MXPA06003198A - Heterocyclic compounds and methods of making and using thereof - Google Patents

Abstract

Compounds of formula (I), and methods and/or compositions comprising compounds that are effective in modulating inflammatory responses, such as those resulting from AGE and glycated protein accumulation are provided. Methods and/or compositions comprising compounds that are effective in modulating smooth muscle cell proliferation and the diseases or conditions related thereto are also provided.

Description

HETEROCICLIC COMPOUNDS AND METHODS OF ELABORATION AND USE OF THEMSELVES Field of the Invention The present invention relates to compounds, pharmaceutical compositions, and methods of making and using them. Background of the Invention Glycated proteins and advanced glycation end products (AGE) contribute to cell damage, for example, diabetic tissue injury. This can occur by at least two main mechanisms: modulation of cellular functions through interactions with specific receptors of the cell surface, and alteration of the extracellular matrix that leads to the formation of protein cross-links. Studies suggest that the interactions of AGE and glycated protein with cells promote inflammatory processes and oxidative cell damage. AGEs increase the oxidation and atherogenicity capacity of lipoproteins. Additionally, AGEs that bind to matrix proteins induce synthesis of IL-7, TNF-α, VCAM-1, Heme-oxygenase, insulin-like growth factor, IL-6 and active TNF-β. Diseases for which the accumulation of AGE and glycated protein is a suspected etiological factor include, without limitation and without REF: 171253 limitation, vascular complications of diabetes, microangiopathies, renal failure and Alzheimer's disease. The exact mechanism by which high plasma glucose concentration causes microvascular damage, as seen in diabetes, is not fully understood. A potential mechanism by which hyperglycemia can be linked to microangiopathies is through the non-enzymatic glycation process of critical proteins. The non-enzymatic glycation of critical proteins is analyzed in Nonenzymatic glycosylation and the pathogenesis of diabetic disorders, Ann. Intern. Med., 1984 (101) 527-537; Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease, Proc. Nati Acad. Sci. U S A., 1994 (91) 9436-40; Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease, J. Am. Soc. Nephrol., 2000 (11) 1656-66; and Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis., Circ. Res., 1999 (84) 489-97). Non-enzymatic glycation, that is, the binding of proteins with glucose, leads to the formation of glycated proteins. The first step in this glycation pathway involves the nonenzymatic condensation of glucose with free amino groups in the protein, mainly the epsilon-amino groups of the lysine residues, which form adducts from Atereo. These early glycation products may undergo additional reactions such as rearrangements, dehydration and condensation to form irreversible end-of-glycation (AGE) products. These are a highly reactive group of molecules whose interaction with specific receptors on the cell surface leads to pathogenic results. The accumulation of glycated proteins in the base membranes of patients with diabetes has been demonstrated and is thought to be included in the development of diabetic nephropathy and retinopathy. See Immunohistochemical localization of glycated protein in diabetic rat kidney., Diabetes Res. Clin, Pract., 1990 (8) 215-9; and Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. , J. Am. Soc. Nephrol., 1996 (7) 183-90. See Inhibitors of AGE formation, such as aminoguanidine, have been shown to block the formation of AGE and prevent development of diabetes complications, including diabetic retinopathy (Aminoguanidine prevente diabetes-induced arterial wall protein cross-linking, Science, 1986 (232) 1629- 1632; Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine., Proc. Nati. Acad. Sci. US A., 1996 (93) 3902-7; and Potential benefit of inhibitors of advanced glycation end products in the progression of type II diabetes: a study with aminoguanidine in C57 / BLKsJ diabetic mice., Metabolism, 1998 (47) 1477-80. A characterized AGE receptor is the RAGE, receptor for AGE. See Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ. Res. 1999 (84) 489-97; and Roles of the AGE-RAGE system in vascular injury in diabetes., Ann. NY Acad. Sci. 2000 (902) 163-70; discussion 170-2. Several in vitro and in vivo studies demonstrate that blocking RAG either by antibodies or by adding a soluble form of the receptor inhibits diabetic vasculopathy including diabetic atherosclerosis. See Receptor- ediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyper-permeability in diabetic rats., J. Clin. Invest., 1996 (97) 238-43; Advanced glycation end products interacting with their endothelial receptor induces expression of vascular cell adhesion molecule-1 (VCAM-i) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes., J. Clin. Invest., 1995 (96) 1395-403; and Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end products., Nat. Med. 1998 (4) 1025-31. Unlike AGE, RAGE appears to mediate the binding of several different ligands that are involved in physiology as well as in normal pathology. See Blockade of RAGE-amphoterin signaling suppresses tumor growth and metastases., Nature, 2000 (405) 354-60; RAGE mediates a novel proinflammatory axis: a central cell surface receptor for SlOO / calgranulin polypeptides., Cell., 1999 (97) 889-901; and Amyloid-beta peptide-receptor for advanced glycation end product interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease., Proc. Nati Acad. Sci., USA., 1997 (94) 5296-301. In this way, just blocking the RAGE can have other unintended consequences. In addition, since RAGE block can lead to the accumulation of AGE in circulation, the long-term effects of RAGE blockage are unknown and can be more dangerous than the pathology to be treated. A useful method to block the effects of AGE will be to develop inhibitors that block AGE-induced signaling. See Activation of the receptor for advanced glycation end products triggers to p2l (ras) -dependent mitogen-activated protein kinase pathway regulated by oxidant stress., J. Biol. Chem., 1997 (272) 17810-4; and Cell activation by glycated proteins .; AGE receptors, receiver recognition factors and functional classification of AGEs. , Cell. Mol. Biol. (Noisy-le-grand), 1998 (44) 1013-23. However, the sequence of signaling events that leads to inflammation is not clear. Accordingly, what is needed are compounds that can block AGE-induced activities, particularly AGE-induced inflammation, or more particularly, AGE-induced signaling events. Other chronic conditions for which there are no adequate and effective therapies are the treatments of anti-proliferative disorders. Smooth muscle cell hyperplasia (SMC) is an important factor in the development of atherosclerosis and is also responsible for the significant number of failure rates after vascular procedures such as angioplasty and bypass surgery. coronary artery. See The comparative pathobiology of atherosclerosis and restenosis. Am. J. Cardiol. 86: 6H-11H (2000); and Restenosis: a challenge for pharmacology. Trends Pharmacol Sci. 21: 274-9. In the normal vessel, the SMCs are inactive, but proliferate when damage to the endothelium occurs. Growth modulators that occur naturally, many of which are derived from the endothelium, they strictly control the proliferation of SMC in vivo. Abnormal proliferation of vascular smooth muscle cells (VSMC) may contribute to the pathogenesis of vascular occlusive lesions, including atherosclerosis, re-narrowing of vessels after successful angioplasty (restenosis), and graft atherosclerosis after of coronary transplant. VSMC are analyzed in The comparative pathobiology of atherosclerosis and restenosis. Am. J. Cardiol. 86: 6H-11H; and Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 100: 587-9. Many humans and animals have limited lifetimes and limited lifestyles due to these conditions. Currently there are no known effective pharmacological treatments available that control these occlusive pathologies, particularly restenosis. Percutaneous coronary artery intervention procedures (PTCA) are the inpatient procedure in patients, most common in the United States of America. According to the American Heart Association, approximately one third of patients who undergo balloon angioplasty have restenosis of the widened segment in the time period of approximately six months. It may be necessary to perform another angioplasty or coronary artery bypass surgery in arteries with restenosis. A key feature of restenosis is an injury response that results in the activation of an inflammatory cascade and remodeling of the cells both inside and outside the carotid artery wall. This includes excessive growth of connective tissue and smooth muscle in the lumen of the artery known as neointimal hyperplasia. Currently there are no effective pharmacological treatments available that control the pathogenesis of vascular occlusive lesions, such as, without limitation, arteriosclerosis, atherosclerosis, restenosis, atherosclerosis of the graft after coronary transplantation. The identification of effective therapeutic products with minimal side effects restores quality of life without requiring additional surgical procedures such as coronary artery bypass surgery. Smooth muscle cell hyperplasia (SMC) is a major event in the development of atherosclerosis and may also contribute to failure rates after vascular procedures such as angioplasty and coronary artery bypass surgery. In the normal vessel, the SMCs are inactive, but proliferate when damage to the endothelium occurs. Growth modulators that occur naturally, many of which are derived from the endothelium, strictly control in vivo proliferation of SMCs. Accordingly, there is a need for methods and compositions for the alteration of gene expression in arterial wall cells that inhibit thrombosis and the proliferation of SMCs. In particular, what is needed are methods and compositions that inhibit the proliferation of SMCs and related intimal hyperplasia.

U.S. Patent No. 6,028,088 refers to thiazolidine-dione-specific compounds, which are described as antiproliferating, anti-inflammatory and anti-infective agents. According to the description, these specific compounds are used in the treatment of certain endocrine diseases, malignant and non-malignant proliferative diseases, and cardiovascular disorders. In this way, there is a need for treatments of vascular occlusive pathological conditions and in particular restenosis. Since the occurrence is frequent, the treatments currently available are expensive and the conditions are reluctant to many pharmacological therapies. The mechanisms involved in the control of vascular conditions related to the SMC function are not clear and conventional preventive therapy against the activation of SMCs is not available. Accordingly, methods and compositions are needed for the treatment and prevention of vascular occlusive conditions. In particular, methods and compositions are needed to prevent and treat restenosis after treatments of vascular diseases. The present invention relates to overcoming these and other deficiencies in the art. Brief Description of the Invention The present invention relates to compounds of the formula (I), and to methods and / or compositions comprising compounds that are effective in the modulation of inflammatory responses, such as those resulting from the accumulation of glycated protein. and AGE. The present invention also relates to methods and / or compositions comprising compounds that are effective in modulating the proliferation of smooth muscle cells and diseases or conditions related thereto. The present invention provides compounds and compositions that inhibit inflammatory responses, particularly that which results from accumulation of glycated protein and AGE. Additionally, the present invention provides compounds and compositions that inhibit proliferation of muscle cells, which can be mediated by pro-inflammatory cytokines such as IL-6, IL-1, TNF-a, MCP-1. , or by inducing the expression of perlecan, a heparin sulfate proteoglycan (HSPG).

The present invention provides novel compounds of the formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of these compounds, optionally in combination with other active ingredients.

The present invention also provides a process for preparing compounds of the formula (I) as defined above, their salts, and pharmaceutically acceptable compositions thereof. The present invention also provides novel compounds of formula (II), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of these compounds, optionally in combination with other active ingredients.

The present invention also provides a process for preparing compounds of the formula (II), as defined above, their pharmaceutically acceptable salts and compositions thereof. The present invention also provides novel compounds of the formula (III), including but not limited to, their pharmaceutically acceptable salts and pharmaceutical compositions containing them, or their mixtures, or in combination with other active ingredients.

The present invention also provides a process for preparing compounds of the formula (III) as defined above, their salts and pharmaceutically acceptable compositions thereof. The present invention also provides novel compounds of formula (IV), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of these compounds, optionally in combination with other active ingredients.

The present invention also provides a process for preparing compounds of formula (IV) as defined above, their salts and pharmaceutically acceptable compositions thereof. The present invention provides novel compounds of the formula (V), their pharmaceutically acceptable salts and pharmaceutical compositions containing one or more of these compounds, optionally in combination with other active ingredients.

The present invention also provides a process for preparing compounds of the formula (V) as defined above, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions. According to one aspect of the present invention, a method for using a compound of the formula (I) comprises the treatment and / or prophylaxis of inflammatory conditions, such as those mediated by the accumulation of glycated protein or AGE. These inflammatory conditions include diabetic vascular complications, including diabetic retinopathy, microangiopathies, renal failure and Alzheimer's disease. According to another aspect of the present invention, a method for inhibiting the proliferation of smooth muscle cells comprises administering an effective amount of a compound contemplated in this way. The present invention also provides methods for inhibiting an inflammatory response, including inflammatory responses in endothelial cells, which comprises administering an effective amount of a compound contemplated in this way. The present invention also provides methods for inhibiting thrombosis which comprises administering an effective amount in a compound contemplated herein. The present invention also provides a method for treating or preventing organ transplant vasculopathy in a subject comprising the step of administering a therapeutically effective amount of a compound contemplated herein. The transplanted organ may include, without limitation, liver, kidney, heart, lung, pancreas, pancreatic islets and skin. This method may further comprise the step of administering a therapeutically effective amount of an immunosuppressant agent. The immunosuppressive agent may include, without limitation, CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, T andmoglobulin, and Zenapax. The present invention also provides a method for treating or preventing restenosis in a subject comprising administering a therapeutically effective amount of a compound contemplated herein. The present invention also provides a method for treating or preventing atherosclerosis in a subject comprising administering a therapeutically effective amount of a compound contemplated herein. The present invention also provides a method for treating inflammatory mediated disease in a subject comprising the step of administering a therapeutically effective amount of a compound contemplated herein. More specifically, the inflammatory mediated disease may be an autoimmune disease. In this regard, the autoimmune disease may be alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, pemphigoid bullosa, cardiomyopathy, celiac dermatitis-esprue, fatigue immune dysfunction syndrome chronic (CFIDS), chronic inflammatory demyelinating polyineruropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves disease, Guillain's disease -Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic purple thrombocytopenia (ITP), IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigusvulgaris, pernicious anemia, polyarteristis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, rigid man syndrome, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo and Wegener's granulomatosis. The present invention further provides a method for treating or preventing cancer in a subject comprising administering a therapeutically effective amount of a compound contemplated herein. In addition, the present invention provides a method for treating or preventing metastasis in a subject comprising administering a therapeutically effective amount of a compound contemplated herein to the subject. Still another aspect of the present invention provides the methods, by using the compound of the formula (I), which also comprises the treatment and / or prophylaxis of proliferating conditions, particularly for inhibition of smooth muscle cell proliferation, comprising the administration of compositions comprising compounds of the formula (I). In accordance with the present invention, the uses of these compositions comprise prevention and treatment of vascular occlusive conditions including atherosclerosis and restenosis. Yet another aspect of the present invention provides methods for the treatment and / or prophylaxis of diseases mediated by inflammatory conditions and cellular proliferative conditions, by using the compound of formula (I). Yet another aspect of the present invention provides treatment and / or prophylaxis of a disease or disorder mediated by cell adhesion molecules such as VCAM-1, where the diseases are inflammatory disorders selected from rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, transplantation of organs or allograft rejection, autoimmune diabetes or multiple sclerosis; a cardiovascular disease selected from atherosclerosis, restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nephropathy or diabetic retinopathy and one of the cell adhesion molecules is VCAM-1. Yet another aspect of the present invention provides treatment and / or prophylaxis of a disease by distributing the compound (s) of the formula (I) at the site of the disease by using a compound (s) of the Formula (I) in coated vascular endoprostheses. The present invention further provides pharmaceutical compositions containing compounds of the general formula (I), their salts, or any mixture thereof in combination with a carrier, solvent, diluent or suitable medium typically employed in preparing these compositions. Still further, the present invention provides various compounds and compositions that can each be administered by a route that is oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, bronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebelar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal or transdermal. The compositions of the present invention may also include formulations of the described compounds which may be suitable for oral, rectal, ophthalmic, (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal and epidural). The formulations can be conveniently presented in a unit dosage form and can be prepared by conventional pharmaceutical techniques. These techniques include the step of bringing into association the active ingredient and the carrier (s) or pharmaceutical excipient (s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product. Yet another aspect of the present invention provides novel intermediates, a process for their preparation and use of the intermediates in processes for preparing the compound of the formula (I), its salts and pharmaceutically acceptable compositions thereof. Definitions It is to be understood that this invention is not limited to the particular methodology, particular protocols, particular cell lines, particular constructions and particular reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. As used in this, and in the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly indicates otherwise. Thus, for example, reference to a "compound" is a reference to one or more of these compounds and includes equivalents thereof, known to those skilled in the art and above. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art at the time this invention was made. All publications and patents mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the constructions and methodologies described in the publications, which may be used in conjunction with the invention currently. described. The publications described above and throughout the text are provided only for description before the filing date of the present application. Nothing herein is to be considered as an admission that the inventors are not entitled to proceed with the description under the previous invention.

As used herein, the term "compound" includes both singular and plural, and includes any individual entity or combined entities having activity that can be measured in the assays of the present invention and combinations, fragments, analogs or derivatives of these entities. The term "glycated protein" as used herein, the term includes proteins linked to glucose, either enzymatically or nonenzymatically, mainly by condensation of the free epsilon-amino groups in the protein with glucose, forming Amadori adducts . Additionally, the glycated protein, as used herein, includes not only proteins that contain these initial glycation products, but also glycation products that result from additional reactions such as rearrangements, dehydration and condensations that form irreversible advanced glycation end products. (AGE). It should be understood that any agent that causes the test cells or components to respond measurably is contemplated by the present invention. Enhanced formation and accumulation of glycated proteins and AGE is thought to play a major role in the pathogenesis of diabetic complications, and atherosclerosis, which leads to the development of a variety of diabetic complications including nephropathy, retinopathy and neuropathy. There is ample in vivo evidence suggesting that diabetes-related complications can be reduced by (1) preventing protein glycation, (2) by breaking the cross-links in the glycated proteins (The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation., Diabetologia., 2000 (43) 660-4) (or (3) by blocking the interaction of the glycated protein with the receptors, despite the importance with AGEs in the pathogenesis of microangiopathies In the case of diabetics, there are currently no known drugs available that block the formation of AGE The term "phenylamine" refers to a primary and secondary benzenamide, more commonly known as aniline.The amino group in the aniline can be optionally substituted with hydrogen, alkyl ( C-C12, straight or branched chain), cycloalkyl (C3-C10), or optionally substituted aryl groups The phenyl ring of this aniline derivative may be optional optionally substituted with one or more functional groups, or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino , arylamino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate. If applicable, these groups can be represented in protected or protected forms used in normal organic synthesis. The term "naphthylamine" refers to a primary or secondary α- or β-naphthylamines. The ring substructure in naphthylamine can optionally be substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio , amino, alkylamino, arylamino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate. These groups can be represented in protected or unprotected forms used in normal organic synthesis. The term "naphthylalkyl-amine" refers to a primary or secondary α- or β-naphthylalkyl-amine (for example 2-α-naphthylethylamine). The term "benzalkyl amine" refers to a primary or secondary benzylalkylamine (e.g., phenylethylamine.) These sub-structures or aryl-alkyl compounds may be optically active or optically inactive. the naphthylalkyl- and benzylalkyl-amines may optionally be substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, ammonium, alkylamino, arylamino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate. If applicable, these groups can be represented in protected or unprotected forms used in normal organic synthesis. The term "quinolinyl-amine" refers to primary or secondary quinolinyl amines. These amines may be in optically active or inactive forms. The aryl (ring) substructure of the quinolyl-amine may be optionally substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomofolino, piperazinyl, pyridyl, thienyl, furanyl, pyrrolyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate . These groups can be represented in protected or unprotected forms used in normal organic synthesis. The term "heteroaryl-amine" refers to pyrroles, pyrazoles, imidazoles and Índoles. The aryl (ring) sub-structure of the heteroarylamine may be optionally substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, phosphate, phosphonic acid or phosphonate. These groups can be represented in protected or unprotected forms used in normal organic synthesis. The term "polynucleotide" generally refers to polymeric forms of nucleotides of any length, whether ribonucleotides or deoxynucleotides. Thus, this term includes, without limitation, DNA or RNA of single strand, double strand or multiple strands. The polynucleotides may further comprise genomic DNA, cDNA or DNA-RNA hybrids. In addition, the polynucleotides of the present invention can be produced synthetically. The polynucleotides can comprise chemically modified, biochemically modified, or derivatized nucleotides. For example, a polynucleotide may comprise, in part, modified nucleotides such as nucleotides. methylated or nucleotide analogues. The polynucleotides can also comprise sugars, closures, nucleotide branching, and linking groups such as fluororibose and thioate. In addition, the nucleotide sequence can be interrupted by the non-nucleotide components. In addition, a polynucleotide can be modified after polymerization to facilitate its binding to other polynucleotides, proteins, metal ions, labeling components or a solid support. The structure of the polynucleotide may comprise modified or optionally substituted phosphate and / or sugar groups. Alternatively, the structure of the polynucleotide may comprise a polymer of synthetic subunits such as phosphoramidites and thus may be an oligodeoxynucleoside phosphoramidate or a phosphoramidate phosphodiester oligomer. See Peyrottes et al., NULL. ACIDS RES. (1996) 24: 1841-1848, and Chaturvedi et al.,? UCL. ACIDS RES. (1996) 24: 2318-2323. The term "homology", as used herein, refers to the degree of complementarity. There may be partial homology or complete homology (ie, identity). A partially complementary sequence is one that inhibits at least partially an identical sequence from hybridization to a target polynucleotide.; refers to the use of the term "substantially homologous". The inhibition of hybridization of the sequence completely complementary to the target sequence can be examined using a hybridization assay (Southern or Northern blot, solution hybridization (under conditions of low severity.) A substantially homologous sequence or probe will compete for and inhibit binding (ie, hybridization) of a completely homologous sequence, or probe, to the target sequence under conditions of low severity This does not mean that the conditions of low severity are such that non-specific binding is allowed, the conditions of Low severity requires that the binding of two sequences to each other is a specific (ie, selective) interaction.The absence of non-specific binding can be proved by the use of a second target sequence that lacks even a partial degree of complementarity (eg example, less than about 30% identity), in the absence of non-specific binding, the probe does not hybridize will go to the second non-complementary objective sequence. The term "gene" refers to a polynucleotide sequence that comprises coding sequences necessary for the production of a polypeptide or precursor, and may also include expression control sequences. The polynucleotide can be encoded by a full-length coding sequence or by any portion of the coding sequence. The gene can be derived in whole or in part from any source known to the person skilled in the art which includes a plant, a fungus, an animal, a bacterial genome or episome, eukaryotic, nuclear or plasmid DNA, DNA, cDNA, DNA viral or chemically synthesized DNA. A gene may constitute an uninterrupted coding sequence or may include one or more introns, joined by appropriate splice junctions. In addition, a gene may contain one or more modifications in either the coding or untranslated regions that may affect certain properties of the polynucleotide or polypeptide, such as the biological activity or chemical structure of the expression product, the rate of expression, or the way of expression control. These modifications include, without limitation, mutations, insertions, deletions and substitutions of one or more nucleotides. In this regard, the modified genes can be referred to as "variant" of the "native" gene (discussed below). "Gene expression" refers to the process by which a polynucleotide sequence undergoes successful transcription and translation such that detectable levels of the nucleotide sequence are expressed. The term "gene expression profile" refers to a group of genes that represent a particular cell or tissue type (e.g., neuron, coronary artery endothelium, or disease tissue) at any activation state. In one aspect, a gene expression profile is generated from cells exposed to a compound of the present invention. This profile can be compared to a gene expression profile generated from the same type of cell before treatment with a compound of the present invention. In addition, a series of gene expression profiles can be generated from cells treated with a compound of the present invention, specifically at different doses or courses of time to assess the effects of the compound. A gene expression profile is also known as a gene expression signature. The term "differential expression" refers to both quantitative as well as qualitative differences in the tissue and temporal expression patterns of a gene. For example, a differentially expressed gene may have its expression activated or completely inactivated under normal conditions versus disease. This qualitatively regulated gene may exhibit a pattern of expression within a given type of tissue or cell that is detectable under either control or disease conditions, but is not detectable in both, "differentially expressed polynucleotide" as used herein, refers to a polynucleotide sequence that uniquely identifies a differentially expressed gene so that detection of the differentially expressed polynucleotide in a sample correlates with the presence of a gene differentially expressed in a sample.

Similarly, a differentially expressed protein may have its expression activated or completely inactivated under normal conditions versus disease. This qualitatively regulated protein may exhibit an expression pattern within a given type of tissue or cell that is detectable in either the control or disease conditions, which is not detectable in both. A "differentially expressed protein" as used herein, refers to an amino acid sequence that uniquely identifies a differentially expressed protein so that the detection of differentially expressed protein in a sample correlates with the presence of a protein differentially expressed in a sample. "Cell type" as used herein, refers to a cell of a given source (e.g., tissue or organ), a cell in a given state of differentiation, or a cell associated with a given pathology or genetic construct . The term "polypeptide" refers to a polymeric form of amino acids of any length, which may include translated, untranslated, chemically modified, biochemically modified and derivatized amino acids. A polypeptide may be present naturally, recombinantly or synthetically or any combination thereof.

In addition, the term "polypeptide" as used herein refers to proteins, polypeptides and peptides of any size, structure or function For example, a polypeptide may comprise a chain of amino acids together retained by peptide bonds. alternatively comprising a long chain of amino acids jointly retained by peptide bonds In addition, a polypeptide may also comprise a naturally occurring protein or peptide fragment A polypeptide may be a single molecule or may be a complex of several molecules In addition, these polypeptides may also have modified peptide structures.The term "polypeptide" further comprises immunologically labeled proteins and infusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusion proteins with gu sequences heterologous and homologous, and fusion proteins with or without N-terminal residues of methionine. The term "protein expression" refers to the process by which a polynucleotide sequence is subjected to successful transcription and translation such that detectable levels of the amino acid or protein sequence are expressed.

The term "protein expression profile" refers to a group of proteins that represent a particular type of cell or tissue (e.g., neuron, coronary artery endothelium, or disease tissue). In one aspect, a protein expression profile is generated from cells exposed to a compound of the present invention. This profile can be compared to a protein expression profile generated from the same cell type before treatment with a compound of the present invention. In addition, a series of protein expression profiles can be generated from cells treated with a compound of the present invention, specifically, at different doses or time course to assess the effects of the compound. A protein expression profile is also known as a "protein expression signature." As used herein "a biomolecule" includes polynucleotides and polypeptides. In addition, a "biomolecular sequence," as used herein, is a term that refers to all or a portion of a polynucleotide sequence. A biomolecular sequence can also refer to an entire portion of a polypeptide sequence. A "host cell" as used herein, refers to a microorganism, a prokaryotic cell, a eukaryotic cell or cell line grown as a unicellular entity that can be used, or has been used, as a receptor for a recombinant vector or other polynucleotide transfer, and includes the progeny of the original cell that has been transfected. It is understood that the progeny of a single cell can not necessarily be completely identical in morphology or in complement of total or genomic DNA as the origin due to natural, accidental or deliberate mutation. In the context of a biomolecule, for example, Perlecan, the term "functional equivalent" refers to a protein or polynucleotide molecule that possesses functional or structural characteristics that are substantially similar to all or part of the active Perlecan protein or active polynucleotides encoding for Perlecan. A functional equivalent of a native Perlecan protein may contain modifications depending on the need for these modifications for a specific structure or the performance of a specific function. The term "functional equivalent" is intended to include the "fragments", "mutants", "derivatives", "alleles", "hybrids", "variants", "analogs" or "chemical derivatives" of the native Perlecan. In the immunoglobulin context, the term "equivalently functional" refers to immunoglobulin molecules that exhibit immunological binding properties that are substantially similar to the immunoglobulin of origin. As used herein, the term "immunological binding properties" refers to non-covalent interactions of the type that occur between an immunoglobulin molecule and an antigen for which immunoglobulin is specific. In reality, a functional equivalent of a monoclonal antibody immunoglobulin, for example, can inhibit the binding of the monoclonal antibody of origin to its antigen. A functional equivalent may comprise the F (ab ') 2 fragments / F (ab) molecules, the Fv fragments, the single variable chain fragment exhibited in phage (scFv), individual domain antibodies, chimeric antibodies or the like while the immunoglobulin exhibits the characteristics of the immunoglobulin of origin. As used herein, the term "isolated" refers to a polynucleotide, a polypeptide, an antibody or a host cell that is in an environment different from that in which the polynucleotide, polypeptide, or antibody is naturally occurring. host cell. A polynucleotide, polypeptide, antibody or isolated host cell is generally substantially purified. As used herein, the term "substantially purified" refers to a compound that is removed from its natural environment and is at least about 60% free, at least about 65% free, at least about 70% free, less than about 75% free, at least about 80% free, at least about 83% free, at least about 85% free, at least about 88% free, at least about 90% free, at least about 91% free, at least about 92% free, at least about 93% free, at least about 94% free, at least about 95% free, at least about 96% free, at least about 97% free, at least about 98% free, at least about 99 Free%, at least approximately 99.9% free, at least approximately 99.99% free, of other components with which it is naturally associated. For example, a composition containing A is "substantially free of" B when at least about 85% by weight of the total of A + B in the composition is A. Alternatively, A comprises at least about 90% by total A + B in the composition, even moreover, at least about 95% or even 99% by weight. "Diagnosis" as used herein, generally includes a determination of the susceptibility of a subject or a disease or disorder, a determination as to whether a subject is currently affected by a disease or disorder, a prognosis of a subject affected by a disease or disorder (e.g., identification of pre-metastatic or metastatic cancerous states, cancer states, or cancer sensitivity to therapies), and teramétrieos (e.g., monitoring the condition of a subject to provide information regarding the effect or efficiency of the therapy). The term "biological sample" encompasses a variety of sample types obtained from an organism that can be used in a diagnostic, monitoring or other assay. The term encompasses blood and other liquid samples of biological origin, samples of solid tissue such as a biopsy specimen, or cultures or tissue cells derived therefrom and their progeny. The term specifically encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, urine, amniotic fluid, biological fluids, and tissue samples. The term also encompasses samples that have been manipulated in any way after procuring or obtaining such as treatment for reagents, solubilization, or enrichment for certain components. The terms "individual", "subject", "host" and "patient" refer to any mammalian subject whose diagnosis, treatment or therapy is desired. The individual, subject, host or patient is optionally a human.

Other subjects may include, without limitation, cattle, horses, dogs, cats, guinea pigs, rabbits, rats, primates and mice. The terms "treatment", "treating", "treating" as used herein refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be prophylactic since it can completely or partially prevent a disease or symptom of it and / or it can be therapeutic since it can completely or partially stabilize or cure a disease and / or adverse effect attributable to the disease. "Treatment" as used herein, covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing disease or symptom from occurring in a subject that may be predisposed to the disease or symptom , but has not yet been diagnosed as having it; (b) inhibit the symptom of disease, that is, stop its development; or (c) alleviating the symptom of the disease, that is, causing regression of the disease or symptom. The term "therapeutically effective amount" refers to an amount of, for example, a compound contemplated herein, which is effective to prevent, ameliorate, treat or delay the onset of a disease or condition. A "prophylactically effective amount" refers to an amount of, for example, a compound contemplated in this way as being effective in preventing a disease or condition. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and / or surfactants, which is useful for distributing a drug to a mammal. The compounds of the present invention can be distributed by a liposome. The components of the liposome are commonly arranged in a two-layer formation, similar to the lipid arrangement of the biological membranes. "Hybridization", defined broadly, refers to any process by which a polynucleotide sequence is joined to a complementary sequence through base pairs. Hybridization conditions can be defined for example by the salt or formamide concentrations in the pre-hybridization and hybridization solutions, or by the hybridization temperature, and are well known in the art. Hybridization can occur under various conditions of severity. Hybridization can also refer to the binding of a capture-protein agent to a target protein under certain conditions, such as normal physiological conditions.

As used herein, the term "activation" refers to any alteration of a signaling or biological response pathway that includes, for example, increases above the basal levels, restoration to the basal levels from an inhibited state, and Stimulation of the route above the basal levels. The term "biological activity" refers to the biological behavior and effects of a peptide or protein. The biological activity of a protein can be affected at the cellular level and at the molecular level. For example, the biological activity of a protein can be affected by changes at the molecular level. For example, an antisense oligonucleotide can prevent the translation of a particular mRNA, thereby inhibiting the biological activity of the protein encoded by the mRNA. In addition, an antibody can bind to a particular protein and inhibit the biological activity of this protein. The term "oligonucleotide" as used herein refers to a polynucleotide sequence comprising, for example, from about 10 nucleotides (nt) to about 1000 nt. Oligonucleotides for use in the present invention are, for example, from about 15 nt to about 150 nt, or from about 150 nt to about 1000 nt in length. The oligonucleotide may be an oligonucleotide that occurs naturally or a synthetic oligonucleotide. Oligonucleotides can be prepared by the phosphoramidite method (Beaucage and Carruthers, TETRAHEDRON LETT. (1981) 22: 1859-1862), or by the triester method (Matteucci et al., J. AM CHEM SOC. (1981) 103: 3185), or by other chemical methods known in the art. The term "microarray" generally refers to the type of genes or proteins represented in a microarray by oligonucleotides (polynucleotide sequences) or protein binding agents, and where the type of genes or proteins represented in the microarray is dependent on the purpose proposed of the microarray. For example, to monitor the expression of human genes or human proteins). The oligonucleotides or binding agents or protein in a given microarray may correspond to the same type, category, or group of genes or proteins. Protein genes can be considered to be of the same type if they share some common characteristics such as species of origin (eg, human, mouse, rat); state of illness (for example, cancer); function (e.g., protein kinases, tumor suppressors); same biological process; (for example, apoptosis, signal transduction, cell cycle regulation, proliferation, differentiation). For example, a type of microarray can be a "cancer microarray" in which each of the microarray oligonucleotides or protein binding agents corresponds to a gene or protein associated with a cancer. An "epithelial microarray" can be a microarray of oligonucleotides or protein binding agents that correspond to a single epithelial gene or unique protein. Similarly, a "cell cycle microarray" can be a type of microarray in which the oligonucleotides or protein binding agents correspond to unique genes or proteins associated with the cell cycle. The term "detectable" refers to a pattern of polynucleotide expression that is detectable via standard polymerase chain reaction (PCR) techniques, is inverted transcriptase (RT) -PCR, differential display and Northern analysis, which are well known to those skilled in the art. Similarly, polypeptide expression patterns can be detected "via standard techniques that include immunoassays such as Western blots." A "target gene" refers to a polynucleotide, often derived from a biological sample, to which a DNA probe is designed. oligonucleotide in a specific manner to hybridize It is either the presence or absence of the target polynucleotide that is to be detected, or the amount of the target polynucleotide to be quantitated The target polynucleotide has a sequence that is complementary to the polynucleotide sequence The target polynucleotide may also refer to the specific sequence of a larger polynucleotide to which the probe is directed or to the entire sequence (eg, gene or mRNA) whose expression levels it is desired to detect. "target protein" refers to a polynucleotide, often derived from a biological sample, to which a protein capture agent hybridizes or binds in a specific way. It is either the presence or absence of the target protein that is going to be detected, or the amount of the target protein that is to be quantified. The target protein has a structure that is recognized by the corresponding protein capture binding agent targeted to the target. The target protein or amino acid may also refer to the specific sub-structure of a larger protein to which the protein capture agent is directed or to the entire structure (eg gene or mRNA) whose expression levels it is desired to detect. The term "complementary" refers to topological compatibility or co-correspondence of the interacting surfaces of a probe molecule and its target. The objective and its probes can be described as complementary, and in addition, the characteristics of the contact surface are complementary to each other. Hybridization or pairing in base pairs between nucleotides or nucleic acids, such as for example between the two strands of a double-stranded DNA molecule or between an oligonucleotide probe and a target are complementary. The term "background" refers to non-specific binding or other interactions between, for example, polynucleotides, polypeptides, small molecules and polypeptides, or small molecules and polynucleotides. "Background" may also refer to non-specific binding or interactions in the context of trials that include immunoassays. In the context of microarrays, the term "background" refers to hybridization signals that result from the non-specific binding, or other interactions, between the labeled target polynucleotides and the components of the oligonucleotide microarray (e.g., the oligonucleotide probe). , control probes, and microarray support) or between the target proteins and protein binding agents of a protein microarray. The background signals can also be produced by intrinsic fluorescence of the microarray components themselves. The individual background signal can be calculated from the entire microarray, or a different background signal can be calculated for each target protein or target polynucleotide. The background can be calculated as the average intensity of the hybridization signal, where a different background signal is calculated for each target gene or target protein. Alternatively, the background can be calculated as the average intensity of hybridization signal produced by hybridization to probes that are not complementary to any sequence found in the sample (e.g., probes directed to polynucleotides of the opposite direction or to genes not found in the shows such as bacterial genes where the sample is mammalian polynucleotides). The background can also be calculated as the average signal intensity produced by regions of the microarray that lack probes or protein binding agents altogether. A "small molecule" refers to a compound or molecular complex, whether synthetic, naturally derived or partially synthetic, composed of carbon, hydrogen, oxygen and nitrogen, which may also contain other elements and which may have a molecular weight of less than about 15,000, less than about 14,000, less than about 13,000, less than about 12,000, less than about 11,000, less than about 10,000, less than about 9,000, less than about 8,000, less than about 7,000, less than about 6,000, less than about 5,000, less than about 4,000, less than about 3,000, less than about 2,000, less than about 1,000, less than about 900, less than about 800, less than about 700, less than about 600, less than about 500, less than approximately 400, less than approximately 300, less than approximately 200, or less than about 100. The term "fusion protein" refers to a protein composed of two or more polypeptides which, although typically bound in their native state, are joined by their respective amino and carboxyl terms through a peptide bond to form a single continuous polypeptide. It is understood that the two or more polypeptide components can be linked either directly or indirectly through a peptide linker / separator. The term "normal physiological conditions" means conditions that are typical within a living organism or a cell. Although some organs or organisms provide extreme conditions, the intra-organ and intracellular environment normally varies around pH 7 (ie from pH 6.5 to pH 7.5), contains water as the predominant solvent, and there is a temperature above 0 ° C. and below 50 ° C. The concentration of various salts depends on the organ, organism, cell or cell compartment used as a reference. The term "grouping" refers to a group of clones or biomolecular sequences related to each other by sequence homology. In one example, groupings are formed based on the specific degree of homology and / or overlap (e.g., severity). "Grouping" can be done with the sequence data. For example, a biomolecular sequence that is thought to be associated with a particular biological or molecular activity in a tissue can be compared against another library or sequence database. This type of search is useful for searching for homologous and presumably functionally related sequences in other tissues or samples, and can be used to stylize the methods of the present invention since grouping within one or more of the base of the invention can be used. data for grouping biomolecular sequences before performing a method of the invention. Sequences that show sufficient homology to the representative sequence are considered part of a "cluster." This "sufficient" homology may vary within the needs of a person skilled in the art. As used in this, the term "internal database" refers to a database maintained within a local network of computers. It contains, for example, biomolecular sequences associated with a project. It may also contain information associated with sequences that include, but are not limited to, a library in which a given sequence is found and descriptive information about a similar gene associated with the sequence. The internal database is optionally maintained as a private database behind a curtain of fire within a corporate network. However, the present invention contemplates an internal database that is available to the public. The internal database can include sequence database generated by the same company that maintains the database and can also include sequence data obtained from external sources. The term "external database" as understood herein, refers to a database located outside of all internal databases. Typically, a company network that differs from the company network that maintains the internal database will maintain an external database. The external database can be used, for example, to provide some descriptive information in biomolecular sequences stored in the internal database. For example, the external database may be GenBank and associated databases maintained by the National Center for Biotechnology Information (NCBI), which is part of the National Library of Medicine.

Detailed Description of the Invention The present invention relates to compounds of the general formula (I), their analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. Additionally, the present invention relates to pharmaceutical compositions comprising compounds of the general formula (I), their analogues, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, either individually or in combination thereof. Still further, the present invention relates to methods of using compounds of the general formula (I), their analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, either individual or in any combination thereof. Still further, the present invention relates to methods for making compounds of the formula (I), their analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. Compounds of Formula I to General (I) The present invention relates to compounds of the formula (I), and to methods and / or compositions comprising the compounds that are effective in modulating inflammatory responses, such as those which result of the accumulation of glycated protein and AGE. The present invention also relates to methods and / or compositions comprising compounds that are effective in modulating the proliferation of smooth muscle cells and diseases or conditions related thereto. According to one aspect of the present invention, various compounds of the general formula (I) are provided its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates. According to this aspect, In this and other aspects, L is -Y-G = Z-Ar-, (CH2) and Q is R1, R2, and R3 are independently hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group , an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an aryisulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group , an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, n aralkylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof, wherein any two of R 1, R 2 and R 3 in combination optionally form a 5-membered or 6-membered saturated cyclic ring. members having 1 to 3 heteroatoms, wherein the heteroatoms are O, S or N. The cyclic ring formed by any two of R1, R2 or R3 may be oxlanyl, 1,3-dioalanyl, or 1,4-dioxalanyl . R4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, an cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclic group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an aryisulfonyl group, a heteroarylsulfonyl group, an alkylsulphinyl group , an aryl sulfyl group, an aralkylsulfinyl group, a heteroarylsulfyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, an fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof. Any of R1, R2, R3 and R4 independently optionally are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group , an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aryisulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the GRU a heterocycle is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group . According to this and other aspects, A, B, D and J independently are O, S, N, >; CH, or (~ CH2 ~) n; ? 'is an optional chemical bond; E is O, S, or -NR; K is N, C, or CH; Y and Z independently are 0, -NR, (-CH2-) U, or S (= 0) u; G is - (CH2) 5, - (CH2) S-CH = CH- (CH2) S-, or - (CH2) S-C = C- (CH2) s; , Xi, X2, X3, and X independently are 0, S, or -NR; F is 0, S, or -NR; Y1 and Y2 independently are 0 or S; n, w, u independently are an integer of 0-2; p, t, m, s, v independently are an integer of 0-5, and Ar 'is a substituted and unsubstituted phenyl group or a substituted or unsubstituted naphthyl group. R and R5 independently are hydrogen, potassium, sodium, a hydroxy group, a halogen group, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group. The groups provided above are as follows: "Halogen" is fluorine, chlorine, bromine or iodine; "Alkyl" group is a linear or branched (C1-C10) alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl. "Cycloalkyl" group is a (C3-C7) cycloalkyl group which may be mono- or polycyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. "Alkoxy" is (C1-C10) alkyl-O-, wherein the (C1-C10) alkyl group is as defined above. Exemplary alkyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy. "Cycloalkoxy" is a group (C3-Cd) cycloalkoxy. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. "Alkenyl" is a group (C2-C6) alkenyl. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl. "Cycloalkenyl" is a group (C3-C7) cycloalkenyl.

Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. "Alkoxyalkyl" is a group (C? -C6) alkoxy (C? ~ C? O) alkyl, wherein the alkoxy and alkyl groups are as defined above. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl. "Alkenyloxy" is (C2-Ce) alkenyl-O-, where the (C2-C6) alkenyl group is as defined above. Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy. "Cycloalkenyloxy" is (C3-C7) cycloalkenyl-O, wherein (C3-C7) cycloalkenyl is as defined above. Exemplary cycloalkenyloxy groups include cyclohetenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy. "Acyl" is H-CO- or (C1-C10) alkyl-CO-, where the group (Ci-Cao) alkyl is as defined above. Exemplary acyl groups include acetyl, propionyl. "Acyloxy" is (C? -C6) acyl-O-, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy. "Aryl" is a monocyclic or polycyclic ring system of about 5 to 14 carbon atoms. Example groups include phenyl, naphthyl. "Aryloxy" is an aryl-O- group, where the aryl group is as defined above. Exemplary aryloxy groups include phenoxy, naphthyloxy. "Aroyl" is the group aryl-CO-, wherein the aryl group is as defined above. Exemplary aroyl groups include benzoyl, 1-naphthoyl.

"Aroyloxy" is the aroyl-O- group, wherein the aroyl group is as defined above. Exemplary aroyloxy groups include benzoyloxy, 1-naphthoyloxy. "Aralkyl" is the aryl- (C1-C10) alkyl group, wherein the aryl and (C1-C10) alkyl groups are as defined above. Exemplary aralkyl groups include benzyl, 2-phenylethyl. "Aralkenyl" is an aryl- (C2-C6) alkenyl group, wherein the aryl and (C2-Cg) alkenyl groups are as defined above. "Aralkynyl" is the aryl- (C2-C6) alkynyl group, wherein the aryl group is as defined above. "Aralkoxy" is the aralkyl-O- group, wherein the aralkyl group is as defined above. Exemplary aralkoxy groups include benzyloxy, 2-phenethyloxy. "Heterocyclyl" is a non-aromatic saturated monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from O, S or N. Exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl. "Heterocyclenyl" is a monocyclic or polycyclic nonaromatic hydrocarbon ring system of about 5 to 10 carbon atoms, having at least one heteroatom selected from 0, S or N and a double bond. Exemplary heterocyclenyl groups include 1,2,3,4-tetrahydropyrimidine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1, 2, 3, β-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl. "Heteroaryl" is a monocyclic or polycyclic aromatic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from 0, S or N. Exemplary heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxole, 1,3-benzoxathiol, quinazolinyl, pyridyl, thiophenyl. "Heteroaralkyl" is a heteroaryl- (C? ~ C? O) alkyl, wherein the heteroaryl and (Cx-Cio) alkyl groups are as defined above. Exemplary heteroalkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl. "Heteroaryloxy" is heteroaryl-O-, wherein the heteroaryl group is as defined above. Exemplary heteroaryloxy groups include pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, phthalazinyloxy, indolyloxy, quinazolinyloxy, pyridyloxy, thienyloxy. "Heteroaralkoxy" is heteroaralkyl-O-, wherein the heteroaralkyl group is as defined above. Exemplary heteroaralkoxy groups include thienylmethyloxy, pyridylmethyloxy. "Alkylcarbonyl" or "acyl" is (C? -C10) alkyl-CO-, wherein the (C1-C10) alkyl group is as defined above. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl. "Alkoxycarbonyl" is (C? -C10) alkyl-O-CO-, wherein the (C1-C10) alkyl group is as defined above. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl. "Arylcarbonyl or" aroyl "is aryl-CO-, wherein the aryl group is as defined above.Example arylcarbonyl include phenylcarbonyl, naphthylcarbonyl," Aryloxycarbonyl "is aryl-O-CO-, wherein the aryl group is as is defined above Example aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl, "Aralkoxycarbonyl" is aryl- (C? -C6) alkoxy-CO-, wherein the aryl group and (C? -C3) alkoxy are as defined above. Exemplary aralkoxycarbonyl groups include benzyloxycarbonyl, 2-phenethyloxycarbonyl, "Heteroarylcarbonyl" is heteroaryl-CO-, wherein heteroaryl is as defined above, Example heteroarylcarbonyl groups include pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl. "Alkylsulfonyl" is (C1-C10) alkyl-S02-, wherein the (C1-C10) alkyl group is as defined above. or include methylsulfonyl, ethylsulfonyl, propylsulfonyl. "Ariisulfonyl" is aryl-S02-, wherein the aryl group is as defined above. Exemplary aryisulfonyl groups include benzenesulfonyl. "Heteroarylsulfonyl" is heteroaryl-S02-, wherein the heteroaryl group is as defined above. Exemplary heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolysulfonyl, pyrazolylsulfonyl, pyrrolylsulfonyl, pyridazinylsulfonyl, phthalazinylsulfonyl, quinazolinylsulfonyl, pyridylsulfonyl, thienylsulfonyl. "Alkylsulfinyl" is (C? -C?) Alkyl-SO-, wherein the group (Ci-Cio) alkyl is as defined above. Exemplary alkylsulfinyl groups include methylisulfinyl, ethylisulfinyl, propylsulfinyl. "Arylsulfinyl" is aryl-SO-, wherein the aryl group is as defined above. Exemplary aryisulfonyl groups include phenylsulfinyl. "Heteroarylsulfinyl" is heteroaryl-SO-, wherein the heteroaryl group is as defined above. Exemplary heteroarylsulfinyl groups include pyrazinylsulfinyl, isothiazolylsulfinyl, oxazolylsulfinyl, pyrazolysulfinyl, pyrrolylsulfinyl, pyridazinylsulfinyl, phthalazinylsulfinyl, quinazolinylsulfinyl, pyridylsulfinyl, and thienylsulfinyl. "Aralkylsulfinyl" is aryl- (C1-C10) alkyl-SO- wherein the aryl group and (C? -C10) alkyl are as defined above. Exemplary aralkylsulfinyl groups include benzylsulfinyl, 2-phenethylsulfinyl. "Alkylthio" is (C1-C10) alkyl-S-, where (C? ~ C?) Alkyl is as defined above. Exemplary alkylthio groups include methylthio, ethylthio, and propylthio. "Arylthio" is aryl-S-, wherein the aryl group is as defined above. Exemplary arylthio groups include phenylthio groups. "Heteroarylthio" is heteroaryl-S-, wherein the heteroaryl group is as defined above. Exemplary heteroarylthio groups include pyrazinylthio, isothiazolylthio, oxazolylthio, pyrazolylthio, pyrrolylthio, pyridazinylthio, phthalazinylthio, quinazolinylthio, pyridylthio, and thienylthio. "Aralkylthio" is aryl- (C? ~ C10) alkyl-S- wherein the aryl and (C? -C10) alkyl groups are as defined above. Exemplary aralkylthio groups include benzylthio, and 2-phenethylthio. "Aryloxyalkyl" is aryl-O- (C1-C10) alkyl, wherein the aryl and (C1-C10) alkyl groups is as defined above. Exemplary aryloxyalkyl groups include phenoxymethyl, phenoxyethyl, and phenoxypropyl. "Aralkoxyalkyl" is aryl- (C1-C10) alkyl-O- (Ci- C? O) alkyl, wherein the (C1-C10) alkyl and aryl group is as defined above. Exemplary aralkoxyalkyl groups include benzyloxymethyl, benzyloxyethyl, and benzyloxypropyl. "Fused heteroarylcycloalkyl" is fused heteroaryl and (C3-Cg) alkyl cycle, wherein the heteroaryl and (C3-C6) alkyl groups are as defined herein. Exemplary fused heteroarylcycloalkyl groups include 5, 6, 7, 8-tetrahydroquinolinyl, and 5,6,7,8-tetrahydroisoquinolyl. "Fused heteroarylcycloalkenyl" is fused heteroaryl and (C3-C6) alkenyl cycle, wherein the heteroaryl and cyclo (C3-Ce) alkenyl groups are as defined herein. Exemplary fused heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl. "Fused heteroarylheterocyclenyl" is fused heteroaryl and heterocyclenyl, wherein the heteroaryl and heterocyclenyl groups are as defined herein. Exemplary fused heteroarylheterocyclenyl groups include 7,8-dihydro [1,7] naphthyridinyl, 1,2-dihydro [2,7] naphthyridinyl. "Carboxylic acid or its derivatives" can be amides or esters. Exemplary carboxylic acid groups include CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh, COOCH3, COOC2H5 or COOC3H7. "Sulfonic acid or its derivatives" can be amides or esters. Exemplary sulfonic acid groups include S02NH2, S02NHMe, S02NMe2, S02NHCF3, COOCH3, COOC2H5, or COOC3H7. As used herein: Ra is hydrogen, a hydroxy group, a halogen, a nitro group or an optionally substituted amino group; Rb is an alkyl group, an alkoxy group, an alkenyl group or an alkoxyalkyl group; Rc is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group; Rla is hydrogen, a hydroxy group, a halogen group, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group , a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; Rlb is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group or a heteroarylcarbonyl group; Rlc is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof. R2a is hydrogen, a hydroxy group, a halogen group, a nitro group, a carboxy group, a carbamoyl group or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R2b is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, m heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group or a heteroarylcarbonyl group; R 2c is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, a aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; R3a is hydrogen, a hydroxy group, a halogen group, a nitro group, a carboxy group, a carbamoyl group, or an amino group optionally substituted alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group , a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group or a cycloalkenyloxy group; R3b an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group or a heteroarylcarbonyl group; R3c is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof: Ra is hydrogen, a hydroxy group, a halogen group, a nitro group, or an optionally substituted amino group, an alkyl group, a group cycloalkyl, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R4b is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group or an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group or a heteroaralkoxy group; Rc is an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, or an aralkylsulfinyl group, an alkylthio group, an arylthio group, heteroarylthio, aralkylthio, fused heteroarylcycloalkyl group one, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; R5a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group; R5b is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R5c is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group or a heteroaryl group; R'a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =) or a tio group (S =); R'b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, a group aryloxycarbonyl, a heteroaryl group, a heterocyclyl group, or an aralkyl group; R 'c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group; R ', a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 = ), or a thio group (S =); R ', b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, a group aryloxycarbonyl, a heteroaryl group, a heterocyclyl group, or an aralkyl group; R "'is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group. R9a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a thio group (S =); R9b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; R9c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with halogen, a group hydroxyl, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent in the group heterocyclyl is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group or an aryl group; R10a is hydrogen, halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a thio group (S =); R10b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; R10c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl, a nitro group, an amino group, an alkyloxy group or any combination thereof, and wherein the heterocycle group is optionally a morpholino group substituted group, a thiomorpholinyl group or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group. Rlla is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a thio group (S =); Rllb is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; Rllc is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, wherein the heterocycle group is an optionally substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; R12a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a thio group (S =); R12b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; R12c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group that is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group , or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, a alkyl group, an alkoxy group, or an aryl group; R13a is hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =) or a thio group (S =); R13b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; R13c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group or any combination thereof, wherein the heterocycle group is optionally a morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; R14a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =) or a thio group (S =); R1 b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group , a heteroaryl group or a heterocyclyl group, an aralkyl group; Ra c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group or a piperazinyl group the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; R 0a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a tio group (S =); R20b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; R20c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an aryl sulfyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; R21a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a thio group (S =); R21 is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; R21c is an alkylsulfonyl group, an alkylsulfonyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a group hydroxyl, a nitro group, an amino group, an alkyloxy group, or any combination thereof, wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group. Ga is - (CH2) S ~, where s is an integer of 0-5; Gb is - (CH2) S-CH = CH- (CH2)? -, where s is an integer of 0-5; Gc is - (CH2) S-C = C- (CH2) s ~, where s is an integer of 0-5; Za is O; Zb is NR; Zc is (-CH2) U or S (= 0) u, where u is an integer of 0-2; Ea is O; Eb is S; Ec is NR; pa is 0-1; bp is 2-3; pc is 4-5; va is 0-1; vb is 2-3; vc is 4-5; wa is 0; wb is 1; wc is 2; Xa is O; Xb is S; and Xc is -NR. According to the present invention, several compounds of the general formula (I) having the general formula (II) are provided its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts and its pharmaceutically acceptable solvates. Except as otherwise provided herein, all symbols are as defined above in conjunction with the formula (I) - According to another aspect of the present invention, there are provided several compounds of the general formula (I) having the general formula (III) its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates. Except as otherwise provided, all symbols are as defined above in conjunction with formula (I). R 'and R "independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, a group aroyl, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group. In one aspect of the present invention, R1, R2, R3 and R5 are as defined above; R 4 is an optionally substituted aryl group, and in some cases, is a phenyl group optionally substituted with a halogen, an alkoxy group or both; E is 0 or -NR, where R is as defined above; G is - (CH2) S or - (CH2) S-CH = CH- (CH2) s ~; s is an integer of 1-3; and R 'and R "are as defined above, and in some cases, independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group , an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group or an acyl group. Numerous compounds having the general formula (III) are contemplated by the present invention. Various configurations of these compounds provided herein are also encompassed by this invention, as provided below. where all the symbols are as defined above in conjunction with the formula (I). Thus, by way of example, and not only by way of limitation, the present invention contemplates the following example compounds: where all the symbols are as defined above in conjunction with the formula (I). By way of further example, the present invention contemplates several compounds having the following general formula: where all the symbols are as defined above in conjunction with the formula (I). According to various aspects of the present invention, R, R5, R ', R ", and E of the formula (30) are selected to produce various compounds of the formula (30-1) up to the formula (30-243) ) as follows: 1 li Formula R R > R R E -1 Ra R5a R, a R "a Ea -2 Rb R5a R, a R "a Ea -3 Rc R5a R, a R "a Ea -4 Ra R5b R | B R "to Ea -5 Rb R5b R, a R ,, a Ea -6 Rc R5b Rra R "to Ea -7 Ra R5c R, ß R "to Ea -8 Rb R5c R, a R "to Ea -9 Rc R5c R- R "to Ea -10 Ra R5a R'b R "to Ea -11 Rb R5a R, b R "to Ea -12 Rc R5a R, b R "to Ea -13 Ra R5b R, b R "to Ea -14 Rb R5b R, b R "to Ea -15 Rc R5b Rrb R "to Ea -16 Ra R5c R'b R "to Ea -17 Rb R5c Rrb R "to Ea -18 Rc R5c R'b R "to Ea -19 Ra R5a R'c R "to Ea -20 Rb R5a R, c R "to Ea -21 Rc R5a R'c R "to Ea -22 Ra R5b RfC R "to Ea -23 Rb R5b R, c R "to Ea -24 Rc R5b R'c R "to Ea -25 Ra R5e RrC R ,, a Ea -26 Rb R5c R, c R ,, a Ea -27 Rc R5c R, c R "ü Ea -28 Ra R5a R'a R..b Ea -29 Rb R5a R'a R "b Ea -30 Rc R5a R, a Rr, b Ea, -31 Ra R5b R'a R "Ea -32 Rb R5b R, a R "b Ea -33 Rc R5b R'a R "b Ea -34 Ra R5c R, a R "b Ea -35 Rb R5c R, a R "b Ea -36 Rc R5c R, a R ,, b Ea -37 Ra R5_ R, b R "b Ea -38 R R5a R 'R "b Ea -39 Rc R5a Rrb R ,, b Ea -40 Ra R5b R, b R "b Ea -41 Rb R5b R'b R "b Ea -42 Rc R5b R'b R "b Ea -43 Ra R5c R, b R ,, b Ea -44 Rb RSc R'b R "b Ea -45 Rc R5c R, b R "b Ea 30-46 Ra R5a R» c R ,, b Ea -47 Rb R5a R'c R », b Ea -48 Rc R5a R, c Rnb Ea -49 Ra R5b R'c Rnb Ea -50 R R5b R'c R ,, b Ea -51 Rc R5b R, c R "Ea -52 Ra R5c R'c R "b Ea -53 R R5c R, c R "b Ea -54 Rc R5c R'c R "b Ea -55 Ra R5a Rra R "c Ea -56 R R5a R, a R ,, c Ea -57 Rc R5a R, a R "c Ea -58 Ra R5b R, a R ,, c Ea -59 Rb R5b R, a R "c Ea -60 Rc R5b R'a R "c Ea -61 Ra R5c R'a Ruc Ea -62 R R5c R'a R "c Ea -63 Rc R5o R, a R "c Ea -64 Ra R5a R, b R "c Ea -65 R R5a R, b R ,, c Ea -66 Rc R5a R, b R "c Ea -67 Ra R5b R, b R "c Ea -68 Rb R5b R, b R "c Eß -69 Rc R5b R, b R "c Ea -70 Ra R5c Rlb R "c Ea -71 R RSc R.b R ,, c Ea -72 Rc R5c R, b R "c Ea -73 Ra R5a R, c R "c Ea -74 Rb R5a R, c R "c Ea -75 Rc R5a R, c R ,, c Ea -76 Ra R5b R, c R "c Ea -77 R R5b R, c R "c Ea -78 Rc R5b RrC R "c Ea -79 Ra R5c R'c R "c Ea -80 Rb RS_ R.c R ,, c Ea -81 Rc R5c R, c R ', c Ea -82 Ra R5a R, a R, ta Eb -83 Rb R5a R, a R "a Eb -84 Rc R5a R'a R "Q Eb -85 Ra R5b R, a R, a E -86 Rb R5b R, a R ,, a Eb -87 Rc R5b R (a R "a Eb -88 Ra R5c R'a R "to E -89 Rb R5c R, a R "to E -90 Rc R5c R'a R ,, a Eb -91 Ra R5a R, b R ,, a Eb -92 Rb R5a R, b R "a Eb -187 Ra R 5c R, c R "a Ec -188 Rb R: 5c R, c R "a Ec -189 Rc R: 5c R (c R "a Ec -190 Ra R 5a R, a R ,, b Ec -191 Rb R 5a R1a R "b Ec -192 Rc R 5a R, a R "Ec -193 Ra R 5b R, a R "b Ec -194 Rb R 5b R, a R "b Ec -195 Rc R 5b R, a R "b Ec -196 Ra R 5c R, a R "b Ec -197 Rb R 5c R'a R "b Ec -198 Rc R 5c R'a R ,, b Ec -199 Ra R 5a R, b R..b Ec -200 Rb R 5a R, b R ,, b Ec -201 Rc R 5a R, b R "b Ec -202 Ra R 5b R, b R "b Ec -203 Rb R 5b R, b R ,, b Ec -204 Rc R 5b Rrb R ,, b Ec -205 Ra R 5c R, b R ,, Ec -206 R R 5c R, R "b Ec -207 Rc R 5c R'b R ,, b Ec -208 Ra R 5a R, c R "b Ec -209 Rb R 5a R, c R "b Ec -210 Rc R 5a R, c R "b Ec -211 Ra R 5b R, c R "b Ec -212 Rb R 5b R, c R "b Ec -213 Rc R 5b R, c R "b Ec -214 Ra R 5c R, c R-, b Ec -215 Rb R 5c R.c Rtb Ec -216 Rc R 5c R, c R "b Ec -217 Ra R 5a R, a R "c Ec -218 Rb R 5a R, a R "c Ec -219 Rc R 5a R'a R "c Ec -220 Ra R 5b R, a R "c Ec -221 R R 5b R, a R "c Ec -222 Rc R 5b R, a R "c Ec -223 Ra R 5c R, a R "c Ec -224 Rb R 5c R, a Rr, c Ec -225 Rc R 5c R'a R "c Ec -226 Ra R 5a R, b R "c Ec -227 R R 5a R, b R ,, c Ec -228 Rc R 5a R, b R "c Ec -229 Ra R 5b R'b R "c Ec -230 Rb R 5b R, b R ,, c Ec -231 Rc R 5b R, b R ,, c Ec -232 Ra R 5c R'b R "c Ec -233 Rb R 5c R 'R ,, c Ec where all the symbols are as defined above. In one aspect of formula (30) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group; R5 is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R 'and R "are independently hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a aryl group, or a benzyloxy group; and E is O, S, or NH. In another aspect of formula (30) of the present invention, R is hydrogen, an alkyl, potassium, sodium group; R5 is hydrogen or an alkyl group; and all other symbols are as defined above in conjunction with formula (I); In another aspect of formula (30) of the present invention, E is O, S, or NH; R 'and R "independently are -H, -Cl, -Br, or -CH3; R5 is -H, -CH3, or -CH2CH2CH3; and R is -H, K, or Na. Examples of the compounds of the formula (30) include, but are not limited to: The present invention also contemplates various compounds of the formula in general (III) having the formula: wherein all symbols are as defined above with respect to formula (I). According to various aspects of the present invention, R1, R2, R4, E, R 'and R "of the formula (31) are selected to produce various compounds of the formulas (31-1) to (31-729) as follows: Formula R1 4 R * ER 'R "31-1 R the R¿ R4a Ea R'a R ,, a 31-2 R Ib R: 2a R4a Ea R'a R" a 31-3 the R: 2a R4a Ea R, a R "a 31-4 R: the R: 2b R4a Ea R, a R» a 31-5 R Ib R 2b R4a Ea R, a Rr.a 31-6 le R 2b R4a Ea RIa R "a 31-7 R the R 2c R4a Ea R'a R "a 31-8 Rl R2c R4a Ea R, a R" a R! C R2c 31-9 R4a Ea R, a R "a 31-10 Rla R2a R4b Ea Rra R, a R4b 31-11 Rl R2a Ea R, a R, a R4b 31-12 Rlc R2a Ea R, a R ,, a Rla R2b R4b 31-13 Ea R'a R ,, a R2b R4b 31-14 Rl Ea R, a R "a Rlc 31-15 R2b R4b Ea R, a R "a Rla R2c R4b 31-16 Ea R, a R "a R.b R4b 31-17 R c Ea R, a R "a Rlc R4b 31-18 R2c Ea R, a R "a Rla 31-19 R2a R4 * Ea R, a R "a Rlb R4c 31-20 R2a Ea R, a R "a Rlc R2a R4c 31-21 Ea R'a R "a R4c 31-22 R, a R2 Ea R, a R" a 31-23 Rlb R4c R2 Ea R, a R "a Rlc R "a 31-24 R2b R4c Ea R'a R4c 31-25 Rla R2c Ea R'a R "a 31-26 R3b R2c R4c Ea R'a R "a Rlc R2c 31-27 R4c Ea R'a R "a 31-28 RIa R2a R4a Eb R'a R "a R4a 31-29 Rlb R2a Eb R, a R" a Rlc 31-30 R2a R4a Eb R, a R "a R4a 31-31 Rla R2b E R, a R" a 31-32 Rlb R2b R4a Eb R'a R ,, a R2b R4a 31-33 Rlc Eb R, a R "a R2c 31-34 Rla R4a E R'a R" a 31-35 Rlb R2c R4a Eb R, a R "a R2c 31-36 R, c R4a Eb R'a R" a 31-37 Rla R2a R4b E R, a R "a R2a 31-38 Rl R4b Eb R, a R" a Rlc R2a 31-39 R4b E R, a R ,, a 31-40 Rla R2b R4b E R'a R "a Rlb 31-41 R2b R4b Eb R, a R "a 31-42 Rlc R2b R4b R1a Eb R "a Rla R2c R4b R, at 31-43 Eb R "a 31-44 R, b R4b R2c Eb R, a R ,, a 31-45 R] or R2c R4b Eb R, a R "a 31-46 Rla R2a R4c Eb Ra R "a Rlb R4c 31-47 R2a E R'a R "a RIc R4c 31-48 R2a Eb R, a R "a Rla R4c 31-49 R2b E R, a R..a R2b R4c 31-50 Rlb E R'a Rpa R2b 31-51 R3c R4c Eb R'a R ,, a 31-52 Rla R2c R4c E R, a Rpa 31-53 Rlb R2c R4c E R'a R "a 1-54 Rlc R2c R40 Eb R, a R" a 31-243 R, c R "c R '4c Ec R, e R" 31-244 Rj «R2a R 4a Ea R, a R rtb 31-245 Rl R2a R 4a Ea R, a tb R ' 31-246 Rlc R2a R 4a Ea R.a R "b 31-247 Rla R2b R 4a Ea Rnb R, at 31-248 R] b R2b R 4a Ea R, a R "b 31-249 Rle R2b R 4a Ea R'a R " 31-250 Rla R2c R 4a Ea R, a R, 31-251 Rlb R2c R 4a Ea R, a R " 31-252 Rlc R2c R 4a Ea R, a R "b 31-253 Rla R2a R 4b Ea R'a R, 31-254 R] b R2a R 4b Ea R, a R .b 31-255 Rlc R2a R 4b Ea Ra R rtb 31-256 Rla R2b R 4b Ea R, a R1 rrb 31-257 Rlb R2b R 4b Ea R, a R " 31-258 Rlc R2b R 4b Ea Rra R "b 31-259 Rla R2c R 4b Ea R, a R "b 31-260 RIb R2c R 4b Ea R, a R "b 31-261 Rlc R2c R 4b Ea R, a R rib 31-262 Rla R2a R 4c Ea R, a R " 31-263 Rlb R2a R 4c Ea R'a R1 rrb 31-264 Rlc R2a R 4c Ea R, a R1 rib 31-265 Rla R2b R 4c Ea R'a R "D 31-266 Rlb R2b R, a R, rb R4c Ea 31-267 R! C R2b R4c Ea R'a R "b 31-268 Rla R2C R4c Ea R, a rb 31-269 Rlb R2c R 4c Ea R, a R «rb 31-270 RIc R2c R 4c Ea R'a R irb 31-271 Rla R2a R 4a R, a R " 31-272 Rlb R2a R 4a R, a R rb 31-273 Rle R2a R 4a ED R, a Rllb 31-274 Rla R2b R 4a Eb R, a Rrrb 31-275 RIb R2b R 4a R, a R "b 31-276 Rlc R2b R 4a Eb R, a R "b 31-277 Rla R2C R 4a Ra R "b 31-278 RIb R2c R 4a R'a R "b 31-279 Rlc R2c R 4a r.b R "R 31-280 Rla R2a R 4b R'a rrb R 31-281 Rlb R2a R 4b Eb R, a r R ' 31-282 Rlc R2a R 4b R, a «b R 31-283 Rla R2b R 4b ED R, a R ,, b 31-284 Rlb R2b R 4b R, a R "b 31-285 Rlc R2b R 4b R, a R "b 31-286 Rla R2c R 4b Ed R, a R "b 31-287 RIb R2c R 4b R, a R "b 31-288 R) c R2e R 4b R, a R, .t 31-289 R'a R2a R 4c ED R, a R rtb 31-290 Rlb R2a R4C Eb R, a R "b 31-291 R2a R4e Rlc Eb R, R "b 31-292 Rla R2b R4c Eb R, a R "b 31-293 Rlb R2b R4c Eb R, a R "b 31-294 Rlc R2b Rc Eb R, a R "b 31-295 Rla R2c R4c Eb R'a R "b 31-296 R3b R2c R4c E R, a R " 31-297 Rlc R2c R4c Eb R "R" b 31-298 R3a R2a R4a Ec R'a R "b 31-299 Rlb R2a R4a Ec R'a R., b 31-300 R2a Rlc R4a Ec R'a R, rb 31-301 Rla R2b R4a Ec R'a R "b 31-302 Rlb R2b R4a Ec R'a RI, b 31-303 Rlc R2b R4a Ec R, a R "b 31-304 Rla R2c R4a Ec R'a R, rb 31-305 RIb R2c R4a Ec R, a R "b 31-306 Rlc R2c Ra Ec R, a R "b 31-307 Rla R2a R4b Ec R, a R, .b 31-308 Rlb R2a R4 Ec R, a R "b 31-309 Rlc R2a R4b Ec R, a Rl.b 31-310 Rla R2b R4b Ec R, a R "b 31-311 Rlb R2b R4b Ec R, a R "b 31-312 Rlc R2b R4 Ec Ra R ,, b 31-313 Rla R2c R4b Ec R, a R "b 31-314 Rlb R2c R4b Ec R "R" b 31-315 Rlc R2c R4b Ec R, a R " 31-316 Rla R2a R4c Ec R'a R, -b 31-317 Rlb R2a R4c Ec R, a R "b 31-318 Rlc R2a R4e Ec R, a R "b 31-319 Rla R2b R4c Ec R, a R "b 31-320 Rlb R2 R4e Ec R, a R "b 31-321 Rlc R2b R4e Ec R'a R "b 31-322 Rla R2c R4c Ec R.a R, .b 31-323 Rlb R2c R4c Ec R'a R "b 31-324 Rlc R2c R4e Ec R, a R "b 31-325 Rla R2a R4a Ea R, b R "b 31-326 Rlb R2a R4a Ea R, b R "b 31-327 Rlc R2a R4a Ea R.b R "b 31-328 Rla R2b R4a Ea R, R "b 31-329 Rlb R2b R4a Ea R, b R "b 31-330 Rlc R2 R4a Ea Rb R..b 31-331 Rla R2C R4a Ea R, b R "b 31-332 Rlb R2c R4a Ea R, b R "b 31-333 R? C R2c R4a Ea R, b R, .b 31-334 Rla R2a R4 Ea R'b R, rb 31-335 Rlb R2a R4 E "R.b R" b 31-336 Rlc R2a R4 Ea R, b R "b 31-384 R2b Ric R4a Ec R, b R" b 31-385 Rla R2c R4a Ec R, b R "b 31-386 R] b R2c R4a Ec R'b R "b 31-387 Rlc R2c R4a Ec R'b R "b 31-388 Rla R2a R4b Ec R, b R "b 31-389 Rlb R2a R4b Ec R'b R "b 31-390 Rlc R2a R4b Ec R, b R "b 31-391 Rla R2b R4b Ec R, b R " 31-392 Rlb R2b R4b Ec R, b Rpb 31-393 Rlc R2b R4b Ec Rtb R " 31-394 Rla R2c R4b Ec R.b R "b 31-395 RIb R2c R4b Ec R, b R "b 31-396 Rlc R2c R4b Ec R, b R " 31-397 Rla R2a R4c Ec R, b R "b 31-398 Rlb R a R4c Ec R, b R "b 31-399 Rlc R2a R4c Ec R, b R, .b 31-400 Rla R2b R4c Ec R.b R, .b 31-401 Rlb R2b R4c Ec R, b R "b 31-402 Rle R2b R4c E ° R.b R., b 31-403 Rla R2c R4c Ec R'b R "b 31-404 Rlb R2c R c Ec R, b R " 31-405 R) e R2c R4c Ec R.b R "b 31-406 Rla R2a R a Ea R, c R "b 31-407 Rlb R2a R4a Ea R, c R "b 31-408 Rlc R22 R4a Ea R, c R "b 31-409 Rla R2 R4a Ea R, c R "b 31-410 Rlb R2b R4a Ea R, c R ,, b 31-411 Rlc R2b R4a Ea R, c R "b 31-412 Rla R2c R4a Ea R, c R "b 31-413 RIb R2c R a Ea R, c R "b 31-414 Rlc R2c R4a Ea R, c R "b 31-415 R3a R2a R4b Ea R, e R "* 31-416 Rlb R2a R4b Ea R'c Rr, b 31-417 Rle R2a R4b Ea R, c R "b 31-418 Rla R2b R4b Ea R, c R "b 31-419 Rlb R2b R4b Ea Rc R "b 31-420 Rlc R2b R4b Ea R, c R *, 31-421 Rla R2c R4b Ea R, e R "b 31-422 Rlb R2c R4b Ea R, e R "b 31-423 Rle R2c R4b Ea R'c R "b 31-424 Rla R2a R4c Ea R'c R "b 31-425 Rlb R2a R4c Ea R * c R " 31-426 Rlc R2a R4c Ea R.c R "b 31-427 Rla R2b R4c Ea R.e R "b 31-428 RIb R2b R4c Ea R.c R "b 1-429 Rlc R2b R4e Ea R, c R.rb 1-430 Rla R2e R4e Ea R, c R" b 31-619 Rla R2c R4e Eb R, R..c 31-620 Rlb R2c R4c Eb R'b R..c 31-621 Rle R2c R4c Eb R, b R "e 31-622 Rla R2a R4a Ec Rb R "c 31-623 Rlb R2a R4a Ec R'b R "c 31-624 Rlc R2a R4a Ec Rrb R "c 31-625 Rla R2b R4a Ec R, b R "c 31-626 Rlb R2b R4a Ec R, b R., e 31-627 Rle R2b R4a Ec R, b R., c 31-628 RJa R2c R4a Ec R.b R "c 31-629 R, b R c R4a Ec R, b R "c 31-630 Rle R2c R4a Ec R, b R "c 31-631 R1a R2a R4b Ec R, b R ,, c 31-632 Rlb R2a R4b Ec R, b R "c 31-633 Rlc R2a R4b Ec R, b R "c 31-634 Rla R2b R4b Ec R, b R, .c 31-635 Rlb R2b R4b Ec R, b R, c 31-636 Ric R2b R4b Ec R, b R ,, c 31-637 Rla R2c R4b Ec R, b R "c 31-638 Rlb R2 = R4b Ec R, b R "e 31-639 Rlc R2C R4b Ec R, b R "c 31-640 Rla R2a R4C Ec R, b R, .c 31-641 Rlb R2a R4c Ec R, b Rr, c 31-642 RIc R2a R4c Ec R, b R "c 31-643 Rla R2b R4e Ec R, b R, .e 31-644 RI R2b R4c Ec R'b R "c 31-645 Rlc R2b R4c E ° R, b R "° 31-646 Rla R2c R4c Ec R, R "c 31-647 Rlb R2c R4c Ec R, b R ,, c 31-648 Rlc R2c R4c Ec R, b RMC 31-649 Rla R2a R4a Ea R'c R., c 31-650 Rlb R2a R4a Ea R, c R, re 31-651 Rlc R2a R4a Ea R, c R "c 31-652 Rla R2b R4a Ea R, c R., c 31-653 Rlb R2b R4a Ea R, c R "c 31-654 Rlc R2b R4a Ea R, c R "° 31-655 Rla R2c R4a Ea R, c R "c 31-656 Rlb R2c R4a Ea R, c R "c 31-657 Rlc R2c R4a Ea R, c Rt, c 31-658 Rla R2a R4b Ea R '° R1.c 31-659 Rlb R2a R4b Ea R '° R ,, c 31-660 RJc R2a R4b Ea R, c R "c 31-661 Rla R2b R b Ea R, c R c 31-662 R! B R2b R4b Ea R, c R "c 31-663 Rlc R2b R4b Ea R, c R "c 31-664 Rla R20 R4b Ea R'c R "c 31-665 Rlb R2c R4 Ea R * c R "c Rle R4b 31-666 R2C Ea R, c R" c 31-667 Rla R2a R4c Ea R.c R "c 31-668 Rl R2a R4c Ea R'c R "c Rlc 31-669 R2a R4c Ea R, c R "c 31-670 Rla R2b R4c Ea R, c R "c R2b 31-671 R3b R4c Ea R, c R" c 31-672 RJc R2b R4c Ea R'c R "c 31-673 R2c Rla R4c Ea R'c R "c 31-674 Rlb R2c R c Ea R, c R "c 31-675 RIc R2c R4c EB R, c R ,, c 31-676 Rla R2a R4a Eb R, c R "c 31-677 Rlb R2a R4a Eb R, c R "° 31-678 Rlc R2a R4a Eb R, c R, rc 31-679 Rla R2b R4a E R '° R.rc 31-680 Rlb R2b R4a Eb R, c R "c 31-681 R] c R2b R4a Eb R, c R "c 31-682 R] to R2c R4a Eb R, c R "c 31-683 Rlb R2e R4a Eb R, c 'R "c 31-684 Rlc R2c R4a E R, c R "c 31-685 Rla R2a R4b Eb RIC R ** c 31-686 Rlb R2a R4b Eb R, c R ,, c 31-687 Rlc R2a R4b E R, c R "c 31-688 Rla R2b R4b Eb R! C R "c 31-689 Rlb R2b R4b Eb R, c R ,, c 31-690 Rlc R2b R4b E R, c R "c 31-691 Rla R2e R4b Eb R, c R "e 31-692 Rl R2c R4b E R'c R "c 31-693 RJc R2e R4b E R.c R "c 31-694 Rla R a R4e Eb R'c R "e 31-695 Rlb R2a R4c Eb R, c Rr, c R4e 31-696 R, c R2a E R, c R "c 31-697 R] to R2b R4c Eb R, c R "c 31-698 RIb R2b R4c E R, c R "° 31-699 Rle R2b R4e Eb R'c R "c 31-700 Rla R2c R4c E R, e R "c 31-701 Rlb R2c R4c E R, c R "c 31-702 Rle R2c R4c Eb R, e R "c 31-703 Rla R2a R4a Ec R, e R "e 31-704 R1b R2a R4a Ec R, e R "c 31-705 Rlc R2a R a Ec R, c R "c 31-706 Rla Rzb R4a Ec R, c R "c 31-707 Rlb R2b R4a Ec R, c R ,, c 31-708 Rlc R2b R4a Ec R, c R "c 31-709 Rla R2c R a Ec R, c R, .c 31-710 Rlb R2c R4a Ec R, c R "c Rlc R4a 1-711 R2c Ec R, c R "c 31-712 Rla R2a R4b Ec R, c R, rc 31-713 Rlb R2a R4b Ec R, c R "c 31-714 Rlc R2a R4b Ec R, c R" c 31-715 Rla R2b R4b Ec R, c R , c 31-716 RIb R2b R4b Ec R, c R "c 31-717 R10 R2b R4b Ec RfC R" c 31-718 Rla R2c - R4b Ec R, e R ,, c 31-719 Rlb R2c R4b E ° R, c R "c 31-720 Rlc R2c R4b Ec R? C R ,, c 31-721 Rla R2a R4c Ec R, c R" c 31-722 Rlb R2a R4c Ec R'c R "c 31-723 Rlc R2a R4c Ec R'c R ,, c 31-724 Rla R2 R4c Ec R'c R "c 31-725 RJb R2b R c Ec R, c R" c 31-726 Rlc R2b R4c Ec R, c R "c 31-727 R! A R2C R4c Ec R, c R ,, c 31-728 Rlb R2c R4c Ec R, c R "c 31-729 Rle R2c R4c Ec R, c R, re where all the symbols are as defined above. In one aspect of formula (31) of the present invention, R1 and R2 are independently hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group , a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group; R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, a group, aroyl, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a group heterocyclyl, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; R1 and R "are independently hydrogen, a halogen group, a nitro group, a mono or disubstituted amino group, a hydroxy group," an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, a group aryloxycarbonyl, or heteroaryl group, a heterocyclyl group, or an aralkyl group; and all other symbols are as defined above in conjunction with formula (I). In another aspect of formula (31) of the present invention, R1 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a group cycloalkyl, an alkoxy group; R2 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group; R 4 is a substituted or unsubstituted aryl group, R 'is hydrogen, a halogen or an alkyl group; and R "is a hydrogen, a halogen or an alkyl group; and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of formula (31) of the present invention, R1 is hydrogen, or an alkoxy group; R2 is hydrogen, or an alkoxy group; R 4 is a substituted or unsubstituted aryl group, R 'is hydrogen, a halogen, or an alkyl group; R * 'is hydrogen, a halogen, or an alkyl group; and E is O, S, or NH. In yet another aspect of formula (31) of the present invention, R 1 -H or -OCH 3; R2 is -H or -0CH3; R 4 is a substituted aryl group, R 1 is -H, -Cl, -Br, or -CH 3; and R "is -H, -Cl, -Br, or -CH3, and E is O, S, or NH.The present invention further contemplates various compounds of the general formula (III) having the general formula: where all the symbols are as defined above in conjunction with the formula (I). According to various aspects of the present invention, R4 R ', and R1' of the formula (32) are selected to produce various compounds of the formula (32-1) up to formula (32-27) as follows: Formula R4 RR "32-1 R4a Ra R" to 32-2 R4b R, to R "to 32-3 R4c R, to R" to 32-4 R4a R, b R "to 32-5 R4b R, b R , a 32-6 R4c R, b R "a 32-7 R4a R, c R" a 32-8 R4b R, e R "a 32-9 R4c R, c R" a 32-10 R4a R, a R "32-11 R4b R, a R" b 32-12 R4c R? A R "32-13 R4a R, b R, rb 32-14 R4 R'b R" b 32-15 R4o Rb R, rb 32 -16 R4a R, c R "32-17 R4b R, c R" 32-18 R4c R, c R ,, b 32-19 R4a R, a R "c 32-20 R4 R, a R ', c 32 -21 R4c R, a R "c 32-22 R4a R'b R ,, c 32-23 R4b R, R ,, c 32-24 R4e R, b R" c 32-25 R a R '° R " c 32-26 R4b R'c R "c 32-27 R4c R * ° R ,, c where all the symbols are as defined above. In one aspect of the present invention, R 4 is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, or an alkoxy group, a cycloalkoxy group, R 'is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group; R "is hydrogen, a halogen, a nitro group, a group an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group ( =), a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group;, and all other symbols are as defined above with respect to formula (I). In one aspect of the present invention, R 4 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, or an aralkoxy group; R 'is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group; R "is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =) , a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; and all other symbols are as defined above with respect to formula (I). In one aspect of the present invention, E is O or NR; R4 is optionally substituted with a group alkyl or an alkoxy group, ', - and R' and R "are as defined above. Examples of these compounds include, without limitation and without limitation.

The present invention also contemplates several compounds having the general formula: (33), wherein R4 is as defined above in conjunction with formula (I). In one aspect of formula (33) of the present invention, R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a group cycloalkoxy, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group or a cycloalkenyloxy group. 12 In another aspect of the formula (33) of the present invention, R 4 is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, or an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, or an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group or a heteroaralkoxy group. In still another aspect of the formula (33) of the present invention, R 4 an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an aryl sulphonyl group, or a group, aralkylsulfinyl, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof , or sulfonic acid to a derivative thereof. In still another aspect of formula (33) of the present invention, R4 is Examples of these compounds include, but are not limited to: The present invention also contemplates several compounds having the general formula: where all the symbols are as defined above in conjunction with the formula (I). wherein R20 and R21 are independently hydrogen halogen, a nitro group, an amino group, an ono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =) , a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, or an aryl group, a benzyloxy group, an acyl group an acyloxy group, an aroyl group, a group alkoxycarbonyl, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, arylsulfinyl, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, or a thiomorpholinyl group, a piperazinyl group, wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, an aryl group; and all other symbols are as defined above. According to various aspects of the present invention R, Rs, R20, R21, R 'and R "of the formula (34) are selected to produce various compounds of the formula (34-1) up to the formula (34-729) ) as follows: Formula R R5 R¿0 R21 R 'R " 34-1 Ra R5a R20a R21a R, a R "a 34-2 R R5a R20a R2Ia R, a Rr, a 34-3 Rc R5a R20a R21a R, a R "a 34-4 Ra R5b T 20P R21a R, a R "3 34-5 Rb R5b R20a R2Ia R, a R "a 34-6 Rc R5b R20a R21a R, a R ,, a 34-7 Ra R5c 20a R21a R, a R "a 34-8 Rb R5c 20a R21a R.a R,? A 34-9 Rc R5c R20a R21a R, a R ,, a 34-10 Ra R5a R 0b R2Ia R, a R "a 34-11 Rb R5a R20b R21a R, a R "a 34-12 Rc R5a R20b R2Ia R, a R "a 34-13 Ra R5b R20b R21a R, a R "a 34-14 R R5b R20b R21a R, a R "a 34-15 Rc R5b R20b R21a R, a R "a 34-16 Ra R5c R20b R21a R, a R "a 34-17 Rb R5c t? 20b R21a R, a R "a 34-18 Rc R5c R20b R21a R'a R ,, a 34-19 Ra R5a R20c R2, a R, a R "a 34-20 Rb R5a R20c R21a R, a R "a 34-21 Rc R5a R20c R21a R, a R "a 34-22 Ra R5b R20c R21a R, a R "a 34-23 R R5b R20c R21a R, a R, ra 34-24 Rc R5 R20c R21a R'a R "a 34-25 Ra R5c R20c R21a R, a R "a 34-26 R R5c t > 20c R2U R, a R "a 34-27 Rc R5c R20c R21a R, a R "a 34-28 Ra R5a 20a R21b R, a R "a 34-29 R R5a R20a R21b R, a R "a 34-30 Rc R5a R20a R21b R'a R "a 34-31 Ra R5b R20a R21b R, a R "a 34-32 R R5b R20a R21b R'a R "a 34-33 Rc R5b R20a R21b R, a R "a R5c R20a R21b R, a R, .a 34-34 Ra R5e 34-35 R R20a R2] R "R" to R20a R, a R, .a 34-36 Rc R5c R2, b R20b R2, b R..a 34-37 Ra R5a R'a R5a R20b R2Jb R, a R..a 34-38 Rb R20b 34-39 Rc R5a R2Ib R'a R ,, a R5b R20b 34-40 Ra R23b R'a R a R20b 34-41 Rb R5b R2I R'a R "a R20b R" a 34-42 Rc R5 R2i R'8 R5e R2.b R "a 34-43 Ra R20b R, a R20b R, a 34-44 Rb R5c R21b R "a R5e R20b 34-45 Rc R2, b R, a R" a R5a R20c R21b 34-46 Ra R'a R "a R20c R2Ib R, a 34-47 Rb R5a R "a R5a R20c R21b R, a 34-48 Rc R" a R5b R20e R21b R, a R "a 34-49 Ra R5b R20c R2, b R, at 34-50 Rb R "at R20c R21b 34-51 Rc R3b R'a R" at R5e R2Jb Rra 34-52 Ra R20c R "at R20e R21b Ra 34-53 Rb R5c R "to R5e R, ra 34-54 Rc R20c R ib R, a R20a R, a Rrra 34-55 Ra R5a R2Ic -r, 20a R, a R "a 34-56 Rb R5a R21c R20a R21e 34-57 Rc R5a R, a R "a R5b t, 20a R21e R, a 34-58 Ra R" a R5b R20a R2Ie R, a 34-59 Rb R "a R5b R20_ R21e R, .a 34-60 Rc R, a R5c R21e R "a 34-61 Ra R20a R "R5c 34-62 Rb R20a R2Ic R, a R" a R5e R20a R21c 34-63 Rc R, a R "a R5a R20b R21e R, a R, .a 34-64 Ra R20b R21c 34-65 Rb R5a R "R" to R20b 34-66 Rc R5a R21c Ra R "to R20b R2.c R, to 34-67 Ra R5b R" to R5b R20b R2Ie 34-68 Rb R 'a R' a 34-69 R ° R20b R2Ic R, a R5b R "a R5e R21c R, a 34-70 Ra R20b R" a R20b R21c 34-71 Rb R5c R, a R "a R20b R21c R, a R..a 34-72 Rc R5c R20c R21c R "a 34-73 Ra R5a R, a R20c R21c R "a 34-74 Rb R5a R, a R 0c R21c R "a 34-75 Rc R5a R'a R20e R2Je 34-76 Ra R5b R, a R, .a R20c R2Jc R, a 34-77 Rb R5b R "a R20e R21c 34-78 Rc R5 R, a R" a R20e R2Jc Rr, a 34-79 Ra R3c R'a R5c R20c R2Jc R, a R "a 34-80 Rb 34-81 Rc R5c R20e R21c R, s R "a 34-82 Ra R5a R21a R20a R'b R * 'a 34-83 Rb R5a R2, a R20a R, b R ,, a 34-84 Rc R20a R5a R21a R, b R "a 34-85 Ra R5b R20a R21a R, b R "a 34-86 Rb R5b R21a R20a R, b R "a 34-87 Rc R5b R20a R2, a Rrb R "a 34-88 Ra R5c R20a R21a R, b R "a R5c 34-89 Rb R20a R 1 a Rrb R" a 34-90 Rc R5c R20a R21a R, b R ,, a 34-91 Ra R5ß R20b R21a R, b R, .a 34-92 Rb R5a R20b R21a R, b R ,, a 34-93 Rc R5a R20b R, b R2] to R., a 34-94 Ra R5b R20b R2ia R'b R "a 34-95 Rb R5b R20b R21a R, R, .a 34-96 Rc R5b R20b R21a R'b R "a 34-97 Ra R5c R20b R2! A R, b R "a 34-98 R R5c R20b R2Ia R, b R, .a 34-99 Rc R5c R20b R21a Rtb R "a 34-100 Ra R5a R20e R2Ia R, R "a 34-101 Rb R5a R20c R2Ia R, R "a 34-102 Rc R5a R20c R21a R'b R "a 34-103 Ra R5b R20C R21a R, R "a 34-104 Rb R5b R20c R21 a R, b R "a 34-105 Rc? R20C R21a R, b R "a 34-106 Ra R5c R20 = R21a R, b R "a 34-107 Rb R5e R20e R21 R, b R "a 34-108 Rc R5c R20c R2.a R, b R "a 34-109 Ra R5o R20a R21b R, b R, .a 34-110 Rb R5a R20a R2Ib R, b R "a 34-111 Rc R5a R20a R2, b R, b R, .a 34-112 Ra R5b R20a R2Ib R.b R "a 34-113 R R5b R20a R21 b R.b R "a 34-114 R ° R5b R20a R21b R, b R "a 34-115 Ra R5c R20a R 1b R, b R..a 34-116 R R5c R20a R21b R, b R "a 34-117 Rc R5c R20a R21b R.b R "a 34-118 Ra R a R20b R21b R, b R "a 34-119 Rb R5a R20b R21b R, b R "a 34-120 Rc R5a R20b R, b R21b R ,, a 34-121 Ra R5b R20b R21 R, b R.ra 34-122 Rb R? R20b R2Jb Rb R "a 34-123 Rc R5 R20b R2Ib R, b R ,, a 34-124 Ra R5c R20b R2Ib R, b R "a R20b 34-125 R R5c R2I R'b R" a 34-126 Rc R5c R20b R2Ib R, b R., a 34-127 Ra R5a R20c R2Ib R, b R..a -128 R R5a R20c R2Ib R, b R "a -129 Rc R5a R20c R2Ib R, b R" a -130 Ra R5b R20c R2Ib R, b R "a -131 Rb R5b R20c R2lb R, b R "a -132 Rc R5b R20c R2, b R, b R" a -133 Ra R5c R20c R2Ib Rlb R "a -134 Rb R5c R20c R2.b Rb R" a -135 R20c Rc R5c R2Ib R, b R "a -136 R5a R20a Ra R2Ie R, b R" a -137 Rb R5a R20a R21e R, b R "a -138 R20a R21c Rc R5a R, b R" a -139 Ra R5b R20a R21c R, b R "a -140 R R5b R20a R21c R, b R" a -141 Rc R5b R20a R21c R, b R "a -142 R21c Ra R5c R20a R, b R" a -143 Rb R5e R20a R2 , c R, b R "a -144 Rc R5c R20a R2ic R, b R" a -145 Ra Ria R20b R2, e R 'R, .a -146 Rb R5a R20b R2) e R'b R "a -147 Rc R5a R20b R2Ic R, b R "a -148 Ra R5b R20b R2Je R, b R" a -149 R R5b R20b R2, c R, b R, a -150 Rc R5b R20b R2, e R, b R " a -151 RSc Ra R20b R21c R'b R "a -152 Rb R5c R20b R21c R, b R" a -153 Rc R5c R20b R2Jc R, b R "a -154 Ra R5a R20c R21c R, b R" a - 155 Rb R5a R20c R21e R, b R "a -156 Rc R5a R20c R21e Rrb R" at -157 Ra R5b R20c R21e R, b R "at -158 Rb R5 R20c R2Ie Rfb R" at -159 Rc R5 R 0 c R21e Rrb R "a -160 Ra R5c R20c R2J = R, b R" a -161 Rb R5c R20c R21c R, b R "a -162 R ° R3c R20c R21c R'b R" a -163 Ra RSa R20a R2 , a R'c R "a -164 Rb R5a R20a R21a R, c R" a -165 Rc R5a R20a R21a R, c R "a -166 Ra R21a R5b R20a R, e R" a -167 Rb R5b R20a R2Ia R'c R "a -168 Rc R5b R20a R21a R, c R..a -169 Ra R5c R21a R 0a R'c R" a -170 Rb R5c R20a R21a Re R "a -171 Rc R5c R20a R2, a R, c R., at -172 Ra R5a R20b R21a R'c R "at -173 Rb R5a R20b R21a R, e R" at -174 Rc R5a R20b R2Ja R'c R "at 34-175 Ra R5b R20b R2 'a R, c R "a 34-176 Rb R5b R20b R2, a Rc R "a 34-177 Rc R5b R20b R21a R'c R ', a 34-178 Ra R5c R20b R21a R'c R "a 34-179 Rb R5c R20b R2] a Rc R ,, a 34-180 Rc R5c R20b R2, a R'c R "a 34-181 Ra R5a R20c R21a R'c R ,, a 34-182 Rb R5a R20c R21a R, c R "a 34-183 Rc R5a R20c R21a R, c R, a 34-184 Rü R5b R20c R21a R, c R "a 34-185 Rb R5 R20c R 1a R, c R "a 34-186 Rc R5b R 0c R21a R ° R "a 34-187 Ra R5c R20c R2la R, c R "a 34-188 Rb R5c R20c R21a Rc R "a 34-189 Rc R5c R20c R 1a R'c R "a 34-190 Ra R5a R20a R, b Rc R "a 34-191 Rb R5a R20a R21b R, c R "a 34-192 Rc R5a R 0a R2, b R, c R "a 34-193 Ra R5b R20a R21b R'c R "a 34-194 Rb R5b R20a R21b R, c R "a 34-195 Rc R5b R20a R21b R'c R "a 34-196 Ra R5c R20a R21b Rc R "a 34-197 Rb R5c R 0a R21b R, c R ,, a 34-198 Rc R5c R20a R 1b R, c R ', a 34-199 Ra R5a R20b R21b R, c R "a 34-200 Rb R5a R20b R Ib R, c R "a 34-201 Rc R5a R20 R21b R, c R "a 34-202 Ra R5b R20b R21b R'c R "a 34_203 Rb R5b R20b R21b R, c Rtta 34-204 Rc R5b R20b R21b R, c R "a 34-205 Ra R5c R20b R21b R, c R "a 34-206 Rb R5c R20b R21b R, c R "a 34-207 Rc R5c R20b R2, b R, c R "a 34-208 Ra R5a R20c R21 R, c R "a 34-209 Rb R5a R 0c R2Ib R, c R "a 34-210 Rc R5a R20G R21 R, c R "a 34-211 Ra R5b R20c R21b R, c R "a 34-212 Rb R5b R20c R21b R, c R "a 34-213 Rc R5b R20c R21b R, c R "a 34-214 Ra R5c R20c R21b R '° R "a 34-215 Rb R5c R20c R21b R, c R ,, a 34-216 Rc R5c R 0c R21b R, c R ,, a 34-217 Ra R3a R20a R2! C R, c R "a 34-218 R R5a R20a R2 R, c R "a 34-219 Rc R5a R20a R2! C R'c R "a 34-220 Ra R5b R20a R21c R, c R "a 34-221 Rb R5b R 0a R2ic R, c R "a 34-222 Rc R5b R20a R21c R, c R" a 34-223 Ra R5c R20a R21c R, c R "a 34-224 R R5 ° R20a R 1c R'c R "a 34-225 Rc R5c R20a R21c R'c R "a 34-226 Ra R5a R20b R21c R, c R "a 34-227 Rb R5a R20b R 1c R'c R "a 34-228 Rc R5a R20b R21c R'c R "a 34-229 Ra R5b R20b R21c R, c R "a 34-230 Rb R5b R20b R21 c R, c R" a 34-231 Rc R5b R20b R2Ic R'c R "a 34-232 Ra R5c R20b R21c R, c R ,, a 34-233 Rb R5c R20b R21c R, c R "a 34-234 Rc R3c R20b R Ic R'c R "a 34-235 Ra R5a R20c R 1 c R, c R "a 34-236 Rb R5a R20c R2] c R, c R "a 34-237 Rc R5a R 0c R21c R'c R "a 34-238 Ra R5b R20c R2ic R * c R ,, a 34-239 Rb R5 R20c R2Ic R, c R "a 34-240 Rc R5b R20c R21 c R, c R "a 34-241 Ra R5c R20c R2Ic R '° R "a 34-242 Rb R c R20c R21c R, c R "a 34-243 R ° R5c R20c R21c R'c R "a 34_244 Ra R5a R20a R2Ia R, a R "b 34-245 R R5a R20a R21a R, a R ,, b 34-246 Rc RSa R20a R2la R, a R, b 34-247 Ra R5b R20a R21a R, a R "b 34-248 Rb R5b R20a R21a R, a R "b 34-249 Rc R5b R20a R2Ia R, a R" b 34-250 Ra RSc R20a R21a R, a R ,, b 34-251 R R5c R20a R2Ia R'a R ,, b 34-252 Rc R5c R 0a R2, a R, a R " 34-253 Ra R3a R20b R2J to R'a R "b 34-254 Rb R5a R20b R Ia R, a R ,, b 34-255 Rc R5a R20b R2, a R, a R ,, b 34-256 Ra R? R20b R21a R'a R " 34-257 Rb R5b R20b R21a R, a R "b 34-258 Rc R5b R20b R21a R'a R ,, b 34-259 Ra R5 ° R 0b R2Ia R, a R " 34-260 Rb R5c R20b R21 to R, a R "b 34-261 Rc R3c R20b R21a R, ü R ', b 34-262 Ra R a R20c R21a R, a R "b 34-263 R R5a R20c R21a R, a R "b 34-264 Rc R5ü R20c R21a R'a R " 34-265 Ra R ^ R20c R2, a R'a R "b 34-266 Rb R5b R20c R2, a R'a R "b 34-267 Rc R3 R20c R23 to R, a R " 34-268 Ra R5c R20c R21a R'a R "34-269 Rb R5c R20c R21a R, a R" b 34-270 Rc R5c R20c R2, a R'a R "b 34-271 R R5a R20a R21b R'a R '* b 34-272 Rb R5a R20a R21b R'a R "b 34-273 Rc R5a R20a R 1 R, a R "b 34-274 Ra R3b R20a R2Jb Ra R "b 34-275 R R3b R20a R2, R, a R "b 34-276 Rc R5b R20a R25b R, a R "b 34-277 Ra R5c R20a R 1b R'a R "b 34-278 Rb R5c R20a R21b R'a R "b 34-279 Rc R5c R20a R21b R, a R "b 34-280 Ra R5a R20b R21b R'a R "b 34-281 Rb R5a R20b R21b R, a R "b 34-282 Rc R5a R20b R21b R'a R "b 34-283 Ra R5b R20b R21b R, a R "b 34-284 Rb R5b R20b R21b R, a R, b 34-285 Rc R5b R20b R2Jb Ra R "b 34-286 Ra R5c R20 R21b R, a R "b 34-287 Rb R5c -R20 R2Ib R'a R ,, b 34-288 R ° R5c R20b R21b R, a R "b 34-289 Ra R5a R20c R 1b R, a R "b 34-290 Rb R5a R20c R2, R'a R ,, b 34-291 Rc R5a R20c R21b R'a R "b 34-292 Ra R5b R20c R21b R, a R "b 34-293 Rb R5b R20c R21b R, a R "b 34-294 Rc R5b R20c R21b Ra R'rb 34-295 Ra R5c R20c R21b R'a R ,, b 34-296 Rb R5c R20c R2Ib R, a R "b 34-297 Rc R5c R 0c R21b R, a R ,, b 34-298 Ra R5a R20a R21c R, a R "b 34-299 Rb R5a R20a R2! C R, a R "b 34-300 Rc RSa R20a R21c R, a R "b 34-301 Ra R5b R20a R21c R, a R "b 34-302 Rb R5b R20a R21c R, a R ', b 34-303 Rc R5b R20a R 1c R, a R "b 34-304 Ra R3 ° R20a R21c R, a R " 34-305 Rb R5c R20a RI C R, a R "b 34-306 Rc R5c R20a R2! C R, a R" b 34-307 Ra R5a R 0b R 1c R, a R "b 34-308 Rb R5a R20b R21c Ra R "b 34-309 Rc R5a R20 R21c R, a R "b 34-310 Ra R5b R20b R21c R'a R ,, b 34-311 Rb R5b R20b R21c Ra R ,, b 4-312 Rc R5b R20b R2] c R, a R " 34-313 Ra R5c R20 R21c R, a R " 34-314 Rb R5c R20b R21c R, a R "b 34-315 Rc R5c R20b R 1c R, a R "b 34-316 Ra R5a R20c R21c R'a R" b 34-317 R R5a R20c R2, c R, a R "b 34-318 Rc R5a R20c R 1c Ra R "b 34-319 Ra R5b R20c R2! C R, a R "b 34-320 Rb R5b R20c R2I ° R'a R "b 34-321 Rc R5b R20c R2Jc R, a R "b 34-322 Ra R5c R20 ° R21c R, a R "b 34-323 Rb R5c R20c R21c R, a R "b 34-324 Rc R5c R20c R21c R'a R "b 34-325 Ra R5a R20a R21a R'b R " 34-326 Rb R5a R20a R2Ia R'b R "b 34-327 Rc R5a R20a R2Ia R, b R ,, b 34-328 Ra R5b R20a R21a R, b R "b 34-329 R R5 R20a R21a R, b R "b 34-330 Rc R5b R20a R2, a R, R "b 34-331 Ra R5c R20a R21a R, b R "b 34-332 R R5c R20a R2Ia R, b R ,, b 34-333 Rc R5c R20a R21a R, b R "b 34-334 Ra R5a R20 R21a R, b R "b 34-335 Rb R3a R20b R21a R, b R "b 34-336 Rc R5a R20b R21a R, b R "b 34-337 Ra R5b R20b R2, a R'b R "b 34-338 Rb R5 R20b R2! A R, b R "b 34-339 Rc R5b R 0b R21a R'b R '* b 34-340 Ra R5c R20b R21a R, b R "b 34-341 Rb R5c R20b R2, a R, R "b 34-342 Rc R5c R20b R2, a R, b R "b 34-343 Ra R5a R20c R21a R | b R "b 34-344 Rb R5a R20c R2] a R, b R "b 34-345 Rc R3a R20q R21a R, b R ,, b 34-346 Ra R5b R20c R2a R'b R ,, b 34-347 Rb R5b R20c R2Ia R, b R "b 34-348 Rc R5b R2Dc R21a Rb R " 34-349 Ra R5c R20c R21a R, b R "b 34-350 Rb R5c R20c R21a R, b R "b 34-351 Rc R5c R20c R2Ia R, b R ,, 34-352 Ra R5a R20a R2Ib R'b R "b 34-353 R R5a R20a R 1b R 'R" b 34-354 Rc R5a R20a R21b R, b R "b 34-355 Ra R5b R20a R21 R'b R "b 34-356 Rb R55 R20a R21b R, R "b 34-357 Rc R3b R20a R2ib R, R "b 34-358 Ra R5c R20a R2Ib R, b R "b 34-359 R R5c R20a R2Ib R, b R "b 34-360 Rc R5c R20a R21b R, R "b 34-361 Ra R5a R20b R21b R, b R "b 34-362 R R5a R20b R21b Rb R "34-363 R ° R5a R20b R2Jb R'b Rr.b 34-364 Ra R5b R20b R21b R? B Rr, b 34-365 Rb R5b R20b R21b R, b R, .b 34-366 Rc R5b R20b R21b R, b R "b 34-367 Ra R5c R20b R2Jb R, b Rr, b 34-368 Rb R5c R20b R2, b R, b R "b 34-369 Rc R5c R20b R21b R, b R "b 34-370 Ra R5a R20c R21b R, b R., b 34-371 Rb R5a R20c R2, b R, b R, b 34-372 Rc R5a R20e R21b R, b R "b 34-373 Ra R5b R20e R21b R, b R "b 34-374 Rb R5b R20c R21b R, b R..b 34-375 Rc R5b R20e R21b Rrb R "b 34-376 Ra R5c R20c R, b R21b R "b 34-377 R R5c R20c R21b R, b R "b 34-378 Rc R5c R20c R2.b R, b Rnb 34-379 Ra RSa R20a R21c R.b R "b 34-380 Rb RSa R20a R21c R, b R "b 34-381 Rc R5a R20a R21c Rrb R, .b 34-382 Ra R5b R20a R21c R.b R "b 34-383 Rb R5b R 0a R21c R, b R "b 34-384 Rc R5b 20a R21c R, b R "b 34-385 Ra R5e R20a R21c R, b R., b 34-386 Rb R5c R20a R21e R.b R "b 34-387 Rc R5e R20a R2Ic R, b R, .b 34-388 Ra R5a R20b R2Ic R, b R "b 34-389 Rb R5a R20b R2Ic R.b R., b 34-390 Rc R5a R20b R2IC Rb R ?? b 34-391 Ra RSb R20b R2! C R, b R "b 34-392 Rb R5b R20b R21c R, b R "b 34-393 Rc Rsb R20b R2Jc Rrb R "b 34-394 Ra R5c R20b R21c Rrb R "b 34-395 Rb RSc R20b R21c R, b R "b 34-396 Rc RSc 20b R2Jc R, b R, rb 34-397 Ra R5a R20c R2Ie R, b R "b 34-398 Rb R5a R20c R21e R, b R..b 34-399 Rc R3a R20c R2Jc R, b R "b 34-400 Ra R5b R20c R2! C R, b R "b 34-401 Rb R5b R20c R21e R'b R "b 34-402 Rc Rsb R 0c R21e R, b R "b 34-403 Ra RSe R20c R21e R, b R "b 34-404 Rb RSc R20c R21e R, b R ?? b 34-405 Rc R5c 20c R2, c R, b R "b 34-406 Ra RSa R20a R2Ja R'c R "b 34-407 R R3a R20a R21a R, c R-.b 34-408 R ° R3a R20a R2] to R'c R "b 34-409 Ra R3b 20a R 1a R'c R "b 34-410 Rb R5b R20a R21a R, c R" 34-411 Rc R5b R20a R21a R'c R "b 34-412 Ra R5c R20a R21a R, c R "b 34-413 Rb R5c R20a R2I R, c R "b 34-414 Rc R5c R20a R2! A R, c R "b 34-415 Ra R5a R20b R2, a R, c R "b 34-416 Rb R3a R20 R2, a R, c R " 34-417 Rc R3a R 0 R2Ia R, c R "34-418 Ra R5b R20 R21a Rc R" b 34-419 Rb R5b R20b R2Ia R, c R "b 34-420 Rc R5b R20 R21a R, c R "b 34-421 Ra R5c R20b R2Ia R, c R "b 34-422 R R5c R20b R21a Rc R "b 34-423 Rc R5c R20b R21a Rc R "b 34-424 Ra R5a R20c R 1a R, c R "b 34-425 Rb R5a R20c R21a R, c R " 34-426 Rc R5a R20c R21a R, c R ,, b 34-427 Ra R5b R20c R21a R, c R ,, b 34-428 Rb R5b R20c R21a R, c R "b 34-429 Rc R5b R20c R21a R, c R "b 34-430 Ra R5c R 0c R 1a Rc R "b 34-431 R R5c R20c R21a R, c R "b 34-432 Rc R5c R20c R21a R'c R "b 34-433 Ra R5a R20a R21b R, c R " 34-434 R R5a R20a R21 b R, c R "b 34-435 Rc R5a R20a R21 R, c R ,, b 34-436 Ra R5 R20a R21b R, c R "b 34-437 R R5b R20a R21 R, c R" 34-438 Rc R5b R20a R21b R, c R "b 34-439 Ra R5c R20a R21b R, c R "b 34_440 Rb R5c R20a R21 R'c R »b 34-441 Rc R5c R 0a R21b R, c R ,, b 34. 442 Ra R5a R20b R21b R, c R ,, b 34-443 Rb R5a R20b R21b R, c R "b 34-444 Rc R5a R 0b R2, b R, c R "b 34-445 Ra R5b R20b R21b R, c R "b 34-446 R R? R20b R21b R'c R "b 34.447 Rc Rsb R20b R2ib RlC R" b 34-448 Ra R5c R20b R21b R, c Rl | b 34-449 Rb R5c R20b R21b R, c R "b 34-450 Rc R3c R20b R2, b R, c R " 34-451 Ra R5a R20c R21 b R, c R "b 34-452 Rb R5a R20c R21 b R'c R "b 34-453 'Rc R5a R20c R2i b Rc R " 34-454 Ra R5b R20c R21 R «c R ,, b 34-455 Rb R5b R20c R2I b R'c R "b 34-456 Rc R5b R 0c R21b Rc R "b R20c R21b 34-457 Ra R5c R, c R" b 34-458 Rb R5c R20c R21b Rc R "b 34-459 Rc R5c R20c R2Ib Rre R., b 34-460 Ra R5a R20a R21c R, c R "b R20a R5a R21e 34-461 Rb R'c R" b 34-462 Rc R5a R20a R2, c R, c R "b 34-463 Ra R5b R20a R2IC R ° R "b 34-464 Rb R5b R20a R21c R ° R "b 34-465 Rc R5b R20a R2, c R, c R ,, b 34-466 R20a Ra R5c R 1c Rre R "b 34-467 Rb R5c R20a R2Jc Rre R "b 34-468 Rc R5c R20a R 1c R, c R '-, b 34-469 Ra R5a R20b R21e R, e R "b 34-470 R R5a R2Qb R21c R, c R "b 34-471 Rc R5a R20b R21e R, c R "b 34-472 Ra R3b R20b R21e R.c R., b 34-473 Rb R3b R20b R2Ie R, c R "b 34-474 Rc R5b R20b R21 c R, c R., b 34-475 Ra R5c R20b R21e R, e R "b 34-476 Rb R5c R20b R21c R, c R "b 34-477 Rc R5c R20b R2IC R '° R "b 34-478 Ra R5a R20c R2Ie R, c R ,, b 34-479 R R5a R20e R2! C R, e R "b 34-480 Rc R3a R20c R2Ie R, c R "b 34-481 Ra R5b R20e R2Ic R, e R ,, b 34-482 Rb R5b -p20c R21c R, c R ,, b 34-483 Rc R5b R20e R21c R, c R "b R5c 34-484 Ra R20c R2Ie R, c R ,, b 34-485 Rb R5c 20c R2.e R, c R "b R5c 34-486 Rc R 0e R2.c R, c R" b 34-487 Ra R5a R20a R2Ia R'a R "c 34-488 Rb R3a R20a R21a R, a R "c 34-489 Rc R5a R20a R21a Rta R "c 34-490 Ra R? R21a R20a R, a R "c 34-491 Rb R5 R20a R21a R, a R "c 34-492 Rc R5b R20_ R21a R, a R "c 34-493 Ra R5e R20a R2Ia R, a R "c 34-494 Rb R5c R20a R21a R, a R "c 34-495 Rc R3c 20a R21 R, a R, rc 34-496 Ra R5a R20b R2, to R.a R "c 34-497 R R5a R20b R21a R, a R "e 34-498 Rc R5a R20b R21a R, to RIIC 34-499 Ra R3b R20b R21a R, a R ,, c 34-500 Rb R5b R20b R2Ja Ra R, c 34-501 Rc R5b R20b R2, a R, a R "C 34-502 R5c R20b R2Ja R, a Ra R "c 4-503 Rb R5c R20b R21a R, a R ,, c R20b -504 Rc R5c R2, a R'a R ,, c R20c -505 Ra R5a R21a R ' a R ,, c R20c R21a -506 Rb RSa R, a R "° R5a 20c R21a R, .c -507 Rc R, a 20c R21a R" c -508 Ra R5b R'a R20c R21a R "c -509 Rb R5b R, a R5b R20c R21a R, rc -510 Rc R'a R20c R21a -511 Ra R5c R, a R "c R20c R21a R" c -512 Rb R5c R * a R20e R, .c -513 Rc R5c R23a Ra R21b R "c -514 Ra R5a R20a R, a R20a R21b Rra R" e -515 Rb R5a R20a -516 R, a R "c Rc R5a R2, b R5b R20a R21b Rra R "c -517 Ra R20a R" c -518 Rb R5b R21b R, a R5b -o20a R2, b -519 RG R, a R "e R5c R20a R21b -520 Ra R" R "c R20a R21a R21b Ra R, .c -521 Rb R5c R5c R20a -522 Rc R21b Rta R" e R20b R, a -523 Ra R5a R21b R "c R20b R21b Ra Rr, c -524 Rb R3a R5a R20b -525 Rc R21 R'a R "c R20b R" c -526 Ra R5b R21b R, a R20b R21b -527 Rb R511 R, a R "c R5b R20b R21b RIa R" c -528 Rc RSc R20b R21b R, c - 529 Ra R, a R5c R20b R21b R "e -530 Rb R, a R5c R20b R21b -531 Rc R'a R" c R5a R20c -532 Ra R2Ib R'a R "c RSa R20c R21b -533 Rb R'a R "c R20c R2Ib R, a -534 Rc R3q R" c R20c -535 R2Ib Ra R5b R'a R "c -536 R5b -o 20c Rb R21b R, a R" c -537 Rc R5b R20c R21b R, a R "c R5c -r.20c R2Jb -538 Ra R" R "c 20c R21b R, a -539 Rb R5c R" ° R5c R20c R2Jb -540 Rc R'a R "c R20a -541 R21e R, a Ra R5a R "c R20a R21c -542 Rb R5a R, a R" c R20a R, a R "c -543 Rc R5a R21c -544 Ra R5b R20a R21c R, a R" c R5b R20a R21e -545 Rb R, a R " c R20a R21c R., c -546 Rc Rsb Ra R20a R2, c -547 Ra R5c R'a R "c R5e R20a -548 Rb R2! C R, a R "c 20a -549 Rc R3c R21c R'a R" c R20b R21c, R, a -550 Ra R5a R "c 34-551 Rb R5a R20b R21c R, a R" c 34-552 Rc R5a R20b R2Jc R.a R, .e R20b R2Jc 34-553 Ra R5b R, a R ,, c 34-554 Rb R5b R20b R2Ie R'a R "c 34-555 Rc R5b R20b R2Ic R, a R "e R21e 34-556 Ra R5c R20b R, a R" ° 34-557 Rb R5c R20b R2Ie R, a R "c 34-558 Rc R3c R20b R2Ie Ra R "c 34-559 Ra R3a R20c R2Ic R'a R "c 34-560 Rb R5a R20e R2Ic Ra R "c R, a 34-561 Rc R5a R20e R21c R" c 34-562 Ra R5"R20e R21c R, a R" c 34-563 Rb R3b R20c R21c R, a R "c 34-564 Rc R5b R20e R21c R "R" c 20c R21c 34-565 Ra R5c R R "R" c 34-566 Rb R5c R20c R2] c R'a R, .e 34-567 Rc R5c R20c R2, c R, a R "c 34-568 Ra R5a R20a R2Ia R, b R "c 34-569 Rb R5a R20a R2) to R, b R "c 34-570 Rc R5a R20a R21a R, b R ,, c 34-571 Ra R5b R20a R21a R'b R "c 34-572 Rb R5b R20a R21a R'b R "c 34-573 Rc R5b R20a R21a R, b R ,, c 34-574 20a Ra R5c R R21a R'b R "e 34-575 Rb R5c R20a R21a R, b R "c 34-576 Rc R5c R20a R21a R, b R "c 34-577 Ra R5a R20b R2! A Rrb R "c 34-578 Rb R5a R20b R2Ia Rrb R ,, c 34-579 Rc R5a R20b R2i a R, b R "° 34-580 Ra R3b R20b R2Ia R'b R "c 34-581 Rb R5b R20b R21o R, b R "c 34-582 Rc R5b R20b R21a R, b R ,, c 34-583 Ra R5c R20b R2, a R, b R "c 34-584 Rb R5e R20b R21a R, b R "c 34-585 Rc R5c R20b R21a R, b R "c 34-586 Ra R3a R20c R21a R, b R "c 34-587 Rb R5a R20c R2, a R, b R "e 34-588 Rc R5a R20c R21a R, b R "c 34-589 Ra R3b R20c R2] to R'b R "c 34-590 R R3b R20c R21a R, b R "c 34-591 Rc R5b R20e R21a R, b R "c 34-592 Ra R5c 20c R21a R, b R "c 34-593 Rb R5c R20c R2, a R, Rr, c 34-594 R20e Rc R5c R21a Rrb R "c 34-595 Ra R5a R20a R21b Rfb Rrrc 34-596 Rb R5a 20a R21 R, b R "c 34-597 Rc RJa R20a R21b Rb R "c 34-598 Ra R3b R20a R21b Rrb R" c 34-599 R5b R20a R2Jb Rb R'b R "c 34-600 Rc R5b 20a R2, b R, b R "c 34-601 Ra R5c R20a R2lb R, b R "c 34-602 Rb R5c R20a R21b R, b R "c 34-603 Rc R5e R20a R21b R, b R "c 34-604 Ra R5a R20b R21b R 'R "° 34-605 Rb R5a R20b R2Ib R.b R "c 34-606 Rc R5a R20b R21b Rb R "c 34-607 Ra R5b R20b R21b R, R, c 34-608 R5b Rb R20b R2I R, b R "c R5b 34-609 Rc R20b R21b R, b R" c 34-610 Ra R5c R20b R2Jb R, b R, c 34-611 Rb R5c R20b R2Jb R'b R "c R5e 34-612 Rc R20b R21b R, b R" c 34-613 Ra R5a R20c R21b R, b R "c 34-614 Rb R5a R20c R21b Rrb R "c 34-615 Rc R5a R20c R2, b R? B R, .c 34-616 Ra R5b R20c R21b R'b R "c 34-617 Rb R5b R20c R21b Rrb R "c 34-618 Rc R5b R20c R21b R'b R "c 34-619 Ra RSc R20c R21 b R'b R "c 34-620 Rb R5c R20c R2Ib R, b R "c 34-621 Rc R5c 20c R21b R'b R "c 34-622 Ra R5a R20a R2Ic R, b R "c 34-623 Rb R5a R20a R21e Rb R " 34-624 R ° R5a R20a R21 c R, b R "c 34-625 Ra R5b R20a R21c R, b R "c 34-626 Rb R5b -o 20a R21c R, b R "c 34-627 Rc R5b R20a R21e R, b R..c 34-628 Ra R5c 20a R21e R, b R "c 34-629 Rb R5c 20a R21e R, b R "c 34-630 Rc R5c R20a R21c R, b R "c 34-631 Ra R5a R20b R21c Rb R "c 34-632 Rb R5a R20b R2Ic R, b R "e 34-633 Rc R5a R20b R2Ic R, b R "e 34-634 R5b Ra R20b R2Ic R.b R "c 34-635 Rb R3 R20b R21c R.b R "c 34-636 Rc R5b R20b R21c R, b Rr, c 34-637 R5c Ra R20b R21c R, b R "c 34-638 R5e Rb R20b R2Jc R'b R "c 34-639 R5c Rc R20b R2] c R, b R "c 34-640 Ra R5a R20c R21c R, b R "c 34-641 Rb R5a R20c R21c R, b R "c 34-642 Rc R5a 20c R21c R.b R, c 4-643 R5b Ra R20e R21e R, b R "c 34-644 Rb R5b R20c R21c R, R "c R20c R2Ic R, b 4-645 Rc R5b R" c R20c R2Jc R, b R., c 34-646 Ra R5c R20c R21e 34-647 Rb R5c R, b R "° R20e R21c 34-648 Rc R5c R, b R ,, c R20a R21a R, e 34-649 Ra R5a R" c 20a R, c R "C 34-650 R R5a R R21a 34-651 Rc R5a R20a R21a R'c R "c R20a R21a R, e 4-652 Ra R5b R" c R5b R21a R, c 34-653 R R20a R "c 34-654 Rc R5b R20a R21a R.c R "c 34-655 Ra R5c R20a R2Ja R'c R "c R5c -p20a R2Ja 34-656 Rb R, c R" c R5c R20a R21a 34-657 Rc R'c R "c 34-658 Ra R5a R20b R21a R, c R "° R5a R20b R21a 34-659 Rb R * c R" c R5a R20b 34-660 Rc R21a R.c R "c R20b R21a R, c R, .e 34-661 Ra R5b R5b R20b R21a R, c Rr, c 34-662 Rb 34-663 Rc R5b R20b R21a Rc R, .c R5c R20b R2Ia R, e 34-664 Ra R ,, c R5c R20b R2Ia Rrc 34-665 Rb R "c 34-666 Rc R5c R20b R21a Rc R "c R5a R20e R2Ia R, c 34-667 Ra R" c R5a R20e 34-668 Rb R2, a R, c R "c R20c 34-669 Rc R5a R21 a R, c R "c R20c R21a 34-670 Ra R5b R, c R" c R5b R20c R21a 34-671 Rb R * c R "c R20c 34-672 Rc R5 R21a R, c R" c -j, 20c R21a Rc 34- 673 Ra R5c R "c R5c R20c R21a 34-674 Rb R'c R" e R20c 34-675 Rc R5c R21a R'c R "c R5a R, c 34-676 Ra R20a R21b R ,, c 34-677 Rb R5a R20a R21b R'c R "c R5a -r» 20a R21b R, c R, .c 34-678 Rc R20a R21b R, c 34-679 Ra R5 R "c 34-680 R R5b R20a R, e R ,, c R2i R5b R20a R21b R, c Rt | C 34-681 Rc 34-682 Ra R5 ° R20a R21 R'c R "e 34-683 R R5c j20a R21b R.c R..e 34-684 Rc R5e tj20a R2Jb R.c R "c 34-685 Ra R5a R20b R2Jb R, e R "c R20b R21b 34-686 Rb R5a R, c R" c R20b R5a R21b 34-687 Re R, c R, .c R20b R, c Rrrc 34-688 Ra R5 R2, b 34-689 Rb R5b R20b R21b R'c R "c 34-690 Rc R5b R20b R21b Rc R "c R5e R20b 34-691 Ra R21b R, c Rr.c 34-692 RD R5c R20b R21 R, e R" c 34-693 Rc R5c R 2Qb R2, b Re. R "c 34-694 Ra RSa R 20c R23b R, c R" c 34-695 Rb R5a R 20c R21b Rrc R "c 34-696 Rc R5a R 20c R 2Jb Rc R ,, c 34-697 Ra R5b R 20c R 23 b R, c Rl, c 34-698 Rb R: 5b R 20c R 21b Rc R "c 34-699 Rc R 5b R 20c R 21b RrC R., c 34-700 Ra R 5c R 20c R 21b R, c Rr, e 1b 34-701 Rb RR 20c R 2 R, c R., c 34-702 Rc RR 20c R 21b R, c R "c 34-703 Ra R 5a R 20a R 21 c R, c R" e 34-704 Rb R 5a R 20a R 21c R'c R "c 34-705 R ° R 5a R 20a R 21 c R, c R" c 34-706 Ra R 5b R 20a R ¡le R, c R "c 34-707 Rb R 5b R 20a 21c R, c R" c 34-708 Rc RR 20a R 21 c R'c R "c 34-709 Ra RR 20a R 21c R, c R ,, c 34-710 Rb RR 20a R 21c R, c R "c 34-711 R ° RR 20a R: 21c R * c R" c 34-712 Ra R 5a R 20b R 21c Rc R "e 34-713 Rb R 5a R 20b R 21c R, c R "c 34-714 Rc R 5a R 20b R 21c R, c R" c 34-715 Ra RR 20b R 21c R, c R "c 34-716 Rb RR 20b R 21c R, e R, , c 34-717 Rc RR 20b R 2ic R '° R, .c 34-718 R a R 5c R 20b R 21c Rre R "c 34-719 R R 5c R 20b R ~ 2Ic R.c R" e 34-720 Rc R 5c R 20b R: 2Ic R, c R "c 34-721 Ra R; R 20c R 21c R, c R "c 34-722 Rb RR 20c R 21c R, c R" e 34-723 Rc R 5a R: 20c R 21c R, c R "e 34-724 Ra R 5b R 20c R 21c R '° R ,, c 34-725 Rb RR 20c R 21c R, e' C 34-726 Rc R 20c R 21 c R, c R "c 34-727 Ra R 5c R 20c R 21c R, e R "c 34-728 Rb RR 20c R 21c R, e R" c 34-729 Rc RR 20c R 21 c R'c R "c where all the symbols are as defined above. In one aspect of formula (34) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group; R5 is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R 'and R "independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group; a hydroxy group; an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =); an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; and R20 and R21 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =) , a thio group (S =); an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an heteroaryl group, a heterocyclyl group, an aralkyl group. In another aspect of formula (34) of the present invention, R is hydrogen or an alkyl group; Rs is hydrogen or an alkyl group; R "and R" are independently hydrogen or a halogen, and R20 is hydrogen or a halogen, and R21 is hydrogen or a halogen.

In yet another aspect of formula (34) of the present invention, R is -H, CH 3, or CH 2 CH 3; Rs is -H or CH3; R 'and R "independently are -H, -F, or -Cl; R20 is -H, -F, r Cl, or -Br; and R21 is -H, CH3, or -F. Exemplary compounds include, but are not limited to: The present invention also contemplates several compounds having the general formula: where all the symbols are as defined above in conjunction with the formula (I). where R20 and R21 independently are hydrogen a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =) an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, or an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a group heteroaryl, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfenyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, or a thiomorpholinyl group, or a piperazin group ilo, wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and R1 is as defined above. According to some variations of the present invention, R1, R20, and R21 of the formula (35) is selected to produce compounds of the formula (35-1) to the formula (35-27) as follows: 35-22 R ! a R20b R2, c 35-23 Rlb R20b R21e 35-24 Rlc R20b R21c 35-25 Rla R20e R21c 35-26 Rlb R20c R21c 35-27 R1c 20c R2Ic where all the symbols are as defined above. In one aspect of formula (35) of the present invention, R1 is hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group , an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R20 is hydrogen a halogen, a nitro group, an amino group a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a group uncle (S =); and R21 is hydrogen a halogen, a nitro group, an amino group a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), or a uncle group (S =). In another aspect of formula (35) of the present invention, R1 is a halogen, R20 is hydrogen or a halogen, R21 is hydrogen or a halogen. In yet another aspect of formula (35) of the present invention, R1 is Cl or F, R20 is -H or -F, and R21 is -F. Exemplary compounds of the formula (35) include, but are not limited to: The present invention also contemplates several compounds having the general formula: where all the symbols are as defined above in conjunction with the formula (I). According to some variations of the present invention, R, R4, R 'and R "of formula (36) are selected to produce compounds of formula (36-1) up to formula (36-81) as follows: Formula R R4 R 'R "Formula R R4 RR" 36-1 Ra R a R, a R "a 36-42 R ° R4b R, b R" b Rb R4a R, a R "a 36-43 Ra R4c 36 -2 R, b R "b 36-3 R ° R4a R, a R" a 36-44 R R4c R'b R "36-4 Ra R4b R, a R" a 36-45 Rc R4e R, b R "b 36-5 Rb R4b R, a R" at 36-46 Ra R ac R, .b 36-6 Rc R4b R "R" at 36-47 Rb R4a R'c R "b 36-7 Ra R4c R , a R "a 36-48 Rc R4a c Rr, b 36-8 Rb R4C R, a R" a 36-49 Ra R4b R * c R "b 36-9 Rc R4c R, a R" a 36-50 Rb R4b R'c R "b 36-10 Ra R4a R, b R ,, a 36-51 Rc R4b 36-11 Rb R4a R, b Rr, at 36-52 Ra R4c 36-12 Rc R4a R, b R "at 36-53 Rb R c 36-13 Ra R4b R, b R" "36-54 Rc R4c 36-14 Rb R4b R, b R" at 36-55 Ra R4a R'a 'c 36-15 Rc R4 R'b R "a 36-56 Rb R4a R, a R" c 36-16 Ra R4c R, b R "a 36-57 Rc R a R'a R ,, c where all the symbols are as defined above. In one aspect of the formula (36) of the present invention, R is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group; R 4 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, or an alkenyloxy group, or a cycloalkenyloxy group, an acyl group, or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, or an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroalkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and R 'and R1' are independently hydrogen, a halogen, a group, a nitro group, an amino group, a mono- or di-substituted amino group; a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =); an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, or an aryl group, or a benzyloxy group. In one aspect of formula (36) of the present invention, R is hydrogen or an alkyl group; R 4 is a cycloalkenyl group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroalkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and R 'and R "are independently hydrogen, or a halogen. In yet another aspect of formula (36) of the present invention, R is -H or CH3; R 4 is aryl group substituted with halogen; and R1 and R "independently are -H or -Cl; and all other symbols are as defined above in conjunction with formula (I). Examples of the compounds of the formula (36) include, but are not limited to: The present invention also contemplates several compounds having the general formula: where all the symbols are as defined above in conjunction with the formula (I). According to some variations of the present invention, E, R1, and R4 of the formula (37) are selected to produce compounds of the formula (37-1) up to the formula (37-27): Formula ER i R4 37- 1 Ea Ria R4a 37-2 Eb Rla R4a 37-3 Ec RJa R4a 37-4 Ea RIb R4a 37-5 Eb RIb R4a 37-6 Ec - RIb R4a 37-7 Ea Rl e R4a 37-8 Eb Rlc R4a 37- 9 Ec R! C R4a 37-10 Ea Rla R4b 37-11 Eb Ria R4b 37-12 Ec Rla R4b 37-13 Ea Rlb R4b 37-14 Eb Rlb R4b 37-15 Ec RIb R4b 37-16 Ea RIc R4b 37- 17 Eb Rlc R4b 37-18 Ec Rlc R4b 37-19 Ea Rla R4? 37-20 Eb Rla R c 37-21 Ec Rla R4c 37-22 Ea RIb R4e 37-23 Eb Rlb R4c 37-24 Ec Rl R4c 37-25 Ea Rlc R4c 37-26 Eb Rlc R4c 37-27 Ec Rlc R4c where all symbols are as defined above. In one aspect of formula (37) of the present invention, R1 is hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group , an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group; R 4 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group , an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and all other symbols are as defined above in conjunction with formula (I). In another aspect of formula (37) of the present invention, R1 is hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group; R 4 is a cycloalkenyloxy group, an acyl group, or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group , a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and all other symbols are as defined above in conjunction with formula (I). Yet another aspect of formula (37) of the present invention, R1 is hydrogen, or a halogen, or an alkoxy group; R4 is a cycloalkenyl group, is a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group , a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group; and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of formula (37) of the present invention, R1 is hydrogen, a halogen, a group alkoxy; E is 0 or -NR; and R where R22 and R23 are independently hydrogen, halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group ( 0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, or an aryl group, a benzyloxy group, an acyl group an acyloxy group, a group aroyl, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, an aryl group; and all other symbols are as defined above in conjunction with the formula (I) - In yet another aspect of formula (37) of the present invention, R1 is hydrogen or a halogen; E is O or NMe; R 4 is a substituted aryl group or a heterocyclyl group; R22 is hydrogen or an alkoxy group; R22 hydrogen or an alkoxy group; and all other symbols are as defined above in conjunction with formula (I).

In still another aspect of formula (37) of the present invention, R1 is -H, -F, or MeO; E is O or NMe; R4 is or:, where R22 is -H or OMe; and R23 is -F or OMe. An example compound includes, without limitation and without limitation: According to another aspect of the present invention, there are provided several compounds of the general formula (I) having the general formula (IV) its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates. Except as otherwise provided herein, all symbols are as defined above in conjunction with formula (I) - A multitude of compounds having the general formula (IV) with the present invention are contemplated. Examples of these compounds include, but are not limited to: (54); where all the symbols are as defined above in conjunction with the formula (I).

Thus, for example, the present invention encompasses various compounds of the formula (IV) having the formula: where all the symbols are as defined above in conjunction with the formula (I). It should be understood that while various configurations are provided herein, other configurations are contemplated by the present invention. In this way, the compounds that have the formula in general: 91); where all the symbols are as defined above in conjunction with the formula (I), they are also contemplated in this way. According to some variations of the present invention, R, R1, R4, G, and Z of the formulas (88), (89), (90), (91), (92) are selected to produce the compounds of the formulas (88-1), (89-1), (90-1), (91-1), and (92-1) up to formulas (88-729), (89-729), (90-729) ), (91-729), and (92-729) as follows: Formulas R Rl R4 R5 GZ 88-1 89-1 90-1 91-1 92-1 Ra Ria R4a Ria Ga Za 88-2 89-2 90-2 91-2 92-2 Rb Rla R4a R5a Ga za 88- 3 89-3 90-3 91-3 92-3 Rc RIa R4a R5a Ga za 88-4 89-4 90-4 91-4 92-4 Ra Rlb R4a R5a Ga za 88-5 89-5 90-5 91 -5 92-5 R Rl R4_ R5a Ga za 88-6 89-6 90-6 91-6 92-6 Rc RIb R4a R3a Ga za 88-7 89-7 90-7 91-7 92-7 Ra Rlc R a R5a Ga za 88-8 89-8 RIc 90-8 91-8 92-8 Rb R4a R5a Ga za 88-9 89-9 90-9 91-9 92-9 Rc R'c R4a R5a Ga za 88-10 89-10 90-10 91-10 92-10 Ra Rl a R4b R5a Ga za 88-11 89-11 90-11 91-11 92-11 Rb Rla R4b R5a Ga za 4b 88-12 89-12 90-12 91-12 92-12 Rc Rl_ R R5a Ga za 88-13 89-13 90-13 91-13 92-13 Ra Rlb R4b R5a Ga za 88-14 89-14 90-14 91-14 92-14 Rb RIb R4b R5a Ga za 88-15 89-15 90-15 91-15 92-15 Rc Rlb R4b R5a Ga Za 88-16 89-16 90-16 91-16 92-16 Ra Rl c R4b R5_ Ga Za RIc R4b R5_ 88-17 89-17 90-17 91-17 92-17 Rb Ga za R4b 88-18 89-18 90-18 91-18 92-18 Rc RI c R5a Ga za 88-19 89-19 90-19 91-19 92-19 Ra RIa R40 R5a Ga za 88-20 89-20 90-20 91-20 92-20 Rb Rla R4c R5a Ga za RI_ 88-21 89-21 90-21 91-21 92-21 R ° R40 R5a Ga za 88-22 89-22 90-22 91-22 92-22 Ra Rlb R c R5a Ga za 88-23 89-23 90-23 91-23 92-23 Rb Rlb R4c R5a Ga za R5_ 88-24 89-24 90-24 91-24 92-24 Rc Rlb R4c Ga za 88-25 89-25 90-25 91-25 92-25 Ra RIc R4c R5a Ga za 88-26 89-26 90-26 91-26 92-26 Rb Rjc R4o R5a Ga za 88-27 89-27 90-27 91-27 92-27 Rc Rl c R4c R5a Ga za Rl_ R5b 88-28 89-28 90-28 91-28 92-28 Ra R a Ga za RIa R4a 88-29 89 -29 90-29 91-29 92-29 Rb R5b Ga za 88-30 89-30 90-30 91-30 92-30 R ° Rla R4a R5b Ga za Rlb 88-31 89-31 90-31 91-31 92-31 Ra R4a R5b Ga za R4a R5b 88-32 89- 32 90-32 91-32 92-32 Rb R1b Ga za 88-33 89-33 90-33 91-33 92-33 Rc Rlb R4a R5b Ga za Rlc R5b 88-34 89-34 90-34 91-34 92-34 Ra R a Ga Rlc za 88-35 89-35 90-35 91-35 92-35 R R4a R5b Ga za 88-36 89-36 90-36 91-36 92-36 Rc R] c R4a R5b Ga za 88-37 89-37 90-37 91-37 92-37 Ra Rla R4b R5b Ga za 88-38 89-38 90-38 91-38 92-38 Rb Rla R4b R? Ga za 88-39 89-39 90-39 91-39 92-39 Rc Rla R b R5b Ga za 88-40 89-40 90-40 91-40 92-40 Ra Rlb R4b R5b Ga za 88-41 89-41 90-41 91-41 92-41 Rb Rjb R4b R5b Ga za Rjb 88-42 89-42 90-42 91-42 92-42 Rc R4b R5b Ga za 88-43 89-43 90-43 91-43 92-43 Ra RJc R4b R5b Ga za 88-44 89-44 90-44 91-44 92-44 Rb Rlc R4b R5b Ga za 88-45 89-45 90-45 91-45 92-45 Rc R, c R4b R5b Ga za 88-46 89-46 90-46 91-46 92-46 Ra RIa R4c R5b Ga Rbza 88-47 89-47 90-47 91-47 92-47 Rla R4c R5b Ga za 88-48 89-48 90-48 91-48 92-48 Rc Rla R4c R5b Ga za 88-49 89-49 90-49 91-49 92-49 Ra Rlb R4c R5b Ga za Rlb 88-50 89-50 90-50 91-50 92-50 Rb R4c RSb Ga R4o za R5b 88-51 89-51 90-51 91-51 92-51 Rc Rlb Ga RJC za 88-52 89-52 90-52 91-52 92-52 Ra R4c R5b Ga za 8-53 89-53 90-53 91-53 92-53 Rb RJc R4c R5b Ga za 88-54 89-54 90-54 91-54 92-54 Rc Rlc R4c R5b Ga za 8-55 89-55 90-55 91-55 92-55 Ra R3a R5c R4a Ga za 8-56 89-56 90- 56 91-56 92-56 Rb Rla R4a R5c Ga za, Ia 88-57 89-57 90-57 91-57 92-57 Rc R'a R 4a R Ga Ib za 88-58 89-58 90-58 91-58 92-58 R3 R R 4a R Ga a 5c za 88-59 89-59 90-59 91-59 92-59 Rb R. I'bu R 4 R Ga za 88-60 89-60 90-60 91-60 92-60 Rc R R4a 5c R Ga za 88-61 89-61 90-61 91-61 92-61 Ra R R4a 5c R Ga za 88-62 89-62 90-62 91-62 92-62 Rb R R4a R; Ga za 88-63 89-63 90-63 91-63 92-63 Rc R R4a R Ga za 88-64 89-64 90-64 91-64 92-64 Ra R 5c R4 R Ga za 88-65 89-65 90-65 91-65 92-65 R R1 5c R4b R; Ga za 88-66 89-66 90-66 91-66 92-66 Rc R 5c R4b R Ga 4b 5c zs 88-67 89-67 90-67 91-67 92-67 Ra Ri0 R 'R: Ga 4b 5c za 88-68 89-68 90-68 91-68 92-68 Rb Rl ° R R; Ga 4b 5c za 88-69 89-69 90-69 91-69 92-69 Rc Rlb R R Ga 88-70 89-70 90-70 91-70 92-70 Ra Rlc 4b za R R5c Ga RJc za 88-71 89-71 90-71 91-71 92-71 Rb R 4b R5c Ga R5c za 88-72 89-72 90-72 91-72 92-72 Rc Ric R 4b Ga za 88-73 89-73 90-73 91-73 92-73 Ra Rl. R R5c Ga za 88-74 89-74 90-74 91-74 92-74 R R10 R R 5c Ga za 88-75 89-75 90-75 91-75 92-75 Rc Rla R R 5c Ga za 88-76 89-76 90-76 91-76 92-76 Ra RIb R 5c R Ga za 88-77 89-77 90-77 91-77 92-77 Rb RIb R 4c R Ga za 88-78 89-78 90-78 91-78 92-78 Rc Rlb R 4c R; Ga za 88-79 89-79 90-79 91-79 92-79 Ra Rlc R 5c R Ga za 88-80 89-80 90-80 91-80 92-80 R 5c R, c R R Ga 4c 5c 88-81 89-81 90-81 91-81 92-81 Rc R, c R R; Ga 88-82 89-82 90-82 91-82 92-82 Ra -nía R4a 5a za R; G 88-83 89-83 90-83 91-83 92-83 Rb R Ja R4a za l5a G za 88-84 S9-84 90-84 91-84 92-84 R ° R1 5a R4a R G 88-85 89-85 90-85 91-85 92-85 Ra 5 za R1 'R4a R a Gb 88-86 89-86 90-86 91-86 92-86 Rb R1 5a za R4a R Gb 88-87 89-87 90-87 91-87 92-87 Rc R1D 5a za R4a R Gb za 88-88 89-88 90-88 91-88 92-88 Ra Rlc R4a R 5: a Gb za 88-89 89-89 90-89 91-89 92-89 Rb Rlc R 4a R 5a Gb 88-90 89-90 90-90 91-90 92-90 Rc Rlc R 4a 5a za R Gb za 88-91 89-91 90-91 91-91 92-91 Ra R] a R 4b R; 5a Gb 5a 88-92 89-92 90-92 91-92 92-92 Rb R] a R 4b za R G za 88-93 89-93 90-93 91-93 92-93 Rc Rla R 4b R5a 88-94 89-94 90-94 91-94 92-94 Ra Rlb R 4b R5a za Gb 88-95 89-95 90-95 91-95 92-95 Rb R, b 5a za R 4b R Gb 88-96 89-96 90-96 91-96 92-96 Rc R, b 4b za R R 4b 88-97 89-97 90-97 91-97 92-97 Ra RIc R R za 88-98 89-98 90-98 91-98 92-98 Rb Rlc R 4b R GB 88-99 89-99 90-99 91-99 92-99 Rc R, c R 4b 5a za R za 88-100 89-100 90-100 91-100 92-100 Ra R R 4c R 5a za 88-101 89-101 90-101 91-101 92-101 Rb Rla > 4c R "c R 5a za 88-102 89-102 90-102 91-102 92-102 Rc RIa R 4c R 5a za 88-103 89-103 90-103 91-103 92-103 Ra RIb R4cC R 5a za Ib 88-104 90-104 R 4c 89-104 91-104 92-104 Rb R R5a Gb za R 4c 88-105 89 -105 90-105 91-105 92-105 Rc lb R 'R5a Gb za 88-106 89-106 90-106 91-106 92-106 Ra R le R '4c R5a Gb Za Rb 88-107 89-107 90-107 91-107 92-107 R le R 4c R5a Gb Za 4c R5a 88 -108 89-108 90-108 91-108 92-108 Rc R le Bl Gb Za 88-109 89-109 90-109 91-109 92-109 Ra RIa R '4a R5b Gb Za 88-110 89-110 90-110 91-110 92-110 Rb Rla R¿ 4a R5b Gb 4a za 88-111. 89-111 90-111 91-111 92-111 Rc the R R R5b G lb 4a za 88-112 89-112 90-112 91-112 92-112 Ra R 'R5b Gb za 88-113 89-113 90-113 91-113 92-113 R lb 4a RR 'R5b Gb Ib 4a za R5b 88-114 S9-114 90-114 91-114 92-114 Rc RR' Gb za, 1c 88- 115 89-115 90-115 91-115 92-115 Ra R1C R 4a R5b Gb le R4a za 88-116 89-1 16 90-116 91-116 92-116 Rb R R5b Gb le R4a za R5b 88-117 89-117 90-117 91-117 92-117 Rc R1 Gb the 4b za R1 R 'R5b 88 -118 89-118 90-118 91-118 92-118 Ra Gb la za 88-119 89-119 90-119 91-119 92-119 Rb R R 4b R5b Gb the za 4b 88-120 89-120 90-120 91-120 92-120 Rc R R 'R5b Gb, 1b 88-121 89-121 90-121 91-121 92-121 Ra RJ D R 4b R5b Gb za 88-122 89-122 90-122 91-122 92-122 Rb R '° R 4b R5b Gb 88-123 89-123 90-123 91-123 92-123 Rc Rlb R 4b R5b Gbza 88-124 89-124 90-124 91-124 92-124 Ra Rle R 4b R5b Gbza 88-125 89-125 Je 90-125 91-125 92-125 Rb R. JC R 4b R5b Gb za le R4b 88-126 89-126 90-126 91-126 92-126 Rc R R5b Gb R4c 88-127 89-127 90-127 91-127 92-127 Ra Ja R R5b Gb to R4c R5b 88-128 89-128 90-128 91-128 92-128 Rb RG to R 4 'c R5b 88- 129 89-129 90-129 91-129 92-129 Rc R Gb Ib 88-130 89-130 90-130 91-130 92-130 Ra RR 4c R5b za Gb za 131 lb 4c 88-131 89- 90-131 91-131 92-131 Rb RR R5b Gb Ib 4c R5b 88-132 89-132 90-132 91-132 92-132 Rc R R Gb le 4c R5b 88-133 89-133 90-133 91-133 92-133 Ra R R 'Gb Rb 4c R5b 88-134 89-134 90-134 le 91-134 92-134 R R 'Gb 1c za 88-135 89-135 90-135 91-135 92-135 Rc R R 4c R5b Gb the za 4a 88-136 89-136 90-136 91-136 92-136 Ra R R 'R50 Gb the za 88-137 89-137 90-137 91-137 92-137 Rb R R 4a R5c Gb the za 88-138 89-138 90-138 91-138 92-138 Rc R R 4a R5c Gb za lb 88-139 89-139 90-139 91-139 92-139 Ra R R '4a R5c G za 88-140 89-140 90-140 91-140 92-140 Rb R lb R 4a R5c Gb za 88-141 89-141 90-141 91-141 R5c 92-141 R ° Ib R R '4a Gb le za 88-142 89-142 90-142 91-142 92-142 Ra R R R5e Gfa za 88-143 89-143 90-143 91-143 92-143 Rb R R 'R5c Gb le za 88-144 89-144 90-144 91-144 92-144 Rc R1 R 4a R5 ° Gb za 88-145 89-145 90-145 91-145 92-145 Ra R i'l a a R R5c Gb the 88-146 89-146 90-146 91-146 92-146 Rb R R 'R5c za G la za 88-147 89-147 90-147 91-147 92-147 R ° R R 'R5c Gb Ib za 88-148 89-148 90-148 91-148 92-148 R8 RR 4b R5c Gb za lb 88-149 89-149 90-149 91-149 92-149 Rb R »JD R '4b R5c Gb za 4b 88- 150 89-150 90-150 91-150 92-150 Rc R Ib 'R5c Gb za 88-151 89-151 90-151 91-151 92-151 Ra RIc R4b R5c Gb Za 88-152 89-152 90-152 91-152 92-152 Rb Rlc R4b R5c Gb Za 88-153 89-153 90-153 91-153 92-153 Rc Rlc R4b R5c Gb Za Rla R4c 88-154 89-154 90-154 91-154 92-154 Ra R5c Gb Rla R4c 88-155 89-155 90-155 91-155 92-155 Rb R5c Gb R4c za 88-156 89-156 90-156 91-156 92-156 Rc R1a R5c G za 88-157 89-157 90-157 91-157 92-157 Ra R1b R4c R5c Gb za 88-158 89-158 90-158 91-158 92-158 Rb R1b R4c R5c Gb RJb R4c 88-159 89-159 90-159 91-159 92-159 Rc R5c G za 88-160 89-160 90-160 91-160 92-160 Ra Rlc R4c R5c G za 88-161 89-161 90-161 91-161 92-161 Rb Rlc R4c R5c Gb za 88-162 89-162 90-162 91-162 92-162 Rc Rlc R4c R5c Gb za 88-163 89-163 90-163 91-163 92-163 Ra RIa R4a R5a Gc za 88-164 89-164 90-164 91-164 92-164 Rb Rla R4a R5a Gc za 88-165 89-165 90-165 91-165 92-165 Rc RIa R4a R5a Gc za 88-166 89-166 90-166 91-166 92-166 Ra Rlb R4a R5a Gc za 88-167 89-167 90-167 91-167 92-167 R Rlb R4a R5a Gc za 88-168 89-168 90-168 91-168 92-168 Rc Rlb R4a R5a Gc R) c R4a 88-169 89-169 90-169 91-169 92-169 Ra R5a Gc Rlc za 88-170 89-170 90-170 91-170 92-170 R R4a R5a Gc Rlc za 88-171 89-171 90-171 91-171 92-171 Rc R4a R5a G ° za 88-172 89-172 90-172 91-172 92-172 Ra Rla R4b R5a Gc za 88-173 89-173 90-173 91-173 92-173 Rb Rla R4b R5a Gc za 88-174 89-174 90-174 91-174 92-174 Rc RIa R4b R5a Gc za 88-175 89-175 90-175 91-175 92-175 Ra Rlb R4b R5a Gc za 88-176 89-176 90-176 91-176 92-176 Rb Rlb R4b R5a Gc za 88-177 89-177 90-177 91-177 92-177 Rc Rtb R4b R5a Gc za 88-178 89-178 90-178 91-178 92-178 Ra Rlc R4b R5a Gc za 88-179 89-179 90-179 91-179 92-179 Rb Rlc R4b R5a Gc za 88-180 89-180 90-180 91-180 92-180 Rc Rlc R4b R5a Gc Rla R4c 88-181 89-181 90-181 91-181 92-181 Ra R5a Gc za 88-182 89-182 90-182 91-182 92-182 Rb Rla R4c R5a Gc za 88-183 89-183 90-183 91-183 92-183 Rc Rla R4c R5a Gc za 88-184 89-184 90-184 91-184 92-184 Ra Rlb R4c R5a Gc za 88-185 89-185 90-185 91-185 92-185 Rb Rlb R4c R5a Gc za 88-186 89-186 90-186 91-186 92-186 Rc Rlb R4c R5a Gc Rlc R4c 88-187 89-187 90-187 91-187 92-187 Ra R5a Gc za 88-188 89-188 90-188 91-188 92-188 Rb Rlc R4c R5a Gcza R4c 88-189 89-189 90-189 91-189 92-189 Rc Rlc R58 Gc za 88-190 89-190 90-190 91-190 92-190 Ra Rla R4a R5b Gc za 88-191 89-191 90-191 91-191 92-191 R Rla R4a R5b Gc za 88-192 89-192 90-192 91-192 92-192 Rc Rla R4a R5b Gc za 88-193 89-193 90-193 91-193 92-193 Ra Rlb R4a R5b Gc za 88-194 89-194 90-194 91-194 92-194 Rb Rlb R a R5b Gc za 88-195 89-195 90-195 91-195 92-195 Rc Rlb R4a R5b Gc za 88-196 89-196 90-196 91-196 92-196 Ra RJC R4a R5 Gc za 88-197 89-197 90-197 91-197 92-197 Rb Rlc R a R5b Gc za R1c 4a 88-198 89-198 90-198 91-198 92-198 Rc R5b R Gc 4b to R5 91-199 92 -199 Ra R] ab 88-199 89-199 90-199 R 'Gc 88-200 89-200 90-200 91-200 92-200 Rb R the R' 4bza R5 Gc 88-201 89-201 90- 201 91-201 92-201 Rc R. The 4b za R1 R5b Gc za 88-202 89-202 90-202 91-202 92-202 Ra R lb R '4b R5b Gc 88-203 89-203 90-203 91-203 92-203 Rb R] Ib R' 4b R5b za Gc 88- 204 89-204 90-204 91-204 92-204 Rc, 'lb 4b R5b za R1D R Gc za 88-205 89-205 90-205 91-205 92-205 Ra R, 1, cc R 4b R5b Gc 4b R5b 88-206 89-206 90-206 91-206 92-206 Rb R, 11c R Gc le za 88-207 89-207 90-207 91-207 92-207 Rc R R 4b R5b Gc za 88-208 89-208 90-208 91-208 92-208 Ra R? A, 4c R5b Gc za 88-209 89-209 90-209 91-209 92-209 Rb R, I, aa R 4c R5b Gc za 88-210 89-210 90-210 91-210 92-210 Rc Rla R 4c R5b Gc za 88-211 89-211 90-211 91-211 92-211 Ra Rlb R R5b Gc za 88-212 89-212 90-212 91-212 92-212 R Rlb R 'R5b Gc za 88-213 89-213 90-213 91-213 92-213 Rc Rlb R R? Gc za 88-214 89-214 90-214 91-214 92-214 Ra RlG R 4 'c R5fa Gc za 88-215 89-215 90-215 91-215 92-215 Rb R le, 4c R5b Gc za 88-216 89-216 90-216 91-216 92-216 Rc Ric R 4c R5b Gc 88-217 89-217 90-217 91-217 92-217 Ra R; R 4a R5c za Gc za 88-218 89-218 90-218 91-218 92-218 R R l4a R5c Gc za 88-219 89-219 90-219 91-219 92-219 Rc Rla R 4a R5c Gc za 88-220 89-220 90-220 91-220 92-220 Ra R ib R 4a R5c Gc 88-221 89-221 90-221 91-221 92-221 Rb, 1b 4a za R1D R c Gc za 88-222 89-222 90-222 91-222 92-222 Rc Rlb R 4a R5c Gc, 4a 88-223 89-223 90-223 Ra le R1 R5c za 91-223 92-223 Gc za 88-224 89-224 90-224 91-224 92-224 Rb Rle R 4a R5c Gc e 4a 88-225 89-225 90-225 91-225 92-225 Rc Rl R R5e za Gc za 88-226 89-226 90-226 91-226 92-226 RB R the R '4b R5c Gc, 4 z 88-227 89-227 90-227 91-227 92-227 Rb R, 11a R'b R5c Gc the R 4b R5c za 88-228 89-228 90-228 91-228 92-228 Rc R i 1 Gc za 88-229 89-229 90-229 91-229 92-229 Ra R lb R! 4b R5c Gc 88-230 89-230 90-230 91-230 92-230 Rb R1 R 4b R5c za Gc za 88-231 89-231 90-231 91-231 92-231 Rc R1 4b R R5c Gc za 88-232 89-232 90-232 91-232 92-232 Ra R1 4b R 'R5c Gc R5c 88-233 89-233 90-233 91-233 92-233 Rb Rlc R 'Gc za 88-234 89-234 R5c 90-234 91-234 92-234 R ° R > LÍCC R * Gc 88-235 89-235 90-235 91-235 92-235 Ra Rla 4c R5c za? tl Gc za 88-236 89-236 90-236 91-236 92-236 Rb Rla R '4c R5c Gc za 88-237 89-237 90-237 91-237 92-237 Rc R3a R 4c R5c Gc 4c za 88-238 89-238 90-238 91-238 92-238 Ra R5b Til R5c Ge 4c za 88-239 89-239 90-239 91-239 92-239 Rb RR 'R5c Gc 88-240 89-240 90-240 91-240 92-240 Rc R, 1 4c 1bD R R5c za Gc 88-241 89- 241 90-241 91-241 92-241 Ra Rcc 4c R5c za R 'Gc za 88-242 89-242 90-242 91-242 92-242 Rb Rlc 4c R R5c Gc 88-243 89-243 90-243 91-243 92-243 Rc Rlc 4c za The R5c Gc za 88-244 89-244 90-244 91-244 92-244 Ra Rla 4a R R5a Ga z 88-245 89-245 90-245 91-245 92-245 Rb RI a R 4a R 5a Ga R 88-246 89 -246 90-246 91-246 92-246 Rc Rla R 4, aa 5a R Ga Rlb R 88-247 89-247 90-247 91-247 92-247 Ra R 44aa R; Ga, 4a 88-248 89-248 90-248 91-248 92-248 Rb Rl b R4a R: Ga 88-249 89-249 90-249 91-249 92-249 Rc Rlb R4a Rf 5a Ga Rlc 5a 88-250 89-250 90-250 91-250 92-250 Ra R4a R Ga 88-251 89-251 90-251 91-251 92-251 Rb Rl c R 4a 5a Ga 88-252 89-252 90-252 91-252 92-252 Rc R, c R 4a R 5a Ga 88-253 89 -253 90-253 91-253 92-253 Ra R, a R, 44bD R Ga 54 Rla 88-254 89-254 90-2 91-254 92-254 RR 4b R Ga 88-255 89-255 90-255 91-255 92-255 Rc Rla R 4b R5a Ga 88-256 89-256 90-256 91-256 92-256 R Rlb R 4b R5a Ga RIb 88-257 89-257 90-257 91-257 92-257 Rb R 4b R5a Ga Rlb 88-258 89-258 90 -258 91-258 92-258 Rc R 4b R5a Ga 88-259 89-259 90-259 91-259 92-259 Ra RI c R 4b R5a Ga Rlc 88-260 89-260 90-260 91-260 92-260 Rb R 4b R5a Ga 88-261 89-261 90-261 91-261 92-261 Rc Rlc R 4b R5a Ga Zb 88-262 89-262 90-262 91-262 92-262 Ra Rl a R 4c R5a Ga Zb 88-263 89-263 90-263 91-263 92-263 Rb Rla R 4c R5a Ga 88-264 89-264 90-264 91-264 92-264 Rc Rla R 4c R5a Ga 88-265 89-265 90-265 91-265 92-265 Ra Rlb R, 4 * c R Ga 88-266 89-266 90-266 91-266 92-266 Rb RIb R 4c R Ga 88-267 89-267 90-267 91-267 92-267 88-268 89-268 90-268 91-268 92-268 88-269 89-269 90-269 91-269 92-269 88-270 89- 270 90-270 91-270 92-270 88-271 89-271 90-271 91-271 92-271 88-272 89-272 90-272 91-272 92-272 88-273 89-273 90-273 91 -273 92-273 88-274 89-274 90-274 91-274 92-274 88-275 89-275 90-275 91-275 92-275 88-276 89-276 90-276 91-276 92-276 88-277 89-277 90-277 91-277 92-277 88-278 89-278 90-278 91-278 92-278 88-279 89-279 90-279 91-279 92-279 88-280 89- 280 90-280 91-280 92-280 88-281 89-281 90-281 91-281 92-281 88-282 89-282 90-282 91-282 92-282 88-283 89-283 90-283 91 -283 92-283 88-284 89-284 90-284 91-284 92-284 88-285 89-285 90-285 91-285 92-285 88-286 89-286 90-286 91-286 92-286 • 88-287 89-287 90-287 91-287 92-287 88-288 89-288 90-288 91-288 92-288 88-289 89-289 90-289 91-289 92-289 88-290 89 -290 90-290 91-290 92-290 88-291 89-291 90-291 91-291 92-291 88-292 89-292 90-292 91-292 92-292 Ra RIb R 4c R 5b Ga 88-293 89-293 90-293 91-293 92-293 Rb lb R R > 4 * c R 5b Ga 88-294 89-294 90-294 91-294 92-294 Rc R Ib R4e R 5b G8 88-295 89-295 90-295 Laughs R > 4 * c 5b 91-295 92-295 Ra c R Ga Rlc 88-296 89-296 90-296 91-296 92-296 Rb R 4c R Ga Rlc, 4c 88-297 89-297 90-297 91-297 92-297 Rc R4C R Ga Ra RIa, 4a R5c 88-298 89-298 90-298 91-298 92-298 Ga 88-299 89-299 90-299 91-299 92-299 Rb R a RR 4a R5c Ga 'the 88-300 89-300 90-300 91-300 92-300 Rc RRR 4a R 5c Ga Ib a 5c 88 -301 89-301 90-301 91-301 92-301 Ra R1 RR 4 R Ga 'ib 88-302 89-302 90-302 91-302 92-302 Rb RRR 4a 5c R Ga Ib 4 5c 88-303 89 -303 90-303 91-303 92-303 Rc R RR to R Gale 4a 88-304 89-304 90-304 91-304 92-304 Ra RRR Ga Z? "le 4a 88-305 89-305 90-305 91-305 92-305 RRRR Ga Zb, 1c 4a 88-306 89-306 90-306 91-306 92-306 Rc R, c RR Ga Zb Ja 88-307 89-307 90-307 91-307 92-307 Ra RR 4b R Ga 88-308 89-308 90-308 91-308 92-308 Rb RR 4b R Ga 88-309 89-309 90-309 91- 309 92-309 Rc RR 4b R Ga Ib 88-310 89-310 90-310 91-310 92-310 Ra RR 4b R 5c Ga lb 4b 5e 88-311 89-311 90-311 91-311 92-311 Rb RR Ga lb 88-312 89-312 90-312 91-312 92-312 Rc RR 4b R 5c Gale 88-313 89-313 90-313 91-313 92-313 Ra RR 4b R Gale 88-314 89 -314 90-314 91-314 92-314 RRR 4b R Gale 88-315 89-315 90-315 91-315 92-315 Rc RR, 4"b3 R Ga 88-316 89-316 90-316 91 -316 92-316 Ra RR 4c R5c Ga, 1 R5c 88-317 89-317 90-317 91-317 92-317 RR? Aa R 4c Ga 88-318 89-318 90-318 91-318 92-318 Rc R Ja R R5c Ga a, 1b 5c 88-319 89-319 90-319 91-319 92-319 R RiD R R Ga 88-320 89-320 90-320 91-320 92-320 Rb R Ib 4c R R 5c Ga 88-321 89-321 90-321 91-321 92-321 Rc R Ib R 4c R 5c Ga 4c 88-322 89-322 90-322 91-322 92-322 Ra R le c RR 5 Gale 5c 88- 323 89-323 90-323 91-323 92-323 Rb R R4c R Ga R4c 5c 88-324 89-324 90-324 91-324 92-324 Rc le RR Ga la 88-325 89-325 90-325 91 -325 92-325 Ra R R4a R Gb the 88-326 89-326 90-326 91-326 92-326 Rb R R4a R Gb R4a 5a 88-327 89-327 90-327 91-327 92-327 Rc Rla R Gb R4a 88-328 89-328 90-328 91-328 92-328 Ra R! B R Sa L 88-329 89-329 90-329 91-329 92-329 Rb RRR 5a 88-330 89-330 90 -330 91-330 92-330 Rc R Ib RR 5a G °, 1c 4a 88-331 89-331 90-331 91-331 92-331 Ra R1C R R 5a Gb 88-332 89-332 90-332 91-332 92-332 Rb R le R 4a R 5a Gb 88-333 89-333 90-333 91-333 92-333 Rc R, 1Jc < R 4a R Gb Rla 88-334 89-334 90-334 91-334 92-334 Ra R 4b R Gb 88-335 89-335 90-335 91-335 92-335 R Rla R 4b R Gb 88-336 89-336 90-336 91-336 92-336 Rc Rla R, 4 ^ b R 5a Gb 88-337 89-337 90-337 91-337 92-337 Ra 4b 5a Rlb RR 88-338 89-338 90-338 91-338 92-338 R ° R lb R 4b R 5a GD 88-339 89-339 90-339 91-339 92-339 Rc R lb R, 44b0 R 5a Gb 88-340 89-340 90-340 91-340 92-340 Ra R, 1IcC R 4b R 5a Gb 88-341 89-341 90-341 91-341 92-341 Rb R le R 4b R 5a Gb l 88-342 89-342 90-342 91-342 92-342 Rc R. iC R 4b R 5a G 88-343 89-343 90-343 91-343 92-343 Ra Rla R 4c R 5a Gb 1 88-344 89-344 90-344 91-344 92-344 R R,? Aa R 4c R 5a Gb 88-345 89-345 90-345 91-345 92-345 Rc R la R, 4 * c R 5a Gb 88-346- 89-346 90-346 91-346 92-346 Ra R lb R, 4 * c R 5a G 5a 88-347 89-347 90-347 91-347 92-347 Rb R, 1IbD R 4c R Gb Rlb 88-348 89-348 90-348 91-348 92-348 Rc R 4c R 5a Gb 88-349 89-349 90-349 91-349 92-349 Ra R le R4c R 5a Gb c 88-350 89-350 90-350 91-350 92-350 Rb R > l? c R 4c R5a Gb e 88-351 89-351 90-351 91-351 92-351 Rc R lIC R R4c R5a Rb R 88-352 89-352 90-352 91-352 92-352 Ra R R4a R 5b Gb 88-353 89-353 90-353 91-353 92-353 Rb R r R R4a R 5b Gb R, 1laa 88-354 89-354 90-354 91-354 92-354 Rc R 4a R 5b 88-355 89 -355 90-355 91-355 92-355 Ra RI 4a R5b G "Rlb R 88-356 89-356 90-356 91-356 92-356 RR 4a R5b Gb 88-357 89-357 90-357 91-357 92-357 Rc R Ib R 4a R 5b G 88-358 89-358 90-358 91-358 92-358 Ra R, 11cC R 4a R 5b Gb Jc 88-359 89-359 90-359 91-359 92-359 Rb R, JC R 4a R 5b G 4a 88-360 89-360 90-360 91-360 92-360 Rc R le RR Sb Gb a 88-361 89-361 90-361 91-361 92-361 Ra R, 1'a R 4b R 5b G 5b 88 -362 89-362 90-362 91-362 92-362 RR 'R, 4"bD RG 88-363 89-363 90-363 91-363 92-363 Rc R1 R, 4"bD R 5b Gb 88-364 89-364 90-364 91-364 92-364 Ra R "R, 4TOb R 5b Gb 88-365 89-365 90-365 91-365 92-365 Rb R, 11b R 4b R 5b Gb 88-366 89-366 90-366 91-366 92-366 Rc R, 1'b ° R 4b R 5b Gb 88-367 89-367 90-367 91-367 92-367 Ra R, Icc R 4b R 5b Gb Rlc 88-368 89-368 90-368 91-368 92-368 Rb R 4b R 5b Gb 88-369 89-369 90-369 91-369 92-369 Rc R le R 4b R 5b Gb 88-370 89-370 90-370 91-370 92-370 Ra R la R 4c R 5b Gb 88-371 89-371 90-371 91-371 92-371 Rb R la R 4c R 5b to 88-372 89-372 90-372 91-372 92-372 Rc R l R 4c R5b Gb Zb Ra R lb 88 -373 89-373 90-373 91-373 92-373 R 4c R5b Gb zb 88-374 89-374 90-374 91-374 92-374 Rb R, 11b0 R 4c R5b Gb Rc Rlb 88-375 89-375 90-375 91-375 92-375 R 4c R5b zb Gb Zb 88-376 89-376 90-376 91-376 92-376 Ra R 4c R5b Gb 88-377 89-377 90-377 91-377 92-377 R R R 4c R5b z Gb Zb c 88-378 89-378 90-378 91-378 92-378 Rc R, 11c "R 4 R5b Gb zb 88-379 89-379 90-379 91-379 92-379 Ra R, 11a R 4a R5c Gb 88-380 89-380 90-380 91-380 92-380 Rb R la R 4a R5c zb Gb a 4a zb 88-381 89-381 90-381 91-381 92-381 Rc R, 1ja R RSc G 88-382 89-382 90-382 91-382 92-382 Ra R, l, bD R 4a R5c zb Gb 88-383 89-383 90-383 91-383 92-383 Rb R, 11bD R 4a R5c zb Gb z 88-384 89-384 90-384 91-384 92-384 Rc R Ib R4a R 5c, 1c 8-385 S9-385 90-385 91-385 92-385 Ra R, c R 4a R 5c Gb 88-386 89-386 90-386 91-386 88-387 89-387 90-387 91-387 88-388 89-388 90-388 91-388 88-389 89-389 90-389 91-389 88-390 89-390 90-390 91-390 88-391 89-391 90-391 91-391 88-392 89-392 90-392 91-392 88-393 - 89-393 90-393 91-393 88-394 89-394 90-394 91-394 88-395 89-395 90-395 91-395 88-396 89-396 90-396 91-396 88-397 89-397 90-397 91-397 88-398 89-398 90-398 91-398 88-399 89-399 90-399 91-399 88-400 89-400 90-400 91-400 88-401 89-401 90-401 91-401 88-402 89-402 90-402 91-402 88-403 89-403 90-403 91-403 88-404 89-404 90-404 91-404 88-405 89-405 90-405 91-405 88-406 89-406 90-406 91-406 88-407 89-407 90-407 91-407 88-408 89-408 90-408 91-408 88-409 89-409 90-409 91-409 88-410 89-410 90-410 91-410 88-411 89-411 90-411 91-411 88-412 89-412 90-412 91-412 88-413 89-413 90-413 91-413 88-414 89-414 90-414 91-414 88-415 89-415 90-415 91415 88-416 89-416 90-416 91-416 88-417 89-417 90417 91-417 88-418 89-418 90-418 91-418 88-419 89-419 90-419 91-419 88-420 89-420 90-420 91-420 88-421 89-421 90-421 91-421 88-422 89-422 90-422 91-422 88-423 89-423 90-423 91-423 88-424 89-424 90-424 91-424 88-425 89-425 90-425 91-425 88-426 89-426 90-426 91-426 88-427 89-427 90-427 91-427 88-428 89-428 90-428 91-428 88-429 89-429 90-429 91-429 88-430 89-430 90-430 91-430 88-431 89-431 90-431 91-431 88-432 89-432 90-432 91-432 4a 88-433 89-433 90-433 91433 92-433 Ra RJ R R3D Gc 4a 88-434 89-434 90-434 91-434 92-434 Rb R? a R R5b Gc to R5b 88-435 89-435 90-435 91-435 92435 Rc R, 1? a R Gc 88-436 89-436 90-436 91-436 92-436 Ra RJ R 'R5b Gc 88-437 89-437 90-437 91-437 92-437 Rb R: R R5b Gc 88-438 89-438 90-438 91-438 92-438 Rc R, 1JbD R 4a R5b Gc 4a 88-439 89-439 90-439 91-439 92-439 Ra R le R R5b Gc 4a 88-440 89 -440 90-440 91440 92-440 Rb R le R R5b Gc 88-441 89-441 90-441 91441 92-441 Rc R le R 4a R5b Gc, 4b 88-442 89-442 90-442 91442 92-442 Ra R the R5b Gc 88-443 89-443 90443 to 91443 92-443 Rb R, 1, a R 4b R5b Gc 88-444 89-444 90444 91-444 92-444 Rc R la R 4b R5 »Gc 88-445 89-445 90-445 4b 91-445 92-445 Ra R, 11b0 R R5b Gc 88-446 89-446 90-446 91446 92-446 Rb R. IIbD R 4b R5b Gc 88-447 89-447 90-447 91-447 92-447 Rc R. I1b R 4b R5b Gc 88-448 89-448 90448 91-448 92448 Ra RIc R 4b R5b Gc 88-449 89-449 90449 91-449 92-449 Rb R3e R 4b R5b Gc -450 89-450 90-450 91-450 92-450 Rc R! C 88 R 4b R5b Gc 88-451 89-451 90-451 91451 92-451 Ra R 3a R 4c R? Gc 88-452 89-452 90452 91452 92-452 Rb, 1a R 4c R5b Gc 88-453 89-453 90453 91-453 92-453 Rc R R 4c R5b Gc 88-454 89-454 90454 91454 92-454 Ra R R 4c R5b Gc 88-455 89-455 90455 91-455 92-455 R1 R, 11b0 R 4c R5b Gc 88-456 89-456 90456 91-456 92-456 Rc R • I1bD R 4c R5b Gc 1c 88-457 89-457 90457 91-457 92-457 Ra R, 1C R 4c R5b Gc 88-458 89-458 90458 91458 92-458 R R R 4c R5b Gc 88-459 89-459 90459 91-459 92-459 Rc R R 4c R5b Gc 88-460 89-460 90460, 1 91460 92-460 Ra R aa R 4a R5c G ° Rla, 4a 88-461 89-461 90461 91461 92-461 Rb R5c GG 89-462 90462 Rc 88-462 91462 92- 462 RR 4a R5e Gc 88-463 89-463 90-463 91463 92-463 Ra R, I1bD R 4a R5c Gc 88-464 89-464 90464 91464 92464 Rb R Ib R 4a R5c Gc 88-465 89-465 90465 R, 11bD R 4a 91-465 R5c 92-465 Rc Gc, 1c 4a 88-466 89-466 90466 91-466 92-466 Ra R, c R R5c Gc 88-467 89-467 90467 91-467 924-67 R R R4 R5e Gc 88-468 89-468 90468 91-468 92468 Rc R] R 4a R5c Gc 88-469 89-469 90469 91-469 92-469 R8 R R 4b R5c Gc 88-470 89-470 90470 91-470 92-470 Rb R the R 4b R5c Gc, 1a 88-471 89-471 90471 91-471 92-471 Rc R a R 4b R5c Gc 88-472 89-472 90-472 91-472 92-472 Ra Rlb R 4b R5c Gc 88-473 89-473 90473 91-473 92-473 R R. I'b ° R 4b R5c Gc 88-474 89-474 90474 91-474 92474 Rc R. l1bD R 4b R5c Gc 88-475 89-475 90475 91-475 92-475 Ra R, c R 4b R5c Gc 88-476 89-476 90476 91-476 92-476 Rb R R 4b R5c G ° 88-477 89-477 90477 91-477 92-477 Rc RR 4b R5c G ° 8-478 89-478 90478 91-478 92-478 Ra RR 4c R5c Gc 4c 88-479 89-479 R5c 90479 91-479 92 -479 R "RR Gc 88480 89480 90-480 91480 92480 Rc Rla R4c R5c Gc Zb 88481 89-481 90481 91481 92481 Ra RIb R c R5c Gc Z 88-482 89482 90-482 91-482 92482 Rb Rlb R4e R5c Gc Zb 88-483 89483 90483 91-483 92-483 Rc Rlb R5c R c Gc zb R5c 88-484 89484 90484 91484 92-484 Ra Rlc R4c Gc zb 88-485 89485 90485 91-485 92485 Rb RJc R4c R5c Gc zb 88486 89486 90486 91-486 92486 Rc Rlc R4e R5c Gc zb 88487 89-487 90487 91487 92487 Ra R, to R4a R5a Ga zc 88488 89-488 90488 91-488 92-488 R Rla R a R5a Ga zc 88489 89-489 90-489 91489 92-489 Rc Rla R4a R5a Ga z ° 88-490 89-490 90-490 91490 92-490 Ra Rlb R a R5a Ga zc 88-491 89-491 90-491 91491 92491 Rb Rlb R4a R5a Ga zc 88-492 89-492 90492 91492 92-492 Rc Rlb R4a R5a Ga zc Rlc R4a 88-493 89-493 90-493 91-493 92-493 R "R5a Ga zc 88-494 89-494 90494 91494 92494 Rb Rlc R4a R5a Ga zc 88495 89-495 90495 91495 92495 Rc Rlc R4a R5a Ga zc 88-496 89-496 90-496 91-496 92-496 Ra Rla R4b R5a Ga ZLr 88497 89-497 90497 91-497 92497 Rb RIa R4b R5a Ga Zc 88-498 89498 90498 9149S 92498 Rc Rla R * R5a Ga ZL ° RJb 88-499 89-499 90499 91499 92-499 Ra R4b R58 Ga Zc 88-500 89-500 90-500 91-500 92-500 Rb Rlb R4b R5a Ga Zc Rb 88-501 89-501 90-501 91-501 92-501 Rc R4b R5a Ga Zc Rlc 88-502 89-502 90 -502 91-502 92-502 Ra R4b R5a G8 zc 88-503 89-503 90-503 91-503 92-503 Rb Rlc R4b R5a Ga zc 88-504 89-504 90-504 91-504 92-504 Rc Rlc R4b R5a Ga zc 88-505 89-505 90-505 91-505 92-505 Ra R5a R4c R5a Ga zc Rla 89-506 90-506 91-506 92-506 R4c 88-506 Rb R5a Ga zc Rla 88-507 89-507 90 -507 91-507 92-507 Rc R c R5a Ga zc R1b R4e R5a 88-508 89-508 90-508 91-508 92-508 Ra Ga zc 88-509 89-509 90-509 91-509 92-509 Rb Rlb R4c R5a Ga zc 88-510 89-510 90-510 91-510 92-510 Rc Rlb R4c R5a Ga zc 88-511 89-511 90-511 91-511 92-511 Ra Rlc R4e R58 Ga zc 88-512 89-512 90-512 91-512 92-512 Rb Ric R c R5a Ga z ° Rlc 88-513 89-513 90-513 91-513 92-513 Rc R4c R5a Ga R4a R5b zc 88-514 89-514 90-514 91-514 92-514 R Ra Ga zc Rla 88-515 89-515 90-515 91-515 92-515 Rb R4a R5b Ga zc 8-516 89-516 90-516 91 -516 92-516 Rc Rla R4a R5b Ga Rlb zc R4a R5b 88-517 89-517 90-517 91-517 92-517 Ra G8 RIb zc 88-518 89-518 90-518 91-518 92-518 Rb R4a R5b G8 Rlb z 8-519 89-519 90-519 91-519 92-519 Rc R a R5b Ga zc 8-520 89-520 90 -520 91-520 Rle 92-520 Ra R4a R5b Ga zc 8-521 89-521 90-521 91-521 92-521 Rb Rlc R4a R5b Ga zc 8-522 89-522 90-522 91-522 92-522 Rc Rl £ R4a R5b Ga z ° 8-523 89-523 90-523 91-523 92-523 Ra Rla R4b R5b Ga zc 8-524 89-524 90-524 91-524 92-524 Rb Rla R4b R50 Ga zc 8-525 89-525 90-525 91-525 92-525 Rc Ria R4b R5b Ga zc 8-526 89-526 90-526 91-526 92-526 Ra Rlb R4b R5b Ga zc 88-527 89-527 90- 527 91-527 92-527 Rb Rlb R4b R5b G8 zc 88-528 R4b R5b 89-528 90-528 91-528 92-528 Rc RIb Ga zc 88-529 89-529 90-529 91-529 92-529 Ra R! Or R4b R5b Ga zc 88-530 89-530 90-530 91-530 92-530 Rb R3c R4b R5b Ga zc 88-531 89-531 90-531 91-531 92-531 Rc Rlc R4b R5b Ga Rla R5b zc 88-532 89-532 90-532 91-532 92-532 Ra R4c Ga Rla R5b zc 88-533 89-533 90-533 91-533 92-533 Rb R4c Ga Zc 88-534 89-534 90-534 l R5b 91-534 92-534 Rc R a R4c Ga zc 88-535 89-535 90-535 91-535 92-535 Ra Rlb R4c R5b Ga Rlb R5b zc 88-536 89-536 90-536 91-536 92-536 Rb R4c Ga zc 88-537 89-537 90-537 91-537 Rlb R4c R5b 92-537 Rc Ga R5b zc 88-538 S9-538 90-538 91-538 92-538 Ra Rlc R4c G8 e R4c zc 88-539 89-539 90-539 91-539 92-539 Rb RI R5b Ga zc 88-540 89-540 90-540 91-540 92-540 Rc R! C R4c R5b Ga R5e zc 88-541 89-541 90-541 91-541 92-541 Ra Rla R4a Ga zc 88-542 89-542 90-542 91-542 92-542 Rb Rla R4a R5c Ga zc 88-543 89-543 90-543 91-543 92-543 Rc R] a R4a R5c Ga RIb zc 88-544 89-544 90-544 91-544 92 ^ 544 Ra R4a R5c Ga zc 88-545 89-545 90-545 91-545 92-545 Rb R! B R4a R5c Ga zc 88-546 89-546 90-546 91-546 92-546 Rc Rlb R4a R5c Ga zc 88-547 89-547 90-547 91-547 92-547 Ra Rlc R4a R5c Ga zc 88-548 89-548 90-548 91-548 92-548 Rb Rlc R4a R5c Ga zc 88-549 89-549 90-549 91-549 92-549 Rc Rlc R4a R5c G8 RJa zc 88-550 89-550 90-550 91-550 R 92-550 Ra 4b R5e Ga zc 88-551 89-551 90-551 91-551 92-551 Rb Rla R4b R5e Ga R4b R5c zc 88-552 89-552 90-552 91-552 92-552 Rc Rla Ga zc 88-553 89-553 90-553 91-553 92-553 Ra Rlb R4b R5c Ga zc 88-554 89-554 90-554 91-554 92-554 Rb Rlb R4b R5c Ga Rlb R4b R5c zc 88-555 89-555 90-555 91-555 92-555 Rc Ga Rlc z ° 88-556 89-556 90-556 91-556 92-556 Ra R4b R5c G8 z ° 88-557 89-557 90-557 91-557 92-557 Rb Rlc R4b RSc Ga z ° 88-558 89-558 90-558 91-558 92-558 R ° Rlc R4b R5c Ga z ° 88-559 89-559 90-559 91-559 92-559 Ra Rla R4c R5c Ga zc 88-560 89-560 90-560 91-560 92-560 Rb Rla R4c R5c Ga zc 88-561 89-561 90-561 91-561 92-561 Rc Rla R c R5c Ga zc 88-562 89-562 90-562 91-562 92-562 Ra Rlb R4c R5c Ga zc 88-563 89-563 90-563 91-563 92-563 Rb Rlb R4c R5c Ga zc 88-564 89-564 90-564 91-564 92-564 Rc Rlb R4c R5e Ga zc 88-565 89-565 90-565 91-565 92-565 Ra Rlc R4c R5c Ga zc 88-566 89-566 90-566 91-566 92-566 Rb Rlc R4c R5c Ga z ° 88-567 89-567 90-567 91-567 92-567 Rc Rlc R4c R5c Ga z ° 88-568 89-568 90-568 91-568 92-568 Ra Rla R4a R5a Gb zc 88-569 89-569 90-569 91-569 92-569 Rb Rla R4a R58 Gb zc 88-570 89-570 90-570 91-570 92-570 R ° Rla R a R5a Gb zc 88-571 89-571 90-571 91-571 92-571 Ra Rlb R4a R5a Gb zc 88-572 89-572 90-572 91-572 92-572 Rb Rlb R4a RSa Gb zc 88-573 89-573 90-573 91-573 92-573 Rc R.b R4a R5a Gb zc 88-574 89-574 90-574 91-574 92-574 Ra Rlc R4a R5a G Zc 88-575 89-575 90-575 91-575 92-575 Rb Rlc R4a R5a Gb Zc 88-576 89-576 90-576 91-576 92-576 Rc Rlc R a R5a G Zc 88-577 89-577 90-577 91-577 92-577 Ra Rla R4b R5a Gb Z ° 88-578 89-578 90-578 91-578 92-578 Rb Rla R4b R5a G Zc 88-579 89-579 90-579 91-579 92-579 Rc Rla R b R5a Gb Zc 88-580 89-580 90-580 91-580 92-580 Ra Rlb R * R5a Gb Zc 88-581 89-581 90-581 91-581 92-581 Rb Rlb R4b R5a Gb Zc 88-582 89-582 90-582 91-582 92-582 Rc Rlb R4b R5a Gb Zc 88-583 89-583 90-583 91-583 92-583 Ra Rlc R4b R3a Gb Zc 88-584 89-584 90-584 91-584 92-584 Rb RIc R4b R5a Gb Zc 88-585 89-585 90-585 91-585 92-585 Rc RIc R4b R3a Gb Zc 88-586 89-586 90-586 91-586 92-586 Ra RIa R4c R5a Gb Zc 88-587 89-587 90-587 91-587 92-587 Rb Rla R4c R5a Gb Zc 88-588 89-588 90-588 91-588 92-588 RQ Rla R c R5a Gb Zc 88-589 89-589 90-589 91-589 92-589 Ra RIb R4c R5a Gb Zc 88-590 89-590 90-590 91-590 92-590 R Rlb R4 R5a Gb Zc 88-591 89-591 90-591 91-591 92-591 Rc R! B R c R5a Gb Zc 88-592 89-592 90-592 91-592 92-592 Ra Rlc R4c R5a Gb Zc 88-593 89-593 90-593 91-593 92-593 Rb Rlc R4c R5a Gb Zc 88-594 89-594 90-594 91-594 92-594 Rc Rlc R4a R5a Gb Zc 88-595 89-595 90-595 91-595 92-595 Ra Rla R4a R5 Gb Zc 88-596 89-596 90-596 91-596 92-596 R Rla R4a R5b Gb Z0 88-597 89-597 90-597 91-597 92-597 Rc RIa R4a R5b Gb Z ° 88-598 89-598 90-598 91-598 92-598 Ra Rlb R4a R5b G Z ° 88-599 89-599 90-599 91-599 92-599 Rb Rlb R4a R5b Gb Zc 88-600 89-600 90-600 91-600 92-600 Rc R5b R a RSb Gb Za 88-601 89-601 90-601 91-601 92-601 Ra Rlc R4a R * G Zc 88-602 89-602 90-602 91-602 92-602 R Rlc R4a R50 Gb Zc 88-603 89-603 90-603 91-603 92-603 Rc Rlc R4a R? Gb Zc 88-604 89-604 90-604 91-604 92-604 Ra Rla R4b R50 Gb Zc 88-605 89-605 90-605 91-605 92-605 Rb Rla R4b R5b Gb Zc 88-606 89-606 90-606 91-606 92-606 Rc Rla R4b R5b Gb Zc 88-607 89-607 90-607 91-607 92-607 Ra Rlb R4 R5b Gb Zc 88-608 89-608 90-608 91-608 92-608 R Rlb R4b R5b Gb Zc 88-609 89-609 90-609 91-609 92-609 Rc Rlb R4b R5b G Zc 88-610 89-610 90-610 91-610 92-610 Ra Rlc R b R5b Gb Zc 88-611 89-611 90-611 91-611 92-611 Rb Rlc R4b R5b G Zc 88-612 89-612 90-612 91-612 92-612 Rc RIc R b R5b Gb Zc 88-613 89-613 90-613 91-613 92-613 Ra R, a R4c R5b Gb Zc 88-614 89-614 90-614 91-614 92-614 Rb Rta R4c R b G Zc 88-615 89-615 90-615 91-615 92-615 Rc Rla R4c R5b G Zc 88-616 89-616 90-616 91-616 92-616 Ra Rlb R4c R5b Gb Zc 88-617 89-617 90-617 91-617 92-617 Rb Rlb R4c R5b Gb Zc 88-618 89-618 90-618 91-618 92-618 Rc Rlb R4c R5b Gb Zc 88-619 89-619 90-619 91-619 le r, 4c t »5b - > i-re 92-619 Ra R1C R 4c R5b Gü Z 88-620 89-620 90-620 91-620 le 92-620 Rb RR 4c R5b Zc 88-621 89-621 90-621 91-621 92-621 Rc Rlc R4c R Gb 7LT 90-622 4a 88-622 89-622 91-622 92-622 Ra Rla R, 4a R Zc 88-623 89-623 90-623 91-623 92-623 Rb RIa R48 R 5c Zc 88-624 89-624 90-624 91-624 92-624 Rc Rla R4a R 5c Gb Z ° 88-625 89-625 90-625 91-625 92-625 Ra RIb R4a R 5c Gb Zc 88-626 89-626 90-626 91-626 92-626 Rb Rlb R 4a R Zc 88-627 89-627 90-627 91-627 92-627 Rc Rlb, 4"to R Gb Zc 88-628 89-628 - 90-628 91-628 92-628 R8 R, c R 4a R5c Zc, 1c R5c 88-629 89-629 90-629 91-629 92-629 Rb R1C R 4a Zc le R5c 88 -630 89-630 90-630 91-630 92-630 Rc RR 4a Gb Zc 88-631 89-631 90-631 91-631 92-631 Ra R1 R 4b R5c G R5c zc 88-632 89-632 90-632 91-632 92-632 Rb R, 1iaa R 4b Gb Zc 88-633 89-633 90-633 91-633 92-633 RE R, 4b R5c Gb Zc 88-634 89-634 90-634 91-634 92-634 Ra R R 4b R5c Gb Zc 88-635 89-635 90-635 91-635 92-635 Rb R, 1, bD R 4b R5c Gb Zc 4b R5c 88-636 89-636 90-636 91-636 92-636 Rc R, 1JbD R Gb 88-637 89-637 90-637 91-637 92-637 Ra R, 11cC R 4b R5c zc Gb 4b zc 88-638 89-638 90-638 91-638 92-638 Rb R, 1? Cc R R 5c zc 88-639 89-639 90-639 91-639 92-639 Rc R 1c R 4b R 5c zc 88-640 89-640 90-640 91-640 92-640 Ra R! R 4o R 5c 4c zc 88-641 89-641 90-641 91-641 92-641 Rb R, 1? Aa R R 5c zc 88-642 89-642 90-642 91-642 92-642 RG R the R 4c R 5c z ° 88-643 89-643 90-643 91-643 92-643 R8, Ib R1D R 4c R 5c GD zc 88-644 89-644 90-644 91-644 92-644 Rb, 1b 5c R1D R 4c R zc 88-645 89-645 90-645 91-645 92-645 Rc R R 4c R 5c zc 88-646 89-646 90-646 91-646 92-646 R8 R R R 5c z ° 88-647 89-647 90-647 91-647 92-647 Rb R, 11cC R R 5c Gb 88-648 89-648 90-648 91-648 92-648 Rc R le R 4c za R 5c Gb Rla zc 88-649 89-649 90-649 91-649 92-649 Ra R4a R 5a Gc 5a zc 88-650 89-650 90-650 91-650 92-650 Rb Rla R 4a R Gc zc 88-651 89-651 90-651 91-651 92-651 Rc R. l? aa R R 5a Gc zc 88-652 89-652 90-652 91-652 92-652 Ra Rlb R R ~ 5a Gc zc 88-653 89-653 90-653 91-653 92-653 R R lb R R 5a Gc zc 88-654 89-654 90-654 91-654 92-654 R ° R lb R R 5a Gc zc 88-655 89-655 90-655 91-655 92-655 Ra R le R R 5a Gc zc 88-656 89-656 90-656 91-656 92-656 Rb R le R 4a R 5a Gc zc 88-657 89-657 90-657 91-657 92-657 Rc R, 1lcü R 4a R5a Gc zc 88-658 89-658 90-658 91-658 92-658 Ra Rla R 4b R58 Gc the 88-659 89-659 90-659 91-659 92-659 Rb R R 4b R5a zc Gc zc 88-660 89-660 90-660 91-660 92-660 R ° R, 1? Aa R 4b R5a Gc 88-661 89-661 90-661 91-661 92-661 Ra R Ib R 4b R5a zc Gc 88-662 89-662 90-662 91-662 lb zc 92-662 Rb R R, 4b R Gc zc 88-663 89-663 90-663 91-663 92-663 Rc R Ib R, 4 * bD R Gc zc 88-664 89-664 90-664 91-664 92-664 R8 R le R4b R 5a Gc zc 88-665 89-665 90-665 91-665 92-665 Rb R le R4b R 5a Gc zc 88-666 89-666 90-666 91-666 92-666 Rc R le R4b R 5a Gc zc 88-667 89-667 90-667 91-667 92-667 R8 R the R4e R 5a Gc zc 88-668 89-668 90-668 91-668 92-668 Rb Rla R 4c R5a Gc Zc 88-669 89-669 90-669 91-669 92-669 Rc R, 1aa R 4c R5a Gc zc 88-670 89-670 90-670 91-670 92-670 Ra R, R 4c R 5a G ° zc 88-671 89-671 90-671 91-671 92-671 R Rlb R 4c R 5a Gc zc 88-672 89-672 90-672 91-672 92-672 Rc R, 1, bD R 4c R 5a Gc zc 88-673 89-673 90-673 91-673 92-673 Ra R Ic R 4c R5a Gc z ° 88-674 89-674 90-674 91-674 92-674 Rb R, 1IcC R 4c R5a Gc 88-675 89-675 90-675 91-675 92-675 Rc Rlc z ° R R5a Gc zr 88-676 89-676 90-676 91-676 92-676 Ra R. l1a R R50 Gc zc 88-677 89-677 90-677 91-677 92-677 Rb Rla R R5b Gc zc 88-678 89-678 90-678 91-678 92-678 Rc Rla R 4a R5b Gc zc 88-679 89-679 90-679 91-679 92-679 Ra Rlb R 4a R5b Gc zc 88-680 89-680 90-680 91-680 92-680 Rb Rlb R 4a R5b Gc zc 88-681 89-681 90-681 91-681 92-681 Rc R, JJb R R 5b Gc zc 88-682 89-682 90-682 91-682 92-682 Ra Rlc R R 5b Gc zc 88-683 89-683 90-683 91-683 92-683 Rb R, JJcC R 4a R 5b Gc zc 88-684 1c 89-684 90-684 91-684 92-684 Rc R, 1C R 4a R 5b Gc zr 88-685 89-685 90-685 91-685 92-685 Ra R, a R 4b R 5b Gc zc 88-686 89-686 90-686 91-686 92-686 Rb Rla R 4-b R 5b Gc zc 88-687 89-687 90-687 91-687 92-687 Rc Rla R 4b R 5b Gc zc 88-688 89-688 90-688 91-688 92-688 Ra Rlb R 4b R 5b Gc 88-689 89-689 90-689 91-689 92-689 Rb RIb > 4b 5b z ° R * R "Gc zc 88-690 89-690 90-690 91-690 92-690 Rc Rlb R 4b R 5"b Gc zc 88-691 89-691 90-691 91-691 92-691 Ra Rlc R 4b R Gc zc 88-692 89-692 90-692 91-692 92-692 Rb R, 11c R 4b R Gc zc 88-693 89-693 90-693 91-693 92-693 Rc R le R 4b R 5b Gc zc 88-694 89-694 90-694 91-694 92-694 Ra Rla R 4c R 5b Gc zc 88-695 89-695 90-695 91-695 92-695 Rb R1a R 4c R 5b Gc zc 88-696 89-696 90-696 91-696 92-696 Rc R, 11a R 4c R 5b Gc zc 88-697 89-697 90-697 91-697 92-697 Ra Rlb R 4c R 5b Gc 88-698 89-698 90-698 91-698 92-698 Rb Rlb b zc R 4c R 5 G ° RIb, 4c zr 88-699 89-699 90-699 91-699 92-699 Rc R * R 5b Gc 88-700 89-700 90-700 91-700 92-700 Ra Rlc zc R4 R 5b Gc 88-701 89-701 90-701 91-701 92-701 R Rlc zc R4 R 5b Gc 88-702 89-702 90-702 91-702 92-702 Rc Rlc zc R 4c R 5b Gc zr 88-703 89-703 90-703 91-703 92-703 Ra RIa R 4a R- 5c Gc 88-704 89-704 90-704 91-704 92-704 Rb Rla zc R 4a R 5c Gc 88-705 89-705 90-705 91-705 92-705 Rc Rla zc R 4a R 5c Gc zc 88-706 89-706 90-706 91-706 92-706 Ra R, 1'b ° R 4a R 5c Gc zc 88-707 89-707 90-707 91-707 92-707 Rb Rlb R 4a R 5c Gc zc 88-708 89-708 90-708 91-708 92-708 RG Rlb R 4a R 5c Gc zc 88-709 89-709 90-709 91-709 92-709 Ra Rlc R 4a R 5c Gc zc 88-710 89-710 90-710 91-710 92-710 Rb RIc R 4a R 5c Gc 88-711 89-711 90-711 91-711 92-711 Rc Rlc zc R 4a R 5c Gc zc 88-712 89-712 90-712 91-712 92-712 Ra Rla R 4b R Gc zc 8-713 89-713 90-713 91-713 92-713 Rb Rla R 4b R Gc 8-714 89-714 90 -714 91-714 92-714 Rc Rla zc R 4b R Gc zc where all symbols are as defined above. In one aspect of any of the formulas (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, and all other symbols are as defined above in conjunction with the formula (I) . In another aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, Rs is -H, all other symbols are as defined above in conjunction with the formula (I) In another aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, R5 is CH3, all other symbols are as defined above in conjunction with the formula ( I).

In still another aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3; G is - (CH2) S_, where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I). In a further aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or -CH3, R5 is -H; G is (CH2) S_, where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I). In a further aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, R5 is -CH3; G is - (CH2) S_, where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I). In a further aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3; Z is -NR; all other symbols are as defined above in conjunction with formula (I). In a further aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, R5 is -H or Z CH3; Z is -NR; all other symbols are as defined above in conjunction with formula (I).

In a still further aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, G is - (CH2) S_, where s is an integer of 0-5; Z is -NR and all other symbols are as defined above in conjunction with formula (I). In a still further aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, Rs is -H; G is - (CH2) S; where s in integer from 0-5; Z is -NR and all other symbols are as defined above in conjunction with formula (I). In even a further aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, Z is O; all other symbols are as defined above in conjunction with formula (I). In even a further aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3; Rs is -CH3; G is - (CH2) S. (where s in integer from 0-5, Z is -NR and all other symbols are as defined above in conjunction with formula (I) .In a still further aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, Rs is -H or CH3, Z is O, all other symbols are as defined above in conjunction with the formula (I) In a still further aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3; G is - (CH2) S. / where s in integer from 0-5; Z is -NR and all other symbols are as defined above in conjunction with formula (I). In a still further aspect of any of formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3, G is - (CH2) S__ where s in integer from 0-5; Z is O; all other symbols are as defined above in conjunction with formula (I). In yet another aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3; R5 is H; G is - (CH) s.j where s in integer of 0-5; Z is 0; and all other symbols are as defined above in conjunction with formula (I). In one aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R is -H or CH3; Rs is CH3; G is - (CH) B.r where s in integer from 0-5; Z is O; and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of any of the formulas (88), (89), (90), (91) and (92) of the present invention, R4 is a substituted or unsubstituted aryl group, all other symbols are as defined above in conjunction with the formula (I) .

The present invention also encompasses various compounds of the general formula (IV) having the formula: where all symbols are as defined above in conjunction with formula (I). According to various aspects of the present invention, R, R4, R5, G, and Z of the formula (93) are selected to produce the compounds of the formula (93-1) up to (93-243) as follows: Formula RR * R3 G 93-1 Ra R ^ a R 5a Ga Za 93-2 Rb R 4a R 5a Ga Z8 93-3 Rc R 4a R 5a Ga Za 93-4 Ra R 4b R 5a Ga za 93-5 Rb R 4b R 5a Ga za 93-6 Rc R 4b R 5a Ga za 93-7 Ra R 4c R 5a Ga za 93-8 Rb R 4c R 5a G8 93-9 Rc R 4c za R 5a Ga za 93-10 Ra R4a R 5b Ga 93-11 Rb R 4a za R 5b Ga za 93-12 Rc R 4a R 5b Ga za 93-13 Ra R 4b R 5b Ga za 93-14 RR 4b R 5b Ga za 93-15 Rc R 4- b R 5b Ga za 93-16 R8 R 4c R 5b Ga za 93-17 Rb RR 5b Ga z8 93-18 Rc RR 5b Ga za 93-19 Ra R 4a R 5c Ga za 93-20 Rb R4a R 5c Ga 8 93-21 Rc R4a R 5c z Ga za 93-22 Ra R4b R5 ° Ga Za 93-23 R R4b R5c Ga R5c za 93-24 R ° R4b G8 za 93-25 R8 R4c R5c Ga z8 93-26 Rb R4c R5c Ga R5c za 93-27 Rc R4c Ga za 93-28 Ra R48 R5a Gb za 93-29 Rb R4a R5a Gb za 93-30 Rc R4a R3a Gbza 93-31 Ra R4b R5a Gb za 93-32 Rb R4b R5a Gbza 93-33 Rc R4b R5a Gb za 93-34 Ra R4c R5a Gb za 93-35 Rb R4e R5a Gb za 93-36 Rc R4c R5a Gb za 93-37 R8 R4a R5b Gb za 93-38- Rb R a R5b Gb za 93-39 Rc R4a R5b Gb z8 93-40 Ra R4b R5b Gbza 93-41 Rb R4b R5b Gbza 93-42 R ° R4b R5b Gbza 93-43 Ra R4c R5b Gbza 93-44 Rb R4C R5b Gbza 93-45 Rc R4c R5 Gb za 93-46 Ra R4a R5c Gb za 93-47 Rb R4a R5c Gb R5c za 93-48 R ° R4a Gb za 93-49 Ra R4b R5c Gb za 93-50 Rb R4b R5c Gbza 93-51 Rc R4b R5c Gbza 93-52 Ra R4c R5c G za 93-53 Rb R4c R5 ° Gb za 93-54 Rc R4e R5c Gbza 93-55 Ra R4a R5a Gc za 93-56 Rb R4a R5a Gc za 93-57 Rc R4a R5a Gc za 93-58 Rü R4b R5a Gc za 93-59 Rb R4b R5a Gc za 93-60 R ° R4b R5a Gc za 93-61 Ra R4c R5a Gc z8 93-62 Rb R4c R5a Gc z8 93-63 R ° R4c R5a Gc za 93-64 Ra R4a R5b Gcza 3-65 Rb R4a R5b Gcza 3-66 Rc R4a R5b G o za 3-67 Ra R4b R5b Gc za 3-68 Rb R4b R5b Gc za 93-116 Rb R 4c R 5a Gb 93-117 Rc R 4c R 5a Gb 93-118 Ra R 4a R 5b Gb 93-119 Rb R 4a R 5b Gb 93-120 Rc R R 5b Gb 93-121 Ra R 4b R 5b Gb 93-122 Rb R 4b R 5b Gb 93-123 Rc R 4b R 5b Gb 93-124 Ra R 4c R 5b Gb 93-125 Rb, 4c, 5b 93-126 Rc R 4c R 5b Gb 93-127 Ra R R 5c 93-128 R R R 5c G 93-129 Rc R R 5c Gb 93-130 Ra R 4b R5c Gb 93-131 Rb R 4b R5c Gb 93-163 Ra R4a R5a Ga Zc 93-164 Rb R4a R5a Ga Z ° 93-165 Rc R4a R5a Ga Zc R5a 93-166 Ra R4 Ga 5a zc 93-167 R R R4b Ga zc 93-168 Rc R4b R5a Ga zc 93-169 Ra R c R5a Ga zc 93-170 R4c Rb R5a Ga zc 93-171 Rc R4c RSa Ga zc 93-172 Ra R4a R5b Ga zc 93-173 Rb R4a R5 Ga zc 93-174 Rc R4a R5b Ga zc 93-175 Ra R4b R5b Ga zc 93-176 Rb R4b R5b Ga R4b R5b zc 93-177 Rc Ga zc 93-178 Ra R4c R5b Ga zc 93-179 Rb R4c R5b Ga zc 93-180 Rc R4c R5b Ga zc 93-181 R8 R4a R5c Ga zc 93-182 Rb R4a R5c Ga zc 93-183 Rc R4a R5c Ga zc 93-184 R8 R4b R5c Ga zc 93-185 Rb R4b R5e Ga zc 93-186 Rc R4b R5c Ga zc 93-187 Ra R4c R5e Ga zc 93-188 Rb R4e R5c Ga zc 93-189 Rc R4c R5c Ga z ° 93-190 Ra R4a R5a Gb zc 93-191 Rb R4a R5a Gb zc 93-192 Rc R4a R5a Gb zc 93-193 Ra R4b R5a Gb zc 93-194 Rb R4b R5a G zc 93-195 Rc R4b R5a G zc 93-196 R8 R4c R5a Gb zc 93-197 Rb R4c R5a Gb zc 93-198 Rc R4c R5a Gb zc 93-199 Ra R4a R5b Gb R4a R5b zc 93-200 Rb G R5b zc 93-201 Rc R4a Gb zc 93-202 Ra R4b R5b Gb zc 93-203 Rb R4b R5b Gb zc 93-204 Rc R4 R5b Gb zc 93-205 Ra R4c R5b Gb zc 93-206 Rb R4c R5b Gb zc 93-207 Rc R4c R5b Gb zc 93-208 Ra R4a R5c Gb zc 93-209 Rb R4a R5c Gb zc 93-210 Rc R4a R5c Gb Z ° 93-211 Ra R4b R5e Gb Zc 93-212 Rb R4b R5e Gb Zc 93-213 Rc R4b R5c Gb ZO 93-214 Ra R4c R50 Gb Zc 93-215 Rb R4c R5c Gb Zc 93-216 Rc R4c R5c Gb Zc 93-217 Ra R a R5a Gc Zc 93-218 RR to R5a Gc Zc 93-219 Rc R4a R5a Gc Zc 93-220 Ra R4b R5a Gc zc 93 -221 Rb R4b R5a Gc zc 93-222 Rc R4b R5a Gc zc 93-223 Ra R4c R5a Gc zc 93-224 R R4c R5a Gc zc 93-225 Rc R4c R5a Gc zc 93-226 Ra R4a R5b Gc zc 93-227 Rb R a R5b Gc zc 93-228 Rc R4a R5b G ° zc 93-229 Ra R4b R5b Gc zc 93-230 Rb R4b R5b Gc zc 93-231 Rc R4b R5b Gc z 93-232 R1 R4c R5b Gc z 93 -233 R R4c R5b Gc zc 93-234 Rc R4c R5b Gc zc 93-235 Ra R4a R5c Gc zc 93-236 Rb R4a R5c Gc zc 93-237 Rc R4a R5c Gc zc 93-238 Ra R4b R5c Gc zc 93-239 Rb R4b R5c Gc zc 93-240 Rc R4b R5c Gc zc 93-241 Ra R4c R5c Gc zc 93-242 Rb R4c R5c Gc zc 93-243 Rc R4c R5c Gc zc where all symbols are as defined above. In any aspect of any of the formula (93) of the present invention, R is -H or CH3, and all other symbols are as defined above in conjunction with the formula (I).

In any aspect of any of the formula (93) of the present invention, R 4 is a substituted or unsubstituted aryl group; and all other symbols are as defined above in conjunction with formula (I). In any aspect of any of the formula (93) of the present invention, R5 is -H or CH3, and all other symbols are as defined above in conjunction with the formula (I). In yet another aspect of any of the formula (93) of the present invention G is - (CH2) S_, where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of formula (93) of the present invention, R is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group; R 4 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, or an alkenyloxy group, or a cycloalkenyloxy group, an acyl group, or an acyloxy group, or an aryl group, an aryloxy group, an aroyl group, or an aroyloxy group , an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroalkyl group, a heteroaryloxy group, or a heteroaralkoxy group; R5 is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of formula (93) of the present invention, R is hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group; R 4 is a cycloalkenyl group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, an heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroalkyl group, a heteroaryloxy group, or a heteroaralkoxy group; Rs is hydrogen, or a hydroxy group, a halogen, an alkyl group, an alkoxy group; and all other symbols are as defined above in conjunction with formula (I).

In yet another aspect of formula (93) of the present invention, R is hydrogen, or an alkyl group; R 4 is an unsubstituted or substituted aryl group; G is (-CH2 2, (-CHa.) 3, or (-CH2_) 4; Z is O, S, or NH, and R5 is hydrogen or an alkyl group In yet another aspect of formula (93) of the present invention, R is -H or CH3, R4 is a substituted or unsubstituted aryl group, G is (~ CH2_) 2, (-CH2_) 3, or (-CH2_) 4; Z is O, S or NH; Rs is -H or CH3 The present invention also encompasses various compounds of the general formula (IV) as follows: where R9, and R10 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group ( 0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, or an acyloxy group, or an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, an heteroarylthio group, an aralkylthio group, or a heterocyclylsulphonyl group, which is substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, wherein the heterocycle group is optionally a morpholinyl substituted group gone, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined above in conjunction with the formula (I) - According to various aspects of the invention, R, R5, G, Z, R9, and R10 of any of the formulas (94), ( 95), (96), and (97) are selected to produce compounds of the formulas (94-1), (95-1), (96-1), and (97-1) to the formulas (94-729) ), (95-729), (96-729), and (97-729) as follows: Formulas R R5 Ry R TG G 94-1 95-1 96-1 97-1 Ra RR Ga 94-2 95-2 96-2 97-2 Rb RR R30a Ga 5a R10a 94-3 95-3 96-3 97-3 Rc RR Ga 5b 944 95-4 96-4 97-4 Ra RR 9a R] 0a Ga Za 5b R R10a 94-5 95-5 96-5 97-5 RR Ga Za 5b 94-6 95-6 96-6 97-6 Rc R R1 R10a Ga 5c R10a 94-7 95-7 96-7 97-7 Ra RR Ga za R10a 94-8 95-8 96-8 97-8 RR 5c 9a R 'Ga Za 9a R10a 94-9 95-9 96-9 97-9 Rc R 5c R1 Ga Za 5a 94-10 95-10 96-10 97-10 Ra R R9b R 10a Ga za 94-11 95-11 96-11 97-11 RR 5a R9b R10a Ga za 94-12 95-12 96-12 97-12 Rc R 5a R9b RJOa Ga 5b za 94-13 95-13 96-13 97-13 Ra R R9b R10a Ga Za 94-14 95-14 96-14 97-14 RR 5b R9b R10a Ga Za 94-15 95-15 96-15 97-15 Rc R 5b R9b R10a Ga Za 94-16 95-16 96-16 97-16 Ra 94-17 '95-17 96-17 97- 17 Rb 94-18 95-18 96-18 97-18 Rc 94-19 95-19 96-19 97-19 Ra 94-20 95-20 96-20 97-20 Rb 94-21 95-21 96-21 97-21 Rc 94-22 95-22 96-22 97-22 Ra 94-23 95-23 96-23 97-23 Rb 94-24 95-24 96-24 97-24 Rc 94-25 95-25 96 -25 97-25 Ra 94-26 95-26 96-26 97-26 Rb 94-27 95-27 96-27 97-27 Rc 94-28 95-2S 96-28 97-28 Ra 94-29 95-29 96-29 97-29 Rb 94-30 95-30 96-30 97-30 Rc 94-31 95-31 96-31 97-31 Ra 94-32 95-32 96 -32 97-32 Rb 94-33 95-33 96-33 97-33 Rc 94-34 95-34 96-34 97-34 Ra 94-35 95-35 96-35 97-35 Rb 94-36 95- 36 96-36 97-36 Rc 94-37 95-37 96-37 97-37 Ra 94-38 95-38 96-38 97-38 Rb 94-39 95-39 96-39 97-39 Rc 94-40 9540 9640 97-40 Ra 94-41 95-41 9641 97-41 R 94-42 9542 9642 97-42 Rc 94-43 95-43 9643 97-43 Ra 94-44 95-44 96-44 97-44 Rb 94-45 95-45 9645 97-45 Rc 94-46 9546 96-46 9746 Ra R5a R9c R10b Ga Za 94-47 95-47 9647 97-47 R R5a R9c R10b Ga Za 9c R10b 94-48 95-48 96-48 97-48 Rc R5a R Ga Za 94-49 95-49 96-49 97-49 Ra R5b R9e R10b Ga Za 94-50 95-50 96-50 97-50 R R5b R9c R10b Ga b za 94-51 95-51 96-51 97-51 Rc R5 R9c R10b Ga za 94-52 95-52 96-52 97-52 Ra R5c R9c RI0b Ga za 94-53 95-53 96-53 97-53 Rb R5c R9c R10b Ga za 94-54 95-54 96-54 97-54 Rc R5c R9c R10b Ga za 94-55 95-55 96-55 97-55 Ra R5a R9a R10c G8 za 94-56 95-56 96-56 97-56 Rb R5a R9a R10c Ga za 94-57 95-57 96-57 97-57 Rc R5a R9a R10c Ga za 94-58 95-58 96-5 S 97-58 Ra R5b R9a R10c Ga za 94-59 95-59 96-59 97-59 Rb R5b R9a R10c Ga za 94-60 95-60 96-60 97-60 Rc R5b R9a R10c Ga za 94-61 95-61 96-61 97-61 Ra R5c R9a R10e Ga za 94-62 95-62 96-62 97-62 Rb R5c R9a R10e Ga za 94-63 95-63 96-63 97-63 Rc R5c R9a RI0c Ga za 94-64 95-64 96-64 97-64 Ra R5a R9b R10c Ga za 94-65 95-65 96-65 97-65 Rb R5a R9b RI0c Ga za 94-66 95-66 96-66 97-66 Rc R5a R9b R10c Ga za 94-67 95-67 96-67 97-67 Ra R5b R9b R10c Ga za 94-68 95-68 96-68 97-68 Rb R5b R9b R10c Ga za 94-69 95-69 96-69 97-69 Rc R5b R9b R10c Ga za 94-70 95-70 96-70 97-70 Ra R5c R9b R10e Ga za 94-71 95-71 96-71 97-71 Rb R5c R9b R10c Ga R5c R9b 94-72 95-72 96-72 97-72 Rc R10c Ga za 94-73 95-73 96-73 97-73 Ra R5a R9c R10c Ga za 94-74 95-74 96-74 97-74 Rb R5a R9c R10c Ga za 94-75 95-75 96-75 97-75 Rc R5a R9c R10c Ga za 94-76 95-76 96-76 97-76 Ra R5b R9c R10c G8 za 94-77 95-77 96-77 97-77 Rb R5b R9c R10c Ga za 94-78 95-78 96-78 97-78 Rc R5b R9c R10c Ga za 94-79 95-79 96-79 97-79 Ra R5e R9c R10c Ga za 94-80 95-80 96-80 97-80 Rb R5c R9c R10c Ga za 94-81 95-81 96-81 97-81 Rc R5c R9e R10c Ga za 94-82 95-82 96-82 97-82 Ra R5a R9a R10a Gb za 94-83 95-83 96-83 97-83 Rb R5a R9a R10a Gb za 94-84 95-84 96-84 97-84 Rc R5a R9a R10a Gb R5b R9a R10a za 94-85 95-85 96-85 97-85 Ra Gb za 94-86 95-86 96-86 97-86 Rb R5 R9a R10a Gb za 94-87 95-87 96-87 97-87 Rc R5b R9a R10a Gb za 94-88 95-88 96-88 97-88 Ra R5c R9a R10a Gb za 94-89 95-89 96-89 97-89 Rb R5c R9a R10a Gb za 94-90 95-90 96-90 97-90 Rc R5e R9a R10a Gb za 94-91 95-91 96-91 97-91 Ra R5a R9b R10a G za 94-92 95-92 96-92 97-92 Rb R5a R9b R10a G za 94-93 95-93 96-93 97-93 Rc 94-94 95-94 96-94 97-94 Ra 94-95 95-95 96-95 97-95 Rb 94-96 95-96 96-96 97-96 Rc 94-97 95-97 96-97 97-97 Ra 94-98 95-98 96-98 97-98 Rb 94-99 95-99 96-99 97-99 Rc 94-100 95-100 96-100 97-100 Ra 94-101 95-101 96-101 97-101 Rb 94-102 95-102 96-102 97-102 Rc 94-103 95-103 96-103 97-103 Ra 94-104 95-104 96-104 97-104 Rb 94-105 95-105 96-105 97-105 R ° 94-106 95-106 96-106 97-106 Ra 94-107 95-107 96-107 97-107 Rb 94-108 95-108 96-108 97-108 Rc 94-109 95-109 96-109 97-109 Ra 94-110 95-110 96-110 97-110 Rb 94-111 95-111 96-111 97-111 Rc 94-112 95-112 96-112 97-112 Ra 94-113 95-113 96-113 97-113 Rb 94-114 95-114 96-114 97-114 Rc 94-115 95-115 96-115 97-115 Ra 94-116 95-116 96-116 97-116 Rb 94-117 95-117 96-117 97-117 Rc 94-118 95-118 96-118 97-118 Ra 94-119 95-119 96-119 97-119 Rb 94-120 95-120 96-120 97-120 Rc 94-121 95-121 96-121 97-121 Ra 94-122 95-122 96-122 97-122 R 94-123 95-123 96-123 97-123 Rc 94-124 95-124 96-124 97-124 Ra 94-125 95-125 96-125 97-125 Rb 94-126 95-126 96-126 97-126 Rc 94-127 95-127 96-127 97-127 Ra 94-128 95-128 96-128 97-128 Rb 94-129 95-129 96-129 97-129 Rc 94-130 95-130 96-130 97-130 Ra 94-131 95-131 96-131 97-131 Rb 94-132 95-132 96-132 97-132 Rc 94-133 95-133 96-133 97-133 Ra 94-134 95-134 96-134 97-134 Rb 94-135 95-135 96-135 97-135 Rc 94-136 95-136 96-136 97-136 Ra 94-137 95-137 96-137 97-137 Rb 94-13S 95-138 96-138 97-138 Rc 94-139 95-139 96-139 97-139 Ra 94-140 95-140 96-140 97-140 Rb R5b R9a R10c G Za 94-141 95-141 96-141 97-141 Rc R5b R9a R10c G za R9a RI0c 94-142 95-142 96-142 97-142 Ra R5c Gb Rbza R5c 94-143 95-143 96-143 97-143 R9a R10c Gbza 94-144 95-144 96-144 97-144 Rc R5c R9a R10c G za 94-145 95-145 96-145 97-145 Ra R5a R9b R10c Gb Rbza R5a R9b RJ0e 94-146 95-146 96-146 97-146 Gb za 94-147 95-147 96-147 97-147 Rc R5a R9b R10c Gbza R5b 94-148 95-148 96-148 97-148 Ra R9b R10c Gbza R5b R9b R10c 94-149 95-149 96-149 97- 149 Rb Gbza R9b R10e 94-150 95-150 96-150 97-150 Rc R5b Gbza 94-151 95-151 96-151 97-151 Ra R5c R9b R! 0e Gb za 94-152 95-152 96-152 97-152 Rb R5c R9b R10c Gb za 94-153 95-153 96-153 97-153 Rc R5c R9b R, 0c Gb za 94-154 95-154 96-154 97-154 Ra R5a R9c R10c Gb R5a R9e R10c 94-155 95-155 96-155 97-155 Rb Gb za R9c R) 0c 94-156 95-156 96-156 97-156 Rc R5a Gb za 94-157 95-157 96-157 97-157 Ra R5b R9c R10c Gbza R5b 94-158 95-158 96-158 97-158 Rb R9c R10c Gb za 94-159 95-159 96-159 97-159 Rc R b R9c R10e G za 94-160 95-160 96-160 97-160 Ra R5e R9c R.0c Gb za 94-161 95-161 96-161 97-161 Rb R5c R9e R10c Gb za 94-162 95-162 96-162 97-162 Rc R5c R9c RI0e Gb z8 94-163 95-163 96-163 97-163 Ra R5a R9a R10a Gc za 94-164 95-164 96-164 97-164 R R5a R9a R10a Gc za 94-165 95-165 96-165 97-165 Rc R5a R98 R10a Gc za 94-166 95-166 96-166 97-166 Ra R5b R9a RI0a Gc za 94-167 95-167 96-167 97-167 Rb R5b R98 R10a Gc za 94-168 95-168 96-168 97-168 Rc R5b R9a R, 0a Gc za 94-169 95-169 96-169 97-169 Ra R5c R9a R10a Gc za 94-170 95-170 96-170 97-170 Rb R5c R9a R10a Gc za 94-171 95-171 96-171 97-171 R ° R5c R a R10a Gc za 94-172 95-172 96-172 97-172 Ra R5a R9b R10a Gc za 94-173 95-173 96-173 97-173 Rb R5a R9b R10a Gcza R10a 94-174 95-174 96-174 97-174 R ° R5a R9b Gcza R9b R10a 94-175 95-175 96-175 97- 175 Ra R5b Gc za 94-176 95-176 96-176 97-176 Rb R9b R10a Gc za 94-177 95-177 96-177 97-177 Rc R5b R9b 10a Gc za 94-178 95-178 96-178 97-178 Ra R5c R9b R10a G ° R5c za 94-179 95-179 96-179 97-179 Rb R9b R10a Gc za 94-180 95-180 96-180 97-180 Rc R5c R9b R10a Gc za 94-181 95-181 96-181 97-181 Ra R5a R90 R10a Gc za 94-182 95-182 96-182 97-182 Rb R5a R9c R10 Gc za 94-183 95-183 96-183 97-183 Rc R5a R9c R10a Gc Ra za R5b R9c 94-184 95-184 96-184 97-184 R10a Gc za 94-185 95-185 96-185 97-185 Rb? R9c R10a Gc za 94-186 95-186 96-186 97-186 Rc R5b R9c R10a Gc za 94-187 95-187 96-187 97-187 Ra R5c R9c R10a Gc R5c za R9c R10a 94-188 95-188 96-188 97- 188 Rb Gc 9c R10a za 94-189 95-189 96-189 97-189 R ° R5c R Gc za 94-190 95-190 96-190 97-190 Ra R5a R9a RI0b Gc za 94-191 95-191 96-191 97-191 R R5a R9a R10b Gc 7-192 Rc R5a R9a 94-192 R10b 95-192 96-192 9 Gc za 94-193 95-193 96-193 97-193 Ra R5b R9a R10b Gc za 94-194 95-194 96-194 97-194 Rb R5b R9a R10b Gc za 94-195 95-195 96-195 97-195 Rc R5b R9a R10b Gc za 94-196 95-196 96-196 97-196 Ra R5c R9a R30b Gc za 94-197 95-197 96-197 97-197 Rb R5c R9a R10b Gc za 94-198 95-198 96-198 97-198 Rc R5c R98 R10b Gc za 94-199 95-199 96-199 97-199 Ra R5a R9b R10b Gc za 94-200 95-200 96-200 97-200 Rb R5a R9b R10b Gc za 94-201 95-201 96-201 97-201 Rc R5a R9b R10b Gc za 94-202 95-202 96-202 97-202 Ra R5b R9b R10b Gc za 94-203 95-203 96-203 97-203 R R5b R9b R10b Gc za 94-204 95-204 96-204 97-204 Rc R5b R9b R10b Gc za 94-205 95-205 96-205 97-205 Ra R5c R9b R10b Gc R5c R9b R10b 94-206 95-206 96-206 97-206 Rb G ° za 94-207 95-207 96-207 97-207 Rc R5c R9b R! 0 Gc za 94-208 95-208 96-208 97-208 Ra R5a R9c R10b Gc za 94-209 95-209 96-209 97-209 Rb R5a R9c R10b Gc R5_za 94-210 95-210 96-210 97-210 Rc R9c R10b Gc z8 94-211 95-211 96-211 97-21 Ra R5b R9c R10b Gc za 94-212 95-212 96-212 97-212 R R5b R9c R10b Gc za 94-213 95-213 96-213 97-213 Rc R? R9c R10b Gc R5c R9c R10b 94-214 95-214 96-214 97-214 Ra Gc za 94-215 95-215 96-215 97-215 Rb R5c R9c R10b Gc za 94-216 95-216 96-216 97-216 Rc R5c R9c R10b Gc. za 94-217 95-217 96-217 97-217 R8 R5a R9a R10c Gc za 94-218 95-218 96-218 97-218 Rb R5a R9a R10c Gc za 94-219 95-219 96-219 97-219 Rc R3a R9a R10c Gc R5b R9a 94-220 95-220 96-220 97-220 Ra R10c Gc za 94-221 95-221 96-221 97-221 Rb R5b R9a R10c Gc za 94-222 95-222 96-222 97-222 Rc R5b R9a R10c Gc 0c za 94-223 95-223 96-223 97-223 Ra R5c R9a R1 Gc za 94-224 95-224 96-224 97-224 Rb R5 ° R9a R10c Gc za 94-225 95-225 96-225 97-225 Rc R5c R9a RI0c G ° za 94-226 95-226 96-226 97-226 Ra R5a R9b R10c Gc za 94-227 95-227 96-227 97-227 Rb R5a R9b R10c Gc za 94-228 95-22S 96-228 97-228 Rc R3a R9b R10c Gc za 94-229 95-229 96-229 97-229 Ra R5b R9 R10e Gc za 94-230 95-230 96-230 97-230 Rb R5b R9b R10c Gc R5b 94-231 95-231 96-231 97-231 Rc R9b R10c Gc za 94-232 95-232 96-232 97-232 Ra R5c R9b R10c Gc za 94-233 95-233 96-233 97-233 Rb R5e R9b R10c Gcza 94-234 95-234 96-234 97-234 Rc R5c R9b R10c Gc Za 94-235 95-235 96-235 97-235 Ra R3a R9c ROc Gc Za R3a R9c R10c 94-236 95-236 96-236 97-236 Rb Gc Za 94-237 95-237 96-237 97-237 Rc R5a R9c R10c Gc Za 94-238 95-238 96-238 97-238 Ra R5b R9c R10c Gc Za 94-239 95-239 96-239 97-239 Rb R5b R9e R10c Gc Za 94-240 95-240 96-240 97-240 Rc R5b R9c R10c Gc Za 94-241 95-241 96-241 97-241 Ra R3c R9c R10c Gc Za 94-242 95-242 96-242 97-242 Rb R5c R9c R10c Gc Za 94-243 95-243 96-243 97-243 Rc R3c R9c R10c Gc Z8 94-244 95-244 96-244 97-244 Ra R5a R9a R10a Ga Zb 94-245 95-245 96-245 97-245 R R5a R9a R10a Ga Zb 94-246 95-246 96-246 97-246 Rc R5a R9a RlOa Ga zb 94-247 95-247 96-247 97-247 Ra R5b R9a R10a Ga zb 94-248 95-248 96-248 97-248 Rb R5b R9a R10 Ga zb 94-249 95-249 96-249 97-249 Rc R5b R9a RIOa Ga Zb 94-250 95-250 96-250 97-250 Ra R5c R9a R10a Ga Zb 94-251 95-251 96-251 97-251 Rb R5c R9a R10a Ga zb 94-252 95-252 96-252 97-252 Rc R5c R9a R10a Ga zb 94-253 95-253 96-253 97 ^ 253 Ra R5a R9b RIOa Ga R5a zb 94-254 95-254 96-254 97-254 Rb R9b R10a Ga zb 94-255 95-255 96-255 97-255 Rc R5a R9b R10a Ga zb 94-256 95-256 96-256 97-256 R8 R5b R9b R10a Ga zb 94-257 95-257 96-257 97-257 Rb R3b R9b R10a Ga zb 94-258 95-258 96-258 97-258 Rc R5b R9b R10a Ga z 94-259 95-259 96-259 97-259 Ra R5c R9b RJOa Ga zb 94-260 95-260 96-260 97-260 Rb R5c R9b R10a Ga zb 94-261 95-261 96-261 97-261 Rc R5c R9b R10a Ga zb 94-262 95-262 96-262 97-262 R8 R3a R9c R10a Ga z 94-263 95-263 96-263 97-263 Rb R5a R9c R10a Ga zb 94-264 95-264 96-264 97-264 Rc R5a R9c R10a Ga R5b zb 94-265 95-265 96-265 97-265 Ra R9c R10a Ga zb 94-266 95-266 96-266 97-266 Rb R5b R9c RIOa Ga zb 94-267 95-267 96-267 97-267 Rc R5b R9c R10a Ga zb 94-268 95-268 96-268 97-268 Ra R5e R9c R10a Ga R5 zb 94-269 95-269 96-269 97-269 Rb c R9c R10a Ga zb 94-270 95-270 96-270 97-270 Rc R5c R9c R10a Ga zb 94-271 95-271 96-271 97-271 Ra R5a R9a R10b Ga zb 94-272 95-272 96-272 97-272 Rb R5a R9a R10b Ga zb 94-273 95-273 96-273 97-273 Rc R5a R a R10b Ga zb 94-274 95-274 96-274 97-274 Ra R5b R9a R10b Ga zb 94-275 95-275 96-275 97-275 Rb R5b R9a R10b Ga zb 94-276 95-276 96-276 97-276 Rc R5b R9a R10b Ga zb 94-277 95-277 96-277 97-277 Ra R5c R9a R10b Ga R9a zb R10b 94-278 95-278 96-278 97-278 Rb R5c Ga zb 94-279 95-279 96-279 97-279 Re R5c R9a RIOb Ga zb 94-280 95-280 96-280 97-280 Ra R5a R9b R! 0b Ga zb 94-281 95-281 96-281 97-281 Rb R5a R9"R ° b Ga Zb 94-282 95-282 96-282 97-282 Rc R5a R9b R10b Ga Zb 94-283 95-283 96-283 97-283 Ra R5b R9b R10b Ga Zb 94-284 95-284 96-284 97-284 Rb R? R9b R10b Ga Z 94-285 95-285 96-285 97-285 Rc R5b R9 Rl0b Ga Z 94-286 95-286 96-286 97-286 Ra R5c R9b R10b G8 Zb 94-287 95-287 96-287 97-287 Rb R5 ° R9b R10b Ga Zb 94-288 95-288 96-288 97-288 c R5c R9b R10b G8 Zb 94-289 95-289 96-289 97-289 Ra RSa R9 ° R10b Ga Zb 94-290 95-290 96-290 97-290 Rb R5a R c RIO Ga Zb 94-291 95-291 96-291 97-291 Rc R5a R9c R10b Ga Zb 94-292 95-292 96-292 97-292 Ra R5b R9c RIOb Ga Zb 94-293 95-293 96-293 97-293 Rb R5b R9c RIVER Ga Zb 94-294 95-294 96-294 97-294 R ° R5b R9c Ri0b Ga Zb 94-295 95-295 96-295 97-295 Ra R5c R9c RIOb Ga Zb 94-296 95-296 96-296 97-296 Rb R5c R9c R10b Ga Zb 94-297 95-297 96-297 97-297 Rc R5c R9c R10b Ga Zb 94-298 95-298 96-29S 97-298 Ra R5a R9a R10c Ga Zb 94-299 95-299 96-299 97-299 Rb R5a R9a R10c Ga Zb 94-300 95-300 96-300 97-300 Rc R5a R9a R10c Ga Z 94-301 95-301 96-301 97-301 Ra R5b R9a R10c Ga Zb 94-302 95-302 96-302 97-302 Rb R5b R9a RIOc Ga Zb 94-303 95-303 96-303 97-303 Rc R? R9a R10c Ga Zb 94-304 95-304 96-304 97-304 Ra R5c R9a R10c Ga Zb 94-305 95-305 96-305 97-305 Rb RSc R9a R10c Ga Zb 94-306 95-306 96-306 97-306 Rc R5c R9a R10c Ga Z 94-307 95-307 96-307 97-307 Ra R5a R9b R10c Ga Zb 94-308 95-308 96-308 97-308 Rb R5a R9b RI0c Ga Z 94-309 95-309 96-309 97-309 R ° R5a R9b RI0c Ga Zb 94-310 95-310 96-310 97-310 Ra R5b R9 RIOc Ga Z 94-311 95-311 96-311 97-311 Rb R5b R9b R! 0c Ga Zb 94-312 95-312 96-312 97-312 RC R5b R9b R10 ° Ga Zb 94-313 95-313 96-313 97-313 Ra R5c R9b R10c Ga Z 94-314 95-314 96-314 97-314 Rb R5c R9b RI0c G8 Zb 94-315 95-315 96-315 97-315 Rc R5c R9b R10 ° Ga Zb 94-316 95-316 96-316 97-316 Ra R5a R9c R10c Ga Zb 94-317 95-317 96-317 97-317 Rb R5a R9c Ri0c Ga Zb 94-318 95-31 S 96-318 97-318 Rc RSa R9c RÍOc Ga Zb 94-319 95-319 96-319 97-319 Ra R5b R9c R10c Ga Zb 94-320 95-320 96-320 97-320 Rb R3b R9 ° R30c Ga Zb 94-321 95-321 96-321 97-321. Rc R5 R9c R10c Ga Z 94-322 95-322 96-322 97-322 Ra R3c R9c R10c Ga Zb 94-323 95-323 96-323 97-323 Rb R5 ° R9e RIOc Ga Zb 94-324 95-324 96-324 97-324 R ° R5c R c R10c Ga Z 94-325 95-325 96-325 97-325 Ra R5ü R9a RIOa Gb Zb 94-326 95-326 96-326 97-326 Rb R5a R9a R10a Gb Z 94-327 95-327 96-327 97-327 Rc R5a R9a R10a Gb Zb R5b 94-328 95-328 96-328 97-328 Ra R9a RJ0a Gb Z R5b 94-329 95-329 96-329 97-329 Rb R9a R10o Gb Zb 94-330 95-330 96-330 97-330 Rc R5b R9a R10a Gb Zb 94-331 95-331 96-331 97-331 Ra R3c R98 R10a Gb Zb 94-332 95-332 96-332 97-332 Rb R5e R9a R10a Gb Zb c R9a R10a 94-333 95-333 96-333 97-333 Rc R5 Gb Zb 94-334 95-334 96-334 97-334 Ra R5a R9b R10a Gb Z 94-335 95-335 96-335 97-335 Rb R5a R9b RIOa Gb Z 94-336 95-336 96-336 97-336 Rc R5a R9b R10a Gb Z 94-337 95-337 96-337 97-337 Ra R5b R9b R10a Gb R5b z 94-338 95-338 96-338 97-338 Rb R9 R10a Gb z 94-339 95-339 96-339 97-339 Rc R3b R9b R10a Gb R5c zb 94-340 95-340 96-340 97-340 Ra R9b R10a Gb zb 94-341 95-341 96-341 97-341 Rb R5c R9b R10a Gb zb 94-342 95-342 96-342 97-342 Rc R5c R9b R10a Gb. zb 94-343 95-343 96-343 97-343 Ra R5a R9c R10a Gb zb 94-344 95-344 96-344 97-344 Rb RSa R9e R10a G zb 94-345 95-345 96-345 97-345 Rc R5a R9c R10a Gb zb 94-346 95-346 96-346 97-346 Ra R5b R9c R10a G zb 94-347 95-347 96-347 97-347 Rb R5b R9c R10a G zb 94-348 95-348 96-348 97-348 Rc R5b R9c R10a Gb zb 94-349 95-349 96-349 97-349 Ra R5c R9c RI0a Gb zb 94-350 95-350 96-350 97-350 Rb R5c R9c RI0 Gb z 94-351 95-351 96-351 97-351 Rc R5c R9c R10a Gb zb 94-352 95-352 96-352 97-352 Ra R5a R9a R10b Gb zb 94-353 95-353 96-353 97-353 Rb R5a R9a R10b Gb zb 94-354 95-354 96-354 97-354 Rc R5a R9a R10b Gb zb 94-355 95-355 96-355 97-355 Ra R5b R9a R10b Gb zb 94-356 95-356 96-356 97-356 Rb R5b R9a R10b Gb z 94-357 95-357 96-357 97-357 Rc R5b R9a Ri0b Gb zb 94-358 95-358 96-358 97-358 R8 R3c R9a R10b Gb zb 94-359 95-359 96-359 97-359 Rb R5c R9a R10b Gb R9a R10b zb 94-360 95-360 96-360 97-360 Rc R3c Gb zb 94-361 95-361 96-361 97-361 R ° R5a R9b R10b Gb zb 94-362 95-362 96-362 97-362 Rb R5a R9b R10b G zb 94-363 95-363 96-363 97-363 Rc R5a R9b R10b Gb zb 94-364 95-364 96-364 97-364 Ra R5b R9b R, 0b Gb zb 94-365 95-365 96-365 97-365 Rb R5b R9b R10b Gb zb 94-366 95-366 96-366 97-366 Rc R3b R9b R10b Gb zb 94-367 95-367 96-367 97-367 Ra R5c R9b R10b Gb zb 94-368 95-368 96-368 97-368 Rb R5c R9b - R10b G zb 94-369 95-369 96-369 97-369 Rc R5c R9b R10b Gb zb '94 -370 95-370 96-370 97-370 Ra R5a R9c R10b Gb R9c R10b zb 94-371 95-371 96-371 97-371 Rb R5a Gb zb 94-372 95-372 96-372 97-372 Rc R5a R9c R10b Gb zb 94-373 95-373 96-373 97-373 Ra R30 R9c R10b Gb zb 94-374 95-374 96-374 97-374 R R5b R9c R10b Gb zb R5b 94-375 95-375 96-375 97-375 Rc R R 10b GD 94-376 95-376 96-376 97-376 Ra R5c R R10b 94-377 95-377 96-377 97-377 Rb R5c R R10b Gb 94-378 95-378 96-378 97-378 Rc R5c R R10b 94-379 95-379 96-379 97-379 Ra R5a R R10c Gb 9a 94-380 95-380 96-380 97-380 Rb R5a R R10o Gb 94-381 95-381 96-381 97-381 Rc R5a R 9a R10c 5b 94-382 95-382 96-382 97-382- Ra R R 9a R10c GD 94-383 95-383 96-383 97-383 Rb R 5b R 9a R10c Gb 94-384 95-384 96-384 97-384 Rc R 5b R 9a R10c Gb R10 94-385 95-385 96-385 97-385 Ra R 5-c RG 94-386 95-386 96-386 97-386 Rb R 5c R 9a R10c G 94-387 95-387 96-387 97-387 Rc R 5c R 9a R10c Gb 94-388 95-388 96-388 97-388 Ra R 5a R 9b R10c Gb 94-389 95-389 96-389 97-389 Rb R 5a R 9b R 10c 94-390 95-390 96-390 97-390 Rc R 5a R 9b R Oc Gb 94-391 95-391 96-391 97-391 Ra R 5b R 9b R 10c Gb 94-392 95-392 96-392 97-392 Rb R 5b R 9b R10c Gb 94-393 95-393 96-393 97-393 Rc R 5b R 9b R10c Gb 5c 94-394 95-394 96-394 97-394 Ra R R 9b R10c Gb 94-395 95-395 96-395 97-395 Rb R5c R 9b R10c Gb 94-396 95-396 96-396 97-396 R ° R5c R 9b R10c Gb 94-397 95-397 96-397 97-397 Ra R5a R 9c R10c R5a c 94-398 95-398 96-398 97-398 Rb R 9 10c R GD 9c 10c 94-399 95-399 96-399 97- 399 Rc R5a RR Gb 94-400 95-400 96-400 97400 Ra R3b R 9c R 10c 9c 94-401 95401 96-401 97401 Rb R 5b RR 10c 94-402 95-402 96-402 97-402 Rc R 5b R 9c R 10c 94 -403 95-403 96-403 97-403 Ra R 5c R 9c R 10c Gb 94-404 95-404 96-404 97-404 Rb R 5c R 9c 10c Gb 94405 95-405 96-405 97-405 Rc R 5c R9c R10c Gb 94-406 95406 96406 97-406 Ra R5a R9a Ri0a Gc 94407 95407 96-407 97407 R R5a R9a R10B Gc 94408 95-408 96-408 97-408 Rc R5a R9a R10a Gc Z 94-409 95-409 96-409 97-409 Ra R5b R9a R10a Gc R5b 94-410 95-410 96-410 97-410 Rb R9a R10a zb Gc R5b 94-411 95-411 96-411 97-411 Rc R9a R10a z G ° R10a zb 94-412 95-412 96-412 97-412 Ra R5c R9a Gc R5e zb 94-413 95-413 96-413 97413 Rb R9a R 110a Gc R5c 94-414 95-414 96-414 97414 Rc R9a 10a z R G ° 94-415 95-415 96415 97-415 Ra R5a R 9b R 10a Gc R5a 94-416 95-416 96-416 97416 R R9b R 10a Gc R5a 94-417 95-417 96417 97-417 Rc R 9b R 10a Gc 94-418 95-418 96418 97-418 Ra R 5b R9b R10a Gc 94-419 95419 96-419 97-419 R R 5b R9b RIOa Gc 94-420 95-420 96-420 97-420 Rc R 5b R 9b R10a Gc 94-421 95421 96-421 97421 Ra R 5c R 9b 10a Gc 94-422 95-422 96-422 97-422 Rb R5c R9b R10a G ° 94-423 95-423 96-423 97-423 Rc R5c R9b R10a Gc 94-424 95-424 96-424 97-424 Ra R3a R9c R10a Gc 94-425 95-425 96-425 97-425 Rb R5a R9c R10a Gc 94-426 95-426 96426 97-426 Rc RSa R9c R10a Gc 94-427 95-427 96-427 97-427 Ra R5b R9c R10a Gc 94-428 95-428 96-428 97-428 R ° R5b R9c R10a Gc R9c R10a 94429 95-429 96-429 97429 Rc R3b Gc 94430 95-430 96-430 97430 Ra R3c R9c R10a Gc 94-431 95-431 96-431 97-431 Rb R50 R9c R10a Gc 94432 95-432 96-432 97-432 Rc R5c R9 ° R10a Gc 94-433 95-433 96-433 97-433 Ra R3a R9a R10b Gc 94-434 95-434 96-434 97-434 Rb R3a R9a R10b Gc 94-435 95-435 96-435 97435 Rc R5a R9a R10b Gc 94-436 95-436 96-436 97436 Ra R b R9a R10b Gc 94-437 95-437 96-437 97437 Rb R5b R a R10b Gc 94-438 95-438 96-438 97-438 Rc R3b R9a R10b Gc R5c 94-439 95-439 96439 97-439 R8 R98 R10b Gc 94-440 95-440 96-440 97-440 Rb R3C R9a R10b Gc 94-441 95-441 96-441 97-441 Rc R5c R9a R10b Gc 94-442 95442 96-442 97-442 Ra R5a R9b R10b Gc 94-443 95-443 96-443 97443 Rb R a R9b R10b Gc 94-444 95-444 96-444 97444 Rc R5a R9b R10b Gc 94-445 95-445 96-445 97-445 Ra R5b R9b R10b Gc R5b R9b R10b 94-446 95-446 96-446 97-446 Rb Gc R9b RJ0b 94-447 95447 96-447 97-447 Rc R5b Gc 94448 95-448 96-448 97-448 Ra R5c R9b R10b Gc 94-449 95449 96-449 97-449 Rb R5e R9b R10b Gc 94450 95-450 96-450 97-450 Rc R3c R9b R10b Gc 94451 95-451 96-451 97451 Ra R5a R9c R10b Gc 94-452 95-452 96-452 97452 Rb R3a R9c R10b Gc 94453 95453 96-453 97453 Rc R3a R9e R10b Gc 94454 95454 96-454 97-454 Ra R3b R9c R10b Gc 94-455 95-455 96-455 97-455 Rb R5 R9c R10b Gc 94-456 95456 96-456 97-456 Rc R5b R9c R10b Gc 94-457 95-457 96-457 97457 Ra RSc R9c R10b Gc 94458 95-458 96-458 97-458 Rb R3c R9c R10b Gc 94-459 95-459 96459 97459 Rc R5c R9c R10b Gc 94-460 95460 96-460 97-460 Ra R3a R9a R10e Gc 94461 95-461 96-461 97-461 Rb R3a R9ü R10c Gc 94462 95-462 96-462 97-462 Rc R3a R9a R10c Gc 94463 95463 96-463 97-463 Ra R5b R9a R10c Gc 94464 95-464 96-464 97-464 Rb R5b R9a R10c Gc 94-465 95-465 96-465 97-465 Rc R5b R9a R10c Gc 94466 95-466 96-466 97466 Ra R5c R9a R10c Gc 94467 95-467 96467 97467 Rb R5c R9a R10c Gc R5c 94468 95468 96-468 97468 R ° R9a R10c G ° R5a 94-469 95-469 96-469 97-469 Ra R9b R10c Gc Zb 94-470 95-470 96-470 97-470 Rb R3a R9b R10c Gc Zb 5a 94471 95-471 96471 97-471 Rc R R9 R10c Gc z 94-472 95-472 96-472 97-472 Ra R5b R9b R10c Gc R5b zb 94473 95473 96-473 97-473 Rb R9b RJ0c Gc z R5b R9b R10c 94474 95474 96474 97-474 Rc Gc zb 94-475 95475 96475 97-475 Ra R5c R9b R10c Gc z 94476 95-476 96-476 97-476 -Rb R5c R9b R10c Gc zb 94-477 95477 96477 97-477 Rc R5c R9b R10c Gc zb 94478 95478 96-478 97-478 Ra R5a R9c R10c Gc zb 94-479 95-479 96-479 97-479 R R5a R9c R10c Gc 5a zb 94-480 95-480 96-480 97-480 Rc R R9c R10c G ° zb 94-481 95481 96481 97-481 Ra R5b R9c R10c Gc zb 94-482 95482 96-482 97-482 R R5b R9c R! 0c Gc zb 94483 95-483 96-483 97-483 Rc R5b R9e R10c Gc R5c zb 94-484 95484 96-484 97-484 Ra R9c R10c G ° z 94-485 95485 96485 97-485 R R3c R9c R10c Gc zb 94-486 95-486 96-486 97-486 Rc R5c R c R10c Gc zb 94487 95-487 96-487 97487 Ra R5a R9a R0a Ga zc 94-488 95-488 96488 97488 Rb R5a R9a R10a Ga zc 94-489 95-4S9 96-489 97-489 Rc R5a R9a RI0a Ga zc 94-490 95-490 96-490 97-490 Ra R5b R9a R10a Ga zc 94-491 95-491 96-491 97-491 Rb R3b R9a R10a Ga zc 94-492 95-492 96-492 97492 Rc R5b R9a R10a Ga zc 94493 95-493 96-493 97-493 Ra R5c R9a R10a Ga zc 94-494 95-494 96-494 97-494 Rb R3c R9e R10a Ga zc 94-495 95495 96-495 97-495 Rc R3c R9a R10a Ga zc 94-496 95496 96-496 97496 Ra R3a R9b R10a Ga zc R9b 94-497 95-497 96-497 97-497 Rb R5a R10a Ga zc 94-498 95-498 96-498 97498 Rc R5a R9b R10a Ga zc 94-499 95-499 96-499 97-499 Ra R5b R9 R10a Ga zc 94-500 95-500 96-500 97-500 Rb R5b R9b R10a Ga zc 94-501 95-501 96-501 97-501 Rc R5b R9b Rt0a Ga zc 94-502 95-502 96-502 97-502 Ra R5c R9 R10a Ga zc 94-503 95-503 96-503 97-503 Rb R5c R9b R! 0a G1 zc 94-504 95-504 96-504 97-504 Rc R5c R9b R10a Ga zc R5a 94-505 95-505 96-505 97-505 Ra R9c R10a Ga zc 94-506 95-506 96-506 97-506 Rb R3a R9c R10a G8 zc 94-507 95-507 96-507 97-507 Rc R5a R9c R101 Ga zc 94-508 95-508 96-50S 97-508 Ra R3b R9c RI0a Ga R5b zc 94-509 95-509 96-509 97-509 Rb R9c R10a Ga zc 94-510 95-510 96-510 97-510 Rc R5b R9c RI0a G8 zc 94-511 95-511 96-511 97-511 Ra R3c R9c R10a Ga z ° 94-512 95-512 96-512 97-512 Rb R5c R9t R10a Ga zc 94-513 95-513 96-513 97-513 Rc R5c R9c R10a Ga 7? 94-514 95-514 96-514 97-514 Ra R a R9a R10b Ga zc 94-515 95-515 96-515 97-515 R R3a R9a R10b Ga zc 94-516 95-516 96-516 97-516 Rc R5a R9a RJ0b Ga Zc 94-517 95-517 96-517 97-517 R8 R5b R9a R10b Ga 9a R10b zc 94-518 95-518 96-518 97-518 R R5b R Ga zc 94-519 95-519 96-519 97-519 Rc R3b R9a R10b Ga zc 94-520 95-520 96-520 97-520 Ra R5c R9a R10b Ga c zc 94-521 95-521 96-521 97-521 Rb R5 R9a R10b Ga zc 94-522 95-522 96-522 97-522 Rc R5c R9a R10b Ga zc 94-523 95-523 96-523 97-523 R8 R3a R9b R10b Ga zc 94-524 95-524 96-524 97-524 Rb R3a R9 R10b Ga zc 94-525 95-525 96-525 97-525 Rc R3a R9b R10b Ga R5b zc 94-526 95-526 96-526 97-526 Ra R9b R10b Ga zc 94-527 95-527 96-527 97-527 Rb R5b R9b R10b Ga zc 94-528 95-528 96-528 97-528 Rc R5b R9b R10b Ga zc 94-529 95-529 96-529 97-529 Ra R5c R9b R.0b Ga zc 94-530 95-530 96-530 97-530 R R5c R9b R10b Ga zc 94-531 95-531 96-531 97-531 Rc R5c R9b R.0b Ga zc 94-532 95-532 96-532 97-532 Ra R5a R9c R10b Ga zc 94-533 95-533 96-533 97-533 Rb R5a R9c R10b Ga zc 94-534 95-534 96-534 97-534 Rc R5a R9c R10b Ga z ° 94-535 95-535 96-535 97-535 Ra R5b R9c R10b Ga zc 94-536 95-536 96-536 97-536 Rb R3 R9c R10b Ga zc 94-537 95-537 96-537 97-537 Rc R5b R9c R10b Ga zc 94-538 95-538 96-538 97-538 Ra R5c R9e R10b Ga R5c R9c R10b zc 94-539 95-539 96-539 97-539 Rb Ga zc 94-540 95-540 96-540 97-540 R ° R5c R9c R10b Ga zc 94-541 95-541 96-541 97-541 Ra R5ß R9a R10c Ga zc 94-542 95-542 96-542 97-542 Rb R5a R9a R10c Ga zc 94-543 95-543 96-543 97-543 Rc R5a R9a R10c Ga zc 94-544 95-544 96-544 97-544 Ra R5b R9a R10c Ga zc 94-545 95-545 96-545 97-545 R R5b R9a R10c Ga R5b zc 94-546 95-546 96-546 97-546 Rc R9a R10c Ga zc 94-547 95-547 96-547 97-547 Ra R5c R9a R10c Ga zc 94-548 95-548 96-548 97-548 Rb R5c R9a R10c Ga zc 94-549 95-549 96-549 97-549 Rc R5c R9a R10c Ga zc 94-550 95-550 96-550 97-550 Rfl R5a R9b R10c Ga zc 94-551 95-551 96-551 97-551 R R3a R9b R10c Ga zc 94-552 95-552 96-552 97-552 Rc R5a R9b RI0c Ga zc 94-553 95-553 96-553 97-553 Ra R5b R9b R10c Ga zc 94-554 95-554 96-554 97-554 R R5b R9 R10c Ga zc 94-555 95-555 96-555 97-555 Rc R5b R9b R10c Ga zc 94-556 95-556 96-556 97-556 Ra R5c R9b R10c Ga zc 94-557 95-557 96-557 97-557 Rb R5c R9b R10c Ga zc 94-558 95-558 96-55S 97-558 Rc R5c R9b R10c Ga zc 94-559 95-559 96-559 97-559 Ra R5a R9c R10c Ga R9c R10c zc 94-560 95-560 96-560 97-560 Rb R5a Ga zc 94-561 95-561 96-561 97-561 Re R5a R9c R10c Ga zc 94-562 95-562 96-562 97-562 Ra R5b R9c R10c Ga zc R9c R10c 94-563 95-563 96-563 97-563 Rb R5b Ga Zc 94-564 95-564 96-564 97-564 Rc R5b R9c R10c Ga Z < R9o 94-565 95-565 96-565 97-565 Ra R5c R10c Ga zc 94-566 95-566 96-566 97-566 Rb R3c R9c R10c Ga R9c R10c zc 94-567 95-567 96-567 97-567 Rc R3c Ga a zc 94-568 95-568 96-568 97-568 Ra R5 R9a R10a G zc 94-569 95-569 96-569 97-569 Rb R5a R9a R10a Gb R5a R9a R) 0a ze 94-570 95-570 96-570 97-570 Rc. G zc 94-571 95-571 96-571 97-571 Ra R5b R9a R10a G z ° R5b R9a R10a 94-572 95-572 96-572 97-572 Rb Gb zc 94-573 95-573 96-573 97-573 Rc R3b R9a R10a Gb zc 94-574 95-574 96-574 97-574 Ra R3c R9a R10a Gb zc 94-575 95-575 96-575. 97-575 Rb R3c R9a RI0a Gb R5c zc 94-576 95-576 96-576 97-576 Rc R9a R10a Gb zc 94-577 95-577 96-577 97-577 Ra R5a R9b R10a Gb zc 94-578 95-578 96-578 97-578 R R5a R9b R10a Gb zc 94-579 95-579 96-579 97-579 Rc R5a R9b R10a G zc 94-580 95-580 96-580 97-580 Ra R5b R9b R10a Gb R9b R20a zc 94-581 95-581 96-581 97-581 Rb R513 Gb zc 94-582 95-582 96-582 97-582 Rc R5b R9b R10a Gb zc 94-583 95-583 96-583 97-583 Ra R5c R9b R10a Gb zc 94-584 95-584 96-584 97-584 Rb R5c R9b R10a Gb zc 94-585 95-555 96-585 97-585 Rc R5c R9 R10a Gb zc 94-586 95-586 96-586 97-586 Ra R5a R9c R10a Gb zc 94-587 95-587 96-587 97-587 Rb R5a R9c R10a Gb zc 94-588 95-588 96-588 97-588 Rc R3a R9c R10a Gb zc 94-589 95-589 96-589 97-589 Ra R5b R9c R10a Gb zc 94-590 95-590 96-590 97-590 R R5b R9e R10a Gb zc 94-591 95-591 96-591 97-591 Rc R5b R9c R10a Gb zc 94-592 95-592 96-592 97-592 Ra R5c R9c RI0a Gb R5c R9c zc 94-593 95-593 96-593 97-593 Rb R10a Gb zc 94-594 95-594 96-594 97-594 Rc R5e R9c R10a Gb z ° 94-595 95-595 96-595 97-595 Ra R5a R9a R10b Gb zc 94-596 95-596 96-596 97-596 Rb R5a R9a R10b Gb zc 94-597 95-597 96-597 97-597 Rc R5a R9a R10b G zc 94-598 95-598 96-598 97-598 Ra R5b R9a R10b Gb zc 94-599 95-599 96-599 97-599 Rb R5b R9a R10b Gb zc 94-600 95-600 96-600 97-600 Rc R5b R9a R10b Gb zc 94-601 95-601 96-601 97-601 Ra R5c R9a R10b Gb zc 94-602 95-602 96-602 97-602 Rb R5c R9a R10b G R5e zc 94-603 95-603 96-603 97-603 Rc R9a R10b Gb zc 94-604 95-604 96-604 97-604 Ra R5a R9b R10b Gb zc 94-605 95-605 96-605 97-605 Rb RSa R9b R10b G zc 94-606 95-606 96-606 97-606 Rc R3a R9b R10b Gb zc 94-607 95-607 96-607 97-607 Ra R5b R9b R10b Gb R5b R9b R10b zc 94-608 95-608 96-608 97-608 Rb Gb zc 94-609 95-609 96-609 97-609 Rc R5b R9b R10b Gb zc 94-610 95-610 96-610 97-610 R8 R5c R9b R10b Gb Zc 94-611 95-611 96-611 97-611 Rb R5e R9b R10b Gb Zc 9b R10b 94-612 95-612 96-612 97-612 Rc R5c R Gb Zc 94-613 95-613 96-613 97-613 Ra R3a R9c R10b G Zc 94-614 95-614 96-614 97-614 Rb R5a R9c R10b Gb Zc 95-615 96-615 97-615 Rc R9c R10b 94-615 R5a Gb zc 94-616 95-616 96-616 97-616 Ra R5b R9c R10b Gb zc 94-617 95-617 96-617 97-617 Rb R5b R9c R10b Gb zc 94-618 95-618 96-618 97-618 Rc R5b R9c R10b Gb zc 94-619 95-619 96-619 97-619 Ra R5c R9c R10b Gb zc 94-620 95-620 96-620 97-620 Rb R5c R9c R10b Gb zc 94-621 95-621 96-621 97-621 Rc R3c R9c R10b G zc 94-622 95-622 96-622 97-622 Ra R5a R9a R10c G zc 94-623 95-623 96-623 97-623 Rb R5a R9a R10c Gb zc 94-624 95-624 96-624 R3a R9a R10c 97-624 Rc Gb zc 94-625 95-625 96-625 97-625 Ra R5b R9a R10c G zc 94-626 95-626 96-626 97-626 Rb R5b R9a R10e Gb zc 94-627 95-627 96-627 97-627 Rc R5b R9a R10e Gb zc 94-628 95-628 96-628 97-628 Ra R5c R9a R10e Gb zc 94-629 95-629 96-629 97-629 Rb R5c R9a R10c G zc 94-630 95-630 96-630 97-630 Rc R5c R9a R10c Gb zc 94-631 95-631 96-631 97-631 Ra R5a R9b R10e Gb zc 94-632 95-632 96-632 97-632 Rb R5a R9b RI0c Gb zc 94-633 95-633 96-633 97-633 Rc R a R9b R10c Gb zc 94-634 95-634 96-634 97-634 Ra R5b R9b R10e Gb zc 94-635 95-635 96-635 97-635 Rb R5b R9b RI0c Gb zc 94-636 95-636 96-636 97-636 Rc R5b R9b R10c Gb R5c 97-637 Ra R9b R10c zc 94-637 95-637 96-637 G zc 94-638 95-638 96-638 97-638 Rb R5c R9b R10c Gb zc 94-639 95-639 96-639 97-639 Rc R3c R9b R10c Gb zc 94-640 95-640 96-640 97-640 Ra R5a R9e R10c Gb zc 94-641 95-641 96-641 97-641 R R5a R9e R10c Gb zc 94-642 95-642 96-642 97-642 R ° R5a R9c RI0c Gb zc 94-643 95-643 96-643 97-643 Ra R3b R9c RI0c Gb zc 94-644 95-644 96-644 97-644 Rb R5b R9C R10e Gb zc 94-645 95-645 96-645 97-645 Rc R3b R9c R10c Gb zc 94-646 95-646 96-646 97-646 Ra R c R9c R10c Gb zc 94-647 95-647 96-647 97-647 Rb R5c R9e R10c Gb zc 94-648 95-648 96-648 97-648 Rc R5c R9c R10c Gb zc 94-649 95-649 96-649 97-649 Ra R5a R9a R10a Gc zc 94-650 95-650 96-650 97-650 Rb R5a R9a RJOa Gc R5a z ° 94-651 95-651 96-651 97-651 Rc R9a R10a Gc zc 94-652 95-652 R5b 96-652 97-652 Ra R9a RI0a Gc zc 94-653 95-653 96-653 97-653 Rb R3b R9a R10a Gc z ° 94-654 95-654 96-654 97-654 R ° R5b R9a RIOa Gc zc 94-655 95-655 96-655 97-655 Ra R5c R9a R10a G ° zc 94-656 95-656 96-656 97-656 Rb R5c R9a R10a Gc zc 94-657 95-657 96-657 97-657 Rc R5c R9a R10a GG Zc 94-658 95-658 96-658 97-658 Ra R5a R9b R10a Gc Zc 94-659 95-659 96-659 97-659 Rb R5a R9b R10a Gc Zc 94-660 95-660 96-660 97-660 Rc R3a R9 R10a Gc Zc 94-661 95-661 96-661 97-661 Ra R5b R9b R10a Gc Zc 94-662 95-662 96-662 97-662 Rb R? R9b R10a Gc Zc 94-663 95-663 96-663 97-663 Rc R3b R9b RI0 Gc Zc 94-664 95-664 96-664 97-664 Ra - R3c R9b R10a Gc Z ° 94-665 95-665 96-665 97-665 Rb R3c R9b R10a Gc Zc R5c 94-666 95-666 96-666 97-666 Rc R9b R10a Gc Zc 94-667 95-667 96-667 97-667 Ra R5a R9c R10a Gc Zc 94-668 95-668 96-668 97-668 Rb R3a R9c R10a Gc zc 94-669 95-669 96-669 97-669 Rc R3a R9c R10a Gc zc 94-670 95-670 96-670 97-670 Ra R5b R9c R10a Gc zc 94-671 95-671 96-671 97-671 Rb R5b R9c R10a Gc zc 94-672 95-672 96-672 97-672 Rc R5b R9c R10a Gc zc 94-673 95-673 96-673 97-673 Ra R5c R9c R10a Gc zc 94-674 95-674 96-674 97-674 Rb R5c R9C R10a Gc zc 94-675 95-675 96-675 97-675 Rc R5c R9c R10a Gc zc 94-676 95-676 96-676 97-676 Ra R3a R9a RJ0b Gc zc 94-677 95-677 96-677 97-677 Rb R5a R9a R10b Gc zc 94-678 95-678 96-678 97-678 Rc R5a R9a R10b Gc R5b R9a R10b zc 94-679 95-679 96-679 97-679 R8 Gc z ° 94-680 95-680 96-680 97-680 Rb Rs R9a R10b Gc zc 94-681 95-681 96-681 97-681 Rc R5 R9a R10b Gc R5c zc 94-682 95-682 96-682 97-682 Ra R9a R10b Gc zc 94-683 95-683 96-683 97-683 Rb R5c R9a R10b Gc zc 94-684 95-684 96-684 97-684 Rc R3c R9a R10b Gc z ° 94-685 95-685 96-685 97-685 Ra R5a R9b R10b Gc zc 94-686 95-686 96-686 97-686 Rb R5a R9b R10b Gc zc 94-687 95-687 96-687 97-687 Rc R3a R9b R10b Gc zc 94-688 95-688 96-688 97-688 Ra R3b R9b R10b Gc zc 94-689 95-689 96-689 97-689 Rb R5b R9b R10b Gc zc 94-690 95-690 96-690 97-690 Rc R3b R9 R10b Gc zc 94-691 95-691 96-691 97-691 Ra R3c R9b R10b Gc zc 94-692 95-692 96-692 97-692 Rb R3c R9b R10b Gc zc 94-693 95-693 96-693 97-693 R ° R3c R9b R10b Gc zc 94-694 95-694 96-694 97-694 Ra R3a R9c R10b G ° zc 94-695 95-695 96-695 97-695 Rb R5a R9C R10b Gc? 94-696 95-696 96-696 97-696 Rc R3a R9c R10b Gc zc 94-697 95-697 96-697 97-697 Ra R5b R9c R10b Gc R9c R10b zc 94-698 95-698 96-698 97-698 Rb R3b Gc zc 94-699 95-699 96-699 97-699 Rc R5b R9c R10b Gc zc 94-700 95-700 96-700 97-700 Ra R5c R9c R10b Gc zc 94-701 95-701 96-701 97-701 Rb R3c R9c R10b Gc zc 4-702 95-702 96-702 97-702 Rc R5c R9c RI0b G ° zc R5a 4-703 95-703 96-703 97-703 Ra R9a R.0c Gc zc 94-704 95-704 96-704 97-704 Rb R5a R9a RJ0c Gc zc 94-705 95-705 96-705 97-705 Rc R5a R a R10c Gc zc 94-706 95-706 96-706 97-706 Ra R5b R9a R10C Gc zc 94-707 95-707 96-707 97-707 Rb R5b R9a R10c Gc zc 94-708 95-708 96-708 97-708 Rc R5 R9a R10c Gc zc 94- 709 95-709 96-709 97-709 Ra R5c R9a R10c Gc zc 94-710 95-710 96-710 97-710 Rb R5c R9a R10c Gc zc 94-711 95-711 96-711 97-711 Rc R5c R9a R .0c Gc zc 94-712 95-712 96-712 97-712 Ra R3a R9b R10c Gc zc 94-713 95-713 96-713 97-713 Rb R3a R9b R10c Gc zc 94-714 95-714 96-714 97 -714 Rc R5a R9b R10c Gc zc 94-715 95-715 96-715 97-715 Ra R5b R9b R10c Gc zc 94-716 95-716 96-716 97-716 Rb R5b R9b R10c Gc zc 94-717 95-717 96-717 97 -717 Rc R5b R9b R10c Gc zc 94-718 95-718 96-718 97-718 Ra R3c R9b R10c Gc zc 94-719 95-719 96-719 97-719 R R5c R9b R10c Gc zc 94-720 95-720 96-720 97-720 R ° R5c R9b R10c Gc zc 94-721 95-721 96-721 97-721 Ra R5a R9c RI0c Gc zc 94-722 95-722 96-722 97-722 Rb R5a R9c R10c Gc zc 94 -723 95-723 96-723 97-723 Rc R5a R9c RI0c Gc zc 94-724 95-724 96-724 97-724 Ra R5b R9c R10c Gc zc 94-725 95-725 96-725 97-725 Rb R5b R9c R10C Gc zc 94-726 95-726 96-726 97-726 Rc R5b R9c R10c Gc zc 94-727 95-727 96-727 97-727 Ra R5c R9c R10c G ° zc 94-728 95-728 96-728 97 -728 Rb R5c R9c RI0c G ° zc 94-729 95-729 96-729 97-729 Rc R5c R9c R10c Gc zc where all symbols are as defined above In another aspect of formula (94), (95), (96), and (97) of the present invention, R is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R5 is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R9 and R10 independently are hydrogen, a halogen, a nitro group an amino group, an optionally mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 = ), a thio group (S =); G is (-CH2 2, (-CH2_) 3, or (-CH2.) 4 and all other symbols are as defined above in conjunction with formula (I) In another aspect of any of the formulas (94) ), (95), (96), and (97) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group , or an alkoxyalkyl group; Rs is hydrogen, or a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group, R9 and R10 independently are an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, or an acyloxy group, or an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group, and G is (-CH2_) 2, (-CH2 3, or (-CH2 4 and all s other symbols are as defined above in conjunction with formula (I). In yet another aspect of any of formulas (94), (95), (96), and (97) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group, -R5 is hydrogen, or a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R9 and R10 independently are an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulphonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or a combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent of the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and G is (-CH2_) 27 (-CH2.) 3, or (-CH2_) 4 and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of any of the formulas 94), (95), (96), and (97) of the present invention, R is hydrogen an alkyl group; I rent; R9 is hydrogen with a group R10 is hydrogen or an alkoxy group; and G (-CH2_) 2, (-CH2.) 3, or (-CH2.) 4. In yet another aspect of any of the formulas (94), (95), (96), and (97) of the present invention, R is -H or Me; R5 5 is -H or Me; R9 is -H, -OMe, or R10 is -H, -OMe, or -OEt; and G is (-CH2_) 2, (-CH2.) 3, or (-CH2.) 4. The present invention also encompasses various compounds of the general formula (IV) as follows. where all other symbols are as defined above in conjunction with formula (I). According to various aspects of the present invention, R, R1, R5, G, and Z of any of the formulas (98), (99), (100), and (101) are selected to produce compounds of the formulas ( 98-1), (99-1), (100-1), and (101-1) up to formulas (98-243), (99-243), (100-243), and (101-243) like; g-ue: Formulas R R1 3 G z Rla 98-1 99-1 100-1 101-1 Ra R5a Ga za 98-2 99-2 100-2 101-2 R Rla R5a Ga za 98-3 99-3 100-3 101-3 Rc R1a R5a Ga za 98-4 99-4 100-4 101-4 Ra RIb R5a Ga za 98-5 99-5 100-5 101-5 Rb Rlb R5a Ga Rlbza 98-6 99 -6 100-6 101-6 Rc R5a Ga za 98-7 99-7 100-7 101-7 Ra Rl c R a Ga za 98-8 99-8 100-8 101-8 Rb Rlc R5a Ga Rlc za R5p 98-9 99-9 100-9 101-9 Rc Ga za 98-10 99-10 100-10 101-10 Ra Rla R5b Ga za 98-11 99-11 100-11 101-11 Rb Rla R5b Ga za 98 -12 99-12 100-12 101-12 R ° Rla R5b Ga zp 98-13 99-13 100-13 101-13 Ra Rlb R5b Ga Rib za 98-14 99-14 100-14 101-14 Rb R5b Ga 98-15 99-15 100-15 101-15 Rc Rlb R5b Ga Rlc za 98-16 99-16 100-16 101-16 Ra R5b Ga za 98-17 99-17 100-17 101-17 Rb Rlc R5b Ga za 98-18 99-18 100-18 101-18 R ° Rlc R5b Ga za 98-19 99-19 100-19 101-19 Ra Rla R5c Ga Rla za 98-20 99-20 100-20 101-20 Rb R5c Ga za 98-21 99-21 100-21 101-21 Rc Rla R5c Ga za Rlb 98-22 99-22 100-22 101-22 Ra R5c Gtt za 98-23 99-23 100-23 101-23 Rb Rlb R5c Ga Rlb R5 98-24 99-24 100-24 101-24 Rc c Ga za Rlc 98-25 99-25 100-25 101-25 Ra R5c Ga za Rlc R5c 98-26 99-26 100-26 101-26 Rb Ga za 98-27 99-27 100-27 101-27 Rc R5c Rlc Ga za 98-28 99-28 100-28 101-28 Ra Rla R5a Gb za 98-29 99-29 100-29 101-29 Rb R, a R5a G za 98-30 99-30 100-30 101-30 Rc RIa R5a Gb za 98-31 99-31 100-31 101-31 R * R ?? Rja Guza Rb 98-32 99-32 100-32 101-32 RIb R5a Gb za 98-33 99-33 100-33 101-33 Rc Rlb R5a Gb za 98-34 99-34 100-34 101-34 Ra Rlc R5a Gb za 98-35 99-35 100-35 101-35 Rb RIc R5a Gb za 98-36 99-36 100-36 101-36 Rc Rlc R5a Gbza 98-37 99-37 100-37 101-37 Ra R1a R5fa Gbza 98-38 99-38 100-38 101-38 Rb Rla R5b Gbza 98-39 99-39 100-39 101-39 Rc Rlß R5b Gbza 98-40 99-40 100-40 101-40 Ra Rlb R5b Gbza 98-41 99-41 100-41 101-41 R Rlb R5b Gbza 98-42 99-42 100-42 101-42 Rc Rlb R5b Gbza 98-43 99-43 100-43 101-43 Ra Rlc R5b Gbza 98-44 9944 100-44 101-44 Rb Rlc R5b Gb za 98-45 99-45 100-45 101-45 Rc Rlc R5b Gbza 98-46 99-46 100-46 10146 Ra R, a R5c Gb za 98-47 99-47 100-47 101-47 Rb Rla R5c G za 98-48 99-48 10048 101-48 Rc Rla R5c Gb za 98-49 ^ 9 100-49 101-49 Ra Rlb R5c Gbza 98-50 99-50 100-50 101-50 R Rlb R5c Gbza 98-51 99-51 100-51 101-51 Rc RIb R5c Gbza 98-52 99-52 100-52 101-52 Ra Rlc R5c Gbza 98-53 99-53 100-53 101-53 Rb Rlc R5c G za 98-54 99-54 100-54 101-54 Rc Rlc R5c Gb ZB 98-55 99-55 100-55 101-55 Ra Rla R5a Gc za 98-56 99-56 100-56 101-56 Rb Rla R5a Gc za 98-57 99-57 100-57 101-57 Rc Rla R5a Gc za 98-58 99-58 100-58 101-58 Ra Rlb R5a Gc za 98-59 99-59 100-59 101-59 Rb Rl R5a Gc za 98-60 99-60 100-60 101-60 Rc Rl R5a G ° za 98-61 99-61 100-61 101-61 Ra Ric R5a Gc za 98-62 99-62 100-62 101-62 Rb Rlc R5a Gc za 98-63 99-63 100-63 101-63 Rc R] c R5a G ° za 98-64 99-64 100-64 101-64 Ra Rla R5b Gc za 98-65 99-65 100-65 101-65 Rb Rla R5b Gc za 98-66 99-66 100-66 101-66 R ° Rla R5b Gc za 98-67 99-67 100-67 101-67 Ra RIb R5b Gc za 98-68 99-68 100-68 101-68 98-69 99-69 100-69 101-69 98-70 99-70 100-70 101-70 98-71 99-71 100-71 101-71 98-72 99-72 100-72 101-72 98-73 99-73 100-73 101-73 98-74 99-74 100-74 101- 74 98-75 99-75 100-75 101-75 98-76 99-76 100-76 101-76 98-77 99-77 100-77 101-77 98-78 99-78 100-78 101-78 98 -79 99-79 100-79 101-79 98-80 99-80 100-80 101-80 98-81 99-81 100-81 101-81 98-82 99-82 100-82 101-82 98-83 99-83 100-83 101-83 98-84 99-84 100-84 101-84 98-85 99-85 100-85 101-85 98-86 99-86 100-86 101-86 98-87 99- 87 100-87 101-87 .98-88 99-88 100-88 101-88 98-89 99-89 100-89 101-89 98-90 99-90 100-90 101-90 Rc R: R3a Ga 98-91 99-91 100-91 101-91 Ra Rla R5b zb Ga 98-92 99-92 100-92 101-92 Rb Rla R5b zb Ga 98-93 99-93 100-93 101-93 Rc Rla R5b zb Ga z 98-94 99-94 100-94 101-94 Ra Rlb R3b Ga 98-95 99-95 100-95 101-95 Rb RIb R5b zb Ga zb 98-96 99-96 100-96 101-96 Rc Rlb R * Ga 98-97 99-97 100-97 101-97 Ra Rlc R5b zb Ga z 98-98 99-98 100-98 101-98 Rb R R5 Ga z 98-99 99-99 100-99 101-99 Rc "R R5b Ga 8-100 99-100 100-100 101-100 Ra R 8-101 99-101 100-101 101-101 Rb R 8-102 99- 102 100-102 101-102 Rc R 8-103 99-103 100-103 101-103 Ra R 8-104 99-104 100-104 101-104 Rb R 8-105 99-105 100-105 101-105 Rc R 8-106 99-106 100-106 101-106 Ra 8-107 99-107 100-107 101-107 RR 8-108 99-108 100-108 101-108 Rc 8-109 99-109 100-109 101 -109 Ra Rh 8-110 99-110 100-110 101-110 Rb R 8-111 99-111 100-111 101-111 Rc R 8-112 99-112 100-112 101-112 Ra R 8-113 99 -113 100-113 101-113 Rb R 8-114 99-114 100-114 101-114 Rc R 98-115 99-115 100-115 101-115 Ra R1c 98-116 99-116 100-116 101-116 Rb Rle 98-117 99-117 100-117 101-117 Rc Rle 98-118 99-118 100-118 101-118 Ra Rla 98-119 99-119 100-119 101-119 Rb Rla 98-120 99-120 100-120 101-120 Rc Rla 98-121 99-121 100-121 101-121 Ra R1Ib 98-122 99-122 100-122 101-122 Rb RIb 98-123 99-123 100-123 101-123 Rc RIb R 5b Gb 98-124 99-124 100-124 101-124 98-125 99-125 100-125 101-125 98-126 99-126 100-126 101-126 98-127 99-127 100-127 101-127 98- 128 99-128 100-128 101-128 98-129 99-129 100-129 101-129 98-130 99-130 100-130 101-130 98-131 99-131 100-131 101-131 98-132 99 -132 100-132 101-132 98-133 99-133 100-133 101-133 98-134 99-134 100-134 101-134 98-135 99-135 100-135 101-135 98-136 99-136 100-136 101-136 98-137 99-137 100-137 101-137 98-138 99-138 100-138 101-138 98-139 99-139 100-139 101-139 98-140 99-140 100- 140 101-140 98-141 99-141 100-141 101-141 98-142 99-142 100-142 101-142 98-143 99-143 100-143 101-143 98-144 99-144 100-144 101 -144 98-145 99-145 100-145 101-145 98-146 99-146 100-146 101-146 98-147 99-147 100-147 101-147 98-148 99-148 100-148 101-148 98-149 99-149 100-149 101-149 98-150 99-150 100-150 101-150 98-151 99-151 100-151 101-151 98-152 99-152 100-152 101-152 98- 153 99-153 100-153 101-153 98-154 99-154 100-154 101-154 98-155 99-155 100-155 101-155 98-156 9 9-156 100-156 101-156 98-157 99-157 100-157 101-157 98-158 99-158 100-158 101-158 98-159 99-159 100-159 101-159 98-160 99- 160 100-160 101-160 8-161 99-161 100-161 101-161 98-162 99-162 100-162 101-162 Rc Rl = R5c Gc z 98-163 99-163 100-163 101-163 Ra Rla R5a Ga Rla zc 98-164 99-164 100-164 101-164 Rb R5a Ga zc 98-165 99-165 100-165 101-165 Rc RIa R5a Ga zc 98-166 99-166 100-166 101-166 Ra Rlb R5a Ga zc 98-167 99-167 100-167 101-167 Rb Rlb R3a Ga zc 98-168 99-168 100-168 101-168 Rc Rlb R5a Ga zc 98-169 99-169 100-169 101-169 Ra Rlc R5a Ga zc 98-170 99-170 100-170 101-170 Rb Rlc R3a Ga zc 98-171 99-171 100-171 101-171 Rc Rlc R5a Ga z ° 98-172 99-172 100-172 101-172 Ra Rla R5b Ga zc 98-173 99-173 100-173 101-173 R Rla R5b Ga zc 98-174 99-174 100-174 101-174 Rc Rla R5b Ga zc 98-175 99-175 100-175 101-175 Ra RIb R5b Ga zc 98-176 99-176 100-176 101-176 R Rlb R5b Ga zc 98-177 99-177 100-177 101-177 Rc Rlb R3b Ga zc 98-178 99-178 100-178 101-178 Ra RIc R5b Ga zc 98-179 99-179 100-179 101-179 Rb RIc R5b Ga zc 98-180 99-180 100-180 101-180 Rc Rlc R5b Ga zc 98-181 99-181 100-181 101-181 Ra Rla R5c Ga zc 98-182 99-182 100-182 101-182 R RIa R5c Ga zc 98-183 99-183 100-183 101-183 Rc Rla R5c Ga zc 98-184 99-184 100-184 101-184 Ra Rlb R5c Ga zc 98-185 99-185 100-185 101-185 Rb R! R5c Ga zc 98-186 99-186 100-186 101-186 Rc Rlb R5c Ga zc 98-187 99-187 100-187 101-187 Ra Rlc R3c Ga zc 98-188 99-188 100-188 101-188 Rb Rlc R5c Ga zc 98-189 99-189 100-189 101-189 Rc Rlc R5e Ga zc 98-190 99-190 100-190 101-190 Ra Rla R5a Gb 98-191 99-191 100-191 101-191 R Rla RSa G zc 98-192 99-192 100-192 101-192 Rc RIa RSa Gb zc 98-193 99-193 100-193 101-193 Ra Rlb R5a Gb zc 98-194 99-194 100-194 101-194 Rb RI R5a Gb zc 98-195 99-195 100-195 101-195 Rc Rlb R5a Gb zc 98-196 99-196 100-196 101-196 Ra Rlc R5a Gb zc 98-197 99-197 100-197 101-197 Rb Rlc R3a Gb zc 98-198 99-198 100-198 101-198 R ° Rlc R5a Gb zc 98-199 99-199 100-199 101-199 Ra Ria R3b Gb zc 98-200 99-200 100-200 101-200 Rb RIa Ra Gb zc 98-201 99-201 100-201 101-201 Rc R] a R3b Gb ze 98-202 99-202 100-202 101-202 Ra Rlb R? Gb zc 98-203 99-203 100-203 101-203 R R1b R5b G zc 98-204 99-204 100-204 101-204 Rc RJb R5b Gb zc 98-205 99-205 100-205 101-205 Ra Rlc R5b Gb zc 98-206 99-206 100-206 101-206 R Rlc RSb Gb 98-207 99-207 100-207 101-207 Rc Rlc R5b Gb zc 98-208 99-208 100-208 101-208 Ra RIa RSc G zc 98-209 99-209 100-209 101-209 Rb 98-210 99-210 100-210 101-210 Rc 98-211 99-211 100 -211 101-211 Ra 98-212 99-212 100-212 101-212 R 98-213 99-213 100-213 101-213 Rc 98-214 99-214 100-214 101-214 Ra 98-215 99- 215 100-215 101-215 R 98-216 99-216 100-216 101-216 Rc 98-217 99-217 100-217 101-217 Ra Rla R 5a Gc zc 98-218 99-218 100-21 S 101 -218 Rb 98-219 99-219 100-219 101-219 Rc '98-220 99-220 100-220 101-220 Ra 98-221 99-221 100-221 101-221 Rb 98-222 99-222 100 -222 101-222 Rc Rlb R 5a Gc zc 98-223 99-223 100-223 101-223 Ra Rle R 5a Gc zc 98-224 99-224 100-224 101-224 R Rle R 5a Gc zc 98-225 99-225 100-225 101-225 Rc Rle R 5a Gc zc 98-226 99-226 100- 226 101-226 Ra Rla R 5b G ° zc 98-227 99-227 100-227. 101-227 Rb Rla R5b G ° zc 98-228 99-228 100-228 '101-228 Rc Rla R5b Gc zc 98-229 99-229 100-229 101-229 Ra Rlb R5b Gc zc 98-230 99-230 100-230 101-230 Rb RIb R 5b Gc zc 98-231 99-231 100-231 101-231 R ° RIb R 5b Gc zc 98-232 99-232 100-232 101-232 Ra Rle R 5b Gc zc 98 -233 99-233 100-233 101-233 Rb Rle R 5b Gc zc 98-234 99-234 100-234 101-234 Rc Rc Gc zc 98-235 99-235 100-235 101-235 Ra Rla R 5b Gc zc 98-236 99-236 100-236 101-236 Rb Rla R5c Gc zc 98-237 99-237 100-237 101-237 Rc Rla R 5c Gc zc 98-238 99-238 100-238 101-238 Ra RIb R 5c R Gc zc 98-239 99-239 100-239 101-239 R RIb R Gc zc 98-240 99-240 100-240 101-240 Rc Rlb R 5c Gc 1c zc 98-241 99-241 100-241 101-241 Ra R Gc zc 98-242 99-242 100-242 101-242 R Rle R lo R Gc zc 98-243 99-243 100-243 101-243 Rc RR 5c Gc zc where all the other symbols are as defined above. In another aspect of any of the formulas (98), (99), (100), and (101) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group an optionally substituted amino group, an alkyl group, an alkoxy group, a alkenyl group, or an alkoxyalkyl group; R1 is hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group; a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R5 is hydrogen, or a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group; a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; all other symbols are as defined above in conjunction with formula (I). In another aspect of any of the formulas (98), (99), (100), and (101) of the present invention, G is - (- CH2) S. where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I). In another aspect of any of the formulas (98), (99), (100), and (101) of the present invention, G is - (- CH2) S.

CH = CH- (CH2) s_, where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I).

In another aspect of any of the formulas (98), (99), (100), and (101) of the present invention, G is - (- CH2) S.

C = C- (CH2) S_, where s is an integer of 0-5; and all other symbols are as defined above in conjunction with formula (I). In another aspect of any of formulas (98), (99), (100), and (101) of the present invention, Z is O, and all other symbols are as defined above in conjunction with the formula (I ). In another aspect of any of the formulas (98), (99), (100), and (101) of the present invention, Z is NR, and all other symbols are as defined above in conjunction with the formula (I) ). In another aspect of any of formulas (98), (99), (100), and (101) of the present invention, Z is (- (- CH2.) U or S (= 0) u, where u is an integer of 0-2, and all other symbols are as defined above in conjunction with formula (I) In yet another aspect of any of the formulas (98), (99), (100), and ( 101) the present invention E is O, and all other symbols are as defined above in conjunction with formula (I) In yet another aspect of any of the formulas (98), (99), (100), and (101) the present invention E is S, and all other symbols are as defined above in conjunction with formula (I). In yet another aspect of any of the formulas (98), (99), (100), and (101) the present invention E is NR, and all other symbols are as defined above in conjunction with the formula (I) . Examples of the compounds having the formula in general (IV) include, but are not limited to: According to another aspect of the present invention, various compounds of the formula are provided in general (I) having the following general formula (V) its tautomeric forms, its stereoisomers, polymorph substances, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates. Except as otherwise provided herein, all symbols are as defined above in conjunction with formula (I). Examples of compounds having the general formula (V) contemplated by the present invention include, without limitation, (107); (114); (121); (128); where all the other symbols are as defined above in conjunction with the formula (I). The present invention contemplates several compounds of the general formula (V) having the formula: wherein R 11, R 12, R 13 and R 14 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, a group acyloxy, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxy group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a a substituted morpholinyl, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are defined as above in conjunction with formula (I). In one aspect of formula (141) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group; and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; and all other symbols are as defined in conjunction with formula (I). In another aspect of the formula (141) of the present invention, R1 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a group cycloalkyl, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R 2 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a group cycloalkyl, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R11 is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a group carboxy, a cyano group, an oxo group (0 =), a thio group (S =); and all other symbols are as defined in conjunction with formula (I). In yet another aspect of the formula (141) of the present invention, R11 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R 12 is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a group carboxy, a cyano group, an oxo group (0 =), a thio group (S =); and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R12 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an aryisulfonyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in conjunction with formula (I). In a further aspect of the formula (141) of the present invention, R 13 is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a group carboxy, a cyano group, an oxo group (0 =), a thio group (S =); and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R13 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxy group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R14 is hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, , a cyano group, an oxo group (0 =), a thio group (S =); and all the other symbols are as defined in conjunction with the formula (I) - In yet another aspect of formula (141) of the present invention, R 14 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclylsulfonyl group, which is optionally substituted with a halogen, a hydroxy group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocycle group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R is hydrogen or an alkyl group, and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R is -H, CH3, or C2HS, and all other symbols are as defined in conjunction with formula (I). In still another aspect of formula (141) of the present invention, R1 is hydrogen or an alkyl group, and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R1 is -H, CH3, or C2HS, and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R 2 is hydrogen or an alkyl group, and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R2 is -H, CH3, or C2HS, and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R11 is hydrogen, a halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in conjunction with formula (I) - In another aspect of formula (141) of the present invention, R11 is -H, -Cl, -OCH3, or -SCH3, and all other symbols are as defined in conjunction with formula (I). In a further aspect of formula (141) of the present invention, R 12 is hydrogen, a halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in conjunction with formula (I). In a different aspect of formula (141) of the present invention, R12 is H, Cl, -OCH3, or -SCH3, and all other symbols are as defined in conjunction with formula (I). In a further aspect of formula (141) of the present invention, R13 is hydrogen, a halogen, or an alkyl group, and all other symbols are as defined in conjunction with the formula (I) In yet a further aspect of formula (141) of the present invention, R 13 is -H, -F, or CH 3, and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R14 is hydrogen, a halogen, or an alkyl group, and all other symbols are as defined in conjunction with formula (1). In a further aspect of formula (141) of the present invention, R 14 is -H, -F, or -CH 3, and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R1 and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R11; R12; R13, and R14 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group ( =), a thio group (S =), an alkyl group, or a cycloalkyl group, an alkoxy group; and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (141) of the present invention, R1 and R2 independently are hydrogen, a hydroxy group, a halogen, an alkoxy group; R11, R12_R13, and R14 independently are hydrogen, a halogen, a hydroxy group, an alkoxy group; and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (141) of the present invention, R1 and R2 independently are -H or -OCH3; R11 is -Cl, -OCH3, or -SCH3; R12 is -Cl, -OCH3, or -H; R es - H, CH3, or C2HS; R13 is F or CH3; R14 is F or CH3; v is 0 or 1; and all other symbols are as defined in conjunction with formula (I). The present invention also contemplates various compounds of the general formula (V) as follows: where all the other symbols are as defined in conjunction with the formula (I). According to various aspects of the present invention, R, R1, and R2 of the formula (142) to produce various compounds of the formula (142-1) up to the formula (142-27) as follows: Formula R RJ R¿ 142-1 Ra Rla R2a 142-2 R Rla R2a 142-3 Rc Rla R2a 142-4 Ra Rlb R2a 142-5 Rb Rlb R2a 142-6 Rc Rlb R2a 142-7 Ra Rlc R2a 142-8 Rb Rlc R2a 142-9 Rc R, c R2a 142-10 Ra Rla R2b 142-11 Rb Rla R2b 142-12 Rc Rla R2b 142-13 Ra Rlb R2b 142-14 Rb RIb R2b 142-15 Rc Rlb R2b 142-16 Ra Rlc R2 142-17 Rb Rlc R2b 142-18 Rc Rlc R2b 142-19 Ra Rla R2c 142-20 R Rla R2c 142-21 Rc Rla R2c 142-22 Ra R1b R2c 142-23 R Rjb R2c 142-24 Rc R ] b R2o 142-25 Ra Rlc R2c 142-26 Rb Rlc R2c 142-27 Rc Rlc R2 ° where .all the symbols are as defined above. In one aspect of formula (142) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; and R1 and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, a alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group. In another aspect of formula (142) of the present invention, R1 and R2 are independently a halogen or an alkyl group; and R is hydrogen, an alkyl group - + _NQ "or -K In yet another aspect of formula (142) of the present invention, R1 is -OCH-, or -F; R2 is -OCH3 O -Cl; R is - - \% \ -NO, H or C2H2-K] The present invention also contemplates several compounds of the general formula (V) as follows: where all the symbols are as defined above in conjunction with the formula (I). In one aspect of formula (143) of the present invention, R1 and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R13 and R14 are independently hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 = ), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; and all other symbols are as defined in conjunction with formula (I). In another aspect of the formula (143) of the present invention, R1 and R2 independently are an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group; a heterocyclyl group, a heteroaryl group, a hetero-alkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group; R13 and R14 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 = ), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (143) of the present invention, R1 and R2 independently are hydrogen, an alkyl group, or an alkoxy group; R13 and R14 independently are hydrogen, a halogen, an alkyl group, or an alkoxy group; and all other symbols are as defined in conjunction with formula (I). In still another aspect of formula (143) of the present invention, R1 and R2 are -H or -OCH3; R13 is CH3 or -F; R14 is -H or -F; and all other symbols are as defined in conjunction with formula (I). The present invention also contemplates various compounds of the general formula (V) having the formula: wherein all the symbols are as defined above in conjunction with the formula (I). According to various aspects of the present invention, R, R1, R2, v, and p of the formula (144) are selected to produce various compounds of the formula (144-1) through (144-243) as follows: 144-126 Rc Rlc R2b vb pb 144-127 Ra Rla R2c vb pb 144-128 R Rla R2c v pb 144-129 Rc Rla R2c vb pb 144-130 Ra Rlb R2c vb pb 144-131 Rb Rl R2c vb pb 144-132 Rc Rib R2c vb pb 144-133 Ra RIc R2c vb pb 144-134 Rb Rlc R2c vb pb 144-135 Rc Rlc R2c vb pb 144-136 Ra Ria R2a vc pb 144-137 Rb Ria R2a vc pb 144-138 R ° Rla R2a vc p 144-139 Ra Rl R2a vc pb 144-140 Rb Rl R2a vc pb 144-141 Rc Rlb R2a vc pb 144-142 Ra Rlc R2a vc pb 144-143 Rb Rlc R2a see p 144-144 Rc Rlc R2a vc pb 144-145 Ra Rla R2 vc pb 144-146 Rb Rla R2b vc pb 144-147 Rc R, a R2b vc pb 144-148 Ra Rl R2b vc pb 144-149 Rb RIb R2b vc pb 144-150 Rc RIb R2b vc p 144-151 Ra Rlc R2b vc pb 144-152 Rb Ric R2b vc pb 144-153 Rc RIc R2b vc pb 144-154 Ra RIa R2c vc pb 144-155 Rb Rla R2c vc pb 144-156 Rc Rla R2c vc pb 144-157 Ra Rlb R2c vc pb 144-158 Rb Rlb R2c vc p 144-159 Rc Rlb R2c vc pb 144-160 Ra Rlc R2c vc pb 144-161 Rb R1c R2c v ° pb 144-162 Rc R, c R2c vc pb 144-163 Ra Rla R2a Va pc 144-164 Rb Rla R2a Va pc 144-165 Rc Rla R2a Va pc 144-166 Ra Rlb R a va pc 144-167 Rb Rlb R2a goes pc 144-168 Rc Rlb R2a goes pc 144-169 R3 Rlc R2a goes pc 144-170 Rb Rlc R2a goes pc 144-171 Rc Rlc R2a goes p ° 44-172 Ra Rla R2b goes pc where all the symbols are as defined above. In one aspect of formula (144) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or a alkoxyalkyl group; R1 and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, a group alkenyl, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in conjunction with formula (I). In another aspect of formula (144) of the present invention, R1 and R2 are independently hydrogen, an alkyl group, or an alkoxy group; and all other symbols are as defined in conjunction with formula (I). In yet another aspect of formula (144) of the present invention, R1 and R2 are -OCH3; and all other symbols are as defined in conjunction with formula (I). The present invention also contemplates vartios compounds of the general formula (V) having the formula: where all the symbols are as defined above in conjunction with the formula (I). According to various aspects of the present invention, R, R1, R2, R11, and R12 of the formula (145) are selected to provide compounds of the formula (145-1) up to formula (145-243) as follows: Formula R R1 R2 R "Rl2 145-1 Ra Rla R2a R "'Ri2a 145-2 Rb Rla R2a RIla R12a 145-3 Rc Rla R2a RUa R, 2a 145-4 Ra Rlb R2a Rlla R! 2a 145-5 Rb RIb R2a RUa R12a 145-6 Rc Rlb R2a Rn. R12a 145-7 Ra R, c R2a Rlla R12a 145-8 Rb Rlc R2a Rlla R12a 145-9 R ° Rlc R2a RUa RI2a 145-10 Ra Rla R2b RJl R12a 145-11 R Rla R2b RHa R12a 145-12 Rc Rla R2b Rpa R12a 145-13 Ra Rlb R2b Rlla R12a 145-14 Rb Rlb R2b Rlla R12a 145-15 Rc Rlb R2b R11a RJ2a 145-16 Ra Rlc R2b Rna R12a 145-17 Rb Rlo R2b Rl the R12a 145-18"Rc Rlo R2b Rlla R12a 145-19 Ra Rla R2c Rlla RI2a 145-20 Rb Rla R2c Rlla R12a 145-21 Rc Rla R2o Rna R12a 145-22 Ra Rlb R2c Rlla R12a 145-23 Rb Rlb R2c Rlla R12a 145-24 Rc Rlb R20 Rlla R12a 145-25 Ra RIC R2c R1, to R12a 145-26 Rb RJC R20 Rlla R12a 145-27 Rc Rlc R2e Rlla R) 2a 145-28 Ra RJa R2a Rllb RI2a 145-29 Rb Rla R2a Rllb R12a 145-30 Rc Rla R2a Rpb R12a 145-31 Ra Rlb R2o Rllb R12a 145-32 Rb RJb R2a R. lb R12a 145-33 Rc R, b R2a RUb R12a 145-34 Ra RIc R2a RJ lb R12a 145-35 R Rlc R2a Rllb R12a 145-36 Rc Rlc R2a Rl lb R12a 145-37 Ra Rla R2b Rllb R12a 145-38 Rb Rla R2b Rllb R12a 145-39 Rc Rla R2b Rnb R12a 145-40 Ra Rlb R b RI lb R12a lb R12a 145-41 Rb Rlb R2b Rlb 145-42 Rc RIb R2b Rll R12a 145-43 Ra Rl c R2b Rl lb R12a 145-44 Rb Rlc R2b Rl lb R12a 145-45 Rc R] c R2b Rl lb R12a 145-46 Ra Rla R2c Rl lb RI2a 145-47 R Rla R2c RI lb R12a 145-48 Rc Rla R2c Ri lb Rl2a 145-49 Ra Rlb RZc Rl lb R1 to Rl lb R12a 145-50 R Rlb R2c 145-51 Rc Rlb R2c Rl lb R12a 145-52 Ra Rlc R2c Rl lb R12a 145-53 Rb Rlc R2c R "b R123 145-54 Rc Rlc R20 Rnb R12a 145-55 Ra RIa R2a Rllc RI2a 145-56 Rb Rla R2a Rpc R12a R2a Rl ic R12a 145-57 Rc R 145-58 Ra R1b R2a Rllc R12a 145-59 R Rlb Rllc R2a R12a R1 a 145-60 Rc R] R2a R1, c 145-61 Ra Rlc R2a Rpc Rí2a 145-62 Rb Rlc R2a Rpc R12a 145-63 Rc Rlc R2a Rllc R12a 145-64 Ra Rla R2b Rllo R12a 145-65 Rb Rla R2b Rlle R12a 145-66 Rc Rla R2b Rllc R12a 145-67 Ra Rlb R2b Rn ° R12a 145-68 Rb R1b R2b Rllc RI2a 145-69 Rc Rlb R2b R13c R12a 145-70 Ra Rlc R2b Rllc Rl2a Rlle 145-71 Rb Rlc R2b R12a RI2a 145-72 Rc Rlc R2b Rllc 145-73 Ra Rla R2c Rl lc R12 2c 145-215 Rb RIc R Rt! B R12c 145-216 R ° Rcc R2c Rllb R12c 145-217 Ra Rla R2a R11c RI2c 145-218 Rb Rla R2a Rllc RI2e 145-219 Rc Rla R2a Rl lc RI2c 145-220 Ra RIb R2a RIIc RI2c 145-221 Rb Rlb R2a Rllc R12c 145-222 Rc Rjb R2a Rl lc R12e 145-223 Ra Rlc R2a Rlle R12c 145-224 b Rlc R a Rl lc R12c 145-225 Rc Rlc R2a RIlc R12c 145-226 Ra Rla R2b RIlc R12c 145-227 Rb Rla Rb Rl lc R, 2c 145-228 Rc Rla R2b Rllc R12e 145-229 Ra Rlb R2b Rllc R12c 145-230 Rb Rib R2b Rllc R12c 145-231 Rc Rib R2b RI lc RI2c 145- 232 Ra Rlc R2b Rllc R12c 145-233 Rb Rlc R2b R "c R12e 145-234 Rc Rlc R2b Rlle R12c 145-235 Ra R, a R2c RHc R12c 145-236 Rb RIa R2c Rllc R12c 145-237 Rc RJa R2c Rpc R12c 145-238 Ra Rlb R2c Rllc R12c 145-239 R Rlb R2c Rlle R12c 145-240 Rc Rlb R2c Rlle R12c 145-241 Ra Rlc R2c R ,, c RI2c 145-242 Rb Rlc R2c RUc R12c 145-243 Rc Rlc R2c Rll «R12c where all the symbols are as defined above. In one aspect of formula (145) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or a group alkoxyalkyl; R1 and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, a group alkenyl, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and R11 and R12 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group ( =), a thio group (S =), an alkyl group, or a cycloalkyl group, an alkoxy group. In another aspect of formula (145) of the present invention, R is hydrogen or an alkyl group; R1 and R2 independently are hydrogen, a hydroxy group, a halogen, an alkoxy group; and R11 and R12 independently are hydrogen, a halogen, a hydroxy group, or an alkoxy group. In yet another aspect of formula (145) of the present invention, R is -H or C2H5; R1 and R2 are -OCH3; and R11 and R12 independently are -H, -F, or CH3. The present invention also contemplates further compounds of the general formula (V) having the formula: wherein R is as defined above in conjunction with the formula (I). In one aspect of formula (146) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group. In another aspect of formula (146) of the present invention, R is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group. In yet another aspect of formula (146) of the present invention, R is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group. In yet another aspect of formula (146) of the present invention, R is -H or an alkyl group. In yet another aspect of formula (146) of the present invention, R is -H or C2H5. Additional examples of the compounds having the general formula (V) include, without limitation: It is contemplated that any compound shown or described herein, including the compounds of the various formulas shown or described above, may be provided as a pharmaceutically acceptable salt. The pharmaceutically acceptable salts that form part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N, N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethanol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine , purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, inaglumine, ethylenediamine, N, N'-diphenylethylenediamine, N, N'-dibenzylethylenediamine, N-benzylphenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine , dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, or spermidine; chiral bases such as alkylphenylamine, glycinol, or phenyl glycinol; salts of natural acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; non-natural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl; Ammonium salts or substituted ammonium salts and aluminum salts. The salts may include acid addition salts where it is appropriate to be sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates. The pharmaceutically acceptable solvates can be hydrates or can comprise other crystallization solvents such as alcohols. Processes for preparing the compounds The compounds of the present invention can be repaired according to the following processes. However, it should be understood that other processes having other process conditions can be used to form the compounds of the present invention. Process 1 According to one aspect of the present invention, there is provided a process for preparing a compound of the general formula II) wherein R1 is attached to B; R2 is attached to J; R3 is -H; A, B, D and J are independently -CH; R1 and R2 independently are an alkoxy group or an aralkoxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group in the third and / or fourth position respectively; X and E are each O, G is - (CH2) S_, - (CH2) S-CH = CH- (CH2) S_, or - (CH2) S-CH = CH- (CH2) S_, where s is an integer of 0-5; F is O, S or -NR; Y and Z independently are O, -NR, (-CH2-) n, or S (= 0) n, where n is an integer of 0-2; Y1 and Y2 independently are 0 or S; R and R5 independently are hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, an acyl group, a group aryl, an aralkyl group, a heterocyclyl group or a heteroaryl group; and "Ar" is an optionally substituted group or an optionally substituted naphthyl group. The process comprises first renting the Rutin hydrate of the formula (lia). where "Ruth" is routine; R1 is attached to B; R2 is attached to J; R3 is H; A, B, D and J independently are -CH, R1 and R2 independently are a hydroxy group; R 4 is a phenyl group optionally substituted with a hydroxy group in the third and / or fourth positions; X, Y, and E are O; and "" is an optional chemical bond; to a compound of the formula (lia), wherein R1 is attached to B; R2 is attached to J; R3 is H; A, B, D and J independently are -CH; R1 and R2 independently are an alkoxy group or an aryloxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group in the third and fourth positions; X, Y, and E are O; and all these symbols are as defined above. The alkylation is carried out using an alkyl halide alkylation or aralkylating agent. Examples of agents that may be suitable include Mel, EtI, EtBr, n-PrI, n-PrBr, i-PrBr, i-PrI, n-BuCI, or s-BuBr; a dialkylsulfate such as dimethisulfate or diethylsulfate, an aralkyl halide such as benzyl halide. The reaction can be carried out in the presence of an alkali, for example, sodium hydride (NaH), potassium hydride (KH), potassium tert-butoxide (t-BuOK), potassium acetate (KOAc), acetate sodium (NaOAc), n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi), tert-butyllithium (t-BuLi), lithium-diisopropyl-amide (LDA), sodium carbonate ( Na2C03), potassium carbonate (K2C03), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHC03), sodium hydroxide (NaOH), potassium hydroxide (KOH), or any mixture thereof. The solvent used is, for example, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexametaphosphoric acid (HMPA), 1,4-dioxane, acetone, dimethyl ether, diethyl ether, tetrahydrofuran (THF), or any mixture thereof. According to one aspect of the invention, the reaction temperature can be from about -30 ° C to about 250 ° C, for example from about 30 ° C to about 100 ° C. The duration of the reaction may be from about 0.5 hours to about 100 hours, for example, from about 20 hours to about 80 hours. The reaction can be carried out under an inert atmosphere of, for example, nitrogen (N2) argon (Ar) or helium (He). Then, the compound of the formula (lia) is hydrolyzed to a compound of the formula (Ilb). where R1 is attached to B; R2 is attached to J; R3 is H; A, B, D and J are independently -CH; R1 and R2 independently are an alkoxy group or an aralkoxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group in the third and fourth positions; X, Y, and? they are O; and all these symbols are as defined above. The hydrolysis is optionally carried out using an inorganic acid, such as hydrochloric acid (CH1), sulfuric acid (H2SO4) or a mixture thereof with water. The reaction temperature can be maintained from about -30 ° C to about 250 ° C, for example, from about 50 ° C to about 150 ° C. The duration of the reaction may be from about 0.5 hours to about 100 hours, for example, from about 1 hour to about 50 hours. Then the compound of the formula (Ilb) is reacted with a compound of the formula (lie), where "Hal" is a halogen; "Ar ', G, Z and Rs are as defined above, and" "is an optional chemical bond, to obtain a compound of the formula (lid) where R1 is attached to B; R2 is attached to J; R3 is H; A, B, D, and J are independently -CH; R1 and R2 independently are an alkoxy group or an aralkoxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group in the third and fourth positions; and all other symbols are as defined above. This reaction is carried out in the presence of a base eg NaH, KH, KOtBu, KOAc, NaOAc, NaOEt, KOEt, n-BuLi, S-BuLi, t-BuLi, LDA, Na2C03, K2C03, NaHCO3, KHC03 , NaOH, or KOH. The reaction is optionally carried out in the presence of a solvent, for example, DMF, DMSO, HMPA, 1,4-dioxane, acetone, dimethyl ether, diethyl ether, THF, or any mixture thereof. The reaction temperature can be maintained from about -30 ° C to 150 ° C, for example, from about 30 ° C to about 100 ° C. The duration of the reaction can be from about 1 hour to about 50 hours, for example, from about 2 hours to about 25 hours. The reaction can be carried out under an inert atmosphere of N2, Ar, or He. Finally, the compound of the formula (lid) is condensed with a compound of the formula (lie), where F, Y1, and Y2 are as defined above, to obtain a compound of the formula (II) where all the symbols are as defined above. The condensation can be carried out using a base, for example, Et3N, diethylamine, diisopropylethylamine, diisopropylamine, DBU, piperidine, or any mixture thereof. The reaction can be carried out in the presence of an acid, for example, benzoic acid, formic acid, acetic acid, or any mixture thereof. The reaction can be carried out in the presence of a solvent, for example, benzene, toluene, xylene, ethanol, i-propanol, bitanol, DMF, DMSO, 1,4-dioxane, or any mixture thereof. The mixture can be maintained at a temperature of from about 30 ° C to about 300 ° C, for example, from about 50 ° C to about 200 ° C. The duration of the reaction can be from about 10 hours to about 150 hours, for example, from about 20 hours to about 80 hours. The reaction can be carried out under an inert atmosphere of N2, Ar, or He.

Process 2 According to another aspect of the present invention, there is provided a process for treating a compound of formula (II). All symbols are as defined above, except that X and E are O.

First, a compound of the formula (Ilf) where X and E are O; and all the other symbols are as defined above, acylate to compound of the formula (ng) The acylation can be carried out by using an acylating agent such as, for example, acetic anhydride. The reaction is carried out optionally in the presence of a base such as for example Na 2 CO 3, K2C03, NaHCO3, KHC03, NaOH, KOH, or any mixture thereof. The reaction can be maintained at a temperature of from about -30 ° C to about 150 ° C, for example, from about 10 ° C to about 50 ° C. The duration of the reaction may be from about 10 minutes to about 5 hours, for example, from about 20 minutes to about 2 hours. The compound of the formula (Ilg) then it is rearranged to the compound of the formula (Ilh) where X and E are O; and all other symbols are as defined above. This reaction is optionally carried out in the presence of a solvent, for example, DCM, CHC13, 1,2-dichloroethane, carbon tetrachloride, carbon disulfide, nitrobenzene, 1,2-dichlorobenzene, or any mixture thereof. The reaction can be carried out in the presence of a Lewis acid, such as aluminum chloride (A1C13), zinc chloride (ZnCl2), or tin chloride (SnCl4), or in the presence of UV light. The reaction temperature can be maintained from about 50 ° C to about 300 ° C, for example, from about 80 ° C to about 200 ° C. The duration of the reaction may be from about 10 minutes to about 50 hours, for example, from about 20 minutes to about 10 hours. The reaction can be carried out under anhydrous reaction conditions. The compound of the formula (Ilh) is then condensed to a compound of the formula (Ili) where X and E represent O and all other symbols are as defined above. The reaction is carried out in the presence of a base, for example, Na 2 CO 3, K 2 CO 3, NaHCO 3, KHCO 3, NaOH, KOH, or any mixture thereof. The reaction temperature can be maintained from about 30 ° C to about 50 ° C, for example, from about 0 ° C to about 20 ° C. The duration of the reaction can be from about 2 hours to about 50 hours, for example, from about 5 hours to about 20 hours. The compound of the formula (Ili) is then subjected to a cyclization reaction? to form a compound of the formula (Ilb) where all the symbols are as defined above. This reaction is carried out using a base, for example, Na 2 CO 3, K 2 CO 3, NaHCO 3, KHCO 3, NaOH, KOH, or any mixture thereof. The reaction temperature can be maintained from about -30 ° C to about 50 ° C, for example, from about -5 ° C to about 30 ° C. The duration of the reaction may be from about 0.5 hours to about 10 hours, for example, from about 0.2 hours to about 5 hours. The compound of the formula (Ilb) is then reacted with a compound of the formula (lie) where "Hal" is a halogen; and all the other symbols are as defined above, to obtain a compound of the formula (lid) where all the symbols are as defined above. The compound of the formula (lid) is then reacted with a compound of the formula (lie) where F is O, S, or -NR; Y1 and Y2 independently are O or S, to obtain a compound of the formula (II) where E and X are O; and all other symbols are as defined above. The conversion of the compound of the formula (Ilb) to a compound of the formula (II) is carried out as provided in Process 1. Process 3 According to another aspect of the present invention, a process for preparing a composed of the formula (II), where X is O, E is -NR, and all these symbols are as defined above. First, a compound of the formula (IIj) where all the symbols are as defined above, it becomes an (Ilk), where all the symbols are as defined above. This reaction can be carried out using a base, for example, Na 2 CO 3, K 2 CO 3, NaHCO 3, KHCO 3, NaOH, KOH, or any mixture thereof. The reaction can be carried out in the presence of a solvent, for example, benzene, toluene, xylene, methanol, ethanol, i-propanol, butanol, DMF, DMSO, 1,4-dioxane, or any mixture thereof. The reaction temperature can be maintained from about -30 ° C to about 150 ° C, for example, from about 20 ° C to about 80 ° C. The duration of the reaction may be from about 0.5 hours to about 20 hours, for example, from about 2 hours to about 10 hours. The compound of the formula (Ilk) is then reacted with a compound of the formula (Ilm) R4 Y ^ 1"19 '(Tlm) or where "Hal" is a halogen, and R4 is as defined above, to obtain a compound of the formula (A) where all the symbols are as defined above. This reaction can occur in the presence of a bromination agent, for example, bromine, water with bromine, N-bromosuccinamide, copper bromide, or any mixture thereof. The solvent is acetic acid, propanoic acid, Butanoic acid, pentanoic acid, hexanoic acid, dichloromethane (DCM), chloroform (CHC13), 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, or any mixture thereof. The reaction can be carried out in the presence of a catalytic amount of hydrobromic acid. The reaction temperature can be from about -10 ° C to about 150 ° C, for example, from about 0 ° C to about 40 ° C. The duration of the reaction may be from about 1 hour to about 72 hours, for example, about 1 hour. hours to approximately 20 hours. Alternatively, the reaction can be carried out in the presence of a solvent, for example, acetonitrile, DMF, DMSO, DCM, CHC13, 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, or 5 HMPA, 1,4-dioxane, acetone, dimethyl ether, diethyl ether, THF, water, or any mixture thereof. The reaction can be carried out in the presence of a base, for example, NaH, KH, KO '? U, KOAc, NaOAc, n-BuLi, s-BuLi, t-BuLi, LDA, Na2C03, K2C03, NaHCO3, KHC03, NaOH, KOH, an amine base such as Et3N, diethyl-amine, diisopropylethylamine, diisopropylamine, DBU, or any mixture thereof. The reaction temperature can be from about -78 ° C to about 150 ° C, for example, from about -30 ° C to 40 ° C. The duration of the reaction may vary from about 10 minutes to about 72 hours, for example, from about 30 minutes to about 15 hours. The reaction can be carried out under an inert atmosphere maintained by N2, Ar, or He. The compound of the formula (Un) is then converted to a compound of the formula (Ilb) where X is O, E is -NR, and all other symbols are as defined above. This reaction can be carried out using polyphosphoric acid. Optionally, the reaction can be carried out in the presence of a solvent, for example, acetonitrile, DMSO, 1,4-dioxane, THF, water, or any mixture thereof. The reaction temperature may be from about 0 ° C to 300 ° C, for example, from about 50 ° C to about 180 ° C. The duration of the reaction can be from about 10 minutes to about 72 hours, for example from about 2 to 15 hours. The reaction can be carried out under an inert atmosphere maintained by N2, Ar, or He. The compound of the formula (Ilb) is then reacted with a compound of the formula (lie) where all the symbols are as defined above, to obtain where E is -NR, and all other symbols are as defined above. The compound of the formula (lid) is then reacted by a compound of the formula (lie) where all the symbols are as defined above, to obtain a compound of the formula (II) where X is O, E is -NR, and all these symbols are as defined above. Process 4 According to another aspect of the present invention, there is provided a compound for preparing a compound of the formula (IV). The process includes the following: where all the symbols are as defined above. The conversion of a compound of the formula (IVa) to a compound of the formula (IVc) can be carried out using an appropriate acyl chloride of the formula IVb in the presence of a base, for example, Na 2 CO 3, K 2 CO 3, NaHC03, KHC03, NaOH, KOH, triethylamine, diisopropylethylamine, or any mixture thereof. The reaction can be carried out in a solvent, for example, benzene, toluene, xylene, DMF, DMSO, 1, -dioxane, dichloromethane, CHC13, 1,2-dichloroethane, carbon tetrachloride, or any mixture thereof. The temperature of the reaction can be maintained from about -30 ° C to about 150 ° C, for example, from about 20 ° C to about 80 ° C. The duration of the reaction may be from about 6 hours to about 72 hours, for example, from about 2 hours to about 24 hours. The reaction can be carried out under an inert atmosphere of N2, Ar, or He. The conversion of a compound of the formula (IVc) to a compound of the formula (IVd) can be carried out using a base, for example, NaH, KH, KOtBu, KOAc, NaOAc, NaOEt, KOEt, n-BULi, s-BULi, t-BULi, LDA, Na2C03, K2C03, NaHCO3, KHC03, NaOH, KOH, or any mixture thereof. The reaction can be carried out in a solvent, for example, benzene, toluene, xylene, methanol, ethanol, i-propanol, t-butanol, or any mixture thereof. The reaction temperature can be maintained from about -70 ° C to about 250 ° C, for example, from about -10 ° C to about 150 ° C. The duration of the reaction can be from about 5 hours to about 150 hours, for example, from about 20 to about 100 hours. The reaction can be carried out under an inert atmosphere of N2; Ar, or He. The conversion of the compound of the formula (IVd) to a compound of the formula (IV) can be carried out as provided in Process 1. Process 5 According to another aspect of the present invention, a process for preparing a compound of the formula (Va). The process includes: The conversion of a compound of the formula (Ilb) to a compound of the formula (lid) can be carried out as provided in Process 1. The conversion of the compound of the formula (lid) to a compound of the formula ( Va) can be carried out by reacting the compound of the formula (lid) with a compound of the formula (IIp) in the presence of a reagent, for example, EDCI or CDI and a solvent, for example, DMF, chloroform , dichloromethane, dimethylacetamide, tetrahydrofuran, dioxane, ether, or any mixture thereof. The ambient temperature of the reaction can be maintained from about 10 ° C to about 60 ° C, for example, from about 20 ° C to about 35 ° C. The duration of the reaction may be from about 5 hours to about 12 hours, for example, from about 10 hours to about 12 hours. The reaction can be carried out under a nitrogen atmosphere.

Process 6 According to another aspect of the present invention, there is provided a process for preparing a compound of the formula (Vb).

The process includes: Vía vib Conversion of a compound of the formula (Vía) to a compound of the formula (VIb) was carried out in the presence of formamide in a nitrogen atmosphere. The reaction temperature can be maintained from about 10 ° C to about 70 ° C, for example, 25 ° C to about 45 ° C. The duration of the reaction may be from about 1 hour to about 9 hours, for example, from about 2 to about 4 hours. The conversion of the compound of the formula (VIb) to a compound of the formula (Vb) was carried out as provided in Process 5. It should be understood that any of the reactions presented herein, any reactive group in the molecule The substrate can be protected according to conventional chemical practice. Suitable protecting groups include, for example, ter-arylbutyldimethylsilyl, methoxymethyl, triphenyl, methyl, benzyloxycarbonyl, or tetrahydropyran (THP) to protect a hydroxyl or phenolic hydroxy group; N-tert-butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenylmethoxycarbonyl (-N-FMOC), benzophenoneimine, or propargyloxycarbonyl (POC) to protect an amino or anilino group; acetal protection for an aldehyde; and protection with acetal for a ketone. The methods of formation and removal of these protective groups are those conventional methods appropriate to the molecule that is protected. The enantiomers of the compound of the formula (II) can be prepared by using reagents in their individual enantiomeric form in the process whichever is applicable or by carrying out the reaction in the presence of reagents or catalysts in their individual enantiomeric form. Individual enantiomers can also be prepared by solving the racemic mixture by methods The conventional stereoisomers of the compounds of the present invention can be prepared by using reagents in their individual enantiomeric form in the process, by carrying out the reaction in the presence of reagents or catalysts. in its individual enantiomeric form, or by solving the mixture of stereoisomers by conventional methods. Some of the methods include using microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mannlic acid, camphorsulfonic acid, tartaric acid, lactic acid, whichever is applicable, or chiral bases such as brucine, cinchona-alkaloids and their derivatives . The commonly used methods are compiled by JAQUES, ENANTIOMERS, RACEMATES A? D RESOLUTIO? (1981) . Where appropriate, the compounds of the formula (I) can be resolved by: treating with chiral amines, amino acids, aminoalcohols derived from amino acids; by using conventional reaction conditions to convert the acid to an amide; by separating the diastereomers by fractional crystallization or chromatography; and by preparing the stereoisomers of the compound of the formula (I) by hydrolyzing the pure diastereomeric amide. The stereoisomers of the present invention can also include E and Z isomers or their mixtures in various ratios. Formulations and Pharmaceutical Compositions The present invention provides compounds of the general formula (I), pharmaceutical compositions comprising one or more compounds of the general formula (I), their salts or their pharmaceutically acceptable compositions, in combination with pharmaceutically acceptable carriers and diluents. The pharmaceutical compositions of the present invention can be used for the treatment of bacterial infections. They can also be used for the treatment of bacterial infections associated with multidrug resistance. The pharmaceutical compositions of the present invention can also be used to modulate inflammatory responses, particularly those resulting from the accumulation of glycated protein and AGE. The pharmaceutical compositions of the present invention can also be used to modulate the proliferation of smooth muscle cells and diseases or conditions related thereto. The compositions provided herein may also be used to treat vascular occlusive conditions, such as stenosis, restenosis and atherosclerosis; inflammatory mediated diseases, such as autoimmune diseases; and hyperproliferative diseases, such as cancer. A. Pharmaceutically acceptable salts The compositions of the present invention optionally include one or more salts of the compounds of the present invention contained herein. These salts are commonly referred to as "non-toxic pharmaceutically acceptable salts". However, other salts may be useful in the preparation of the compounds of the present invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts which can be formed, for example, by mixing a solution of the compound with a solution and a pharmaceutically acceptable acid, for example, hydrochloric acid, sulfuric acid, fumaric acid , maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, or any mixture thereof. Additionally, where the compounds of the invention have an acidic portion, suitable pharmaceutically acceptable salts thereof may include salts and alkali metals, for example, sodium or potassium salts; alkaline earth salts, for example, calcium or magnesium salts; salts formed with suitable organic ligands, for example, quaternary ammonium salts; or any mixture thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyl nitrate, metiisulfato, mucate, napsylate, nitrate, N-methylglucamine-ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate. B. Alternative Forms of the Compounds Where the compounds of the present invention have at least one chiral center, they can therefore exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the compounds of the present invention have geometric isomers, it is to be understood that all these isomers and mixtures thereof are encompassed within the scope of the present invention. Additionally, some of the crystalline forms for the compounds may exist as polymorphic substances and are contemplated herein. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and these solvates are also intended to be encompassed herein. Where the processes for the preparation of the compounds according to the invention give a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. In addition, the compounds of the present invention can be prepared in racemic form. Alternatively, individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. The compounds can be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by formation of salts with an optically active acid, for example, (+) di-p-toluoyl-d-tart acid and / or acid (+) - di-p-toluoyl-1-tart, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation or removal of chiral auxiliary products. Alternatively, the compounds can be resolved using a chiral HPLC column. The compounds of the present invention are optionally formulated and administered as a prodrug. In general, prodrugs comprise functional derivatives of the claimed compounds that are capable of being activated or converted enzymatically into the most active source form. Thus, in the methods of the treatment of the present invention, the term "administer" encompasses the treatment of the vus disorders described with the specifically described compound or with a compound that can not be described specifically, but which becomes specific compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example in DESIGN OF PRODRUGS (1985); ihnan, 14 BIOCHEM. SOC. TRANS. 375-82 (1986); STELLA ET AL. , Prodrugs: A Chemical Approach to Targeted Drug Delivery in DIRECTED DRUG DELIVERY 247-67 (1985), each of which is incorporated herein by reference in its entirety.

The prodrugs of the present invention include, without limitation, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, prodrugs modified with D-amino acids, glycosylated prodrugs, prodrugs containing β- lactam, prodrugs containing optionally substituted phenoxyacetamide or prodrugs containing optionally substituted phenylacetamide, 5-fluorocytosine, and other 5-fluorouridine prodrugs that can be converted to the most active drug. Enzymes that can be used in the methods and compositions of the present invention include, without limitation, alkaline phosphatase to convert phosphate-containing prodrugs into free drugs; aryl sulfatase for converting sulfate-containing prodrugs into free drugs, cytosine deaminase to convert non-toxic 5-fluorocytosine to the anti-cancer drug, 5-fluorouracil, -proteases, such as serratia-protease, thermolysin, subtilisin, carboxypeptidases, and cathepsins , such as cathepsins B and L, to convert peptide-containing prodrugs into free drugs; D-alanylcarboxypeptidases for converting prodrugs containing D-amino acid substituents; carbohydrate cleavage enzymes such as β-galactosidase and neuraminidase for converting glycosylated prodrugs into free drugs; β-lactamase to convert β-lactam-derived drugs into free drugs; and penicillin-amidases, such as penicillin V-amidase or penicillin G-amidase, to convert derivative drugs in their amine nitrogens with phenoxyacetyl or phenylacetyl groups, respectively, into free drugs. Alternatively, antibodies with enzymatic activity, also known in the art as "abzymes" can be used to convert the prodrugs of the present invention into free active drugs. See, for example Massey, 328 NATURE 457-48 (1987). C. Pharmaceutical Auxiliary Products In addition to the compounds contemplated herein, the pharmaceutical compositions of the present invention optionally comprise at least one suitable carrier or auxiliary such as, but not limited to, a diluent, binder, stabilizer, buffer, salt, lipophilic solvent, preservative, adjuvant or any combination thereof. Pharmaceutically acceptable auxiliaries are typically used. In the examples and methods for preparing these sterile solutions are described, for example in REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)), incorporated herein by reference in its entirety. The pharmaceutically acceptable carriers are routinely selected to be suitable for the mode of administration, solubility and / or stability to the compound. The pharmaceutical additive excipients useful in the present invention include, without limitation, proteins, peptides, amino acids, lipids and carbohydrates (eg, sugars, including monosaccharides, di-, tri-, tetra- and oligo-saccharides; sugars; derivatized such as alditols, aldonic acids, esterified sugars, and polysaccharides), which may be present individually or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein or any combination thereof. Representative amino acid components that may also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine and aspartame. Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose; disaccharides such as lactose, sucrose, trehalose, cellobiose; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol-sorbitol (glucitol), myoinositol. Pharmaceutical compositions comprising the compounds of the present invention may also include buffer or a pH adjusting agent. Typically, the buffer is a salt prepared from an organic acid or base. Exemplary buffers include organic acid salts such as citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid salts; Tris; tromethamine hydrochloride; phosphate buffers, or any combination thereof. Additionally, the pharmaceutical compositions of the invention optionally include excipient / polymeric additives, such as polyvinylpyrrolidones, ficoles (a polymeric sugar) dextrates (eg, cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrins), polyethylene glycols, flavoring agents, anti-microbial agents, sweeteners, oxidants, antistatic agents, surfactants (e.g., polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol) , chelating agents (e.g., EDTA), and any combination thereof. Pharmaceutical excipients and exemplary additives are described REMINGTON: THE SCIENCE & PRACTICE OF PHARMACY (19th ed., Williams &Williams (1995)) and PHYSICIAN'S DESK REFERENCE (52nd ed., Medical Economics (1998)), each of which is incorporated herein by reference in its entirety. 1. Pharmaceutical compositions for oral administration For oral administration in the form of a tablet or capsule, a compound can be combined with an inert pharmaceutically acceptable, non-toxic, oral carrier, such as ethanol, glycerol, water or any mixture thereof. . In addition, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch; gelatin, natural sugars such as glucose or bet-lactose, corn sweeteners; natural and synthetic gums such as acacia gum, tragacanth or sodium alginate, carboxymethylcellulose; polyethylene glycol; waxes; or any combination thereof. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or any combination thereof. The disintegrates include, without limitation, starch, methylcellulose, agar, bentonite, xanthan or any combination thereof. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, amylaceous capsules or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus. A tablet may be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets are typically prepared by compressing, in a suitable machine, the active ingredient in a fluid form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, preservative, surface dispersing or active agent. The molded tablets are typically made by molding, in a suitable machine, a mixture of the wetted powder compound with an inert liquid diluent. The tablets are optionally coated or labeled and can be formulated to provide a slow or controlled release of the active ingredient therein. The compositions of the present invention are optionally incorporated in a biodegradable polymer, thus allowing the sustained release of the compound. The polymer is implanted in the vicinity where the distribution of the drug is desired, for example, at the site of restenosis. These biodegradable polymers are described, for example, Brem et al., 74 J. NEUROSURG. 441-46 (1991). Suitable examples of sustained release compositions include semipermeable matrices of solid hydrophobic polymers containing a compound of the present invention, matrices that are formed into formed articles, e.g., films or capsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate), or poly (alcoholvinyl)), polylactides (U.S. Patent No. 3,773,919, incorporated herein by reference in its whole), copolymers of L-glutamic acid and ethyl-L-glutamate, ethylene-non-degradable vinyl acetate, degradable copolymers of lactic acid-glycolic acid such as LUPRON DEPOT® (Tap Pharmaceuticals, Inc., Chicago, IL) (microspheres) injectables composed of lactic acid-glycolic acid and leuprolide acetate copolymer), and poly-D- (-) - 3-hydroxybutyric acid. 2. Pharmaceutical compositions for parenteral administration As used herein, "parenteral" includes subcutaneous injections, intravenous, intramuscular, intraperitoneal or infusion techniques. Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the proposed recipient, and sterile aqueous and non-aqueous suspensions optionally including of suspension and dispersing agents. The formulations may be presented in unit dose or multiple dose containers, eg, sealed ampoules and flasks, and may be stored in a lyophilized condition (freeze drying) requiring only the addition of the sterile liquid carrier, eg, water for injections, immediately before use. The spontaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets such as those described above. For parenteral administration, suspensions and sterile solutions are desired. Isotonic preparations containing generally suitable preservatives are used when intravenous administration is desired. The pharmaceutical compositions can be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Inert liquid carriers include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil and organic solvents such as sol-ketal and glycerol formal. The formulations can be prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from about 0.005% to 30% by weight of the active ingredient, for example, a compound of the present invention. 3. Pharmaceutical compositions for other routes of administration Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored base or a flavored medium, usually sucrose and acacia gum or tragacanth.; Pills comprising the active ingredient in a base or inert medium such as gelatin and glycerin, or sucrose and acacia gum, and buccal washes comprising the compound to be administered in a suitable liquid carrier. Liquid forms may include suitably flavored suspension or dispersing agents, such as synthetic and natural gums, for example, tragacanth gum, acacia gum and methyl cellulose. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a silicate. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations comprising the active ingredient and an appropriate carrier. The compounds can also be entrapped in microcapsules prepared, for example, by co-accumulation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly (methylmethacrylate) microcapsules, respectively, in drug delivery systems, colloidal (eg example, liposomes, alumina microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. REMINGTON'S PHARMACEUTICAL SCIENCES (A. Osol ed., 16th ed. (1980)), incorporated herein by reference in its entirety. The compounds contemplated herein are optionally formulated as liposomes. Liposomes can be prepared by any suitable method, such as those described in U.S. Patent Nos. 5,013,556; 4,485,045; 4,544,545; WO 97/38731; Epstein et al., 82 PROC. NATL. ACAD. SCI. USA 3688 (1985); and Hwang et al., 77 PROC. NATL. ACAD. SCI. USA 4030 (1980), each of which is incorporated herein by reference in its entirety. The compounds of the present invention can also be administered in the form of liposome distribution systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of the present invention can also be distributed by the use of monoclonal antibodies as individual carriers to which the molecules of the compound are coupled. The compounds of the present invention can also be coupled with soluble polymers as carriers of selectable target drugs. These polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-enoxidopolylysine optionally substituted with palmitoyl residues.

D. Pharmaceutically acceptable preservatives The present invention provides stable formulations, conserved solutions and formulations containing a preservative, and conserved formulations of multiple uses suitable for pharmaceutical or veterinary use, comprising at least one compound contemplated herein in a pharmaceutically acceptable formulation. The preserved formulations contain at least one known preservative comprising at least one of minor, m-cresol, p-cresol, o-cresol, chlorocresol, aleonolbenzyl, nitritophenylmercuric, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate). ), acrylparaben (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate 5 and timirosal, or any mixture thereof, in an aqueous ingredient. Any suitable concentration or mixture, such as 0.001-5%, or any range or value therein including, without limitation, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, may be used. 0.1, 0.2, 0.3, 0.4. , 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 , 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9. Non-limiting examples include, without preservative, 0.1-2% m-cresol (eg 0.1, 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (eg 0.5, 0.9, 1.1., 1-5, 1.9, 2.0, 2.5%), 0.001-0.5%, 0.001-0.5% thimerosal (for example, 0.005, 0.01), 0.001-2.0% phenol (for example 0.05, 0.25 , 0.28, 0.5, 0.9, 1.0%), and 0.0005-1.0% alkylparabens (for example 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%). Optionally, other excipients are added to the diluent, for example, isotonicity agents, buffers, antioxidants, preservatives, conservation enhancers. An isotinicity agent, such as glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is typically added to provide improved pH control. The formulations can cover a wide variety of pH such as from about pH 4 to about pH 10, specifically, a range of about pH 5 to about pH 9, more specifically, a range of about 6.0 to about 8.0. In accordance with one aspect of the present invention, the formulations of the present invention have a pH between about 6.8 and about 7.8. Suitable buffers include phosphate buffers, for example, sodium phosphate and phosphate buffered saline (PBS). Other additives, such as pharmaceutically acceptable stabilizers such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene monopalmitate (20) sorbitan), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (copolymers) of polyoxyethylene-polyoxypropylene block), and PEG (polyethylene glycol) or non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic polyols "11, other block copolymers, burners such as EDTA and EGTA are optionally added to Pharmaceutical compositions for reducing aggregation These additives are particularly useful if a pump or plastic container is used to administer the pharmaceutical composition The presence of the pharmaceutically acceptable surface active agent mitigates the predisposition of the composition to be added during any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to oteger the sensitive or reactive groups or any of the molecules in question. This can be achieved by means of conventional protecting groups, such as those described in PROTECTIVE GROUPS IN ORGANIC CHEMISTRY (1973); and GREENE AND WUTS, PROTECTIVE GROUPS IN ORGANIC SY? THESIS (1991), each of which is incorporated herein by reference in its entirety. The protecting groups can be removed in a convenient subsequent step using methods known in the art.

E. Combination Therapy In addition, co-administration or sequential administration of the compounds of the present invention and other therapeutic agents, such as chemotherapeutic agents, immunosuppressive agents, cytosines, cytotoxic agents, nucleolytic compounds, radioactive isotopes, receptors, may be desirable. and prodrug activation enzymes, which may occur naturally or may be produced by recombinant methods. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in any order, where there is a period of time while both (or all) of the active therapeutic agents simultaneously exercise their biological activities. The compounds of this invention are optionally administered in combination with an antirheumatic agent (eg, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, sodium-gold thiomalate, hydroxychloroquine sulfate, luflenomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroidal anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an anti-cancer, an antimicrobial (eg, aminoglycoside, an antifungal, an anti-parasite) , an antiviral, a carbapenem, cephalosporin, a luoroquinolone a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an anti-psoriatic, a corticosteroid, an anabolic steroid, an agent related to diabetes, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium-related hormone, an antidiarrheal, an anti-tussive, an anti-emetic, an anti-ulcer, a laxant e, an anticoagulant, an erythropoietin (e.g., epoetin alfa), a filgrastim, (e.g., G-CSF, Neupogen), a sargramostima (GM-CSF, Leucine), an immunization, an immunoglobulin, an immunosuppressant (e.g. , basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mithriat, a cyclopegist, an alkylating agent, an anti-metabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, an antimanic agent, an anti-psychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta-agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine, or analogous thereof, dornase-alpha (Pulmozyme), a cytosine, or any combination thereof. These anti-cancer or antimicrobial compounds may also include toxin molecules that associate, bind, co-formulate, co-administer, or are administered sequentially, in any order, with at least one of the compounds of the present invention. The term "toxin" includes both endotoxins and exotoxins produced by naturally occurring, mutant or recombinant bacteria, or viruses, which can cause any pathological condition in humans and other mammals, including toxin cap, which can result in death . The toxin can optionally act to selectively kill the pathological cell or tissue. The pathological cell can be a cancer cell or another. These toxins can be, without limitation, purified or recombinant toxin or toxin fragment comprising at least one functional cytotoxic domain of the toxin, for example, selected from at least one of resin, diphtheria toxin, venom toxin. or a bacterial toxin. These toxins may include, but are not limited to, thermally labile enterotoxin (LT) from E. coli, enterotoxinic, thermally stable enterotoxin (ST), Shigella cytotoxin, Aeromonas enterotoxins, toxin-1 toxic shock syndrome (TSST-). 1), enterotoxins A Staphylococcal (SEA), B (SEB), or C (SEC), Streptococcal enterotoxins. These bacteria include, without limitation, strains of a species of enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli (for example, strains of serotype 0157: H7), Staphylococcus species (for example, Staphylococcus aureus, Staphylococcus pyogenes), Shigella species (eg, Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei), Salmonella species (eg, Salmonella typhi, Salmonella choleraisis, Salmonella enteritidis), Clostridium species (eg , Clostridium perfringens, Clostridium difficile, Clostridium botulinum), Camphlobacter species (eg, Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species, (eg, Heliobacter pylori), Aeromonas species (eg, Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae), species of Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (for example, Vibrios cholerae, Vibrios parahemolyticus), and species of Klebsiella, Pseudomonas aeruginosa, and Streptococci. See, for example, Stein, ed. , INTERNAL MEDICINE 1-13 (3rd ed. Little, Brown and Co., Boston) (1990); EVANS ET AL. , BACTERIAL INFECTIONS OF HUMANS: EPIDEMIOLOGY AND CONTROL 239-254 (2nd ed. Plenum Medical Book Co., New York) (1991); MANDELL ET AL. , PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES (3 d., Churchill Livingstone) (1990); BERKOW ET AL. , THE MERCK MANUAL (16th ed. Merck and Co.) (1992); Wood et al. , 76 FEMS MICROBIOLOGY IMMUNOLOGY 121-134 (1991); Marrack et al., 248 SCIENCE 705-711 (1990), each of which is incorporated herein by reference in its entirety. The compound of the present invention is optionally administered in combination with at least one immunosuppressive agent for use in, for example, treating or preventing a vascular occlusive condition, such as transplant vasculopathy. Suitable immunosuppressive agents include, but are not limited to, CellCept (Roche Labs.), Gengraf (Abbott Labs., Inc.), Micrhogam (Ortho-Clinical), Neoral (Novartis), Orthoclone OKT3 (Ortho-Biotech), Prograf (Fujisawa), Rapamune (Wyeth-Ayerst), Sandimmune (Novartis) , Thymoglobulin (SangStat), Zenapax (Roche), or any combination thereof.

The therapeutic agent can be administered simultaneously or sequentially, in any order and at various times with a compound of the present invention comprising a chemotherapeutic agent. A "chemotherapeutic agent" is a compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busolfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocuone, meturedopa and uredopa; ethylene imines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaftazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembiein, phenesterin, predidnimustine, trofosfamide, uracil mustard; nitroureas such as cannustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomisins, actinomycin, autramycin, azaserin, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromocycins, dactinomycin, daunorubicin, detorubicin, 6-diaz-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idambycin , marcellomycin, mitomycins, mycopenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamicin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, tiamiprin, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, deoxyuridine, doxifluridine, enocythabin, floxuridine, 5-FU; androgens such as calusterone, dromostalone proipionate, epithiostanol, mepitiostane, testolactone; anti-suprarenal such as aminoglutethimide, testolactone; mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone, - aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; adatraxate, defofamine; demecolcine; diazicuone; elfornitin, elliptinium acetate, etoglucide, gallium nitrate, -hydroxyurea; lentinan; lonidamine; mitoguazone, mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin, - podofillinic acid, - 2-ethylhydrazide; procarbazine; PSK ™ 1; razoxane; sizofran; spirogermanium, - tenuazonic acid, triazicuone; 2, 2 A "-trichlorotriethylamine; urethane; vindesine; decarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacitosina; arabinoside ("Ara-C") cyclophosphamide; thiotepa; taxoids, for example, paclitaxel (TAXOL ™ 1, Bristol-Myers Squibb Oncology, Princeton, NJ) and doxetaxel (TAXOTERE1"11, Rhone-Poulenc Rorer, Antony, France), chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate; platinum analogues such as cisplatin and carboplatin, vinblastine, platinum, etoposide (VP-16): phosphamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeioda, bandronate, CPT-11, inhibitor of topoisomerase RFS 2000, difluoromethylornithine (DMFO), retinoic acid, esperamycins, capecitabine, and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.Also included in this definition are the anti-hormonal agents that act to regulate or inhibit the action hormone in tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibitor 4 (5) -imidazoles, 4-hydroxy tamoxifen, trioxifene, ketoxifene, onapristone , and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin; and pharmaceutically acceptable salts, acid or derivatives of any of the foregoing. The therapeutic agent may comprise a cytosine. The term "cytosine" is a generic term for proteins released by a cell population that act in another cell as intracellular mediators. As used herein, the term "cytosine" includes proteins from natural or recombinant cell culture sources and biologically active equivalents of native sequence cytosines. Examples of these cytosines are lymphosines, monosines and traditional polypeptide hormones. Included among the cytosines are growth hormones such as human growth hormone, m-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone, thyroxine, insulin; pro-insulin; prolaxin; pro-relaxin; glycoprotein hormones such as fulcrum stimulating hormone (FSH), thyroid stimulating hormone (TSH), and leutinizing hormone (LH); liver growth factor; fibroblast growth factor; prolactin; placental lactogen; factor- and -ß tumor necrosis; Mullerian inhibition substance; peptide associated with mouse gonadotropin; inhibin; activin; Vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factor such as NGF-3; platelet growth factor; transformation growth factors (TGF) such as TGF-α and TGF-β; insulin-like growth factor -I and -II factor, erythropoietin (EPO); osteoinductive factors, - interferons such as interferon-? "ß Y-colony stimulation factors (CFS) such as macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), and granulocyte-CSF (GCSF); interleukins (IL) such as IL -1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15 a tumor necrosis factor such as TNF-α or TNF-β; and other polypeptide factors including LIF and equipment ligand (KL) The compounds of the present invention can be administered in combination with an anti-inflammatory agent that includes , without limitation, adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone and dexamethasone), non-spheroidal agents (salicylic acid derivatives, ie, aspirin; aminophenol, ie acetaminophen, indole and indeno-acetic acids (indomethacin, sulindac, and etodalac), heteroaryl-acetic acids (tolmetin, diclofenac, and ketorolac, aric acid) ilpropionic (ibuprofen and derivatives), anthralnyl acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxifentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold thiomalate-sodium). Non-spheroidal anti-inflammatory drugs commercially available, include but are not limited to: Anaprox (Roche Labs), Arthrotec (Searle), Cataflam (Novartis), Celebrex (Pfizer), Clinoril (Merck), Dolobid (Merck), Feldene (Pfizer), Indocin (Merck), Lodine (Wyeth-Ayerst), Mobic (Boehringer Ingelheim), Motrin (McNeil Consumer), Naprosyn (Roche Labs.), Orudis (Wyeth-Ayerst), Oruvail (Wyeth-Ayerst), Ponstel (First Horizon), Relafen (GlaxoSmithKline), Tolectin (Ortho-McNeil), Toradol (Roche Labs., Inc.), Vioxx (Merck), Voltaren (Novartis), Advair (GlaxoSmithKline), Flovent (GlaxoSmithKline), Pulmicort (AstranZeneca ), and Vanceril (Schering), Asacol (Procter &Gamble), Colazal (Salix), Dipentum (Pharmacia &Upjohn), and Rowasa (Solvay). The compounds of the present invention can be administered in combination with an anti-rheumatic agent. Commercially available anti-rheumatic agents include but are not limited to Anaprox (Roche Labs.), Arava (Aventic), Arthrotec (Searle), Azulfidine (Pharmacia & amp;; Upjohn), Cataflam (Novartis), Celebrex (Pfizer), Celestone (Schering), Cuprimine (Merck), Enbrel (Immunex), Feldene (Pfizer), Gengraf (Abbott), Indocin (Merck), Lodine (Wyeth-Ayerst), Naprosyn (Roche Labs.), Neoral (Novartis), Pediapred (Celltech), Prednisone (Roxanne), Remicade (Centocor), Solu-Medrol (Pharmacia &Upjohn), Triliate (Purdue Frederick), and Voltaren (Novartis). In addition, the compounds of the present invention can be used in combination with any cardiovascular agent including, but not limited to, adrenergic blockers such as Cardura (Pfizer), Dibenzyline (Well Spring), Hytrin (Abbott), Minipress (Pfizer), and Minizide (Pfizer), - adrenergic stimulants such as Aldoclor (Merck), Aldomet (Merck), Aldoril (Merck), Catapres (Boehringer Ingelheim), Clorpres (Bertek), and Tenex (Robins); alpha / beta adrenergic blockers such as Coreg (GlaxoSmithKline), and Normodyne (Schering); angiotensin-converting enzyme inhibitors such as Accupril (Parke-Davis), Aceon (Solvay), Altace (Monarch), Captopril (Mylan), Enalaprilat (Baxter Anesthesia), Lotensin (Novartis), Mavik (Abbott), Monopril (Bristol-Myers Squibb), Prinivil (Merck), Univasc (Schwarz), Vaotec (Merck), and Zestril (AstraZeneca); angiotensin-converting enzyme inhibitors such as Lexxel (AstraZeneca), Lotrel (Novartis), Tarka (Abbott), Accuretic (Parke-Davis), Lotensin (Novartis), Prinzide (Merck), Uniretic (Schwarz), Vaeretic (Merck), and Zestoretic (AstraZeneca); angiotensin II receptor antagonists such as Atacand (AstraZeneca), Avapro (Briston-Myers) Squibb), Cozaar (Merck), Diovan (Novartis), Micardis (Boehringer Ingelheim), and Teveten (Unimed); antiarrhythmics (Groups I-IV), anti-lipemic agents such as bile acid sequestrants, fibric acid derivatives, inhibitors of HMG-CoA reductase, and nicotinic acid; blocking agents Beta-adrenergic; calcium channel blockers; inotropic agents; vasodilators including coronary vasodilators, natriuretic peptides, and peripheral vasodilators; and vasopressors. According to one aspect of the present invention, the therapeutic agent comprising a small molecule toxin, including maytansin, calicheamicin, trichothene, and CC 1065. According to another aspect of the present invention, the therapeutic agent comprises one or more Calicheamicin molecules. Members of the antibiotic calicheamicin family are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. The structured analogs of calicheamicin are also known. See Hinman et al., 53 CANCER RESEARCH 3336-42 (1993); Lode et al., 58 CANCER RESEARCH 2925-28 (1998), incorporated herein by reference in its entirety. The therapeutic agent may comprise one or more enzymatically active toxins and fragments thereof. Examples of these toxins include active fragments in conjunction with diphtheria toxin, diphtheria A chain, endotoxin A chain (from pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, diantine proteins, proteins of Phytolaca americana (PAPI, PAPAU, and PAP-S), inhibitor of momordica charantia, curcin, inhibitor of crotin sapaonaria officinalis, gelonin, mitogellin, restrictoein, phenomycin, enomycin and trichothecenes. See, for example WO 93/21232, incorporated herein by reference in its entirety. The present invention also contemplates therapeutic agents having neurolytic activity such as a ribonuclease and a deoxyribonuclease. In addition, a variety of radioactive isotopes are available for the production of radioconjugated binding partners. Examples include Y30, At222, Ret86, Re186, Sm153, Bi "212, p32 and the radioactive isotopes of Lu. The compound of the present invention can be conjugated to a receptor, such as streptavidin, for use in pre-screening as Tumor Target Briefly, the compound-receptor conjugate is administered to the patient and the unbound conjugate is removed from the circulation with a depuration agent, then a ligand, such as biotin, which is conjugated to a cytotoxic agent is administered. 1. Administration schedule According to one aspect of the present invention, a compound described herein is administered before a second therapeutic agent Administration of the compound can occur at any time from several minutes to several hours prior to administration of the second therapeutic agent The compound can be administered alternatively at any time from several hours to several days, possibly several days. weeks, and up to several months before the second therapeutic agent. More specifically, a compound of the present invention can be administered at least at about at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, at least about 21 minutes, at least about 22 minutes, at least about 23 minutes, at least approximately 24 minutes, at least approximately 25 minutes utes, at least about 26 minutes, at least about 27 minutes, at least about 28 minutes, at least about 29 minutes, at least about 30 minutes, at least about 31 minutes, at least about 32 minutes, at least about 33 minutes, at least about 34 minutes, at least about 35 minutes, at least about 36 minutes, at least about 37 minutes, at least about 38 minutes, at least about 39 minutes, at least about 40 minutes, at least about 41 minutes, at least about 42 minutes, at least about 43 minutes, at least about 44 minutes, at least about 45 minutes, at least about 46 minutes, at least about 47 minutes, at least about 48 minutes, at least about 49 minutes, at least about 50 minutes, at least approximately 51 minutes, at least approximately 52 min utes, at least about 53 minutes, at least about 54 minutes, at least about 55 minutes, at least about 56 minutes, at least about 57 minutes, at least about 58 minutes, at least about 59 minutes, or at least about 60 minutes before the second therapeutic agent. Additionally, a compound of the present invention can be administered at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours , at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, or at least about 24 hours before the second therapeutic agent. In addition, a compound of the present invention can be administered at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days , at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at less about 29 days, at least about 30 days or at least about 31 days before the administration of the second therapeutic agent. A compound of the present invention can be administered at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks , at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks before the second therapeutic agent. Additionally, a compound of the present invention can be administered at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least about eight months, at least about nine months, at least about ten months, at least about eleven months, or at least about twelve months before the second therapeutic agent. According to another aspect of the present invention, a compound of the present invention is administered after the therapeutic agent. Administration of a compound can occur at any time from several minutes to several hours after administration of the therapeutic agent. A compound can alternatively be administered at any time from several to several days, possibly several weeks, or even up to several months after the second therapeutic agent. More specifically, a compound of the present invention can be administered at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, at least about 21 minutes, at least about 22 minutes, at least about 23 minutes, at least approximately 24 minutes, at least approximately 25 mi minutes, at least about 26 minutes, at least about 27 minutes, at least about 28 minutes, at least about 29 minutes, at least about 30 minutes, at least about 31 minutes, at least about 32 minutes, at least about 33 minutes, at least about 34 minutes, at least about 35 minutes, at least about 36 minutes, at least about 37 minutes, at least about 38 minutes, at least about 39 minutes, at least about 40 minutes, at least about 41 minutes, at least about 42 minutes, at least about 43 minutes, at least about 44 minutes, at least about 45 minutes, at least about 46 minutes, at least about 47 minutes, at least about 48 minutes, at least about 49 minutes, at least about 50 minutes, at least about 51 minutes, at least about 52 minutes, at less about 53 minutes, at least about 54 minutes, at least about 55 minutes, at least about 56 minutes, at least about 57 minutes, at least about 58 minutes, at least about 59 minutes, or at least about 60 minutes after the second therapeutic agent. More specifically, a compound of the present invention can be administered at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours hours, or at least approximately 24 hours after the second therapeutic agent. In addition, a compound of the present invention can be administered at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days , at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at less approximately 24 days, at least approximately 25 days, at least approximately 26 days, at least approximately 27 days at least about 28 days, at least about 29 days, at least about 30 days or at least about 31 days after the second therapeutic agent A compound of the present invention can be administered at least about 1 week, at least about 2 weeks , at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least approximately 20 weeks after the second therapeutic agent. Additionally, a compound of the present invention can be administered at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about seven months, at least approximately eight months, at least approximately nine months, at least approximately ten months, at least approximately eleven months, or at least approximately twelve months after the second therapeutic agent. The compound of the formula (I) may also be administered in conjunction with other drugs used in the treatment of cardiovascular diseases, and include inhibitors of platelet aggregation such as aspirin, antithrombotic agents such as coumadin, calcium channel blockers such as dilteazem. and nephidipine, angiotensin-converting enzyme (ACE) inhibitors such as captopril and enalopril and β-blockers such as propranolol. The compound can also be administered in combination with non-spheroidal anti-inflammatory agents such as ibuprofen, indomethacin, sulindac or COX II inhibitors such as rofecoxib or celecoxib. A therapeutic amount of the compound of the formula (I) can also be administered with a caticosteroid. It can also be administered in combination with a TNF-α modulating agent for example etanercept or inf liximab. A therapeutic amount of the compound of the formula (I) can also be administered with inhibitors of HMG-CoA-reductose, PPAR-INHIBITORS. , HDL elevators or retinoids. Methods of Administration The compounds of the present invention can be administered by any suitable means, including, for example, a parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intrabronchial, intra-abdominal, 1x Otracapsular, intracavitary, intracavitary, intracellular, intracerebellar, intracerebroventricular, intracranial, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial , intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal or transdermal. A. Lung / Nasal Administration 0 There are several desirable characteristics of an inhalation device for the administration of a compound of the present invention. For example, the distribution by the inhalation device is disadvantageously reliable, reproducible and accurate. For pulmonary administration, at least one pharmaceutical composition is distributed in an effective particle size to reach the lower airways of the lung or sinuses. The inhalation device optionally distributes small dry particles, typically about 10 μm, for example, about 1-5 μm, for good breathing capacity. The pharmaceutical composition of the present invention can be distributed with any suitable inhalation device or nasal device. Devices capable of depositing aerosol formulations in the cavity of a patient's sinuses or alveoli include, but are not limited to, metered dose inhalers, nebulizers, dry powder generators, and sprinklers. Other devices suitable for directing pulmonary or nasal administration are also known in the art. All these devices can be used for the administration of a pharmaceutical composition in an aerosol. These aerosols can comprise either solutions (both aqueous and non-aqueous) or solid particles. Dosage-dose inhalers, such as the Ventolin1 ™ 1 metered dose inhaler, typically use a propellant gas and require actuation during aspiration. See, for example WO 98/35888; WO 94/16970. Dry powder inhalers such as Turbuhaler101 (Astra), Rotahaler101 (Glaxo), Diskus ™ * (Glaxo), Spiros inhaler (Dura), devices marketed by Inhale Therapeutics, the Spinhalerm powder inhaler (Fisons), use a respiratory drive of a mixed powder. See, for example, U.S. Patent Nos. 5,458,135; 4,668,218; WO 97/25086; WO 94/08552; WO 94/06498; and EP 0 237 507, each of which is incorporated herein by reference in its entirety. Nebulizers, for example, AERx ™ 1, Aradigm, the Ultravent ™ nebulizer (Mallinckrodt), and the Acorn XXm nebulizer (Marquest Medical Products) produce aerosols of solutions, while metered dose inhalers and dry powder inhalers generate small particle aerosols. These specific examples of commercially available inhalation devices are proposed to do something, representative of specific devices suitable for the practice of the invention and are not proposed to limit the scope of the invention. Where the carrier is a solid, formulations suitable for nasal administration include a thicker powder having a particle size, eg, from about 20 to 500 microns is administered in a manner in which the powdered tobacco is administered, that is, by rapid inhalation through the nasal passage from a container of dust held close to the nose. When the carrier is a liquid, formulations suitable for administration such as for example nasal spray or nasal drops include oily or aqueous suspensions of the active ingredient. 1. Administration as a spray A spray comprising a pharmaceutical composition of the present invention can be produced or by forcing a suspension or solution of the compound contemplated herein through a nozzle under pressure. The size and configuration of the nozzle, the applied pressure, the lipid feed rate are chosen to achieve the desired result and the desired particle size. An electroroad can be produced, for example, an electric field in conjunction with a nozzle or capillary feed. Typically, the particles of at least one compound distributed by a sprinkler have a particle size of less than about 20 μm, less than about 19 μm, less than about 18 μm, less than about 17 μm, less than about 16 μm, less about 15 μm, less than about 14 μm, less than about 13 μm, less than about 12 μm, less than about 11 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm. The pharmaceutical compositions according to the present invention suitable for use with a sprayer or sprayer typically include a compound contemplated herein in an aqueous solution at a concentration of from about 0.1 mg to about 100 mg of a compound contemplated herein per mL. of solution or mg / gm, or any range or value therein including, without limitation, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / mL or m9 '/ tI - La The pharmaceutical composition may include agents such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant and for example zinc. The pharmaceutical composition may also include an excipient or agent for the stabilization of the compound, such as a buffer, a reducing agent, a bulk protein or a carbohydrate. Bulk proteins useful in pharmaceutical compositions suitable for use in a sprayer or sprayer include albumin, protamine or the like. Typical carbohydrates useful in pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose or the like. The pharmaceutical composition may also include a surfactant, which can reduce or prevent surface-induced aggregation of the pharmaceutical composition caused by atomization of the solution by forming an aerosol. Various conventional surfactants may be employed such as polyoxyethylene fatty acid esters and polyoxyethylene sorbitol fatty alcohol esters and esters. The amounts will generally vary between 0.001 and 10% by weight of the formulation. Suitable surfactants include, without limitation, and without limitation, polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20 or the like. Additional agents known in the art can also be included in the pharmaceutical composition. 2. Administration by a nebulizer A pharmaceutical composition of the present invention can be administered by a nebulizer such as a jet nebulizer or an ultrasonic nebulizer. Typically, in a jet nebulizer, a source of compressed air is used to create a high velocity air jet through an orifice. As the gas expands beyond the nozzle, a region of low pressure is created, which draws a solution of the protein in composition through a capillary tube connected to a liquid reservoir. The liquid stream from the capillary tube is sheared into unstable filaments and droplets as it exits the tube, creating the aerosol. A variety of configurations, flow rates, baffle equipment can be employed to achieve the desired performance characteristics of a given jet nebulizer. In an ultrasonic nebulizer, high frequency electric energy is used to create mechanical vibratory energy, which typically employs a piezoelectric transducer. This energy is transmitted to the formulation of the protein in composition either directly or through a coupling fluid, creating an aerosol that includes the protein in composition. Advantageously, the particles of the pharmaceutical composition distributed by a nebulizer have a particle size of less than about 20 μm, less than about 19 μm, less than about 18 μm, less about 17 μm, less than about 16 μm, less about 15 μm, less than about 14 μm, less than about 13 μm, less than about 12 μm, less than about 11 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm. Pharmaceutical compositions comprising a compound of the present invention suitable for use with a nebulizer, either jet or ultrasonic, typically include a concentration of about 0.1 mg to about 100 mg of a compound contemplated herein per mL of solution or mg / gm, or any range or value therein that includes, without limitation, 0.1, 0.2. , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / mL or mg / gm. The pharmaceutical composition can include agents such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant and for example zinc. The pharmaceutical composition may also include an excipient or agent for stabilization of the compound such as a buffer, a reducing agent, a bulk protein or a carbohydrate. Bulk proteins useful in pharmaceutical compositions suitable for use in a sprayer include albumin, protamine or the like. Typical carbohydrates useful in the pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose or any combination thereof. The pharmaceutical composition may also include a surfactant, which can reduce or prevent the surface-induced aggregation of the pharmaceutical composition caused by the atomization of the solution in the formation of an aerosol. Various conventional surfactants may be employed such as polyoxyethylene fatty acid esters, and alcohols, and polyoexethylene-sorbitol fatty acid esters. The amounts will generally vary between 0.001 and 10% by weight of the formulation. Suitable surfactants for the purposes of the invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20 or the like. Additional agents known in the art can also be included in the pharmaceutical composition. 3. Administration by a metered dose inhaler In a metered dose inhaler (MDI), a propellant, a compound of the present invention and any excipient or other additives are contained in a can as a mixture that includes a liquefied, compressed gas. The actuation of the dosing valve releases the mixture as an aerosol, typically containing particles in the size range of less than about 20 μm, less than about 19 μm, less than about 18 μm, less than about 17 μm, less than about 16 μm, less than about 15 μm, less than about 14 μm, less than about 13 μm, less than about 12 μm, less than about 11 μm, less than about 10 μm, less than about 9 μm, less than about 8 μm, less than about 7 μm, less than about 6 μm, less than about 5 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm. The desired size of the aerosol particles can be obtained by employing a formulation of a compound of the present invention produced by various methods known to those skilled in the art including, but not limited to, jet milling, spray drying. , condensation at critical point. Suitable metered-dose inhalers include those manufactured by 3M or Glaxo and employing a hydrofluorocarbon propellant. Pharmaceutical compositions for use with a metered dose inhaler device will generally include a finely divided powder containing a compound contemplated herein as a suspension in a non-aqueous medium, for example, suspended in a propellant with the aid of an agent surfactant. The propellant may be any conventional material used for this purpose such as chlorofluorocarbon, or hydrochlorofluorocarbon, or hydrofluorocarbon, or hydrocarbon including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1-tetrafluoroethane, HFA-134a (hydrofluoroalkane-134a), HFA-227 (hydrofluoroalkane-227) or similar. The surfactant can be chosen to stabilize the compound of the present invention as a suspension in the propellant, to protect the active agent against chemical degradation. Suitable surfactants include sorbitan triolate, soy lecithin, oleic acid or the like. In some cases, aerosols are formed in solution using solvents such as ethanol. One skilled in the art will recognize that the methods of the present invention can be achieved by pulmonary administration of a compound contemplated herein by devices not described herein. B. Mucous Administration For absorption through mucosal surfaces, the compositions and methods of the present invention for administering a compound contemplated herein include an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, a bioactive peptide, and an aqueous continuous phase, which promotes absorption through the mucosal surface by achieving mucoadhesion of the emulsion particles. See, for example, United States Patent No. 5,514,670. The mucosal surfaces suitable for the application of the compositions of the present invention can include corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, abdominal, intestinal and rectal administration. Pharmaceutical compositions for vaginal or rectal administration, such as suppositories, may contain as excipients, for example, polyalkylene glycols, petrolatum, cocoa butter. The pharmaceutical compositions for intranasal administration can be solid and contain excipients, for example, lactose or they can be aqueous or oily solutions of nasal drops. For buccal administration, the excipients include sugars, calcium stearate, magnesium stearate, pregelatinized starch. See, for example, U.S. Patent No. 5,849,695. c. Transdermal Administration The pharmaceutical compositions of the present invention can be administered via transdermal routes using forms of transdermal skin patches. For transdermal administration, a compound of the present invention is encapsulated in a delivery device such as a liposome or polymeric nanoparticle, microparticle, microcapsule, or microsphere (collectively referred to as "microparticles" unless otherwise noted). Any suitable dispensing device can be used, for example, microparticles made of synthetic polymers, such as polyoxyacids, for example, polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyandrydrides and polyphosphazenes, and natural polymers such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides, and any combination thereof. See, for example, U.S. Patent No. 5,814,599, incorporated herein by reference in its entirety. To be administered in the form of a transdermal delivery system, the administration of the dose may be continuous rather than intermittent from beginning to end of the dose regimen. Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, pastes comprising the ingredient to be administered in a pharmaceutically acceptable carrier. According to one aspect of the present invention, a transdermal patch is used as a topical distribution system. The topical compositions can be mixed with a variety of carrier materials including, for example, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, myristyl-propionate PPG2, or any mixture thereof, for to form, for example, alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in gel or cream formulations. Examples of these carriers and methods of formulations can be found in REMINGTON'S PHARMACEUTICAL SCIENCES (1990), incorporated herein by reference in its entirety. The pharmaceutical formulations may contain from about 0.005% to about 10% by weight of the active ingredient, for example, from about 0.01% to 5% by weight of the active ingredient. D. Prolonged Administration It may be desirable to distribute the compounds of the present invention to the subject for extended periods of time, for example, for periods of one week to one year for individual administration. Certain medical devices may be employed to provide intermittent continuous dosing or at the request of a patient. The devices may include a pump or diffusion apparatus, or any other device containing a drug reservoir and optionally diagnostic or monitoring components to regulate the distribution of the drug. Various forms of slow release, deposit or implant dose can be used. For example, a dosage form may contain a non-toxic pharmaceutically acceptable salt of the compound contemplated herein having a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, mono- or di-sulfonic acids of naphthalene, polygalacturonic acid, or any mixture thereof; (b) a salt with a polyvalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, or any mixture thereof, or with an organic cation formed of for example, N, N'-dibenzyl-ethylenediamine or ethenylenediamine; or (c) combinations of (a) and (b), for example, a zinc tannate salt. Additionally, the compounds of the present invention or a relatively insoluble salt, such as those described above, can be formulated in a gel, for example, an aluminum monostearate gel with, for example, sesame oil, suitable for injection. Exemplary salts include, but are not limited to, zinc salts, zinc ethanoate salts, pamoate salts and any mixture thereof. Another type of slow release depot formulation for injection may contain the compound or salt dispersed or encapsulated in a non-toxic, non-antigenic and slow-degradation polymer such as a polylactic acid / polyglycolic acid polymer, for example, as described in U.S. Patent No. 3,773,919. The relatively soluble compounds or salts thereof can also be formulated in cholesterol matrix silastic tablets, particularly for use in animals. Additional slow-release, depot or implant formulations, for example, gas or liquid liposomes, are described, for example, in U.S. Patent No. 5,770,222; SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS (1978), incorporated herein by reference in its entirety. Dose Determination In general, the compounds contemplated herein may be used alone or in conjunction with other therapeutic agents at appropriate doses to obtain optimum efficiency while minimizing any potential toxicity. The dose regimen using a compound of the present invention can be selected according to a variety of factors including the type, species, age, weight, sex, medical condition of the patient; the severity of the condition to be treated; the administration route; the liver and kidney function of the patient; and the particular compound employed. A skill physician or veterinarian can easily determine and prescribe the effective amount of the drug required to prevent, counteract or stop the progress of the condition. Optimal precision in achieving drug concentrations within the range that produces maximum efficiency with minimal toxicity may require a regimen based on the kinetics of the compound's ability to a target site. The distribution, equilibrium and elimination of a drug can be considered when determining the optimal concentration for a treatment regimen. The doses of a compound contemplated herein can be adjusted when combined to achieve desired effects. On the other hand, the doses of these different therapeutic agents can be optimized and combined independently to achieve a synergistic result where the pathology is reduced more than it would be if only any agent were used. In particular, the toxicity and therapeutic efficacy of a controlled compound can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine LD50. (the lethal dose to 50% of the population) and the ED50 the therapeutically effective dose in 50% of the population). The dose ratio between the toxic and therapeutic effect is the therapeutic index and can be expressed as the LD50 / EDS0 ratio. Compounds that exhibit high therapeutic indices are typically used. Although compounds that exhibit toxic side effects can be used, care must be taken to design a distribution system that targets these to the affected tissue site in order to minimize potential damage to uninfected cells and thereby reduce the secundary effects . In general, the compounds of the present invention can be administered in a manner that maximizes efficiency and minimizes toxicity. The data obtained from cell culture assays and animal studies can be used in the formulation of a variety of doses for use in humans. The doses of these compounds are generally within a range of circulating concentrations that include EDS0 with little or no toxicity. The dose may vary within this range depending on the dosage form employed and the route of administration used. For any compound used in the methods of the invention, the therapeutically effective dose can be added initially from assays in cell culture. A dose can be formulated in animal models to achieve a range of circulating plasma concentrations that includes ICS0 (the concentration of the test compound achieving maximum mean inhibition of symptoms) as determined in the cell culture. This information can be used to determine exactly useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography. In addition, administration of the doses of the pharmaceutical compositions of the present invention can be optimized using a pharmacokinetic / pharmacodynamic modeling system. For example, one or more dose regimens may be chosen and a pharmacokinetic / pharmacodynamic model may be used to determine the pharmacokinetic / pharmacodynamic profile of one or more dose regimens. Then, one of the dosage regimens for administration can be selected which achieves the desired pharmacokinetic / pharmacodynamic response based on the particular pharmacokinetic / pharmacodynamic profile. See, WO 00/67776, incorporated herein by reference in its entirety. Methods are known in the art to determine the effective doses for therapeutic and prophylactic purposes for the described pharmaceutical compositions or the described combinations of drugs, whether or not they are formulated in the same composition. For therapeutic purposes, the term "co-effective amount," as used herein, means the amount of each active compound or pharmaceutical agent, alone or in combination, that produces the biological or medical response in a tissue, animal system. or human being that is being sought by a researcher, veterinarian, medical doctor, or other practitioner, which includes relief of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progress of a disorder), the term "co-effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, which inhibits in a subject the onset or Progression of a disorder as sought by an investigator, veterinarian, medical doctor or other physician. In this manner, the present invention provides combinations of two or more therapeutic agents wherein, for example, (a) each therapeutic agent is administered in a therapeutically or prophylactically effective amount, independently; (b) at least one therapeutic agent in the combination is administered in an amount that is subtherapeutic or sub-pro-lactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional therapeutic agents according to to this invention; or (c) both therapeutic agents are administered in an amount that is subtherapeutic or subprophylactic if administered alone, but are therapeutic or prophylactic when administered together. The combinations of three or more therapeutic agents are analogously possible. Methods of combination therapy include co-administration of an individual formulation containing all active agents; essentially the contemporary administration of more than one formulation; and the administration of two or more active agents formulated separately. Dosage The pharmaceutical compositions of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times a day. In the case of oral administration, the daily dose of the compositions can be varied over a broad range from about 0.0001 to about 1,000 mg per patient per day. The range can be more particularly from about 0.001 mg / kg to 10 mg / kg of body weight per day, about 0.1-100 mg, about 1.0-50 mg or about 1.0-20 mg per day for adults (at about 60). kg). For oral administration, the pharmaceutical compositions can be provided in a form of labeled or unlabeled tablets containing approximately 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200 , 250, 300, 350, 400, 450, 500, 550, 600, 650, or 700 mg of the active ingredient for the symptomatic adjustment of the dose for the patient to be treated.

In the case of injections, it is usually convenient to take an intravenous route in an amount of approximately 0.01-30 mg, approximately 0.1-20 mg or approximately 0.1-10 mg per day to adults (approximately 60 kg). In the case of other animals, the dose calculated by 60 kg can also be administered. The daily dose of the pharmaceutical compositions can be varied over a wide range from about 5 to about 1000 mg per adult human per day. For oral administration, the pharmaceutical compositions are optionally provided in the form of tablets containing 5.0, 10.0, 15.0, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, or 700 milligrams of the active ingredient for the symptomatic adjustment of the dose to the patient to be treated. An effective amount of the drug is typically provided at a dose level from about 0.1 mg / kg to about 20 mg / kg of body weight per day. According to one aspect of the present invention, the dose level is from about 0.2 mg / kg to about 10 mg / kg of body weight per day. According to another aspect of the present invention, the dose level is from about 0.5 mg / kg to about 10 mg / kg of body weight per day. The compounds can be administered at a rate of about 1 to about 10 times per day.

Doses of a compound of the present invention may optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and / or 100-500 mg / kg / administration or any range, value or fraction thereof, or to achieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0 , 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0, 5.5 ., 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 1 2.9, 13.0, 13.5, 13.9, 14, 14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and / or 5000 ug / mL of serum concentration by single or multiple administration or any interval, value or fraction of the same.

As a non-limiting example, the treatment of humans or animals can be provided as a one-time or periodic dose of a compound of the present invention from 0.1 to 100 mg / kg such as 0.5, 0.9, 1.0, 1.1, 1.5, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 , 34, 35, 36, 37, 38, 39, or 40, or alternatively or additionally, at least one of the week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, or alternatively or additionally, at least one of 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years or any combination thereof, use Do individual, infusion or repeated doses. Specifically, the pharmaceutical compositions of the present invention can be administered at least once a week over the course of several weeks. According to an aspect of the present invention, the pharmaceutical compositions are administered at least once a week for several weeks to several months. According to another aspect of the present invention, the pharmaceutical compositions are administered once a week for four to eight weeks. According to yet another aspect of the present invention, the pharmaceutical compositions are administered once a week for four weeks. More specifically, the pharmaceutical compositions can be administered at least once a day for about 2 days, at least once a day for about 3 days, at least once a day for about 4 days, at least once a day. for about 5 days, at least once a day for about 6 days, at least once a day for about 7 days, at least once a day for about 8 days, at least once a day for about 9 days, at less once a day for approximately 10 days, at least once a day for approximately 11 days, at least once a day for approximately 12 days, at least once a day for approximately 13 days, at least once a day for approximately 14 days, at least once a day for approximately 15 days, at least once a day for approximately 16 days, at least once a day for approximately at least 17 days, at least once a day for approximately 18 days, at least once a day for approximately 19 days, at least once a day for approximately 20 days, at least once a day for approximately 21 days, at least once a day for approximately 22 days, at least once a day for approximately 23 days, at least once a day for approximately 24 days, at least once a day for approximately 25 days, at least once a day for approximately 26 days, at least once a day for approximately 27 days, at least once a day for approximately 28 days, at least once a day for approximately 29 days, at least once a day for approximately 30 days, or at least once a day for approximately 31 days. Alternatively, the pharmaceutical compositions may be administered about once a day, approximately once every 2 days, approximately once every 3 days, approximately once every 4 days, approximately once every 5 days, approximately once every 6 days. , approximately once every 7 days, approximately once every 8 days, approximately once every 9 days, approximately once every 10 days, approximately once every 11 days, approximately once every 12 days, approximately once every 13 days, about once every 14 days, about once every 15 days, about once every 16 days, about once every 17 days, about once every 18 days, about once every 19 days, about once every 20 days, about once every 21 days, approximately once every 22 days, approximately once every 23 days, approximately once every 24 days s, approximately once every 25 days, approximately once every 26 days, approximately once every 27 days, approximately once every 28 days, approximately once every 29 days, approximately once every 30 days, or approximately once every 31 days. days. The pharmaceutical compositions of the present invention may alternatively be administered at about once a week, approximately once every 2 weeks, approximately once every 3 weeks, approximately once every 4 weeks, approximately once every 5 weeks, approximately once every 6 weeks, approximately once every 7 weeks, approximately once every 8 weeks, approximately once every 9 weeks, approximately once every 10 weeks, approximately once every 11 weeks, approximately once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, about once every 16 weeks, about once every 17 weeks, about once every 18 weeks, about once every 19 weeks, approximately once every 20 weeks. Alternatively, the pharmaceutical compositions of the present invention may be administered approximately once each month, approximately once every 2 months, approximately once every 3 months, approximately once every 4 months, approximately once every 5 months, approximately every 6 months, approximately once every 7 months, approximately once every 8 months, approximately once every 9 months, approximately once every 10 months, approximately once every 11 months, or approximately once every 12 months. Alternatively, the pharmaceutical compositions may be administered at least once a week for about 2 weeks, at least once a week for about 3 weeks, at least once a week for about 4 weeks, at least once a week. week for about 5 weeks, at least once a week for about 6 weeks, at least once a week for about 7 weeks, at least once a week for about 8 weeks, at least once a week for about 9 weeks, at least once a week for approximately 10 weeks, at least once a week for approximately 11 weeks, at least once a week for approximately 12 weeks, at least once a week for approximately 13 weeks. weeks, at least once a week for approximately 14 weeks, at least once a week for approximately 15 weeks, at least once a week mana for approximately 16 weeks, at least once a week for approximately 17 weeks, at least once a week for approximately 18 weeks, at least once a week for approximately 19 weeks, or at least once a week for approximately 20 weeks. Alternatively, the pharmaceutical compositions may be administered at least once a week for approximately 1 month, at least once a week for approximately 2 months, at least once a week for approximately 3 months, at least once. per week for approximately 4 months, at least once a week for approximately 5 months, at least once a week for approximately 6 months, at least once a week for approximately 7 months, at least once a week week for approximately 8 months, at least once a week for approximately 9 months, at least once a week for approximately 10 months, at least once a week for approximately 11 months, or at least once a week week for approximately 12 months.

Methods for using the compounds A. Modulation of proteoglycan of heparan sulfate The present invention provides methods and compositions comprising the identification of compounds for the treatment and prevention of vascular diseases, particularly cardiovascular diseases. More specifically, the present invention relates to methods and compositions for the treatment or prevention of proliferation of smooth muscle cells, such as "antiproliferative" compounds that affect the synthesis of proteoglycans. Methods for detecting compounds or molecules that induce HSPG synthesis comprise the addition of these compounds to assays and the measurement of HSPG synthesis, include, without limitation, the production of Syndecan, Glypican and Perlecan. Methods for measuring induction of Perlecan synthesis are also contemplated herein. Although some aspects of the present invention are described with respect to Perlecan, it is important to note that the compositions, methods and assays described herein are equally applicable in the context of other HSPG including Sindican and Glypican. The production of HSPG is important in the regulation of SMC proliferation and the methods and compositions described herein provide high-throughput detection of molecules that induce the production of HSPG and regulate the proliferation of SMC. Additionally, the present invention comprises methods and compositions for gene therapy, comprising administering compositions comprising nucleic acids that affect the synthesis or expression of HSPG, particularly Perlecan. For example, vectors comprising Perlecan-encoding nucleic acids or active Perlecan fragments are provided to cells, for example, cells from circulatory tissue such as, for example, endothelial cells. These vectors are known to those skilled in the art and can be administered in formulations that enhance the uptake of the vector by the cells. The present invention also encompasses methods and compositions for inducing the synthesis or expression of HSPG, including but not limited to HSPG such as Syndecan, Glypican and Perlecan, and also comprises induction of synthesis of HSPG active fragments, e.g. assets of Perlecan. As used herein, when an HSPG is referred to, the entire molecule or fragments are included herein. For example, Perlecan refers to complete Perlecan molecule or fragments thereof. Perlecan fragments may have the same or different effects on cells. All these fragments and assets are contemplated in the present invention. A major extramolecular HSPG in the matrix of blood vessels is Perlecan, a protein originally identified in the basement membrane. It interacts with extracellular matrix proteins, growth factors and receptors. Perlecan is also present in base membranes other than blood vessels and in other extracellular matrix structures. It consists of a core protein of Mr. -450,000 kDa to which three chains of HS of ~ 70 kDa bind to one end of the molecule. The core protein of Perlecan has a complex functional organization consisting of five consecutive domains with homologies to molecules comprised in the control of cell proliferation, lipoprotein binding and cell adhesion. The I N-terminal domain (aa -1-195) contains binding sites for HS chains. Domain II comprises four repeats homologous to the ligand-binding portion of the LDL receptor. Domain III has homology to the laminin IVa and IVb domains and is thought to measure cell binding. SMC hyperplasia is a major event in the development of atherosclerosis and is also responsible for the significant number of failure rates after vascular procedures such as angioplasty and coronary artery bypass surgery, particularly due to restenosis. The proliferation of SMCs of the arterial wall in response to local injury is a major feature of many vascular proliferative disorders. While it is not desired to be a theory, it is generally thought that the endothelium regulates the growth of the underlying SMCs. In the normal vessel, SMCs are inactive, but proliferate when damage to the endothelium occurs. Growth modulators that occur naturally, many of which are derived from the endothelium, strictly control the in vivo proliferation of SMCs. Although not intended to be by a particular mechanism, it is believed that extracellular HSPGs measured inactivity in SMCs. In inactive SMCs, fasting in serum, Perlecan synthesis is induced, for example, Perlecan inhibits DNA synthesis and SMC proliferation, and Perlecan blockage results in stimulation of DNA synthesis even in the absence of serum and growth factors. The induction of Perlecan and other HSPG is an important event for the inhibition of SMC growth. Known antiproliferative agents fail to inhibit the proliferation of SMC when the effects of Perlecan are blocked. In this manner, the present invention comprises methods and compositions for mediating Perlecan and other HSPG syntheses, expression and amounts are taught for the maintenance of SMCs in an inactive state. These methods and compositions of the present invention also comprise treatment and prevention of vascular diseases, more specifically pathologies related to the proliferation of SMC. In particular, these pathologies include atherosclerosis and restenosis. The present invention also comprises methods and compositions for the treatment and prevention of vascular occlusive conditions including, without limitation and without limitation, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis. These methods and compositions comprise methods for the inhibition of the growth of smooth muscle cells (SMC) and the proliferation thereof, and for induction of inactivity in smooth muscle cells. The present invention further comprises methods and compositions for inducing HSPG synthesis and expression including, for example, the induction of HSPG such as Syndecan, Glypican and Perlecan, for example, Perlecan synthesis and gene expression. Neointimal hyperplasia is commonly seen after various forms of vascular injury and a major component in the vein graft response to surgical collection and implantation in high-pressure arterial circulation. In neointimal hyperplasia, the smooth muscle cells in the middle layer of the vessel wall become activated, divide, proliferate and migrate to the inner layer. The resulting normal, neointimal cells express pro-inflammatory molecules, which include cytosines, chemokines, and adhesion molecules that additionally activate a cascade of events that lead to occlusive neointimal disease and eventual injury. The proliferation of SMCs in response to local injury is a major feature of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. Although it is not desired to join any particular theory, it is generally believed that the endothelium regulates the growth of the underlying SMCs. In normal vessels, the SMCs are inactive, but proliferate when damage to the endothelium occurs. The endothelium, in addition to producing a variety of growth factors, also generates key growth inhibitors. HSPGs are components of vascular cell membranes and extracellular matrix that are believed to control a variety of vascular functions including functioning as a barrier against molecules and cationic macromolecules, which protect the main structural component of the base membrane, type IV collagen, lytic protease attack, binding to ketosines and growth factors that include, but are not limited to, basic fibroblast growth factor (bFGF), factor of vascular endothelial growth (VEGF), hepatocyte growth factor (HFG), keratinocyte growth factor (KGF); and transforming growth factor ß (TGF-ß), which function as storage for these cytosines, regulate the fate of mesodermal cells, heart placement, activation in vasculogenesis and angiogenesis after ischemic damage, affecting between cell actions with additive proteins and blood vessels, which induce smooth muscle cell proliferation during atherosclerosis, which act to increase cellular spread, which inhibit chemotaxis, and which affects the metabolism of lipoproteins and non-promgenic characteristics of endothelial cells. Additionally, it is believed that HSPGs have different functions in different locations. For example, while cell surface HSPGs function as co-receptors for growth factors and support cell growth, extracellular HSPGs can inhibit cell growth. Although it is currently believed that endothelial HSPGs inhibit the proliferation of SMCs, it is not known if SMCs synthesize antiproliferative HSPG that acts as autocrine inhibitors. Not wishing to be bound by any particular mechanism, it is currently believed that HSPGs inhibit DNA synthesis and SMC proliferation and block HSPG resulting in stimulation of DNA synthesis even in the absence of serum and growth factors. In fact, known antiproliferative agents fail to inhibit SMC proliferation when the effects of HSPG are blocked. Examples of HSPGs include Syndecan, Glypican and Perlecan, which are generated within the cardiovascular system. The SCMs express Syndecans 1,2 and 4 Glypican-1 and Perlecan. The regulation of the expression of HSPG in these cells, however, is not known. Cell growth stimulators such as platelet derived growth factor (PDGF), thrombin, serum, oxidized low density lipoproteins (LDL) and lysolecithin have been shown to decrease HSPG, and in particular, decrease Perlecan. In contrast, cellular antiproliferative agents, TGF-β, apolipoprotein E and heparin stimulate HSPG. The present invention comprises methods and compositions for the treatment and prevention of proliferation of smooth muscle cells, including vascular occlusive pathologies. These methods comprise administering compositions comprising therapeutic agents capable of inhibiting the proliferation of SMCs. The administration of these therapeutic agents that are effective in inhibiting SMC proliferation, such as the aforementioned tisolidinadiione compositions are administered to humans and animals suspected of having or having had, for example, vasculopathy or those who have undergone to angioplasty or other procedures that damage the endothelium. The effective amounts are administered to humans and animals in doses that are safe and effective. Administration routes include, without limitation, intravenous, subcutaneous, transdermal, nasal and inhalation therapies. These therapeutic agents can be used in conjunction with other therapeutic agents or altered patient activities, such as changes in exercise or diet. The compounds of the present invention are also useful in the treatment or prophylaxis of at least one cardiovascular disease in a cell, tissue, organ, animal or patient that includes, without limitation, cardiac stunning syndrome, myocardial infarction, failure congestive heart attack, attack, ischemic attack, hemorrhage, atherosclerosis, atherosclerosis, restenosis, atherosclerotic diabetic disease, hypertension, hypertension, renovascular hypertension, syncope, stroke, syphilis of the cardiovascular system, heart failure, choriopulmonary, primary pulmonary hypertension, cardiac arrhythmias, rhythms atrial ectopics, atrial palpitation, atrial fibrillation (sustained or paroxysmal), post-perfusion syndrome, inflammatory response of cardiopulmonary bypass, chaotic or multifocal atrial tachycardia, QRS tachycardia of regular narrowing, specific arrhythmias, ventricular fibrillation, bundle of His arrhythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, or coronary artery disease, angina pectoris, myocardial infarction, heart disease, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart disease, endocarditis, pericardial disease, cardiac tumors, aortic and peripheral aneurysms, aortic dissection, inflammation of the aorta, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, arterial occlusive disorders, peripheral atherosclerotic disease, thromboangitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, tr venous ombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperfusion injury, post-pump syndrome, ischemia-reperfusion injury, and dyslipidemia.

These methods optionally comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one compound to a cell, tissue, organ, animal or patient in need of this modulation, treatment or therapy. 1. Assessment of HSPG Activity The present invention comprises methods and compositions for determining therapeutic agents that are capable of affecting the proliferation of SMC. These assays are taught herein and can be used as assays to determine agents that affect the amount or activity of HSPG, for example, Perlecan, in these assays. For example, in one assay, Perlecan is induced in cells by certain inducers, and the response was measured. Potential therapeutic agents are then added to one assay after replication and the effect of Perlecan induction is determined. Using these methods and compositions, therapeutic agents are determined that either can inhibit Perlecan, can elevate the induction of Perlecan, or have no effect at all. These therapeutic agents can then be used in animals with SMC proliferation pathologies. The present invention also comprises compositions comprising the compounds identified by the methods as having a desired activity. The compositions have utility in treatment of cells, tissues, or whole organisms. These compositions are formulated for use in methods of administration in an amount effective to treat conditions such as biological conditions including, but not limited to, vascular occlusive lesions including atherosclerosis, transplant vasculopathy, cardiac allograft vasculopathy, restenosis, and atherosclerosis of the graft after coronary transplantation. The compositions may comprise other compounds that include compounds with activities and pharmaceutical adjuncts that are needed for the administration of the compound or compounds with the desired activity. The compositions may additionally be administered exclusively or in conjunction with other pharmaceutical compositions and surgical methods to treat proliferation of smooth muscle cells and vascular occlusive diseases, including without limitation, before, during or after PTCA procedures. In the assays of the present invention, the compound initially has known activities, effect or known effects. The activity of the compound is unknown, since the effects of the compound in the assays of the present invention are not yet determined. The compound may have many other known activities, and may be a compound having other therapeutic uses. Any agent that causes the test cells or components to respond in a measurable manner and is contemplated by the present invention. The present invention comprises methods and compositions for measuring the activity of unknown compounds. These methods comprise assays for specific activity of biological components comprised in a known cellular response. The assays provide a measurable response in which the activity of the unknown compounds is determined. This response can be measured by methods known to those skilled in the art, for example, in an ELISA. One aspect of the present invention comprises measuring the effects of the compounds on the SMC proliferation in response to an HSPG induction agent. According to one aspect of the present invention, a compound suspected of effecting HSPG synthesis is added to the cells in the assay. The response of the cells can be measured by determining HSPG synthesis levels measured by methods known to those skilled in the art and comparing the amount of HSPG synthesis in untreated cells. The compound can have a stimulating effect, an inhibitory effect, a stabilizing effect, or no effect at all. According to another aspect of the present invention, composition suspected of effecting SMC proliferation is designed to smooth muscle cells in growth medium or serum free medium. The change in cell proliferation can be measured by methods known to those skilled in the art and compared to the proliferation of cells not treated with the compound. The composition may have a stimulating effect, an inhibitory effect, a stabilizing effect, or no effect at all. The compositions with stimulation effect HSPG, particularly Perlecan stimulation effects, are useful as antiproliferative therapeutics, specifically, the inhibition of SMC proliferation and, thus, the treatment of vascular occlusive conditions. These selective activators of, for example, Perlecan include all organic molecules, peptides, peptoids or polynucleotides that act directly on Perlecan to modulate biological activity or increase the biological stability of the protein. In addition, Perlecan selective activators can increase Perlecan biosynthesis by increasing transcription of the Perlecan gene, by increasing the biological stability of Perlecan APNm, or by increasing translation of Perlecan mRNA into the protein. Additionally, Perlecan selective activators can block or decrease the effects of agents or proteins that inhibit Perlecan activity. The present invention also comprises methods and compositions for assays that can be used to identify these selective Perlecan activators or inhibitors. These assays readily determine activators that favor expression and inhibitors that reduce the expression of the amount of Perlecan and its biological activity. In general, these assays include, but are not limited to, promoter-based assays to identify compounds that affect Perlecan and assays for the biological activity of Perlecan in partially purified recombinant proteins, or lysates of cells expressing Perlecan in the presence or absence of compounds of interest. Perlecan measurements include assays for biological activity and quantification of the Perlecan protein, using ELISA determinations or Western blotting, or quantification of RA? of Perlecan using RT-PCR, or Northern blots. Direct and indirect methods of measuring changes without Perlecan are contemplated by the present invention. The assay methods contemplated herein are dependent upon the indirect measurement of Perlecan through the measurement of activity determinants or deletion of Perlecan. Additionally, the direct determination of the change in the amount of Perlecan protein can be made using other immunological methods, such as Western blots, densitometric measurements or ELISA methods. Alternatively, direct determination of the change in the amount of Perlecan mRNA can be achieved using RT-PCR or Northern analysis methods that are known to one skilled in the art. Measurements can also be made directly using cell lysates, and purified or partially purified Perlecan protein which is either a recombinant or natural form of the protein. The means for measuring biological activity are known to those skilled in the art. Another method to identify or determine compounds that affect the Perlecan comprises identifying compounds that interact with the promoter regions of the Perlecan gene, or interact and affect the proteins that interact with the promoter region, and are important in the transcriptional regulation of Perlecan expression. . In general, the method comprises a vector comprising regulatory sequences of the Perlecan gene and an indicator region controlled by regulatory sequences, such as an enzyme, in a promoter-indicator construct. The protein product of the reporter region is referred to herein as an indicator enzyme or an indicator protein. The regulatory region of the Perlecan sequence comprises a variety of nucleotides from about -4000 to +2000, where the transcription initiation site is +1, eg, from 2500 to +1200, for example, from -1500 to +800. in relation to the transcription initiation site. The cells are transfected with the vector and then treated with the compounds of interest. For example, the transfected cells are treated with a compound suspected of performing Perlecan transcription and the activity levels of the Perlecan regulatory sequences are compared to the level of activity in cells that were not treated with the compound. The level of activity of the Perlecan regulatory sequences is determined by measuring the amount of the indicator protein or by determining the activity of the indicator enzyme controlled by the regulatory sequences. An increase in the amount of the indicator protein or the activity of the indicator enzyme shows a stimulatory effect in the Perlecan, by positively affecting the promoter, while a decrease in the amount or the indicator protein or the activity of the indicator enzyme shows a negative effect on the promoter and in this way, on the Perlecan. Additionally, the present invention comprises methods and compositions for identifying selective inhibitors of the Perlecan protein or its biological activity. These selective Perlecan inhibitors are small organic molecules, peptides, peptoids, or polypeptides that act directly on the Perlecan to the promoter region of Perlecan to modulate the extent or to decrease the biological activity of the protein. In addition, Perlecan selective inhibitors can define Perlecan biosynthesis by decreasing the transcription of the Perlecan gene, by decreasing the biological stability of Perlecan NMR or by decreasing the translation of Perlecan NMR into the protein. Additionally, two selective Perlecan inhibitors can block or decrease the effects of agents or proteins that increase Perlecan activity. Table 1 presents examples that have been shown to induce HSPG.

Table 1 B. Modulation of Heparanase HSPGs are important components of the sub-endothelial extracellular matrix and the basement membrane of blood vessels Rosenberg et al., 99 J. CLIN. INVEST. 2062-70 (1997). The base membranes are continuous sheets of extracellular matrix composed of collagenous and non-collagenous proteins and proteoglycans that separate parenchymal cells from the underlying interstitial connective tissue. They have characteristic permeabilities and play a role in the maintenance of the tissue architecture. In addition to the HPSG, the basal lamina consists predominantly of a complex network of adhesion proteins, fibronectin, laminin, collagen and vitronectin. Wight et al., 6 CURR. OPIN. LIPIDOL. 326-334 (1995). Heparan sulfate (HS) is an important structural component of the basal lamina: each of the adhesion proteins interacts with the HSPG side chains (HS) within the matrix. In this way, HSPG functions as a barrier to the extravasation of metastatic and inflammatory cells. The cleavage of HS by enoglycosidase-Heparanase produced by metastatic tumor cells and inflammatory cells destroys the filtration properties of the sheet. In addition, degradation of HS can aid in the disassembly of the extracellular matrix and thereby facilitate cell migration by allowing blood and bone cells to escape into the bloodstream. Vlodavsky et al., 12 INVASION METÁSTASIS 112-127 (1992).

Heparanase activity has been described in various tissues and cell types including liver, placenta, platelets, fibroblasts, neutrophils, activated T and B lymphocytes, monocytes, and endothelial cells (7-16). Nakajima et al., (31) CANCER LETT. 277-283 (1986); Nakajima et al., 36 J. CELL. BIOCHEM. 157-167 (1988); Ricoveri et al., 46 CANCER RES. 3855-3861 (1986); Gallagher et al., 250 BIOCHEM. J. 719-726 (1988); Dempsey et al., 10 GLYCOBIOLOGY 467 (2000); Goshen et al., 2 MoL. HUM REPROD. 679 (1996); Parish et al., 76 IMMUNOL CELL BIOL. 104-113 (1998); Gilat et al., 181 J. ExP. MED. 1929-1934 (1995); Graham, et al., 39 BIOCHEM. MOL. BIOL. INT. 56371 (1996); Pillarisetti et al., 270 J. BIOL. CHEM. 29760-29765 (1995). There is increasing interest in heparan sulfate compounds and their related enzymes due to a possible relationship between changes in normal activity and tumor invasion and tumor metastatic activity. An important process in tissue invasion by tumor cells transported in blood and white cells comprises their passage through the layer of vascular endothelial cells and the subsequent degradation of the underlying basal lamina or base membranes and extracellular matrix with a battery of Protease glycosidase secreted. Nakajinia et al., 220 SCIENCE 611-613 (1983); Vlodavsky et al., 12 INVASION METÁSTASIS 112-127 (1992).

It has been shown that Heparanase activity correlates with the metastatic material of human and animal tumor cell lines. Nakajima et al., 31 CANCER LETT. 277-283 (1986); Nakajima et al., 212 PROG CLIN BIOL RES. 113-122 (1986); Freeman et al., 325 BIOCHEM. J. 229-237 (1997); Vlodavsky et al., 5 NAT. MED. 793-802 (1999); Hulett et al., 5 NAT MED. 803-809 (1999). It is also known that they regulate the activity of the growth factor. Many growth factors remain bound to heparan sulfate in storage form and are disassociated by Heparanase during angiogenesis, improving the survival rate of cancer cells. Serum Heparanase levels in rats were greater by more than one order of magnitude after injection to the highly metastatic mammary adenocarcinoma cell rats. In addition, the activity of Heparanase in the sera of rats that have MTLn3 tumors, correlated well with the degree of metastasis. In addition, Heparanase activity in serum / urine in patients with cancer was shown to be 2-4 times increased in particular where tissue metastases occurred. Because cleavage of HS seems to be essential for the passage of metastatic tumor cells and leukocytes through the basement membranes, studies of Heparanase inhibitors provide the potential to develop a novel and highly selective class of anti-metastatic and anti-inflammatory drugs. In this way, the present invention also relates to compounds that modulate Heparanase activity. These compounds are useful in the treatment and / or prevention of cancer including, but not limited to, malignant and non-malignant growth of cells, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B cell ALL, cell T or FAB, acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodiplasmatic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-cancerous lymphoma hodgkin, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, nasoparingeal carcinoma, malignant histiocytosis, paraneoplastic syndrome / hypercalcemia of malignancy, solid tumors, adenocarcinomas, sarcomas, malignant melanoma, hemangioma, metastatic disease, related bone resorption to cancer, bone pain related to cancer. According to another aspect of the present invention, the compounds contemplated by the present invention are useful in the modulation of Heparanase activity for a means to treat and prevent autoimmune diseases. By way of background, in the normal course of resolving a disease in an infected tissue, the inactive, local immune effector cells in the body become activated after recognizing antigens from the infecting organism as foreign. In the activation of these effector cells in the body, signaling molecules are synthesized and secreted (chemokines, lymphokines and cytokines) that attract additional immune effector cells to the site of infection, where they are also activated. Once activated, these immune effector cells become able to leave the vasculature and enter the infected tissue where they begin to bring and distribute the infectious agent and the infected tissue. This process continues until the infection is eradicated. However, occasionally, the immune system does not work well or reacts excessively to the initial insult, which can lead to the initiation of chronic and acute, debilitating and life-threatening diseases. This may occur when (1) the immune system mistakenly identifies a cell surface molecule in normal tissue as a foreign molecule, (2) the synthesis and secretion of chemokines, cytokines and lymphokines does not close after the eradication of the disease, or (3) The immune system overreacts to the apparent infection and destroys large amounts of surrounding normal tissue. In normal activity, activated effector cells attract other effector cells to the blood vessels near the infection. To be "effective" these activated cells must leave the blood vessels and enter the affected tissue. The process of leaving the circulation and entering the infected tissue comprises two different steps. First, the immune effector cells must bind to the luminal / apical surface of the walls of the blood vessel. This is achieved through the interaction of adhesion molecules in the immune effector cells with their locally-favored cognate receptors in expression in the endothelial cells that line the vasculature near the site of infection. Second, after binding to the apical surface and before entering the inflamed tissue, the immune effector cells must cross the basement membrane (BM) and the extracellular matrix (ECM) that surrounds the basal portion of the blood vessels and gives the Vessels their shape and resistance. The BM and the ECM consist of structural proteins embedded in a fiber mesh that consists mainly of complex structures that contain carbohydrates (glycosaminoglycans), of which the main constituent is heparin sulfate proteoglycan (HSPG). In order to cross this barrier, the immune-infecting cell must weaken or destroy it, which is achieved through the local secretion of proteases and heparanase (s).

In this way, the inhibition of heparanase using the compounds of the present invention finds utility in treating arthritis and other autoimmune diseases. More specifically, the compounds of the present invention are useful in the treatment or prophylaxis of at least one immunologically related disease in a cell, tissue, organ, animal, or patient, including, without limitation, rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile rheumatoid arthritis of systemic onset, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, anti-phospholipid syndrome, iridocyclitis / uveitis / neuritis optics, idiopathic pulmonary fibrosis, systemic vasculitis / wegener's granulomatosis, sarcoidosis, vasectomy / orchitis inversion procedures, allergic / atopic diseases, asthma, allergic rickets, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, rejection of organ transplantation I gain, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram-positive sepsis, gram-negative sepsis, crop negative sepsis, fangal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma / hemorrhage, burns , exposure to ionizing radiation, acute pancreatitis, respiratory effort syndrome in adults, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, Crohn's disease, sphingoform cell anemia, diabetes, nephrosis, atopic diseases, hypersensitivity reactions, allergic rickets , hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, haemolytic disease, thrombocytopenia, graft rejection of any organ or tissue, rejection of kidney transplant, rejection of heart transplant, rejection of liver transplant, rejection of pancreas transplant, rejection azo of lung transplantation, rejection of bone marrow transplantation (MBT), rejection of allograft of skin, rejection of cartilage transplantation, rejection of bone graft, rejection of small intestine transplantation, rejection of fetal thymus implant, rejection of parathyroid transplant, rejection of any organ or tissue xenograft, allograft rejection, anti-receptor hypersensitivity reactions, Graves' disease, Raynoud's disease, type B insulin-resistant diabetes, myasthenia gravis, mediated cytotoxicity, type III hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and cutaneous changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, anti-phospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, disease idiopathic of Addison, diabetes mellitus, chronic active hepatitis, vitili or, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic / idiopathic, Wilson's disease, hemacromatosis, alpha deficiency -1-antitrypsin, diabetic retinopathy, hashimoto thyroiditis, osteoporosis, assessment of hypothalamic-pituitary-adrenal axis, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematofagocytic lymphohistiocytosis, dermatological conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerural nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, ankylosing spondylitis, Behcet's disease, pemphigoid gout, cardiomyopathy, celiac sprue-dermatitis, syndrome of chronic fatigue immune dysfunction (CFIDS), chronic inflammatory demyelinating polyneuropathy, Chung-Strauss disease, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves disease, Guillain- Barre, Hashimoto's thyroiditis, idiopathic purple thrombocytopenia (ITP), IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Cogan syndrome, polychondritis, polyglandular syndromes, polymialgia reum tica, polimiocitis and dermatomiocitis, primary agammaglobulinemia, Raynaud's phenomenon, Reiter, rheumatic fever, Sjögren's syndrome, stiff-man syndrome, arthritis Takayusu, temporal arteritis / giant cell arteritis, Wegener's granulomatosis syndrome; therapy with okt3, anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy (for example, including, without limitation, to-astemia, anemia, cachexia), chronic salicylate poisoning. 1. Heparanase Assays The present invention also relates to methods for assessing Heparanase activity. In this regard, one can evaluate, using these assays, the effect of the compounds of the present invention. Additional candidate compounds also useful in the methods of treatment of the present invention can also be evaluated by using the assays discussed herein. Additionally, the present invention also contemplates compositions and methods for assays that measure any glycosidase activity including, but not limited to, any enzyme with glycosaminoglycan degradation activity, chondroitinase, heparan sulfate endoglycosidase, heparan sulfate exoglycosidase, polysaccharide-liases, keratanases, hyaluronidase, glucanase, amylase, and other glycosidases and enzymes. Thus, in one aspect, the present invention comprises compositions and methods for the measurement of cellular and enzymatic activities. These tests can be used to measure these activities, both qualitatively and quantitatively. In addition, assays described herein for determining the presence of these activities can be used in methods for diagnosing metastases, inflammatory conditions and metastatic potentials. In addition, assays of the present invention can also be used to detect compounds that alter, whether they stimulate or inhibit, these cellular and enzymatic activities. The existentotes Heparanase assays require preparation of the radiolabeled substrate and separation of the degraded products from the non-cleaved substrate. See Goshen et al., 2 MoL. HUM REPROD. 679-84 (1996); Nakajima et al., 31 CANCER LETT. 277-83 (1986). Other Heparanase assays require biosynthetic radiolabelling of HSPG associated with matrix and detection of HS chain degradation by gel filtration analysis of the radiolabelled material released from the matrix. Vlodasky et al., 12 INVASION METÁSTASIS 112-27 (1992). Solid phase Heparanase assays have also been developed where HS and heparin chains chemically and biosynthetically radiolabelled to a solid support, with release of the radiolabel from the solid support which is a measure of the enzymatic activity. Assays using these methods are taught in U.S. Patent No. 4,859,581, which is hereby incorporated herein by reference in its entirety. Also, previous studies have radiolabeled both Heparin and HS by iodination in glucosaline residues that occur naturally or by N-acetylation of the partially de-N-sulphated substrate. These procedures require the use of radioactive iodine, which is a powerful emitter and therefore extremely dangerous. For example, a sensitive radioactive assay for Heparanase requires affinity chromatography of the Heparanase excised products in high-histidine glycoprotein columns, Sepharose. Freeman and Parish, 325 BIOCHEM. J. 229-37 (1997). Also, there are some non-radioactive assays available for Heparanase. An assay for Heparanase comprises the measurement of the optical density (at 230 nm) of unsaturated uronic acids formed during the degradation of heparin. A color-based assay for measuring Heparanase activity uses the ability of heparin to interfere with color development during the interaction of the protein with the bright blue dye of Coomasie Kahn and Newman, 196 ANAL. BIOCHEM. 373-76 (1991). In another heparanase assay, a composition comprising biotin-HS is mixed with a biological sample such as a tumor sample, body fluid, or another fluid suspected of having Heparanase activity, to form a reaction mixture. This sample can be pretreated to remove polluting or reactive substances such as endogenous biotin. After incubation, an aliquot or portion of the reaction mixture is removed and placed in a biotin binding plate. After washing with buffers, a streptavidin-enzyme conjugate was added to the biotin binding plate. Reagents for the enzyme are added to form a detectable color product. For example, a decrease in color formation of a known standard indicates that there is Heparanase activity in the sample. The biotin binding plate comprises any means for binding to biotin, for example, to a solid surface. See WO 02/23197, which is expressly incorporated herein by reference in its entirety.

In general, a method for measuring Heparanase activity comprises binding a binding partner to a substrate for the enzyme to be measured. Incubation with a sample comprising the enzyme to be measured allows the activity to be measured by the enzyme in a reaction mixture. A portion or a complete reaction mixture, depending on the amount needed, is then mixed with the complementary binding partner, so that the binding partners join together. This is the first binding reaction. After the incubation to allow the union, washings are carried out. A complementary binding partner, complementary to the first binding partner attached to the substrate, is added. This complementary binding partner may be the same or not as the first complementary binding partner. This is the second binding reaction. The complementary binding partner in the second binding reaction is labeled in such a way that it is detectable. For example, the complementary binding partner is labeled with an enzyme that causes a detectable color change when appropriate reaction conditions exist. Some methods comprise the use of binding partners that include, but are not limited to, biotin and Streptavidin. Other ways to bind one of the binding partners such as biotin can be used at any biotin-binding step, either by binding biotin to the plate or in detecting available biotins. The number of biotins, or other binding partner, that are available for the second binding is the quantitative result of the assay. "Complementary binding partner" means one of the pair of binding partners, such as biotin and Streptavidin or an antibody or its antigen. Biotin is the complementary binding partner of Streptavidin; Streptavidin is the complementary binding partner of biotin. An antibody that binds specifically to biotin is also a biotin-complementary binding partner. In the above method, the labeled binding partner, i.e., the enzyme labeled streptavidin can be labeled with any detectable label including, without limitation, enzymes, dyes, chemiluminescence products, and other methods known in the art. This method comprises labeling with any enzyme that produces a color change in its substrate that is detectable. This method is safe, easy and effective and can be used in both qualitative and quantitative methods. Using the above methods, the amount of enzyme activity in a sample can be determined. Also, the above methods can be used to determine compounds that can inhibit the activity of the enzyme. For example, a composition comprising the candidate compound is added to a known amount of Heparanase and either before or during the incubation of Heparanase and its substrate binding partner. If the partner alters Heparanase activity, the assay methods of the present invention will show a change in the amount of the detectable label. These assays are used to determine high performance of the activity of the candidate compounds. See WO 02/23197, which is expressly incorporated herein by reference in its entirety. C. Inflammation Modulation The present invention relates to methods and compositions comprising compounds or molecules that have specific biological effects and are useful as therapeutic agents. In particular, the present invention relates to methods and compositions comprising compounds or molecules that are effective in effecting inflammation. More particularly, the present invention relates to methods and compositions comprising compounds or molecules that are effective in inhibiting inflammation caused by the accumulation or presence of glycated proteins or AGEs. The present invention also provides compositions and methods of treatment of biological conditions that include, but are not limited to, vascular complications of vascular diseases induced by type I and type II diabetes., other vasculopathies microangiopathies, renal failure, Alzheimer's syndrome and inflammation-induced diseases such as atherosclerosis. The present invention has utility in the inhibition of inflammation or cellular activation by glycated proteins or AGE. The pharmacological inhibition of cell activation induced by AGE provides the basis for therapeutic intervention in many diseases, most notably in diabetic complications and in Alzheimer's disease. Therapeutic approaches for the inhibition of AGE-induced inflammation include, but are not limited to, blocking protein glycation, blocking AGE interactions with receptors and blocking inflammatory responses associated with signaling or signaling induced by AGE. For example, one method of the present invention is to block the effects of AGE by inhibiting AGE-induced signaling. The sequence of these signaling events leading to inflammation is not clear, but the inhibition of these signaling events leads to reduced or non-inflammatory results. Compounds that block the promotion of AGE-induced expression of inflammatory molecules were determined using detection assays. The present invention comprises methods and compositions comprising compounds or molecules such as the thiazolidinedione compounds provided herein. Other aspects of the present invention comprise methods and compositions comprising compounds that block inflammation induced by glycated protein. Additional aspects of the present invention comprise thiazolidinedione compounds that are capable of inhibiting the effects of AGE. Still further aspects of the present invention employ compositions comprising the compounds of the formulas contemplated herein that block the inflammation induced by glycated proteins. The formation and enhanced accumulation of glycated proteins and AGE is taught to play an important role in the pathogenesis of diabetic complications, and atherosclerosis, which lead to the development of a variety of diabetic complications including neuropathy, retinopathy, and neuropathy. There is abundant evidence in vivo suggesting that complications related to diabetes can be reduced by 1) preventing glycation of proteins, 2) by breaking down the cross-links in glycated proteins or p 3) by blocking the interaction of glycated proteins with receptors. Despite the importance of AGEs in the pathogenesis of diabetic microangiopathies, there are currently no known drugs available that block the formation of AGE.

Aminoguanidine, which prevents the formation of AGE, is actively demanded as a therapy for diabetic vasculopathy. However, it is not clear if this drug will affect the normal metabolism of glucose or the glycosylation of proteins. In addition, some studies show that although aminoguanidine reduces AGE formation, it does not inhibit glomerular base thickness in diabetic rats or improve endothelial function. See, for example, Birrell et al., 43 DIABETOLOGY 110-16 (2000); Wada et al., 42 DIABETOLOGY 743-47 (1999); Soulis et al., 50 KIDNEY INT. 627-34 (1996). In addition to inhibitors of AGE formation, AGE crosslinkers are also actively demanded as a therapy for vasculopathy. N-Fenacylthiazolium bromide (PTB) is a prototype AGE cross-linking switch that reacts with and cleaves protein cross-links derived from covalent AGEs. Although the PTB reduces the accumulation of AGE, it does not prevent vascular permeability. Cooper et al., 43 DIABETOLOGY 660-64 (2000); Oturai et al., 49 (8) METABOLISM 996-1000 (2000). The inhibition of reactions with AGE receptors is an alternative approach to the treatment of related pathologies. RAGE, a known receptor for AGE, is a possible therapeutic goal. Blocking RAGE also inhibited the AGE-induced information. However, due to the multiple functions of RAGE and possible long-term side effects of accumulated AGEs in plasma, this method is not currently followed in humans. Using the methods and compositions of the present invention, more specific inhibitory compounds can be used for treatments. The endothelium is the target organ of diabetes damage. Laight et al., 15 DIABETES ME . BEEF. REV. 274-82 (1999); Stehouwer et al., 34 CARDIOVASC. 55-68 (1997). The promotion of the expression of molecules comprised in endothelial inflammation, such as IL-6 and protein-1 chemoattractant monoliths (MCP-1) leads to endothelial dysfunction and vasculopathy. See Stehouwer et al., 34 CARDIOVASC. 55-68 (1997); Libby, 247 J. INTERN. MED. 349-58 (2000); Van Lente, 293 CLINIC. CHIMICA. Minutes. 31-52 (2000). A total approach to the understanding and treatment of diabetes and its complications is to interfere with the regulation of genes, such as those that lead to the production of cytokines, and inhibit AGE-induced inflammation. The effectiveness of the compounds of the present invention in the inhibition of AGE-induced and glycated protein inflammation can be determined using the assays described herein and in U.S. Provisional Patent Application Serial Number 60 / 259,306, which it is incorporated herein by reference in its entirety. These assays comprise the measurement of the specific activity of biological components comprised in a known cellular response. The assays provide a measurable response in which the activity of the compounds is determined. One aspect of the present invention comprises measuring the effects of the compounds on an inflammatory response by cells to the presence of a stimulating agent. Yet another aspect of the present invention includes an assay comprising endothelial cells that are stimulated by the addition of a glycated protein, the stimulating agent. Endothelial cells respond by producing specific cytokines. The amount of cytokines produced is determined by measurement protocols known to those skilled in the art. The compounds of the present invention are then added to the assay and the production of cytokines is measured. From the comparison of the test without the compound with the test with the compound, the biological effect of the compound can be determined. The compound may have an inhibitory effect, a stimulating effect, or none at all. Compounds for the treatment of inflammation include those that have an inhibitory effect. The assays comprise endothelial cells that are stimulated in an inflammatory response by the presence of glycated proteins, glycated human serum albumin. These endothelial cells produce cytokines. A method according to the present invention comprises measuring the amount of the cytokine IL-6, and other aspect of the present invention comprises measuring the amount of the cytokine MCP-1. Preferably, although not required, the amount of cytokine produced is determined using immunological methods, such as ELISA assays. The methods of the present invention are not limited by the type of assay used to measure the amount of cytokine produced and any method known to the person skilled in the art and further developed can be used to measure the amount of cytokines produced in response to the stimulating agent. and the compound that has unknown activity. IL-6 is a pro-inflammatory cytokine that is known to play a key role in the pathogenesis of diabetes and atherosclerosis. See Horii et al., 39 KIDNEY INT. SUPPL. 71-5 (1993); Huber et al., 19 ARTERIOSCLER THROMB. VASC. BIOL. 2364-67 (1999); Shikano et al., 85 NEPHRON 81-5 (2000); Pickup et al., 8 (67) LIFE SCI. 291-300 (2000). IL-6 also promotes the growth of renal mesangial cells that contribute in this way to nephropathy. See Kado et al., 36 HIGH. DIABETOL. 67-72 (1999). The serum level of IL-6 in diabetic subjects was significantly higher than in normal healthy controls (3.48 +/- 3.29 pg / mL vs. 0.784 +/- 0.90 pg / mL, mean +/- SD). In addition to the level of urinary IL-6 is a good indicator of diabetic neuropathy. Serum IL-6 is useful in the evaluation of atherosclerosis and neuropathy. MCP-1, another pro-inflammatory cytokine, is highly expressed in human atherosclerotic lesions and it is postulated that it plays a central role in the recruitment of monoliths in the arterial wall and the development of lesions. Libby, 247 J. INTERN. MED. 349-58 (2000). Recent results show that MCP-1 is also a key pathogenic molecule in diabetic nephropathy. See Either et al., 51 KIDNEY INT. 69-78 (1997); Banba et al. 58 KIDNEY INT. 684-90 (2000). The glycated albumin stimulates the endothelial production of IL-6 and MCP-1. The effects of glycated albumin on the production of IL-6 are comparable with that of TNFa, a known inducer of IL-6. Due to the well established role of these cytokines in vascular diseases, the detection of compounds that block the AGE induction of these cytokines provides a new approach to identify therapeutic agents that block AGE-induced inflammation in vivo. Once the baseline response to the stimulating agent for cytokine production is established by the endothelial cells, which thus comprise the control levels for the detection assay, the methods comprise the addition of the compounds having unknown activities. . The effect of the compound on the baseline response is determined by comparing the amount of the cytokine produced in the presence of the stimulating agent and the amount of cytokine produced in the presence of the stimulating agent and the compound of the present invention. In one method, compounds that have inhibitory effects on the inflammation of cells in the presence of glycated alumina are then used as therapeutic agents. One or more compounds can be added to the detection assay. Combinations or mixtures of compounds can be added. Different amounts and formulations of the compounds are added to determine the effects in the detection test. The detection assay can also be used to determine stimulatory compounds or compounds that have no effect on the assay. Table 2 presents examples that have inhibited the Proinflammatory cytokines IL-6 and MCP-1.

Table 2 The present invention also contemplates compositions comprising the compounds identified by the methods as having a desired activity. The compositions have utility in the treatment of whole cells, tissues or organisms. These compositions are formulated for administration in an amount effective for the treatment of conditions such as biological conditions including, without limitation, vascular complications of vascular diseases induced by type I and type II diabetes, other vascular diseases, microangiopathies, renal failure, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis. The compositions may comprise pharmaceutical adjuncts that are needed for the administration of the compound or compounds with the desired activity. In addition, the compounds of the present invention are useful for the treatment or prophylaxis of at least one immune-related disease in a cell, tissue, organ, animal or patient that includes, but is not limited to, rheumatoid arthritis, rheumatoid arthritis juvenile, juvenile rheumatoid arthritis of systemic onset, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, anti-phospholipid syndrome, iridocyclitis / uveitis / optic neuritis, idiopathic pulmonary fibrosis , systemic vasculitis / wegener's granulomatosis, sarcoidosis, vasectomy / orchitis inversion procedures, allergic / atopic diseases, asthma, allergic rickets, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, sickness and graft-versus-host, systemic inflammatory response syndrome, sepsis syndrome, gram-positive sepsis, gram-negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma / hemorrhage, burns, exposure to ionizing radiation, acute pancreatitis, respiratory effort syndrome in adults, rheumatoid arthritis, alcohol induced hepatitis, chronic inflammatory pathologies, Crohn's disease, sphingoform cell anemia, diabetes, nephrosis, atopic diseases, hypersensitivity reactions, allergic rhinitis, fever hay, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic disease, thrombocytopenia, graft rejection of any organ or tissue, rejection of kidney transplant, rejection of heart transplant, rejection of transplant of liver, rejection of pancreas transplant, rejection of transplant of lung, rejection of bone marrow transplantation (MBT), rejection of allograft of skin, rejection of cartilage transplantation, rejection of bone graft, rejection of small intestine transplantation, rejection of fetal thymus implant, rejection of parathyroid transplant, Xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves' disease, Raynoud's disease, insulin-resistant diabetes type B, myasthenia gravis, mediated cytotoxicity, type III hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, anti-phospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease , diabetes mellitus, chronic active hepatitis, vitiligo, vasculitis, s ndrome cardiotomy post-MI, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic / idiopathic, Wilson's disease, hemacromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis, evaluation of hypothalamic-pituitary-adrenal axis, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease , chronic obstructive pulmonary disease (COPD), familial haematophagocytic lymphohistiocytosis, dermatological conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, ankylosing spondylitis, Behcet's disease, pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss disease, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia- fibromyosi tis, Graves disease, Guillain-Barré, Hashimoto's thyroiditis, idiopathic purple thrombocytopenia (ITP), IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, syndrome of Cogan, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, Sjögren's syndrome, rigid man syndrome, Takayasu's arthritis, temporal arteritis / giant cell arteritis, Wegener's granulomatosis; therapy with okt3, anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy (for example, including, without limitation, to-asthenia, anemia, cachexia), chronic salicylate poisoning. See, for example, The Merck Manual, 12th-17th Editions, Merck & Company, Rahway, NJ (1972, 1977, 1982, 1987, 1992, 1999); Pharmacotherapy Handbook, Wells et al., Eds., Second Edition, Appleton and Lange, Stamford, Conn. (1998, 2000). D. Hyperproliferative Diseases Several of the compounds of the present invention have cytotoxic activity and thus are also useful in the treatment or prophylaxis of at least one hyperproliferative disease in a cell, tissue, organ, animal, or patient including, but not limited to, and without limitation, malignant and non-malignant cell growth, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) of B cells, ALL of T cells or ALL of FAB, acute myeloid leukemia (AML), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia, (CLL), hairy cell leukemia, myelodiplasmic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, a non-Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome / hypercalcemia of malignancy, solid tumors, adenocarcinomas, sarcoma s, malignant melanoma, hemangioma, static disease, bone resorption related to cancer, bone pain related to cancer or any combination thereof. Drug-Coated Medical Devices The compounds of the present invention can be used alone or in combination with other agents in conjunction with delivery devices to effectively prevent and treat vascular disease, and in particular, vascular disease caused by injury and / or by transplantation. . Various medical treatment devices used in the treatment of vascular disease may eventually induce additional complications. For example, balloon angioplasty is a procedure used to increase blood flow through an artery and is the predominant treatment for coronary vessel stenosis. As noted above, however, the procedure typically causes a certain degree of damage to the vessel wall, thereby potentially exacerbating the problem at a later time point. Although other ods and diseases may cause similar injury, the exemplary compounds of the present invention will be described with respect to the treatment of restenosis and related complications after percutaneous transluminal coronary angioplasty and other arterial / venous procedures and the like, including the union of arteries, veins and other channels that carry fluids in other organs or sites of the body, such as the liver, lung, bladder, kidney, brain, prostate, neck and legs. The local distribution of a compound of the present invention and optionally, other therapeutic agents from a vascular stent prevents vessel withdrawal and remodeling through the retraction action of the vascular stent. In addition, drug-coated vascular endoprosthetics can prevent multiple components of neointimal hyperplasia or restenosis as well as reduced inflammation and reduced thrombosis. Local administration of a compound of the present invention and other therapeutic agents to coronary arteries with vascular endoprosthetics may also have additional therapeutic benefit. For example, higher tissue concentrations of the compounds of the present invention and other therapeutic agents can be achieved using local distribution instead of systemic administration. In addition, reduced systemic toxicity can be achieved using local distribution instead of systemic administration while maintaining higher tissue concentrations. When using local distribution from a vascular endoprosthesis instead of systemic administration, an individual procedure may be sufficient with better patient compliance. An additional benefit of combination therapy of therapeutic agent and / or compound can reduce the dose of each of the therapeutic agents, thus limiting their toxicity, while a reduction in restenosis, inflammation and thrombosis is still achieved. Local therapy based on vascular endoprosthetics is therefore a means to improve the therapeutic relationship (efficiency / toxicity) of anti-restenosis, anti-inflammatory and anti-thrombotic therapeutic agents. Although the exemplary compounds of the present invention are described herein with respect to the treatment of restenosis and other related complications, it is important to note that the local distribution of a compound of the present invention, either alone or as part of a combination of therapeutic agent , it can be used to treat a wide variety of conditions using any number of medical devices, or to improve the function and / or life of the device. For example, infraocular lenses, placed to restore vision after cataract surgery, are frequently compromised by the formation of a secondary cataract. The latter are often the result of cell excrescence of the lens surface and can potentially be minimized by combining a drug or drugs with the device. Other medical devices that frequently fail due to the accumulation and growth of tissue of proteinaceous material in, on and around the device, such as shunts for colostomy bag attachment devices, dialysis grafts, hydrocephaluses, ear drainage tubes, conductors for pacemakers and implantable defibrillators can also benefit from the drug-device / drug combination approach. Other surgical devices, sutures, staples, anastomosis devices, vertebral discs, bone spikes, suture anchors, hemostatic barriers, clamps, screws, plates, tweezers, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of bandages , bone substitutes, intraluminal devices, and vascular supports can also provide improved benefit to the patient using this drug-device combination approach. Any type of medical device may be coated in some manner with a compound of the present invention, either alone or as part of a combination of therapeutic agent that improves treatment with respect to the individual use of the therapeutic device or agent. In addition to the various medical devices, the coatings may be used to deliver a compound of the present invention in combination with other therapeutic agents including anti-proliferative / anti-mitotic agents including natural products such as vinca alkaloids (eg vinblastine, vincristine and vinorelbine), paclitaxel, epidipodophyllotoxins (eg, etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin) and mitomycin, enzymes- (L-asparaginase that metabolize systemically L-asparagine and stripped cells that do not have the ability to synthesize their own asparagine); antiplatelet agents such as G (GP) Ilb / lIIa inhibitors and vitronectin receptor antagonists; anti-proliferative / anti-mitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide, and analogs, melphalan, chlorambucil), ethylene imines, and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs, streptozocin), trazenos-dacarbazinine (DTIC); anti-proliferative / anti-mitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine) (cladribine)); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (for example estrogen); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; anti-migratory agents; antisecretory (breveldine), - anti-inflammatory agents such as adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, tiamcinolone, betamethasone, and dexamethasone), non-spheroidal agents (salicylic acid derivatives, ie, aspirin derivatives of para-aminophenol, ie, acetaminophen, indole and indeno-acetic acids (indomethacin, sulidac, and etodalac), heteroaryl-acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxifentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, sodium and gold thiomalate), immunosuppressants (Ciclosporin, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate, mofetil); angiogenic agents; vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF); angiotensin receptor blockers; nitric oxide donors; anti-sense oligonucleotides combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors. Although any number of vascular stent may be used in accordance with the present invention, for simplicity, limited numbers of vascular stent will be described herein. The person skilled in the art will recognize that any number of vascular endoproses can be used with respect to the present invention. In addition, other medical devices can be used as noted above. A vascular endoprosthesis is commonly used as a tubular structure left inside the lumen of a duct to release an obstruction. Typically, vascular endoproses are inserted into the lumen in a non-expended form and then expanded autonomously, or with the aid of a second device in situ. A common method of expansion is through the use of an angioplasty balloon mounted on a catheter that is inflated within the stenosed vessel or passageway of the body in order to cut and interrupt the obstructions associated with the vessel wall components and to obtain a enlarged lumen A vascular stent may resemble an expandable cylinder and may comprise a fenestrated structure for placement in a blood vessel, duct or lumen to retain the vessel, duct or open lumen, more particularly to protect a segment of the artery from restenosis after angioplasty. The vascular stent may expand circumferentially and maintain an expanded configuration that is circumferential or radially rigid. The vascular endoprosthesis can be axially flexible when flexed in a band, for example, the vascular stent avoids any externally protruding component. The vascular stent can be manufactured using any number of methods. For example, the vascular stent may be fabricated from a hollow or formed steel tube that can be machined using laser, electric discharge grinding, etching or other means. The vascular stent is inserted into the body and placed in the desired location in an unexpanded form. The expansion is effected in a blood vessel by a balloon catheter, where the final diameter of the vascular stent is a function of the diameter of the balloon catheter used. It should be appreciated that a vascular stent according to the present invention can be incorporated into a shape memory material that includes, for example, an appropriate alloy of nickel and titanium or stainless steel. The structures formed of stainless steel can be made self-expanding by configuring the stainless steel in a predetermined manner, for example, by twisting it into a braided configuration. After the vascular stent has been formed it can be compressed to occupy a space small enough to allow its insertion into a blood vessel or other tissue by the insertion means, wherein the insertion means includes a suitable catheter, or flexible rod. Upon emergence of the catheter, the vascular stent may be configured to expand in the desired configuration where expansion is automatic or activated by a change in pressure, temperature or electrical stimulation. In addition, a vascular stent may be modified to comprise one or more reservoirs. Each of the deposits can be opened or closed as desired. These deposits can be specifically designed to retain the combination of therapeutic agent / therapeutic agent to be delivered. Despite the design of the vascular endoprosthesis, it is preferred to have the therapeutic agent / therapeutic agent combination dose applied with sufficient specificity and a sufficient concentration to provide an effective dose in the affected area. In this regard, the size of the deposit in the bands is made one size to adequately apply the therapeutic agent / therapeutic agent combination dose in the desired location and in the desired amount. Alternatively, the entire interior and exterior surface of the vascular stent may be coated with the combination of therapeutic agent / therapeutic agent in the therapeutic dose amounts. The coating techniques may vary depending on the combination of therapeutic agent / therapeutic agent. Also, the coating techniques may vary depending on the material comprising the vascular endoprosthesis or intraluminal medical device. One or more compound of the present invention and in some cases another therapeutic agent as a combination, can be incorporated into or fixed in the vascular stent in various ways. For example, the compound can be incorporated directly into a polymeric matrix and sprayed onto the outer surface of the vascular stent. The compound elutes from the polymer matrix during time and enters the surrounding tissue. The compound typically remains in the vascular stent for at least three days up to about six months, for example between seven and thirty days. Any number of non-erodible polymers can be used in conjunction with the compound. According to one aspect of the present invention, the polymer matrix comprises two layers. The base layer comprises a solution of poly (ethylene-covinylacetate) and polybutylmethacrylate. The compound is incorporated in this base layer. The outer layer comprises only polybutylmethacrylate and acts as a diffusion barrier to prevent the compound from eluting too quickly. The thickness of the outer layer or top layer determines the rate at which the matrix compound elutes. Essentially, the compound is eluted from the matrix by diffusion through the polymer matrix. The polymers are permeable, thus allowing solids, liquids and gases to escape from them. The total thickness of the polymer matrix is from about one to about twenty microns or greater. It is important to note that the primer layers and metal surface treatments can be used before the polymer matrix is fixed to the medical device. For example, acid cleaning, alkaline-based cleaning (base), salinization and parylene deposition may be used as part of the entire process described above. The solution of poly (ethylene-co-vinylacetate), polybutylmethacrylate and the compound can be incorporated in or on the vascular stent in various ways. For example, the expression can be sprayed on the vascular stent or the vascular stent can be immersed in the solution. The solution can be sprayed on the vascular stent and then allowed to dry. The solution can be charged electrically to one polarity and the vascular stent is electrically charged to the opposite polarity. In this way, the solution and the vascular endoprosthesis can be linked together. By using this type of spray process, waste is reduced and more precise control over the thickness of the coating is achieved. Other methods include spin coating and plasma polymerization. Drug-coated vascular endoprosthetics are manufactured by several companies including Johnson & amp; amp; amp;; Jonson, Inc. (New Branswick, NJ), Guidant Corp. (Santa Clara, CA), Medtronic, Inc. (Minneapolis, MN), Cook Group Incorporated (Bloomington, IN), Abbott Labs., Inc. (Abbott Park, IL), and Boston Scientific Corp. (Natick, MA). See for example, U.S. Patent Number 6,273,913; U.S. Patent Application Number 20020051730; WO 02/26271; and WO 02/26139, each expressly incorporated herein by reference in its entirety. Expression Profiles and Methods of Using Microarrays The present invention contemplates a variety of microarrays that can be used to study and monitor gene expression in response to treatment with the compounds of the present invention. For example, the microarrays of the present invention may be derived from, or representative of, e.g., a specific organism or cell type, including human microarrays, vascular microarrays, microarrays of inflammation, cancer microarrays, apoptosis microarrays, microarrays of tumor suppressor and shrink, cell-cell interaction microarrays, cytosine and cytosine receptor microarrays, blood microarrays, cell cycle microarrays, neuroarrays, mouse microarrays and rat microarrays, or combinations thereof. The arrangements may represent diseases including cardiovascular diseases, vasculopathic conditions, inflammatory diseases, autoimmune diseases, neurological diseases, immunological diseases, various cancers, infectious diseases, endocrine disorders and genetic diseases. Alternatively, the microarrays useful in assessing the efficiency of the compounds of the present invention may represent a particular type of tissue that includes, without limitation, tissue from the heart, liver, prostate, lung, nerve, muscle or connective tissue; for example, coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascular endothelium, pulmonary artery endothelium, myometrial microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, epithelium renal cortex, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast neural progenitor cell, skeletal muscle, astrocytes, smooth aortic muscle, cells mesangial, smooth muscle of coronary artery, bronchial smooth muscle, uterine smooth muscle, pulmonary fibroblast, osteoblasts, prostate stromal cells or combinations thereof. The present invention further contemplates microarrays comprising a gene expression profile comprising one or more polynucleotide sequences that include complementary and homologous sequences, wherein the gene expression profile is generated from a cell type treated with a compound of the present invention and it is selected from the group comprising coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascular endothelium, pulmonary artery endothelium, myometrial microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, epithelium prostate, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cells, skeletal muscle, astrocytes, muscle smooth aort ico, mesangial cells, smooth muscle of coronary artery, bronchial smooth muscle, uterine smooth muscle, pulmonary fibroblast, osteoblasts, and prostate stromal cells.

The present invention contemplates microarrays comprising one or more protein binding agents, wherein a protein expression profile is generated from a cell type treated with a compound of the present invention and is selected from the group comprising the endothelium of coronary artery, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascular endothelium, pulmonary artery endothelium, myometrial microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, epithelium proximal renal tubule, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cells, smooth muscle, astrocytes, smooth aortic muscle, mesangial cells, smooth muscle of coronary artery, bronchial smooth muscle, muscle l uterine iso, lung fibroblast, osteoblasts and prostate stromal cells. More specifically, the present invention contemplates methods for the reproducible measurement and titration of the expression of specific mRNAs or proteins in, for example, a specific set of cells. One method comprises and uses microdissection techniques with laser capture, T7-based RNA amplification, production of amplified RNA cDNA, and DNA microarrays containing immobilized DNA molecules for a wide variety of specific genes, including HSPG such as Perlecan, to produce a profile of gene expression analysis for very small numbers of specific cells. The desired cells are identified individually and bound to a substrate by laser capture technique, and the captured cells are then separated from the remaining cells. The RNA is then extracted from the captured cells and amplified approximately one million times using the T7-based amplification technique, and the cDNA can be prepared from amplified RNA. A variety of specific DNA molecules are prepared which hybridize with specific polynucleotides of the microarray, and the DNA molecules are immobilized on a suitable substrate. The cDNA made from the captured cells is applied to the microarray under conditions that allow hybridization of the cDNA to DNA immobilized in the microarray. The expression profile of the captured cells is obtained from the analysis of the hybridization results using the amplified RNA or cDNA made from the amplified RNA of the captured cells, and the immobilized DNA molecules, specific in the microarray. Hybridization results show that, for example, the genes of those represented in the microarray as probes hybridize to the cDNA of the captured cells, and / or the amount of specific gene expression. The results of the hybridization represent the gene expression profile of the captured cells. The gene expression profile of the captured cells can be used to compare the gene expression profile and a different set of captured cells. For example, gene expression profiles can be generated from treated (and untreated) cells with a compound of the present invention. The similarities and differences provide useful information to determine the differences between the same cell type under different conditions, more specifically, the change in gene expression in response to treatment with a compound of the present invention. The techniques used for the analysis of gene expression are equally applicable in the context of protein expression profiles. The total protein can be isolated from a cell sample and hybridized to a microarray comprising a plurality of protein binding agents, which can include antibodies, receptor proteins, small molecules. Using any of the several assays known in the art, Hybridization can be detected and analyzed as described above. In the case of fluorescent detection, algorithms can be used to extract a protein expression profile representative of the particular cell type. In this regard, the change in protein expression in response to the treatment of cells with a compound of the present invention can be evaluated. Thus, in one aspect, the present invention relates to at least one microarray corresponding to a population of genes isolated from a particular type of tissue or cell that is used to detect changes in gene transcript levels that result from exposing the selected tissue or cells to a candidate drug such as a compound of the present invention. A biological sample derived from an organism, or an established cell line, may be exposed to the candidate drug in vivo or ex vivo. Subsequently, the gene transcripts, mainly mRNA, from the tissue or cells are isolated by methods well known in the art. SAMBROOK ET AL., MOLECULAR CLONING: A LAB. MANUAL (2001). The isolated transcripts are then contacted with a microarray under conditions where the transcripts are hybridized with a corresponding probe to form hybridization pairs. In this way, the arrangement provides a model of transcriptional sensitivity after exposure to a particular drug candidate. A hybridization signal can then be detected in each hybridization pair to obtain a gene expression profile. Gene and / or protein expression profiles and microarrays can also be used to identify compounds of activation or non-activation of a particular gene such as Perlecan or another HSPG. Compounds that increase the ratios of transcription or stimulate, maintain or stabilize the activity of a protein are considered active and compounds that decrease the proportions or inhibit the activity of a protein are considered non-active. In addition, the biological effects of a compound can be reflected in the biological state of a cell. This state is characterized by cellular constituents. One aspect of the biological state of a cell is its transcriptional state. The transcriptional state of a cell includes the identities and quantities of the RNA constituent species, especially mRNA, in the cell under a given set of conditions. In this manner, the gene expression profiles, microarrays and algorithms analyzed herein can be used to analyze and characterize the transcriptional status of a given cell or tissue after exposure to an activating or non-activating compound, specifically a compound of the present invention. Microarray techniques and methods for analyzing the results are well known in the art. See for example United States Patents Numbers 6,263,287; 6,239,209; 6,218,122; 6,197,599; 6,156,501; 5,874,219; 5,837,832; 5,700,637; 5,445,934; Patent Application of the United States Numbers. 2001/0014461 Al; 2001/0039016 Al; 2001/0034023 Al; WO 01/94946; and WO 01/77668. See also, Haab et al., 2 GENOME BIOLOGY 1-12 (2001); Brown et al., 97 PROC. NATL. ACAD. SCI. USA 262-7 (2000); Getz et al., 97 PROC. NATL. ACAD. SCI. USA 12079-84 (2000); Harrington et al., 3 CURRENT OPINION MICROBIOL 285-91 (2000); Holter et al., 97 PROC. NATL. ACAD. SCI. USA 8409-14 (2000); MacBeath et al., 289 SCIENCE 1760-63 (2000); Duggan et al., 21 NATURE GENET 10-14 (1999); Lipshutz et al., 21 NATURE GENET 5-9 (1999); Eisen et al., 95 PROC. NATL. ACAD. SCI. USA 14863-68 (1998); Ermolaeva et al., 20 NATURE GENET. 19-23 (1998); Towards et al., 26 NUCLEIC ACIDS RES. 3865-66 (1998), Lockhart et al., NUCLEIC ACIDS SYMP. BE. 11-12 (1998); Schena et al., 16 TRENDS BIOTECHNOL. 301-6 (1998); Shalon, 46 PATHOL. BIOL. 107-9 (1998); Welford et al., 26 NUCLEIC ACID RES. 3059-65 (1998); Blanchard et al., 11 BIOSENSORS BIOELECTRONICS 687-90 (1996); Lockhart et al., 14 NATURE BIOTECHNOL. 1675-80 (1996); Schena et al., 93 PROC. NATL. ACAD. SCI. USA 10614-19 (1996); Tomayo et al., 96 PROC. NATL. ACAD. SCI. USA 2907-12 (1996); Schena et al., 270 SCIENCE 467-70 (1995). Creation of database. Access to Database and Associated Methods of Use The present invention comprises a variety of methods including methods for providing diagnostics and predictors in relation to biomolecules including HSPGS, In particular, Perlecan. The present invention further comprises methods for providing diagnostics and predictors that relate to the efficiency of the compounds of the present invention. The present invention still further contemplates methods for providing databases of expression profiles, and methods for producing these databases, for normal tissues and with disease. The expression profiling database may be an internal database designed to include adaptation information about the expression profiles generated to assess the effect of the compounds of the present invention and through other sources and methods. This information may include, for example, the databases in which a given biomolecule was found, patient information associated with the expression profile, including age, cancer or type or tumor progress, information regarding a compound of the present invention such as dose and administration information, descriptive information about the related cDNAs associated with the sequence, cell or tissue source, sequence data obtained from external sources, expression profiles for a given gene and the related disease state or course of the disease, for example if the expression profile refers to or means a particular disease state, and methods of preparation. Expression profiles can be used in data of protein microarrays and / or polynucleotides obtained from publicly available or patent sources. The database can be divided into two sections: one to store the sequences and expression profiles, related and the other to store the associated information. This database can be maintained as a private database with a firewall inside the central computer installation. However, this invention is not limited and the database of expression profiles can be made available to the public. The database can be a networked system that connects the network server with clients. The network can be any of several conventional network systems, including a local area network (LAN) or a wide area network (WA?). as is known in the art (e.g. Ethernet). The server may include a computer program to access the database information to process user requests and to provide an interface to serve information to the client machines. The server can support the global web (World Wide Web) and maintain a Web site and Web browser for the use of clients. Client / server environments, database servers and networks are well documented in the technical, commercial and patent literature.

Through the Web browser, clients can build search requests to retrieve data from, for example, a microarray database and a database of expression profiles. For example, the user can "point and click" to user interface elements such as buttons, scrollable menus, and scroll bars. Client requests can be transmitted to a Web application that formats them to produce a request that can be used to obtain information from the system database based on, for example, based on the microarray or expression data obtained by the client and / or other phenotypic or genotypic information. Specifically, the system may present expression data based on the expression profiles of microarrays obtained from a patient treated with a compound of the present invention and use the system to obtain a diagnosis based on that information based on a comparison by the patient. system of the client expression data with the expression data contained in the database. By way of example, the system compares the expression profiles presented by the client with expression profiles contained in the database and then provides the client with the diagnostic information based on the best match of the agent expression profiles with the profiles of expression of the database. Thus, in one aspect, the comparison of the expression profiles helps the practitioners in determining the efficiency of the treatment with a compound of the present invention. Based on this comparison, the physician may alter or adjust the treatment regimen. In addition, the Web site can provide hyperlinks to public databases such as the GenBank and associated database maintained by the National Center for Biotechnology Information (NCBI), part of the National Library of Medicine as well as any link that provides pertinent information for analysis of gene expressions; genetic disorders and scientific literature. Information is contemplated that includes, without limitation, identifiers, types of identifiers, biomolecular sequences, identifiers of common groups (identifiers of GenBank template, Unigen, Incyte and others, and names of species associated with each gene. invention also provides a system for specifically accessing and comparing bioinformation expression profiles and other information that is useful in the context of the compositions and methods of the present invention.The computer system may comprise a computer processor, suitable memory that is coupled operatively to the computer processor, and a computer process stored in the memory running in the computer processor and comprising a means for matching an expression profile of a biomolecular sequence of a patient with the expression profile and secu identification information gins of the biomolecular sequences in a database. More specifically, the computer system is used to match an expression profile generated from a biological sample treated with a compound of the present invention with the expression profile and other information in a database. Additionally, the system for accessing and comparing information contained in biomolecular databases comprises a computer program comprising a computer code that provides an algorithm for matching an expression profile generated from a patient, for example, treated with a compound of the present invention, with the expression profile and sequence identification information of sequences of biomolecular sequences in a biomolecular database. The present invention contemplates, for example, the use of a Graphical User Interface ("GUI") for accessing the expression profile information stored in a biomolecular database. The GUI can be composed of two frames. A first table can contain a selectable list of biomolecular databases accessible by the user. When a biomolecular database is selected in the first frame, a second table can display information resulting from the comparison in the form of pairs of the base of expression profiles with the expression profile supplied by the client as described above, together with other phenotypic or genotypic information. The second frame of the GUI can contain a list of expression information of biomolecular sequences and profiles contained in the selected database. Additionally, the following table may allow the user to select a subset, including all biomolecular sequences, and performs an operation on the list of biomolecular sequences. The user can select the subset of biomolecular sequences by selecting a selection box associated with each biomolecular sequence. The operations that can be performed include, without limitation, downloading all the biomolecular sequences listed in a database spreadsheet with classification information, saving the selected subset of biomolecular sequences to a user file, downloading all the biomolecular sequences listed in a database spreadsheet without classification information and display the classification information in a selected subset of biomolecular sequences. If the user chooses to display classification information in a selected subset of biomolecular sequences, a second GUI may be presented to the user. The second GUI may contain a listing of one or more external databases used to create the expression profile databases as described above. Additionally, for each external database, the GUI may display a list of one or more fields associated with each external database. The GUI may allow the user to select or deselect each of one or more fields displayed in the second GUI. The GUI can also allow the user to select or deselect each of one or more external databases. The methods of the present invention also relate to commercial and different uses of the compositions and methodologies of the present invention. In one aspect, the methods include marketing, selling or licensing the methodologies compositions of the present invention in the context of providing consumers, ie, patients, medical practitioners, medical service providers, researchers and distributors and pharmaceutical manufacturers, with databases of expression profiles including, in particular, databases produced according to the use of the compounds of the present invention. The methods of the present invention include establishing a distribution system for distributing the pharmaceutical compositions of the present invention for sale and may optionally include the establishment of a sales group for the commercialization of the pharmaceutical composition. The present invention provides a method for carrying out target discovery which comprises identifying, by one or more of the methods, the discovery of prior drugs, a test compound as described above, which modulates the expression level of a gene to a activity of a gene product such as Perlecan; carry out the therapeutic profiling of identified agents, or additional analogs thereof, for efficiency and toxicity in animals; and optionally formulating a pharmaceutical composition that includes one or more of the agents identified as having an acceptable therapeutic profile; and optionally license or sell the rights for additional drug developments of the identified agents. The present invention is further illustrated by the following preparations and examples, which are not considered in any way as limitations imposed on the scope thereof. It will be clear to one skilled in the art that other modifications, modalities and equivalents thereof exist which do not depart from the spirit of the present invention and / or the scope of the appended claims. Preparation 1 1- [4- (2-Bromoethoxy) phenyl] -1-ethanone A mixture of 4-hydroxyacetophenone (20 g, 147 mmol) and potassium carbonate (81 g, 588 mmol) was placed in a 2 L round bottom flask and acetone (1 L) was added. To this reaction mixture was added dibromoethane (38 mL) in one portion and then the reaction mixture was allowed to reflux for 36 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered, the residue was washed with acetone (2 x 100 mL), and the filtrates were combined and concentrated under reduced pressure. The crude product was chromatographed on silica gel using 10-15% ethyl acetate / petroleum ether (2 L) to give the title compound 7 g (20%) as a white solid. P.f. 58-61 ° C. IR: dmax (KBr, cm "1) 1678, 1603; XH NMR (200 MHz, CDC13): d 7.93 (d, J = 8.87 Hz, 1H), 6.93 (d, J = 8.87 Hz, 2H), 4.35 (t, J = 6.18 Hz, 2H), 3.67 (t, J = 6.28 Hz, 2H), 2.55 (s, 3H); Mass (Cl method, I-butane): 245 (MH +, 100), 243 (M +, 100).

Preparation 2 2- (3,4-Dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone Step (i): 3 - [(6-0- (deoxy-aL-mannopyranosyl) -β-glucopyranosyl) oxy] -2- (3,4-dimethoxyphenyl) -5,7-dimethoxy-4H-1-benzopyran - 4 - ona A mixture of Rutin hydrate (1) (80 g) was placed 120. 5 mmol) and potassium carbonate (320 g, 2319 mmol) was placed in a 2-L three-necked round bottom flask, equipped with a reflux condenser with nitrogen atmosphere and dropping funnel and added (1.5 L) . Dimethyl sulfate sulfate (160 mL) was added dropwise to this reaction mixture. The reaction mixture was refluxed at 60 ° C for 68 hours. Then the reaction mixture was cooled to 25 ° C and the separated solid was filtered. The residue was washed with acetone (1 L) followed by methanol (500 mL), the filtrates were combined and concentrated under reduced pressure to give the title compound (80 g, 91%), as a yellow gummy solid. Step (ii): 2- (3, 4-dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone The compound obtained in step (i) (80 g, 110 mmol) was placed in a 2 L single neck round-bottomed flask and hydrochloric acid (20%, 1 L) was added at 25 ° C. The reaction mixture was refluxed at 100 ° C for 2 hours and then cooled to 25 ° C. The solid was filtered, washed with isopropanol (200 mL) and dried under vacuum to give the title compound (27.5 g, 70%) as a pale yellow solid. p.f. 192-194 ° C. GO; ? ma? (KBr, cm "1): 3279, 2925, 1609, 1516; RMNXH (200 MHz, CDC13): d 7.83-7.79 (m, 2H), 7.00 (d, J = 9.14 Hz, ÍH), 6.56 (d, J = 1.88 Hz, 1H), 6.36 (s, ÍH), 3.99 (s, 6H), 3.96 (s, 3H), 3.93 (s, 3H), Mass (Cl method, I-butane): 359 (M +, 100).

Preparation 3 1- (4- { 2- [2- (3,4-Dimethoxy phenyl) -5,7-dimethoxy-4 -oxo-4H-3-chromenyloxy] ethoxy} phenyl) -1-ethanone A mixture of the compound obtained in Preparation 2 (25g, 69.6 mmol), a compound obtained in Preparation 1 (21.5 g, 88.4 mmol) and potassium carbonate (77 g, 557 mmol) was placed in a round-bottomed flask of 1 L and DMF (400 mL) was added to the reaction mixture. The reaction mixture was heated to 80 ° C with stirring for 3 hours under a nitrogen atmosphere, the reaction mixture was cooled to 25 ° C and poured slowly into ice-cold water (1 L). The separated solid was filtered and washed with water (2 x 500 mL). Triturate with methanol and filter to give the title compound (31.5 g, 87%) as a pale brown solid, after drying under vacuum. p.f. 143-144 ° C. IR:? Max (KBr, cm "1): 1668, 1624, 1600; RMN1H (200 MHz, CDC13): d 7.87 (d, J = 8.79 Hz, 2H), 7.71-7.67 (m, 2H), 6.87- 6.76 (m, 3H), 6.51 (s, ÍH), 6.36 (s, ÍH), 4.47 (d, J = 4.40 Hz, 2H), 4.29 (t, J = 4. 40 Hz, 2H), 3.97 (s, 3H), 3.90 (s, 9H), 2.54 (s, 3H); Mass (Cl method, I-butane): 521 (MH +, 30), 385 (100).

Preparation 4 4-Fluorophenylacetate 4-Fluorophenol (20 g, 178.5 mmol) was placed in a 1 L single neck round bottom flask to which sodium hydroxide solution (12 g in 100 mL water) was added. The reaction mixture was stirred for 5-10 min at 25 ° C and crushed ice (50 g) was added thereto followed by acetic anhydride (30 mL). The reaction mixture was stirred for 15 min at the same temperature. and water (300 mL) followed by hydrochloric acid (6 N) was added thereto., 60 mL). The mixture was extracted with chloroform (3 x 100 mL), the combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (26 g, 95%) as a white solid. IR:? Max (KBr, was "1): 1764; RMNXH (200MHz, CDC13): 7.05 (s, 2H), 7.01 (s, 2H), 2.27 (s, 3H); Mass (Cl method, I-butane): 155 (M + 1, 100).

Preparation 5 (2-Hydroxy-4-fluoro-phenyl) -1-ethanone A mixture of 4-fluorophenylacetate obtained in Preparation 4 (25g, 223 mmol), with aluminum chloride (89 g, 670 mmol), was placed in a 1 L single neck round bottom flask, equipped with a condenser air and calcium chloride protective tube. The reaction mixture was heated at 120-125 ° C for 30 min, and then at 165 ° C (generation of HCl gas was observed). The mixture was stirred at the same temperature for 30 min and then cooled to room temperature. Water (500 mL) was added second by 6N HCl (150 L). The mixture was extracted with chloroform (3 x 200 mL), the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (21 g, 84%) as a white solid. IR:? Max (KBr, cm "1): 3442, 1650; RMN2H (200MHz, CDCl3): 11.98 (s, H, exchangeable D20), 7.43-7.37 (m, ÍH), 7.27-7.17 (m, ÍH) 6.98-6.91 (m, 1H), 2.62 (s, 3H), Mass (Cl method, I-butane): 155 (M + l, 47).

Preparation 6 1- (5-Fluoro-2-hydroxyphenyl) -3- (4-methoxyphenyl) -2-propen-1-one To a mixture of (2-hydroxy-4-fluoro-phenyl) -1-ethanone (3 g, 19.7 mmol) obtained in Preparation 5, and 4-fluorobenzaldehyde (4.37 g, 19.7 mmol) in methanol was added slowly sodium hydroxide at 0 ° C, under N2 atmosphere. The reaction mixture was allowed to stir for 10 hours at 0-10 °. Water (100 mL) was added thereto followed by 6 N HCl (15 mL). The separated solid was filtered and dried under vacuum to give 3 g (41%) of the title compound as a yellow solid IR:? Max (KBr, cm'1): 3500, 1642; RM ^ H (200MHz, CDC13): 12.6 (s, ÍH, interchangeable D20), 7.92 (d, J = 15.3 Hz, 2H), 7.76-7.55 (m, 3H), 7.41 (d, J = 15.3 Hz, 2H), 7.0-6.94 (m, 2H), 3.87 (s, 3H); Mass (Cl method, I-butane): 272 (M +, 100%).

Preparation 7 6-Fluoro-2- (4-methoxy phenyl) -3-hydroxy-4H-4-chromenone The chalcone product (3.0 g, 11 mmol), obtained in Preparation 6, was dissolved in methanol (30 mL) and cooled to 0 ° C. This mixture was added with sodium hydroxide solution (20 mL, 20%) and then the reaction mixture was stirred at the same temperature for 5-10. Hydrogen peroxide was added to this mixture and stirring was continued at 0-10 ° C for 1 hour. Water (100 mL) was added thereto followed by 6 N HCl (30 mL). The separated solid was filtered completely and dried under vacuum to give 1.0 g (32%) of the title compound as a yellow solid. IR:? Max (KBr, cm "1): 3261, 1602, 1559; 'RMN1 !! (200MHz, CDCl3): d 8.23 (d, J = 9.13 Hz, 2H), 7.90-7.85 (m, ÍH), 7.63-7.56 (m, ÍH), 7.48-7.38 (m, ÍH), 7.06 (d, J = 9.13 Hz, 2H), 3.91 (s, 3H); Mass (Cl method, I-butane): 287 (M + l, 100%).

Preparation 8 1- (4-. {2- [6-Fluoro-2- (4-methoxyphenyl) -4-oxo-4H-3-chromenyloxy] phenyl) -1-ethanone A mixture of the product obtained in Preparation 7 (0.3 g, 1.04 mmol), a compound obtained in Preparation 1 (0.25 g, 1.04 mmol) and potassium carbonate (0.86 g, 6.2 mmol) was placed in a round bottom flask of 1 L and DMF (15 mL) was added to the mixture. The mixture was heated to 80 ° C with stirring for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and poured slowly into ice-cooled water (1 L). The solid that separated was filtered and washed with water (2 x 500 mL). Triturate with ethanol and filter to give the title compound (0.4 g, 85%), as a pale brown solid, after drying under vacuum.

Preparation 9 N-Methyl anthranilic acid To a solution of methyl-N-methyl anthranilate (20 g, 121 mmol) in methanol (100 mL) was placed in a 250 mL single neck round bottom flask, a solution of NaOH (9.69 g, 242 g) was added. mmol) in 25 mL of water at 0-10 ° C. The reaction mixture was heated at 50 ° C for 6 hours and then cooled to room temperature. The methanol was completely removed from the reaction mixture and water (100 mL) was added. The mixture was washed with ether (3 x 50 mL) and the aqueous layer was acidified (pH ~ 5-6). with 2N HCl cooled with ice. The solid that separated was filtered, washed with water (2 x 50 mL) and dried under vacuum to give the title compound 17.0 g (93%) as a white solid. p.f -178-180 ° C. RMNXH (200MHz, CDC13): d7.99 (dd, 1H, J = 1.34 Hz), 7.46-7.25 (m, 1H), 6.70-6.58 (m, 2H), 2.93 (s, 3H); Mass (Cl method): 152 (M + l, 100%).

Preparation 10 2 -Bromo-1- (4-methylphenyl) -1-ethanone To a stirring solution of 20 g (150 mmol) of 4-methylacetophenone in 100 mL of glacial acetic acid was added catalytic amount of HBr (0.5 mL) followed by 21.40 g (134 mmol) of bromine dissolved in acetic acid (30 mL ) Drop by drop 10-15 ° C. The reaction mixture was stirred at 25-35 ° C for 5 hours, then poured into water (100 mL). The solid that separated is filtered to give the required product (20 g, 65%). RMNXH (200MHz, CDCl3): d 7.88 (d, J = 8.3Hz, 2H), 7.29 (d, 8Hz, 2H), 4.42 (s, 2H), 2.41 (s, 3H).

Preparation 11 2- (4-Methyl phenyl) -2-oxo ethyl-2-methylaminobenzoate To a solution of N-methylanthranilic acid (10.0 g, 66 mmol), obtained in Preparation 9, in 100 mL of dimethyl formamide, placed in a 250 ml round neck flask with a single neck, a solution of KOH (3.89 g, 69 mmol) in 10 mL of water was added and The mixture was stirred for 45 min at 25-35 ° C. The mixture was placed at 10 ° C, and bromoketone (16.9 g, 79 mmol), obtained in Preparation 10, was added. The reaction mixture was stirred for 10 hours at room temperature and then placed in ice water (500 mL). ). The solid that separated was filtered, washed with water (2 x 100 mL) and dried under vacuum to give a title compound (11.0 g, 58%) as a white solid. p.f. 96-98 ° C. IR (KBr, cm "1): 3382, 1684, 1674; NMRH (200MHz, DMSO-d6): d 7.91-7.87 (m, 3H), 7.47-7.34 (m, 3H), 6.75-6.57 (in, 2H), 5.62 (s, 2H), 3.32 (s, NH) , 2.83 (d, J = 4.3 Hz, 3H), 2.38 (s, 3H); Mass (Cl method): 284 (M + 1, 100%).

Preparation 12 3-Hydroxy-l-methyl-2- (4-methylphenyl) -1, -dihydro-4-quinolinone Polyphosphoric acid (PPA, 80 g) was heated at 140 ° C under nitrogen atmosphere in a 250 mL single neck round bottom flask. 2- (4-Methylphenyl) -2-oxo-ethyl-2-methylaminobenzoate (10 g, 35 mmol) obtained in Preparation 11 was added in small portions and the mixture was stirred at 140 ° C for 6 hours. The mixture was cooled to 25-35 ° C and ice water was added to the mixture and stirred for 30 min. The solids that separated were filtered, washed with water and dried under vacuum to give the title compound (60.0 g, 73%) as a brown solid. p.f. 216-218 ° C IR (KBr, cm "1): 3433, 1598; RMNXH (200MHz, DMSO-d6): d 8.44 (d, J = 8.3 Hz, 1H), 8.06-7.91 (m, 2H), 7.75-7.61 (m, 1H), 7.48-7.35 (m, 4H), 5.21 (bs, OH), 3.70 (s, 3H), 2.43 (s, 3H); Mass (Cl method): 266 (M + l, 100%) Preparation 13 4- (2-Bromoethoxy) benzaldehyde A mixture of 4-hydroxybenzaldehyde (10.0 g, 82 mmol) and potassium carbonate (46 g, 326 mmol) was placed in a 2L round bottom flask, and DMF (150 mL) was added. The mixture was stirred for 45 min and dibromoethane (46 g) was added in one portion, then the reaction mixture was allowed to stir at 25-35 ° C for 96 hours under nitrogen atmosphere. The reaction mixture was cooled to 25-35 ° C and then poured into water (500 mL). The mixture was extracted with EtOAc (3 x 100 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using 10-15% ethyl acetate / petroleum ether to give the title compound (8.50 g, 45%) as a white solid. IR (KBr, cm "1): 3439, 1682, 1602, 1577; RMN ^? (200MHz, CDCl3): d 9.88 (s, ÍH), 7.86 (d, J = 8.8Hz, 2H), 7. 03 (d, J = 8.8Hz, 2H), 4.40 (t, 2H, J = 6.2Hz), 3.69 (t, J = 5.9Hz, 2H); Mass (Cl method): 231 (M + 231, 100%).

Preparation 14 1- (3- { 2- [l-Methyl-2- (4-methylphenyl) -4-oxo-l, 4-dihydro-3-quinolinyloxy] ethoxy A mixture of hydroxy compound obtained in Preparation 12 (3.0 g, 11 mmol), the bromoke compound obtained in Preparation 1 (2.43 g, 10 mmol) and potassium carbonate (6.24, 45 mmol) was placed in a bottom flask. 1 L round and DMF (30 mL) was added. The mixture was heated to 80 ° C with stirring and kept at this temperature for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25 ° C and poured slowly into ice-cooled water (1 L). The solid that separated was filtered and washed with water (2 x 500 mL). Triturated with methanol and filtered to give the title compound (2.8 g, 64%), as a pale brown solid, after drying under vacuum RMNXH (200MHz, CDCl 3): d 8.60 (d, J = 7.8Hz, 1H) , 7.74-7.21 (m, 10H), 6.93 (d, J = 8.3Hz, ÍH), 4.37 (t, J = 4.4Hz, 2H), 4.02 (t, J = 4.9Hz, 2H), 3.52 (s, 3H), 2.56 (s, 3H), 2.37 (s, 3H). Mass (Cl method): 428 (M + 1, 428, 100%).

Preparation 15 4- (2-Bromo-ethoxy) -benzoic acid ethyl ester Step (i) To a solution of 4-hydroxybenzoic acid (15 g, 108. 6 mmol) in ethanol (200 mL) was added S0C12 (16 mL, 217. 4 mmol) at 0 ° C under anhydrous condition. The mixture was refluxed for 7 hours with stirring. After completion of the reaction, the mixture was concentrated under vacuum and the residue was neutralized using aqueous NaHCO 3 solution until the pH reached 7.0. The separated solid was filtered, washed with water (2 x 50 mL), and dried under vacuum to give the desired compound in 89% yield (16 g). Step (ii) A mixture of the 4-hydroxybenzoic ester (5 g, 30.12 mmol) and anhydrous K 2 CO 3 (4.62 g, 33.51 mmol) in acetone 50 mL) was stirred at 50 ° C for 30 min, under nitrogen atmosphere. 1,2-Dibromoethane (34 g, 180.7 mmol) was added to the mixture at the same temperature and continuous stirring for 6 hours. The mixture was filtered and the residue was washed with acetone (2 x 25 mL). The filtrates were collected, combined and concentrated. The residue was purified by crystallization from hexane to give the desired product in 96% yield (6.0 g).

Preparation 16 Ethyl acid ester 4-. { 2- [2- (3, 4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} A mixture of 2- (3,4-dimethoxyphenyl) -3-hydroxy-5,7-dimethoxy-4H-4-chromenone (4 g, 11.17 mmol) obtained in Preparation 2, 4- (2-ethyl) ethyl ester Bromo-ethoxy) -benzoic acid (3.66 g, 13.40 mmol) obtained in Preparation 15 and K2C03 (4.62 g, 33.51 mmol) in DMF (20 mL) was stirred at 80 ° C for 9 hours under Nitrogen atmosphere. The mixture was poured into water (60 mL) and stirred for 30 min. The separated solid was filtered, washed with water (2 x 20 mL) and dried under vacuum to give the desired product in 68% yield (4.2 g).

Preparation 17 Acid 4-. { 2- [2- (3, 4-Dimethoxy-phenyl) -5,7-dimethoxy-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic To a solution of the ethyl ester of acid 4-. { 2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic acid (4 g, 7.27 mmol) obtained in Preparation 16, in a mixture of methanol (40 mL) and dioxane (40 mL) was added to a KOH solution (2.0 g, 36.36 mmol) in water (10 mL) at 25-35 ° C and the. The mixture was stirred at 60 ° C for 6 hours. Then the solvent was removed from the mixture under vacuum and the residue was acidified with cold HCl. The separated solid was filtered, washed with cold water (2 x 3 L) and dried under vacuum. The crude product was further purified by crystallization from methanol to give the desired acid in 84% yield (3.2 g).

Preparation 18 2- (Toluene-4-sulfonylamino) -succinnamic acid To a solution of L-Aspergin (15 g, 100 mmol), NaOH (4.4 g, 110 mmol) in a mixture of water (75 mL) and dioxane (75 mL) was added p-toluenesulfonyl chloride (20.9 g, 110 mg). mmol) at 0 ° C. After stirring for 1 min, an additional amount of NaOH (4.4g, 110 mmol) in water (75 mL) was added to the reaction mixture at the same temperature. Stirring was continued for 1 hour and then dioxane was removed from the mixture under low vacuum. The residue was washed with ethyl acetate (2 x 30 mL), the aqueous layers were collected, combined and acidified with concentrated HCl slowly with stirring at 0 ° C. The separated solid was filtered and washed with cold water (2 x 30 mL) to give the desired product in 59% yield (17 g). p.f. : 198-200 ° C.

Preparation 19 3-Amino-2- (toluene-4-sulfonylamino) propionic acid ethyl ester Step (i): 3-Amino-2- (toluene-4-sulfonylamino) -propionic acid To a cold solution (0 ° C) and stirring NaOH (1.95 g, 48.95 mmol) in water (8.7 mL) was added bromine (0.36 mL, 6.99 mmol) slowly and dropwise. After 5 min, a cold solution of the Preparation 18 (2.0 g, 6.99 mmol) and NaOH (0.55 g) in water (6.4 mL). The solution was stirred for 20 min at 0 ° C and then for 30 min at 90 ° C. The solution was cooled to 0 ° C and the pH adjusted to 7.0 by slow addition of concentrated HCl. The prepared solid was filtered, washed with cold EtOAc (2 x 25 mL) and dried under vacuum to give the desired compound of 61% yield (1.1 g). p.f. 225-226 ° C.

Step (ii) 3-Amino-2- (toluene-4-sulfonylamino) propionic acid ethyl ester To a cold (0 ° C) solution and with stirring of the compound (2 g, 7.75 mmol), obtained in step (i), in ethanol (20 mL) was added S0C12 (1.25 mL, 17.05 mmol) under anhydrous condition. The mixture was refluxed for 12 hours with stirring. After completion of the reaction, the mixture was concentrated under vacuum to give the hydrochloride salt of the title compound in 90% yield (2.0 g). This was used in the next step without further purification.

Preparation 20 4- (3,4-Dimethoxyphenylcarboxamido) -1-methyl-3-propyl-lH-5-pyrazolecarboxamide A mixture of 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxamide (19.57 g, 107.5 mmol) and triethylamine (54.4 g, 134.38 mmol) in dichloromethane (300 mL) were taken in a round-bottomed flask of 3 liter necks equipped with a nitrogen balloon, pressure compensation addition funnel and a septum. The mixture was added to a solution of 3,4-dimethoxy-1-benzenecarbonyl chloride (21.5 g, 107.5 mmol) in dichloromethane (100 mL) at 0 ° C through a pressure equalizing addition funnel over a period of time. of 0.5 hours under nitrogen atmosphere. The reaction temperature was increased to 25 ° C after the addition and the contents were stirred for another 12 hours. The dichloromethane was removed from the reaction mixture under reduced pressure and the solid obtained was washed with cold water (2 x 150 mL), filtered and dried under vacuum to obtain the title compound 33 g, (89%) as a solid white. p.f. : 176-178 ° C. IR: Vmax (KBr, cm "1): 3370, 3243, 2960, 1682, 1631; RMNXH (200 MHz, CDC13): d 7.81 (s, 1H), 7.49 (d, J = 6.45Hz, 2H), 6.94 (d, J = 8.86Hz, ÍH), 3.99-3.96 (m, 9H), 2.53 (t, J - 7.22Hz, 2H), 1.68-1.57 (m, 2H), 0.92 (t, J = 7.51Hz, 3H); Mass (Cl method, I-butane): 347 (MH +, 100).

Preparation 21 5- (3,4-Dimethoxyphenyl) -l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo [4, 3-d] pyrimidin-7-one The 4- (3, -dimethoxyphenylcarboxamido) -l-methyl-3-propyl-lH-5-pyrazolecarboxamide, obtained in Preparation 20 (17 g, 49.13 mmol) in tert-butanol (350 mL) was taken in a single-liter round neck background equipped with a reflux condenser and to this is added carefully potassium tert-butoxide (16.55g, 147.38 mmol) and the contents were refluxed for 63 hours under nitrogen atmosphere. The reaction mixture was cooled to 25-35 ° C and terbutanol was completely removed under vacuum. To the residue was added cold water (200 mL) followed by the addition of dilute hydrochloric acid (3N) with stirring until the pH was constant at 7. The solid formed was completely filtered and dried under vacuum to give the title compound at 13 g (81%) as a white solid, mp : 210-212 ° C. IR: V max: (KBr, cm "1): 3438, 3204, 1670; RMtvH (200 MHz, DMSO-ds): d 12.3 (bs, interchangeable D20, ÍH), 7.73 (m, 2H), 7.08 (d , J = 8.32 Hz, 1H), 4.15 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 2.81 (t, J = 7.25 Hz, 2H), 1.83-1.72 (m, 2H), 0.96 (t, J = 7.24 Hz, 3H); Mass (Cl method, i-butane): 329 (M + 1, 100). Preparation 22 1- [4- (2-Bromoethylamino) phenyl] -1-ethanone To a suspension of 60% NaH (5.93 g, 247.08 mmol) in DMF (80 mL) taken in a one-liter two-necked round bottom flask with a pressure equalizing addition funnel and a septum was added a solution of p-aminoacetophenone (20 g, 148.1 mmol) in DMF (60 mL) in droplets through the addition funnel of pressure compensation under nitrogen atmosphere at 0 ° C and the contents were stirred for 2 hours at 25 ° C. So, to the stirred solution was added 1,2-dibromoethane (97.48 g, 518.5 mmol) in drops and the contents were further stirred for a further 18 hours at 90 ° C. The reaction mixture was cooled to 25-35 ° C and cold water (650 mL) was carefully added while stirring. The organic products were extracted with ethyl acetate (3 x 200 mL) and the combined organics were washed with water (2 x 100 mL) followed by washing with brine. The separated organic products were dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica gel using 15-20% ethyl acetate, petroleum ether (3 L), to give the title compound 5.1 g (14%) as a pale yellow solid m.p. 92-94 ° C. IR: Vmax: (Br, cm "1): 3360, 2927, 1650; NMRaH (200 MHz, CDCl 3): d 7.84 (d, J = 8.89 Hz, 2H), 7.48 (d, J = 8.58 Hz, 2H), 3.68-3.52 (m, 4H), 2.51 (s, 3H); Mass (Cl method, I-butane): 244 (M + 2, 10), 162 (100). Preparation 23 1- (4- { 2- [5- (3,4-Dimethoxyphenyl) -l-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4, 3-d ] pyrimidin-6-yl] ethylamino.} phenyl) -1-ethanone A mixture of 5- (3,4-dimethoxyphenyl) -l-methyl-3-propyl-6,7-dihydro-lH-pyrazolo [4, 3-d] pyrimidin-7-one obtained in Preparation 21 (2 g , 6.09 mmol), 1- [4- (2-bromoethylamino) -phenyl] -1-ethanone obtained in Preparation 22 (1.55 g, 6.405 mmol) and potassium carbonate (4.213 g, 3.5 mmol) were taken in a flask of round bottom in 100 mL and DMF (20 mL) was added thereto. The reaction mixture was stirred at 25 ° C for 16 hours under nitrogen atmosphere. The reaction mixture was poured slowly into ice water (100 mL). The separated solid was filtered, washed with water (2 x 5 mL), dried under vacuum to give the title compound 2.6 g (87%), as a pale yellow solid. p.f .: 182- 184 ° C. IR: Vmax (KBr, cm "1): 3381, 2927, 1660, 1599; NMR1 !! (200 MHz, DMS0-d6): d 7.93 (d, J = 5.68 Hz, 2H), 7.71 (d, J = 8.31 Hz, 2H), 7.03 (d, J = 8.79 Hz, ÍH), 6.91 (s, ÍH), 6.69 (d, J = 8.79 Hz, 2H), 4.84 (m, 2H), 4.10 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.72 (t, J = 4.5 Hz, 2H), 2.91 (t, J = 7.33 Hz, 2H), 2.40 (s, 3H), 1.89-1.78 (m, 2H), 0.93 (t, J = 7.32 Hz, 3H); Mass (Cl method, I-butane): 490 (M + 1, 100). Preparation 24 6, 7-Dimethoxyquinazolin-4 (3H) -one A mixture of 2-amino-4,5-dimethoxybenzoic acid (29.6 g, 0.15 mol) and formamide (0.6 mol, 24 mL) was stirred vigorously under a nitrogen atmosphere. The mixture was heated at 145 ° C for 4 hours. After completion the reaction mixture was cooled and water (120 mL) was added. The solid was filtered, washed with cold water (2 x 20 mL) followed by hexane (2 x 20 mL) to give 12.5 g of the desired product in 40% yield. p.f. 295-296 ° C (lit 296-297 ° C). NMR1H (DMS0-d6, 200 MHz) 12.0 (bs, exchangeable D20, 1H), 7. 97 (s, ÍH), 7.44 (s, 1H), 7.10 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H). Reference: LeMahieu, R. A .; Carson, M.; Nason, W. C.; Parrish, D. R.; Welton, A. F.; Baruth, H. W.; Yaremko, B. J.

Med. Chem. 1983, 26, 420. Example 1 5- [-1- (4- { 2- [2- (3,4-Dimethoxyphenyl) -5,7-dimethoxy-4-oxo-4h- 3-Chromynyloxy] ethoxy.} Phenyl) ethylidene] -1,3-thiazolan-2,4-dione A mixture of the compound (31 g, 59.6 mmol), obtained in Preparation 3, thiazolidine-1,3-dione (40 g, 341 mmol), benzoic acid (14.5 g, 118.8 mmol) and piperidine (10.1 g, 118.8 mmol) were placed in a 1 L single neck round bottom flask, to this was added toluene (600 mL). The round-bottomed flask was equipped with deán stark apparatus, which was connate to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and allowed to pass through a column of silica gel. The product was eluted by using 0.5-1% MeOH / CHCl3 (5 L) to give the title compound, 22 g (60%) as an off-white solid. p.f .: 205-206 ° C. GO: ? max (KBr, crn "1): 3220, 1735, 1698, 1627, 1604; XH NMR (200 MHz, CDC13): d 9.07 (bs, 1H, interchangeable with D20), 7.76-7.69 (m, 2H), 7.26 (d, J = 8.30 Hz, 2H), 6.90 (d, J = 8.79 Hz, 1H), 6.81 (d, J = 8.79 Hz, 2H), 6.52 (s, 1H), 6. 37 (s, 1H), 4.47 (t, J = 4.40 Hz, 2H), 4.29 (t, J = 4.40 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.91 (s, 6H), 2.69 (s, 3H); Mass (ES method): 619 (M +, 100). Example 2 Example 2 was prepared according to the methodology provided in Example 1.

NMR ^ (200 MHz, CDC13): d 12 (s, exchangeable D20), 7.68-7.44 (m, 4H), 7.10-6.84 (m, 4H), 6.51 (s, ÍH), 4.37-4.33 (m, 4H), 3.90 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.71 (s, 3H), 2.50 (s, 3H). P.f. : 120-124 ° C.

Example 3 Example 3 was prepared according to the methodology provided in Example 1. 2 H NMR (200 MHz, CDC13): d 8.65 (s, exchangeable D20), 7.75-7.71 (m, 2H), 7.28-7.23 (m, 2H), 6.90-6.79 (m, 2H), 6.70 (s, ), 6.53 (s, ÍH), 6.37 (s, ÍH), 4.49 (s, 2H), 4.25 (s, 2H), 3.97 (s, 3H), 3.91 (s, 9H), 2.68 (s, 3H) . P.f .: 210-214 ° C. Example 4 Example 4 was prepared according to the methodology provided in Example 1. 2 H NMR (200 MHz, CDC13): d 9.18 (s, exchangeable D20, HH), 7.92 (s, 1H), 7.91-7.81 (m, HH), 7.69 (s, HH), 6.95 (d, J = 8.79) Hz, ÍH), 6.65 (s, 2H), 6.54 (s, 1H), 6.34 (s, ÍH), 4.42 (s, 4H), 3.95 (s, 6H), 3.93 (s, 3H), 3.91 (s , 3H), 3.80 (s, 6H). P.f. : 207-210 ° C.

Example 5 Example 5 was prepared according to the methodology provided in Example 1.

AH NMR (200 MHz, CDC13): d 7.79 (d, J = 8.36 Hz, 2H), 7.66 (s, 2H), 7.27 (d, J = 9.7 Hz, 2H), 6.94 (d, J = 8.9 Hz, ÍH), 6.5 (s, 1H), 6.36 (s, ÍH), 4.22 (t, J = 6.74 Hz, 2H), 3.96 (s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.39 (t, J = 6.74 Hz, 2H), 2.54 (s, 3H). P.f. : 138-142 ° C.

Example 6 Example 6 was prepared according to the methodology provided in Example 1.

XR NMR (200 MHz, CDC13): d 7.72-7.67 (d, J = 10.78, 3H), 6.86 (d, J = 8.36 Hz, 1H), 6.64-6.52 (m, 3H), 6.37 (s, 1H) , 4.47 (s, 2H), 4.27 (s, 2H), 3.98 (s, 3H), 3.91 (s, 9H), 2.53 (s, 3H), 2.51 (s, 3H). P.f. : 126-130 ° C.

Example 7 Example 7 was prepared according to the methodology provided in Example 1.

NMR K (200 MHz, CDC13): d 8.31 (s, interchangeable D20, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.64 (s, ÍH), 7.36 (d, J = 10.2 Hz, 2H) , 7.28 (m, 2H), 7.01 (d, J = 8.79 Hz, ÍH), 6.58 (s, ÍH), 6.43 (s, ÍH), 4.2 (s, 2H), 4.0 (s, 3H), 3.97 ( s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.56 (s, 2H), 2.7 (s, 3H). P.f .: 192-195 ° C.

Example 8 Example 8 was prepared according to the methodology provided in Example 1.

XH NMR (200 MHz, CDC13): d 8.17 (s, exchangeable D20, HH), 7.76 (d, J = 8.3 Hz, HH), 7.68 (s, HH), 7.28 (s, 1H), 7.11 (m, ÍH), 6.98-6.89 (m, 2H), 6.52 (s, ÍH), 6.37 (s, ÍH), 4.48 (bs, 2H), 4.41 (bs, 2H), 3.97 (s, 3H), 3.91 (s) , 9H), 3.13 (t, J = 7.3 Hz, 2H), 1.6-1.4 (m, 2H), 0.92 (s, J = 7.3 Hz, 3H). P.f .: 204-208 ° C.

Example 9 Example 9 was prepared according to the methodology provided in Example 1.

NMR U (200 MHz, CDCl 3): d 8.27 (s, exchangeable D20, HH), 7.76 (d, J = 8.53 Hz, HH), 7.67 (s, 1H), 7.34 (s, HH), 7.17 (m, ÍH), 6.97-6.89 (m, 2H), 6.53 (s, ÍH), 6.37 (s, ÍH), 4.5 (s, 2H), 4.4 (s, 2H), 3.98 (s, 3H), 3.92 (s) , 9H), 2.68 (s, 3H). P.f. : 230-233 ° C.

Example 10 Example 10 was prepared according to the methodology provided in Example 1.

XH NMR (200 MHz, CDC13): d 8.25 (s, interchangeable D20, ÍH), 7.75 (d, J = 6.74 Hz, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 7.21 (s, 1H), 6.90 (d, J = 8.4 Hz, 2H), 6.52 (s, 1H), 6.37 (s, 1H), 4.5 (bs, 2H), 4.39 (bs, 2H), 3.98 (s, 3H), 3.91 (s, 6H), 3.90 (s 3H), 2.69 (s, 3H). P.f. : 235-236 ° C.

Example 11 Example 11 was prepared according to the methodology provided in Example 1. 1 H-NMR (200 MHz, CDC13): d 7.74 (d, J = 8.3 Hz, ÍH), 7.69 (s, HH), 7.24 (d, J = 7.9 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 6.10 Hz, 2 H), 6.76 (s, 1H), 6.5 (s, 1H), 4.33 (s, 2H), 4.2 (s, 2H), 3.90 (s, 3H) , 3.85 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 2.53 (s, 3H). P.f. : 225-228 ° C.

Example 12 Example 12 was prepared according to the methodology provided in Example 1.

AH NMR (200 MHz, CDC13): d 7.76-7.69 (m, 2H), 7.3 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 1H), 6.87-6.84 (m, 3H ), 6.50 (S, ÍH), 4.33 (s, 2H), 4.22 (s, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.81 (S, 3H), 3.77 (s, 3H) 2.51 (s, 3H). P.f .: 195-198 ° C. Example 13 5- [-1- (4-. {2- [6-Fluoro-2- (4-methoxyphenyl) -4-oxo-4 H -3-chromenyloxy] ethoxy] phenyl) ethylidene] -1, 3-thiazolan-2, 4-dione A mixture of the compound obtained in Preparation 8 (0.35 g, 0.72 mmol), thiazolidine-1,3-dione (0.54 g, 4.68 mmol), benzoic acid (0.19 g, 1.56 mmol) and piperidine (0.13 g, 1.56 mol) were placed in a 50 mL single neck round bottom flask, to which was added toluene (15 mL). The round bottom flask was equipped with a Dean-Stark apparatus, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and allowed to pass through a silica gel column. The product was eluted using 0.5-1% MeOH / CHCl3 (5 L) to give the title compound0.32 g (75%) as an off-white solid. P.f .: 210-212 ° C. RMN ^? (200 MHz, CDC13): d 12.2 (s, interchangeable D20, H), 8.14 (d, J = 8.87 Hz, 2H), 7.91-7.77 (m, ÍH), 7.71 (d, J = 8.6 Hz, 2H) , 7.36 (d, J = 8.59 Hz, 2H), 7.02 (d, J = 9.14 Hz, 2H), 6.92 (d, J = 8.59 Hz, 2H), 4.44 (s, 2H), 4.24 (s, 2H) 3.81 (s, 3H), 2.5 (s, 3H).

Example 14 This compound was prepared according to the procedure provided in Example 13.

XH NMR (200 MHz, CDC13): d 12.2 (s, exchangeable D20, HH), 8.14 (d, J = 8.87 Hz, 2H), 7.91-7.784 (m, HH), 7.75 (d, j = 8.6 Hz, 2H), 7.38-7.34 (d, J = 8.59 Hz, 2H), 7.02 (d, J = 9.14 Hz, 2H), 6.92 (d, J = 8.59 Hz, 2H), 4.44 (s, 2H), 4.24 ( s, 2H), 3.81 (S, 3H), 2.5 (s, 3H). P.f .: 227-230 ° C.

Example 15 This compound was prepared according to the procedure provided in Example 13.

RMN ^? (200 MHz, CDC13): d 12.21 (s, interchangeable D20, 1H), 8.1 (m, 2H), 7.85-7.74 (m, 3H), 7.23 (m, 2H), 7.02 (d, J = 7.79 Hz, 2H), 6.62 (d, J = 8.06 Hz, 2H), 6.44 (s, interchangeable D20, 1H), 4.14 (s, 2H), 3.82 (s, 3H), 3.35 (s, 2H), 2.5 (s, 3H). P.f. : 182-185 ° C.

Example 16 This compound was prepared according to the procedure provided in Example 13.

XH NMR (200 MHz, CDC13): d 12.2 (s, interchangeable D20, 1H), 8.13 (d, J = 3.23 Hz, 1H), 7.99 (d, J = 5.1 Hz), 7.71 (, ÍH), 7.73 -7.69 (d, J = 8.05 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 7.31 (m, 1H), 7.00 (d, J = 8.85 Hz, 2H), 4.62 (s, 2H) , 4.43 (s, 2H), 2.5 (S, 3H). P.f .: 238-240 ° C.

Example 17 This compound was prepared according to the procedure provided in Example 13. 1 H-NMR (200 MHz, CDC13): d 12.31 (s, exchangeable D20, 1H), 8.13 (d, J = 3.8 Hz, HH), 7.96 (d, J = 5.1 Hz, HH), 7.85-7.77 (m, 1H), 7.71 (d, J = 8.33 Hz, 2H), 7.4-7.3 (m, 2H), 6.96 (d, J = 8.87 Hz, 2H), 6.93-6.92 (m, HI), 4.62 (s, 2H) ), 4.4 (s, 2H), 2.5 (s, 3H). P.f .: 218-220 ° C.

Example 18 This compound was prepared according to the procedure provided in Example 13 2 H-NMR (200 MHz, CDC13): d 12.1 (s, exchangeable D20, 1H), 8.08 (d, J = 2.95 Hz, HH), 7.99 (d, J = 4.83 Hz 2H), 7.91-7.78 (m, HH) ), 7.72 (d, J = 8.06 Hz, interchangeable D20, 1H), 4.33 (t, J = 5.36 Hz, 2H), 3.59 (t, J = 5.64 Hz, 2H), 2.62 (s, 3H). P.f. : 218-219 ° C.

Example 19 This compound was prepared according to the procedure provided in Example 13.

XR NMR (200 MHz, CDC13): d 8.21-8.14 (m, ÍH), 7.87-7.85 (m, ÍH), 7.77 (d, J = 8.3 Hz, 2H), 7.36-7.26 (, 4H), 6.88 (d, J = 8.8 Hz, 31-1), 4.46 (s, 2H), 4.21 (s, 2H), 2.5 (s, 3H). P.f. : 262-265 ° C.

Example 20 This compound was prepared according to the procedure provided in Example 13.

NMR aH (200 MHz, CDC13): d 12.27 (s, exchangeable D20, HH), 9.35 (s, HH), 8.67 (d, J = 4.57 Hz, 1H), 8.48 (d, J = 8.33 Hz, HH) , 7.97-7.91 (m, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.56-7.50 (m, 1H), 7.35 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.6 Hz 2H), 4.53 (s, 2H), 4.23 (s, 2H), 2.5 (s, 3H). P.f .: 251-254 ° C.

Example 21 This compound was prepared according to the procedure provided in Example 13.

XH NMR (200 MHz, CDC13): d 10.4 (bs, exchangeable D20, HH), 8.06-8.00 (m, HH), 7.78-7.65 (m, 4H), 7.48-7.40 (m, 2H), 7.14 (d) , J = 7.79 Hz, 2H), 7.01 (d, J = 8.86 Hz, ÍH) 6.84 (d, J = 8.06 Hz, 2H), 6.04 (S, 2H), 4.44 (s, 2H), 4.18 (s, 2H). P.f .: 198-200 ° C.

Example 22 This compound was prepared according to the procedure provided in Example 13.

AH NMR (200 MHz, CDC13): d 10.43 (bs, interchangeable D20, 1H), 8.15-8.07 (m, 2H), 7.96 (d, J = 4.88 Hz, 1H) 7.84-7.73 (m, 2H), 7.53 -7.46 (m, ÍH), 7.32-7.28 (m, ÍH), 7.19-7.15 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.79 Hz, 2H), 4.62 (m, 2H), 4.32 (m, 2H). P.f. : 166-168 ° C.

Example 23 This compound was prepared according to the procedure provided in Example 13. 2 H NMR (200 MHz, CDC13): d 8.12 (bs, D20 exch), 8.08-8.04 (m, 3H), 7.83-7.74 (m, 3H), 7.51 (d, J = 8.3 Hz, 2H), 7.29 ( d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.89 Hz, 2H), 4.46 (m, 2H), 4.24 (m, 2H), 2.48 (S, 3H). P.f. : 220-222 ° C.

Example 24 5- [1- (4-. {2- [l-Methyl-4-oxo-2- (4-methylphenyl) -1,4-dihydro-3-quinolinyloxy] ethoxy) phenyl} methylidene] -1,3-thiazolan-2, 4-dione A mixture of the compound obtained in Preparation 14 (150 mg, 0.36 mmol), thiazolidine-1,3-dione (64 mg, 0.54 mmol), benzoic acid (88 mg), 0.72 mmol) and piperidine (61 mg, 0.72 mmol) were placed in a 1 L single neck round bottom flask, to which was added toluene (600 mL). The round bottom flask was equipped with a Dean-Stark apparatus, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and allowed to pass through a column of silica gel. The product was eluted by using 0.5-1% MeOH / CHCl3 (5 L) to give the title compound, 100 mg (54%) as a brown solid. P.f .: 250-252 ° C. X H NMR (200 MHz, CDC13): d 12.5 (s, NH), 8.33 (d, 1H, J = 8.2 Hz), 7.78 (m, 2H), 7.52-7.22 (m, 8H), 6.88 (d, 2H) , J = 8.3 Hz), 4.23 (s, 2H), 3.99 (s, 2H), 3.47 (s, 3H), 2.34 (s, 3H).

Example 25 This compound was prepared according to the procedure provided in Example 24.

X H NMR (200 MHz, CDC13): d 12.5 (s, NH), 8.34 (d, ÍH, J = 7.8 Hz), 7.78-7.47 (m, 11H), 6.90 (d, 2H, J = 8.4 Hz), 4.23 (s, 2H), 3.99 (s, 2H), 3.47 (s, 3H). P.f .: 250-252 ° C.

Example 26 This compound was prepared according to the procedure provided in Example 24.

RMN ^? (200 MHz, CDC13): d 12.22 (s, NH), 8.34 (d, 2H, J = 8.1 Hz), 7.8 (s, 2H), 7.53-7.26 (m, 6H), 6.82 (d, 2H, J = 8.3 Hz), 4.25 (S, 2H), 3.97 (s, 2H), 3.48 (s, 3H), 2.63 (s, 3H). P.f. : 196-198 ° C.

Example 27 This compound was prepared according to the procedure provided in Example 24.

XH NMR (200 MHz, CDC13): d 12.25 (bs, NH), 8.34 (d, ÍH, J = 7.8 Hz), 7.78 (d, 2H, J = 2.9 Hz), 7.45-7.28 (m, 7H), 6.80 (d, 2H, J = 8.8 Hz), 4.23 (s, 2H), 3.94 (s, 2H), 3.48 (s, 3H), 2.64 (s, 3H), 2.35 (s, 3H). P.f .: 228-232 ° C.

Example 28 This compound was prepared according to the procedure provided in Example 24.

RMN ^? (200 MHz, CDC13): 12.3 (NH, ÍH), 8.33 (d, ÍH, J = 8.2 Hz), 7.77 (d, 2H, J = 3.2 Hz), 7.46-7.27 (m, 6H), 6.95 (d , ÍH, J = 7.5 Hz), 6.78 (d, 2H, J = 8.8 Hz), 4.22 (s, 2H), 3.92 (s, 2H), 3.46 (S, 3H), 2.62 (s, 3H), 2.33 (s, 3H). P.f .: 210-212 ° C.

Example 29 3- (4-. {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy acid ethyl ester} -benzoylamino) -2- (toluene-4-sulfonylamino) -propionic 0 To a solution of acid 4-. { 2- [2- (3, 4-dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy} -benzoic acid obtained in Preparation 17 (3 g, 5.74 mmol), 3-amino-2- (toluene-4-sulfonylamino) -propionic acid ethyl ester obtained in Preparation 19 (2.22 g, 6.89 mmol) in DMF ( 20 mL) was added EDCl (1.64 g, 8.61 mmol), HOBt (1 g, 7.46 mmol) and? -methyl-morpholine (2.0 g, 20.09 mmol) at 25-35 ° C under a nitrogen atmosphere. The mixture was stirred at the same temperature for 12 hours. After the end of the reaction, the mixture was poured into water (60 mL) and stirred for 30 min. The separated solid was filtered, washed with water (2 x 20 mL) and dried under vacuum. The crude product was further purified by recrystallization from ethanol to give the desired product in 51% yield (2.3 g). 2 H NMR (CDCl 3, 200 MHz) 7.73-7.65 (m, 5H), 7.25 (d, J = 8.8Hz, 2H), 6.88-6.73 (m, 4H), 6.52 (d, J = 2Hz, 1H), 6.36 (d, J = 2Hz, ÍH), 5.91 (d, J = 7.8Hz, interchangeable D20, 1H), 4.47 (m, 2H), 4.23 (m, 2H), 4.10-3.91 (m, 16H), 3.8 ( m, ÍH), 2.37 (S, 3H), 1.14 (t, J = 7.3Hz, 3H). Example 30 This compound was prepared according to the procedure provided in Example 29 RMN ^? (CDCI3, 200 MHz) 10.06 (m, interchangeable D20, ÍH), 8.82 (s, ÍH), 8.17-8.06 (m, 2H), 7.74 (d, J = 8.3Hz, 2H), 7.27-7.19 (m, 3H), 6.24 (d, J = 7.8Hz, interchangeable D20, ÍH), 4.15-4.01 (, 3H), 3.84-3.70 (m, 2H), 3.77-3.51 (m, 1H), 2.31 (s, 3H) , 1.41 (d, J = 6.3Hz, ÍH), 1.25-1.13 (m, 5H).

Example 31 This compound was prepared according to the procedure provided in Example 29.

X-ray NMR (CDCI3, 200 MHz) 9.30 (bs, interchangeable D20, 1H), 7.76 (d, J = 8.1Hz, 2H), 7.60 (d, J = 6Hz, ÍH), 7.47 (s, 1H), 7.21 ( d, J = 8.1 Hz, 211), 6.99. (d, J = 7.5Hz, 111), 6. 76 (d, J 9.0Hz, interchangeable D20, ÍH), 6.53 (s, ÍH), 6.41 (s, ÍH), 4.17 (m, 2H), 4.02- 3.86 (m, 15H), 3.46-3.39 (m, 2H), 2.35 (s, 3H), 1.06 (t, J = 7.0Hz, 3H). Example 32 This compound was prepared according to the procedure provided in Example 29.

IN "H (DMSO-dg, 200 MHz), 8.32 (d, J = 8.8Hz, 2H), 8.10 (d, J = 8.0Hz, 1H), 7.80-7.50 (m, 7H), 7.28 (d, J = 7.8Hz, 2H), 7.03 (d, J = 8.60Hz, 1H), 6.85 (d, J = 8.3Hz, 2H), 4.43 (m, 2H), 4.37-4.26 (m, 2H), 4.07-4.03 (m, 2H), 3.79 (m, 8H), 3.47 (m, ÍH), 2.30 (s, 3H), 0.95 (t, J = 7.3Hz, 3H). Ejenplo 33 This compound was prepared according to the procedure provided in Example 29.

KMN J = 8.0Hz, ÍH), 7.83 (d, J = 7.0Hz, ÍH), 7.69-7.47 (m, 7H), 7.28 (d, J = 8.0Hz, 2H), 6.73 (d, J = 8.9Hz , 2H), 4.39 (bs, 2H), 4.07 (bs, 2H), 3.82-3.75 (m, 2H), 3.34 (m, 3H), 2.30 (s, 3H), 0.95 (t, J = 7.0Hz, 3H). Example 34 This compound was prepared according to the procedure provided in Example 29, RM? 2H (CDC13, 200 MHz), 8.25 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.73-7.65 (m, 5H), 7.52 (d, J = 7.9 Hz, ÍH), 7.40 (t, J = 7.0Hz, ÍH), 7.24 - 7.18 (m, 4H), 6.74 (d, J = 8.6 Hz, 2H), 6.64 (m, interchangeable D20, 1H), 5.69 (d, J = 7.3 Hz, interchangeable D20, 1H), 4.52 (m, 211), 4.22 (m, 211), 4.10 - 3.99 (m, 3H), 3.95 - 3.85 (m, 1H), 3. 69 - 3.59 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.13 (t, J = 7.0Hz, 311). Example 35 This compound was prepared according to the procedure provided in Example 29.

NMR E (CDC13, 200 MHz), 7.87 - 7.84 (m, 1H), 7.70 - 7.64 (m, 3H), 6.93 - 6.72 (m, 5H), 6.53 (d, J = 3.0 Hz, ÍH), 6.37 - 6.29 (m, 2H), 4.46 (m, 2H), 4.23 (m, 2H), 4.17 - 4.06 (m, 2H), 3.96 - 3.74 (m, 15 H), 1.18 (t, J = 7.0Hz, 3H ). Example 36 This compound was prepared according to the procedure provided in Example 29 XH NMR (CDC13, 200 MHz), 8.25 (d, J = 7.81 Hz, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.70-7.67 (m, 3H), 7.54 (d, J = 8.3 Hz , ÍH), 7.41 (t, J = 7.3 Hz, HH), 7.29 - 7.24 (m, 4H), 7.14 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.01 (m, 1H, interchangeable D20), 5.65 (d, J = 8.4 Hz, ÍH, interchangeable D20), 4.52 - 4.51 (m, 2H), 4.21 (m, 2H), 4.02-3.92 (m, 3H), 3.59 - 3.40 (m, 4H), 2.51 (s, 3H), 2.40 (s, 3H), 1.06 (t, J = 7.3Hz, 3H).

Example 37 This compound was prepared according to procedure 9.

XH NMR (CDC13, 200 MHz) 7.75-7.66 (m, 3H), 7.29 (m, 2H), 7.09 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 9.3 Hz, 2H), 6.72 ( d, J = 8.3 Hz, 2H), 6.52 (s, ÍH), 6.36 (s, ÍH), 5.99 (m, interchangeable D20, 1H), 5.62 (d, J = 7.7 Hz, interchangeable D20, 1H), 4.46 (m, 2H), 4.20 (m, 2H), 4.14-3.87 (m, 16H), 3.49 (m, 3H), 2.40 (s, 3H), 1.10 (t, J = 7.3Hz, 3H).

Example 38 This compound was prepared according to the procedure provided in Example 29.

XH NMR (CDCl3, 200 MHz) 7.67-7.59 (m, 3H), 7.26 - 7.23 (m, 3H), 7.15 - 7.10 (m, 3H), 6.84 (d, J = 8.6 Hz, 2H), 6.01 (bs) , D20 interchangeable, 1H), 5.78 (bs, interchangeable D20, ÍH), 4.39 - 4.30 (m, 4H), 3.98 - 3.88 (m, 10H), 3.60 - 3.36 (m, 3H), 2.38 (s, 3H) , 1.06 (t, J = 7.0Hz, 3H).

Example 39 This compound was prepared according to the procedure provided in Example 29.

XR NMR (CDCl3, 200 MHz) 8.30 (s, exchangeable D20, HH), 8.26 (s, 1H), 7.69-7.57 (m, 4H), 7.47 (s, HH), 7.26 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 6.98 (d, J = 8.6 Hz, 2H), 4.36 (bs, 4H), 4.02 (m, ÍH), 3.92-3.87 (m, 9H), 3.33 (m, 1H ), 2.27 (s, 3H), 0.93 (t, J = 7.3Hz, 3H).

Example 40 This compound was prepared according to the procedure provided in Example 29.

XR NMR (CDC13, 200 MHz) 8.13 (s, ÍH), 7.89-7.78 (m, 1H), 7. 69 (d, J = 8.0 Hz, 2H), 7.60 (s, ÍH), 7.12 (s, ÍH), 6.96 - 6.74 (m, 4H), 6.35 (d, J = 8.1 Hz, ÍH), 4.41 - 4.31 (rn, 4H), 4. 21 - 4.17 (m, ÍH), 4.13 - 4.02 (m, 2H), 3.99 (s, 6H), 3.86 - 3.84 (m, ÍH), 3.78 - 3.68 (m, ÍH), 1.15 (t, J = 7.3Hz, 3H).

Example 41 This compound was prepared according to the procedure provided in Example 29 1H-NMR (CDC13, 200MHz): d 8.09 (d, 2H, J = 8.8Hz), 7.58 (d, 2H, J = 8.3Hz), 7.26 (m, 3H), 6.98 (d, 2H, J = 8.3Hz) ), 5.18 (s, 2 H), 4.77 (s, 2H), 4.30 (s, 3H), 4.03 (s, 3H), 3.95 (s, 3H), 3.55-3.40 (m, 1H), 3.07-2.95 (q, 2H, J = 7.3Hz), 2.37 (s, 3H), 1.98-1.87 (q, 2H, J = 7.8Hz), 1.13-1.03 (, 6H). Example 42 This compound was prepared according to the procedure provided in Example 29 2 H NMR (CDC13, 200MHz): d 12.0 (bs, ÍH), 8.43 (m, 3H), 7.9 (m, ÍH), 7.75 (m, 2H), 7.55-7.10 (in, 5H), 6.05 (s, 1H), 5.39 (s, ÍH), 4.2 (m, 2H), 4.0-3.6 (m, 8H), 2.4 (s, 3H), 1.3-0.9 (m, 3H).

EXAMPLE 43 3- (4-. {2- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy acid} - benzoylamino) -2- (toluene-4-sulfonylamino) -propionic To a solution of 3- (4-. {2- [2- (3,4-dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] - ethyl ester ethoxy.}. -benzoylamino) -2- (toluene-4-sulfonylamino) -propionic (500 mg, 0.73 mmol) obtained in Example 29 in a mixture of ethanol (10 mL) and dioxane (10 mL) was added a solution of K, C03 (300 mg, 2.19 mmol) in water (5 mL) at 25-35. ° C and the mixture was stirred at the same temperature for 24 hours. Then the solvent was removed from the mixture under vacuum and the residue was acidified with cold HCl. The separated solid was filtered, washed with cold water (2 x 5 mL) and dried under vacuum to give the desired acid in 52% yield (250 mg). XH NMR (DMSO-d6, 200 MHz) 12.9 (bs, interchangeable D20, 1H), 8. 32 (s, interchangeable D20, ÍH), 8.13 (d, J = 8.3Hz, 1H), 7.72- 7.63 (m, 4H), 7.32 (d, J = 7.3Hz, 2H), 7.14 (d, J = 8Hz , ÍH), 6.86 (s, ÍH), 6.52 (s, ÍH), 4.26 (s, 2H), 3.90-3.82 (m, 15H), 2.33 (s, 3H). Example 44 This compound was prepared according to the procedure provided in Example 43.

NMR E DMSO-ds, 200 MHz) d 12.9 (bs, interchangeable D20, ÍH), 8.32 (s, interchangeable D20, ÍH), 8.13 (d, J = 8.3Hz, 1H), 7.72-7.63 (m, 4H) , 7.32 (d, J = 7.3Hz, 2H), 7.14 (d, J = 8Hz, ÍH), 6.86 (s, 1H), 6.52 (s, ÍH), 4.26 (s, 2H), 3.90-3.82 (m, 15H), 2.33 (s, 3H). Example 45 This compound was prepared according to the procedure provided in Example 43.

XH NMR (DMSO-d6, 200 MHz): d 9.72 (bs, interchangeable D20, 1H), 8.59 (s, 1H), 8.37 (d, J = 6.2 Hz, 1H), 8.14 (d, J = 9.4Hz, ÍH), 7.60 (d, J = 8Hz, 2H), 7.19 (d, J = 8.0Hz, 2H), 3.76-3.43 (m, 4H), 2.49 (s, 3H), 1.31 (d, J = 6.0Hz , 2H), 1.11 (s, 2H). Example 46 5- [(E, Z) -1- (4- { 2- [5- (3,4-Dimethoxyphenyl) -l-methyl-7-oxo-3-propyl-6,7-dihydro- lH-pyrazolo [4, 3-d] irimidin-6-yl] ethylamino.} phenyl) ethylidene] l, 3-thiazolan-2,4-dione A mixture of 1- (4-. {2- [5- (3,4-dimethoxyphenyl) -1-methyl-7-oxo-3-propyl-6,7-dihydro-IH-pyrazolo [4, 3- d] pyrimidin-6-yl] ethylamino.} phenyl) -1-ethanone obtained in Preparation 23 (2.4g, 4.91 mmol), thiazolidene-2,4-dione (2.87g, 24.54 mmol), benzoic acid (1.20 g, 9.81 mmol) and piperidine (0.84 g, 9.81 mmol) was taken in a 100 mL single neck round bottom flask, to which was added toluene (60 mL). The round bottom flask (RBF) was equipped with a dean, stark apparatus, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 35 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and stirred for one hour. The solid product formed was completely filtered. The pure product was obtained by triturating the solid with isopropanol (5 mL), filtered thoroughly and dried under vacuum to give the title compound as a pale green solid (1.51g, 2.56 mmol). P.f .: 215-218 ° C. IR: V max (KBr, cm "1): 3380, 2956, 1679; 2 H NMR (200 MHz, DMSO-d6): d 12.1 (bs, interchangeable D20, 1H), 7.95 (d, J = 6.98 Hz, 2H ), 7.22 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 7.86 Hz, ÍH), 6.70 (d, J = 8.59 Hz, 2H), 6.53 (bs, interchangeable D20, 1H), 4.82 ( m, 2H), 4.07 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H), 3.67 (m, 2H), 2.90 (t, J = 7.25 Hz, 211), 2.59 (s, 3H) ), 1.88-1.77 (m, 2H), 0.95 (t, J = 7.25 Hz, 3H), Mass (ESMS): 589 (MH +, 100), Purity = 94.5%.

Example 47 This compound was prepared according to the procedure provided in Example 43.

NMR E d 12.5 (bs, interchangeable D20, ÍH), 8.40-8.42 (m, 2H), 7.75 (s, 1H), 7.59-7.50 (m, 5H), 7.19 (d, J = 8.3Hz, 2H ), . 07 (m, 2H), 4.62 (m, 2H), 4.10 (s, 3H), 2.95 (t, J = 7. 32Hz, 2H), 1.86-1.83 (m, 2H), 0.97 (t, J = 7.32Hz, 3H) Example 48 This compound was prepared according to the procedure provided in Example 46.

NMR E d 12.4 (bs, interchangeable D20, ÍH), 8.36 (m, 2H), 7.48-7.31 (m, 7H), 4.94 (m, 2H), 4.05 (s, 3H), 3.64 (m, 2H), 2.91 (m, 2H), 2.60 (s, 3H), 1.85-1.82 (m, 2H), 0.98 (t, J = 6.84Hz, 3H). Example 49 This compound was prepared according to the procedure provided in Example 46.

NMR aH d 12.28 (bs, interchangeable D20, ÍH), 7.93 (m, 2H), 7.49-7.29 (m, 4H), 7.04 (d, J = 8.86Hz, 1H), 4.93 (m, 2H), 4.04 ( s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.64 (m, 2H), 2.90 (t, J = 7.52Hz, 2H), 2.59 (s, 3H), 1.89-1.78 (m, 2H), 0.96 (t, J = 7.25Hz, 3H). Example 50 This compound was prepared according to the procedure provided in Example 46.

XR-NMR 7.95-7.90 (m, 2H), 7.67 (s, 1H), 7.44-7.33 (m, 3H), 6.95 (d, J = 8.63Hz, 2H), 4.65- 4.59 (m, 2H), 4.33 -4.21 (m, 7H), 3.03 (m, 4H), 2.80 (t, J = 7.25Hz, 2H), 2.53-2.34 (m, 4H), 2.23 (s, 3H), 1.79-1.69 (m, 2H) ), 1.30 (t, J = 6.99Hz, 3H), 0.95 (t, J = 7.25Hz, 3H). Example 51 This compound was prepared according to the procedure provided in Example 46.

NMR XE d 7.34-7.16 (m, 7H), 6.97-6.88 (m, 2H), 4.42 (s, 2H), 4. 37-4.22 (m, 4H), 4.18 (s, 3H), 2.84 (t, J = 7.33Hz, 2H), 2. 63 (s, 3H), 1.83-1.72 (m, 2H), 0.93 (t, J = 7.32Hz, 3H).

Example 52 This compound was prepared according to the procedure provided in Example 46.

NMR X d 12.5 (bs, interchangeable D20, 1H) 7.98 (d, J = 7.53Hz, 2H), 7.72 (s, ÍH), 7.51 (d, J = 8.59Hz, 2H), 7.08-7.01 (m, 3H) ), 4.76 (m, 2H), 4.18 (m, 2H), 4.1 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 2.91 (t, J = 6.99Hz, 2H), 2.08-2.04 (m, 4H), 1.89-1.78 (m, 2H), 0.97 (t, J = 7.25Hz, 3H). Example 53 This compound was prepared according to the procedure provided in Example 46.

NMR E d 12.52 (bs, interchangeable D20, ÍH), 8.01-7.96 (m, 2H), 7.72 (s,), 7.3 (d, J = 8.64Hz, 2H), 7.12-7.02 (m, 3H), 4.85 -4.8 (m, 2H), 4.4-4.32 (m, 2H), 4.13 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 2.91 (t, J = 7.25Hz, 2H), 2.5-2.39 (m, 2H), 1.86-1.82 (m, 2H), 0.97 (t, J = 7.26Hz, 3H). Example 54 This compound was prepared according to the procedure provided in Example 46. 1 H NMR 12.25 (bs, interchangeable D20, IH), 8.01-7.96 (m, 2H), 7.42-6.97 (m, 5H), 5.02 (m, 2H), 4.56 (m, 2H), 4.07 (s, 3H) ), 3.86 (s, 3H), 3.83 (s, 3H), 2.91 (t, J = 7.25, 2H), 3.36 (s, 3H), 1.89-1.78 (m, 2H), 0.97 (t, J = 7.25) Hz, 3H). Example 55 This compound was prepared according to the procedure provided in Example 46.

NMR XH d 8.52 (bs, interchangeable D20, 1H), 8.07 (d, J = 6.72Hz, 2H), 7.41-7.33 (m, 2H), 6.97-6.92 (m, 3H), 5.07 (m, 2H), 4.49-4.48 (m, 2H), 4.19 (s, 3H), 4.02 (s, 3H), 3.96 (s, 3H), 3.03 (t, J = 7.52Hz, 2H), 2.69 (s, 3H), 1.98 -1.86 (m, 2H), 1.04 (t, J = 7.25Hz, 3H).

Example 56 5- [1- (3-f luoro-4- { 2- [2- (4-fluoro-phenyl) -l-methyl-4-oxo-1,4-dihydro -qui or lin -3- iloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-2-fluoro-phenoxy) -ethoxy] -2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.45 g, 1.0 mmol), 2,4-thiazolidenedione (0.703 g, 6.01 mmol), benzoic acid (225 mg, 1.84 mmol), and piperidine (150 mg, 1.76 mmol) was taken in a round-bottomed flask of a only neck, to this was added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 1% MeOH-CHC13 to give the title compound, 209 mg (38%) as a white solid. XR NMR (200 MHz, DMSO-d6): d 12.31 (bs, interchangeable D20, NH), 8.32 (d, J = 8.0 Hz, ÍH), 7.79 (d, J = 3.2 Hz, 2H), 7.50-6.99 ( m, 8H), 4.27 (s, 2H), 4.06 (s, 2H), 3.47 (s, 3H), 2.64 (s, 3H).

P.f. : 220 ~ 222 ° C Example 57 5- [1- (3-Chloro-4. {2- [2- (2-fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro- quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (2-fluoro-phenyl) -l-methyl-lH-chenolin-4-one (400 mg, 0.86 mmol), 2,4-thiazolidenedione (504 mg, 4.3 mmol), benzoic acid (250 mg, 2.04 mmol), and piperidine (160 mg, 1.88 mmol) was taken in a 50 mL single neck round bottom flask, a this was added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated in vacuo. The residue was purified by column chromatography followed by washing with ether to give the title compound 200 mg (41%) as an off-white solid. XR NMR (200 MHz, DMS0-ds): dl2.39 (s, NH.}., 8.43 (d, J = 8.0 Hz, ÍH), 7.89 (d, J = 3.0 Hz, 2H), 7.54 (s, 4H), 7.41-7.27 (m, 3H), 7.12 (d, J = 8.6Hz, ÍH), 4.41 (s, 2H), 4.16 (s, 2H), 3.59 (s, 3H), 2.71 (s, 3H) Mp: 220-222 ° C Example 58 5- [1- (4- { 2- [2 - (4-fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-chenolin -3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (4-fluoro-phenyl) -l-methyl-1H-quinolin-4-one (39 g, 9 mmol), 2 , 4-thiazolidenedione (63.5 g, 54 mmol), benzoic acid (22.2 g, 18.1 mmol), and piperidine (16 g, 18.79 mmol) was taken in a single neck round bottom flask, to which was added toluene (500 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated in vacuo. The residue was purified by column chromatography using 0-1% MeOH-CHCl 3 to give the title compound 24 g (50%) as a light brown solid. XR NMR (200 MHz, DMS0-d6): dl2.09 (bs, interchangeable D20, 1H), 8.34 (d, J = 7.8Hz, ÍH), 7.80 (d, J = 3.4Hz, 2H), 7.53-7.22 (m, 7H), 6.82 (d, J = 8.2Hz, 2H), 4.23 (s, 2H), 3.96 (s, 2H), 3.48 (s, 3H), 2.64 (s, 3H). Mp: 228-230 ° C Example 59 5- [1- (3- { 2- [2- (3,4-Dimethoxy-phenyl) -6-fluoro-4-oxo-4H-chromen-3-yloxy ] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (3-Acetyl-phenoxy) -ethoxy] -2- (3,4-dimethoxy-phenyl) -6-fluoro-chromen-4-one (0.5 g, 1.04 mmol), 2 , 4-thiazolidenedione (0.79 g, 6.6 mmol), benzoic acid (0.27 g, 2.2 mmol), and piperidine (0.19 g, 2.23 mmol) was taken in a single neck round bottom flask, to which was added toluene ( 35 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C, stirred for 6 hours at room temperature and filtered. The solid was triturated with i-PrOH (20 mL) and filtered to give the title compound 0.38 g (63%) as an off-white solid. RMN ^? (200 MHz, DMSO-de): d 12.88 (bs, interchangeable D20, ÍH), 7.89-7.71 (m, 5H), 7.28 (s, ÍH), 7.06 (d, J = 8.6 Hz, 1H), 6.96 ( d, J = 7.5 Hz, 1H), 6.87 (d, J = 8.32 Hz, 1H), 6.75 (s, ÍH), 4.43 (s, 2H), 4.20 (s, 2H), 3.76 (s, 3H), 2.6 (s, 3H). P.f. : 228-230 ° C Example 60 5- [1- (4- { 2- [2- (4-Chloro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3- iloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (4-chloro-phenyl) -l-methyl-1H-quinolin-4-one (1.19 g, 2.45 mmol), , 4-thiazolidenedione (1.72 g, 14.70 mmol), benzoic acid (0.59 g, 4.83 mmol), and piperidine (0.415 g, 4.82 mmol) was taken in a single neck round bottom flask, to which was added toluene ( 100 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated in vacuo. The residue was purified by column chromatography using 6% MeOH-CHC13 to give the title compound 0.73 g (30%) as a light brown solid. XR NMR (200 MHz, DMSO-d6): 8.32 (d, J = 7.5 Hz, HH), 7.79 (s, 2H), 7.97-7.32 (m, 7H), 6.79 (d, J = 8.5 Hz, 2H) , 4.24 (s, 2H), 3.96 (s, 2H), 3.47 (s, 3H), 2.69 (s, 3H). Mp: 238-240 ° C Example 61 5- [1- (3- { 2- [2- (3,4-Difluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin -3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (3-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -l-methyl-lH-quinolin-4-one (1.0 g, 2.22 mmol) , 2,4-thiazolidenedione (1.56 g, 13.36 mmol), benzoic acid (325 mg, 2.67 mmol), and piperidine (325 mg, 3.82 mmol) was taken in a single neck round bottom flask, to which was added toluene. (30 L). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography to give the title compound 488 mg (40%) as a light brown solid. XR NMR (200 MHz, DMSO-d6): d 12.31 (NH, HH), 8.32 (d, HH, J = 7.8Hz), 7.81 (s, 2 H), 7.62-7.30 (m, 5H), 6.95 ( d, ÍH, J = 7.8 Hz), 6.77 (d, 2H, J = 9.7Hz), 4.26 (s, 2 H), 3.95 (s, 2H), 3.49 (s, 3H), 2.64 (s, 3 H). Mp: 236-240 ° C Example 62 5- [1- (4-. {2 - [l-ethyl-2- (4-fluoro-phenyl) -4-oxo-l, 4-dihydro-quinolin-3 -yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -l-ethyl-2- (4-fluoro-phenyl) -lH-quinolin-4-one (0.6 g, 1.35 mmol), 2 , 4-thiazolidenedione (0.946 g, 8.08 mmol), benzoic acid (200 mg, 1.64 mmol), and piperidine (200 mg, 2.35 mmol) was taken in a single-neck round bottom flask, to which was added toluene (30 ml). mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using MeOH-CHCl3 to give the title compound 333 mg (45%) as a light brown solid. XR NMR (200 MHz, DMSO-d6): d 12.09 ((bs, ÍH, interchangeable d20), 8.35 (d, J = 7.8Hz, ÍH), 7.87-7.77 (m, 2H), 7. 55-7.23 (m, 7H), 6.83 (d, J = 8.7Hz, 2H), 4.23 (s, 2H), 4.02-3.98 (m, 4H), 2.64 (s, 3H), 1.16 (t, J = 6.8Hz, 3H). Mp: 214-216 ° C Example 63 5- [1 (4- (2- [2 (3,4-Difluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy ] -ethoxy.}. -phenyl) -ethylidene] -thiazolidine-2, -dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -l-methyl-lH-quinolin-4-one (1.75 g, 3.89 mmol) , 2,4-thiazolidenedione (2.74 g, 23.38 mmol), benzoic acid (475 mg, 3.89 mmol), and piperidine (331 mg, 3.89 mmol) were taken into a single neck round bottom flask, to which was added toluene. (30 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using MeOH-CHC13 to give the title compound 830 mg (39%) as a light brown solid.

NMR? (200 MHz, DMSO-d6): d 12.24 (bs, NH, interchangeable D20), 8.32 (d, J = 8.0 Hz, ÍH), 7.81 (s, 2H), 7.66-7.32 (m, 6H), 6.80 ( d, J = 8.6 Hz, 2H), 4.25 (s, 2H), 3.97 (S, 2H), 3.49 (s, 3H), 2.64 (s, 3H). P.f. : 248-250 ° C Example 64 5- [l- (4- { 2- [7-chloro-2- (4-fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro -quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-chloro-2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.4 g, 0.85 mmol), 2,4-thiazolidenedione (0.502 g, 4.29 mmol), benzoic acid (190 mg, 1.55 mmol), and piperidine (145 mg, 1.70 mmol) was taken in a round bottom neck flask individual, to this was added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and filtered. The solid was treated with i-PrOH under reflux for 2 hours and then filtered. The solid was washed with hexane and purified by column chromatography to give the title compound 200 mg (41%) as a white solid. 1 H NMR (200 MHz, DMSO-d 6): d 12.10 (bs, exchangeable D20, ÍH), 8.32 (d, J = 7.5Hz, ÍH), 7.89 (s, ÍH), 7.48-7.27 (m, 7H), 6.82 (d, J = 8.0 Hz, 2H), 4.23 (s, 2H), 3.95 (s, 2H), 3. 45 (s, 3H), 2.63 (s, 3H). P.f. : 292-296 ° C Example 65 5- [1- (4- { 2- [2- (4-Fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -ethylamino} .-phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenylamino) -ethoxy] -2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.4 g, 0.93 mmol), 2 , 4-thiazolidenedione (0.65 g, 5.6 mmol), benzoic acid (225 mg, 1.84 mmol), and piperidine (180 mg, 2.11 mmol) was taken in a single-neck round bottom flask, to which was added toluene (100 g. mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 0-2% MeOH-CHC13 to give the title compound 200 mg (41%) as a yellow solid. NMR aH (200 MHz, DMS0-d6): d 8.61 (d, J = 8.3 Hz, 2H), 7.77 (t, J = 8.2 Hz, 2H), 7.56-7.19 (m, 6H), 6.56 (d, J = 8.3 Hz, 2H ), 5.99 (bs, NH), 3.94-3.92 (m, 2H), 3.53-3.41 (m, 4H), 3.18 (s, 2H), 2.68 (s, 3H). P.f. : 130-132 ° C EXAMPLE 66 5- (4-. {2- [2- (4-Fluorophenyl) -l-methyl-4-oxo-l, 4-dihydro- (quinolin-3-yloxy] -ethoxy.} - benzylidene) -thiazolidine-2, -dione A mixture of compound 4-. { 2- [2- (4-Fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -ethoxy} -benzaldehyde (0.3 g, 0.719 mmol), 2,4-thiazolidenedione (0.168 g, 1.43 mmol), benzoic acid (30 mg, 0.24 mmol), and piperidine (30 mg, 0.35 mmol) was taken in a round bottom flask of an individual neck, to this was added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was refluxed for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 50 ° C and filtered. The residue was washed with hot MeOH and dried under vacuum to give the title compound 200 mg (54%) as a brown solid. XR NMR (200 MHz, DMSO-d6): d 12.5 (s, NH, interchangeable D20), 8.35 (d, J = 8.1Hz, ÍH), 7.81 (d, J = 3.2 Hz, 2H), 7.72 (s, ÍH), 7.51-7.47 (en, 5H), 7.29-7.25 (m, 2 H), 6.88 (d, J = 8.6 Hz, 2H), 4.20 (s, 2H), 3.99 (s, 2H), 3.50 ( s, 3H). P.f. : 225-228 ° C EXAMPLE 67 5- (4-. {2- 2- (4-Bromo-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -ethoxy.} - benzylidene ) -thiazolidine-2,4-dione A mixture of compound 4-. { 2- [2- (4-Bromo-phenyl) -1-methyl-4-oxo-l, 4-dihydroquinolin-3-yloxy] -ethoxy} -benzaldehyde (0.125 g, 0.25 mmol), 2,4-thiazolidenedione (0.178 g, 1.5 mmol), benzoic acid (63 mg, 0.51 mmol), and piperidine (45 mg, 0.52 mmol) was taken in a round bottom flask of an individual neck, to this was added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was refluxed for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The separated solid was filtered, washed with diethyl ether and dried under vacuum to give the title compound 80 mg (53%) as a light brown solid. 2 H NMR (200 MHz, DMSO-d 6): d 8.35 (d, J = 8.8 Hz, ÍH), 7.87- 7.39 (m, 11H), 6.89 (d, J = 8.7 Hz, 2H), 4.24 (bs, 2H) ), 4.01 (bs, 4H), 1.16 (t, J = 6.8Hz, 3H). P.f .: 151-154 ° C Example 68 5- [1- (4- { 2- [2- (5-Fluoro-2-methyl-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -ethoxy.}. -phenyl) -ethylidene] -thiazolidine-2, -dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (5-fluoro-2-methyl-phenyl) -l-methyl-lH-quinolin-4-one (0.25 g, 0.56 mmol), 2,4-thiazolidenedione (0.394 g, 3.37 mmol), benzoic acid (142 mg, 1.16 mmol), and piperidine (100 mg, 1.17 mmol) was taken in a single neck round bottom flask, to this toluene (50 mL) was added. The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 3-20% EtOAc-CHCl3 to give the title compound 80 mg (26%) as a brown solid.

NMR (200 MHz, DMSO-d6): d 12.30 (s, exchangeable D20, HH), 8.35 (d, J = 7.8Hz, HH), 7.80 (s, 2H), 7.47-7.16 (m, 5H), 6.96 (d, J = 7.8 Hz, ÍH), 6.79 (d, J = 9.1 Hz, 2H), 4.31-4.26 (m, 2H), 3.95 (m, 2H), 3.52 (s, 3H), 2.62 (s, 3H), 2.21 (s, 3H). P.f. : 192-196 ° C Example 69 5- [1- (3- { 2- [2- (4-Fluoro-2-methyl-phenyl) -1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -ethoxy.}. -phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (3-acetyl-phenoxy) ethoxy] -2- (4-fluoro-2-methyl-phenyl) -l-methyl-lH-quinolin-4-one (0.25 g, 0.56 mmol ), 2, 4-thiazolidenedione (0.394 g, 3.37 mmol), benzoic acid (150 mg, 1.22 mmol), and piperidine (100 mg, 1.17 mmol) was taken in a single-neck round bottom flask, to this added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 3-20% EtOAc-CHCl3 to give the title compound 120 mg (39%) as a brown solid. NMR E (200 MHz, DMSO-d6): d 11.22 (bs, 1H), 8.59 (d, J = 7.2 Hz, 1H), 7.76-6.63 (m, 10H), 4.45-4.26 (m, 2H), 4.0-3.98 (m, 2H), 3.58 (S, 3H), 2.67 (s, 3H), 2.15 (s, 3H). Mp: 225-226 ° C Example 70 5- [1- (4- { 3- [2- (4-Fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3 -iloxy] -propoxy.}. -phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [3- (4-acetyl-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.40 g, 0.898 mmol), 2 , 4-thiazolidenedione (0.631 g, 5.39 mmol), benzoic acid (225 mg, 1.82 mmol), and piperidine (175 mg, 2.05 mmol) was taken in a single neck round bottom flask, to which was added toluene ( 30 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 1% MeOH-CHCl3 to give the title compound 130 mg (27%) as a white solid. XR NMR (200 MHz, DMSO-d6): d 12.27 (bs, NH, interchangeable D20), 8.30 (d, J = 7.8 Hz, ÍH), 7.81 (s, 2H), 7.55-7.3 (m, 7H), 6.88 (d, J = 7.8 Hz, 2H), 4.01 (s, 2H), 3.62 (s, 2H), 3.49 (s, 3H), 2.68 (s, 3H), 1.82 (s, 2H). P.f. : 262-264 ° C Example 71 5- [1- (3- { 3- [2- (4-Fluro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -propoxy. .-phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [3- (3-Acetyl-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -1-methyl-1H-quinolinone (0.45 g, 1011 mmol), 2, 4-thiazolidenedione (0.710 g, 6.06 mmol), benzoic acid (300 mg, 2.46 mmol), and piperidine (300 g, 3.52 mmol) was taken in a single-necked round-bottomed flask, to which was added toluene (50 g. mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 0.3% MeOH-CHCl 3 to give the title compound 187 mg (34%) as a light brown solid. XR NMR (200 MHz, DMSO-d6): d 12.29 (NH, HH), 8.31 (d, HH, J = 7.8 Hz), 7.78 (s, 2H), 7.56-7.22 (m, 6H), 6.97 (d , ÍH, J = 7.5Hz), 6.80 (d, 2H, J = 6.7 Hz), 3.99 (s, 2H), 3.58-3.55 (m, 2H), 3.46 (s, 3H), 2.66 (s, 3H) , 1.79 (s, 2H). P.f. : 168 ~ 170 ° C Example 72 5- [1- (3-Chloro-4. {3- [2- (4-fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -propoxy.}. -phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [3- (4-acetyl-2-chloro-phenoxy) -propoxy] -2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.40 g, 0.86 menol), 2,4-thiazolidenedione (0.603 g, 5.16 mmol), benzoic acid (150 mg, 1.23 mmol), and piperidine (300 mg, 3.52 mmol) was taken in a single neck round bottom flask, to this toluene (50 mL) was added. The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 2% MeOH-CHC13 to give the title compound 140 mg (30%) as a light brown solid. X H NMR (200 MHz, DMSO-d 6): d 12.31 (NH, ÍH), 8.32 (d, 1H, J = 7.8Hz), 7.80 (d, 2H, J = 2.9 Hz), 7.48-7.13 (m, 7H) ), 7.02 (d, ÍH, J = 8.3 Hz), 4.29 (s, 2H), 4.07 (s, 2H), 3.47 (s, 3H), 2.64 (s, 3H), 1.82 (s, 2H).

P.f 232-234 ° C Example 73 5- [1- (4-. {2- [7-Fluoro-2- (4-fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yloxy] -ethoxy.}. -phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-fluoro-2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.40 g, 0.89 mmol), 2,4-thiazolidenedione (0.521 g, 4.45 mmol), benzoic acid (200 mg, 1.63 mmol), and piperidine (150 mg, 1.76 mmol) was taken in a single neck round bottom flask, to this toluene (50 mL) was added. The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 0.5-1% MeOH-CHC13 to give the title compound 100 mg (21%) as a brown solid. NMR aH (200 MHz, DMS0-d6): d 12.24 (bs, HH), 8.39 (t, J = 7.30 Hz, ÍH), 7.67 (d, J = 11.8 Hz, 1H), 7.52 (t, J = 8.30) Hz, 2H), 7.3.6 (t, J = 8.80 Hz, 5H), 6.82 (d, J = 8.8 Hz, 2H), 4. 22 (S, 2H), 3.95 (s, 2H), 3.33 (s, 3H), 2.63 (s, 3H). Mp: 276-278 ° C Example 74 5- [1- (4- { 2 - [2- (3, 4-Difluoro-phenyl) -7-fluoro-l-methyl-4-oxo-l, 4 -dihydro-quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2, -dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -2- (3, -difluoro-phenyl) -7-fluoro-l-methyl-lH-quinolin-4-one (0.40 g, 0.85 mmol), 2,4-thiazolidenedione (0.50 g, 4.28 mmol), benzoic acid (190 mg, 1.55 mmol), and piperidine (145 mg, 1.70 mmol) was taken in a single-necked round bottom flask, a this was added toluene (50 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 50 ° C, filtered and washed with hot toluene. The solid was treated with toluene under reflux for 10 hours, filtered, washed with hot MeOH and dried to give the title compound 125 mg (26%) as a white solid. X H NMR (200 MHz, DMSO-d 6): d 12.23 (s, ÍH), 8.39 (t, J = 8.6 Hz, ÍH), 7.68-7.32 (m, 71H), 6.81 (d, J = 8.6 Hz, 2H ), 4.25 (s, 2H), 3.97 (s, 2H), 3.43 (s, 3H), 2.64 (s, 31H). P.f. 270-272 ° C Example 75 5- [1- (4- { 2- [2- (3,4-Difluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3 -yloxy] -ethoxy.} - 3-fluorophenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-Acetyl-2-fluoro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -1-methyl-lH-quinolin-4-one (0.40 g , 0.856 mmol), 2,4-thiazolidenedione (0.701 g, 5.99 mmol), benzoic acid (200 mg, 1.64 mmol), and piperidine (200 mg, 2.35 mmol) was taken in a single neck round bottom flask, to this toluene (30 mL) was added. The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 1-2% MeOH-CHCl 3 to give the title compound 170 mg (35%) as a light brown solid. NMR aH (200 MHz, DMSO-d6): d 12.29 (NH, HH), 8.32 (d, HH, J = 7.8 Hz), 7.80 (d, 2H, J = 2.9 Hz), 7.62-6.99 (m, 7H) ), 4.28 (s, 2H), 4.07 (s, 2H), 3.48 (s, 3H), 2.64 (s, 3H). Mp: 204-206 ° C Example 76 5- [1- (4- { 2- [7-Chloro-2- (3,4-difluoro-phenyl) -l-methyl-4-oxo-1, - dihydro-quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -7-chloro-2- (3,4-difluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.60 g) , 1.2 mmol), 2,4-thiazolidenedione (0.872 g, 7.0 mmol), benzoic acid (151 mg, 1.2 mmol), and piperidine (105 mg, 1.2 mmol) was taken in a single neck round bottom flask, a • toluene (20 mL) was added. The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using MeOH-CHC13 to give the title compound 150 mg (21%) as a white solid. 2 H NMR (200 MHz, DMSO-d 6): d 12.21 (bs, exchangeable D 20, NH), 8.30 (d, J = 8.8 Hz, 1H), 7.89 (s, ÍH), 7.62-7.30 (m, 6H), 6.79 (d, J = 8.8 Hz, 2H), 4.24 (s, 2H), 3.94 (s, 2H), 3. 45 (s, 3H), 2.62 (s, 3H). Mp: 296-298 ° C Example 77 5- [1- (3-Chloro-4- { 2- [7-chloro-2- (3,4-difluoro-phenyl) -l-methyl-4-oxo -1,4-dihydro-quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] - A mixture of the compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -7-chloro-2- (3,4-difluoro-phenyl) -1-methyl-1H-quinolin-4- ona (0.50 g, 0.96 mmol), 2,4-thiazolidenedione (0.677 g, 5.0 mmol), benzoic acid (117 mg, 0.96 mmol), and piperidine (95 mg, 0.96 mmol). It was taken in a round bottom flask with an individual neck, to this was added toluene (20 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using MeOH-CHCl3 to give the title compound 120 mg (20%) as a white solid. XR NMR (200 MHz, DMS0-d6): d 12.25 (bs, interchangeable D20, NH), 8.26 (d, J = -8.3 Hz, 1H), 7.86 (s, 1H), 7.46-7.19 (m, 6H), 6.99 (d, J = 8.8 Hz, ÍH), 4.20 (s, 2H), 4.02 (s, 2H), 3. 39 (s, 3H), 2.57 (s, 3H). P.f. : 140-142 ° C Example 78 5- [1- (4- { 2- [6-Fluoro-2- (4-fluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro- quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-phenoxy) -ethoxy] -6-fluoro-2- (4-fluoro-phenyl) -l-methyl-lH-quinolin-4-one (0.4 g, 0.82 mmol), 2,4-thiazolidenedione (0.581 g, 4.96 mmol), benzoic acid (650 mg, 5.32 mmol), and piperidine (500 mg, 5.87 mmol) was taken in a round-bottomed flask of a individual neck, to this was added toluene (30 mL). He RBF was equipped with deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 0.5-1% MeOH-CHC13 to give the title compound 80 mg (16%) as a light brown solid. XR NMR (400 MHz, DMSO-ds): d 12.27 (bs, interchangeable D20, NH), 8.35 (dd, J = 8.9, 7.0 Hz, 1H), 7.64 (d, J = 12 Hz, ÍH), 7.55- 7.47 (m, 3H), 7.39-7.23 (m, 3H), 7.04 (d, J = 8.6 Hz, ÍH), 4.28-4.26 (m, 2H), 4.07-4.06 (m, 2H), 3.42 (s, 3H), 2.63 (s, 3H). P.f. : 245-248 ° C Example 79 5- [1- (3-Chloro-4. {2 - [2- (3, 4-difluoro-phenyl) -6-fluoro-1-methyl-4-oxo- 1, 4-dihydro-quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -6-fluoro-1-methyl-1H-quinolin-4- ona (1.4 g, 2.70 mmol), 2,4-thiazolidenedione (1.96 g, 16.7 mmol), benzoic acid (600 mg, 4.91 mmol), and piperidine (470 mg, 5.51 mmol) was taken in a round-bottomed flask of an individual neck, to this was added toluene (30 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 72 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and concentrated. The residue was purified by column chromatography using 0.5-1% MeOH-CHCl3 to give the title compound 40 mg (8.%) as a light brown solid. NMR (400 MHz, DMSO): d 12.27 (bs, exchangeable D20, NH), 8.40-8.33 (m, 1H), 7.64 (d, J = 12.0 Hz, ÍH), 7.55-7.47 (m, 3H), 7.39 -7.23 (m, 3H), 7.04 (d, J = 8.6 Hz, ÍH), 4.30 (m, 2H), 4.08 (m, 2H), 3.42 (s, 3H), 2.63 (s, 3H). P.f. : 215-218 ° C Example 80 5- [1- (3-Chloro-4- { 2- [2- (3,4-difluoro-phenyl) -l-methyl-4-oxo-l, 4- dihydro-quinolin-3-yloxy] -ethoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [2- (4-acetyl-2-chloro-phenoxy) -ethoxy] -2- (3,4-difluoro-phenyl) -l-methyl-lH-quinolin-4-one (97 g , 200 mmol), thiazolidine-2,4-dione (141 g, 1200 mmol), benzoic acid (44 g, 361 mmol) and piperidine (35 g, 411.7 mmol) was taken in a single neck round bottom flask. , to this was added toluene (1000 mL). The Redondo flask was equipped with deán stark device, which was connected to a condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and allowed to pass through a column of silica gel. The product was eluted using 0.3-0.9% MeOH / CHCl3 MeOH to give the title compound, 37 g (32%) as an off-white solid. XR NMR (200 MHz, CDCl 3) d 12.30 (s, HH), 8.32 (m, 1H), 7.77 (m, 2H), 7.52 (ddd, J = 8.0, 2.0, 0.8 Hz, HH), 7.48 (d, J = 2.0 Hz, HH), 7.45 (m, HH), 7.25 (m, HH), 7.35 (dd, J = 10.0, 2.4 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, ÍH), 4.31 (dd, J = 3.4, 6.8 Hz, 2H), 4.09 (dd, J = 3.4, 6.8 Hz, 2H), 3.47 (s, 3H), 2.63 (s) , 3H). Mp: 212-214 ° C Example 81 5- [1- (4- { 3- [2- (3,4-Dimethoxy-phenyl) -5,7-dimethoxy-4-oxo-4H-chromen-3 -iloxy] -propoxy.}. -phenyl) -ethylidene] -thiazolidine-2,4-dione A mixture of the compound 3- [3- (4-acetyl-phenoxy) -propoxy] -2- (3,4-dimethoxy-phenyl) -7-ethyl-5-methoxy-chromen-4-one (0.30 g, 0.562 mmol), 2,4-thiazolidenedione (330 mg, 2.82 mmol), benzoic acid (132 mg, 1.08 mmol), and piperidine (96 mg, 1.13 mmol) was taken into a single-neck round bottom flask in 50 mL of toluene ( 15 mL). The RBF was equipped with a deán stark device, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 48 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 ° C and was filtered. The solid was dried to give the title compound 189 mg (34%) as a white solid. NMR? E (200 MHz, CDC13): d 8.38 (s, ÍH), 7.68-7.65 (m, 2H), 7.3-7.25 (m, 2H), 6.91-6.85 (m, 3H), 6.51 (s, ÍH) ), 6.37 (s, 1H), 4.25-4.13 (m, 4H), 3.97-3.91 (m, 12H), 2.7 (s, 1H), 2.25-2.19 (m, 2H) Pf : 198-200 ° C Examples 82-91 The following compounds are easily prepared by one skilled in the art using the procedures set forth above Use of compound 82.- 5- [1- (3-Chloro-4- { 2- [2- (3, -difluoro-phenyl) -4-oxo-4H-chromen-3-yloxy] -ethoxy}-phenyl) -ethylidene] -thiazolidine-2,4-dione 83. 5- [1- (3-Chloro-4- { 3- [2- (3,4-difluoro-phenyl) -4 -oxo-4H-chromen-3-yl] -propoxy.} - phenyl) -ethylidene] -thiazolidine-2,4-dione 84.- 5- [1- (3-Chloro-4-. {3- [2- (3,4-difluoro-phenyl) -4-oxo-4H-chromen-3-yloxy] -propyl.} - phenyl) -ethylidene] -thiazolidine-2,4-dione 85.- 5- [ 1- (3-Chloro-4- {3- [2- (3, 4-difluoro-phenyl) -l-methyl-4-oxo-l, 4-dihydro-quinolin-3-yl] -propoxy}-phenyl) -ethylidene] -thiazolidine-2,4-dione 86.- 5- [1- (3-Chloro-4- { 3- [2- (3, -difluoro-phenyl) -l- methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] -propyl.} - phenyl) -ethylidene] -thiazolidine-2,4-dione 87.- 5- [1- (3-Chloro- 4- { 2- [5- (3, -difluoro-phenyl) -1,3-dimethyl-7-oxo-l, 7-dihydro-pyrazolo [4, 3-d] pyrimidin-6-yl] - ethoxy.}.-phenyl) -ethylidene] -thiazolidine-2,4-dione 88.- 5- [1- (3-Chloro-4-. {3- [5- (3, 4-di fluoro-phenyl) -1,3-dimethyl-7-oxo-l, 7-dihydro-pyrazolo [4, 3-d] pyrimidin-6-yl] -propoxy} phenyl) -ethylidene] -thiazolidine-2,4-dione 89. - 3- [2- (3-Chloro-4. {2- [2- (3,4-difluoro-phenyl) -4-oxo-4H-chromen-3-yloxy] -ethoxy acid ethyl ester} - phenyl) -acetylamino] -2- (toluene-4-sulfonylamino) -propionic 90.- Ethyl ester of 4- acid. { 2- (2-difluoro-phenyl) -1-methyl-4-oxo-l, -dihydro-quinolin-3-yloxy] -ethoxy} phenyl) -acetylamino] -2- (toluene-4-sulfonylamino) -propionic 91, 3- (4-. {2- [2- (3,4-Difluorophenyl) -l-methyl-4-ethyl ester -oxo-l, 4-dihydro-quinolin-3-yloxy] -ethoxy.} - benzoylamino) -2- (toluene-4-sulfonylamino) - • propionic. In a similar manner, other starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the reference examples or their obvious chemical equivalents (Ref .: (i) J. HET., CHEM., 1999 (36) 141; (ii) For preparation of bromoketone see (a) J. MED CHEM. 1996 (39), 2939-2952; (b) J. HET CHEM., 1972 (9) 887; (b) INDIAN J. CHEM. SECT., 1990 ( 29) 77, (c) TETRAHEDRON LETT, 1997 (38) 3581, (d) CHEM, PHARM, BULL, 1992 (40) 1170). The pharmaceutically acceptable salts are prepared by reacting the compounds of the formula (I) wherever applicable with 1 to 4 equivalents of a base, for example, sodium hydroxide, sodium methoxide, sodium hydride, t-butoxide potassium, calcium hydroxide, magnesium hydroxide or any mixture thereof, in the presence of a solvent, for example, ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol or any mixture thereof. Organic bases for example lysine, arginine, diethanolamine, choline, tromethamine, guanidine, or any derivative or mixture thereof, may also be used. Alternatively, the acid addition salts where applicable are prepared by treatment with acids, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, or any mixture thereof, in the presence of a solvent, for example, ethyl acetate, ether, alcohols, acetone, THF, dioxane, or any mixture thereof. The salts of the amino acid groups and other groups can be prepared by reacting the compounds of the formula (I) with the respective groups in the presence of a solvent, for example, alcohols and ketones, or any mixture thereof. The various polymorphic substances of a compound of the general formula (I) according to the present invention can be prepared by crystallization of the compound of the formula (I) under different conditions, for example, by using different solvents or their mixtures for recrystallization; when making crystallizations at different temperatures; or by using several cooling modes, ranging from very fast or very slow cooling during crystallizations. Heating or melting the compound followed by gradual or rapid cooling may also obtain polymorphic substances. The presence of polymorphic substances can be determined by single probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder x-ray diffraction or other techniques. The pharmaceutically acceptable solvents of the compound of the formula (I) forming part of this invention can be prepared by conventional methods such as dissolving the compounds of the formula (I) in the presence of a solvent, for example, water, methanol, ethanol , etc., for example, water and recrystallization or use different crystallization techniques. The regioisomers of a compound of the formula (I) can be prepared by modifying the reaction conditions, for example, by using reagents, for example, acid base or base acid, or by reaction with hydrazine base l ibre instead of its salt with diketone. The molar ratio can also change the formation of the regioisomers. It is noted that with respect to this date, the best method known to the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (59)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of the general formula (I) its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, characterized in that -Y-G-C II- wherein L is -Y-G = Z-Ar-, Xi, or - (CH2) t-; where Q is R1, R2, and R3 are independently hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group , an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an aryisulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group , an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, a carboxylic acid or a derivative thereof, or a sulphonic acid or a derivative thereof, wherein any two of R1, R2 and R3 in combination optionally form a 5-membered or saturated cyclic ring. members having 1 to 3 heteroatoms, wherein the heteroatoms are O, S or N; where R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, a group aralkynyl, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, an aralkyl group sulfinyl, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; where A, B, D and J independently are 0, S, N, > CH, or (-CH2-) n; where ? 'is an optional chemical bond; where E is 0, S, or -NR; wherein K is N, C, or CH; wherein Y and Z independently are 0, -NR, (- CH2-) U, or S (= 0) u; wherein G is - (CH2) 5, - (CH2) S-CH = CH- (CH2) s-, or - (CH2) S-C-C- (CH2) S; wherein X, Xi, X2, X3, and X independently are o, S, or -NR; wherein F is 0, S, or -NR; where Y1 and Y2 independently are 0 or Sien where n, w, u independently are an integer of 0-2; where p, t, m, s, v independently are an integer of 0-5; where R and R5 independently are hydrogen, potassium, sodium, a hydroxy group, a halogen group, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group and wherein? Ar 'is a substituted and unsubstituted phenyl group or a substituted or unsubstituted naphthyl group. Compound according to claim 1, characterized in that any of R1, R2, R3 and R4 is independently substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyan group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a group aryl, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an aryisulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or cu any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, a group alkyl, an alkoxy group, or an aryl group. 3. Compound of the general formula (II) its tautomeric forms, its stereoisomers, its substances 10 polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, characterized in that R1, R2, and R3 are independently hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, -j_5 a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, a group acyl, an acyloxy group, An aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an group ? [- aryloxycarbonyl, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, an heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof, wherein any two of R1, R2 and R3 in combination optionally form a saturated cyclic ring of 5 members or 6 members having 1 to 3 heteroatoms, wherein the heteroatoms are O, S or N; wherein R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group , a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group,. an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, a group alkylsulfonyl, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulphinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; wherein A, B, D and J independently are 0, S, N, > CH, or (-CH2-) n; where ? 'is an optional chemical bond; where E is 0, S, or -NR; wherein Y and Z independently are 0, -NR, (-CH2-) U, or S (= 0) u; wherein G is - (CH2) 5, - (CH2) S-CH = CH- (CH2) s-, or - (CH2) s-C = C- (CH2) s; wherein X is 0, S, or -NR; wherein F is 0, S, or -NR; wherein Y1 and Y2 independently are 0 or S; where n, and u independently are an integer of 0-2; where s is an integer of 0-5; where R and R5 independently are hydrogen, potassium, sodium, a hydroxy group, a halogen group, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group and wherein? Ar 'is a substituted and unsubstituted phenyl group or a substituted or unsubstituted naphthyl group. Compound according to claim 3, characterized in that any of R1, R2, R3 and R4 is independently substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group ( S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, a group aryloxycarbonyl, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl group -sulfonyl, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a gru piperazinyl, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group. 5. Compound of the general formula (III) its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates. characterized in that R1, R2, and R3 are independently hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, an cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, A cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group , an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, a carboxylic acid or a derivative thereof, or a sulfonic acid or a derivative thereof, wherein any two of R1, R2 and R3 in combination they optionally form a 5-membered or 6-membered saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are 0, They are; wherein R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group , a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group , an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, an aral group quilsulfinyl, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; where ? 'is an optional chemical bond; where E is O, S, or -NR; wherein Z is O, -NR, (-CH2-) U, or S (= 0) u; wherein G is - (CH2) 5, - (CH2) S-CH = CH- (CH2) s-, or - (CH2) s-C = C- (CH2) s; where u is an integer of 0-2; where s is an integer of 0-5; wherein R and R5 independently are hydrogen, potassium, sodium, a hydroxy group, a halogen group, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group , an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group and wherein R 'and R "independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, haloalkoxy a group, cycloalkyl, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl- sulfonyl. Compound according to claim 5, characterized in that any of R1, R2, R3 and R4 is independently substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di-substituted amino group, a group hydroxy, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, a group arylsulfonyl, an arylsuMinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group , or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, a group alkyl, an alkoxy group, or an aryl group. Compound according to claim 5, characterized in that one or both of R 'and R "are independently substituted with a halogen, a hydroxyl group, a nitro group, an amino group, or an alkyloxy group. Compound according to claim 5, characterized in that one or both of R 'and R "are independently substituted with a heterocyclyl group comprising a morphonyl group, a thiomorpholino, or a piperazine. 9. Compound of formula (III) according to claim 5, characterized in that the compound is 25 10. Compound of the general formula (IV) their tautomeric forms, their stereoisomers, their polymorphic substances, their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates, characterized in that wherein R1 and R2 are independently hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a group carbamoyl, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, a group acyloxy, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, a group a Rlykylsulfinyl, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, a carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof, wherein either of two of R1, R2 and R3 in combination optionally form a 5-membered or 6-membered saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S or N; wherein R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group , a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group , an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, an aral group quilsulfinyl, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, a carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; where D and J independently are 0, S, N, > CH, or CH2; where ? 'is an optional chemical bond; where E is O, S, or -NR; wherein K is N, C, or CH; wherein Z is 0, -NR, (CH2) U, or S (= 0) u; wherein G is - (CH2) 5, - (CH2) S-CH = CH- (CH2) s-, or - (CH2) S-C = C- (CH2) S; wherein X is 0, S, or -NR; wherein F is 0, S, or -NR; wherein Y1 and Y2 independently are 0 or S; where u is an integer of 0-2; where s is an integer of 0-5; where R and R5 independently are hydrogen, potassium, sodium, a hydroxy group, a halogen group, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group and wherein Ar 'is a substituted and unsubstituted phenyl group or a substituted or unsubstituted naphthyl group. 11. Compound according to claim 10, characterized in that any of R1, R2, R3 and R4 is independently substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S = ), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl-sulfonyl group , which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a group p iperazinyl, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group. 12. Compound of formula (IV), according to claim 10, characterized in that the compound is: 13 Compound of the formula (V) its tautomeric forms, its stereoisomers, its polymorphic substances, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, characterized in that R1, R2, and R3 are independently hydrogen, a hydroxy group, a halogen, a group nitro, carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, cycloalkenyloxy, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an aryisulfonyl group, a het group eroariisulfonilo an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl, aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof , or sulfonic acid or a derivative thereof, wherein any two of R1, R2 and R3 in combination optionally form a 5-membered or 6-membered saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, They are; wherein R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group , a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group , an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, an aralkyl group uilsulfinilo, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; wherein A, B, D and J independently are 0, S, N, > CH, or (-CH2-) n; where E is 0, S, or -NR; wherein K is N, C, or CH; wherein L is -Y-G = Z-Ar-,, or - (CH2) t-; wherein Y and Z independently are 0, -NR, (- CH2-) U, or S (= 0) u; wherein G is - (CH2) 5, - (CH2) S-CH = CH- (CH2) s-, or - (CH2) S-C = C- (CH2) S; wherein X, Xi, X2, X3, and X4 independently are 0, S, or -NR; wherein X is 0, S, or -NR; wherein n and w independently are an integer of 0-2; where p, t and v independently are an integer of 0-5; wherein R is hydrogen, potassium, sodium, a hydroxy group, a halogen group, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, a group acyl, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group and wherein? Ar 'is a substituted and unsubstituted phenyl group or a substituted or unsubstituted naphthyl group. 14. Compound according to claim 13, characterized in that any of R1, R2, R3 and R4 is independently substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or disubstituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo group (0 =), a thio group (S =), an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, a aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group , an aralkylthio group, or a heterocyclyl-sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a g substituted morpholinyl radical, a thiomorpholinyl group, or a piperazinyl group, wherein the substituent on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group. 15. Compound of formula (V), according to claim 13, characterized in that the compound is: 16. Method of treatment or prophylaxis of a disease mediated by an inflammatory response or proliferation of smooth muscle cells in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound of according to claim 1. 17. Method according to claim 16, characterized in that the inflammatory response includes a vascular complication of diabetes, wherein the vascular complication of diabetes comprises diabetic retinopathy, microangiopathies, renal failure or Alzheimer's disease. Method according to claim 16, characterized in that the inflammatory response results from a glycated protein or an accumulation of advanced glycation end products. 19. Method according to claim 18, characterized in that the glycated protein or the accumulation of advanced glycation end products was measured by a pro-inflammatory cytokine. 20. Method according to claim 19, characterized in that the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-a, or MCP-1. 21. Method according to claim 16, characterized in that the proliferation of smooth muscle cells is inhibited by inducing the expression of Perlecan. 22. Method according to claim 16, characterized in that the proliferation of smooth muscle cells is measured by a pro-inflammatory cytokine. 23. Method according to claim 22, characterized in that the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-a, or MCP-1. 24. Method of treatment or prophylaxis of an unwanted inflammation in a human or animal, characterized in that it comprises administering to the human or animal with undesired inflammation, a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 25. Method of treatment or prophylaxis of an unwanted smooth muscle cell proliferation in a human or animal, characterized in that it comprises administering to the human or animal undesired smooth muscle cell proliferation, a composition comprising a therapeutically or prophylactically effective amount of A compound according to claim 1. 26. Method of treatment or prophylaxis of a disease or disorder mediated by a cell adhesion molecule, characterized in that it comprises administering to a patient in need thereof a composition comprising an amount therapeutically or prof The method according to claim 26, characterized in that the disease or disorder mediated by cell adhesion molecules is an inflammatory disorder or cardiovascular disease. 28. Method according to claim 27, characterized in that the inflammatory disorder is rheumatoid arthritis, osteoarthritis, asthma, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, or multiple sclerosis. 29. Method according to claim 27, characterized in that the cardio vascular disease is atherosclerosis, restenosis, coronary artery disease, angina, dyslipidemia, small artery disease, diabetes mellitus, diabetic nephropathy or diabetic retinopathy. 30. Method according to claim 26, characterized in that the cell adhesion molecules are VCAM-1. 31. Method according to claim 26, characterized in that it further comprises administering a therapeutically and prophylactically effective amount of at least some other medication comprising a platelet aggregation inhibitor, an antithrombotic agent, a calcium channel blocker, an enzyme inhibitor. of angiotensin conversion, a β-blocker, a non-steroidal anti-inflammatory agent, a COX II inhibitor, a corticosteroid, a TNF-α modulating agent, a reductose inhibitor of HMGCoA, a PPAR- α agonist, an HDL-up , or a retinoid. 32. Method according to claim 31, characterized in that at least some other medication is aspirin, dilteazem, nephidipine, captopril, enalopril, propanalol, ibuprofen, indomethacin, sulidac, rofecoxib, celecoxib, etanercept or infliximab. 33. Method for the treatment or prophylaxis of cancer in human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 34. Method according to claim 33 , characterized in that the cancer comprises melanoma, prostate cancer, leukemia, lymphoma, non-small lung cancer, central nervous system cancer, breast cancer, colon cancer, ovarian cancer, or renal cancer. 35. Method for inhibiting smooth muscle cell proliferation in human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 36. Method for inhibiting a inflammatory response in an endothelial cell in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 37. Method for treating or preventing transplant vasculopathy of organ in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 38. Method according to claim 37, characterized in that The organ is a liver, a kidney, a heart, a lung, a pancreas, a pancreatic islet, and skin. 39. Method according to claim 37, characterized in that it comprises administering a therapeutically or prophylactically effective amount of an immunosuppressive agent. 40. Method according to claim 39, characterized in that the immunosuppressive agent is CellCept, Gengraf, Micrhogam, Neoral, Orthoclone 0KT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, and Zenapax. 41. Method according to claim 39, characterized in that the administration is oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebelar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic , intramyocardial, intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprosthetic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal or transdermal. 42. Method according to claim 39, characterized in that the immunosuppressive agent is administered before the composition. 43. Method according to claim 39, characterized in that the immunosuppressive agent is administered after the composition. 44. Method according to claim 39, characterized in that the immunosuppressive agent is administered simultaneously with the composition. 45. Method for treating or preventing restenosis in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 46. Method for treating or preventing atherosclerosis in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 47. Method for treating a disease mediated by inflammation in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 48. Method according to claim 47, characterized in that the disease mediated by inflammation is an autoimmune disease. 49. Method according to claim 48, characterized in that the autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, pemphigoid bullosa, cardiomyopathy, celiac sprue dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyineruropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, disease of Graves, Guillain-Barre disease, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic purple thrombocytopenia (ITP), IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, méniére's disease, mixed connective tissue disease , multiple sclerosis, myasthenia gravis, penfigus vulgaris, pernicious anemia, polyarteristis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis , sarcoidosis, scleroderma, Sjögren's syndrome, rigid man syndrome, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo and Wegener's granulomatosis. 50. Method for treating or preventing metastasis in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 51. Method of the modulating activity of Perlecan in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 52. Method for the modulation of Heparanase in a human or animal, characterized because it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 53. Vascular endoprostheis, characterized in that it is coated, with a composition comprising a compound according to claim 1. 54. C Pharmaceutical composition, characterized in that it comprises a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent, excipient, or solvate thereof. 55. Pharmaceutical composition according to claim 54, characterized in that it is in the form of a tablet, capsule, powder, syrup, solution, suspension. 56. Medical device coated with a composition, characterized in that it comprises a compound according to claim 1. 57. Medical device according to claim 56, characterized in that the medical device is a shunt, a colostomy bag attachment device, ear drainage tubes, pacemaker conductors and implantable defibrillators, a suture, a staple, an anastomosis device, a vertebral disc, a bone spike, a suture anchor, a hemostatic barrier, a clamp, a screw, a plate, a clamp, a vascular implant, a tissue adhesive or sealant, a tissue scaffold, a bone substitute, an intraluminal device, and a vascular support. 58. Method for the treatment or prophylaxis of cardiovascular disease in a human or animal, characterized in that it comprises administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 59. Method of compliance with claim 58, characterized because the cardiovascular disease is atherosclerosis, restenosis, coronary artery disease, angina, dyslipidemia, small artery disease, diabetes mellitus, diabetic nephropathy or diabetic retinopathy.