyronyl, -Co- _I QaIlCyICOOR _2I and -Co-i ₀ alkylCONR ₂₂ R ₂₃ wherein R ₂₁ , R ₂₂ and R ₂₃ are independently selected from the group consisting of hydrogen, alkyl, aryl, or R ₂₂ and R ₂₃ are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined herein.

[0081] The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term "alkyloxyalkyl" represents an alkyloxy group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

[0082] The term "alkyloxycarbonyl" (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl) represents a substituted or unsubstituted alkyloxy group as defined above having the indicated number of carbon atoms attached through a carbonyl bridge.

[0083] The term "alkylthio" (e.g. methylthio, ethylthio, propylthio, cyclohexenylthio and the like) represents a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term "alkylthioalkyl" represents an alkylthio group attached through an alkyl or substituted alkyl group as defined above having the indicated number of carbon atoms.

[0084] The term "alkylamino" (e.g. methylamino, diethylamino, butylamino, N- propyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, and the like) represents one or two substituted or unsubstituted alkyl groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The substituted or unsubstituted alkyl groups maybe taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 10 carbon atoms with at least one substituent as defined above. The term "alkylaminoalkyl" represents an alkylamino group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0085] The term "alkylhydrazino" (e.g. methylhydrazino, diethylhydrazino, butylhydrazino, (2-cyclopentyl)propylhydrazino, cyclohexanehydrazino, and the like) represents one or two substituted or unsubstituted alkyl groups as defined above having the indicated number of carbon atoms attached through a nitrogen atom of a hydrazine bridge. The substituted or unsubstituted alkyl groups maybe taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 10 carbon atoms with at least one substituent as defined above. The term "alkylhydrazinoalkyl" represents an alkylhydrazino group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0086] The term "alkylcarbonyl" (e.g. cyclooctylcarbonyl, pentylcarbonyl, 3- hexenylcarbonyl and the like) represents a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. The term "alkylcarbonylalkyl" represents an alkylcarbonyl group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0087] The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy, 3- pentenylcarboxy and the like) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen. The term "alkylcarboxyalkyl"

represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.

[0088] The term "alkylcarbonylamino" (e.g. hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl and the like) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen group may itself be substituted with a substituted or unsubstituted alkyl or aryl group. The term "alkylcarbonylaminoalkyl" represents an alkylcarbonylamino group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0089] The term "alkylcarbonylhydrazino" (e.g. ethylcarbonylhydrazino, tert- butylcarbonylhydrazino and the like) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of a hydrazino group.

[0090] The term "aryl" represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-phenyl, 4-naphtyl and the like). The aryl substituents are independently selected from the group consisting of halogen, -OH, -SH, - CN, -NO ₂ , trihalomethyl, hydroxypyronyl, Q.ioalkyl, arylC _o- ioalkyl, Co-ioalkyloxyCo- _l oalkyl, arylCo-ioalkyloxyCo-ioalkyl, Co-ioalkylthioCo-ioalkyl, arylCo-ioalkylthioCo-ioalkyl, Co-ioalkylaminoCo-ioalkyl, arylCo-ioalkylaminoC _0- ioalkyl, N-aryl-N-C _0- ioalkylaminoCo- _l oalkyl, Ci-ioalkylcarbonylCo-ioalkyl, arylCo-ioalkylcarbonylCo-ioalkyl, Ci-ioalkylcarboxyCo- _l oalkyl, arylCo-ioalkylcarboxyCo-ioalkyl, Ci-ioalkylcarbonylaminoCo-ioalkyl, arylCo- ₁₀ alkylcarbonylaminoCo-ioalkyl, -Co- _IO aIlCyICOOR _2I , and -Co _-10 alkylCONR ₂₂ R ₂₃ wherein R _2b R ₂ 2 and R ₂₃ are independently selected from the group consisting of hydrogen, alkyl, aryl or R ₂₂ and R ₂₃ are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined above.

[0091] The definition of "aryl" includes but is not limited to phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl and the like.

[0092] The term "arylalkyl" (e.g. (4-hydroxyphenyl)ethyl, (2- aminonaphthyl)hexenyl and the like) represents an aryl group as defined above attached

through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0093] The term "arylcarbonyl" (e.g. 2-thiophenylcarbonyl, 3- methoxyanthrylcarbonyl and the like) represents an aryl group as defined above attached through a carbonyl group.

[0094] The term "arylalkylcarbonyl" (e.g. (2,3- dimethoxyphenyl)propylcarbonyl, (2-chloronaphthyl)pentenyl-carbonyl and the like) represents an arylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.

[0095] The term "aryloxy" (e.g. phenoxy, naphthoxy, 3-methylphenoxy, and the like) represents an aryl or substituted aryl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term "aryloxyalkyl" represents an aryloxy group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0096] The term "aryloxycarbonyl" (e.g. phenoxycarbonyl, naphthoxycarbonyl) represents a substituted or unsubstituted aryloxy group as defined above having the indicated number of carbon atoms attached through a carbonyl bridge.

[0097] The term "arylthio" (e.g. phenylthio, naphthylthio, 3-bromophenylthio, and the like) represents an aryl or substituted aryl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term "arylthioalkyl" represents an arylthio group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0098] The term "arylamino" (e.g. phenylamino, diphenylamino, naphthylamino, N-phenyl-N-naphthylamino, o-methylphenylamino, p- methoxyphenylamino, and the like) represents one or two aryl groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The term "arylaminoalkyl" represents an arylamino group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylamino" represents an aryl group attached through an alkylamino group as defined above having the indicated number of carbon atoms. The term "N-aryl-N- alkylamino" (e.g. N-phenyl-N-methylamino, N-naphthyl-N-butylamino, and the like) represents one aryl and one a substituted or unsubstituted alkyl group as defined above

having the indicated number of carbon atoms independently attached through an amine bridge.

[0099] The term "arylhydrazino" (e.g. phenylhydrazino, naphthylhydrazino, 4- methoxyphenylhydrazino, and the like) represents one or two aryl groups as defined above having the indicated number of carbon atoms attached through a hydrazine bridge. The term "arylhydrazinoalkyl" represents an arylhydrazino group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylhydrazino" represents an aryl group attached through an alkylhydrazino group as defined above having the indicated number of carbon atoms. The term "N-aryl-N-alkylhydrazino" (e.g. N-phenyl-N-methylhydrazino, N-naphthyl-N- butylhydrazino, and the like) represents one aryl and one a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms independently attached through an amine atom of a hydrazine bridge.

[0100] The term "arylcarboxy" (e.g. phenylcarboxy, naphthylcarboxy, 3- fluorophenylcarboxy and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge. The term "arylcarboxyalkyl" represents an arylcarboxy group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms.

[0101] The term "arylcarbonylamino" (e.g. phenylcarbonylamino, naphthylcarbonylamino, 2-methylphenylcarbonylamino and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen group may itself be substituted with an a substituted or unsubstituted alkyl or aryl group. The term "arylcarbonylaminoalkyl" represents an arylcarbonylamino group attached through a substituted or unsubstituted alkyl group as defined above having the indicated number of carbon atoms. The nitrogen group may itself be substituted with a substituted or unsubstituted alkyl or aryl group.

[0102] The term "arylcarbonylhydrazino" (e.g. phenylcarbonylhydrazino, naphthylcarbonylhydrazino, and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of a hydrazino group.

[0103] The terms "heteroaryl", "heterocycle" or "heterocyclic" refers to a monovalent unsaturated group having a single ring or multiple condensed rings, from 1 to 8

carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring. The heteroaryl groups in this invention can be optionally substituted with 1 to 3 substituents selected from the group consisting of: halogen, -OH, - SH, -CN, -NO ₂ , trihalomethyl, hydroxypyronyl, Ci.ioalkyl, arylCo-ioalkyl, Co-ioalkyloxyCo. _l oalkyl, Co-ioalkylthioCo-ioalkyl, arylC _0- ioalkylthioCo-ioalkyl, Co-ioalkylaminoCo-ioalkyl, arylCo-ioalkylaminoCo-ioalkyl, N-aryl-N-Co-ioalkylaminoCo- i _O alkyl, Ci-ioalkylcarbonylCo-ioalkyl, arylCo-ioalkylcarbonylCo-ioalkyl, Ci-ioalkylcarboxyCo- i _O alkyl, arylCo-ioalkylcarboxyCo-i ₀ alkyl, Ci-ioalkylcarbonylaminoCo-ioalkyl, arylCo- loalkylcarbonylaminoCo-ioalkyl, -Co-ioalkylCOOR ₂ i, and -Co-ioalkylCONR ₂₂ R ₂₃ wherein R _2I , R ₂₂ and R ₂₃ are independently selected from the group consisting of hydrogen, alkyl, aryl, or R ₂₂ and R ₂₃ are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined above.

[0104] The definition of "heteroaryl" includes but is not limited to thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, pyrrolyl-2,5-dione, 3-pyrrolinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, indolizinyl, indazolyl, phthalimidyl (or isoindoly- 1,3-dione), imidazolyl, 2H-imidazolinyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolidinyl-2,5-dione, imidazolidinyl-2,4-dione, 2-thioxo-imidazolidinyl-4-one, imidazolidinyl-2,4-dithione, thiazolidinyl-2,4-dione, 4- thioxo-thiazolidinyl-2-one, piperazinyl-2,5-dione, tetrahydro-pyridazinyl-3,6-dione, 1,2- dihydro-[l,2,4,5]tetrazinyl-3,6-dione, [l,2,4,5]tetrazinanyl-3,6-dione, dihydro-pyrimidinyl- 2,4-dione, pyrimidinyl-2,4,6-trione, lH-pyrimidinyl-2,4-dione, 5-iodo-lH-pyrimidinyl-2,4- dione, 5-chloro-lH-pyrimidinyl-2,4-dione, 5-methyl-lH-pyrimidinyl-2,4-dione, 5- isopropyl-lH-pyrimidinyl-2,4-dione, 5-propynyl-lH-pyrimidinyl-2,4-dione, 5- trifluoromethyl-lH-pyrimidinyl-2,4-dione, 6-amino-9H-purinyl, 2-amino-9H-purinyl, 4- amino-lH-pyrimidinyl-2-one, 4-amino-5-fluoro-lH-pyrimidinyl-2-one, 4-amino-5-methyl- lH-pyrimidinyl-2-one, 2-amino-l,9-dihydro-purinyl-6-one, l,9-dihydro-purinyl-6-one, IH-

[l,2,4]triazolyl-3-carboxylic acid amide, 2,6-diamino-N ₆ -cyclopropyl-9H-purinyl, 2- amino-6-(4-methoxyphenylsulfanyl)-9H-purinyl, 5,6-dichloro-lH-benzoimidazolyl, 2- isopropylamino-5,6-dichloro-lH-benzoimidazolyl, 2-bromo-5,6-dichloro-lH- benzoimidazolyl, 5-methoxy-lH-benzoimidazolyl, 3-ethylpyridyl, 5-methyl-2-phenyl- oxazolyl, 5-methyl-2-thiophen-2-yl-oxazolyl, 2-furan-2-yl-5-methyl-oxazolyl, 3-methyl- 3H-quinazolin-4-one, 4-methyl-2H-phthalazin-l -one, 2-Emyl-6-methyl-3H-pyrimidin-4- one, 5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine and the like. For the purposes of this application, the terms "heteroaryl", "heterocycle" or "heterocyclic" do not include carbohydrate rings (i.e. mono- or oligosaccharides).

[0105] The term "saturated heterocyclic" represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic saturated heterocyclic group covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 1-piperidinyl, 4- piperazinyl and the like).

[0106] The saturated heterocyclic substituents are independently selected from the group consisting of halo, -OH, -SH, -CN, -NO ₂ , trihalomethyl, hydroxypyronyl, C ₁ . ₁₀ alkyl, arylCo _-lo alkyl, Co-^alkyloxyCo-ioalkyl, arylCo-ioalkyloxyCo-ioalkyl, Co- ioalkylthioCcMoalkyl, arylCo-ioalkylthioCo-ioalkylj Co-ioalkylaminoCo-ioalkyl, arylC _0- i oalkylaminoCo _-10 alkyl, N-aryl-N-C _0- i oalkylaminoCo-i oalkyl, C ₁ . _\ oalkylcarbonylC _0- i oalkyl, arylCo.iQalkylcarbonylCo-iQalkyl, d-ioalkylcarboxyCo-ioalkyl, arylCo-ioalkylcarboxyCo- _l oalkyl, Q-ioalkylcarbonylammoCo-ioalkyl, arylCo-ioalkylcarbonylaminoCo-ioalkyl, -Co- i ₀ alkylCOOR ₂₁ , and -Co-ioalkylCONR ₂₂ R ₂₃ wherein R ₂ i, R ₂₂ and R ₂₃ are independently selected from the group consisting of hydrogen, alkyl, aryl, or R ₂₂ and R ₂₃ are taken together with the nitrogen to which they are attached forming a saturated cyclic or unsaturated cyclic system containing 3 to 8 carbon atoms with at least one substituent as defined above.

[0107] The definition of saturated heterocyclic includes but is not limited to pyrrolidinyl, pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithienyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and the like.

[0108] The term "alpha-beta-unsaturated carbonyl" refers to a molecule that has a carbonyl group directly attached to a double or triple bonded carbon and which would be obvious to one of ordinary skill and knowledge in the art. The definition of alpha-beta-

unsaturated carbonyl includes but is not limited to acrolein, methyl vinyl ketone, and the like.

[0109] The term "acetal" refers to a molecule that contains a carbon atom Ci that is directly attached to a hydrogen atom (Hi), a substituted carbon atom (C ₂ ) and two oxygen atoms (Oi and O ₂ ). These oxygen atoms are in turn attached to other substituted carbon atoms (C ₃ and C ₄ ), which would be obvious to one of ordinary skill and knowledge in the art. The definition of acetal includes but is not limited to 1,1-dimethoxypropane, 1,1- bis-allyloxybutane and the like.

[0110] The term "cyclic acetal" refers to an acetal as defined above where C ₃ and C ₄ , together with the oxygen atoms to which they are attached, combine thru an alkyl bridge to form a 5- to 10-membered ring, which would be obvious to one of ordinary skill and knowledge in the art. The definition of cyclic acetal includes but is not limited to 2- methyl-[l,3]dioxolane, 2-ethyl-[l,3]dioxane, 2-phenyl-[l,3]dioxane, 2 2-phenyl- hexahydro-pyrano[3,2-d][l,3]dioxine and the like.

5

[0111] The term "ketal" refers to a molecule that contains a carbon atom Ci that is directly attached to two substituted carbon atom (C ₂ and C ₃ ) and two oxygen atoms (Oi and O ₂ ). These oxygen atoms are in turn attached to other substituted carbon atoms (C ₄ and C ₅ ), which would be obvious to one of ordinary skill and knowledge in the art. The definition of acetal includes but is not limited to 2,2-dimethoxy-butane, 3,3-diethoxy- pentane and the like.

[0112] The term "cyclic ketal" refers to a ketal as defined above where C ₄ and C ₅ , together with the oxygen atoms to which they are attached, combine thru an alkyl bridge to form a 5- to 10-membered ring, which would be obvious to one of ordinary skill and knowledge in the art. The definition of cyclic acetal includes but is not limited to

2,2,4,5-tetramethyl-[l,3]dioxolane, 2,2-diethyl-[l,3]dioxepane, 2,2-dimethyl-hexahydro- pyrano[3,2-d][l,3]dioxine and the like.

5

[0113] A "C-carboxy" group refers to a -C(=O)OR groups where R is as defined herein.

[0114] An "acetyl" group refers to a -C(O)CH ₃ , group.

[0115] A "trihalomethanesulfonyl" group refers to a X ₃ CS(=O) ₂ - group where X is a halogen.

[0116] A "cyano" group refers to a -CN group.

[0117] An "isocyanato" group refers to a -NCO group.

[0118] A "thiocyanato" group refers to a -CNS group.

[0119] An "isothiocyanato" group refers to a -NCS group.

[0120] A "sulfmyl" group refers to a -S(=O)-R group, with R as defined herein.

[0121] A "S-sulfonamido" group refers to a -S(=O) ₂ NR, group, with R as defined herein.

[0122] A "N-sulfonamido" group refers to a RS(=O) ₂ NH- group with R as defined herein.

[0123] A "trihalomethanesulfonamido" group refers to a X ₃ CS(=O) ₂ NR- group with X and R as defined herein.

[0124] An "O-carbamyl" group refers to a -OC(=O)-NR, group-with R as defined herein.

[0125] An "N-carbamyl" group refers to a R0C(=0)NH- group, with R as defined herein.

[0126] An "O-thiocarbamyl" group refers to a -OC(=S)-NR, group with R as defined herein.

[0127] An "N-thiocarbamyl" group refers to an ROC(=S)NH- group, with R as defined herein.

[0128] A "C-amido" group refers to a -C(=O)-NR ₂ group with R as defined herein.

[0129] An "N-amido" group refers to a RQ=O)NH- group, with R as defined herein.

[0130] The term "perhaloalkyl" refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[0131] In another embodiment of the invention, there are provided pharmaceutical compositions comprising at least one of the compounds of the invention, or a pharmaceutically acceptable pro-drug or salt thereof, in a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a combination thereof, for enteral, parenteral, topical or ocular administration.

[0132] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0133] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0134] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0135] In another embodiment of the invention, there are provided pharmaceutical compositions comprising at least one of the compounds of the invention, in a pharmaceutically acceptable vehicle, for the treatment of conditions involving cancer, cellular differentiation and proliferation, wound healing, metabolism of lipids and

carbohydrates, obesity, atherosclerosis, arteriosclorosis, intermittent claudication, cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary heart disease, heart insufficiency, cataracts, diabetes, type 1 diabetes, type 2 diabetes, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, metabolic syndrom X, cystic fibrosis related diabetes, polycistic ovarian syndrom, gestational diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, hypertension, essential hypertension, acute hypertensive emergency, hypertriglyceridemia, insulin resistance, myocardial ischemia, tissue ischemia, energy homoeostasis, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, inflammatory or immune disease, rheumatoid arthritis, asthma, acute coronary syndrome, angia pectoris, unstable angia, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non- Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, inflammatory bowel disease, irritable bowel syndrome, chronic obstructive pulmonary disease, or psoriasis.

[0136] In another embodiment of the invention, there are provided pharmaceutical compositions comprising at least one of the compounds of the invention in combination with other therapeutic agents for the treatment of conditions involving cancer, cellular differentiation and proliferation, wound healing, metabolism of lipids and carbohydrates, obesity, atherosclerosis, arteriosclorosis, intermittent claudication, cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary heart disease, heart insufficiency, cataracts, diabetes, type 1 diabetes, type 2 diabetes, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, metabolic syndrom X, cystic fibrosis related diabetes, polycistic ovarian syndrom, gestational diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, hypertension, essential hypertension, acute hypertensive emergency, hypertriglyceridemia, insulin

resistance, myocardial ischemia, tissue ischemia, energy homoeostasis, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, inflammatory or immune disease, rheumatoid arthritis, asthma, acute coronary syndrome, angia pectoris, unstable angia, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non- Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, inflammatory bowel disease, irritable bowel syndrome, chronic obstructive pulmonary disease, or psoriasis. Examples of other therapeutic agents include, but are not limited to, other PPAR modulators such as such as thiazolidinediones, Actos, Pioglitazone, Avandia, Rosiglitazone, Ciglitazone, Darglitazone, Englitazone, Troglitazone and the like, insulin and insulin analogs such as regular insulin, Aspart (Novolog), insulin Glargine (Lantus), Lente insulin, Lispro insulin (Humalog), NPH insulin, premixed insulin, Ultralente insulin, GLP-I (7-37) (insulinotropin) and GLP-I (7-36)-NH ₂ and the like, sulfonyl ureas such as Amaryl, Glimepiride, DiaBeta, Glyburide, Diabinese, Chlorpropamide, Dymelor, Acetohexamide, Glucotrol, Glipizide, Glucotrol XL, Glipizide, Glynase PresTab, Glyburide, Micronase, Glyburide, Orinase, Tolbutamide, Tolinase, Tolazamide and the like, biguanides such as Glucophage, metformin, Glucophage XR, metformin hydrochloride extended release and the like, alpha-glucosidase inhibitors such as Glyset, Miglitol, Precose, Acarbose and the like, meglitinides such as Prandin, Repaglinide and the like, D-phenylalanine derivatives such as Starlix, Nateglinide and the like, combination oral agents such as Glucovance and the like, anti-hypercholesteremics such as Policosanol, Octacosanol, and the like, statins such as Lipitor, Atorvastatin, Zocor, Simvastatin, Pravachol, Pravastatin, Lescol, Fluvastatin, Mevacor, Lovastatin, Crestor, Rosuvastatin and the like, Acipimox, Benfiuorex, Buformin, Camiglibose, Clomoxir, Deriglidole, Efaroxan, Emiglitate, Etomoxir, Fenfluramine, Fluparoxan, Glibenclamide, Idazoxan, Isaglidole, Linogliride, LysPro insulin, MDL-25,637, MDL-73,945, Meglitinide, Midaglizole, Naglivan, Nateglinide, Phenformin, Symlin, Voglibose, AC-2993, BRL-35135, BRL- 37344, CL-316,243, ICI-D7114, L-386,398, RO-16-8714, WAG-994, alpha 2-antagonists, imidazolines, fatty acid oxidation inhibitors, beta-agonists, phosphodiesterase Inhibitors, lipid-lowering agents, antiobesity agents, vanadate, vanadium complexes, peroxovanadium complexes, amylin antagonists, glucagon antagonists, gluconeogenesis inhibitors, somatostatin analogs and antagonists, or antilipolytic agents.

[0137] In another embodiment of the invention, there are provided methods of modulating cellular differentiation and proliferation comprising contacting said cells or tissues with one or more of the compounds or compositions of the invention.

[0138] In another embodiment of the invention, there are provided methods of treating a mammalian subject, particularly a human, suspected of having, or being prone to a disease or condition involving cancer, cellular differentiation and proliferation, wound healing, metabolism of lipids and carbohydrates, obesity, atherosclerosis, arteriosclorosis, intermittent claudication, cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease, early coronary heart disease, heart insufficiency, cataracts, diabetes, type 1 diabetes, type 2 diabetes, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, metabolic syndrom X, cystic fibrosis related diabetes, polycistic ovarian syndrom, gestational diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, hypertension, essential hypertension, acute hypertensive emergency, hypertriglyceridemia, insulin resistance, myocardial ischemia, tissue ischemia, energy homoeostasis, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, inflammatory or immune disease, rheumatoid arthritis, asthma, acute coronary syndrome, angia pectoris, unstable angia, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non-Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, inflammatory bowel disease, irritable bowel syndrome, chronic obstructive pulmonary disease, or psoriasis, by administering a therapeutically or prophylactically effective amount of one or more of the compounds or compositions of the invention.

[0139] In some embodiments, in the above methods, the one or more of the compounds or compositions of the invention is administered in combination with other therapeutic agents for treatment of conditions involving cancer, cellular differentiation and proliferation, wound healing, metabolism of lipids and carbohydrates, obesity, atherosclerosis, arteriosclorosis, intermittent claudication, cardiovascular disease, cardiomyopathy, cardiac hypertrophy, left ventricular hypertrophy, coronary artery disease,

early coronary heart disease, heart insufficiency, cataracts, diabetes, type 1 diabetes, type 2 diabetes, type 1.5 diabetes, latent autoimmune diabetes in adults, maturity onset diabetes, beta-cell apoptosis, hemochromatosis induced diabetes, impaired glucose tolerance, metabolic syndrom X, cystic fibrosis related diabetes, polycistic ovarian syndrom, gestational diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, hyperlipoproteinemia, hypertension, essential hypertension, acute hypertensive emergency, hypertriglyceridemia, insulin resistance, myocardial ischemia, tissue ischemia, energy homoeostasis, exercise tolerance, chronic heart failure, mild chronic heart failure, arrhythmia, cardiac dysrythmia, syncopy, heart attack, myocardial infarction, Q-wave myocardial infarction, stroke, inflammatory or immune disease, rheumatoid arthritis, asthma, acute coronary syndrome, angia pectoris, unstable angia, cardiac bypass reocclusion, diastolic dysfunction, systolic dysfunction, non-Q-wave cardiac necrosis, catabolic changes after surgery, acute pancreatitis, inflammatory bowel disease, irritable bowel syndrome, chronic obstructive pulmonary disease, or psoriasis. Examples of other therapeutic agents include, but are not limited to, other PPAR modulators such as such as thiazolidinediones, Actos, Pioglitazone, Avandia, Rosiglitazone, Ciglitazone, Darglitazone, Englitazone, Troglitazone and the like, insulin and insulin analogs such as regular insulin, Aspart (Novolog), insulin Glargine (Lantus), Lente insulin, Lispro insulin (Humalog), NPH insulin, premixed insulin, Ultralente insulin, GLP-I (7-37) (insulino tropin) and GLP-I (7-36)-NH ₂ and the like, sulfonyl ureas such as Amaryl, Glimepiride, DiaBeta, Glyburide, Diabinese, Chlorpropamide, Dymelor, Acetohexamide, Glucotrol, Glipizide, Glucotrol XL, Glipizide, Glynase PresTab, Glyburide, Micronase, Glyburide, Orinase, Tolbutamide, Tolinase, Tolazamide and the like, biguanides such as Glucophage, metformin, Glucophage XR, metformin hydrochloride extended release and the like, alpha-glucosidase inhibitors such as Glyset, Miglitol, Precose, Acarbose and the like, meglitinides such as Prandin, Repaglinide and the like, D-phenylalanine derivatives such as Starlix, Nateglinide and the like, combination oral agents such as Glucovance and the like, anti-hypercholesteremics such as Policosanol, Octacosanol, and the like, statins such as Lipitor, Atorvastatin, Zocor, Simvastatin, Pravachol, Pravastatin, Lescol, Fluvastatin, Mevacor, Lovastatin, Crestor, Rosuvastatin and the like, Acipimox, Benfluorex, Buformin, Camiglibose, Clomoxir, Deriglidole, Efaroxan, Emiglitate,

Etomoxir, Fenfluramine, Fluparoxan, Glibenclamide, Idazoxan, Isaglidole, Linogliride, LysPro insulin, MDL-25,637, MDL-73,945, Meglitinide, Midaglizole, Naglivan, Nateglinide, Phenformin, Symlin, Voglibose, AC-2993, BRL-35135, BRL-37344, CL- 316,243, ICI-D7114, L-386,398, RO-16-8714, WAG-994, alpha 2-antagonists, imidazolines, fatty acid oxidation inhibitors, beta-agonists, phosphodiesterase Inhibitors, lipid-lowering agents, antiobesity agents, vanadate, vanadium complexes, peroxovanadium complexes, amylin antagonists, glucagon antagonists, gluconeogenesis inhibitors, somatostatin analogs and antagonists, or antilipolytic agents.

[0140] In another embodiment of the invention, there are provided methods for treating a mammalian subject, particularly a human, suspected of having, or being prone to side effect(s) of other antineoplastic or antitumor agents for the treatment of cancer.

[0141] In some embodiments, in the above methods, the one or more of the compounds or compositions of the invention is administered alone or in combination with other antineoplastic or antitumor agents, in a pharmaceutically acceptable carrier, diluent, or excipient, for treatment of conditions comprising side effect(s) of said antineoplastic or antitumor agents.

[0142] In some embodiments, in the above methods, the one or more of the compounds or compositions of the invention is administered alone or in combination with other antineoplastic or antitumor agents, in a pharmaceutically acceptable carrier, diluent, or excipient, for treatment of conditions comprising side effect(s) of said antineoplastic or antitumor agents. Examples of other antineoplastic or antitumor agents include, but are not limited to, Busulfan, Carboplatin, Cisplatin, Cyclophosphamide, Cytosine arabinoside, Etoposide, 5-Fluorouracil, Melphalan, Methotrexate, Mitoxantrone, Taxol, Interferon, Fareston, Arzoxifene, Evista, Tamoxifen, Gemzar, Irinotecan and the like.

[0143] In some embodiments, the administering step in the above methods comprises administering the compound of the invention and the other therapeutic agent simultaneously. These embodiments include those in which the compound of the invention and the other therapeutic agent are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains both compounds. The embodiments also include those in which each compound is in a separate administrable composition, but the patient is directed to take the separate compositions nearly

simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.

[0144] In other embodiments the administering step comprises administering one of the compounds of the invention and the other therapeutic agent first and then administering the other one of the compound of the invention and the other therapeutic agent. In these embodiments, the patient may be administered a composition comprising one of the compounds and then at some time, a few minutes or a few hours, later be administered another composition comprising the other one of the compounds. Also included in these embodiments are those in which the patient is administered a composition comprising one of the compounds on a routine or continuous basis while receiving a composition comprising the other compound occasionally.

[0145] In one embodiment, the present invention provides a process for preparing a compound of formula 5. Such a process can be performed, for example, by contacting a compound of formula 3 with a compound of formula 4 under conditions suitable to form a compound of formula 5, as set forth below:

[0146] Compounds of Formula 3 and 4 may be prepared by known processes. Compound 3 is typically contacted with compound 4 in the presence of a catalyst or Lewis Acid. Catalysts or Lewis Acids contemplated for use in the practice of this particular invention process are typically sodium acetate, piperidinium acetate and the like. Solvents contemplated for use in the practice of this particular invention process are typically aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene and the like, polar solvents, such as for example, acetic acid, acetonitrile, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidine, dimethyl sulfoxide and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about O ⁰ C up to about 15O ⁰ C.

[0147] In another embodiment, the present invention provides a process for preparing a compound of formula 6. Such a process can be performed, for example, by contacting a compound of formula 5 with a reducing agent under conditions suitable to form a compound of formula 6, as set forth below:

[0148] Reducing agents contemplated for use in the practice of this particular invention process are typically metals, such as for example, magnesium and the like, hydride reagents, such as for example, lithium borohydride and the like, hydrogenation mixtures, such as for example, H ₂ /Pd/C, H ₂ /Pt, H ₂ /Raney nickel, H ₂ /nickle boride, H ₂ /Pt0 ₂ , H ₂ /Rh, H ₂ /Ru, H ₂ /Zn0 ₂ , H ₂ /RhCl(Ph ₃ P) ₃ and the like, dihydropyridines, such as for example, diethyl-l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate and the like. Solvents contemplated for use in the practice of this particular invention process are typically alcoholic solvents, such as for example, methanol, ethanol and the like, aromatic solvents, such as for example, benzene, toluene, dichlorobenzene, xylene, pyridine and the like, or any suitable mixtures thereof. The process is typically carried out at a temperature in the range of about O ⁰ C up to about 15O ⁰ C. When hydrogen gas is used, the process is typically carried out at a pressure in the range of about 1 atm up to about 100 atm. An acid catalyst maybe used in combination with the hydrogenation mixtures described herein. Acids contemplated for use in the practice of this particular invention process are typically acetic acid, trifluoroacetic acid, hydrochloric acid, and the like.

[0149] Before the present compounds, compositions and methods are disclosed and described, it is to be understood that aspects of the present invention are not limited to specific synthetic methods, specific pharmaceutical carriers, or to particular pharmaceutical formulations or administration regimens, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0150] It is also noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly

dictates otherwise. Thus, for example, reference to "a bicyclic aromatic compound" includes mixtures of bicyclic aromatic compounds, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

[0151] Certain pharmaceutically acceptable salts of the invention are prepared by treating the novel compounds of the invention with an appropriate amount of pharmaceutically acceptable base. Representative pharmaceutically acceptable bases are ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, lysine, arginine, histidine, and the like. The reaction is conducted in water, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from about O ⁰ C to about 100 ⁰ C, preferably at room temperature. The molar ratio of compounds of structural Formula 1 or Formula 2 to base used is chosen to provide the ratio desired for any particular salts. For preparing, for example, the ammonium salts of the starting material, compounds of Formula 1 or Formula 2 can be treated with approximately one equivalent of the pharmaceutically acceptable base to yield a neutral salt. When calcium salts are prepared, approximately one-half a molar equivalent of base is used to yield a neutral salt, while for aluminum salts, approximately one-third a molar equivalent of base will be used.

[0152] The compounds of the invention according to Formula 1 or Formula 2, including the pharmacologically acceptable pro-drugs or salts thereof, are useful to regulate or modulate cellular differentiation, cellular proliferation and energy homoeostasis. As noted above, the compounds of the invention are thus useful in the treatment of conditions involving cancer, inflammation, wound healing, metabolism of lipids and carbohydrates, obesity, diabetes that are regulated by the aforementioned entities.

[0153] The compounds of the invention may be conveniently formulated into pharmaceutical compositions composed of one or more of the compounds together with a pharmaceutically acceptable carrier as described in Remington's Pharmaceutical Sciences, latest edition, by E. W. Martin (Mack Publ. Co., Easton Pa.).

[0154] The compounds of the invention may be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection,

topically, transdermally, or the like, although oral or topical administration is typically preferred. The amount of active compound administered will, of course, be dependent on the subject being treated, the subject's weight, the manner of administration and the judgment of the prescribing physician. The dosage will be in the range of about 1 microgram per kilogram per day to 50 milligram per kilogram per day.

[0155] Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels and the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include, as noted above, an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents and the like.

[0156] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administr able-compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, referenced above.

[0157] For oral administration, fine powders or granules may contain diluting, dispersing, and/or surface active agents, and may be presented in water or in a syrup, in capsules or sachets in the dry state, or in a non-aqueous solution or suspension wherein suspending agents may be included, in tablets wherein binders and lubricants may be included, or in a suspension in water or a syrup. Wherever required, flavoring, preserving,

suspending, thickening, or emulsifying agents may also be included. Tablets and granules are preferred oral administration forms, and these may be coated.

[0158] Parenteral administration, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, as emulsions, or as sustained release delivery system.

[0159] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate permeation. Transmucosal administration can be through nasal sprays, for example, or using suppositories.

[0160] For topical administration, the agents are formulated into ointments, creams, salves, powders and gels. In one aspect, the transdermal delivery agent can be DMSO. Transdermal delivery systems can include, such as for example, patches.

[0161] Pharmaceutical compositions containing the compounds of the invention as an active ingredient can take the form of tablets, capsules, powders, suspensions, solutions, emulsions as well as salves and creams, and can be used for parenteral (intravenous, intradermal, intramuscular, intrathecal etc.) injections, infiltration, topical application, central injection at spinal cord, oral, rectal, intravaginal and intranasal administering or for local application. Such compositions can be prepared by combining the active ingredient(s) with pharmaceutically acceptable excipients normally used for this purpose. Such excipients can comprise aqueous and non-aqueous solvents, stabilizers, suspension agents, dispersing agents, moisturizers and the like, and will be known to the skilled person in the pharmaceutical field. The composition may further contain likewise suitable additives such as for instance polyethylene glycols and, if necessary, colorants, fragrances and the like.

[0162] The pharmaceutical compositions will preferably contain at least 0.1 volume % by weight of the active ingredient. The actual concentration will depend on the human subject and the chosen administering route. In general this concentration will lie between 0.1 and 100% for the above applications and indications. The dose of the active ingredient to be administered can further vary between 0.1 mg and 100 mg per kg body

weight, preferably between 0.1 mg and 50 mg per kg body weight, and most preferably between 0.5 mg and 20 mg per kg body weight.

[0163] The desired dose is preferably presented in the form of two, three, four, five, six or more sub-doses which are administered at appropriate intervals per day. These sub-doses can be administered in the form of dosage units containing for instance from 1 to 1500 mg, preferably from 5 to 1000 mg and most preferably from 10 to 700 mg active constituent per dosage unit, and if the condition of the patient requires the dose can, by way of alternative, be administered as a continuous infusion.

EXAMPLES

[0164] Used herein, the following abbreviations have the following meanings: Me refers to methyl (CH ₃ -), Et refers to ethyl (CH ₃ CH ₂ -), i-Pr refers to isopropyl ((CH ₃ J ₂ CH ₂ -), t-Bu or tert-butyl refers to tertiary butyl ((CH ₃ ) ₃ CH-), Ph refers to phenyl, Bn refers to benzyl (PhCH ₂ -), Bz refers to benzoyl (PhCO-), MOM refers to methoxymethyl, Ac refers to acetyl, TMS refers to trimethylsilyl, TBS refers to ter- butyldimethylsilyl, Ms refers to methanesulfonyl (CH ₃ SO ₂ -), Ts refers to p-toluenesulfonyl (P-CH ₃ PhSO ₂ -), Tf refers to trifluoromethanesulfonyl (CF ₃ SO ₂ -), TfO refers to trifluoromethanesulfonate (CF ₃ SO ₃ -), DMF refers to N,N-dimethylformamide, DCM refers to dichloromethane (CH ₂ Cl ₂ ), THF refers to tetrahydrofuran, EtOAc refers to ethyl acetate, Et ₂ O refers to diethyl ether, MeCN refers to acetonitrile (CH ₃ CN), NMP refers to 1-N- methyl-2-pyrrolidinone, DMA refers to N,N-dimethylacetamide, DMSO refers to dimethylsulfoxide, DCC refers to l^-dicyclohexyldicarbodiimide, EDCI refers to l-(3- dimethylaminopropyl)-3-ethylcarbodiimide, Boc refers to tert-butylcarbonyl, Fmoc refers to 9-fluorenylmethoxycarbonyl, TBAF refers to tetrabutylammonium fluoride, TBAI refers to tetrabutylammonium iodide, TMEDA refers to N,N,N,N-tetramethylethylene diamine, Dess-Martin periodinane or Dess Martin reagent refers to l,l,l-triacetoxy-l,l-dihydro-l,2- benziodoxol-3(lH)-one, DMAP refers to 4-N,N-dimethylaminopyridine, (i-Pr) ₂ NEt or DIEA or Hunig's base refers to N,N-diethylisopropylamine, DBU refers to 1,8- Diazabicyclo[5.4.0]undec-7-ene, (DHQ) ₂ AQN refers to dihydroquinine anthraquinone-1,4- diyl diether, (DHQ) ₂ PHAL refers to dihydroquinine phthalazine-l,4-diyl diether, (DHQ) ₂ PYR refers to dihydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD) ₂ AQN refers to dihydroquinidine anthraquinone-l,4-diyl diether, (DHQD) ₂ PHAL refers to dihydroquinidine phthalazine-l,4-diyl diether, (DHQD) ₂ PYR refers to

dihydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, LDA refers to lithium diisopropylamide, LiTMP refers to lithium 2,2,6,6-tetramethylpiperdinamide, n-BuLi refers to n-butyllithium, t-BuLi refers to tert-butyl lithium, IBA refers to 1 -hydroxy- 1,2- benziodoxol-3(lH)-one 1 -oxide, OsO ₄ refers to osmium tetroxide, m-CPBA refers to meta- chloroperbenzoic acid, DMD refers to dimethyl dioxirane, PDC refers to pyridinium dichromate, NMO refers to N-methyl morpholine-N-oxide, NaHMDS refers to sodium hexamethyldisilazide, LiHMDS refers to lithium hexamethyldisilazide, HMPA refers to hexamethylphosphoramide, TMSCl refers to trimethylsilyl chloride, TMSCN refers to trimethylsilyl cyanide, TBSCl refers to tert-butyldimethylsilyl chloride, TFA refers to trifluoroacetic acid, TFAA refers to trifluoroacetic anhydride, AcOH refers to acetic acid, Ac ₂ O refers to acetic anhydride, AcCl refers to acetyl chloride, TsOH refers to p- toluenesulfonic acid, TsCl refers to p-toluenesulfonyl chloride, MBHA refers to 4- methylbenzhydrylamine, BHA refers to benzhydrylamine, ZnCl ₂ refers to zinc (II) dichloride, BF ₃ refers to boron trifluoride, Y(OTf) ₂ refers to yttrium (III) trifluoromethanesulfonate, Cu(BF ₄ ) ₂ refers to copper (II) tetrafluoroborate, LAH refers to lithium aluminum hydride (LiAlH ₄ ), NaHCO ₃ refers to sodium bicarbonate, K ₂ CO ₃ refers to potassium carbonate, NaOH refers to sodium hydroxide, KOH refers to potassium hydroxide, LiOH refers to lithium hydroxide, HCl refers to hydrochloric acid, H ₂ SO ₄ refers to sulfuric acid, MgSO ₄ refers to magnesium sulfate, and Na ₂ SO ₄ refers to sodium sulfate. ¹ H NMR refers to proton nuclear magnetic resonance, ¹³ C NMR refers to carbon 13 nuclear magnetic resonance, NOE refers to nuclear overhauser effect, NOESY refers to nuclear overhauser and exchange spectroscopy, COSY refers to homonuclear correlation spectroscopy, HMQC refers to proton detected heteronuclear multiplet-quantum coherence, HMBC refers to heteronuclear multiple-bond connectivity, s refers to singlet, br s refers to broad singlet, d refers to doublet, br d refers to broad doublet, t refers to triplet, q refers to quartet, dd refers to double doublet, m refers to multiplet, ppm refers to parts per million, IR refers to infrared spectrometry, MS refers to mass spectrometry, HRMS refers to high resolution mass spectrometry, EI refers to electron impact, FAB refers to fast atom bombardment, CI refers to chemical ionization, HPLC refers to high pressure liquid chromatography, TLC refer to thin layer chromatography, Rr refers to retention factor, R _t refers to retention time, GC refers to gas chromatography, min is minutes, h is hours, rt or

RT is room temperature, g is grams, mg is milligrams, L is liters, mL is milliliters, mol is moles and mmol is millimoles.

[0165] For all of the following examples, standard work-up and purification methods can be utilized and will be obvious to those skilled in the art. Synthetic methodologies that make up the invention are shown in Scheme 1. This Scheme is intended to describe the applicable chemistry through the use of specific examples and is not indicative of the scope of the invention.

Hydrolysis

Scheme 1

[0166] The following non-limiting examples illustrate the inventors' preferred methods for carrying out the process of the invention.

Example 1 Preparation of 5-formyl-2-hydroxy-benzoic acid

[0167] A solution of salicylic acid (3Og, 0.217mol) and hexamethylenetetramine (2Og, 0.143mol) in water (25OmL) was heated to reflux for 16 hrs, cooled and acidified with 4N-HC1 (25OmL); the pale yellow crystalline product was collected by filtration, dried and extracted with benzene (4x10OmL) at 7O ⁰ C. The solid was filtered, extracted with boiling water (3x200mL) and filtered to give the product. Yield = 4.5g, 12.6%; yellow solid; Rf =0.375 in 20% EtOH-EtOAc.

Example 2 Preparation of 5-formyl-2-methoxybenzoic acid methyl ester

[0168] To a two-necked round bottom flask was added 5-formyl~2-hydroxy- benzoic acid (9g, 54.8mmol), acetone (15OmL), anhydrous potassium carbonate (9.1g, 65.8mmol) and dimethyl sulfate (7.8mL, 82.3mmol). The mixture was heated to reflux under nitrogen for 5 hrs and filtered. The solvent was removed and the residue was dissolved in chloroform (5OmL), washed with cold 5% aqueous potassium carbonate, water, and dried over Na ₂ SO ₄ . The solvent was removed and the crude residue was purified by flash column chromatography (20% EtOAc-H exane eluant). Yield = 4.1 g, 50%; white solid; i?/=0.58 in 50% EtOAc-Hexane.

Example 3 Preparation of 5-formyl-2-methoxybenzoic acid

[0169] A solution of 5~formyl-2-methoxy-benzoic acid methyl ester (500mg, 2.57mmol) in methanol (1OmL) was stirred for 5 min. Aqueous potassium hydroxide (IM, 1OmL) was added and the resulting mixture was stirred at ambient temperature for Ih. The solution was acidified to pH=4 using dilute 2M HCl; the solvent was removed and the residue was dissolved in tert-butyl alcohol (2OmL). The solution was diluted with diethyl ether (6OmL x 2), washed with brine (4OmL), dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product. Yield = 420mg, 91%; canary yellow solid; R _f =0.325 in 100% EtOAc

Example 4 Preparation of 4-memoxy-3-(4-trifluoromethyl)benzylamido benzaldehyde

[0170] To a stirred solution of 5-formyl-2-methoxybenzoic acid (Ig, 5.55mmol) in 2OmL of THF-CH ₂ Cl ₂ (3:1) was added l-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCl, 1.16g, β.lmrnol), under nitrogen, at ambient temperature and the mixture was allowed to stir at ambient temperature for 10 min. 4-(trifiuoromethyl)- benzyl amine (0.986g, 5.6mmol) was added dropwise and stirring was maintained at ambient temperature for 4h and the solvent was removed under vacuum. The crude residue was extracted with EtOAc (5OmL x 2) and the combined organic layers were washed with IN HCl (2OmL), sat. NaHCO _{3 (} 20mL), brine and dried with anhydrous Na ₂ SO ₄ . The solvent was removed under vacuum to give the product as a pale yellow solid. Yield: 0.940 g (50%). R _r : 0.5 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 4.02 (s, 3H); 4.74 (d, 2H); 7.14 (d, IH); 7.48 (d, 2H); 7.61 (d, 2H); 8.06 (dd, IH); 8.12 (br. s, IH); 8.75 (d, IH); 10.0 (s, IH).

Example 5

Preparation of 5-r4-methoxy-3-f4-trifluoiOmethyl ^' )benzylamido]benzylidene-3-(β- carboxyethyDrhodanine

[0171] A 5OmL round bottom flask fitted with Dean-Stark head was charged with 4-methoxy-3-(4-trifluoromethyl)benzylamido benzaldehyde (0.9g, 2.67mol), rhodanine-3 -propionic acid (0.496g, 2.42mmol), sodium acetate (35mg) and 25mL of toluene. The reaction was placed in a preheated oil bath (13O ⁰ C) and refluxed for Ih, cooled to ambient temperature and the yellow precipitate was filtered, washed with toluene (1OmL), water (1OmL) and dried. Yield: 1.1 g (87%). R _f : 0.4 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-

NMR (DMSO-d ₆ ) δ ppm: 2.52 (t, 2H); 3.96 (s, 3H); 4.20 (t, 2H); 4.60 (d, 2H); 7.34 (d, IH); 7.54 (d, 2H); 7.7 (d, 2H); 7.78 (d, IH); 7.80 (s, IH); 7.98 (d, IH); 8.92 (t, IH).

Example 6

Preparation of 5-[4-memoxy-3-(4-trifluoromemyl)benzylamido ^" lbenzyl-3-(β- carboxyethvDrhodamne

[0172] A mixture of 5-[4-methoxy-3-(4- trifluoromethyl)benzylamido]benzylidene-3-(β-carboxyethyl)- rhodanine (27mg,

0.05mmol), 1, 4-dihydro-3,5-dicarbethoxy-2,6-dimethylpyridine (DHP, 26mg, O.lmmol) and silica gel (125mg) was taken up in 0.5mL of 1,4-dioxane and heated at 100 ⁰ C for 12h. The reaction was monitored by NMR, and upon completion was diluted with water and extracted with EtOAc (5mL x 2), washed with brine and dried over anhydrous Na ₂ SO ₄ . The crude residue was purified by PTLC using 10% CH ₃ OH-CH ₂ Cl ₂ to give 5-[4-methoxy-3- (4-trifluoromethyl)benzylamido]-benzyl-3-(β-carboxyethyl)rh odanine as a foamy white solid. Yield: 15mg (57%). R _f : 0.4 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 2.48-2.60 (m, IH); 2.78-2.90 (m, IH); 3.25 (dd, IH); 3.45 (dd, IH); 3.94 (s, 3H); 4.10-4.20 (m, IH); 4.32-4.48 (m, 2H); 4.74 (d, 2H); 6.94 (d, IH); 7.30 (dd, IH); 7.46 (d, 2H); 7.60 (d, 2H); 8.0 (d, IH); 8.29 (t, IH). Calculated Mass for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ : 526.55. Mass (EI): m/e 525 [M-H] ^" ; 527 [M+H] ⁺ ; 549 [M+Na] ⁺ ; 565 [M+K] ⁺ .

Example 7 Preparation of 2-(N-Methyl-N-(2-pyridyl)amino)ethanol

[0173] A solution of 2-chloropyridine (11.35g, O.lmol) and N-methyl-2- aminoethanol (7.5g) was heated at 12O ⁰ C, under nitrogen, for 24h. The reaction was poured into ice-water and extracted with EtOAc (3 x 15OmL). The solvent was removed and the

crude residue was purified by flash chromatography to give the product. Yield: 8.5g (56%), R _f : 0.6 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 3.07 (s, 3H), 3.72 (dd, 2H), 3.85 (dd, 2H), 5.42 (br s, IH), 6.55 (m, 2H), 7.45 (m, IH), 8.4 (m, IH).

Example 8 Preparation of 4-[2-(N-M ethyl-N-(2-pyridyl)amino)ethoxy1benzaldehvde

[0174] To a solution of 2-(N-Methyl-N-(2-pyridyl)amino)ethanol (Ig, 6.57mmol) in 5mL of anhydrous DMF was added 4-fluorobenzaldehyde (Ig, 8mmol) and the reaction mixture was stirred at ambient temperature for 10 min. To this stirred mixture was added t-BuOK (0.8g, 7.14mmol) and stirring was maintained for 4h. The reaction mixture was cooled in a ice bath and quenched with water (5OmL), extracted with EtOAc (5OmL x 2) and the combined organic layers were washed with water (5OmL), brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed to give the product as an oil. Yield: 1.1 Ig (66%). R _f : 0.75 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 3.18 (s, 3H); 4.02 (t, 2H); 4.30 (t, 2H); 6.52 (d, IH); 6.58 (m, IH); 7.0 (d, 2H); 7.46 (m, IH); 7.8 (d, 2H); 8.16 (m, IH).

Example 9

Preparation of 4-r2-(N-Methyl-N-(2-pyridyl)amino)ethoxyl-benzylidene-3-(β- carboxyethylVrhodanine

[0175] Prepared according to Example 5. Yield: 0.33 g (75%). R _f : 0.45 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.60 (t, 2H); 3.08 (s, 3H); 3.92 (t,

2H); 4.2 (m, 4H); 6.55 (t, IH); 6.65 (d, IH); 7.12 (d, 2H); 7.50 (t, IH); 7.6 (d, 2H); 7.78 (s, IH); 8.08 (d, IH); 12.5 (br. s, IH).

Example 10

Preparation of 4-[ ^" 2-(N-Methyl-N-( ^' 2-pyridyl)ainino)ethoxy]-benzyl-3-(β-carboxyetliyl)- rhodanine

[0176] Prepared according to Example 6. Yield: 13mg (59%). R _f : 0.45 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (acetone-d ₆ ) δ ppm: 2.55 (q, 2H); 3.1-3.25 (m, IH); 3.15 (s, 3H); 3.45 (dd, IH); 3.95 (t, 2H); 4.1-4.2 (m, 4H); 4.8 (q, IH) 6.54 (m, IH); 6.62 (d, IH); 6.9 (d, 2H); 7.2 (d, 2H); 7.48 (mlH); 8.10 (m, IH). Calculated Mass for C _2J H ₂₃ N ₃ O ₄ S ₂ : 445.56. Mass (EI): m/e 444.7 [M-H] ^' ; 446.5[M+H] ⁺ .

Example 11 Preparation of 2-(2-benzoxazolylmethylamino)ethanol

[0177] A solution of 2-chlorobenzoxazole (4 g, 26mmol) in anhydrous THF (2OmL) was added dropwise to an ice cooled, stirred solution of 2-(methylamino)ethanol (2.18g, 28.6mmol) in anhydrous THF (25mL) containing Et ₃ N (2.6mL) under nitrogen atmosphere. The reaction mixture was stirred at O ⁰ C for Ih and at ambient temperature for another hour. The precipitate was removed by filtration and washed with THF (1OmL) and the combined mother liquors were evaporated. The crude residue obtained was extracted with EtOAc (5OmL x 2), washed with brine and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave the product as a low melting solid. Yield: 5g (100%). R _f : 0.3 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 3.34 (s, 3H); 3.7 (t, 2H); 3.92 (t, 2H). 7.0 (t, IH); 7.12 (t, IH); 7.24 (d, IH). 7.32 (d, IH).

Example 12 Preparation of 2-(2-benzoxazolylmemylamino)ethanol methylsulfonyl ester

min

[0178] To an ice cooled solution of 2-(2-benzoxazolylmethylamino)ethanol (3g, 15.6mmol) in dry CH ₂ Cl ₂ (2OmL) was added Et ₃ N (1.7g, 17mmol) and the solution was stirred at O ⁰ C for 10 min. Methanesulfonyl chloride (1.89g, 16.5mmol) was added dropwise under a nitrogen atmosphere and the reaction was stirred at O ⁰ C for 30 min, poured into ice water (10OmL) and extracted with CH ₂ Cl ₂ (5OmL x T). The combined organic layers were washed with sat. NaHCO ₃ (5OmL), brine (3OmL) and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent afforded the product as a white solid. Yield: 3.7 g (88%). R _f -: 0.6 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 3.0 (s, 3H); 3.35 (s, 3H); 3.9 (t, 2H); 4.5 (t, 2H). 7.04 (t, IH); 7.14 (t, IH); 7.26 (d, IH). 7.36 (d, IH).

Example 13 Preparation of 4-[ ^" 2-f2-benzoxazolylmethylamino)ethoxylbenzaldehyde

[0179] To a stirred solution of 4-hydroxybenzaldehyde (0.542g, 4.4mmol) in anhydrous DMF (15mL), under nitrogen, was added t-BuOK (0.497g, 4.4mmol) in portions at ambient temperature and the mixture was allowed to stir for 10 min. A solution of 2-(2- benzoxazolylmethylamino)ethanol methylsulfonyl ester (Ig, 3.7mmol) in anhydrous DMF (1OmL) was added dropwise and the reaction mixture was stirred at ambient temperature for 2h and 8O ⁰ C for Ih. The mixture was cooled to ambient temperature, poured into ice water (10OmL), extracted with EtOAc (10OmL x 2) and the combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ , and passed through a short bed of silica gel. The solvent was removed to give the product as a pale yellow solid. Yield: 0.65 g (65%). R _f : 0.45 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ) δ ppm: 3.38 (s, 3H); 4.0 (t, 2H); 4.4 (t, 2H); 7.0 (d, 2H); 7.02 (m, IH); 7.15 (t, IH); 7.26 (d, IH); 7.36 (d, IH); 7.82 (d, 2H); 9.82 (s, IH).

Example 14

Preparation of 4-r2-(2-benzoxazolylmethylamino)ethoxy1benzylidene-3-(3-carb oxyethyl)- rhodanine

[0180] Prepared according to example 5. Yield: 0.39 g (80%). R _f : 0.55 in CH ₃ OH-CH ₂ Cl ₂ (10:90). ¹ H-NMR (DMSOd ₆ ) δ ppm: 2.55 (t, 2H); 3.24 (s, 3H); 3.9 (t, 2H); 4.2 (t, 2H); 4.6 (t, 2H); 6.98 (t, IH); 7.12 (t, 3H); 7.25 (d, IH); 7.35 (d, IH); 7.6 (d, 2H); 7.76 (s, IH).

Example 15

Preparation of 4-[2-(2-benzoxazolylmethylammo)ethoxy]benzyl-3 -(β-carboxyethyl)- rhodanine

[0181] Prepared according to example 6. Yield: 14mg (58%). R _f : 0.55 in CH ₃ OH-CH ₂ Cl ₂ (90:10). ¹ H-NMR (CDCl ₃ ) δ ppm: 2.36 (m, IH); 2.52 (m, IH); 3.3 (m, 5H); 3.9 (m, 2H); 4.22 (m, 4H); 4.43 (m, IH); 6.8 (d, 2H); 7.0-7.2 (m, 3H); 7.26 (d, 2H); 7.4 (d, IH). Calculated Mass for C ₂₃ H ₂₃ N ₃ O ₅ S ₂ : 485.58 Mass (EI): m/e 484.7 [M-H] ^" ; 486.5[M+H] ⁺ .

Example 16 Preparation of l-[4-(diethoxymethyl)phenyi ^~ lethanol

[0182] To a solution of 4-(diethoxymethyl)benzaldehyde (2Og, lOOmmol) in anhydrous THF (8OmL) was added methyl lithium-lithium bromide complex (11.88g, 72mL of 1.5 M in Hexane, 1 lOmmol) dropwise, -78 ⁰ C, over an hour. The reaction mixture

was allowed to warm to ambient temperature, poured into 20OmL of ice-water, stirred for 10 min and the layers were separated. The aqueous layer was extracted with ether (30OmL). The combined organic layers were washed with water (20OmL), brine (10OmL), dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduce pressure to yield the product as a colorless oil. Yield: 22g (99%). Rf. 0.5 in EtOAc-Hexane (50:50). ). ¹ H-NMR (acetone- d ₆ ) δ ppm: 1.2(t, 6H); 1.4 (d, 3H); 3.55(m, 4H); 4.12(d, IH); 4.8(m, IH); 5.55(s, IH); 7.4(s, 4H).

Example 17 Preparation of 4-{diethoxymethyl)-acetophenone

[0183] To a mixture of l-[4-(diethoxymethyl)-phenyl]-ethanol (3.25g, 14.5mmoi), N-methylmorpholine (2.57g, 22mmol) and powdered 4A molecular sieves (7.25g) in acetonitrile (3OmL) was added lmol% of tetrapropylammonium perruthenate (TPAP, 52 mg), under nitrogen atmosphere, at O ⁰ C. The mixture was brought to ambient temperature and stirred for 1 h. The solvent was evaporated under reduced pressure and the mixture was diluted with EtOAc (10OmL) and filtered through a short pad of celite. The filtrate was washed with water (10OmL), brine (5OmL) and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave 4-(diethoxymethyl) acetophenone as a colorless oil. Yield: 3.0 g (94%). Rf. 0.7 in EtOAc-Hexane (30:70). 1H-NMR(acetone-d ₆ ) δ ppm: 1.2(t, 6H); 2.6(s, 3H); 3.6(m, 4H); 4.15(m, 2H); 5.6(s, IH); 7.6(d, 2H); 8.0(d, 2H).

Example 18 Preparation of ethyl-2-r4-(diethoxymethyl)benzoyl1 acetate

[0184] To a suspension of NaH (0.675g, 28mmol) in anhydrous THF (2OmL) was added diethyl carbonate (2 g, 17mmol) at O ⁰ C. The reaction mixture was brought to ambient temperature, stirred for 30 min and a solution of 4-(diethoxymethyl)acetophenone (2.5g, 11.26mmol), absolute ethanol (0.ImL) in anhydrous THF (15mL) was added

dropwise. The mixture was heated to 5O ⁰ C for 3h, cooled to ambient temperature, poured into ice water (20OmL) and extracted with ether (10OmL x 3). The combined ether layers were washed with water (10OmL), brine (5OmL) and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave the product as a viscous oil. Yield: 2.95g (92%). Kf. 0.7 in EtOAc-Hexane (30:70). 1H-NMR(acetone-d< ₅ ) δ ppm: 1.2(t, 9H); 2.8(s, 2H); 3.6(q, 6H); 4.15(m, 2H); 5.6(s, IH); 7.6(d, 2H); 8.0(d, 2H).

Example 19 Synthesis of 2-phenyl-4-chloromethvl-5-methvloxazole

[0185] A solution of 2,3-butanedione monooxime (1Og, lOOmmol) and benzaldehyde (11.66g, lOβmmol) in acetic acid (10OmL) was cooled to O ⁰ C and dry HCl gas was bubbled through the solution for 40 min. Diethyl ether (10OmL) was added to the reaction mixture to precipitate the product and the resulting slurry was stirred for 30 min at O ⁰ C. The white precipitate was filtered and rinsed with ether (2OmL) and taken up in 20OmL of water and 12mL of cone. NH ₄ OH. The mixture was extracted with CHCl ₃ (15OmL x 2), washed with brine and dried over anhydrous MgSO ₄ . Evaporation of the solvent under reduced pressure afforded 2-phenyl-4,5-dimethyloxazole-3-oxide as a white crystalline solid. Yield: 1Og (53%). R _f : 0.6 in CH ₂ Cl ₂ -CH ₃ OH (90:10). ¹ H-NMR(CDCl ₃ ) δ ppm: 2.2 (s, 3H); 2.4(s, 3H); 7.5 (m, 3H); 8.45(m, 2H).

[0186] To a solution of 2-phenyl-4,5-dimethyloxazole-3-oxide (4g, 21.1mmol) in CHCl ₃ (4OmL) was added POCl ₃ (3.6 g, 23.4mmol) dropwise at ambient temperature. The mixture was heated to reflux for an hour, cooled to ambient temperature, poured into ice water (30OmL), extracted with CHCl ₃ (10OmL x 2), washed with brine and dried over anhydrous Na ₂ SO ₄ . The crude product obtained on removal of the solvent was dissolved in hot Hexane (20OmL), decanted away from the insoluble dark material and cooled to O ⁰ C to allow the product to crystallize out. The solid was filtered and dried. Yield: 2.75g (64%). R _f : 0.6 in EtOAc-Hexane (20:80). ¹ H-NMR(CDCl ₃ ) δ ppm: 2.22 (s, 3H); 4.6(s, 2H); 7.45 (m, 3H); 8.0(m, 2H).

Example 20 Preparation of 4-[3-(5-Methyl-2-phenyl-4-oxazolyDpropionyr|benzaldehyde

[0187] A solution of ethyl-2-[4-(diethoxymethyl)benzoyl] acetate (3.35g, l lmmol) in anhydrous THF (2OmL) was added dropwise to a suspension of NaH (0.288 g, 12mmol) in anhydrous THF (2OmL) at O ⁰ C, over 30 min. The reaction mixture was brought to ambient temperature and stirred for another 30 min. A solution of 5-methyl-2-phenyl-4- oxazolylmethyl chloride (2g, 10.9mmol) in THF (1OmL) was added and the mixture was heated to reflux for 5Oh, cooled to ambient temperature and concentrated. The residue obtained was extracted with EtOAc (10OmL x 2), washed with brine and dried over anhydrous Na ₂ SO ₄ . The gummy solid obtained on removal of the solvent was dissolved in a mixture of acetic acid (3OmL) and concentrated HCl (7mL) and heated at 12O ⁰ C for 2h. The reaction mixture was cooled in an ice bath, diluted with water (15OmL) and extracted with EtOAc (10OmL x2). The combined organic extracts were washed with water (20OmL), brine (5OmL) and dried over anhydrous Na ₂ SO ₄ . After removal of the solvent, the crude residue was purified by flash chromatography using 30% EtOAc-Hexane to yield the product as a yellow solid. Yield: 1.8g (52%). R _f : 0.5 in EtOAc-Hexane (60:40). ¹ H-NMR (CDCl ₃ ) δ ppm: 2.4 (s, 3H); 2.96 (t, 2H); 3.48 (t, 2H); 7.4 (m, 3H), 7.95 (m, 4H), 8.12 (d, 2H); 10.1 (s, IH).

Example 21 Preparation of 4-r3-(5-Methyl-2-phenyl-4-oxazolyl ^' )prorjionyllbenzylidene-3-(β- carboxyethvDrhodanine

[0188] Prepared according to Example 5. Yield: 0.240 g (61%). R _f : 0.45 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (DMSO-d ₆ ) δ ppm: .2.3 (s, 3H); 2.6 (t, 2H); 2.8 (t, 2H); 3.4 (t, 2H); 4.2 (t, 2H); 7.44 (m, 3H), 7.7 (d, 2H), 7.84 (m, 3H); 8.1 (d, 2H); 12.4-12.8 (br. s, IH).

Example 22

Preparation of 4-[3-(5-Methyl-2-phenyl-4-oxazolyl)propionyllbenzyl-3-(3- carboxyethvDrhodanine:

[0189] Prepared according to Example 6. Yield: 14mg (56%). Rf. 0.6 in CH ₃ OH-CH ₂ Cl ₂ (10:90). ¹ H-NMR (acetone-d ₆ ) δ ppm: 2.38 (s, 3H); 2.58 (t, 2H); 2.88 (t, 2H); 3.4 (t, 2H); 3.6 (dd, 2H); 4.18 (t, 2H); 4.9 (q, IH); 7.46 (m, 5H); 7.96 (m, 4H). Calculated Mass for C ₂₆ H ₂₄ N ₂ O ₅ S ₂ : 508.61 Mass (EI): m/e 507.9 [M-H] ^" ; 509.6[M+H] ⁺ , 531.4 [M+Na] ⁺ .

Example 23 Preparation of 1 ,4-dihydro-3 ,5-dicarbethoxy-2,6-dimethylpyridine(DHP)

[0190] To a mixture of ammonium acetate (0.195g, 2.5mmol) and hexamethylenetetramine (0.28Og ₅ 2mmol) was added ethyl acetoacetate (0.65Og, 5mmol) followed by absolute ethanol (4mL) under nitrogen atmosphere. The reaction mixture was heated to 100 ⁰ C for 90 min and cooled to ambient temperature. A lime green solid separated out and was filtered, washed with ethanol (5mL) and dried. Yield: 0.410 g (81%). R _f : 0.3 in EtOAc-Hexane (30:70). ¹ H-NMR(CDCl ₃ ) δ ppm: 1.26(t, 6H); 2.2 (s, 6H); 3.26(s, 2H); 4.18(q, 4H); 5.18(s, IH).

Example 24 Preparation of (5-methyl-2-phenyl-oxazol-4-yl)-acetonitrile

[0191] To a stirred solution of 2-phenyl-4-chloromethyl-5-methyloxazole (2.07 g, 10 mmol) in DMF (14 rnL) was added potassium cyanide (0.976 g, 15 mmol) and potassium iodide (1.23 g, 7.5 mmol) and the mixture was heated at 85 ⁰ C for 3h. The reaction mixture was cooled to ambient temperature and an aqueous solution of potassium carbonate was added (500 mg in 50 mL). The light brown precipitate was filtered, washed with water (100 mL) and dried. Yield: 2.0 g (100%). Rf. 0.3 in EtOAc-hexanes (20:80). ¹ H- NMR(CDCl ₃ ) δ ppm: 2.42 (s, 3H); 3.62 (s;2H); 7.46 (m, 3H); 8.0 (m, 2H).

Example 25 Preparation of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid

[0192] To a solution of (5-methyl-2-phenyl-oxazol-4-yl)-acetonitrile (2.0 g, 10 mmol) in 30 mL of 2-methoxyethanol was added potassium hydroxide (3.36 g, 60 mmol) in 16 mL of water. The reaction mixture was heated at HO ⁰ C for 3 h, cooled to ambient temperature and quenched with 2N HCl (25 mL). The solution was extracted with CH ₂ Cl ₂ (30 mL x 2), washed with water (100 mL), brine and dried over anhydrous Na ₂ SO ₄ . The crude solid (1.73 g) obtained upon removal of the solvent was recrystallized from toluene to give 1.42 g of the product as an off-white solid. Yield = 66%; R _f : 0.3 in 10% CH ₃ OH/CH ₂ C1 ₂ . ¹ H-NMR(CDCl ₃ ) δ ppm: 2.4 (s, 3H); 3.6 (s, 2H); 7.45 (m, 3H); 8.0 (m, 2H).

Example 26 Preparation of 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol

[0193] Borane-THF complex (12 mL of 1.0 M solution in THF, 12 mmol) was added dropwise to a solution of 5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (1.42 g, 6.54 mmol) in anhydrous THF (10 mL), under nitrogen atmosphere. After stirring for 2 h at ambient temperature, the reaction was quenched with CH ₃ OH (3 mL) and allowed to stir at ambient temperature for 1 h. The reaction mixture was diluted with 1 N NaOH (5 mL) and extracted with CH ₂ Cl ₂ (25 x 2 mL). The organic layer was washed with water (50 mL), brine (10 mL) and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave the product as a pale yellow solid. Yield: 1.25 g (95%). R _f : 0.7 in 10% CH ₃ OH/CH ₂ C1 ₂ . ¹ H- NMR(CDCl ₃ ) δ ppm: 2.36 (s, 3H); 2.7 (t, 2H); 3.92 (t, 2HO; 7.42 (m, 3H); 8.0 (m, 2H).

Example 27 Preparation of methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester

[0194] To an ice cooled solution of 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (0.555 g, 2.73 mmol) in dry CH ₂ Cl ₂ (1OmL) was added Et ₃ N (0.33 g, 3.27 mmol) and the solution was stirred at O ⁰ C for 10 min under a nitrogen atmosphere. Methanesulfonyl chloride (0.345g, 3.0 mmol) was added dropwise and the reaction was stirred at O ⁰ C for 30 min, poured into ice water (50 mL) and extracted with CH ₂ Cl ₂ (3OmL x 2). The combined organic layers were washed with sat. NaHCO ₃ (2OmL), brine (1OmL) and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent afforded the product as an off-white solid. Yield: 0.72 g (94%). R _f : 0.4 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.4 (s, 3H); 2.96 (t, 5H); 4.52 (t, 2H); 7.42 (m, 3H); 8.0 (m, 2H).

Example 28 Preparation of 4-r2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy ^' l-benzaldehvde

[0195] tert-BuOK (0.344 g, 3.0 mmol) was added in portions to a stirred solution of 4-hydroxybenzaldehyde (0.375 g, 3.0 mmol) in anhydrous DMF (20 niL), under nitrogen, at ambient temperature and the mixture was allowed to stir for 10 min. A solution of methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (0.72 g, 2.56 mmol) in anhydrous DMF (5 mL) was added dropwise and the reaction mixture was stirred at ambient temperature for 10 min and 8O ⁰ C for Ih. The mixture was cooled to ambient temperature, poured into ice water (10OmL), extracted with EtOAc (10OmL x 2) and the combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ . The crude solid obtained on evaporation of the solvent was purified by flash column chromatography using 30% EtOAc-hexane. The solvent was removed to give the product as a white solid. Yield: 0.500 g (65%). R _f : 0.7 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 2.4 (s, 3H); 3.14 (t, 2H); 4.4 (t, 2H); 7.0 (d, 2H); 7.42 (m, 3H), 7.8 (d, 2H), 8.0 (m, 2H); 9.9 (s, IH).

Example 29

Preparation of 3-(5- {4-[ ^" 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy ^" |-benzylidene} -4-oxo-2- thioxo-thiazolidin-S-vD-propionic acid

[0196] Prepared according to Example 5. Yield: 0.330 g (75%). R _f : 0.5 in CH ₃ OH-CH ₂ Cl ₂ (10:90). ¹ H-NMR (DMSO-d ₆ ) δ ppm: .2.37 (s, 3H); 2.48 (t, 2H); 2.98 (t, 2H); 4.18 (t, 2H); 4.32 (t, 2H); 7.12 (d, 2H), 7.48 (m, 3H), 7.58 (d, 2H); 7.76 (s, IH); 7.9 (m, 2H).

Example 30

Preparation of S-fS-H-^-^-methyl-Σ-phenyl-oxazol^-ylVefhoxy ^' l-benzyll^-oxo^- thioxo-thiazolidin-S-yD-propionic acid

[0197] Prepared according to Example 6. Yield: 30 mg (60%). R _f : 0.4 in CH ₃ OH-CH ₂ Cl ₂ (5:95). ¹ H-NMR (CDCl ₃ ZCD ₃ OD) δ ppm: 2.36(s, 3H); 2.5 (m, 2H); 2.86 (t, 2H); 3.1 (dd, IH); 3.38 (d of d, IH); 4.2 (q, 4H); 4.38 (d of d, IH); 6.82 (d, 2H); 7.08 (d, 2H); 7.42 (m, 3H); 7.96(m, 2H). Calculated Mass for C ₂₅ H ₂₄ N ₂ O ₅ S ₂ : 496.6; Mass (EI): m/e 495.6 [M-H] ^" ; 497.6 [M+H] ⁺ , 519.7 [M+Na] ⁺ .

Example 31 Preparation of (5- {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-benzylidenej-4 -oxo-2- thioxo-thiazolidin-3-yl)-acetic acid

[0198] A 5OmL round bottom flask fitted with Dean-Stark head was charged with 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (50 mg, 0.162 mmol), rhodanine-N-acetic acid (29 mg 0.150 rrrmol), piperidine acetate (20 mg) and 7 mL of toluene. The reaction was placed in a pre-heated oil bath (13O ⁰ C) and heated to reflux for 90 min, cooled to ambient temperature and the yellow precipitate was filtered, washed with toluene (1OmL), and dried. Yield: 65 mg (84%). R _f : 0.45 in CH ₃ OH-CH ₂ Cl ₂ (20:80). ¹ H- NMR (DMSO-d ₆ ) δ ppm: 2.36 (s, 3H); 2.98 (t, 2H); 4.34 (t, 2H); 4.72 (s, 2H); 7.13(d, 2H); 7.47 (m, 3H); 7.62 (d, 2H); 7.83 (s, IH); 7.9 (m, 2H).

Example 32

Preparation of (5- {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl -benzyl} -4-oxo-2-thioxo- thiazolidin-3-vD-acetic acid

[0199] Prepared according to Example 6. Yield: 6.0 mg (40%). R _f : 0.3 in CH ₃ OH-CH ₂ Cl ₂ (10:90). ¹ H-NMR (CDCl ₃ ZCD ₃ OD) δ ppm: 2.3(s, 3H); 2.86 (t, 2H); 3.6-3.8 (m, 2H); 4.2-4.4 (m, 4H); 4.8 (2d, IH); 6.82 (2d, 2H); 7.1 (2d, 2H); 7.4 (m, 3H); 7.9 (m, 2H).

Example 33 Preparation of 2,4-thiazolidinedione Potassium Salt

[0200] To a hot solution of 2,4-thiazolidinedione (2.34 g, 20 mmol) in 5 mL of ethanol was added a solution of KOH (1.23 g, 22 mmol) in 5 mL of ethanol. The mixture was stirred at 7O ⁰ C for Ih and cooled in an ice-bath. A white crystalline solid separated out and was filtered, washed with ethanol (15 mL) and dried. Yield: 2.42 g (78%).

Example 34 Preparation of (2,4-dioxo-thiazolidin-3-yl)-acetic acid ethyl ester

[0201] A suspension 2,4-thiazolidinedione potassium salt (1.09g, 7 mmol) in acetone (20 mL) and ethyl bromoacetate (1.2 g, 7.01 mmol) was heated to reflux for 4h, cooled to ambient temperature and filtered. Evaporation of the solvent gave the product as an oil. Yield: 1.4 g (98%). R _f : 0.6 in 50% EtOAc-hexane. ¹ H-NMR(CDCl ₃ ) δ ppm: 1.3 (t, 3H); 4.05 (s, 2H); 4.25 (q, 2H); 4.35 (s, 2H).

Example 35

Preparation of (5-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyl-benzylidene }-2,4-dioxo- thiazolidin-3-vD-acetic acid ethyl ester

[0202] A 5OmL round bottom flask fitted with Dean-Stark head was charged with 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (80 mg, 0.26 mmol), (2,4-dioxo-thiazolidin-3-yl)-acetic acid ethyl ester (51 mg, 0.25 mmol), piperidine acetate (20 mg) and 7 mL of toluene. The reaction was placed in a pre-heated oil bath (13O ⁰ C) and heated to reflux for 1Oh, and cooled to ambient temperature. The solvent was removed and the crude residue was dissolved in EtOAc (50 mL), washed with water (50 mL) and dried. Purification by flask chromatography gave the product as a white solid. Yield: 80 mg (63%). Rf. 0.5 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.3 (t, 3H); 2.4 (s, 3H); 3.0 (t, 2H); 4.23 (q, 2H); 4.33 (t, 2H); 4.46 (s, 2H); 7.0 (d, 2H); 7.42 (m, 5H); 7.86 (s, IH); 8.0 (m, 2H).

Example 36 3-(2,4-Dioxo-thiazoridin-3-yl)-propionic acid tert-butyl ester

[0203] To a mixture of 2,4-thiazolidinedione potassium salt (1.09g, 7 mmol) and potassium iodide (1.16 g, 7 mmol) in anhydrous DMF (10 mL) was added 3-bromo- propionic acid tert-butyl ester (1.46 g, 7.01 mmol). The reaction was heated to 95 ⁰ C for 4h, cooled to ambient temperature, poured into water (50 mL) and extracted with ether (50 x 2 mL). The ether layer was washed with saturated NaHCO ₃ (10 ml), brine and dried over anhydrous Na ₂ SO ₄ . Evaporation of the solvent gave the product as an oil. Yield: 0.65 g (39%). R _f . 0.6 in 40% EtOAc-hexane. ¹ H-NMR(CDCl ₃ ) δ ppm: 1.44 (s, 9H); 2.58 (t, 2H); 3.92 (t, 2H); 3.97 (s, 2H).

Example 37 4-(2,4-Dioxo-thiazolidin-3-yl)-butyric acid ethyl ester

[0204] Prepared according to Example 36. Yield: 1.43 g (90%). R _f : 0.5 in 40% EtOAc-hexane. ¹ H-NMR(CDCl ₃ ) δ ppm: 1.25 (t, 3H); 1.95 (m, 2H); 2.32 (t, 2H); 3.7 (t, 2H); 3.95 (s, 2H); 4.15 (q, 2H).

Example 38 Preparation of 2-thioxo-thiazolidin-4-one Potassium Salt

[0205] Prepared according to Example 33. Yellow crystalline solid. Yield: 1.7 g (68%).

Example 39 4-(4-Oxo-2-thioxo-thia2olidin-3-yl)-butyric acid ethyl ester

[0206] Prepared according to Example 36. Yield: 0.5 g (32%). R _f : 0.8 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.3 (t, 3H); 1.05 (m, 2H); 2.4 (t, 2H); 3.7 (t, 2H); 3.98 (s, 2H); 4.08 (t, 2H); 4.15 (q, 2H).

Example 40

3-(5-{4-r2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxyl-benzyl idene}-2,4-dioxo-thiazolidin-3- yl)-propionic acid tert-butyl ester

[0207] Prepared according to Example 35. Yield: 0.71 g (82%). R _f : 0.8 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (s, 9H); 2.4 (s, 3H); 2.64 (t, 2H); 3.05 (t, 2H); 4.0 (t, 2H); 4.35 (t, 2H); 6.9 (d, 2H); 7.44 (m, 5H); 7.84 (s, IH); 8.2 (m, 2H).

Example 41

3-(5-(4-r2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxyl-benzyl |-2.4-dioxo-thiazolidin-3-yl)- propionic acid tert-butyl ester

[0208] A solution of 3-(5-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzylidene}-2,4-dioxo-thiazolidin-3-yl)-propionic acid tert-butyl ester (0.106 g, 0.2 mmol) in anhydrous 1,4-dioxane (5 mL) was hydrogenated in the presence of 10% palladium on charcoal (0.175 g) at ambient temperature and atmospheric pressure for 15 h. The solution was filtered through Celite, the filter pad was washed with ethyl acetate (75 mL), and the combined filtrates were evaporated to dryness under reduced pressure. The crude residue was purified by column chromatography with 30% EtOAc -hexane to give the product as a colorless oil. Yield: 0.10 g (95%). R _f : 0.7 in 40% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (s, 9H); 2.4 (s, 3H); 2.5 (t, 2H); 3.03 (m, 3H); 3.5 (dd, IH); 3.82 (t, 2H); 4.25 (t, 2H); 4.4 (dd, IH); 6.82 (d, 2H); 7.1 (d, 2H); 7.42 (m, 3H); 8.0 (m, 2H).

Example 42

3-(5-{4-r2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy1-benzvU -2,4-dioxo-thiazolidin-3-yl)- propionic acid

[0209] Trifluoro acetic acid (2 mL) was added dropwise to a solution of 3-(5-{4- [2-( 5 -methyl-2 -phenyl-oxazol-4-yl) -ethoxy] -b enzyl } -2 ,4-dioxo -thiazolidin-3 -yl)-propionic acid tert-butyl ester (0.12 g, 0.22 mmol) in CH ₂ Cl ₂ (4 mL). The solution was stirred for 30 min at ambient temperature and the solvent was evaporated under reduced pressure. The resulting solid was purified by column chromatography using 50% EtOAc-hexane to give the product as a colorless crystalline solid. Yield: 0.093 g (89%). R _f : 0.2 in 50% EtOAc- hexane. ¹ H-NMR (CDC1 ₃ /CD ₃ OD) δ ppm: 2.36 (s, 3H); 2.46 (t, 2H); 2.98 (t, 2H); 3.06 (dd, IH); 3.34 (m, IH); 3.8 (t, 2H); 4.2 (t, 2H); 4.4 (dd, IH); 6.8 (d, 2H); 7.08 (d, 2H); 7.4 (m, 3H); 8.0 (m, 2H)

Example 43 . 4-(5-(4-r2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy1-benzylide ne}-2,4-dioxo-thiazolidin-

[0210] Prepared according to Example 35. Yield: 0.46 g (88%). R _f : 0.7 in 40% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.3 (t, 3H); 2.02 (m, 2H); 2.38 (t, 2H); 2.44(s, 3H); 3.02 (t, 2H); 3.84 (t, 2H); 4.15 (q, 2H); 4.35 (t, 2H); 6.98 (d, 2H); 7.44 (m, 5H); 7.83 (s, IH); 8.0 (m, 2H).

Example 44

4-( 5- {4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxyl -benzyl} -2,4-dioxo-thiazolidin-3-yl)- butyric acid ethyl ester

[0211] Prepared according to Example 41. Yield: 0.45 g (99%). R _f : 0.7 in 40% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.24 (t, 3H); 1.86 (m, 2H); 2.32 (t, 2H); 2.4(s, 3H); 3.0 (t, 2H); 3.1 (dd, IH); 3.42 (dd, IH); 3.64 (t, 2H); 4.12 (q, 2H); 4.25 (t, 2H); 4.4 (dd, IH); 6.8 (d, 2H); 7.18 (d, 2H); 7.42 (m, 3H); 8.0 (m, 2H).

Example 45

4-(5- {4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy] -benzylidenej -4-oxo-2-thioxo- thiazolidin-3-yl)-butyric acid ethyl ester

[0212] Prepared according to Example 35. Yield: 0.32 g (83%). R _f : 0.6 in 40% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (t, 3H); 2.1(m, 2H); 2.39 (t, 2H); 2.42(s, 3H); 3.05 (t, 2H); 4.2 (m, 4H); 4.35 (t, 2H); 7.0 (d, 2H); 7.46 (m, 5H); 7.67 (s, IH); 8.1 (m, 2H).

Example 46

4-(5-H-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy1-benzyl} -4-oxo-2-thioxo-thiazolidin-3- vD-butyric acid ethyl ester

[0213] Prepared according to Example 6. Yield: 0.12 g (60%). R _f : 0.6 in 40% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.3 (t, 3H); 1.9 (m, 2H); 2.3 (t, 2H); 2.4 (s, 3H); 3.0 (t, 2H); 3.1 (dd, IH); 3.45 (dd, IH); (m, 4H); 4.0 (t, 2H); 4.15(q, 2H); 4.25 (t, 2H); 4.4 (dd, IH); 6.84 (d, 2H); 7.12 (d, 2H); 7.44 (m, 3H); 7.98 (m, 2H).

Example 47

4-(5-{4-r3-(5-Methyl-2-phenyl-oxazol-4-yl ^' )-propionyl1-benzylidene}-2,4-dioxo- thiazolidin-3-yl)-butyric acid ethyl ester

[0214] To a solution of 4-[3-(5-methyl-2-phenyl-4-oxazolyl)-propionyl]- benzaldehyde (0.319 g, 1 mmol), and 4-(2,4-dioxo-thiazolidin-3-yl)-butyric acid ethyl ester (0.5 g, 2 mmol), in absolute ethanol (20 rnL) was added piperidine (43 mg, 0.5 mmol). The reaction was heated to reflux for 24h, cooled to ambient temperature and the solvent was removed. The crude residue was dissolved in EtOAc (80 mL), washed with water (50 mL),

IN HCL (10 mL), brine (10 mL) and dried. Purification by flask chromatography gave the product as colorless oil. Yield: 0.225 g (43%). R _f : 0.6 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (t, 3H); 2.04 (m, 2H); 2.4 (t, 2H); 2.46 (s, 3H); 3.0 (t, 2H); 3.55 (t, 2H); 3.84 (t, 2H); 4.16 (q, 2H); 7.45 (m, 3H); 7.58 (d, 2H); 7.88 (s, IH); 8.06 (m, 4H).

Example 48

4-(5-{4-r3-(5-Methyl-2-phenyl-oxazol-4-yl ^' )-propionyl]-benzyl}-2,4-dioxo-thiazolidin-3- vD-butvric acid ethyl ester

[0215] Prepared according to Example 41. Yield: 0.200 g (88%). R _f : 0.65 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.25 (t, 3H); 1.86 (m, 2H); 2.34 (t, 2H); 2.42(s, 3H); 2.96 (t, 2H); 3.2 (dd, IH); 3.45 (t, 2H); 3.55 (dd, IH); 3.66 (t, 2H); 4.12 (q, 2H); 4.45 (dd, IH); 7.3 (d, 2H); 7.45 (m, 3H); 7.95 (d, 2H); 8.05 (m, 2H).

Example 49

4-(5-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propionyl]-ben zylidenel-4-oxo-2-thioxo- thiazolidin-3-yl)-butyric acid ethyl ester

[0216] Prepared according to Example 35. Yield: 0.48 g (87%). Rf. 0.55 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (t, 3H); 2.1(m, 2H); 2.4 (t, 2H); 2.44(s, 3H); 3.0 (t, 2H); 3.5 (t, 2H); 4.15 (q, 2H); 4.22 (t, 2H); 7.42 (m, 3H); 7.56 (d, 2H); 7.71 (s, IH); 8.0 (m, 2H); 8.07 (d, 2H).

Example 50

4-(5- {443 -(5-Methyl-2-phenyl-oxazol-4-yl)-propionyl1 -benzyl }-4-oxo-2-thioxo- thiazolidin-3-yl)-butyric acid ethyl ester

[0217] Prepared according to Example 6. Yield: 0.4 g (89%). R _f : 0.5 in 50% EtOAc-hexane. ¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (t, 3H); 1.92 (m, 2H); 2.3 (t, 2H); 2.4 (s, 3H); 2.95 (t, 2H); 3.22 (dd, IH); 3.4 (t, 2H); 3.55 (dd, IH); 4.0 (t, 2H); 4.15(q, 2H); 4.45 (dd, IH); 7.3 (d, 2H); 7.4 (m, 3H); 7.92 (d, 2H); 7.98 (m, 2H).

Example 51 PPAR-γ co-transfection assay

[0218] HepG2 cells were cultured in Essential Minimum Eagle's Medium (EMEM) with 10% fetal bovine serum. Cells were transfected using the calcium phosphate:DNA co -precipitation method. A 10-cm plate of cells was transfected with 5μg of luciferase reporter construct, 5μg of β-galactosidase expression vector, 1 μg of PPAR- γ expression vector, and pUC19 as carrier, to a total of 20 μg. β-galactosidase (5μg) was included in each transfection to monitor transfection efficiency. Cells were incubated 6 hours at 37 ⁰ C in a CO ₂ incubator, re-suspended in fresh media containing 10% serum with or without compounds (96-well plate, 15000 cells per well), and incubated at 37 ⁰ C in a CO ₂ incubator. Luciferase and β-galactosidase assays were performed 36-44 hours post- transfection, and the normalized luciferase response was determined as relative light units divided by β-galactosidase activity (A575/min).

[0219] The EC ₅₀ data is set forth in the table below.

[0220] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.