CA2540460A1 - 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

HETEROCYCLIC COMPOUNDS AND

FIELD OF THE INVENTION
The present invention relates to compounds, pharmaceutical compositions, and methods of making and use thereof.
2o BACKGROUND OF THE INVENTION
Glycated proteins and advanced glycation end products (AGE) contribute to cellular damage, for example, diabetic tissue injury. This can occur by at least by two major mechanisms: modulation of cellular functions through interactions with specific cell surface receptors, and alteration of the extracellular matrix leading to the formation of protein cross-links. Studies suggest that glycated protein and AGE interactions with cells promote inflammatory processes and oxidative cellular injury. AGE increases lipoprotein oxidisability and atherogenicity. Further, AGE binding to matrix proteins induces synthesis of IL-l, TNFa, VCAM-1, Heme oxygenase, insulin like growth factor, IL-6 and activates NF-?B. Diseases for which glycated protein and AGE accumulation is a suspected 3o etiological factor include, but are not limited to, vascular complications of diabetes, microangiopathies, renal insufficiency, and Alzheimer's disease.

The exact mechanism by which high plasma glucose causes microvascular damage, as seen in diabetes, are not completely understood. One potential mechanism by which hyperglycemia can be lil~lced to microangiopathies is through the process of non-enzymatic glycation of critical proteins. Non-enzymatic glycation of critical proteins is discussed in Nonenzymatic glycosylation and the pathogenesis of diabetic complications, Ann. Intern.
Med., 1984(101)527-537; Advanced glycation end products up-regulate gene expression found in diabetic glomerular diseas, Proc. Natl. 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 l0 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, i.e., the linking of proteins with glucose, leads to the formation of glycated proteins. The first step in this glycation pathway involves the non-enzymatic condensation of glucose with free amino groups in the protein, primarily the epsilon-amino groups of lysine residues, forming the .Amadori adducts. These early glycation products can undergo further reactions such as rearrangements, dehydration, and condensations to form irreversible advanced glycation end products (AGE).
These are a highly reactive group of molecules whose interaction with specific receptors on the cell-surface that may lead to pathogenic outcomes. Accumulation of glycated proteins have been demonstrated in the basement membrane of patients with diabetes and are thought to be involved 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. Arn. 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 prevents 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. Natl. Acad. Sci. U S
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 C57BLI~sJ
diabetic mice., Metabolism, 1998(47)1477-80.
One characterized AGE receptor is 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 RAGE
either by antibodies or by adding a soluble form of the receptor inhibits diabetic vasculopathy including diabetic atherosclerosis. See Receptor-mediated endothelial cell dysfunction in to diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats., J. Clin. Invest., 1996(97)238-43;
Advanced glycation end products interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) 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 endproducts., Nat. Med. 1998(4)1025-31. Other than AGE, RAGE appears to mediate the binding of several other ligands that are involved in normal physiology as well as pathology. See Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases., Nature, 2000(405)354-60; RAGE mediates a novel proinflammatory axis: a central cell surface receptor for 5100/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. Natl. Acad. Sci., USA., 1997(94)5296-301. Thus, merely blocking RAGE might have other unintended consequences. Moreover, since blocking RAGE could lead to accumulation of AGE in circulation, the long-team effects of blocking RAGE are unknown and may be more harmful than the pathology sought to be treated.
One useful method to block AGE effects would be to develop inhibitors that block AGE induced signaling. See Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant 3o stress., J. Biol. Chem., 1997(272)17810-4; and Cell activation by glycated proteins.; AGE
receptors, receptor recognition factors and functional classification of AGEs., Cell. Mol.
Biol.(Noisy-le-grand), 1998(44)1013-23. However, the sequence of these signaling events leading 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 adequate and effective therapies do not exist are treatments of antiproliferative disorders. Smooth muscle cell (SMC) hyperplasia is an important factor in the development of atherosclerosis and also is responsible for the significant number of failure rates following vascular procedures such as angioplasty and coronary artery bypass surgery. 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, SMC are quiescent, but they proliferate when damage to the endothelium occurs. Naturally occurring growth modulators, many of which are derived from the endothelium, tightly control SMC
proliferation in vivo.
Abnormal vascular smooth muscles cell (VSMC) proliferation may contribute to the pathogenesis of vascular occlusive lesions, including atherosclerosis, vessel re-narrowing after successful angioplasty (restenosis), and graft atherosclerosis after coronary transplantation. VSMC is discussed 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 lifespans and lifestyles because of such conditions. Currently there are no known effective pharmacological treatments available that control these occlusive pathologies, particularly restenosis.
Percutaneous coronary artery intervention (PTCA) procedures are the most common in-patient hospital procedure in the United States. According to the American Heart Association, about one-third of the patients that undergo balloon angioplasty have restenosis of the widened segment within approximately six months. It may be necessary to perform another angioplasty or coronary artery bypass surgery on restenosed arteries.
A key feature of restenosis is an injury response that results in 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 into the lumen of the artery known 3o as neointimal hyperplasia. Currently there are no effective pharmacological treatments available that control the pathogenesis of vascular occlusive lesions, such as, but not limited to, arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after coronary transplantation. Identification of effective therapeutics with minimal side effects will restore quality of life without requiring additional surgical procedures such as coronary artery bypass surgery.
Smooth muscle cell (SMG) hyperplasia is a major event in the development of atherosclerosis and also may contribute to failure rates following vascular procedures such as angioplasty and coronary artery bypass surgery. In the normal vessel, SMC are quiescent, but they proliferate when damage to the endothelium occurs. Naturally occurring growth modulators, many of which are derived from the endothelium, tightly control SMC
proliferation in vivo. Accordingly, there is a need for methods and compositions for the to alteration of gene expression in arterial wall cells to inhibit thrombosis and SMC
proliferation. In particular, what is needed are methods and compositions that inhibit SMC
proliferation and related intimal hyperplasia.
U.S. Patent No. 6,028,088 is directed to specific thiazolidinedione compounds, which are described as antiproliferative, anti-inflammatory and antiinfective agents. According to the disclosure, these specific compounds are used in the treatment of certain endocrine diseases, malignant, and non-malignant proliferative diseases, and cardiovascular disorders.
Thus, there is a need for treatments of vascular occlusive pathologic conditions, and particularly, restenosis. Since occurrence is frequent, the currently available treatments are costly and the conditions are refractory to many pharmacological therapies.
The mechanisms involved in the control of vascular conditions related to SMC function are not clear and no conventional preventive therapy against SMC activation is available.
Accordingly, methods and compositions for treatment and prevention of vascular occlusive conditions are needed.
In particular, methods and compositions to prevent and treat restenosis following treatments of vascular tissues are needed. The present invention is directed to overcoming these and other deficiencies in the art.
SUMMARY OF THE INVENTION
The present invention is related to compounds of formula (I), and to methods and/or compositions comprising compounds that are effective in modulating inflammatory 3o responses, such as those resulting from AGE and glycated protein accumulation. The present invention also is directed to methods and/or compositions comprising compounds that are effective in modulating smooth muscle cell proliferation and the diseases or conditions related thereto.
The present invention provides compounds and compositions that inhibit inflammatory responses, particularly those resulting from AGE and glycated protein accumulation. Further, the present invention provides compounds and compositions that inhibit smooth muscle cell proliferation, which may be mediated by pro-inflammatory cytokines lilce IL-6, IL-l, TNF-a, MCP-l, or by inducing the expression of perlecan, a heparin sulfate proteoglycan (HSPG).
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l0 The present invention provides novel compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of such 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 such compounds, optionally in combination with other active ingredients.

B\,A E R4 F~NR
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Y-G_Z-Ar-=~~Y2 ( ) R
X
2o The present invention also provides a process for preparing compounds of the formula (II) as defined above, their salts, and pharmaceutically acceptable compositions thereof.
The present invention also provides novel compounds of 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.

R~

R~ ~: . ~ ~ o_G_Z cIIn ~3 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 cor~taining one or more of such compounds, optionally in combination with other active ingredients.
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F' D~~ 1I E ~ R4 s N R (I~
vJ _ I 2 I~-G-Z_ArY~
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The present invention also provides a process for preparing compounds of the 1o formula (IV) as defined above, their salts, and pharmaceutically acceptable compositions thereof.
The present invention provides novel compounds of formula (V), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of such compounds, optionally in combination with other active ingredients.
RBA 1 ~E~R4 X4 s~p? W Ar R2 B ~ _ _ K ~-CCFi2~ v C X~CH2~~C-O-R
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Ra ~' X~ Xs 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 of using a compound of formula (I) comprises treatment and/or prophylaxis of inflammatory conditions, such as those mediated by AGE or glycated protein accumulation. Such inflammatory conditions include diabetic vascular complications, including diabetic retinopathy, mieroangiopathies, renal insufficiency and Alzheimer's disease.
According to another aspect of the present invention, a method of inhibiting smooth muscle cell proliferation comprises administering an effective amount of a compound contemplated hereby. The present invention also provides methods for inhibiting an inflammatory response, including inflammatory responses in endothelial cells, comprising administering an effective amount of a compound contemplated hereby. The present invention also provides methods for inliibiting thrombosis comprising administering an effective amount of a compound contemplated hereby.
l0 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 hereby. The transplanted organ may include, but is not limited to, liver, kidney, heart, lung, pancreas, pancreatic islets, and skin. Such a method may further comprise the step of administering a therapeutically effective amount of an immunosuppressive agent. The immunosuppressive agent may include, but is not limited to, CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, 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 hereby. 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 hereby.
The present invention also provides a method for treating disease mediated by inflammation in a subject comprising the step of administering a therapeutically effective amount of a compound contemplated hereby. More specifically, the disease mediated by inflammation 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, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis 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, Sjogren's syndrome, stiff man syndrome, systemic lupus erythematosus, Takayasu 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 hereby. Moreover, the present invention provides a method for treating or preventing metastases in a subject comprising administering a therapeutically effective amount of a compound contemplated hereby to the subject.
Still another aspect of the present invention provides the methods, by using compound of formula (I), which also comprises treatment and/or prophylaxis of proliferative conditions, particularly for inhibition of proliferation of smooth muscle cells, comprising administration of compositions comprising compounds of formula (I). In accordance with the present invention, uses of such compositions comprise prevention and treatment of vascular occlusive conditions including atherosclerosis and restenosis.
Still another aspect of the present invention provides the methods for the treatment and/or prophylaxis of diseases mediated by inflammatory conditions and cellular proliferative conditions, by using the compound of formula (I).
Still yet another aspect of the present invention provides treatment and/or prophylaxis of a disease or disorder mediated by cell adhesion molecules like VCAM-l, where the diseases are inflammatory disorders selected from rheumatoid arthritis, osteoarthrites, asthama, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes or multiple sclerosis; a cardiovascular disease selected from athresclerosis, restenosis, coronary artery disease, angina, small artery disease, diabetes mellitus, diabetic nepropathy or diabetic retinopathy and one of the cell adhesion molecules is VCAM-1.

Still another aspect of the present invention provides treatment and/or prophylaxis of of a disease by delivering the compounds) of formula (I) at the site of the disease by using a compounds) of formula (I) coated stems.
The present invention further provides pharmaceutical compositions containing compounds of the general formula (I), their salts, or any mixture thereof in combination with a suitable carrier, solvent, diluent, or medium typically employed in preparing such compositions.
Still further, the present invention provides various compounds and compositions that each may be administered by a route that is oral, parenteral, subcutaneous, intramuscular, to intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, 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 also may include formulations of the compounds disclosed, 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, 2o and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques.
Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carner(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Still yet another aspect of the present invention provides novel intermediates, a process for their preparation and use of the intermediates in processes for preparation of compound of formula (I), their salts, and pharmaceutically acceptable compositions thereof.
so DEFINITIONS
It is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, constructs, and 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 herein 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 such compounds and includes equivalents thereof known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art at the time this invention 1 o was made.
All publications and patents mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the constructs and methodologies that are described in the publications, which might be used in connection with the presently described invention. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention.
As used herein, the term "compound" includes both the singular and the plural, and includes any single entity or combined entities that have activity that can be measured in the assays of the present invention and combinations, fragments, analogs or derivatives of such entities.
The term "glycated protein", as used herein, includes proteins linleed to glucose, either enzymatically or non-enzymatically, primarily by condensation of free epsilon-amino groups in the protein with glucose, forming Amadori adducts. Furthermore, glycated protein, as used herein, includes not only proteins containing these initial glycation products, but also glycation products resulting from further 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 cells or components of the assay to respond in a measurable manner is contemplated by the present invention. Enhanced formation and accumulation of glycated proteins and AGE are thought to play a major role in the pathogenesis of diabetic complications, and atherosclerosis, leading to the development of a range of diabetic complications including nephropathy, retinopathy and neuropathy. There is ample in vivo evidence that suggests that diabetes-related complications can be reduced by (1) preventing glycation of proteins, (2) by breaking the cross-links in 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 glycated protein interaction with receptors. Despite the importance of AGE in the pathogenesis of diabetic microangiopathies, there are no currently available medications known to block AGE
formation.
The term "phenylamine" refers to a primary or secondary b enzeneamine, more commonly known as aniline. The amino group on the aniline may be optionally substituted to with hydrogen, alkyl (C~-C~Z, straight chain or branched), cycloallcyl (C~-Clo), or optionally substituted aryl groups. The phenyl ring of this aniline derivative may be optionally substituted with one or more functional groups, or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitre, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amide, sulfonamide, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate. If applicable, these groups can be represented in protected or unprotected forms used in standard organic synthesis.
The term "naphthylamine" refers to a primary or secondary a- or 13-naphthylamine.
The ring substructure in the naphthylamine may be optionally substituted with one or a combination of functional groups such as allcyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitre, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amide, sulfonamide, sulfonyl, sulfate, sulfon.ic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, p5rrazoyl, phosphate, phosphonic acid, or phosphonate. These groups can be represented in protected or unprotected forms used in standard organic synthesis.
The term "naphthylalkyl amine" refers to a primary or secondary a- and 13-naphthylallcyl amine (for example, 2-a-naphthylethyl amine). The tern?
"benzalkyl amine"
refers to a primary or secondary benzylalkyl amine (for example, phenylcthyl amine). These aryl alkyl substructures or compounds can be optically active or optically inactive. The aryl (ring) substructures of the naphthylalkyl and benzalkyl amines can be optionally subsituted with one or a combination of functional groups, such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, tluoxy, alkoxy, aryloxy, haloallcyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carbolyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, phosphoric acid, or phosphonate. If applicable these groups can be represented in protected or unprotected forms used in standard organic synthesis.
The term "quinolinyl amine" refers to primary or secondary quinolyl amines.
These amines can be in optically active or inactive forms. The aryl (ring) substructure of the quinolyl amine may be be optionally substituted with one a combination of functional groups such as alkyl, allcenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, l0 allcoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, aryl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, phosphoric acid, or phosphonate. These groups can be represented in protected or unprotected forms used in standard organic synthesis.
The term "heteroaryl amines" refers to pyrroles, pyrazoles, imidazoles, and indoles.
The aryl (ring) substructure of the heteroaryl 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, allcyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, phosphate, phosphoric acid, or phosphonate.
These groups can be represented in protected or unprotected forms used in standard organic synthesis.
The ternz "polynucleotide" refers generally to polymeric forms of nucleotides of any length, either ribonucleotides or deoxynucleotides. Thus, this term includes, but is not limited to, single-stranded, double-stranded, or mufti-stranded DNA or RNA.
Polynucleotides may further comprise genomic DNA, cDNA, or DNA-RNA hybrids.
Moreover, the polynucleotides of the present invention may be synthetically produced.
Polynucleotides may comprise chemically modified, biochemically modified, or derivatized nucleotides. For example, a polynucleotide may comprise, in part, modified nucleotides such as methylated nucleotides or nucleotide analogs.
Polynucleotides also may comprise sugars, caps, nucleotide branches, and linking groups such as fluororibose and thioate. In addition, the sequence of nucleotides may be interrupted by non-nucleotide components. Furthermore, a polynucleotide may be modified after polymerization to facilitate its attachment to other polynucleotides, proteins, metal ions, labelsng components, or a solid support.
The backbone of the polynucleotide may comprise modified or optionally substituted sugar and/or phosphate groups. Alternatively, the backbone of the polynucleotide may comprise a polymer of synthetic subunits such as phosphoramidites and thus may be an oligodeoxynucleoside phosphoramidate or a mixed phosphoramidate-phosphodiester oligomer. See Peyrottes et al., Nuct,. ACIDS IZES. (1996) 24:1841-1848, and Chaturvedi et al., NucL. Acms RES. (1996) 24:2318-2323.
The term "homology", as used herein, refers to a degree of complementarity.
There may be partial homology or complete homology (i.e., identity). A partially complementary sequence is one that at least partially inhibits an identical sequence from hybridizing to a target polynucleotide; it is referred to using the functional term "substantially homologous".
The inhibition of hybridization of the completely complementary sequence to the target sequence may be examined using a hybridization assay (Southern or Northern blot, solution hybridization) under conditions of low stringency. A substantially homologous sequence or probe will compete for and inhibit the binding (i.e., the hybridization) of a completely homologous sequence or probe to the target sequence under conditions of low stringency.
This is not to say that conditions of low stringency are such that non-specific binding is 2o permitted; low stringency conditions require that the binding of two sequences to one another be a specific (i.e., selective) interaction. The absence of non-specific binding may be tested by the use of a second target sequence which lacks even a partial degree of complementarity (for example, less than about 30% identity); in the absence of non-specific binding, the probe will not hybridize to the second non-complementary target sequence.
The term "gene" refers to a polynucleotide sequence that comprises coding sequences necessary for the production of a polypeptide or precursor, and also may include expression control sequences. The polypeptide can be encoded by a full length coding sequence or by any portion of the coding sequence. The gene may be derived in whole or in part from any source known to those of ordinary skill in the art including a plant, a fungus, an animal, a 3o bacterial genome or episome, eukaryotic, nuclear or plasmid DNA, cDNA, viral DNA, or chemically synthesized DNA. A gene may constitute an uninterrupted coding sequence or it may include one or more introns, bound by the appropriate splice junctions.
Moreover, a gene may contain one or more modifications in either the coding or the untranslated regions that could affect certain properties of the polynucleotide or polypeptide~
such as the biological activity or the chemical structure of the expression product, the rate of expression, or the manner of expression control. Such modifications include, but are not limited to, mutations, insertions, deletions, and substitutions of one or more nucleotides. In this regard, such modified genes may be referred to as "variants" 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.
l0 The term "gene expression profile" refers to a group of genes representing a particular cell or tissue type (for example, neuron, coronary artery endothelium, or disease tissue) in any activation state. In one aspect, a gene expression profile is generated from cells exposed to a compound of the present invention. This profile may be compared to a gene expression profile generated from the same type of cell prior to treatment with a compound of the present invention. Furtherniore, a series of gene expression profiles may be generated from cells treated with a compound of the present invention, specifically, at different doses or a time-course to assess the effects of the compound. A gene expression profile also is known as a gene expression signature.
The term "differential expression" refers to both quantitative as well as qualitative 2o differences in the temporal and tissue expression patterns of a gene. For example, a differentially expressed gene may have its expression activated or completely inactivated in normal versus disease conditions. Such a qualitatively regulated gene may exhibit an expression pattern within a given tissue or cell type that is detectable in 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 is correlated with the presence of a differentially expressed gene in a sample.
Similarly, a differentially expressed protein may have its expression activated or completely inactivated in normal versus disease conditions. Such a qualitatively regulated 3o protein may exhibit an expression pattern within a given tissue or cell type that is detectable in either control or disease conditions, but 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 detection of the differentially expressed protein in a sample is correlated with the presence of a differentially expressed protein in a sample.
"Cell type" as used herein, refers to a cell from a given source (for example, tissue or organ), a cell in a given state of differentiation, or a cell associated with a given pathology or genetic makeup.
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 naturally occurring, recombinant, or synthetic, or any combination of these.
Moreover, 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 string of amino acids held together by peptide bonds. A polypeptide may alternatively comprise a Iong chain of amino acids held together by peptide bonds. Moreover, a polypeptide also may comprise a fragment of a naturally occurring protein or peptide. A
polypeptide may be a single molecule or may be a mufti-molecular complex. In addition, such polypeptides may have modified peptide backbones as well.
The term "polypeptide" further comprises immunologically tagged proteins and fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusion proteins with heterologous and homologous leader sequences, and fusion proteins with or without N-terminal methionine residues.
The term "protein expression" refers to the process by which a polynucleotide sequence undergoes successful transcription and translation such that detectable levels of the amino acid sequence or protein are expressed.
The term "protein expression profile" refers to a group of proteins representing a particular cell or tissue type (for example, 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 may be compared to a proteizi expression profile generated from the same type of cell prior to treatment with a compound of the present invention. Furthermore, a series of protein expression profiles may be generated from cells treated with a compound of the present invention, specifically, at different doses or a time-course to assess the effects of the compound. A protein expression profile also is known as a "protein expression signature".

As used herein, a "biomolecule" includes polynucleotides and polypeptides.
Moreover, a "biomolecular sequence", as used herein, is a term that refers to all or a portion of a polynucleotide sequence. A biomolecular sequence also may refer to all or a portion of a polypeptide sequence.
A "host cell" as used herein, refers to a microorganism, a prokaryotic cell, a eukaryotic cell or cell line cultured as a unicellular entity that may be, or has been, used as a recipient for a recombinant vector or other transfer of polynucleotides, and includes the progeny of the original cell that has been transfected. It is understood that the progeny of a single cell may not necessarily be completely identical in morphology or in genomic or total l0 DNA complement as the original parent due to natural, accidental, or deliberate mutation.
In the context of 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 native Perlecan protein or native Perlecan-encoding polynucleotides. A functional equivalent of a native Perlecan protein may contain modifications depending on the necessity of such 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 native Perlecan.
In the context of immunoglobulins, the term "functional equivalent" refers to 2o immunoglobulin molecules that exhibit immunological binding properties that are substantially similar to the parent immunoglobulin. As used herein, the term "immunological binding properties" refers to non-covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. Indeed, a functional equivalent of a monoclonal antibody immunoglobulin, for example, may snhibit the binding of the parent monoclonal antibody to its antigen. A functional equivalent may comprise F(af)Z fragments, Flab) molecules, Fv fragments, single chain fragment variable displayed on phage (scFv), single domain antibodies, chimeric antibodies, or the like so long as the immunoglobulin exhibits the characteristics of the parent immunoglobulin.
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, the polypeptide, the antibody, or the host cell naturally occurs. An isolated polynucleotide, polypeptide, antibody, or 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, at Ieast about 75% free, at least about 80% free, at Ieast 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 about 99.9% free, or at least about 99.99% free from 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 A+B in the composition is A. Alternatively, A comprises at least about 90% by weight of the total of A+B in the composition, further still, at least about 95% or even 99% by weight.
"Diagnosis" as used herein, generally includes a determination of a subject's susceptibility to a disease or disorder, a determination as to whether a subject is presently affected by a disease or disorder, a prognosis of a subject affected by a disease or disorder (for example, identification of pre-metastatic or metastatic cancerous states, stages of cancer, or responsiveness of cancer to therapy), and therametrics (for example, monitoring a subject's condition to provide information as to the effect or efficacy of therapy)_ The term "biological sample" encompasses a variety of sample types obtained from an organism which may be used in a diagnostic, monitoring, or other assay_ The term encompasses blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen, or tissue cultures or cells derived therefrom and the progeny thereof. The term specifically encompasses a clinical sample, and further 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 procurement such as treatment with reagents, solubilization, or enrichment for certain components.
The terms "individual", "subject", "host", and "patient" refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired. The individual, subject, host, or patient is optionally a human. Other subjects may include, but are not limited to, cattle, 3o horses, dogs, cats, guinea pigs, rabbits, rats, primates, and mice.
The teens "treatment", "treating", "treat", are used herein to refer generally to obtaining a desired pharmacological andlor physiologic effect. The effect may be prophylactic in that it may completely or partially prevent a disease or symptom thereof andlor may be therapeutic in that it rnay partially or completely 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 the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom, but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.
The expression "therapeutically effective amount" refers to an amount of, for example, a compound contemplated hereby, that is effective for preventing, ameliorating, treating, or delaying the onset of a disease or condition.
A "prophylactically effective amount" refers to an amount of, for example, a compound contemplated hereby that is effective for preventing a disease or condition.
A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant, which is useful for delivery of a drug to a mammal. The compounds of the present invention may be delivered by a liposome. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
"Hybridization", broadly defined, refers to any process by which a polynucleotide 2o sequence binds to a complementary sequence through base pairing.
Hybridization conditior~s can be defined by, for example, the concentrations of salt or formamide in the prehybridization and hybridization solutions, or by the hybridization temperature, and are well known in the art. Hybridization can occur under various conditions stringency.
Hybridization also may refer to the binding of a protein-capture agent to a target protein under certain conditions, such as normal physiological conditions.
As understood herein, the term "activation" refers to any alteration of a signaling pathway or biological response including, for example, increases above basal levels, restoration to basal levels from an inhibited state, and stimulation of the pathway above basal levels.
3o The term "biological activity" refers to the biological behavior and effects of a protein or peptide. The biological activity of a protein may be affected at the cellular level and the molecular level. For example, the biological activity of a protein may be affected by changes at the molecular level. For example, an antisense oligonucleotide may prevent translation of a particular mRNA, thereby inhibiting the biological activity of the protein encoded by the mRNA. In addition, an antibody may bind to a particular protein and inhibit that protein's biological activity.
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 ohigonucleotide may be a naturally occurring oligonucleotide or a synthetic ohigonucleotide. Ohigonucheotides may be prepared by the phosphoramidite method (Beaucage and Carruthers, TETRAHEDRON LETT. (1981) 22:1859-1862), or by the triester method (Matteucci et ah., J. Atn. CHEM. SoC. (1981) 103:3185), or by other chemical methods known in the art.
The term "microarray" refers generally to the type of genes or proteins represented on a microarray by oligonucleotides (polynucleotide sequences) or protein-binding agents, and where the type of genes or proteins represented on the microarray is dependent on the intended purpose of the microarray (for example, to monitor expression of human genes or proteins). The oligonucheotides or protein-binding agents on a given microarray may correspond to the same type, category, or group of genes or proteins. Genes or proteins may be considered to be of the same type if they share some common characteristics such as species of origin (for example, human, mouse, rat); disease state (for example, cancer);
function (for example, protein kinases, tumor suppressors); same biological process (for example, apoptosis, signal transduction, cell cycle regulation, proliferation, differentiation).
For example, one microarray type may be a "cancer mieroarray" in which each of the microarray oligonucleotides or protein-binding agents correspond to a gene or protein associated with a cancer. An "epithelial microarray" may be a microarray of oligonucheotides or protein-binding agents corresponding to unique epithelial genes or proteins. Similarly, a "cell cycle microarray" may be an microarray type 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 polynucheotide expression pattern which is detectable via the standard techniques of pohymerase chain reaction (PCR), reverse transcriptase-(RT) PCR, differential display, and Northern analyses, which are well known to those of skill in the art. Similarly, polypeptide expression patterns may be "detected" via standard techniques including immunoassays such as Western blots.
A "target gene" refers to a polynucleotide, often derived from a biological sample, to which an oligonucleotide probe is designed specifically to hybridize. It is either the presence s or absence of the target polynucleotide that is to be detected, or the amount of the target polynucleotide that is to be quantified. The target polynucleotide has a sequence that is complementary to the polynucleotide sequence of the corresponding probe directed to the target. The target polynucleotide also may refer to the specific subsequence of a larger polynucleotide to which the probe is directed or to the overall sequence (for example, gene or to mRNA) whose expression levels it is desired to detect.
A "target protein" refers to a polypeptide, often derived from a biological sample, to which a protein-capture agent specifically hybridizes or binds. It is either the presence or absence of the target protein that is 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 15 protein-capture agent directed to the target. The target protein or amino acid also may refer to the specific substructure of a larger protein to which the protein-capture agent is directed or to the overall structure (for example, gene or mRNA) whose expression levels it is desired to detect.
The term "complementary" refers to the topological compatibility or matching 2o together of the interacting surfaces of a probe molecule and its target.
The target and its probe can be described as complementary, and furthermore, the contact surface characteristics are complementary to each other. Hybridization or base pairing 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 25 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" also may refer to the non-specific binding or other interactions in the context of assays including immunoassays.
3o In the context of microarrays, the term "background" refers to hybridization signals resulting from non-specific binding, or other interactions, between the labeled target polynucleotides and components of the oligonucleotide microarray (for example, the oligonucleotide probes, control probes, the microarray support) or between target proteins and the protein-binding agents of a protein microarray. Background signals also may be produced by intrinsic fluorescence of the microarray components themselves. A
single background signal may be calculated for the entire microarray, or a different background signal may be calculated for each target polynucleotide or target protein. The background may be calculated as the average hybridization signal intensity, or where a different background signal is calculated for each target gene or target protein.
Alternatively, background may be calculated as the average hybridization signal intensity produced by hybridization to probes that are not complementary to any sequence found in the sample (for to example, probes directed to polynucleotides of the opposite sense or to genes not found in the sample such as bacterial genes where the sample is mammalian polynucleotides).
The background also can be calculated as the average signal intensity produced by regions of the microarray which lack any probes or protein-binding agents at all.
A "small molecule" refers to a compound or molecular complex, either synthetic, naturally derived, or partially synthetic, composed of carbon, hydrogen, oxygen, and nitrogen, that also may contain other elements, and that 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 about 400, less than about 300, less than about 200, or less than about 100.
The term "fusion protein" refers to a protein composed of two or more polypeptides that, although typically not joined in their native state, are joined by their respective amino and carboxyl termini through a peptide linkage to form a single continuous polypeptide. It is understood that the two or more polypeptide components can either be directly joined or indirectly joined through a peptide linker/spacer.
The term "normal physiological conditions" means conditions that are typical inside a living organism or a cell. Although some organs or organisms provide extreme conditions, 3o the infra-organismal and infra-cellular environment normally varies around pH 7 (i.e., from pH 6.5 to pH 7.5), contains water as the predominant solvent, and exists at a temperature above 0°C and below 50°C. The concentration of various salts depends on the organ, organism, cell, or cellular compartment used as a reference.
The term "cluster" refers to a group of clones or biomolecular sequences related to one another by sequence homology. In one example, clusters are formed based upon a specified degree of homology and/or overlap (for example, stringency).
"Clustering" may be performed with the sequence data. For instance, a biomolecular sequence thought to be associated with a particular molecular or biological activity in one tissue might be compared against another library or database of sequences. This type of search is useful to Look for homologous, and presumably functionally related, sequences in other tissues or samples, and to may be used to streamline the methods of the present invention in that clustering may be used' within one or more of the databases to cluster biomolecular sequences prior to performing a method of the invention. The sequences showing sufficient homology with the representative sequence are considered part of a "cluster". Such "sufficient"
homology may vary within the needs of one skilled in the art.
As used herein, the term "internal database" refers to a database maintained within a local computer network. It contains, for example, biomolecular sequences associated with a project. It also may contain information associated with sequences including, but not limited to, a library in which a given sequence is found and descriptive information about a likely gene associated with the sequence. The internal database is optionally maintained as a 2o private database behind a firewall within an enterprise network. However, the present invention contemplates an internal database that is available to the public.
The internal database may include sequence data generated by the same enterprise that maintains the database, and also may include sequence data obtained from external sources.
The term "external database", as understood herein, refers to a database located outside all internal databases. Typically, an enterprise network differing from the enterprise network maintaining the internal database will maintain an external database.
The external database may be used, for example, to provide some descriptive information on 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 3o Information (NCBI), which is part of the National Library of Medicine.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. Further, the present invention is directed to pharmaceutical compositions comprising compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, either individually or in any combination thereof Still further, the present invention is directed to methods of use of compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, either individually or in any combination thereof. Even further, the present invention is directed to methods of making compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.
Compounds of General Formula (I) The present invention is related to compounds of formula (IJ, and to methods and/or compositions comprising compounds that are effective in modulating inflammatory responses, such as those resulting from AGE and glycated protein accumulation.
The present 2o invention also is directed to methods and/or compositions comprising compounds that are effective in modulating smooth muscle cell proliferation and the diseases or conditions related thereto.
According to one aspect of the present invention, various compounds of general formula (I) R~
R2 B\.A ~ ~~
D~JJ Kw its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates are provided. According to this aspect, R~
R~ B ~
D,';J ~Kw C is R~ R~
R2 B~A 1 E R4 B~A E R4 p, J ~ ~-Q (la) R p J ~ ~-Q (Ib) ~3 X . or X
-Y-G-C-In this and other aspects, L is -Y-G=Z-Ar- ~ X~ , or -(CHZ)t -, and Q is Y~
X4 S(O}W-Ar ~NR
-(CHa)v C-X-(CH2}p Y2 X~ ~C O R

R or 3 R1, R'', and R3 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, 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 heteroarallcyl 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 allcylsulfmyl group, an arylsulfinyl group, a heteroarylsul~nyl group, an aralkylsul~nyl 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 RI, R2, and R3 in combination optionally form a 5-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S, or N. The cyclic ring formed by any two of R', R2, or R3 may be oxlanyl, 1,3-dioalanyl, or 1,4-dioxalanyl.

R4 1S hydrogen, a hydroxy group, a halogen, a vitro 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 cycloalleenyl 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 allcylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfmyl group, an arylsulfinyl group, an arallcylsulfinyl group, a heteroarylsulfmyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalleyl group, a fused heteroarylcycloallcenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof.
Any of RI, RZ, R3, and R4 independently optionally are substituted with hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, 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 allcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulfmyl 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 vitro 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 piper~inyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alleoxy group, or an aryl group.
According to this and other aspects, A, B, D, and J independently are O, S, N, >CH, or (CHZ)"; '----' is an optional chemical bond; E is O, S, or -NR; K is N, C, or CH; Y and Z
independently are O, -NR, fCH2~", or S(=O)"; G is -(CH~)S , -(CHZ)S CH=CH-(CHZ)S-, or -(CHZ)S C=C-(CHZ)S ; X, X~, XZ, X3, and X4 independently are O, S, or -NR; F is O, S, or -NR; Yl and YZ independently are O or S; n, w, a independently are an integer from 0-2; p, t, m, s, v independently are an integer from 0-5, and 'Ar' is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl group.
R and RS independently are hydrogen, potassium, sodium, 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, 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 (CI-Clo)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-C~) cycloalkyl group which may be mon or polycyclic.
Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
'Allcoxy' is (C~-C~o)alkyl-O-, wherein the (C~-C~o)alkyl group is as defined above.
Exemplary alkyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy.
'Cycloalkoxy' is a (C3-C6)cycloalkoxy group. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.
'Alkenyl' is a (CZ-C6)alkenyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl.
'Cycloalkenyl' is (C3-C~)cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl.
'Alkoxyalkyl' is a (Cl-C6)alkoxy(CI-Clo)alkyl group, where alkoxy and alkyl groups are as defined above. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl.
'Allcenyloxy' is (C~-C6)alkenyl-O-, where the (C2-C6)allcenyl group is as defined above. Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy.
'Cycloalkenyloxy' is a (C3-C~)cycloalkenyl-O-, where the (C3-C~)cycloalkenyl group is as defined above. Exemplary cycloalkenyloxy groups include cycloethenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy.

'Acyl' is H-CO- or (C~-Cio)alkyl-CO-, where (Cl-C1o)alkyl group is as defined above. Exemplary aeyl 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 monocylic or polycyclic ring system of about 5 to 14 carbon atoms.
Exemplary 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 aryl-CO- group, wherein the aryl group is as defined above.
Exemplary 1o aroyl groups include benzoyl, 1-naphthoyl.
'Aroyloxy' is the amyl-O- group, wherein the aroyl group is as defined above.
Exemplary aroyloxy groups include benzoyloxy, 1-naphthoyloxy.
'Aralkyl' is the aryl-(C1-Clo)alkyl group, wherein aryl and (C~-C~o)alkyl groups are as defined above. Exemplary arallcyl groups include benzyl, 2-phenylethyl.
'Aralkenyl' is aryl-(C~-C6)alkenyl group, wherein aryl and (C~-C6)allcenyl groups are as defined above.
'Aralkynyl' is aryl-(C~-C6)alkynyl group, wherein the aryl and group is as defined above.
'Aralkoxy' is arallcyl-O- group, wherein the aralkyl group 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 hetero atom 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 non-aromatic monocyclie or polycyclic hydrocarbon ring system of about 5 to 10 carbon atoms, having at least one hetero atom selected from O, S or N and one double bond. Exemplary heterocyclenyl groups include 1,2,3,4-tetrahydropyrimidine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahych-opyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl.
'Heteroaryl' is an aromatic 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 heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxole, 1,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl.
'Heteroaralkyl' is a heteroaryl-(C1-C~o)alkyl group, wherein the heteroaryl and (CI
C~o)alkyl groups are as defined above. Exemplary heteroaralkyl groups include thienylmethyl, pyridylinethyl, 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 (C1-Cjo)alkyl-CO-, wherein the (Cl-C~o)alkyl group is as defined above. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl.
'Alkoxycarbonyl' is (CI-C~o)alkyl-O-CO-, wherein the (Cl-Clo)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.
Exemplary arylcarbonyl groups include phenylcarbonyl, naphthylcarbonyl.
'Aryloxycarbonyl' is aryl-O-CO-, wherein the aryl group is as defined above.
Exemplary aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl.
'Aralkoxycarbonyl' is aryl-(Cl-C6)alkoxy-CO-, where aryl and (C~-C6)alkoxy are as defined above. Exemplary aralkoxycarbonyl groups include benzyloxycarbonyl, 2-phenethyloxycarbonyl.
'Heteroarylcarbonyl' is heteroaryl-CO-, wherein heteroaryl is as defined above.
Exemplary heteroarylcarbonyl groups include pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl.
'Alkylsulfonyl' is (C~-CIO)alkyl-SO2-, wherein the (C~-Clo)alkyl group is as defined above. Exemplary alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, 3o propylsulfonyl.
'Arylsulfonyl' is aryl-S02-, wherein the aryl group is as defined above.
Exemplary arylsulfonyl groups include benzenesulfonyl.

'Heteroarylsulfonyl' is heteroaryl-S02-, wherein heteroaryl is as defined above.
Exemplary heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolylsulfonyl, pyrazolylsulfonyl, pyrrolylsulfonyl, pyridazinylsulfonyl, phthalazinylsulfonyl, quinazolinylsulfonyl, pyridylsulfonyl, thienylsulfonyl.
'Alkylsul~nyl' is (CI-C~o)alkyl-SO-, where (C~-CIO)alkyl is as defined above.
Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsul~nyl, propylsulfinyl.
'Arylsul~nyl' is aryl-SO-, wherein the aryl group is as defined above.
Exemplary arylsulfonyl groups include phenylsulfmyl.
'Heteroarylsulfmyl' is heteroaryl-SO-, wherein heteroaryl is as defined above.
Exemplary heteroarylsulfmyl groups include pyrazinylsulfinyl, isothiazolylsul~nyl, oxazolylsul~nyl, pyrazolylsulfinyl, pyrrolylsulfinyl, pyridazinylsulfinyl, phthalazinylsul~nyl, quinazolinylsulfinyl, pyridylsul~nyl, and thienylsul~nyl.
'Aralkylsulfinyl' is aryl-(C~-C~n)alkyl-SO- group, where in aryl and (C~-Clo)alkyl groups are as defined above. Exemplary aralkylsulfmyl groups include benzylsulfinyl, ~-phenethylsul~nyl.
'Alkylthio' is (CI-C~o)alkyl-S-, wherein (Cl-C~o)alkyl is as defined above.
Exemplary alkylthio groups include methylthio, ethylthio, and propylthio.
'Arylthio' is aryl-S-, wherein aryl group is as defined above. Exemplary arylthio groups include phenylthio groups.
'Heteroarylthio' is heteroaryl-S-, wherein heteroaryl is as defined above.
Exemplary heteroarylthio groups include pyrazinylthio, isothiazolylthio, oxazolylthio, pyrazolylthio, pyrrolylthio, pyridazinylthio, phthalazinylthio, quinazolinylthio, pyridylthio, and thienylthio.
'Aralkylthio' is aryl-(Cl-C~o)alkyl-S- group, wherein aryl and (CI-C~o)alkyl groups are as defined above. Exemplary aralkylthio groups include benzylthio, and 2-phenethylthio.
'Aryloxyalkyl' is aryl-O-(Cl-CIO)alkyl, where aryl and (CI-CIO)alkyl groups are as defined above. Exemplary aryloxyalkyl groups include phenoxymethyl, phenoxyethyl, and phenoxypropyl.
'Aralkoxyalkyl' is aryl-(CI-Glo)alkyl-O--(CI-C~o)alkyl, where (C~-Cio)alkyl and aryl groups are as defined above. Exemplary aralkoxyalkyl groups include benzyloxyrnethyl, benzyloxyethyl, and benzyloxypropyl.
'Fused heteroarylcycloalkyl' is fused heteroaryl and cyclo(C3-C6)alkyl, wherein heteroaryl and cyclo(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 cyclo(C3-C6)alkenyl, wherein heteroaryl and cyclo(C3-C6)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 heteroaryl and heterocyclenyl groups are as defined herein. Exemplary fused heteroarylheterocyclenyl groups include 7,8-dihydro[1,7]naphthyridinyl, 1,2-to dihydro[2,7]naphthyridinyl.
'Carboxylic acid or its derivatives' may be amides or esters. Exemplary carboxylic acid groups include CONH~, CONHMe, CONMe2, CONHEt, CONEt~, CONHPh, COOCH3, COOC~HS or COOC3H~.
'Sulfonic acid or its derivatives' may be amides or esters. Exemplary sulfonic acid groups include S02NH~, SO~NHMe, SOZNMeZ, S02NHCF3, COOCH3, COOCZHS, or COOC3H~.
As used herein:
Ra is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group;
2o Rb is an allcyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group;
R° is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group;
Rya is hydrogen, a hydroxy group, a halogen, a vitro 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 arallcyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroarallryl group, a heteroaryloxy group, a heteroarallcoxy group, an allcoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group;
RIB is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an arallcylsulfinyl group, an allcylsulfmyl group, an arylsulfmyl group, a heteroarylsulfinyl group, an aralkylsulfmyl 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;
RZa is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloallcyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group;
RZb is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an amyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a l0 heteroaryl group, a heteroarallcyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group;
RZ° is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an arallcylsulfinyl group, an allcylthio group, an arylthio group, a heteroarylthio group, an arallcylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof;
R3a is hydrogen, a hydroxy group, a halogen, a vitro 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;
R3b is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an amyl group, an aroyloxy group, an aralkyl group, an arallcoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an allcoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group;
R3° is an allcylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an arallcylsulfinyl group, an allcylsul~nyl group, an arylsulfmyl group, a heteroarylsulfinyl group, an aralkylsulfmyl 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;
3o R4a is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloallcoxy 3?

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, 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 heteroarallcyl group, a heteroaryloxy group, or a heteroaralkoxy group;
R4° is an allcoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an allcylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfmyl group, an arylsulfinyl group, or an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio 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;
Rsa is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group;
RSb is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group;
R5~ 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 vitro group, an amino group, a mono- or di-substituted 2o amino group, a hydroxy group, an allcoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group;
R'b is an alkyl group, a cycloalkyl group, an allcoxy 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;
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;
R"a is hydrogen, a halogen, a vitro group, an amino group, a mono- or di-substituted amino group, a hydroxy group, an allcoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group;

R"b is an alkyl group, a cycloalkyl group, an aIkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an amyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an arallcyl group;
R"° is an alkylsulfonyl group, an alkylsul~nyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group.
R9~ is hydrogen, a halogen, a vitro 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(O=) 1o group, or a thio(S=) group;
R96 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 arallcyl group;
R9' is an alkylsulfonyl group, an alkylsul~nyl 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 vitro group, an amino group, an allcyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group;
Rloa is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group;
R'°b is an alk 1 ou a c cloa 1 rou an alkox ou a haloalkox rou a Y ~' P~ Y ~Y g p~ Y ~ p~ Y g p~
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 arallcyl group;
Rl°° is an alkylsulfonyl group, an alkylsulfmyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an arallcylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a vitro group, an amino group, an alleyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.
RI la is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group;
Rl~b is an alkyl group, a cycloalkyl group, an allcoxy group, a haloalkoxy group, a l0 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;
Rn~ is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an allcylthio 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 vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an allcyl group, an allcoxy group, or an aryl group;
Ri2a is hydrogen, a halogen, a vitro 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, or a thio(S=) group;
Ri2b is an allcyl group, a cycloalleyl 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;
R12~ is an alkylsulfonyl group, an alkylsulfmyl 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 vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an allcyl group, an alkoxy group, or an aryl group;
Rl3a is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group;
R~3b 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 amyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group;
RI3c is an alkylsulfonyl group, an alkylsulfmyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an arallcylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a vitro group, an amino group, an alkyloxy group, or any is combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group;
Riaa is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group;
R~4b is an alkyl group, a cycloalkyl group, an allcoxy group, a haloallcoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an amyl group, an allcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group;
Rl~° is an alkylsulfonyl group, an alkylsulf'myl 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 vitro group, an amino group, an alkyloxy group, or any 3o combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group;
R2oa is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group;
Rz°b is an alk 1 ou a c cloal 1 rou an alkox rou a haloalkox rou a Y bn' p~ Y kY g p~ Y g p~ Y g p cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an amyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group;
to Rz°° is an alkylsulfonyl group, an alkylsul~nyl 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 vitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyI group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alleyl group, an alkoxy group, or an aryl group;
Rzla is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group;
Rzib is an al 1 rou a c cloallc 1 ou an alkox ou a haloalkox rou a kY g p~ Y Y ~ p~ Y ~' p~ Y g p~
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;
Rz~~ is an alkylsulfonyl group, an alkylsulfmyl 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 vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group.

Ga is -(CHZ)S-, where s is an integer from 0-5;
Gb is -(CHz)S CH=GH-(CHZ)S-, where s is an integer from 0-5;
G~ is -(CHZ)S-C=C-(CH2)S , where s is an integer from 0-5;
Za is O; Zb is NR; Z~ is f CHZ~" or S(=O)", where a is an integer from 0-2;
Ea is O; Eb is S; E° is NR;
pa is 0-1; pb is 2-3; p~ is 4-5;
va is 0-1; vb is 2-3; v~ is 4-5;
Wa 1S 0; Wb 1S l; W~ 1S ~;
Xa is O; Xb is S; and X~ is -NR.
to According to another aspect of the present invention, various compounds of general formula (I) having general formula (II) B\A E R4 F~NR
R Dr ~ ~ I Y-G-Z-Ar=~Ya ~I) R3 r R
X
its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates are provided. Except as otherwise provided 15 herein, all symbols are as defined above in connection with formula (I).
According to another aspect of the present invention, various compounds of general formula (I) having general formula (III) R~~:, ~ E ~ o_~_ cnn Rs O
its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, 2o and its pharmaceutically acceptable solvates are provided. Except as otherwise provided, all symbols are as defined above in connection 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(O=) group, a thio(S=) group, an alkyl group, a cycloallryl group, an 3~

alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an amyl 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.
In one aspect of the present invention, R', R2, R3, and R5 are as defined above; R4 is an optionally substituted aryl group, and in some instances, is a phenyl group optionally substituted with a halogen, an alkoxy group, or both; E is O or -NR, where R
is as defined above; G is -(CH2)S or -(CH2)S CH=CH-(CH2)S ; s is an integer from 1-3; and R' and R"
1o are as defined above, and in some instances, 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 such compounds provided herein are also encompassed by this invention, as provided below.
R' O
R RQ R~ NR r~ E R4 R
R ~ I I O_G_Z O R ~. ~ ~ O-G-Z~~ / ~ R

O R" (1); O R~~ .R5 O (2)0 R~
R~ ~NR Rz E Ra R, w R R O I I
R2~ I I O-G Z ~ R R ~ O-G-Z ~ g O
R3 I / O R.. R5 NR
R~~ (3)~ °
R~
Rz Ra R' ~ / E R4 o-G_~ ~ o R ~ ~ ~ o-G_z ~ S~O
R O R.. R5-.. N R O R5__.. NR
(5)o O
R~ O Ra E R4 R~ S~ a E R
R I I °-G ~~NR RZ ~ I I o R3 O R..~RS O o R,. R5°.. NR
(7)o O (g)o R' R' Ra Ra R, Ra R, o_G_z~~~ s~o w ~ ~ o-G-z~~~ s~o O R, R5°.. N a O R~~ RS..._ NR
O (9)p O
/ Ra R. ~ E Ra R.
O-G Z \ J S O Ra ~ O-G Z \ J S O
Ra O O
R~~ Rs NR R.. Rs-._. NR
o (11); o (la)o i R~ \ I I O-G_Z~ ~ O
Ra O Ry _ N
~R~~--(,~~s and o (13);
where all symbols are as defined above in connection with formula (I). Thus, by way of example, and not by way of limitation, the present invention contemplates the following exemplary compounds:
R' R' O R4 ~ ~ r~ S R4 R R3 I I O G Z J S O R 3 ~ ~ O G Z
O R" 5..._ O R~RS.... NR
o (14); o (15);
R~
i a R, ~ a R.
R ~ I N I o-G-Z ~~ s o Ra ~, ~ E ~ Oy CHa)5 ~-CI J S o R3 ..
O
O R.. Rs-___ NR R,. Rs -.. N R
o (16); o (17);
R~

R L ~ I I ~(CH2)s'-CH=CI-F(CH2)s Z~~ S O
O R R5____ N, / R
o (18);
R~

Rz r ~
oUoH2)s o=o-(cH~>s z~

R5- ..
~R
0 (19);

i R~ E Ra R E R R
R ~ I I o-G_~I', S O R~ I I O_O_N ~ S O
I" 5.... R O l 5.... NR

R~ R
p (20); o (21);
' ' a R.
R ~ Ra _ ~ R
p-G-(CHZ)u'~ i ~O ~'' ~3 I I O_G-S(-O)u~ J ~O
O R .... NR O R RS..__ NR
p (22); p (23);
MeO~~ E Ra R Me0 / E Ra Me~~ I I O G Z ~ S O ~ ( I O G Z ~ ._ S O
O R.. 5-_ . NR OMe O R R5 NR
p (24); o (25);
Me0 / O Ra R
\ I I O-G z~~J
OMe O " R5'... NR
p (26); (27);
Me / OMe , OMe Me0 o O \ I R Me0 p \ I R' a i ~_ OMe~r~
S~O \ ~ ~ O-G-Z~II~ S~ I O
OMe O R"R5 NR OMe O R~.~NR
p (28); and R p (29);
where all symbols are as defined above in connection with formula (I).
By way of further example, the present invention contemplates various compounds having the following general formula:
(30), where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, R, R5, R, R~, and E of formula (30) are selected to produce various compounds of formula (30-1) through formula (30-243) as follows:

FormulaR R R R E

30-1 Ra R a R'a R"a Ea 30-2 Rb Rsa R'a R"a Ea 30-3 R Rsa R'a R"a Ea 30-4 Ra Rsb R'a R"a Ea 30-5 Rb Rsb R,a R"a Ea 30-6 R~ RSb R'a R"a Ea 30-7 Ra R5~ R'a R"a Ea 30-8 Rb RS R'a R"a Ea 30-9 R R5~ R'a R"a Ea 30-10 Ra Rsa R'b R"a Ea 30-11 Rb Rsa R'b R"a Ea 30-12 R RSa R'b R"a Ea 30-13 Ra RSU 12~b R"a E,a 30-14 Rb R5b R,b R"a Ea 30-15 R Rib Rrb R"a Ea 30-16 Ra RS R'b R"a Ea 30-17 Rb R5~ Rrb R"a Ea 30-18 R R5~ R,b R"a Ea 30-19 Ra Rsa R'~ R"a Ea 30-20 RU RSa R' R"a Ea 30-21 R RSa R'~ R"a Ea 30-22 Ra RSb R'~ R"a Ea 30-23 Rb Rsb R' R"a Ea 30-24 R~ RSb R' R"a Ea 30-25 Ra R5 R' R"a Ea 30-26 Rb R5~ R' R"a Ea 30-27 R~ R5~ R' R"a Ea 30-28 Ra Rsa R'a R"b Ea 30-29 Rb RSa R'a Rb Ea 30-30 R R5a R'a Rr,b Ea 30-31 Ra RSb R'a R"b Ea 30-32 Rb Rsb R'a R"b Ea 30-33 R RSb R'a R"b E,a 30-34 Ra RS R'a R"b Ea 30-35 Rb R5~ R'a R"b Ea 30-36 R~ R5~ R'a R"b Ea 30-37 Ra Rsa R'b R"b Ea 30-38 Rb R5a R~b R"b Ea 30-39 R~ Rsa Rrb Rb Ea 30-40 Ra Rsb R'b R"b Ea 30-41 Rb RSb R'b R"b Ea 30-42 R R5b R'b R"b Ea 30-43 R~ RS R'b R"b Ea 30-44 Rb R5~ R,b R"b Ea 30-45 R~ R5~ R'b R"b Ea 30-46Ra RSa R'c Rrrb Ea 30-47Rb RSa R' Rrrb Ea 30-48R Rsa Rrc Rrrb Ea 30-49Ra Rsb Rrc Rrrb Ea 30-50Rb Rsb Rrc Rrrb Ea 30-51R RSb R'c R"b Ea 30-52Ra RSc R'c R"b Ea 30-53Rb Rsc R'c R"b Ea 30-54Rc Rsc R'c R"b Ea 30-55Ra RSa R'a R"c Ea 30-56Rb Rsa R'a R" Ea 30-57Rc Rsa R'a R" Ea 30-58Ra Rsb R'a R" Ea 30-59Rb Rsb R'a R"c Ea 30-60R Rsb R'a R" Ea 30-61Ra RSc R'a R" Ea 30-62Rb Rsc R'a R" Ea 30-63R Rsc R'a R"c Ea 30-64Ra Rsa Rrb Rrrc Ea 30-65Rb RSa Rrb R" Ea 30-66R R5a Rrb Rrrc Ea 30-67Ra Rsb Rrb Rrrc Ea 30-68Rb Rsb R'b R" Ea 30-69R RSb R'b R" Ea 30-70Ra Rsc R~b Rrrc Ea 30-71Rb RSc Rrb Rnc Ea 30-72Rc Rsc Rrb Rrrc Ea 30-73Ra RSa R'c R"c Ea 30-74Rb R5a R'c R" Ea 30-75Rc R5a R'c R" Ea 30-76Ra Rsb R'c R" Ea 30-77Rb Rsb R'c R" Ea 30-78R RSb R'c R"c Ea 30-79Ra RS' R'c R" Ea 30-80Rb Rsc R'c R"c Ea 30-81R~ R5c R' R"c Ea 30-82Ra Rsa R'a Rrra Eb 30-83Rb R5a Rra Rrra Eb 30-84Rc Rsa R'a Rrra Eb 30-85Ra RSb R'a Rrra Eb 30-86Rb R5b R'a Rrra Eb 30-87Rc RSb R'a R"a Eb 30-88Ra Rsc R'a R"a Eb 30-89Rb RSc R'a R"a Eb 30-90Rc Rsc R'a R"a Eb 30-91Ra RSa R'b R"a Eb 30-92Rb R5a R'b Rrra Eb 30-93 R Rsa Rrb Rrra Eb 30-94 Ra Rsb Rrb Rrra Eb 30-95 Rb Rsb Rrb Rrra Eb 30-96 R Rsb R'b Rrra Eb 30-97 Ra R5 R,b R"a Eb 30-98 Rb Rsc Rrb Rrra Eb 30-99 Rc Rsc R'b R"a Eb 30-100Ra Rsa R'c R"a Eb 30-101Rb Rsa R'c R"a Eb 30-102Rc Rsa R'c R"a Eb 30-103Ra Rsb R' R"a Eb 30-104Rb Rsb R'c R"a Eb 30-105Rc Rsb R'c R"a Eb 30-106Ra Rsc R'c R"a Eb 30-107Rb Rsc R'c R"a Eb 30-108Rc Rsc R'c R"a Eb 30-109Ra Rsa R'a Rrrb Eb 30-110Rb Rsa R'a Rrrb Eb 30-111Rc Rsa R'a R"b Eb 30-112Ra Rsb R'a Rrrb Eb 30-113Rb Rsb R'a R"b Eb 30-lI4Rc Rsb Rra Rrrb Eb 30-115Ra Rsc R'a R"b Eb 30-116Rb Rsc Rra Rrrb Eb 30-117Rc Rsc R'a Rrrb Eb 30-118Ra Rsa R'b Rrrb Eb 30-119Rb Rsa R'b Rrrb Eb 30-120Rc Rsa R'b Rrrb Eb 30-121Ra Rsb Rrb Rrrb Eb 30-122Rb Rsb R'b Rrrb Eb 30-123Rc Rsb R'b R"b Eb 30-124Ra Rsc R'b R"b Eb 30-125Rb Rsc R'b R"b Eb 30-126Rc Rsc Rrb Rrrb Eb 30-127Ra Rsa R'c R"b Eb 30-128Rb Rsa Rrc R,rb Eb 30-129Rc Rsa R'c R"b Eb 30-130Ra Rsb R'c R"b Eb 30-131Rb Rsb R'c R"b Eb 30-132R Rsb R' R"b Eb 30-133Ra Rsc R'c R"b Eb 30-134Rb Rsc R'c R"b Eb 30-135R Rsc R'c R"b Eb 30-136Ra Rsa R'a R"c Eb 30-137Rb Rsa R'a R"c Eb 30-138Rc Rsa R'a R"c Eb 30-139Ra Rsb R'a R" Eb 30-140Rb Rsb R'a R"c Eb 30-141Rc RSb R'a R" Eb 30-142Ra Rsc R'a R"c Eb 30-143Rb Rsc R'a R"c Eb 30-144R Rsc R'a R"c Eb 30-145Ra Rsa R'b R"c Eb 30-146Rb Rsa R'b R"c Eb 30-147Rc Rsa R'b R"c Eb 30-148Ra Rsb R'b R"c Eb 30-149Rb Rsb R'b R"c Eb 30-150R Rsb R'b R" Eb 30-151Ra Rsc R'b R" Eb 30-152Rb Rsc R'b R"c Eb 30-153R Rsc R'b R"c Eb 30-154Ra Rsa R'c R"c Eb 30-155Rb Rsa R'c R" Eb 30-156R Rsa R'c R"c Eb 30-157Ra Rsb R'c R"c Eb 30-158Rb Rsb R'c R"c Eb 30-159R Rsb R'c R"c Eb 30-160Ra Rsc R'c R"c Eb 30-16IRb Rsc R'c R" Eb 30-162R Rsc R'c R"c Eb 30-163Ra Rsa R,a R"a Ec 30-164Rb Rsa R'a R"a Ec 30-165R Rsa R'a R"a Ec 30-166Ra Rsb R'a R"a E

30-167Rb Rsb R'a R"a E

30-168R Rsb R'a R"a Ec 30-169Ra Rsc R'a R"a Ec 30-170Rb Rsc R'a R"a E

30-171Rc Rs R'a R"a Ec 30-I72Ra Rsa R,b R"a Eo 30-173Rb Rsa R'b R"a E

30-174Rc Rsa R'b R"a EC

30-175Ra Rsb R'b R"a Ec 30-176Rb Rsb R'b R"a E

30-177Rc Rsb R'b R"a Ec 30-178Ra Rso R,b R"a Ec 30-179Rb Rsc R'b R"a E

30-180Rc Rsc R'b R"a Ec 30-181Ra Rsa R'c R"a Ec 30-182Rb Rsa R'c R"a Ec 30-1$3Rc Rsa R'c R"a EC

30-184Ra Rsb R'c R"a E

30-185Rb Rsb R'c R"a E

30-186R Rsb R'c R"a Ec 30-187Ra Rsc R'c R"a Ec 30-188Rb Rsc R' R"a Ec 30-189Rc Rsc R'c R"a Ec 30-190Ra Rsa R'a R"b Ec 30-191Rb Rsa R'a R"b Ec 30-192Rc Rsa R'a R"b Ec 30-193Ra Rsb R,a Rrrb Ec 30-194Rb Rsb R'a R"b Ec 30-195Rc Rsb R'a R"b Ec 30-196Ra Rsc R'a Rb Ec 30-197Rb Rsc R'a R"b Ec 30-198Rc Rsc R'a R"b Ec 30-199Ra Rsa R'b R"b Ec 30-200Rb Rsa R'b R"b Ec 30-201Rc Rsa R'b R"b Ec 30-202Ra Rsb R'b R"b Ec 30-203Rb Rsb R'b R"b Ec 30-204Rc Rsb R'b R"b Ec 30-205Ra Rsc R'b R"b Ec 30-206Rb Rsc R'b R"b EC

30-207Rc Rsc R'b R"b E

30-208Ra Rsa R'c R"b Ec 30-209Rb Rsa R'c R"b Ec 30-210Rc Rsa R'c R"b Ec 30-211Ra Rsb R'c R"b Ec 30-212Rb Rsb R'c R"b Ec 30-213Rc Rsb R'c R"b Ec 30-214Ra Rsc R'c R"b Ec 30-215Rb Rsc R'c R"b Ec 30-216Rc Rs R'c R"b Ec 30-217Ra Rsa R,a R"c Ec 30-218Rb Rsa R'a R"c Ec 30-219Rc Rsa R'a R"c Ec 30-220Ra Rsb R'a R"c Ec 30-221Rb Rsb R'a R"c EC

30-222Rc Rsb R'a R"c Ec 30-223Ra Rsc R'a R"c Ec 30-224Rb Rsc R'a R"c Ec 30-225Rc Rsc R'a R" Ec 30-226Ra Rsa R'b R"c Ec 30-227Rb Rsa R,b R"c Ec 30-228R Rsa R'b R"c Ec 30-229Ra Rsb R'b R"c Ec 30-230Rb Rsb R'b R"c Ec 30-231R Rsb R'b R"~ Ec 30-232Ra Rsc R'b R"c Ec 30-233Rb Rsc R'b R" Ec 30-234R Rsc R'b R"c Ec 30-235Ra RSa R'c R"c Ec 30-236Rb Rsa R'c R"c Ec 30-237R R5a R' R"c Ec 30-23$Ra RSb R'c R"c Ec 30-239Rb RSb R'c R"c Ec 30-240R Rsb R'c R"c E

30-241Ra Rsc R'c R" Ec 30-242Rb RSc R'c R"c Ec 30-243Rc RSc R'c R"c Ec where all symbols are as defined above.
In one aspect of formula (30) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group; RS
is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an allcyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R' and R"
independently are hydrogen, a halogen, a vitro group, an amino group, a mono- or di-substituted amino group, an allcyl group, a cycloalkyl group, an alkoxy group, a haloallcoxy group, a cycloallcyl group, an aryl group, or a benzyloxy group; and E is O, S, or NH.
l0 In another aspect of formula (30) of the present invention, R is hydrogen, an alkyl group, potassium, or sodium; RS is hydrogen or an alkyl group; and all other symbols are as defined above in connection 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; RS is -H, -CH3, or -CHZCHZCH3; and R
is -H, I~, or Na.
Examples of compounds of formula (30) include, but are not limited to:
OMe OMe / OMe / OMe Me0 ~ O W I Me0 ~ O \ I
O I ~ H O
OMe O ~O I / /S NH OMe O O N ~ / / NH
O O
/ OMe O NH / OMe O~NH
Me0 ~ O ~ I OMe / S~O Me0 ~ O ~ I OMe S O
/ I O~O I / I ~O
QMe O I / OMe O ~ I
> >

OMe / OMe Me0 O
Me0 \ O \ OMe OMe O I ~ OMe ~~O
'O w ~ / 'ms's \ ''t OMe O O Me0 I / /S H OMe O O I / / NH
O ~ O
/ OMe OMe Me0 \ O \ ~ Me0 I \ O I \ OMe O
OMe ~ / ~O
O O ' / / NH OMe O O CI I / /S NH
O

> >
/ OMe OMe Me0 O \ I Me0 ~ O \ I
OMe O I ~ OMe O
' O~O I \ S~ O~ ~ \ 5 H
OMe O CI / / NH- OMe O B / /
O O
> >
/ OMe , OMe Me0 I \ O I \ I OMe O Me0 \ O ~ I OMe O
O \ / O O S
OMe O O I / /S NNa OMe O ~ I s i N~
o ; and o The present invention also contemplates various compounds of general formula (III) having the formula:
R~
\ ~ O R4 R"
o~/E ~~ s~
R~ O ~/ / NH
R Me O
(31), where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, RI, RZ, R4, E, R', and R" of to formula (31) are selected to produce various compounds of formula (31-1) to (31-729) as follows:
Formula R R R E R' R"

31-1 R a R a R4a Ea R'a R"a 31-2 Rib RZa R4a Ea R,a R"a 31-3 Rl R2a R4a Ea Ria Ra 3I-4 Rya R2b R4a Ea Ria R..a 31-5 R'b R2b R4a Ea R,a Rr,a 31-6 R~ Rzb R4a Ea R,a R"a 31-7 Rya R2c R4a Ea R,a R"a 31-8 R'b Rzc R4a Ea R,a R"a 31-9 R' Rzc R4a Ea R,a R"a 31-10Ria R2a R4b Ea R,a R"a 31-IlRlb Rza R4b Ea R,a R"a 31-12Rlc Rza R4b Ea R,a R"a 31-13Rla Rzb R4b Ea R,a R"a 31-14Rib Rzb R4b Ea R,a R"a 31-15Rlc Rzb R4b Ea R,a R"a 31-16Rla Rzc R4b Ea Ria R..a 3I-17Rlb R2c R4b Ea R,a R..a 31-18Rl Rzc R4b Ea R'a R.,a 31-19Rya Rza R4c Ea R,a R"a 31-20RIb Rza R4c Ea R,a R"a 31-21Roc R2a R4c Ea R,a R"a 31-22Rya R2b R4c Ea R,a R"a 31-23Rlb Rzb R4c Ea R,a R..a 31-24Rlc Rzb R4c Ea Rra R"a 31-25Rla Rzc R4c Ea R~a R"a 31-26Rib Rzc R4c Ea R,a R"a 31-27Roc Rzc R'~c Ea R,a R"a 31-28Rya Rza R4a Eb R,a R"a 31-29Rlb R2a R4a Eb R,a R"a 31-30RIc Rza R4a Eb R,a R"a 31-3IRya R2b R4a Eb R,a R"a 31-32Rib Rzb R4a Eb R,a R"a 31-33Roc Rzb R'~a Eb R'a R"a 31-34Rya Rzc R4a Eb R,a R"a 31-35Rlb Rzc R4a Eb R,a R"a 31-36Rlc Rzc R4a Eb R'a R.,a 31-37Rya Rza R4b Eb R,a R"a 31-38Rlb R2a R4b Eb R,a R"a 31-39Ric Rza R4b Eb R,a R"a 31-40Rya Rzb R4b Eb Ria Rna 31-41Rlb Rzb R4b Eb Ria R..a 31-42Roc Rzb R4b Eb R,a Rna 31-43Rla Rzc R4b Eb R,a R"a 31-44Rlb Rzc R4b Eb R,a R"a 31-45Rlc R2c R4b Eb R,a Raa 31-46Rya Rza R4c Eb R,a R"a 31-47Rlb Rza R4c Eb R,a R"a 31-48Rlc Rza R4c Eb R,a R"a 31-49RIa Rzb R4c Eb R,a R"a 31-50RIb Rzb R4c Eb R,a Rna 31-51Rlc Rzb R4c Eb R,a R"a 31-52Ria Rzc R4c Eb R,a R"a 31-53Rlb R2c R4c Eb R,a R"a 31-54R'c Rz R4c Eb R'a R"a 31-55 Rya Rza R4a Ec R,a R"a 31-56 RIb R2a R4a Ec R,a Rr,a 3I-57 R~ Rza R4a Ec R,a R"a 31-58 Rya R2b R4a Ec R,a R"a 31-59 Rlb R2b R4a Ec R,a R"a 31-60 Roc R2b R4a Ec Rra R"a 31-61 Rya R2c R4a Ec R,a R"a 31-62 Rlb R2c R4a Ec R,a R"a 31-63 Rlc R2c R4a Ec R,a R"a 31-64 Rya R2a R4b Ec R,a Rr,a 31-65 RIb R2a R4b Ec R,a R"a 31-66 Roc Rza R4b Ec R,a R"a 31-67 Rya R2b R4b Ec R,a Rrra 31-68 R'b Rzb R4b Ec R,a R"a 31-69 R~ Rzb Rib Ec R,a R"a 31-70 Rya R2c R~b Ec R,a R,ra 31-71 Rlb R2c R4b Ec R,a R"a 31-72 Rlc R2c R4b Ec R,a R"a 31-73 Rya R2a R4c Ec R,a R"a 31-74 Rib Rza R4c Ec R,a R"a 31-75 Rl R2a R4c Ec R,a R"a 31-76 Rya R2b R4c Ec R,a R"a 31-77 RIb Rzb R4c Ec R,a R"a 31-78 Rl R2b R4c Ec R,a R"a 31-79 Rla Rzc R4c Ec R,a R"a 31-80 Rib Rzc Roc Ec R,a R"a 31-81 Roc Rzc R4c Ec R,a R"a 31-82 RI R2a R4a Ea R,b R"a a 31-83 Rib R2a R4a Ea R,b R,ra 31-84 R~ R2a R4a Ea Rrb R"a 31-85 RIa Rzb R4a Ea R,b R,ra 31-86 RIb R2b R4a Ea Rrb R"a 31-87 R~ Rzb Raa Ea Rrb Rr,a 31-88 Rla Rzc R4a Ea Rrb R"a 31-89 Rlb R2c R4a Ea R~b R"a 31-90 Rlc R2c R4a Ea R,b R"a 31-91 RIa R2a R4b Ea R,b R"a 31-92 Rib R2a R4b Ea R,b Rr,a 31-93 Rlc Rza R4b Ea R,b R"a 31-94 Rla R2b Rab Ea R,b Rr,a 31-95 Rib R2b R4b Ea Rrb R"a 31-96 Rlc R2b R4b Ea R,b R"a 31-97 Rya R2c R4b Ea Rrb R"a 31-98 RIb R2c R4b Ea R,b Rr,a 31-99 RIc R2c R4b Ea R,b R"a 31-100Rya R2a R4c Ea R,b Rr,a 31-101Rlb Rza R4c Ea R,b R"a 31-102Ric Rza R4c Ea R,b R"a 31-103Rya Rzb R4c Ea R,b R"a 31-104Rib R2b R4o E,a R,b R"a 31-105Ric R2b R4c E,a R,b R'ra 31-106Ria R2c R4c E,a Rrb R"a 31-I07Rib Rzc R'ic Ea R~b R"a 31-108Ric Rzc R4c Ea R,b R'ra 31-109Ria Rza R4a Eb R,b R,ra 31-110Rib Rza R4a Eb Rrb R"a 31-111Ric R2a R4a E,b R,b Rr,a 31-112Ria R2b R4a Eb R,b Rr,a ~

31-113Rib R2b R4a E,b R,b R"a 31-114Ric R2b R4a E,b R,b R"a 31-115Ria R2c R4a Eb R'b R"a 31-116Rib R2c R4a Eb R,b R"a 31-117Ric R2c R4a Eb R,b R"a 31-118Ria Rza R4b Eb R,b Rr,a 31-119Rib Rza R4b E,b R,b R,ra 31-120Ric R2a R'ib $b R~b R"a 31-121Ria Rzb R4b Eb R'b R"a 3I-122Rib R2b R4b Eb R,b R"a 31-123Roc R2b Rab Eb R,b R"a 31-124Ria Rzc R4b E,b R,b R"a 31-125Rib R2c R4b E,b R,b R'ra 31-126Ric R2c Rab Eb R'b R"a 31-127Ria Rza R4 gb Rrb Rrra 31-128Rib Rza R4c E,b R,b R"a 31-129Ric R2a R4c Eb R,b R"a 31-130Ria R2b R4c Eb R,b R"a 31-131Rib R2b R4c Eb R,b R"a 31-132Ric R2b R4c Eb R,b R"a 31-133Ria R2c R4c E,b R,b R"a 31-134Rib R2c R4c Eb R,b R"a 31-135Ric R2c R~tc Eb R'b R"a 31-136Ria R2a R4a E,c R,b R"a 31-137Rib R2a R4a Ec R,b R"a 31-138Ric R2a R4a Ec R,b R"a 31-139Ria R2b R4a $ R,b R"a 31-140Rib Rzb R4a E,c R,b R"a 31-141Ric R2b R4a Ec Rrb Rr,a 31-142Ria R2c R4a Ec R,b R"a 31-143Rib R2c R4a E,c R,b Rna 31-144Roc Rzc R4a Ec R,b R"a 31-145Ria R2a R4b Ec R,b R"a 3I-146Rib R2a R4b E R,b R"a 31-147Ric Rza R4b Ec R,b R"a 31-148Ria R2b R4b E,c R,b R"a 31-149Rlb Rzb R4b Ec R,b R"a 31-150RIc Rzb R4b Ec Rrb R"a 31-151Rya R2c R4b Ec R,b R"a 31-152Rib Rzc R4b Ec R,b R"a 31-153Roc Rzc R4b Ec R,b R"a 31-154Rya Rza R4c Ec Rrb R"a 31-155Rlb Rza R4c Ec R,b R"a 31-156Roc Rza R4c Ec Rrb R"a 31-157RIa Rzb R4c Ec R,b R"a 31-158Rlb Rzb R4c Ec R,b R"a 31-159Rlc Rzb R4c Ec Rrb Rrra 31-160RIa Rzc R4c Ec R,b R"a 31-161Rib Rzc R4c Ec R~b Rr,a 31-162R~ R2c R4c Ec Rrb R"a 31-163Rya Rza R4a Ea R,c R,ra 31-164Rib Rza R4a Ea R,c R"a 31-165Rlc Rza R4a Ea R,c R"a 31-166Rya Rzb R4a Ea R,c R,ra 31-167R'b Rzb R4a Ea R,c R"a 31-168Roc Rzb R4a Ea R,c Rr,a 31-169Rya Rzc R4a Ea R,c R"a 31-170Rib Rzc R4a Ea R,c R"a 31-171Rlc Rzc R4a Ea R,c R"a 31-172Rla Rza R4b Ea R,c R"a 31-173Rlb Rza R4b Ea R,c R"a 31-174Rlc R2a R4b Ea R,c R"a 31-175Ria R2b R~tb Ea R,c R,ra 31-176Rlb Rzb Rib Ea R,c R"a 31-177Ric Rzb R4b Ea R,c R"a 31-178R1a Rzc R4b Ea R,c R"a 31-179Rlb Rzc R4b Ea R,c R,ra 31-180Roc Rzc R4b Ea R,c R"a 31-181Rya Rza R4c Ea R,c R"a 31-182Rlb Rza R4c Ea R,c R"a 31-183R~ Rza R4c Ea R,c R,ra 31-184Rya Rzb R4c Ea R,c R"a 31-185R'b Rzb R'~ Ea R'c R"a 31-186Rlc Rzb R4c Ea R,c R"a 31-187Ria Rzc R4c Ea R,c R"a 31-188Rib Rzc R4c Ea R,c R,ra 31-189R~ Rzc R4c Ea R,c R"a 31-190Rya Rza R4a Eb R,c R"a 31-191Rib Rza R4a Eb R,c R"a 31-192Rlc Rza R4a Eb R,c R"a 31-193Rla R2b R4a Eb Rrc R"a 31-194Rib Rzb R4a Eb R,c R"a 31-195RIc Rzb R'~a Eb R'c R,ra 31-196Ria R2c R4a E,b R,c R"a 31-197Rib R2c R4a E,b R,c R"a 31-198Ric R2c R4a Eb R,c R"a 31-199Ria R2a R4b Eb R,c R"a 31-200Rib R2a R4b Eb R,c R"a 31-201Ric Rza R'~b Eb R~c Rna 31-202Ria R2b R4b E,b R,c R"a 31-203Rib R2b R4b E,b R,c R"a 31-204Ric Rzb R4b E,b R,c R"a 31-205Ria R2c R4b Eb R,c R"a 31-206Rib R2c R4b Eb R,c R"a 31-207Ric R2c R4b ~,b R,c R"a 31-208Ria R2a R4c E,b R,c R"a 31-209Rib R2a R4c Eb R,c R"a 31-210Ric R2a R4c E,b R,c R"a 31-211Ria Rzb Rac Eb R,c R"a 31-2I2Rib Rzb R4c Eb R,c R"a 31-213Ric Rzb R4c Eb R,c R"a 31-214Ria Rzc R4c Eb R'c R"a 31-215Rib Rzc R4c Eb R,c R"a 31-216Ric R2c R'ic Eb R'c R"a 31-217Ria R2a R4a E,c R,c R"a 31-218Rib R2a R4a Ec R,c R"a 31-219Ric R2a R4a Ec R,c R"a 31-220Ria R2b R4a E,c R,c R"a 31-221Rib R2b R4a Ec R,c R"a 31-222Ric R2b R4a E,c R,c R"a 31-223Ria R2c R4a Ec R,c R"a 31-224Rib R2c R4a E,c R,c R"a 31-225Ric R2c R4a Ec R,c R"a 31-226Ria R2a R4b E,c R,c R"a 31-227Rib R2a R4b E,c R,c R"a 31-228Ric R2a R4b Ec R,c R"a 31-229Ria Rzb R4b ~-,c R,o R"a 31-230Rib R2b R4b E,c R,c R"a 31-231Ric R2b R4b Ec R,c R"a .

31-232Ria R2o Rib Ec R,c R"a 31-233Rib Rzc R4b Ec R,c R"a 31-234Ric R2c R4b E,c R,c R"a 31-235Ria Rza R4c E,c R,c R"a 31-236Rib R2a R4c Ec R,c R"a 31-237Ric Rza R4c E,c R,c R"a 31-238Ria R2b R4c $ R,c R"a 31-239Rib R2b R4c ~-,c Rrc R"a 31-240Ric R2b R4c E,c R,c R"a 31-241Ria R2c R4c E,c R,c R"a 31-242Rib R2c R4c Ec R,c R"a 31-243Ric Rzc R4c E R~ R~~a 31-244Ria R2a R4a Ea R,a R"b 31-245Rib Rza R4a Ea R,a R"b 31-246Ric Rza R4a Ea R,a R"b 31-247Ria R2b R4a Ea R,a R"b 31-248Rib R2b R4a Ea R,a R"b 31-249RI R2b R4a Ea Rra R"b 31-250Ria R2c R4a Ea R,a R"b 31-251Rib R2c R4a Ea R~a R"b 31-252Ric R2c R4a Ea R,a R"b 31-253Ria R2a R4b Ea R,a R"b 31-254Rib R2a R4b Ea R,a R"b 31-255Ric Rza R4b Ea R,a R"b 31-256Ria R2b R4b Ea R,a R"b 31-257Rib R2b R4b Ea R,a R"b 31-258Ric R2b R4b Ea R~a R"b 31-259Ria Rzc R4b Ea R,a R"b 31-260Rib Rzc R4b Ea R,a R"b 31-261Ric R2c R4b Ea R,a R"b 31-262Ria Rza R4c Ea R,a R"b 31-263Rib Rza R4c Ea R,a R"b 31-264Ric R2a R4c Ea R,a R"b 31-265Ria Rzb R4c Ea R,a R"b 31-266Rib R2b R4c Ea R,a R"b 31-267Ric Rzb R4c Ea R,a R"b 31-268Ria Rzc R4c Ea R,a R"b 31-269Rib Rzc R4c Ea R,a R"b 31-270RI R2c R4c Ea R,a R"b 31-271Ri R2a R4a Eb R,a R"b a 31-272Rib R2a R4a Eb R,a R"b 31-273Ric R2a R4a Eb R,a R"b 31-274RI Rzb R4a Eb R,a R"b a 31-275Rib Rzb R4a Eb R,a R"b 31-276RI Rzb R4a Eb R,a R"b c 31-277RI R2c R4a Eb R,a R"b a 31-278Rib R2c R4a Eb R,a R"b 31-279Ric R2c R4a E,b R,a R"b 31-280Ria R2a R4b Eb R,a R"b 31-281Rib Rza R4b Eb R,a R"b 31-282Ric R2a R4b Eb R,a R"b 31-283Ria R2b R4b Eb R,a R"b 31-284Rib R2b R4b Eb R,a R"b 31-285Ric R2b R4b Eb R,a R"b 31-286Ria R2c R4b Eb R,a R"b 31-287Rib Rzc Rab Eb R,a R"b 31-288Ric R2c R4b E,b R,a R"b 31-289Ria R2a R4c Eb R,a R"b 31-290Rib RZa R4c Eb R,a Rrrb 31-291RI Rza R4c Eb R,a R"b c 31-292RI R2b R4c Eb R,a R"b a 31-293Rib R2b R4c Eb R,a R,rb 31-294Ri RZb R4c Eb R,a R,rb c 31-295RI RZc R4c Eb R,a Rr,b a 31-296Rib R2c R4c Eb R,a R"b 31-297Ric RZc Rac Eb R,a R"b 31-298Ria R2a R4a Ec R,a R"b 31-299Rib Rza R4a Ec R,a R"b 31-300RI RZa Ra Ec R,a Rrrb 31-301Ri R2b R4a Ec R,a Rrrb a 31-302Rib R2b R4a Ec R,a R"b 31-303RI R2b R4a Ec R,a R"b 31-304Ria R2c R4a Ec R,a R,rb 31-305Rib RZc R'~a Ec R,a Rr,b 31-306Ric R2c R4a Ec R,a R"b 31-307RI R2a R4b Ec R,a R"b a 31-308Rib R2a R4b Ec R,a R"b 31-309RI R2a Rib Ec R,a Rnb 31-310RI RZb R4b Ec R,a R,rb a 31-311RIb R'-b R4b Ec R,a R"b 31-312Ric RZb R4b Ec R,a R"b 31-313Ria RZc R4b Ec R,a R"b 31-314Rib R''c R4b E,c R,a R"b 31-315Ric R2c R4b Ec R,a R"b 31-316Ria R2a R4c Ec R,a R"b 31-317Rib R'a R4c Ec R,a R"b 31-318Ric R2a R4c Ec R,a R"b 31-319Ri R2b R4c Ec Rra R"b a 31-320Rib R''b R'~c Ec R,a R"b 31-321Ric RZb R4c Ec Rra R,rb 31-322RI RZc R4c Ec R,a Rr,b a 31-323Rib RZc R4c Ec R'a R"b 31-324Ric R2c R4c Ec R,a R"b 31-325RI R2a R4a Ea R,b R"b a 31-326Rib R2a Raa Ea R,b R"b 31-327Ric R2a R4a Ea R,b R"b 31-328Ria R2b R4a Ea R,b R"b 31-329Rib R2b R4a Ea R,b R"b 31-330Ric R2b R4a Ea R,b R"b 31-331Ria R''c R4a Ea R,b R"b 31-332Rib R2c Raa Ea Rrb R"b 31-333Ric R2c R4a Ea R,b Rr,b 31-334Ria R2a R4b Ea R,b R,rb 31-335Rib R''a R4b Ea Rrb R"b 31-336Ric R''a R4b Ea R,b R"b 31-337Rya R2b R4b Ea R,b Rr,b 31-338Rib R2b R4b R,a R,b R,rb 31-339Rlc Rzb R4b E,a R,b R"b 31-340Rya Rzc R4b E,a R,b R,rb 31-341Rib Rzc R4b E,a R,b R,rb 31-342Roc R2c R4b E,a R,b Rrrb 31-343Rla R2a R4c E,a R,b Rrrb 31-344Rlb R2a R4c Ea R,b Rrrb 31-345Roc Rza R4c Ea R,b R"b 31-346Rla R2b R4c Ea R,b R"b 31-347Rib Rzb R4c E,a R,b R,rb 31-348R~ R2b R4c E,a R,b R"b 31-349Ria R2c R4c Ea R,b R,rb 31-350Rib Rzc R4c $a R,b R"b 31-351Rlc Rzc R4c E,a R,b R"b 31-352Rla Rza R4a E,b R,b Rr,b 31-353Rib R2a R4a E,b R,b R"b 31-354Rlc R2a R4a E,b R,b R"b 31-355Rla Rzb R4a E,b Rrb R"b 31-356Rib R2b R4a Eb R,b R"b 31-357R~ R2b R4a Eb R,b R"b 31-358Rla R2c R4a Eb R,b R"b 31-359Rlb R2c R4a $b R,b R"b 31-360Rlc R2c R4a $b R,b R"b 31-361Rla R2a R4b E,b R,b R"b 31-362Rlb Rza Rdb Eb Rrb R"b 31-363Rlc R2a R4b E,b Rrb R"b 31-364Rla Rzb R4b Eb R,b R"b 31-365Rlb Rzb Rab Eb R,b R"b 31-366Rlc Rzb R4b Eb R'b R"b 31-367Rya R2c R4b Eb R,b R"b 31-368Rlb R2c R4b Eb R,b R"b 31-369Rlc R2c R4b Eb R,b R"b 31-370Rya R2a R4c Eb R,b R"b 31-371Rlb R2a R4 Eb R,b R"b 31-372Rlc R2a Rdc Eb R,b R"b 31-373Rya R2b R4c Eb R,b R"b 31-374RIb Rzb Rac Eb R,b R"b 31-375R' R2b Rac Eb R,b R"b 31-376Rya Rzc R4c Eb R,b R"b 31-377Rlb Rzc R4c $b Rrb R"b 31-378Rlc R2c R4c Eb R,b R"b 31-379Rya R2a R4a Ec R,b R"b 31-380Rlb R2a R4a E,c R,b R"b 31-381Rlc R2a R4a E,c Rrb R"b 31-382R'a Rzb R4a E R'b R"b 31-383Rib R2b R4a E,c R,b R"b 31-384R~ R2b R4a Ec R,b Rrrb 31-385RIa R2c R4a Ec R,b R,rb 31-386Rib R2c R4a Ec R,b R,rb 31-387Rlc R2c R4a Ec R,b R"b 31-388Rya R2a R4b Ec R,b R"b 31-389Rlb R2a R4b Ec Rrb R"b 31-390Rlc R2a R4b Ec R,b Rr,b 31-391Rla R2b R4b Ec Rrb Rrrb 31-392Rlb Rzb R4b Ec R,b R"b 31-393Rlc R2b R4b Ec R,b R,rb 31-394Rla R2c R4b Ec R,b R"b 31-395Rlb R2c Rib Ec R,b Rrrb 31-396Rlc R2c R4b Ec R,b R"b 31-397Rya R2a R4c Ec R,b R"b 31-398Rib R2a Rdc Ec R,b R"b 31-399Rtc R2a R4c Ec Rrb Rr,b 31-400Rla R2b R4c Ec R,b Rr,b 31-401Rlb R2b R4c E R~b R,rb 31-402Rlc R2b R4c Ec R,b R"b 31-403Rla R2c R4c Ec R,b R"b 31-404Rib R2c R4c Ec R,b R"rb 31-405RIc R2c R4c E R'b R"b 31-406Rla R2a R4a Ea R,c Rr,b 31-407Rlb R2a R4a Ea R,c R"b 31-408Rlc R2a R4a Ea Rrc R"b 31-409Rya R2b R4a Ea R,c R"b 31-410Rlb R2b R4a Ea R,c R"b 31-411R~ R2b R4a Ea R,c Rrrb 31-412Rla R2c R4a Ea Rrc R"b 31-413RIb R2c R4a Ea R,c R"b 31-414Rlc Rzc R4a Ea Rrc Rr,b 31-415Rya R2a R4b Ea R,c Rr,b 31-416Rib R2a R4b Ea R,c R"b 31-417RIc R2a R4b Ea Rrc Rr,b 31-418Rya R2b R4b Ea R,c R"b 31-419Rlb R2b R4b Ea R,c R"b 31-420Roc R2b R4b Ea R,c R"b 31-421Rya R2c R4b Ea R,c R"b 31-422RIb R2c R4b Ea R,c R"b 31-423R~ R2c R4b Ea R,c Rrrb 31-424Rla R2a R4c Ea R,c Rr,b 31-425Rib R2a R4c Ea R,c Rrrb 31-426RIc R2a R4c Ea Rrc R"b 31-427Rla R2b R4c Ea R,c R"b 31-428Rib R2b R4c Ea R,c R"b 31-429Rlc R2b R4c Ea Rrc R"b 31-430Rla R2c R4c Ea R,c R"b 31-431Rib Rzc R4c Ea R,c R,rb 31-432Ric Rzc R'ic Ea R'c R,rb 31-433Ria Rza R4a Eb R,c R"b 31-434Rib Rza Rya Eb R'c R"b 31-435Ric Rza R4a Eb R,c Rr,b 31-436Ria Rzb R4a Eb R,c R"b 31-437Rib Rzb R4a Eb R,c R"b 31-438Ric Rzb R4a Eb Rrc R"b 31-439Ria Rzc R4a Eb R,c R"b 31-440Rib Rzc R4a Eb R,c R"b 31-441Ric Rzc R'la Eb R,c R"b 31-442Ria Rza R4b Eb R,c R"b 31-443Rib Rza R4b Eb Rrc R"b 31-444Ric Rza R4b Eb R,c R"b 31-445Ria Rzb R4b Eb R,c R"b 31-446Rib Rzb Rab Eb R,c R"b 31-447Ric Rzb Rab Eb R,c R"b 31-448Ria Rzc R4b Eb R,o R"b 31-449Rib Rzc Rab Eb R,c R"b 31-450Ric Rzc R4b Eb R'c R"b 31-451Ria Rza R4c Eb R,o R"b 31-452Rib Rza R4c Eb R,c Rr,b 31-453~ Ric Rza R4 E,b Rrc R"b 31-454Ria Rzb R4c Eb R,c R,rb 31-455Rib Rzb R4c Eb R'c R"b 31-456Ric Rzb R4c Eb R,c R"b 31-457Ria Rz R4c Eb Rrc R"b 31-458Rib Rzc Rac Eb R,c R"b 31-459Ric Rzc R4c Eb R' R"b 31-460Ria Rza R4a Ec R,c R"b 31-461Rib Rza R4a Ec R,c R"b 31-462Ric Rza R4a Ec Rrc R"b 31-463Ria Rzb R4a Ec R,c R"b 31-464Rib Rzb R4a Ec R,c R"b 31-465Ric Rzb R4a Ec R,c R"b 31-466Ria Rzc R4a Ec R,c R"b 31-467Rib Rz R4a Ec R,c R"b 31-468Ric Rzc R4a Ec R,c R"b 31-469Ria Rza R4b Ec R,c Rr,b 31-470Rib Rza R4b Ec R,c R"b 31-471Ric Rza R4b Ec R,c R,rb 31-472Ria Rzb R4b Eo R,c Rr,b 31-473Rib Rzb Rab Ec R'c R"b 31-474Ric Rzb R4b Ec R, R"b 31-475Ria Rzc R4b Ec R,c Rr,b 31-476Rib Rzc R4b Ec R,c R"b 31-477Ric Rzc R4b Ec R,c R"b 31-478R'a Rza R4c Ec R,c Rrrb 31-479R"' Rza R4c Ec R,c R"b 31-480Roc RZa R4~ Ec R,o R"b 31-481R'a Rzb R4o Ec R,c R"b 31-482R'b Rzb R4c Ec R,c Rrrb 31-483R'c Rzb Rdc Ec R,c R"b 31-484R'a Rzc Rdc Ec R,c R"b 31-485R'b Rzc Rac Ec R,~ R"b 31-486R'c Rzc Rac Ec R,c R"b 31-487R'a Rza R4a Ea R,a R"c 31-488R'b Rza R4a Ea R,a R"c 31-489Ric Rza R4a Ea Rra R"c 31-490Rya Rzb R4a Ea R,a R"c 31-491Rib R''b R4a Ea R'a R"c 31-492R' R2b R4a E, R, R"c c a a 31-493R'a Rzc R4a Ea R,a R"c 31-494Rib Rzc R4a E,a R,a R"c 31-495R~ Rzc R4a Ea R'a R"c 31-496Rya Rza R4b Ea R,a R"c 31-497R'b R2a R4b Ea R,a Rr,c 31-498R'c Rza R4b Ea R,a R"c 31-499R'a Rzb R4b Ea Rra R"c 31-500R'b RZb R4b Ea R,a R"c 31-501R'c RZb R4b Ea R,a Rrrc 31-502R'a Rzc R4b Ea R,a R"c 31-503Rlb Rzc R''b Ea R,a R"c 31-504RIc Rzc R4b Ea R,a R"c 31-505R'a Rza R4c Ea Rra R"

31-506R"' Rza R4c Ea R,a R"c 31-507R'c Rza R4c Ea R,a R"c 31-508Rya Rzb R4c Ea R'a R"c 31-509R'b Rzb R4c Ea R,a R"c 31-510Rlc Rzb R4c Ea R,a R"c 31-511R'a Rzc R4c Ea R,a R"c 31-512R'b Rzc R4c Ea R,a R"c 31-513R'c Rzc R4c Ea R,a R"c 31-514R'a Rza R4a Eb R,a R,rc 31-515R"' Rza R4a Eb R,a R"c 31-516R~ Rza R4a Eb R,a R"c 31-517R'a Rzb R4a Eb R,a R"c 31-S R'b Rzb R4a Eb Rra R"c I

31-519R'c R2b R4a Eb R,a R"c 31-520R'a Rzc R4a Eb R,a R"c 31-521R'b Rzc R4a Eb R,a R,rc 31-522R'c Rzc R4a Eb R,a R"c 31-523R'a Rza R4b Eb R,a R"c 31-524R'b Rza R4b Eb Rra R"

31-525Ric Rza R4b E,b R,a R"c 31-526Ria Rzi' R4b Eb R,a R"c 31-527Rib Rzb R4b Eb R,a R"c 31-528Ric R2b R4b Eb R,a R"c 31-529Ria Rzc R4b Eb R,a R"c 31-530Rib Rzc R4b Eb R,a R"c 31-53IRic Rzc R4b E,b R,a R"

31-532Ria Rza R4c Eb R,a R"c 31-533Rib Rza R4c Eb R,a R"c 31-534Ric Rza R4c Eb R,a R"c 31-535Ria Rzb R4c Eb R,a R"c 31-536Rib R2b R4c Eb R,a R"c 31-537Ric Rzb R4c Eb R,a R"c 31-538Ria Rzc R4c Eb R,a R"c 31-539Rib Rzc R4c ~,b R,a R"c 31-540Ric Rzc R4c E,b R,a R"c 31-541Ria Rza R4a E,c R,a R"c 31-542Rib Rza R4a Ec R,a R"c 31-543Ric Rza Rda Ec R,a R"c 31-544Ria Rzb R4a Ec R,a R"c 31-545Rib Rzb Rya Ec R,a R"c 31-546Ric Rzb R4a Ec R,a R"c 31-547Ria R2c R4a E,c R,a R"c 31-548Rib Rzc R4a Ec R,a R"

31-549Ric R2c R4a Ec R,a R"c 31-550Ria Rza Rib E,c R,a R"c 31-551Rib Rza R4b Ec R,a R"c 31-552Ric R2a R4b Ec R,a R"c 31-553Ria R2b R4b Eo R,a R"c 31-554Rib R2b R4b Ec R,a R"c 31-555Ric R2b R4b Ec R,a R"c 31-556Ria Rzc R4b E,c R,a R"c 31-557Rib Rzc R4b Ec R,a R"c 31-558Ric Rzc R4b E,c R,a R"c 31-559Ria R2a R4c E,c R,a R"c 31-560Rib Rza R4c B R,a R"c 31-561Ric R2a R4c E,c R,a R"c 31-562Ria Rzb R4c Ec R,a R"c 31-563Rib Rzb R4o E,c R,a R"c 31-564Ric Rzb Rac Ec R,a R"c 31-565Ria Rzc R4c Ec R,a R"c 31-566Rib Rzc R4c E,c R,a R"c 31-567Ric Rzc R4c Ec R,a R"c 31-568Ria Rza R4a Ea R,b R"c 31-569Rib Rza R4a Ea R,b R"c 31-570Ric Rza R4a Ea R,b R"c 31-571Ria Rzb R4a Ea R,b R"c 31-572Rlb Rzb R4a E,a R,b R"c 31-573RIc Rzb R4a Ea R,b R"c 31-574Ria R2c R4a Ea R,b R"c 31-575Rlb R2c R4a E,a R,b R"c 31-576Rlc RZc R4a Ea R,b R,rc 31-577RIa R2a R4b E,a R,b R"c 31-578Rlb R2a R4b Ea R,b R"c 31-579RIc Rza R4b Ea R,b R"c 31-580Rla R2b R4b Ea R,b R"c 31-581Rib R2b R4b E,a R,b R,rc 31-582Rlc RZb R4b Ea R,b R,rc 31-583Rla R2c R4b E,a R,b Rrrc 31-584Rlb RZc Rab Ea R,b Rr,c 31-585Rlc R2c R4b Ea R,b R,rc 31-586Rla R?a R4c Ea R,b R"c 31-587Rib RZa R4c Ea R,b R"c 31-588Rlc Rza Rac Ea Rrb Rr,c 31-589Rla Rzb R4c Ea R,b R"c 31-590Rlb Rzb R4c Ea R,b R"

31-591Rlc RZb R4c Ea R,b R"c 31-592Rya Rzc R4c E,a R,b Rr,c 31-593Rlb R2c R4c Ea R,b R"c 31-594Roc RZc R4c E,a R,b R"c 3I-595Rla R2a R4a Eb R,b R"c 31-596Rlb R2a R4a E,b Rrb R,rc 31-597Rlc R2a R4a E,b R,b Rrrc 31-598Ria R2b R4a Eb R,b R"c 31-599Rib R'b R4a E,b R,b Rr,c 31-600Rlc R2b R4a $b Rrb R"c 31-601Rla R2c R4a Eb R,b R"c 31-602Rlb R2c R4a E,b R,b R"c 31-603Roc R2c R4a Eb R'b R"

31-604Rya RZa R4b Eb R,b R"c 31-605Rlb R2a R4b E,b R,b R"c 31-606Roc R2a R4b Eb R,b R"c 31-607R'a R2b R4b E,b R,b Rrrc 31-608Rlb Rzb R4b Eb R,b R"

31-609Roc RZb R4b Eb R,b R"c 31-610Rya R2c R4b Eb Rrb R,rc 31-611Rib Rzc R4b Eb R,b R"c 31-612Rlc Rzc R4b Eb R,b Rr,c 31-613Rja R2a R4c Eb R,b R"c 31-614Rjb RZa R4c Eb Rrb R"c 31-615Rlc R2a R4c E,b R,b R"c 31-616RIa R2b R4c E,b R,b R"c 31-617Rib RZb R4c Eb R,b Rr,c 31-618Roc RZb R4c Eb R,b R"c 31-619R'a Rzc Rdc Eb R,b R"c 31-620R'b Rzc R4c Eb Rrb R"c 31-621Ric Rzc R4c Eb R'b R"

31-622R'a Rza R4a Ec R,b R,rc 31-623R'b Rza R4a Ec R,b R"c 31-624RIc Rza R4a Ec R,b R"c 3I-625R'a Rzb R4a Ec R,b R"c 31-626R'b R2b R4a Ec Rrb R"c 31-627Rlc Rzb R4a Ec R,b Rr,c 31-628R'a Rzc R4a Ec R,b Rr,c 31-629R'b Rzc R4a E R,b R"c 31-630RIc Rzc R4a Ec R,b Rr,c 31-631R'a Rza R4b Ec R,b R"c 31-632R'b Rza Rab Ec R,b R,rc 31-633R'c Rza R4b Ec R,b R"c 31-634R'a Rzb R4b Ec R,b R,rc 31-635R'b Rzb R4b Ec R'b R"c 31-636RIc Rzb R4b Ec R,b Rrrc 3I-637R'a Rzc R4b Ec R,b Rr,c 31-638R'b Rzc Rab Ec Rrb R"c 31-639R'c Rzc R4b Ec R'b R"c 31-640R'a Rza R4c Ec R,b R"c 31-641R'b Rza R4c Ec R,b R"c 31-642R'c Rza R4c Ec R,b R"c 31-643R'a Rzb R'~c Ec R,b R"c 31-644Rib Rzb R4c Ec R'b R"

31-645R'c Rzb R4c Ec R'b R"

31-646Rta Rzc R4c Ec R'b R"

31-647R'b Rzc R4c Ec R'b R"c 31-648Rlc Rzc R4c E R'b R"c 31-649R'a Rza R4a Ea R,c R"c 31-650R"' Rza R4a Ea R,c R"c 31-651Ric Rza R4a Ea R,c R"c 31-652Ria Rzb R4a Ea R,c R"c 31-653Rib Rzb R4a Ea R,c R"c 31-654R'c Rzb R4a Ea R' Rr'c 31-655R'a Rzc R4a Ea R'c R"c 31-656Rib Rzc R4a Ea R'c Rrrc 31-657R'c Rzc R4a Ea Rrc R"

31-658Ria Rza R4b Ea R,c R"c 31-659R'b Rza R4b Ea R,c R"c 31-660R' Rza R4b Ea R,c R"c 31-661R'a Rzb R4b Ea R' R"c 31-662R'b Rzb R4b Ea Rrc Rrrc 31-663R'c Rzb R4b Ea R,c R"c 31-664R'a Rzc R4b Ea R,c R"c 31-665R'b Rzc R4b Ea Rrc R"c 31-666R'c Rzc R4b Ea R,c R"c 31-667R'a Rza R4c Ea R,c R"c 31-668R'b Rza R''c Ea R'c R"c 31-669R'c Rza R4c Ea R,c R"c 31-670R'a Rzb R4c Ea R,c R"c 31-671R'b Rzb R4o Ea R,c R"c 31-672R'c Rzb R4c Ea R,c R"c 31-673R'a Rzc R4c Ea R,c R"c 31-674R'b R2c R4c Ea R,c R"c 31-675R'c Rzc R4c Ea R,c R"c 31-676R'a Rza R4a Eb R,c R"c 31-677R'b Rza R4a Eb R,c R"c 31-678R'c Rza R4a Eb R,c R"c 31-679R'a Rzb R4a Eb R,c R"c 31-680R'b Rzb R4a Eb R,c R"c 31-681R'c Rzb R4a Eb R,c R"c 31-682R'a Rzc R4a Eb R,c R"c 31-683R'b Rzc R4a Eb R,c R"c 31-684R'c Rzc R4a Eb R,c R"

31-685R'a Rza R4b E.,'' R,c R"c 31-686R"' Rza R4b Eb R,c R"c 31-687R'c Rza R4b Eb R'c R"c 31-688R'a Rzb R4b Eb R,c R"c 31-689R'b Rzb Rab Eb R,c R"c 31-690R'c Rzb Rab Eb R' R"c 31-691R'a Rzc R4b Eb R'c Rr,c 31-692R'b Rzc R4b Eb R,c R"c 31-693R'c Rzc R4b Eb R'c R"

31-694R'a Rza R4c Eb R,c R"c 31-695R'b Rza R4c Eb R,c R"c 31-696R'c Rza R4c Eb R'c R"

31-697R'a Rzb R4c Eb R,c R"c 31-698R'b Rzb R4c Eb R,c R"c 31-699R' Rzb R4c Eb R' R"c 31-700R'a Rzc R4c Eb R,c R"c 31-701R'b Rzc R4c Eb R,c R"

31-702R'c Rzc R4c Eb R,c R"c 31-703R'a Rza R4a Ec R,c R"c 31-704R'b Rza R4a Eo R,o R"c 31-705R'c Rza R4a Ec R,c R"c 31-706R'a Rzb R4a Ec R,c R"c 31-707R'b Rzb R4a Ec R,c R"c 31-708R'c Rzb R4a EC R,' R"c 31-709R'a Rzc R4a Ec R,c R"c 31-710R"' Rzo R4a Ec R,e R"c 31-711R'c Rzc R4a Ec R,c R"c 31-712R'a Rza R4b Ec R,c R"c 31-713R'b Rza R4b Ec R,c R"c 31-714R'c Rza R4b Ec R,c R"c 31-715R'a Rzb R4b Ec R,c R"c 31-716R'b Rib Rab Ec R'c R"

31-717R'c Rz'' R4b Ec R, R"

31-718R'a Rzc R4b Ec R,c R"c 31-719Rlb Rzc R4b Ec R'c R"c 31-720RIc Rzc R4b Ec R'c R"

31-721R'a Rza R4c E,c R,c R"c 31-722Rlb Rza R4c Ec R'c R"c 31-723Rlc Rza Rac Ec R,c Rac 31-724Rla Rzb R''c Ec R,c R"c 31-725R'b Rzb R'~ E R'c R"c 31-726R'c Rzb R4c Ec R,c R"c 31-727Rla Rzc R4c Ec R,c R"c 31-728R'b Rzc R4c Ec R'c R"c 31-729Rlc Rzc R4c E R'c R"c where all symbols are as defined above.
In one aspect of formula (31) of the present invention, Rl and Rz independently are hydrogen, a hydroxy group, a halogen, a vitro 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 allcenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; R4 is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloallcoxy 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, 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 heteroarallcyl group, a heteroaryloxy group, or a heteroaralkoxy group; R' and R" independently are hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an allcyl group, a cycloalkyl group, an alkoxy group, a haloallcoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an allcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; and 2o all other symbols are as defined above in connection with formula (I).

In another aspect of formula (31) of the present invention, RI is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group;
R2 is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an allcoxy group;
R4 is a substituted or unsubstituted aryl group, R' is hydrogen, a halogen, or an alkyl group;
and R" is hydrogen, a halogen, or an alkyl group; and all other symbols are as defined above in connection with formula (I).
In yet another aspect of formula (31) of the present= invention, R' is hydrogen or an allcoxy group; RZ is hydrogen or an alkoxy group; R4 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 still another aspect of formula (31) of the present invention, RI is -H or -OCH3; R2 is -H or -OCH3; R4 is a substituted aryl group, R' is -H, -Cl, -Br, or -CH3;
and R" is -H, -Gl, -Br, or -CH3; and E is O, S, or NH.
The present invention further contemplates various compounds of general formula (III) having the general formula:

R.. O
O~ E ~~ S
O ~/ / ~1 H
R~ Me (32), where all symbols are as defined above in connection with formula (I).
2o According to various aspects the present invention, R4, R', and R" of formula (32) are selected to produce various compounds of formula (32-1) through formula (32-27) as follows:
Formula R'' R' R"

32-1 R4a R'a R"a 32-2 Rb R'a R"~

32-3 R4~ R'a R"a 32-4 R4a R~ Rna 32-5 R4b R'b Ri,a 32-6 R4~ R~b Rna 32-7 R4a R' R"a 32-8 R4b R'~ R"~

32-9 R'~ R'~ R"a 32-10 R4a R'a Rr.b 32-11 R4b R'a R"b 32-12 R4~ R'a R'b 32-13 R4a R'b R'b 32-14 R4b R'b R"b 32-15 R4c R'b Rr'b 32-16 Ra R'c R"b 32-17 R4b R'c Rr'b 32-18 R4~ R'c R"b 32-19 R4a Rra Rr.c 32-20 R4b R~a Rr.c 32-21 R4 R'a R"c 32-22 R4a R'b R"c 32-23 R4b R'b R"c 32-24 R4 R'b R"c 32-25 R4a R' Rr.c 32-26 R4b R'c R.c 32-27 R4~ R' R"

where all symbols are as defined above.
In one aspect of the present invention, R~ is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, or a cycloalkoxy group; R' is hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; R" is hydrogen, a halogen, a vitro group, an amino group, a mono- or di-l0 substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, a thio(S=) group, 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 in connection with formula (I).
In another aspect of the present invention, Rø is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an allcenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an ar~yl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, or an aralkoxy group;
R' is hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; R" is hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an allcoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; and all other symbols are as defined above in connection with formula (I).
In one aspect of the present invention, E is O or -NR; Rø is ~ ~ / optionally N S
substituted with an alkyl group or an alkoxy group, ~ ~ \ , or '~ ~ ~ ; and R' and R?
to are defined as above. Examples of such compounds include, but are not limited to:
OMe O\LNH
W O I Ra R.. O \ O \ I Sl O
F~~~'~O~O ( ~ S NH ~ I OMe I
O ~/ / F O~ I \
R~ Me O . O /
OMe OCH3 O
/ I a ~NH
O \ I S O
O ~~// ~ ~
F O ~ I / /S~ H F
O , O \

S
I
O \ H O \ O O
F I / O I O~N I / / ~ H F I / O I O~\r0 I \ S~ H
/ s > ;
O s F
S ~ ~-NH O \ I
O w S w a O
\ ~O I I
I I F / o~°O \ sue( F / O~O \ O ( / / NH
O I / . o N g O ~ I ~ O ~
O ~ ~ H O
~O W / ~N \
O O I ~ /S NH F O O ~ / / NH
o ;and The present invention still further contemplates various compounds having the general formula:
O Ra ~~O
I O~O ~ S
O I , / NH
O
(33), where R4 is as defined above in connection with formula (I).
In one aspect of formula (33) of the present invention, R4 is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group, an alkyl group, a cycloallcyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group.
1o In another aspect of formula (33) of the present invention, R4 is an acyl group, an acyloxy group, an aryl group, an aryloxy group, amyl 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.
In yet another aspect of formula (33) of the present invention, R4 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 aralkylsu~finyl group, an alkylthio group, an arylthio group, a heteroaryIthio group, an aralkylthio group, a fused 2o heteroarylcycloalkyl group, a fused heteroarylcycloalIcenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof.

In still another aspect of formula (33) of the present invention, R4 is O
SMe O , or . Examples of such compounds include, but are not limited to:
s I
0 0 ~ 0 0 O~° I ~ S~ H I s I O~° I ~ S~ ~
o s i o s i o ; o ; arid The present invention further still contemplates various compounds having the general formula:
(34), where all symbols are as defined above in connection with formula (I).
where R''° and RZ~ independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an allcoxy group, a carboxy group, a cyano group, an oxo(O=) group, a thio(S=) group, an allcyl group, a cycloalkyl group, an allcoxy group, a haloallcoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an allcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an allcylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alleylthio 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 vitro group, an amino group, an allcyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined above.
According to various aspects of the present invention, R, R5, R2°, Rzl, R' and R" of formula (34) are selected to produce various compounds of formula (34-1) through formula (34-729) as follows:
FormulaR RS R' R R' R"

34-1 Ra RSa R a R a R'a R"a 34-2 Rb RSa Rzoa Rz~a R,a R"a 34-3 Rc Rsa Rzoa R2~a R,a R"a 34-4 Ra Rsb R2oa R2~a R,a R"a 34-5 Rb Rsb Rzoa Rzla R,a R"a 34-6 Rc RSU R2oa Rzla R,a R"a 34-7 Ra Rsc R2oa R2la R,a R"a 34-8 Rb R5c Rzoa R2ta R,a R"a 34-9 Rc Rsc R2oa R2la R,a R"a 34-10 Ra Rsa R2ob R2la R,a R"a 34-11 Rb Rsa R2ob R2~a R,a R"a 34-12 Rc Rsa R2ob Rua R,a R"a 34-13 Ra Rsb Rzob Rz~a R,a R"a 34-14 Rb R5b R2ob R2~a R,a R"a 34-15 Rc Rsb Rzob Rzta R,a R"a 34-16 Ra RSc R2ob R2~a R,a R"a 34-17 Rb Rsc R2ob R2la R,a R"a 34-18 Rc R5c Rzob Rz~a R,a R"a 34-19 Ra Rsa Rzoc Rz~a R,a R"a 34-20 Rb Rsa R2oc R2la R,a R"a 34-21 Rc RSa Rzoc R2la R,a R"a 34-22 Ra Rsb R2oc R2la R,a R"a 34-23 Rb Rsb R2oc R2ta R,a R"a 34-24 Rc Rsb R2oc R2ta R,a R"a 34-25 Ra R5c Rzoc Rzla R'a R"a 34-26 Rb Rsc R2oc R2la R,a R"a 34-27 Rc R5c R2oc R2~a R,a R"a 34-28 Ra Rsa R2oa R2lb R,a R"a 34-29 Rb Rsa Rzoa Rz~b R,a R"a 34-30 Rc R5a R2oa R2~b R,a R"a 34-31 Ra RSb R2oa R2l R,a R"a 34-32 Rb Rsb R2oa R21 R,a R"a 34-33 Rc Rsb R2oa R2lb R,a R"a 34-34Ra RSc R2oa R2lb R,a R"a 34-35Rb Rsc R2oa R2lb R,a R"a 34-36Rc RSc Rzoa Rub R,a R"a 34-37Ra Rsa Rzob Rub R,a R"a 34-38Rb Rsa Rzob Rub R,a R"a 34-39Rc Rsa Rzob R2lb R,a R"a 34-40Ra Rsb R2ob R2lb R,a R"a 34-41Rb Rsb Rzob Rub R,a R"a 34-42Rc Rsb Rzob R2lb R,a R"a 34-43Ra Rsc R2ob Rub R,a R"a 34-44Rb RSc Rzob R2lb R,a R"a 34-45Rc R$c R2ob Rub R,a R"a 34-46Ra Rsa Rzoc Rub R,a R"a 34-47Rb Rsa R2oc R2lb R,a R"a 34-48Rc Rsa R2oc Rub R,a R"a 34-49Ra RSb R20c R2lb R,a R"a 34-SORb RSb Rzoc Rzlb R,a R"a 34-51Rc RSb R2oc R2lb R,a R"a 34-52Ra RSc R2oc R2lb R,a R"a 34-53Rb Rsc Rzoc R2lb R,a R"a 34-54Rc R5 R2oc R2lb R,a R"a 34-55Ra Rsa R2oa R2lc R,a R"a 34-56Rb RSa R2oa R2lc R,a R"a 34-57Rc R5a R2oa Ruc R,a R"a 34-58Ra R5b R2oa R2lc R,a R"a 34-59Rb Rsb Rzoa Ruc R,a R"a 34-60R RSb Rzoa Ruc R,a R"a 34-61Ra Rsc R20a Rzlc R,a R"a 34-62Rb RSc R2oa Rzlc R,a R"a 34-63Rc Rsc R2oa Rzlc R,a R"a 34-64Ra Rsa R2ob R2lc R,a R"a 34-65Rb Rsa Rzob R2lc R,a R"a 34-66Rc RSa R2ob Ruc R,a R"a 34-67Ra Rsb R2ob R2lc R,a R"a 34-68Rb Rsb R2ob R2lc R,a R"a 34-69Rc Rsb R2ob Rzlc R,a R"a 34-70Ra RSc R2ob R2lc R,a R"a 34-71Rb Rsc R2ob Ruc R,a R"a 34-72Rc Rsc Rzob Ruc R,a R"a 34-73Ra Rsa R2oc Ruc R,a R"a 34-74Rb Rsa R2oc Ruc R,a R"a 34-75Rc R5a R2oc Ruc R,a R"a 34-76Ra Rsb Rzoc Rzlc R,a R"a 34-77Rb Rsb R2oc Rzlc R,a R"a 34-78Rc Rsb Rzoc Ruc R,a R"a 34-79Ra RSc R2oc R2lc R,a R"a 34-80Rb RSc R2oc R2lc R,a R"a 34-81 Rc Rsc R2oc R2lc R,a R"a 34-82 Ra Rsa Rzoa R2la R,b R"a 34-83 Rb Rsa R2oa R2la R,b R"a 34-84 Rc Rsa R2oa Rzla R,b R"a 34-85 Ra Rsb R2oa R2la R,b R"a 34-86 Rb Rsb R2oa R2la R,b R"a 34-87 Rc Rsb R2oa R2la Rrb R"a 34-88 Ra Rsc R2oa R2la Rrb R"a 34-89 Rb Rsc Rzoa R2la Rrb Rr,a 34-90 R Rsc R2oa R2la R,b R"a 34-91 Ra Rsa R2ob Rua R,b R"a 34-92 Rb Rsa R2ob Rua R,b Rrra 34-93 Rc Rsa R2ob R2la R,b R"a 34-94 Ra Rsb R2ob Rua R,b R,ra 34-95 Rb Rsb R2ob Rua R,b Rr,a 34-96 Rc Rsb R2ob Rua R,b R"a 34-97 Ra Rsc R2ob Rua Rrb R"a 34-98 Rb Rsc R2ob R2la R,b R,ra 34-99 Rc Rsc R2ob Rua R,b R,ra 34-100Ra Rsa R2oc Rzla R,b R"a 34-101Rb Rsa R2oc Rua R,b R"a 34-102Rc Rsa Rzoc R2la R,b R"a 34-103Ra Rsb R2oc Ru R,b R"a a 34-104Rb Rsb Rzoc R2l R,b R"a a 34-105Rc Rsb R2oc Rua R,b R"a 34-106Ra Rsc R2oc Rua R,b R"a 34-107Rb Rsc R2oc Rua R,b R"a 34-108Rc Rsc Rzoc Rua R,b R"a 34-109Ra Rsa Rzoa Rub R,b R"a 34-110Rb Rsa Rzoa R2Ib R,b Rr,a 34-111Rc Rsa Rzoa Rub R,b R"a 34-112Ra Rsb R2oa Rzlb R,b R,ra 34-113Rb Rsb R20a Rub R,b R"a 34-114Rc Rsb R2oa R2lb R,b R"a 34-115Ra Rsc R2oa Rub R,b R"a 34-116Rb Rsc R2oa R2lb R,b R"a 34-117Rc Rsc R2oa R2lb Rrb Rr,a 34-lI8Ra Rsa Rzob R2lb R,b R"a 34-119Rb Rsa R2ob Rzlb R,b R"a 34-120Rc Rsa R2ob R2lb R,b R"a 34-121Ra Rsb R2ob Rub R,b Rr,a 34-122Rb Rsb Rzob Rub R,b R"a 34-123Rc Rsb R2ob Rub R,b R"a 34-124Ra Rsc R2ob Rub R,b R"a 34-125Rb Rsc R2ob Rub R,b R"a 34-126R Rsc Rzob Rzlb R,b R"a 34-127Ra Rsa R2oc R2lb R,b R"a 34-128Rb Rsa R2oc R2lb R,b R"a 34-129Rc RSa R2oc R2lb R,b R"a 34-130Ra RSb Rzoc Rzlb R,b R"a 34-131Rb RSb Rzoc R2lb R,b R"a 34-132Rc Rsb R2oc R2lb R,b R"a 34-133Ra Rsc R2oc Rzlb R,b R"a 34-134Rb RSc R2oc R2lb R,b R"a 34-I35Rc RSc R2oc Rzlb R,b R"a 34-136Ra Rsa R2oa R2sc R,b R"a 34-137Rb Rsa R2oa R2lc R,b R"a 34-138Rc R5a R2oa R2lc R,b R"a 34-139Ra R5b R2oa R2ic R,b R"a 34-140Rb Rsb R2oa R2lc R,b R"a 34-141R RSb Rzoa R2lc R,b R"a 34-142Ra Rsc Rzoa R2lc R,b R"a 34-143Rb Rsc R2oa R2lc R,b R"a 34-144Rc Rsc Rzoa Rzlc R,b R"a 34-145Ra Rsa Rzob Rzlc R,b R"a 34-146Rb RSa Rzob R2lc R,b R"a 34-147R Rsa Rzob R2lc R,b R"a 34-148Ra Rsb Rzob Rzlc R,b R"a 34-149Rb Rsb R2ob R2lc R,b R"a 34-150Rc RSb R2ob R2lc R,b R"a 34-151Ra Rsc R2ob R2lc R,b R"a 34-152Rb RSc R2ob R2lc R,b R"a 34-153Rc Rsc Rzob Rzlc R,b R"a 34-154Ra Rsa R2oc Rzlc R,b R"a 34-155Rb RSa Rzoc Ruc R,b R"a 34-156Rc Rsa R2oc R2lc R,b R"a 34-157Ra RSb R2oc R2lc R,b R"a 34-158Rb Rsb Rzoc R2lc R,b R"a 34-159Rc Rsb R2oc R2lc R,b R"a 34-160Ra RSc R2oc Rzlc R,b R"a 34-161Rb Rsc R2oc Rzlc R,b R"a 34-162Rc RSc R2oc R2l R,b R"a c 34-163Ra Rsa R2oa R2la R,c R"a 34-164Rb RSa Rzoa Rzla R,c R"a 34-I65Rc RSa Rzoa R2la R,c R"a 34-166Ra Rsb R2oa Rzla R,c R"a 34-167Rb RSb Rzoa R2la R,c R"a 34-I68Rc Rsb R2oa Rua R,c R"a 34-169Ra RSc Rzoa R2la R,c R"a 34-170Rb R5c R2oa R2la R,c R"a 34-171Rc Rsc Rzoa R2la R,c R"a 34-I72Ra Rsa R2ob R2la R,c R"a 34-I73Rb RSa R2ob R2la R,c R"a 34-174Rc Rsa R2ob Rzla R,c R"a 34-175Ra RSb R2ob Rua R,c R"a 34-176Rb R5b R2ob Rua R,c R"a 34-177Rc R5b Rzob Rua R,c R"a 34-178Ra Rsc Rzob Rua R,c R"a 34-179Rb Rsc R2ob Rz~a R,c R"a 34-180R RSc R2ob Rzta R,c R"a 34-181Ra RSa R2oc Rzta R,c R"a 34-182Rb Rsa R2oc R2ta R,c R"a 34-183Rc Rsa R2oc Rua R,c R"a 34-184Ra R~' R2oc Rzta R,c R"a 34-185Rb RSb R2oc R2la R,c R"a 34-186Rc Rsb R2oc Rua R,c R"a 34-187Ra RSc Rzoc Rua R,c R"a 34-188Rb Rsc Rzoc Rua R,c R"a 34-189Rc Rsc Rzoc Rua R,c R"a 34-190Ra Rsa R2oa R2lb R,c R"a 34-191Rb Rsa Rzoa Rub R,c R"a 34-192Rc RSa R2oa Rub R,c R"a 34-193Ra Rsb R2oa Rub R,c R"a 34-194Rb Rsb R2oa Rub R,c R"a 34-195Rc Rsb R2oa Rub R,c R"a 34-196Ra Rsc Rzoa Rub R,c R"a 34-197Rb Rsc R2oa R2~b R,c R"a 34-198R RSc Rzoa Rub R,c R"a 34-199Ra RSa Rzob R2lb R,c R"a 34-200Rb Rsa R2ob R2tb R,c R"a 34-201Rc RSa Rzob R2~b R,c R"a 34-202Ra Rsb R2ob Rz~b R,c R"a 34-203Rb R~' R2ob Rub R,c R"a 34-204Rc RSb R2ob Rub R,c R"a 34-205Ra Rsc R2ob R2lb R,c R"a 34-206Rb Rsc Rzob R2lb R,c R"a 34-207Rc Rsc Rzob Rub R,c R"a 34-208Ra RSa R2oc Rub R,c R"a 34-209Rb Rsa R2oo Rub R,c R"a 34-210RC RSa R2oc Rub R,c R"a 34-211Ra Rsb R2oc Rub R,c R"a 34-212Rb Rsb R2oc Rzlb R,c R"a 34-213Rc RSb R2oc R2lb R,c R"a 34-214Ra Rsc R2oc Rub R,c R"a 34-215Rb Rsc R2oc Rub R,c R"a 34-216Rc Rsc Rzoc R2~b R,c R"a 34-217Ra Rsa R2oa R2lc R,c R"a 34-218Rb Rsa Rzoa Ruc R,c R"a 34-219R RSa R2oa Ruc R,c R"a 34-220Ra Rsb R2oa R2lc R,c R"a 34-221Rb RSb R2oa R2lc R,c R"a 34-222Rc Rsb Rzoa R2lc R,c R"a 34-223Ra RSc R2oa R2lc R,c R"a 34-224Rb RSc R2oa Ruc R,c R"a 34-225Rc Rsc Rzoa R2lc R,c R"a 34-226Ra Rsa R2ob Rzlc Rrc R"a 34-227Rb RSa Rzob R2lc Rrc R"a 34-228Rc Rsa Rzob R2lc Rrc Rrra 34-229Ra RSb R2ob R2lc R,c R"a 34-230Rb Rsb R2ob R2lc R,c R"a 34-231Rc RSb R2ob R2lc R,c R,ra 34-232Ra Rsc R2ob R2lc R,c R"a 34-233Rb RSc Rzob R2lc R,c R"a 34-234Rc RSc R2ob Rzlc R,c R"a 34-235Ra Rsa R2oc Rzlc R,c R"a 34-236Rb Rsa Rzoc R2lc R,c R"a 34-237Rc RSa Rzoc Rzlc Rrc Rr,a 34-238Ra Rsb R2oc Rzlc Rrc R,ra 34-239Rb Rsb R2oc Rzlc Rrc Rr,a 34-240Rc Rsb Rzoc R2l R,c R"a c 34-241Ra R5c R2oc R2lc R,c R"a 34-242Rb RSc R2oc Rzlc R,c R"a 34-243Rc Rsc Rzoc R2lc R,c R"a 34-244Ra Rsa R2oa R2la R,a R"b 34-245Rb Rsa Rzoa R2la R,a R"b 34-246Rc Rsa R2oa R2la R,a R"b 34-247Ra Rsb R2oa R2la Rra Rrrb 34-248Rb Rsb Rzoa Rzla Rra Rrrb 34-249Rc Rsb R2oa Rzla R,a Rrrb 34-250Ra RSc Rzoa R2la Rra Rr,b 34-251Rb Rsc R2oa R2la R,a R"b 34-252Rc Rsc R2oa R2la R,a R"b 34-253Ra Rsa R2ob R2la Rra R"b 34-254Rb Rsa Rzob Rzla R,a R"b 34-255Rc Rsa R2ob Rzla R,a Rr,b 34-256Ra RSb R2ob Rzla Rra Rr,b 34-257Rb RSb Rzob R2la R,a R"b 34-258Rc Rsb R2ob Rzla R,a R"b 34-259Ra Rsc Rzob R2la R,a R"b 34-260Rb Rsc R2ob Rzla R,a R"b 34-261Rc RSc R2ob R2la Rra R"b 34-262Ra Rsa R2oc Rzla R,a R"b 34-263Rb Rsa Rzoc R2la R,a R,rb 34-264Rc RSa R2oc Rzla R,a R"b 34-265Ra Rsb Rzoc R2la R,a R"b 34-266Rb Rsb R2oc R2la R,a R"b 34-267Rc Rsb Rzoc Rzla R,a R"b 34-268Ra RSc R2oc Rzla R,a R"b 34-269Rb Rsc R2oc R2la R,a R"b 34-270Rc Rsc R2oc R2~a R,a Rr,b 34-271Ra Rsa Rzoa R2~b Rra Rrrb 34-272Rb Rsa Rzoa R2jb Rra Rrrb 34-273Rc Rsa Rzoa R2lb R,a R"b 34-274Ra Rsb R2oa R2lb R,a R"b 34-275Rb Rsb R2oa R2lb R,a R,rb 34-276Rc Rsb R2oa R2lb R,a Rr,b 34-277Ra Rsc R2oa R2lb R,a R"b 34-278Rb Rsc Rzoa Rz~b R,a R,rb 34-279Rc Rsc Rzoa R2lb R,a Rr,b 34-280Ra Rsa R2ob R2lb R,a R,rb 34-281Rb Rsa Rzob R2lb R,a R"b 34-282Rc Rsa Rzob R2lb R,a Rrrb 34-283Ra Rsb Rzob R2~b R,a R"b 34-284Rb Rsb Rzob Rub R,a R"b 34-285Rc Rsb R2ob Rzib Rra R"b 34-286Ra Rsc R2ob Rzlb R,a R"b 34-287Rb Rsc R2ob Rz~b R,a R"b 34-288Rc Rsc R2ob R2lb R,a R"b 34-289Ra Rsa R2oc R2lb R,a R"b 34-290Rb Rsa Rzoc R2lb R,a Rr,b 34-291Rc Rsa R2oc R2lb R,a R"b 34-292Ra Rsb Rzoc R2lb R,a R,rb 34-293Rb Rsb R2oc R2~b R,a R"b 34-294R Rsb R2oc R2lb R,a R"b 34-295Ra Rsc R2oc Rzlb R,a R"b 34-296Rb Rsc Rzoc Rz~b Rra R"b 34-297Rc Rsc Rzoc R2lb Rra Rr,b 34-298Ra Rsa Rzoa R2lc R,a Rrrb 34-299Rb Rsa Rzoa R2~c Rra Rr,b 34-300R Rsa R2oa R''' R,a Rr,b 34-301Ra Rsb Rzoa R2tc R,a R"b 34-302Rb Rsb R2oa Rzic R,a Rrrb 34-303Rc Rsb R2oa R2~c R,a R"b 34-304Ra Rsc Rzo~ Rzlc R,a R,rb 34-305Rb Rsc R2oa Rzlc R,a Rrrb 34-306Rc Rsc R2oa R2lc R,a R"b 34-307Ra Rsa R2ob R2~c R,a R"b 34-308Rb Rsa R2ob Rz~c R,a Rrrb 34-309Rc Rsa R2ob R2~c R,a R,rb 34-310Ra Rsb R2ob R2lc R,a R"b 34-311Rb Rsb Rzob R2~c R,a R"b 34-312Rc Rsb R2ob R2~c Rra R"b 34-313Ra Rsc Rzob R2n R,a R"b 34-314Rb Rsc Rzob RZic R,a R"b 34-315Rc Rsc Rzob R2ic R,a R"b 34-316Ra R5a R2oc R2lc Rra R"b 34-317Rb Rsa R2oc Rzlc Rra R"b 34-318Rc Rsa R2oc Rzlc R,a R"b 34-319Ra Rsb R2oc Rzlc R,a R"b 34-320Rb R5b R2oc R2lo R,a R"b 34-321Rc Rsb R2oc R2lc R,a R"b 34-322Ra RSc Rzoc R2lc Rra R"b 34-323Rb Rsc Rzoc R2lc R,a R"b 34-324Rc RSc Rzoc R2lc R,a R"b 34-325Ra Rsa R2oa R2la R,b R"b 34-326Rb Rsa Rzoa R2la R,b Rr,b 34-327Rc RSa Rzoa R2la R,b R"b 34-328Ra Rsb R2oa Rua R,b R"b 34-329Rb Rsb R2oa R2la R,b R"b 34-330Rc Rsb R2oa R2la Rrb R"b 34-331Ra RSc Rzoa R2la Rrb R"b 34-332Rb R5c R2oa Rzla R,b R,rb 34-333R R5c R2oa Rzla R,b R"b 34-334Ra Rsa R2ob R2la R,b R"b 34-335Rb Rsa R2ob R2la R,b R,rb 34-336Rc RSa R2ob Rzla R,b R,rb 34-337Ra Rsb Rzob Rzla Rrb R"b 34-338Rb Rsb R2ob R2la R,b R"b 34-339R Rsb Rzob R2la R,b R"b 34-340Ra Rsc R2ob Rua R,b R"b 34-341Rb RSc Rzob Rzla R,b Rrrb 34-342Rc RSc Rzob Rzla R,b R"b 34-343Ra RSa R2oc R2la R,b Rr,b 34-344Rb Rsa Rzoc Rzla R,b R"b 34-345Rc Rsa R2oc R2la R,b R"b 34-346Ra Rsb R2oc Rua R,b R"b 34-347Rb Rsb R2oc Rzla R,b R,rb 34-348Rc RSb R2~c Rzla R,b R"b 34-349Ra Rsc Rzoc R2la R,b R"b 34-350Rb Rsc R2oc Rzla R,b R"b 34-351Rc Rsc R2oc R2la R,b R"b 34-352Ra Rsa R2oa R2lb R,b R"b 34-353Rb Rsa R2oa R2lb Rrb Rr,b 34-354R RSa R2oa Rzlb R,b R"b 34-355Ra RSb R2oa R2lb R,b R"b 34-356Rb RSb R2oa Rzlb R,b R"b 34-357Rc Rsb R2oa R2lb R,b R"b 34-358Ra R5c Rzoa R2lb R,b R"b 34-359Rb Rsc Rzoa R2lb R,b R"b 34-360Rc RSc Rzoa R2lb R,b R"b 34-361Ra RSa R2ob Rzlb Rrb R,rb 34-362Rb R5a Rzob Rub R,b R"b 34-363Rc Rsa R2ob R2~b R,b Rrrb 34-364Ra Rsb R2ob R2lb R,b R"b 34-365Rb R5b Rzob R2~b R,b R"b 34-366Rc Rsb Rzob Rz~b R,b R"b 34-367Ra R5c R2ob R2~b R,b R"b 34-368Rb Rsc R20b R2lb R,b R"b 34-369Rc Rsc R20b R2lb R,b R"b 34-370Ra Rsa Rzoc R2lb Rrb R,rb 34-371Rb Rsa Rzoc R2ib R,b R"b 34-372Rc Rsa Rzoc R2~b R,b R"b 34-373Ra R5b R2oc R2~b R,b R"b 34-374Rb Rsb Rzoc Rz~b R,b R"b 34-375Rc Rsb Rzoc R2lb R,b R"b 34-376Ra Rsc R2oc R2lb Rrb R"b 34-377Rb R5c Rzoc R2lb R,b Rrrb 34-378Rc R5c R2oc R2ib R,b R"b 34-379Ra Rsa R2oa R2tc R,b Rrrb 34-380Rb Rsa R2oa R2lc R,b R"b 34-381Rc Rsa R2oa Rzlc R,b R"b 34-382Ra Rsb Rzoa Ruc R,b R"b 34-383Rb R5b R2oa Rztc R,b R,rb 34-384Rc Rsb R2oa Rzic Rrb R,rb 34-385Ra R5c Rzoa R2m Rrb Rr,b 34-386Rb Rsc R2oa R2lc R,b Rr,b 34-387R Rsc Rzoa Rzic R,b R"b 34-388Ra Rsa RZOb Rzic R,b R"b 34-389Rb Rsa Rzob Rzic R,b R"b 34-390Rc Rsa Rzob R2tc R,b Rr,b 34-391Ra Rsb Rzob R2~c R,b R"b 34-392Rb Rsb R2ob R2lc R,b R"b 34-393Rc R5b Rzob Rzlc R,b R"b 34-394Ra Rsc Rzob Rzlc R,b Rr,b 34-395Rb R5c Rzob Rz~c R,b R"b 34-396Rc R5c Rzob Rzm R,b R"b 34-397Ra R5a Rzoc R2~c R,b R"b 34-398Rb R5a R2oc R2lc R,b R"b 34-399Rc R5a R2oc R2~c R,b R"b 34-400Ra R5b Rzoc R2m R,b Rr,b 34-401Rb R5b Rzoc Rzic R,b R"b 34-402R Rsb R2oc Rzic R,b R"b 34-403Ra Rsc R2oc R2~c R,b Rr,b 34-404Rb Rsc R2oc Rzn R,b R"b 34-405Rc Rsc Rzc Rzm R,b R"b 34-406Ra R5a R2oa Rz~a R,c R"b 34-407Rb Rsa R2oa Rzla R,c R"b 34-408Rc Rsa R2oa Rz~a R,c R"b 34-409Ra R5b Rzoa Rz~a R,c R"b 34-410Rb Rsb Rzoa Rz~a R,c R"b 34-411Rc Rsb Rzoa Rzia R,c R"b 34-422Ra Rsc R2oa R2~a R,c R"b 34-413Rb Rsc R2oa R2la R,c R"b 34-414Rc Rsc R2oa R2~a R,c R"b 34-4I5Ra Rsa Rzob R2la R,c R"b 34-416Rb Rsa Rzob R2ta R,c R"b 34-417R Rsa Rzob R2la R,c R"b 34-418Ra Rsb Rzob R2ta R,c R,rb 34-419Rb Rsb R2ob R2~a R,c R"b 34-420Rc Rsb R2ob R2~a R,c R,rb 34-421Ra Rsc R2ob R2~a Rrc R,rb 34-422Rb Rsc R2ob R2~a R,c R"b 34-423Rc Rsc R2ob R2~a R,c R"b 34-424Ra Rsa R2oc R2la R,c R"b 34-425Rb Rsa R2oc R2la R,c R"b 34-426Rc Rsa Rzoc R2~a R,c R,rb 34-427Ra Rsb R2oc Rzla R,c R"b 34-428Rb Rsb R2oc Rzla R,c R"b 34-429Rc Rsb Rzoc R2~a R,c R"b 34-430Ra Rsc R2oc R2~a R,c R"b 34-431Rb Rsc Rzoc Rzla R,c R"b 34-432Rc Rsc Rzoc Rua R,c R"b 34-433Ra Rsa R2oa Rzib R,c R,rb 34-434Rb Rsa R2oa R2tb Rrc R"b 34-435Rc Rsa R2oa R2~b R,c R"b 34-436Ra Rsb R2oa R2ib R,c R"b 34-437Rb Rsb R2oa R2~b R,c R"b 34-438Rc Rsb R2oa R2~b Rrc R"b 34-439Ra Rsc R2oa R2~b R,c Rr,b 34-440Rb Rsc R2oa Rzlb R,c R"b 34-441Rc Rsc R2oa R2lb R,c R"b 34-442Ra Rsa R2ob R2lb R,c R"b 34-443Rb Rsa R2ob Rzlb R,c R"b 34-444Rc Rsa RZOb R2lb R,c R"b 34-445Ra Rsb Rzob R2ib R,c R"b 34-446Rb Rsb R2ob R2~b R,c R"b 34-447Rc Rsb Rzob R2lb R,c R"b 34-448Ra Rsc Rzob Rz~b R,c R"b 34-449Rb Rsc R20b R2lb R,c R"b 34-450Rc Rsc R20b R2~b R,c R"b 34-451Ra Rsa R2oc Rz~b Rrc R"b 34-452Rb Rsa R2oc R2~b Rrc R"b 34-453R Rsa R2oc R2lb R,c R"b 34-454Ra Rsb R2oc R2~b R,c Rr,b 34-455Rb Rsb Rzoc RZlb R,c R"b 34-456Rc Rsb R2oc Rz~b R,c R"b 34-457Ra RSc R2oc Rzlb R,c Rr,b 34-458Rb R5c Rzoc Rzlb R,c R,rb 34-459Rc Rsc R2oc Rzlb R,c R"b 34-460Ra RSa R2oa R2lc R,c R"b 34-461Rb RSa Rzoa R2lc R,c R"b 34-462Rc Rsa R2oa R2lc R,c Rr,b 34-463Ra RSb R2oa R2lc R,c R"b 34-464Rb RSb R2oa R2lc R,c Rr,b 34-465Rc Rsb R2oa R2lc R,c Rr,b 34-466Ra R5c R2oa Rzlc Rrc R"b 34-467Rb Rsc R2oa R2lc Rrc R"b 34-468Rc RSc R2oa Rzlc Rrc R"b 34-469Ra R5a Rzob R2lc R,c R"b 34-470Rb Rsa Rzob R2lc R,c R"b 34-471Rc RSa R2ob R2lc R,c R"b 34-472Ra Rsb R2ob R2lc R,c R"b 34-473Rb Rsb Rzob R2lc R,c R"b 34-474Rc Rsb Rzob R2sc R,c R"b 34-475Ra R5c Rzob R2lc R,c Rr,b 34-476Rb Rsc R2ob R2lc Rrc R"b 34-477Rc Rsc Rzob R2lc R,c R"b 34-478Ra RSa R2oc R2lc R,c R"b 34-479Rb Rsa R2oc R2lc R,c R"b 34-480Rc RSa R2oc Rzlc R,c R"b 34-481Ra RSb R2oc R2lc R,c R"b 34-482Rb RSb R2oc R2sc R,c R"b 34-483R R5b R2oc Ruc R,c R"b 34-484Ra Rsc Rzoc R2lc R,c Rr,b 34-485Rb Rsc Rzoc Rzlc R,c R"b 34-486R Rsc R2oc Rzlc R,c Rr,b 34-487Ra Rsa R2oa R2la R,a R"c 34-488Rb Rsa R2oa R2la Rra R"c 34-489Rc Rsa R2oa R2la R,a R"c 34-490Ra Rsb R2oa R2la R,a R,rc 34-491Rb RSb R2oa R2la R,a R,rc 34-492Rc RSb Rzoa R2la R,a R"c 34-493Ra RSc R2oa R2la R,a R"c 34-494Rb Rsc R2oa R2la R,a R"c 34-495Rc Rsc R2oa R2la R,a R,rc 34-496Ra Rsa R2ob R2la Rra R"c 34-497Rb Rsa R2ob R2la R,a R"c 34-498Rc Rsa R2ob R2la Rra Rr,c 34-499Ra Rsb R2ob R2la R,a R"c 34-500Rb Rsb R2ob R2la R,a R,rc 34-501Rc RSb R2ob Rzla R,a R"c 34-502Ra Rsc R2ob R2la R,a R,rc 34-503Rb Rsc R2ob Rzla R,a R"c 34-504Rc Rsc R2ob R2la R,a R"c 34-505Ra Rsa R2oc R2la R,a R"c 34-506Rb Rsa R2oc Rua Rra R"c 34-507Rc Rsa R2oc Rua R,a R"c 34-508Ra Rsb R2oc Rua R,a R,rc 34-509Rb Rsb R2oc Rua R,a R,rc 34-510Rc Rsb Rzoc R2la R,a R"c 34-511Ra Rsc Rzoc R2la R,a R"c 34-512Rb Rsc R2oc R2la R,a R,rc 34-513Rc Rsc R2oc R2la R,a R"c 34-514Ra Rsa R2oa R2ib R,a R"c 34-515Rb Rsa R2oa R2lb R,a R"c 34-516Rc Rsa Rzoa Rub R,a R"c 34-517Ra Rsb Rzoa Rub R,a R"c 34-518Rb Rsb Rzoa Rub R,a R"c 34-519R Rsb Rzoa Rub R,a R,rc 34-520Ra Rsc R2oa Rub R,a Rirc 34-521Rb Rsc R2oa Rzlb R,a R"c 34-522Rc Rsc Rzoa R2lb R,a R"c 34-523Ra Rsa R2ob Rzlb R,a R"c 34-524Rb Rsa R2ob R2lb R,a R"c 34-525Rc Rsa Rzob Rub R,a R"c 34-526Ra Rsb Rzob R2lb R,a R"c 34-527Rb Rsb R2ob R2lb R,a Rr,c 34-528Rc Rsb Rzob Rub R,a R"c 34-529Ra Rsc R2ob Rzlb Rra R,rc 34-530Rb Rsc R2ob Rzlb R,a R"c 34-531Rc Rsc R2ob Rub R,a Rr,c 34-532Ra Rsa Rzoc Rub R,a R"c 34-533Rb Rsa Rzoc R2lb R,a R,rc 34-534Rc Rsa R2oc R2lb R,a R,rc 34-535Ra Rsb R2oc Rub R,a R"c 34-536Rb Rsb R2oc Rzib R,a R"c 34-537Rc Rsb R2oc Rzlb R,a R"c 34-538Ra Rsc R2oc Rzlb Rra R"c 34-539Rb Rsc Rzoc R2lb R,a Rr,c 34-540Rc Rsc R2oc Rzlb R,a R"c 34-541Ra Rsa R2oa R2lc R,a R"c 34-542Rb Rsa R2oa R2lc R,a R"c 34-543Rc Rsa R2oa Ruc R,a R"c 34-544Ra Rsb R2oa Ruc R,a R"c 34-545Rb Rsb Rzoa R2lc R,a Rr,c 34-546Rc Rsb R2oa Ruc R,a R"c 34-547Ra Rsc R2oa Ruc R,a Rr,c 34-548Rb Rsc R2oa R2lc R,a R"c 34-549Rc Rsc R2oa Ruc Rra R"c 34-550Ra Rsa Rzob R2lc R,a R"c 34-551Rb Rsa R2ob R2lc R,a R,rc 34-552Rc Rsa R2ob R,2m R,a R"c 34-553Ra Rsb R2ob R2~c R,a R"c 34-554Rb Rsb Rzob R2~c R,a Rrrc 34-555Rc Rsb R2ob R2tc R,a R"c 34-556Ra Rsc R2ob Ruc R,a Rrrc 34-557Rb Rsc R2ob R2~c R,a R"c 34-558R Rsc R2ob R2~o R,a R"c 34-559Ra Rsa R2oc Rzlc R,a R"c 34-560Rb Rsa Rzoc R2lc R,a Rr,c 34-561Rc Rsa Rzoc R2lc R,a R"c 34-562Ra Rsb R2oc R2tc R,a R"c 34-563Rb Rsb R2oc R2lc R,a R"c 34-564Rc Rsb Rzoc Ruc R,a R"c 34-565Ra Rsc Rzoc R2~c R,a R"c 34-566Rb Rsc R2oc R2m R,a R"c 34-567Rc Rsc R2oc Rz~c R,a R"c 34-568Ra R5a R2oa R2~a R,b R"c 34-569Rb Rsa Rzoa R2~a R,b R"c 34-570R Rsa R2oa Rzla R,b R"c 34-571Ra Rsb Rzoa R2la R,b R"c 34-572Rb Rsb R2oa R2la R,b R,rc 34-573Rc R5b R2oa R2~a R,b R"c 34-574Ra Rsc R2oa R2~a R,b R"c 34-575Rb Rsc R2oa Rz~a R,b R"c 34-576Rc Rsc R2oa R2la R,b R"c 34-577Ra Rsa R2ob R,2~a R,b R"c 34-578Rb Rsa Rzob R2ta R,b R"c 34-579Rc Rsa R2ob R2~a R,b R"c 34-580Ra Rsb Rzob R2la R,b R"c 34-581Rb R5b R2ob Rz~a R,b R"c 34-582Rc Rsb R2ob Rz~a R,b R"c 34-583Ra Rsc R2ob R2la R,b R"c 34-584Rb Rsc R2ob Rz~a R,b R"c 34-585Rc Rsc Rzob R2~a R,b R"c 34-586Ra Rsa R2oc R2ta R,b R"c 34-587Rb Rsa R2oc R2~a R,b R"c 34-588Rc Rsa R2oc R2~a R,b R"c 34-589Ra Rsb R2oc Rz~a R,b R"c 34-590Rb Rsb R2oc R2~a R,b R"c 34-591Rc Rsb Rzoc R2la R,b R"c 34-592Ra Rsc R2oc R2~a R,b R"c 34-593Rb Rsc R2oc R2~a R,b R,rc 34-594Rc Rsc R2oc R2~a R,b R"c 34-595Ra Rsa R2oa Rz~b Rrb R"c 34-596Rb Rsa Rzoa R2lb R,b R"c 34-597Rc Rsa R2oa R2~b R,b Rr,c 34-598Ra Rsb Rzoa R2~b R,b R,rc 34-599Rb Rsb R2oa Rub R,b R,rc 34-600Rc Rsb Rzoa Rub R,b Rr,c 34-601Ra Rsc Rzoa R2lb R,b R"c 34-602Rb Rsc R2oa Rub R,b R"c 34-603Rc Rsc R2oa Rub R,b R"c 34-604Ra Rsa Rzob Rub R,b R"c 34-605Rb Rsa Rzob Rub R,b R"c 34-606Rc Rsa R2ob Rub R,b Rr,c 34-607Ra Rsb R2ob Rub Rrb Rr,c 34-608Rb Rsb R2ob R2lb Rrb R"c 34-609Rc Rsb R2ob Rub R,b R"c 34-610Ra Rsc R2ob R2lb R,b R"c 34-611Rb Rsc Rzob Rz~b R,b R"c 34-612Rc Rsc Rzob Rzib R,b R"c 34-6I3Ra Rsa R2oc Rub R,b R"c 34-614Rb Rsa Rzoc R2lb R,b R"c 34-615Rc Rsa R2oc Rub Rrb Rr,c 34-616Ra Rsb Rzoc Rub Rrb R"c 34-617Rb Rsb Rzoc R2lb R,b R"c 34-618Rc Rsb Rzoc Rub R,b R"c 34-619Ra Rsc R2oc Rub R,b R"c 34-620Rb Rsc Rzoc R2Ib R,b R"c 34-621Rc Rsc R2c Rz~b R,b R"c 34-622Ra Rsa R2oa Rz~c Rrb R"c 34-623Rb Rsa Rzoa R2lc Rrb R"c 34-624Rc Rsa Rzoa R2~c R,b Rr,c 34-625Ra Rsb R2oa R2~o R,b R,rc 34-626Rb Rsb Rzoa Rzic R,b R"c 34-627Rc Rsb Rzoa Ruc R,b R"c 34-628Ra RSc Rzoa Ruc R,b R,rc 34-629Rb Rs Rzoa R2~c R,b R"c 34-630Rc RsC R2oa Ruc R,b R"c 34-631Ra Rsa Rzob R2lc R,b R"c 34-632Rb Rsa Rzob R2lc R,b R"c 34-633Rc Rsa R2ob Rzlc R,b R"c 34-634Ra Rsb Rzob Ruc R,b R"c 34-635Rb Rsb R2ob Ruc R,b Rr,c 34-636Rc Rsb R20b R2lc R,b R"c 34-637Ra Rsc R2ob Ruc R,b R"c 34-638Rb Rsc R20b Rzlc R,b R"c 34-639Rc Rsc Rzob Rzm R,b R"c 34-640Ra Rsa Rzoc Ruc R,b R"c 34-641Rb Rsa R2oc Rzic R,b R"c 34-642Rc Rsa Rzoc Ru R,b R"c c 34-643Ra Rsb R2oc R2lc R,b Rr,c 34-644Rb Rsb R2oc Ruc R,b R"c 34-645Rc Rsb R2oc R2lc R,b R"

34-646Ra R5c R2oc R2lc R,b R"c 34-647Rb Rsc Rzoc Rzlc R,b R"c 34-648R Rsc Rzoc Rzlc R'b R"c 34-649Ra Rsa R2oa Rzla R,c R"c 34-650Rb Rsa R2oa R2la R,c R"c 34-65IRc Rsa R20a R2la Rrc Rrrc 34-652Ra Rsb R2oa R2la Rrc R,rc 34-653Rb Rsb Rzoa R2la R,c R'rc 34-654R Rsb R2oa R2la R,c R"c 34-655Ra Rsc R2oa R2la R~c R"c 34-656Rb Rsc R2oa R2la R,c R,rc 34-657Rc R$c R2oa Rzla R,c R"c 34-6~8Ra Rsa R2ob Rzla R,c R"c 34-659Rb Rsa R2ob R2la Rrc Rrrc 34-660Rc Rsa R2ob Rzla R,c R"c 34-661Ra Rsb R2ob R2la R,c R"c 34-662Rb Rsb R2ob R2la R,c R,rc 34-663R Rsb R2ob R2la R,c R"c 34-664Ra Rsc Rzob R2la Rn R"c 34-665Rb Rsc R2ob Rua Rrc Rr,c 34-666Rc Rsc R2ob Rzla R'c R'rc 34-667Ra Rsa Rzoc R2la R,c R"c 34-668Rb Rsa R2oc R2la R,c R"c 34-669Rc Rsa Rzoc Rzla Rrc Rr,c 34-670Ra Rsb R2oc Rzla Rrc R"c 34-671Rb Rsb R2oc Rzla R,c R"c 34-672Rc Rsb R2oc R2la R,c R"c 34-673Ra R5c R2oc Rua R,c R"c 34-674Rb R5c R2oc R2la R,c R"c 34-675R Rsc Rzoc R2la R,c R"c 34-676Ra Rsa R2oa Rzlb R,c R"

34-677Rb Rsa R2oa R2lb R,c Rr,c 34-678Rc Rsa Rzoa Rzlb R'c Rr,c 34-679Ra Rsb R2oa R2lb R,c R"c 34-680Rb Rsb R2oa R2lb R,c R"c 34-681Rc Rsb R2oa R2lb R,c R"c 34-682Ra Rsc R2oa R2lb Rrc R,rc 34-683Rb Rsc R2oa R2lb R,c R"c 34-684R Rsc R2oa R2lb R,c R,rc 34-685Ra Rsa R2ob R2lb R,c R"c 34-686Rb Rsa Rzob R2lb R,c R"c 34-687Rc RSa R2~b Rub R,c R"c 34-688Ra Rsb R2ob Rzlb Rrc R"c 34-689Rb Rsb R2ob R2lb R,c R"c 34-690Rc Rsb Rzob R2lb R,c R"c 34-691Ra Rsc R2ob Rzlb R'c Rr,c 34-692Rb R5c Rzob R2~b R,c R"c 34-693Rc Rsc R2ob R2~b R,c R"c 34-694Ra R5a R2oc Rz~b R,c R"c 34-695Rb Rsa Rzoc Rz~b R,c R"c 34-696Rc Rsa Rzoc Rub R,c R"c 34-697Ra R5b R2oc Rzlb R,c R"c 34-698Rb R5b R2oc Rz~b R,c R"c 34-699Rc R5b R2oc Rzib R,c R"c 34-700Ra Rsc R2oc R2~b R,c R"c 34-701Rb Rsc Rzc Rzib R,c R"c 34-702Rc Rsc Rzc R2~b R, R"

34-703Ra R5a Rzoa R2n R,c R"c 34-704Rb Rsa R2oa R2~c R,c R"c 34-705Rc R5a R2oa R2lc R,c R"c 34-706Ra R5b Rzoa R2lc R,c R"c 34-707Rb Rsb R2oa R2m R,c R"c 34-708R R5b R2oa R2~c R,c R"c 34-709Ra R5c R2oa R2lc R,c R"c 34-710Rb R5c Rzoa R2~c R,c R"c 34-711Rc R5c Rzoa Rztc R,c R"c 34-712Ra Rsa R2ob Ruc R,c R"c 34-713Rb Rsa R2ob R2lc R,c R"c 34-714R Rsa R2ob R2lc R,c R"c 34-715Ra R5b Rzob R2m R,c R"c 34-716Rb R5b R2ob Rzm R,c R"

34-717Rc R5b Rzob R2lc R,c R"c 34-718Ra Rsc Rzob Rz~c R,c R"c 34-719Rb Rsc Rzob Ruc Rrc R"

34-720R R5c Rzob Rz~c R,c R"c 34-721Ra Rsa Rzoc R2lc R,c R"c 34-722Rb R5a R2oc R2lc R,c R"c 34-723Rc R5a Rzoc Rz~c R,c R"c 34-724Ra Rsb Rzoc R2lc R,o R"c 34-725Rb Rsb Rzoc Rzo R,c R"c 34-726Rc R5b R2oc R2lc R,c R"c 34-727Ra R5c R2oc R2lc R,c R"c 34-728Rb Rsc Rzoc R2ic R,c R"c 34-729Rc Rsc R2c Rzm R, R"c where all 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, or 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 vitro 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(O=) group, a thio(S=) group; an alkyl group, a cycloallcyl group, an allcoxy group, a haloalkoxy group, a cycloallcyl group, an aryl group, or a benzyloxy group; and RZ° and R21 independently are hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group; an alkyl group, a cycloallcyl 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.
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? independently are hydrogen or a halogen;
RZ° is hydrogen or a halogen; and R2' is hydrogen or a halogen.
In yet another aspect of formula (34) of the present invention, R is -H, CH3, or CHZCH3; R5 is -H or CH3; R' and R? independently are -H, -F, or -Cl;
RZ° is -H, -F, -Cl, or -Br; and R21 is -H, CH3, or -F. Exemplary compounds include, but are not limited to:

S o HaC S
° / I \ ~° / \
° NH /
N o N W Hsc / \
CH3 I i F ~ CH3 o i ~ S ° i ~ ~ S'~°
0 ~
o W I ,~NH I w I °~o ~ o/'NH
N I F o / N ~ CI
CH ( ~ CH3 F ~ F
S o ( o/~NH I ~ I oho I / N w F
N

3 CI _ F

S S
o / I w ~ o / I w I oho ~ o NH I ~ I °~o ~ o NH
/ N W / N ~ F
I / F . CH3 I / F .
> >
o S
~o o / I ~ S

I o I °~H ~ NH ~ °~ ~ NH
o I I o 0 / N I ~ / N I ~ F F
CH3 s F . CH3 / F
Me O o ~ S Ne ~ I
O
O~O ~ I O NH I / I O O
I I O ~ I / /S~ H
N

F ~ O
O O~ ~ I \ NH O NH O
I I O O
N
CH3 I / Br Me O O I
I ~O I I I ~O S O
N I W O S O I / / ~ H
HsC ~F HN--H3~ \\o; and o The present invention also contemplates various compounds having the general formula:
R
R~' (35), 1o where all symbols are as defined above in connection with formula (I).
~7 where Rz° and Rz' 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy s group, an acyl group, an acyloxy group, an amyl 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 aryltl>so group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and R' is defined above.
According to some variations of the present invention, R', Rz°, and Rz' of formula (35) are selected to produce various compounds of fornmla (35-1) to formula (35-27) as follows:
Formula R Rz R ' 35-1 R'a R' a R'a 35-2 R"' Rzoa R2la 35-3 jtl~ Rzoa R2~a 35-4 Rla R2ob Rzia 35-5 R'b Rzob Rzta 35-6 Rl~ Rzob Rz~a 35-7 Rla Rzoc R2~a 35-8 Rlb Rzoc Rua 35-9 RI R2oo R2la 35-10 RIa R2oa R2lb 35-11 R'b Rza R2~b 35-12 Rl Rzoa R2~b 35-13 Rya Rzob Rz~b 35-14 Rib Rzb Rz~b 35-15 R'~ Rzb Rzlb 35-16 R'a Rz 8216 35-17 Rlb Rz Rzib 35-18 R'~ Rz~ Rz'b 35-19 R'a Rzoa RZ' 35-20 R"' Rza Rz' 35-21 R'~ Rzoa Rzlc 35-22 Rya RZOb R2'°
35-23 Rlb Rzob RZ>c 35-24 Roc R20b R2lc 35-25 Rla R2oc R2n 35-26 Rlb Rzoc Rzm 35-27 Rlc R2°c R2m where all symbols are as defined above.
In one aspect of formula (35) of the present invention, R' is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an allcoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; RZ° is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group; and RZ' is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group.
In another aspect of formula (35) of of the present invention, R' is a halogen, R2o is hydrogen or a halogen, and R''I is hydrogen or a halogen.
In yet another aspect of of formula (35) of the present invention, R' is Cl or F, RZ° is -H or -F, and R2' is -F.
Exemplary compounds of formula (35) include, but are not limited to:
CHg / F
F \ N \_ o ~~O
I \ I oho \ I o NH I / I O~O I \ S~ H
CI a tJ I ~ C
CH3 / F ; CHg C
/ \ S
S o I o o / I \ ~o F \ °w/\o \ o NH
I \ I °~o \ o NH I ~- N I \ Cl F N ~ F CH I
CH3 I a F . 3 F F

o S ° / I ~ S~o o~° ~ I ° NH I \ ' °~° ~ ° NH
CI / N I a F . CI / N I y F CI

> >
/ I ~ S~o F I ~ I °~° ~ ° NH
/ N w and F
The present invention further contemplates various compounds having the general formula:
(36), where all symbols are as defined above in connection with 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) through formula (36-81) as follows:
Formula R R" R' R" Formula R R R' R"

36-1 Ra R"a R'a R"a 36-42 R R R' R"

36-2 Rb R4a R'a R"a 36-43 Ra R4 Rib Rrrb 36-3 R~ R4a R'a R"a 36-44 Rb R4~ R'b Rrrb 36-4 Ra R4b R'a R"a 36-45 R~ R~ R'b Rrrb 36-5 Rb R4b R'a R"a 36-46 Ra R4a R' R"b 36-6 R R4b R'a R"a 36-47 Rb R4a R' R"b 36-7 Ra R4 R'a R"a 36-48 R~ R4a R' R"b 36-8 Rb R4~ R'a R"a 36-49 Ra R4b R'~ R.b 36-9 R~ R4~ R'a R"a 36-50 Rb R4b R'~ R"b 36-10 Ra R4a R'b R"a 36-51 R R4b R'~ Rrrb 36-11 Rb R4a Rrb Rna 36-52 Ra R4~ R' Rnb 36-12 R R4a R'b R"a 36-53 RU R4 R'~ R"b 36-13 Ra R'~bRrb Rrra 36-54 R R4~ R'o R~rb 36-14 Rb R4b Rrb Rrra 36-55 R~ R4a R'a R"~

36-15 Ro R4b R'b R"a 36-56 Rb R4a R'~ R"

36-16 Ra R4 R'b R"a 36-57 R R4a R'a R"~

36-17Rb R4c R'b Rr'a 36-58 Ra R4b R'a R"

36-18Rc R4c R'b R"a 36-59 Rb R4b R'a R"c 36-19Ra R4a R'c R"a 36-60 Rc R'~bR'a R"c 36-20Rb R4a R'c Rna 36-61 Ra R4c R'a R~~c 36-21Rc R4a R'c R"a 36-62 Rb R4c R'a R"c 36-22Ra R4b R'c R"a 36-63 Rc R4c R'a R"c 36-23Rb R4b R'c R"a 36-64 Ra Rya R'b R"c 36-24Rc R4b R'c R"a 36-65 Rb R4a R'b R"c 36-25Ra R4c R'c R"a 36-66 R R4a R'b R"c 36-26Rb R4c R'c R"a 36-67 Ra Rib R'b R"c 36-27Rc R4c R'c R"a 36-68 Rb Rib R'b R"c 36-28Ra R4a R'a Rib 36-69 Rc R4b R'b R'~c 36-29Rb R4a R'a R"b 36-70 Ra R4c R'b R"c 36-30Rc R4a Rra R~rb 36-71 Rb R4c R'b R"c 36-31Ra R4b R'a R"b 36-72 Rc R4c Rrb Rirc 36-32Rb R4b R'a R"b 36-73 Ra R4a R'c R"c 36-33Rc R4b R'a R"b 36-74 Rb R4a R'c R"c 36-34Ra R4c R'a R"b 36-75 Rc R4a R'c R"c 36-35Rb R4c R'a R"b 36-76 Ra R4b R'c R"c 36-36R R4c R'a R"b 36-77 Rb R4b R'c R"c 36-37Ra R4a R'b R"b 36-78 R R4b R'c R"

36-38Rb R4a R'b R"b 36-79 Ra R4c Rc R"c 36-39Rc R4a R'b R"b 36-80 Rb R4c Rc Rr'c 36-40Ra R4b R'b Rb 36_81 Rc R4c Rc R"c 36-41Rb R4b R'b R"b where all symbols are as defined above.
In one aspect of formula (36) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an allcoxy group, an alkenyl group, or an alkoxyalkyl group; R4 is an alkenyl group, a cycloallcenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, an aryloxy group, an amyl group, an aroyloxy group, an arallcyl group, an aralkenyl group, an arallc~myl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a to heteroaryloxy group, or a heteroaralkoxy group; and R' and R" independently are hydrogen, a halogen, a vitro group, an amino group, a mono- or di- substituted amino group; a hydroxy group, an allcoxy group, a carboxy group, a cyano group, an oxo(O=) group, a thio(S=) group; an alkyl group, a cycloalkyl group, an allcoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group.

In another aspect of formula (36) of the present invention, R is hydrogen or an alkyl group; R4 is a cycloalkenyl 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 arallcynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and R' and R" independently are hydrogen or a halogen.
In yet another aspect of formula (36) of the present invention, R is -H or CH3; R4 is a halogen substituted aryl group; and R' and R" independently are -H or -Cl; and alI other symbols are as defined above in connection with formula (I).
Examples of compounds of formula (36) include, but are not limited to:
°
I ~ I ono I ~
N
CH3 I , I
o S
HN-o~
> >
O

N ~ ~ o NH
and CH3 ( / F
The present invention also contemplates various compounds having the general formula:
O H
I \ ~ O~N ~ \

O S
HN-i s O (37), where all symbols are as defined above in connection with formula (I).
According to some variations of the present invention, E, R', and R4 of formula (37) are selected to produce compounds of formula (37-1) through formula (37-27):
Formula E R' R'' 37-1 Ea R a R a 37-2 Eb Ria R4a 37-3 E~ R~ a R4a 37-4 Ea R R''a 37-5 Eb RIb R4a 37-6 Ec Rjb Rya 37-7 Ea Rlc Rya 37-8 Eb Roc R4a 37-9 E Ric R4a 37-10 Ea Rya R4b 37-11 Eb Ria R4b 37-12 Ec Ria R4b 37-13 Ea Rib R4b 37-14 Eb Rib R4b 37-15 Ec Rjb R4b 37-16 Ea RIc R4b 37-17 Eb R~ R4b 37-18 Ec Roc R4b 37-19 Ea Rya R4 37-20 Eb Rla R4c 37-21 Ec Rya R4c 37-22 Ea Rib R4c 37-23 Eb Rlb R4c 37-24 E RIb R4c 37-25 Ea Rlc R4c 37-26 Eb Roc R4c 37-27 Ec Roc Rac where all symbols are as defined above.
In one aspect of formula (37) of the present invention, Rl 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, or a cycloalkenyloxy group; R4 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 amyl group, an aroyloxy group, an aralkyl group, an aralkenyl i0 group, an arallcynyl group, an arallcoxy 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 connection with formula (I).
In another aspect of formula (37) of the present invention, R' is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, or an alkyl group; R4 is a cycloallcenyl 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 arallcenyl group, an arallcynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroarallcoxy group; and all other symbols are as defined above in connection with formula (I).
In yet another aspect of formula (37) of the present invention, R' is hydrogen, a halogen, or an alkoxy group; R4 is a cycloalkenyl 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 connection with formula (I).
In still another aspect of formula (37) of the present invention, R' is hydrogen, a R~~
halogen, or an allcoxy group; E is ~ or -NR; and R4 is ~R23 or ~ ~ , where Rzz and R23 independently are hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloallcyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an amyl 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 vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined above in connection with formula (I).
In still another aspect of formula (37) of the present invention, R' is hydrogen or a halogen; E is O or NMe; R4 is a substituted aryl group or a heterocycyl group;
R22 is hydrogen or an alkoxy group; R22 is hydrogen or an alkoxy group; and all other symbols are as defined above in connection with formula (I).
In yet a further aspect of formula (37) of the present invention, Rl is -H, -F, or MeO;

S
E is O or NMe; R4 is ~RZ3 or ~ ~ , where R2z is -H or OMe; and R23 is -F or OMe.
An exemplary compound includes, but is not limited to:
OMe Me0 ~ O ~ I OMe O
O ~ S NH
OMe O
O
According to another aspect of the present invention, various compounds of general formula (I) having general formula (IV) Y~
Ew R4 F~NR
~-G-z_ArY~ I
( ~?

its tautomeric forms, its stereoisomers, its polymorphs, its pharnaceutically acceptable salts, and its pharmaceutically acceptable solvates are provided. Except as otherwise provided herein, all symbols are as defined above in connection with formula (I).
A multitude of compounds having the general formula (IV) are contemplated by the present invention. Examples of such compounds include, but are not limited to:
Y1 v1 D~~ 11 CYR4 F NR Due/ SYR F NR
~~-R~K-G---Z-Ar~Y2 ~~-RZI K-G---Z-ArY2 (38);

D~R1 N~ R4 F~NR R E R4 F~NR

K G--__Z-Ar YZ ~~.i K-G---Z-Ar Y~
R Rs R2 Rs (40); X (41);

Y~ Y1 S~R1I EYR4 F~NR NCR I EYR4 F~NR
y_R~K-G-Z-Ar~y~ ~~_I~K' -G-Z-Ar--~y ~
R5 (42); R~ IXI RS (43)~
y~
R
R E\ Ra F~NR ~' EYRa F NR
HC~J-~~~ _Z-Arv~Y2 DC- K-G-Z-Ar yz Rz R5 (44); RZ ~ R5 (45)~
Y~ Y~
R~ R~ //
E~ R4 F NR ' E~ Ra F~NR
~S_~~K G_-_Z-Ar yZ ~N.I~f~~--G_-_Z-Ar yz R X RS (46); R2 X R5 (47)~
Y~ Y~
D~I1I EYR4 F NR D~I1I E~Ra F~NR
C. II K-G_Z_Ar~Y2 C.~K-G-Z_Ar~Yz H~ R5 H ~ R5 R~ ~ (48); RZ X (49)~
Y~ Y~
D~''I EYRa F~NR D~I,I EYRa F~NR
~~_~K' - G (CH2)u'Ar~Y2 ~~-I~KI - G-'-S(=O)~ Ar-~y2 R ~X R (SO); R~ ICI R (Sl)i Y' R EYRa F~NR
oG/~ I~
~~ R~ K-(CHZ)5-Z-Ar--~yZ
R (52)~
Y~
1 EYR4 F~NR
2I K-(CH2)s CH=CH-(CH~)s Ar--'~yZ
(S3);
Y~
1 E~ R4 F~NR
~CH2)s C =C-(CH2)S'-Ar~Yz R I R
(54);

R1 4 ~1 R1 4 ~i E~R
I EYR ~NR p~I' ~ ' ,NR
~0-~K-G=Z-Ar Yz ~~-I~K-G=Z-Ar~~'~Yz R IOI R5 (55); Rz ISI R5 ~I EYR4 ~F NR ~~~j E~R4 O~NR
~J_~K-G=Z-Ar-C' "Yz Oy-I~K-G=z-Ar-~YZ
R [S~ ~R5 (S7); Rz jXj R5 (5g);

RN NR
p,; ~ I E~R4 S NR D~; I I Ew R
vJ-I~ K-G=Z-Ar-~Yz ~J-I~ K G=Z-Ar~Yz R f~I RS (59); R X R5 (60);
O S
1 EYR4 F~NR pTI1 E~R4 F~NR
vJ-I II K-G=Z_Ar~Yz vJ-I II K-G-Z_Ar~Y2 R X R5 (61); RZ X RS

E\ R F NR DPI I EYR4 F~NR
~J-I~K G=Z-Ar~O vJ-~K-G=Z-Ar \ S
RZ X R5 (63); Rz X R5 (64);

1 /' E~R4 ~F~NR ~I E~ R4 F~NR
~J-~~ N G=Z-Ar--C' "Yz O~~-I I N (CHz)s-Z-Ar~Yz Rz ERs R~ Rs (65);

D~I1I EYR4 F NR OTI I E R F~NR
~-~N-(CHz)s O-Ar~Yz ~-~N-(CHz)s-S-Ar~Yz R ~X RS (67); Rz IX' SRS (6g);
yi O
I EYR4 R ~F~(NR p~I 1I E~R4 ~F~NR
~~-I~N-(CHz)s-N-Ar~yz ~~-~N-(CHz)s-O-Ar-C' "O
R X ~R5 (69); Rz IoI ~R5 DPI i~ E~R4 F NR D/i I 1I EYRQ R F~NR
~J-~N-(CHz)s S-Ar~ ~J-~N-(CHz)s N-Ar~O
II IIO
R X RS (71); Rz O R5 E R O
~I EYR ~NR p~I I Y 1 ,NR
~~-I~ IN-(CHz)s O-Ar~ \\O ~~-~N-(CHz)s S-Ar R ~O R5 (73); Rz X R5 O O
R~ //
i ~I YR R O NR p~I ~I EYRq S~NR
~~-I~N-(CHz)s-N-Ar~O y_~N-(CHz)s-0-Ar-~O
R ~o R5 (75); RZ [~~ RS

D RI ( EYR S NR ~I ~ EYR R S~NR
~~-~N-(CHz)s S-Ar~O ~~-I~N-(CHz)s N-Ar~O
R X RS (77); Rz O R5 (7g);
R, 4 R, q TI EYR \ ,NR ~~ EYR ~t'~R
D~~-I~N- (CHz)z Z-Ar~Yz D~~-I~ IN- (CHz)z O-Ar O
R 'XI R5 (79); Rz ~ R5 (g~);
O
R~ O
4 /, Ew R O NR R E Rq O~NR
,~I '~'~ Y R
~~~~N-(CHz)2 S-Ar~O Oy-I~N-(CHz)z N-Ar~O
~x R5 (81), RZ ~X R5 (8a)~
JO/ /O/
O R~I E~Rq ~S~(NR p~I~1j E~Rq S~NR
~~-~N-(CHz)z-O-Ar~O ~~-I~N-(CHz)z S-Ar~O
R (X~ R5 (g3); Rz (X~ R5 (g4);
~e1 Due! 1' E~ Rq S~NR ~' EYRq F~NR
~~-~N (CHz)z N-Ar~O D~~-I~'N-(CHz)s Z-Ar~Yz RZ ~X( R5 (85); and R2 X R5 (86), where all symbols are as defined above in connection with formula (I).
Thus, for example, the present invention encompasses various compounds of general to compound (IV) having the formula:
R~
N~ R4 N' N G=
N
R O
(8~)~

where all symbols are as defined above in connection with formula (I). It should be understood that while various configurations are provided herein, other configurations are contemplated by the present invention. Thus, compounds having the general formula:

R~ S~NR R~ G
N R4 ~' NYR4 S~NR
/ a _ 5 O / _ N'N I N G=Z \ ~ R N'N I N-G=Z
R
R ~ (gg); R

N\ R4 R N\ Ra ~ N'N ~ N c-z \ /
r _ ~( N'N ( N G=Z \ ~ S~NR R O Rs ~, O a ~O
R R5 ~ (90); ~ R (91);
R
O~N O

N~R4 NN~N G-Z \
and R O (92);
where all symbols are as defined above in connection with formula (I), are also contemplated hereby.
According to some variations of the present invention, R, R', R~ , G, and Z of formulae (88), (89), (90), (91), (92) are selected to produce compounds of formulae (88-1), (89-1), (90-1), (91-1), and (92-1) through formulae (88-729), (89-729), (90-729), (91-729), and (92-729) as follows:
Formulae R R R R5 G 2 88-1 89-1 90-1 91-192-1 Ra R R''aR Ga Za a a 88-2 89-2 90-2 91-292-2 Rb Rla R4a Rsa Ga ~a 88-3 89-3 90-3 91-392-3 R~ Rla R4a R5a Ga za 88-4 89-4 90-4 91-492-4 Ra Rib R4a Rsa Ga za 88-5 89-5 90-5 91-592-5 Rb Rlb R4a R5a Ga ~a 88-6 89-6 90-6 91-692-6 R~ Rib R4a RSa Ga Za 88-7 89-7 90-7 91-792-7 Ra RI~ R4a R5a Ga Za 88-8 89-8 90-8 91-892-8 Rb RI R4a R5a Ga Za 88-9 89-9 90-9 91-992-9 R~ R~~ R4a Rsa Ga Za 88-1089-10 90-10 91-10 92-10 Ra Ria R4b Rsa Ga Za 88-1189-11 90-11 91-11 92-11 Rb Ria R4b Rsa Ga Za 88-1289-12 90-12 91-12 92-12 Rc Ria R4b Rsa Ga Za 88-1389-13 90-13 91-13 92-13 Ra Rib R4b Rsa Ga Za 88-1489-14 90-14 91-14 92-14 Rb Rib R4b Rsa Ga Za 88-1589-15 90-15 91-15 92-15 R Rib R4b Rsa Ga Za 88-1689-16 90-16 91-16 92-16 Ra Ric R4b Rsa Ga Za 88-1789-17 90-17 91-17 92-17 Rb Ric R'ibRsa Ga Za 88-1889-18 90-18 91-18 92-18 Rc Ric R4b R5a Ga Za 88-1989-19 90-19 91-19 92-19 Ra Ria R4c Rsa Ga Za 88-2089-20 90-20 91-20 92-20 Rb Ria R4c Rsa Ga Za 88-2189-21 90-21 91-21 92-21 Rc Ria R4c Rsa Ga Za 88-2289-22 90-22 91-22 92-22 Ra Rib R4c Rsa Ga Za 88-2389-23 90-23 91-23 92-23 Rb Rib R4c Rsa Ga Za 88-2489-24 90-24 91-24 92-24 Rc Rib R4c Rsa Ga Za 88-2589-25 90-25 91-25 92-25 Ra Ric R4c Rsa Ga Za 88-2689-26 90-26 91-26 92-26 Rb Ric R4c Rsa Ga Za 88-2789-27 90-27 91-27 92-27 R Ric R4c Rsa Ga Za 88-2889-28 90-28 91-28 92-28 Ra Ria R4a Rsb Ga Za 88-2989-29 90-29 91-29 92-29 Rb Ria R4a Rsb Ga Za 88-3089-30 90-30 91-30 92-30 R Ria R4a Rsb Ga Za 88-3189-31 90-31 91-31 92-31 Ra Rib R4a Rsb Ga Za 88-3289-32 90-32 91-32 92-32 Rb Rib R4a Rsb Ga Za 88-3389-33 90-33 91-33 92-33 Rc Rib R4a Rsb Ga Za 88-3489-34 90-34 91-34 92-34 Ra Ric R4a Rsb Ga Za 88-3589-35 90-35 91-35 92-35 Rb Ric R4a Rsb Ga Za 88-3689-36 90-36 91-36 92-36 R Ric R4a Rsb Ga Za 88-3789-37 90-37 91-37 92-37 Ra Ria R4b Rsb Ga Za 88-38$9-38 90-38 91-38 92-38 Rb Ria R4b Rsb Ga Za 88-3989-39 90-39 91-39 92-39 R Ria R4b Rsb Ga Za 88-4089-40 90-40 91-40 92-40 Ra Rib R4b Rsb Ga Za 88-4189-41 90-41 91-41 92-41 Rb Rib R4b Rsb Ga Za 88-4289-42 90-42 91-42 92-42 Rc Rib R4b Rsb Ga Za 88-4389-43 90-43 91-43 92-43 Ra Ric R4b Rsb Ga Za 88-4489-44 90-44 91-44 92-44 Rb Ric R4b Rsb Ga Za 88-4589-45 90-45 91-45 92-45 Rc Ric R4b Rsb Ga Za 88-4689-46 90-46 91-46 92-46 Ra Ria R4c Rsb Ga Za 88-4789-47 90-47 91-47 92-47 Rb Ria R4c Rsb Ga Za 88-4889-48 90-48 91-48 92-48 Rc Ria R'icRsb Ga Za 88-4989-49 90-49 91-49 92-49 Ra Rib R4c Rsb Ga Za 88-5089-50 90-50 91-50 92-50 Rb Rib R4c Rsb Ga Za 88-5189-51 90-51 91-51 92-51 Rc Rib R4c Rsb Ga Za 88-5289-52 90-52 91-52 92-52 Ra Ric R4c Rsb Ga Za 88-5389-53 90-53 91-53 92-53 Rb Ric R4c Rsb Ga Za 88-5489-54 90-54 91-54 92-54 Rc Ric R4c Rsb Ga Za 88-5589-55 90-55 91-55 92-55 Ra Ria R4a Rsc Ga Za 88-5689-56 90-56 91-56 92-56 Rb Ria R4a Rsc Ga Za 88-5789-5790-57 91-57 92-57 R Ria R4a R5c Ga Za 88-5889-5890-58 91-58 92-58 Ra Rib R4a R5c Ga Za 88-5989-5990-59 91-59 92-59 Rb Rib R4a Rsc Ga Za 88-6089-6090-60 91-60 92-60 Rc Rib R4a Rsc Ga Za $8-6189-6190-61 91-61 92-61 Ra Ric R4a Rsc Ga Za 88-6289-6290-62 91-62 92-62 Rb Ric Rya R5 Ga Za 88-6389-6390-63 91-63 92-63 Rc Ric R'iaRsc Ga Za 88-6489-6490-64 91-64 92-64 Ra Ria R4b Rsc ~a Za 88-6589-6590-65 91-65 92-65 Rb Ria R4b Rsc Ga Za 88-6689-6690-66 91-66 92-66 Rc Ria R'ibRsc Ga Za 88-67$9-6790-67 91-67 92-67 Ra Rib R4b Rsc Ga Za 88-6889-6890-68 91-68 92-68 Rb Rib R4b Rsc ~a Za 88-6989-6990-69 91-69 92-69 Rc Rib R4b Rsc Ga Za 88-7089-7090-70 91-70 92-70 Ra Ric R4b Rsc ~a Za 88-7189-7190-71 91-71 92-71 Rb Ric R4b Rsc Ga Za 88-7289-7290-72 91-72 92-72 R Ric R'ibRsc Ga Za 88-7389-7390-73 91-73 92-73 Ra Ria R4c Rsc Ga Za $8-74$9-7490-74 91-74 92-74 Rb Ria R4c Rsc Ga Za 88-7589-7590-75 91-75 92-75 R Ria R'icRsc Ga Za 88-7689-7690-76 91-76 92-76 Ra Rib R4c R5 Ga Za 88-77$9-7790-77 91-77 92-77 Rb Rib R4c Rsc Ga Za 88-7889-7890-78 91-78 92-78 R Rib R4c Rsc ~a Za 88-7989-7990-79 91-79 92-79 Ra Ric R4c Rsc Ga Za 88-8089-8090-80 91-80 92-80 Rb Ric R4c Rsc Ga Za 88-8189-8190-81 91-81 92-81 Rc Ric R'icRsc Ga Za 88-8289-8290-82 91-82 92-82 Ra Ria R4a Rsa Gb Za 88-8389-8390-83 91-83 92-83 Rb Ria R4a Rsa Gb Za 88-8489-8490-84 91-84 92-84 Rc Ria R4a Rsa Gb Za $8-8589-8590-85 91-85 92-85 Ra Rib R4a Rsa Gb Za 88-8689-8690-86 91-86 92-86 Rb Rib R4a Rsa Gb Za 88-8789-8790-87 91-87 92-87 Rc Rib R4a Rsa Gb Za 88-8889-8890-88 91-88 92-88 Ra Ric R4a Rsa ~b Za 88-8989-8990-89 91-$9 92-89 Rb Ric R4a Rsa Gb Za 88-9089-9090-90 91-90 92-90 Rc Ric R4a Rsa Gb Za 88-9189-9190-91 91-91 92-91 Ra Ria R4b Rsa Gb Za 88-9289-9290-92 91-92 92-92 Rb Ria R4b Rsa Gb Za 88-9389-9390-93 91-93 92-93 Rc Ria R4b Rsa ~b Za 88-9489-9490-94 91-94 92-94 Ra Rib R4b Rsa Gb Za 88-9589-9590-95 91-95 92-95 Rb Rib R4b Rsa Gb Za 88-9689-9690-96 91-96 92-96 Rc Rib R4b Rsa ~b Za 88-9789-9790-97 91-97 92-97 Ra Ric R4b Rsa Gb Za 88-9889-9890-98 91-98 92-98 Rb Ric R4b Rsa Gb Za 88-9989-9990-99 91-99 92-99 Rc Ric R4b Rsa Gb Za 88-10089-10090-10091-10092-100Ra Ria R'icRsa Gb Za 88-10189-10190-10191-10192-101Rb Ria R4c Rsa Gb Za 88-10289-10290-10291-10292-102Rc Ria R4c Rsa Gb Za 88-10389-10390-10391-10392-103Ra Rib R4c Rsa Gb Za 88-10489-10490-10491-10492-104Rb Rib R4c Rsa Gb Za 88-10589-10590-10591-10592-105R Rib R'icRsa Gb za 88-10689-10690-10691-10692-106Ra Ric R4c R5a Gb za 88-10789-10790-10791-10792-107Rb Ric Rdc R5a Gb ~a 88-10889-10890-1089I-10892-108Rc Ric R4c R5a Gb Za 88-10989-10990-10991-10992-109Ra Ria R4a R5b Gb za 88-11089-11090-11091-11092-110Rb Ria R4a Rsb Gb ~a 88-111.89-11190-11191-11192-111Rc Ria R4a RSb Gb Za 88-112$9-11290-11291-11292-112Ra Rib R4a R5b Gb ~a 88-11389-11390-11391-11392-113Rb Rib R4a R5b Gb za 88-11489-11490-11491-11492-114R Rib R4a R5b Gb ~a 88-11589-11590-11591-11592-115Ra Ric R4a Rsb Gb za 88-11689-11690-11691-11692-116Rb Ric R'iaR5b ~b za 88-11789-11790-11791-11792-117Rc Ric R4a R5b Gb za 88-11889-11890-11891-11892-118Ra Ria R4b R5b Gb za 88-11989-11990-11991-11992-I19Rb Ria R4b Rsb Gb za 88-12089-12090-12091-12092-120R Ria R4b R5b ~b za 88-12189-12190-12191-12192-121Ra Rib R4b R5b Gb za 88-12289-I2290-12291-12292-122Rb Rib R4b R5b Gb za 88-12389-12390-12391-12392-123Rc Rib R4b Rsb (ib Za 88-12489-12490-12491-12492-124Ra Ric R4b R5b Gb za 88-12589-12590-12591-12592-125Rb Ric R4b Rsb Gb ~a 88-12689-12690-1269I-12692-126Rc RI~ R4b Rsb ~b ~a 88-12789-12790-12791-12792-127Ra Ria R4c R5b Gb ~a 88-12889-12890-12891-12892-128Rb Ria R4c Rsb Gb Za 88-12989-12990-12991-12992-129R Ria R4c R5b Gb za 88-130$9-13090-13091-13092-130Ra Rib R4c R5b ~b Za 88-13189-13190-13191-13192-131Rb Rib R4c R5b Gb ~a 88-13289-13290-13291-13292-132R Rib R4c R5b Gb Za 88-13389-13390-13391-13392-133Ra Ric R4c Rsb Gb ~a 88-13489-13490-13491-13492-134Rb Ric R4c R5b Gb Za 88-13589-13590-13591-I3592-135R Ric R4c Rsb Gb Za 88-136$9-13690-13691-13692-136Ra Ria R4a R5c Gb za 88-13789-13790-13791-13792-137Rb Ria R4a Rsc Gb ~a 88-13889-13890-13891-13892-138Rc Ria R4a R5c Gb Za 88-13989-13990-13991-13992-139Ra Rib R4a R5c Gb Za 8$-14089-14090-14091-14092-140Rb Rib R4a R5c Gb Za 88-14189-14190-14191-14192-141Rc Rib R4a R5c Gb Za 88-14289-14290-14291-14292-142Ra Ric R4a Rsc ~b Za 88-14389-14390-14391-14392-143Rb Ric R4a R5c Gb za 88-14489-14490-14491-14492-144R Ric R4a R5c Gb Za 88-14S89-14590-14591-14592-145Ra Ria Rdb R5c Gb za 88-14689-14690-14691-14692-146Rb Ria R4b Rsc Gb za 88-14789-14790-14791-14792-147Rc Ria R4b R5c Gb ~a 88-14889-14890-14891-14892-148Ra Rib R4b R5c Gb Za 88-14989-14990-14991-14992-149Rb Rib R4b R5c Gb Za 88-15089-15090-15091-15092-150Rc Rib R4b R5c Gb za 88-15189-15190-1519I-15I92-151Ra R1c R4b Rsc Gb za 88-15289-15290-15291-15292-152Rb Rlc R'~bRsc ~b za 88-15389-15390-15391-I5392-153R Rlc R4b R5c Gb Za 8$-15489-15490-1549I-15492-154Ra Rya R4c Rsc ~b Za 88-15589-15590-15591-15592-I55Rb R1a R4c R5c ~b Za 88-15689-15690-15691-15692-156R Ria R4c Rsc Gb za 88-15789-15790-15791-15792-157Ra R1b R4c Rsc Gb za 88-I5889-15890-15891-15892-158Rb Rib R4c Rsc Gb Za 88-I5989-15990-15991-15992-159Rc Rib R4c R5c Gb ~a 88-16089-16090-16091-16092-160Ra R~ R4c R5c Gb za 88-I6189-16190-16191-I6192-161Rb Roc R'~cRsc Gb Za 88-16289-16290-16291-16292-162Rc Rlc R'~cRsc Gb za 88-16389-16390-16391-16392-163Ra R1a R4a R5a Gc Za 88-16489-16490-16491-I6492-164Rb R1a R4a RSa Gc Za 88-16589-16590-I6591-16592-165Rc Rya R4a R5a Gc ~a 88-16689-16690-16691-16692-166Ra Rib jZ~aRsa Gc za 88-16789-16790-I6791-16792-167Rb Rlb R4a R5a Gc ~a 88-16889-16890-16891-16892-168R Rlb R4a R5a Gc Za 88-16989-16990-16991-I6992-169Ra Roc R4a R5a Gc za 88-17089-17090-17091-17092-170Rb Roc Ra Rsa G Za 88-17189-17190-17191-17I92-171R Rlc R4a Rsa ~c Za 88-17289-17290-17291-17292-172Ra Rla R4b R5a Gc ~a 88-17389-17390-17391-17392-173Rb R1a R4b R5a Gc Za 88-I7489-17490-17491-17492-174Rc Rla R4b R5a Gc Za 88-17589-17590-17591-17592-175Ra Rib R4b Rsa Gc za 88-17689-17690-17691-17692-176Rb Rlb R4b R5a Gc Za 88-17789-17790-17791-17792-177R RIb R4b Rsa Gc ~a 88-17889-17890-17891-17892-178Ra Roc R4b Rsa Gc Za 88-17989-17990-1799I-17992-I79Rb Rlc R4b R5a Gc za 88-18089-18090-18091-18092-180Rc RIc R4b Rsa Gc Za 88-18189-18190-18191-18192-18IRa Rya R4c Rsa Gc za 88-I8289-18290-18291-18292-182Rb Rya R4c Rsa ~c za 88-18389-18390-18391-18392-183Rc Rla R4c Rsa Gc ~a 88-18489-18490-18491-18492-184Ra R1b R4c Rsa Gc Za 88-18589-18590-18591-18592-185Rb Rlb R4c R5a Gc ~a 88-18689-18690-18691-18692-186Rc Rib R4c R5a Gc ~a 88-18789-18790-18791-18792-187Ra Roc R'~cRsa ~a Za 88-18889-18890-I8891-18892-188Rb RIc Roc Rsa Gc Za 88-18989-18990-18991-18992-189R Ric R4c Rsa Gc Za 88-19089-19090-19091-19092-190Ra Rya R4a Rsb Gc ~a 88-19189-19190-19191-19192-191Rb Rya R4a Rsb ~c za 88-19289-19290-19291-19292-I92R RIa R4a R5b Gc Za 88-19389-19390-19391-19392-193Ra Rlb R4a R5b Gc Za 88-194$9-19490-19491-19492-194Rb Rib R4a Rsb ~c ~a 88-19589-19590-19591-I9592-195R Rlb R4a R5b Gc za 88-19689-I9690-19691-19692-196Ra R~ R4a Rsb Gc Za 88-19789-19790-19791-19792-197Rb Rlc R4a R5b Gc Za 88-19$89-19890-19891-19892-198Rc Ric R4a Rsb Gc Za 88-19989-19990-19991-19992-199Ra Ria R4b Rsb Gc Za 88-20089-20090-20091-20092-200Rb Ria R4b R5b Gc za 88-20189-20190-20191-20192-201Rc Ria R4b R5b Gc za 88-20289-20290-20291-20292-202Ra Rib R4b Rsb Gc Za 88-20389-20390-20391-20392-203Rb Rib R4b Rsb Gc Za 88-20489-20490-20491-20492-204R Rib Rdb Rsb Gc Za 88-20589-20590-20591-20592-205Ra Ric R4b Rsb Gc Za 88-20689-20690-20691-20692-206Rb Ric R'ibRsb Gc Za 88-20789-20790-20791-20792-207Rc Ric R4b R5b G za 88-20889-20890-20891-20892-208Ra Ria R'~ Rsb ~c za 88-20989-20990-20991-20992-209Rb Ria R'~cRsb ~c za 88-21089-2I090-21091-21092-210Rc Ria R4c Rsb Gc Za 88-21189-21190-21191-21192-211Ra Rib R4c Rsb Gc Za 88-21289-21290-21291-21292-212Rb Rib R4c Rsb ~c Za 88-21389-21390-21391-21392-213Rc Rib R4c Rsb Gc za 88-21489-2I490-21491-21492-214Ra Ric R4c Rsi'Gc 2a 88-21589-21590-21591-21592-215Rb Ric R'icRsb Gc za 88-21689-21690-21691-21692-216R Ric R4c R5b ~c Za 88-21789-21790-21791-21792-217Ra Ria R'iaRsc G Za 88-21889-21890-21891-21892-218Rb Ria R'iaRsc G Za 88-21989-21990-21991-21992-219Rc Ria R4a R5c Gc za 8$-22089-22090-22091-22092-220Ra Rib R4a RSc Gc Za 88-22189-22190-22191-22192-221Rb Rib R'iaR5c ~c ~a 88-22289-22290-22291-22292-222Rc Rib R'iaRsc G Za 88-22389-22390-22391-22392-223Ra Ric R4a Rsc Gc za 88-22489-22490-22491-22492-224Rb Ric R4a R5c Gc za 88-22589-22590-22591-22592-225R Ric R4a Rsc ~c ~a 88-22689-22690-22691-22692-226Ra Ria R'ibR5c Gc Za 88-22789-22790-22791-22792-227Rb Ria R'ibRsc Gc Za 88-22889-22890-22891-22892-228Rc Ria R4b R5c ~c Za 88-22989-22990-22991-22992-229Ra Rib R4b RSc Gc za 88-23089-23090-23091-23092-230Rb Rib R4b Rsc Gc Za 88-23189-23190-23191-23192-231Rc Rib jZ'~bR5c Gc Za 88-23289-23290-23291-23292-232Ra Ric R4b Rsc ~c za 88-23389-23390-23391-23392-233Rb Ric R4b Rsc Gc Za 88-23489-23490-23491-23492-234R Ric R4b Rsc Gc za 88-23589-23590-23591-23592-235Ra Ria R4c Rsc ~c za 88-23689-23690-23691-23692-236Rb Ria R'icR5c Gc Za 88-23789-23790-23791-23792-237R Ria R4c Rsc ~c za 88-238$9-23890-23891-23892-238Ra Rib R4c R5c Gc Za 88-23989-23990-23991-23992-239Rb Rib R4c R5c ~c Za 88-24089-24090-24091-24092-240R Rib R4c Rsc Gc Za 88-24189-24190-24191-24192-241Ra Ric R4c R5c Gc za 88-24289-24290-24291-24292-242Rb Ric R4c Rsc ~c ~a 88-24389-24390-24391-24392-243R Ric R'~cRsc Gc Za 88 89-24490-2449I-24492-244Ra Ria R'iaR5a Ga zb $8-24589-24590-24591-24592-245Rb Rta R4a Rsa Ga zb 88-246$9-24690-24691-24692-246R Rya R4a Rsa Ga zb 88-24789-24790-24791-24792-247Ra RIb R4a Rsa Ga zb 88-24889-24890-24891-24$92-248Rb Rib R4a Rsa Ga Zb 88-24989-24990-24991-24992-249Rc Rlb R4a Rsa Ga zb 88-25089-25090-25091-25092-250Ra Roc R4a Rsa Ga Zb 88-25189-25190-25191-25192-251Rb Rlc R4a Rsa Ga zb 88-25289-25290-25291-25292-252R Rlc R4a Rsa Ga Zb 88-25389-25390-25391-25392-253Ra R1a R4b Rsa Ga ~b 88-25489-25490-25491-25492-254Rb Rla R4b Rsa Ga ~b 88-25589-25590-25591-25592-255R Rya R4b Rsa Ga zb 88-25689-25690-25691-25692-256Ra Rlb R4b Rsa Ga zb 88-25789-25790-25791-25792-257Rb Rib R4b Rsa Ga Zb 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Ra Rjb R'~aRsa Ga Zc 88-49189-49190-49191-49I92-491 Rb Rlb R'~aRsa Ga Zc 88-49289-49290-49291-49292-492 Rc RIb R4a R5a Ga zc 88-49389-49390-49391-49392-493 Ra Rlc R4a R5a Ga ~c 88-49489-49490-49491-49492-494 Rb Rlc Ra R5a ~a ~c 88-49589-49S90-49S91-49S92-495 Rc R~ R4a Rsa Ga zc 88-49689-49690-49691-49692-496 Ra Rla R4b R5a Ga Zc 88-49789-49790-49791-49792-497 Rb Rja R4b R5a Ga ~c 88-49889-49890-49891-49$92-498 R Rla R4b RSa Ga 2c 88-49989-49990-49991-49992-499 Ra Rib R4b R5a Ga zc 88-50089-S0090-S0091-50092-500 Rb RIb R4b R5a Ga Zc 88-50189-S0190-50191-50192-501 Rc Rjb R4b R5a Ga zc 88-50289-S0290-50291-S0292-S02 Ra Rlc jZ'~bRsa Ga Zc 88-S0389-50390-50391-S0392-S03 Rb Roc R4b R5a Ga zc 88-S0489-S0490-S0491-50492-S04 R Rlc R4b R5a ~a Zc 88-50589-50590-50591-SOS92-SOS Ra Rya R4c R5a Ga zc 88-50689-S0690-S0691-50692-S06 Rb R1a R4c Rsa Ga ~c 88-50789-50790-S0791-S0792-507 R Rya R4c R5a Ga zc 88-S0889-S0890-S0891-50892-508 Ra RIb R'~cRsa Ga zc 88-50989-50990-S0991-50992-S09 Rb Rlb R4c R5a Ga Zc 88-S1089-51090-51091-51092-S10 Rc R1b R4c Rsa ~a ~c 88-S1189-51190-51191-51192-511 Ra Rlc R4c Rsa Ga ~c $8-S1289-51290-51291-S1292-S12 Rb RIc R4c R5a ~a Zc 88-S 89-S 90-51391-51392-S Rc R~ R'~cRsa ~a Zc 88-S 89-51490-S 91-S 92-514 Ra Rl R4a R5b Ga Zc 14 14 14 a 88-S 89-S 90-51591-51592-515 Rb RIa R4a R5b Ga 2c S S

88-S1689-51690-51691-S1692-516 Rc Rya R4a Rsb Ga Zc 88-51789-51790-51791-51792-S17 Ra Rlb R4a Rsb Ga ~c 88-S1889-51890-51891-S1892-S18 Rb RIb R4a Rsb Ga ~c 88-51989-S1990-51991-51992-S19 Rc Rlb R4a Rsb Ga ~c 88-S2089-52090-52091-S2092-S20 Ra Rlc R4a Rsb ~a Zc 88-52189-52190-52191-52192-S21 Rb Roc R'~aRsb ~a zc 88-52289-52290-52291-52292-S22 R Rlc R4a R5b Ga Zc 88-S2389-S2390-52391-S2392-S23 Ra Rla R4b RSb Ga Zc 88-S2489-52490-52491-52492-S24 Rb Ria R4b R5b Ga Zc 88-S2S89-S2590-52S91-52592-S25 R Rla R4b R5b Ga Zc 88-S2689-52690-S2691-S2692-S26 Ra R1b R4b R5b Ga Zc 88-52789-52790-52791-52792-527Rb Rib Rb Rsb 88-52889-52890-52891-52892-528Rc Rib R4b Rsb Ga Zc 88-52989-52990-52991-52992-529Ra R~ R4b Rsb Ga ~c 88-53089-53090-53091-53092-530Rb Rlc R4b Rsb Ga Zc 88-53189-53190-53191-53192-531R Rlc R4b Rsb Ga zc 88-53289-53290-53291-53292-532Ra Rta R4c R56 ~a ~c 88-53389-53390-53391-53392-533Rb Rla R4c Rsb Ga Zc 88-53489-53490-53491-53492-534Rc Rta R4c Rsb Ga zc 88-53589-53590-5359I-53592-535Ra Rib R4c Rsb Ga zc 88-53689-53690-53691-53692-536Rb Rlb R4c Rsb Ga Zc 88-53789-53790-53791-53792-537Rc Rlb R4c Rsb Ga zc 88-53889-53890-53891-53892-538Ra Roc R4c Rsb ~a zc 88-53989-53990-53991-53992-539Rb RIc R4c Rsb Ga zc 88-54089-54090-54091-54092-540Rc Rlc R4c Rsb Ga Zc 88-54189-54190-54191-54192-541Ra Rla R'~aRsc ~a Zc 88-54289-54290-54291-54292-542Rb Rya R4a Rsc Ga ~c 88-54389-54390-54391-54392-543R Rya R4a Rsc Ga Zc 88-54489-54490-54491-54492-544Ra Rib R4a Rsc Ga zc 88-54589-54590-54591-54592-545Rb Rlb R4a Rsc Ga zc 88-54689-54690-54691-54692-546Rc Rib R4a Rsc Ga zc 88-54789-54790-54791-54792-547Ra Rlc R4a Rsc Ga ~c 88-54889-54890-54891-54892-548Rb Rlc R4a Rsc Ga Zc 88-54989-54990-54991-54992-549Rc RIc R4a Rsc Ga zc 88-55089-55090-55091-55092-550Ra Rya R4b R5c Ga Zc 88-55189-55190-55191-55192-551Rb Rya R4b Rsc Ga Zc 88-55289-55290-55291-55292-552R Rla R4b Rsc Ga zc 88-55389-55390-55391-55392-553Ra Rib R4b Rsc Ga Zc 88-55489-55490-55491-55492-554Rb Rlb R'~bRsc Ga Zc 88-55589-55590-55591-55592-555Rc Rib R4b Rsc Ga Zc 88-55689-55690-55691-55692-556Ra Ric R4b Rsc Ga ~c 88-55789-55790-55791-55792-557Rb Roc R4b Rsc Ga Zc 88-55889-55890-55891-55892-558Rc R~c R4b Rsc ~a zc 8$-55989-55990-55991-55992-559Ra RIa R4c Rsc Ga Zc 88-56089-56090-56091-56092-560Rb R1a R4c Rsc Ga Zc 88-56189-56190-56191-56192-561Rc Rla R4c Rsc Ga Zc 88-56289-56290-56291-56292-562Ra Rlb R4c Rsc Ga zc 88-56389-56390-56391-56392-563Rb Rlb R4c Rsc Ga Zc 88-56489-56490-56491-56492-564Rc Rlb R4c Rsc Ga Zc 88-56589-56590-56591-56592-565Ra Roc R4c Rsc ~a Zc 88-56689-56690-56691-56692-566Rb Roc R4c Rsc ~a zc 88-56789-56790-56791-56792-567Rc R~c R4c Rsc ~a zc 88-56889-56890-56891-56892-568Ra Rla R4a Rsa Gb Zc 88-56989-56990-56991-56992-569Rb R1a R4a Rsa Gb Zc 88-57089-57090-57091-57092-570Rc Rla R4a Rsa ~b zc 88-57189-57190-57191-57192-571Ra Rib R4a Rsa Gb Zc 88-57289-57290-57291-57292-572Rb Rib R4a Rsa Gb zc 88-57389-57390-57391-57392-573Rc Rib R4a Rsa Gb zc 88-57489-57490-57491-57492-574Ra R~ R4a Rsa Gb zc 88-57589-57590-57591-57592-575Rb Roc R4a Rsa Gb zc 88-57689-57690-57691-57692-576Rc Rlc R4a Rsa Gb zc 88-57789-57790-57791-57792-577Ra RIa R4b Rsa Gb zc 88-57$89-57890-57891-57892-57$Rb RIa R4b Rsa Gb zc 88-57989-57990-57991-57992-579Rc Rya R4b Rsa Gb Zc 88-58089-58090-58091-58092-580Ra Rlb R4b Rsa Gb zc 88-58189-58190-58191-58192-581Rb RIb R4b Rsa Gb zc 88-58289-58290-58291-58292-582RC RIb R4b Rsa Gb zc 88-583$9-58390-58391-58392-5$3Ra R1c R4b Rsa Gb zc 88-58489-58490-58491-58492-584Rb RIc R4b Rsa Gb Zc 88-58589-58590-58591-58592-585Rc RIc R4b Rsa Gb zc 88-58689-58690-58691-58692-586Ra Rya R4c Rsa Gb Zc 88-58789-58790-58791-58792-587Rb Rya R4c Rsa Gb Zc 88-58$89-58890-58891-58892-588Rc Rya R4c Rsa Gb zc 88-58989-58990-58991-58992-589Ra jyb R4c Rsa Gb zc 88-59089-59090-59091-59092-590Rb Rlb R4c Rsa Gb zc $8-59189-59190-59191-59192-591Rc Rib R4c Rsa Gb zc 88-59289-59290-59291-59292-592Ra Roc R4c Rsa Gb zc 88-59389-59390-59391-59392-593Rb Roc R4c Rsa Gb zc 88-59489-59490-59491-59492-594R R' Roc Rsa Gb Zc 88-59589-59590-59591-59592-595Ra Rla R4a Rsb Gb Zc 88-59689-59690-59691-59692-596Rb Rla R4a Rsb Gb Zc 88-59789-59790-59791-59792-597Rc Ria R4a Rsb Gb zc 88-59889-59890-59891-59892-598Ra RIb R4a Rsb Gb zc 88-59989-59990-59991-59992-599Rb Rtb R4a R5b Gb Zc 88-60089-60090-60091-60092-600R Rlb R4a Rsb Gb zc $8-60189-60190-60191-60192-601Ra Rlc R4a Rsb Gb zc 88-60289-60290-60291-60292-602Rb Roc R4a R~' Gb Zc 88-60389-60390-60391-60392-603Rc RIc R4a Rsb Gb zc 88-60489-60490-60491-60492-604Ra Rya R4b Rsb Gb zc 88-60589-60590-60591-60592-605Rb R1a R4b Rsb Gb zc 8$-60689-60690-60691-60692-606R Rla R4b Rsb Gb Zc 88-60789-60790-60791-60792-607Ra Rjb R4b Rsb Gb zc 88-60889-60890-60891-60892-608Rb Rlb Rab Rsb Gb Zc 88-60989-60990-60991-60992-609Rc Rlb Rb Rsb Gb Zc 88-610$9-61090-61091-61092-610Ra Roc R4b Rsb Gb zc 88-61189-61190-61191-61192-611Rb Rlc Rab Rsb Gb Zc 88-61289-61290-61291-61292-612R RIc R4b Rsb Gb Zc 8$-61389-61390-61391-61392-613Ra Rya R4c Rsb Gb zc 88-61489-61490-61491-61492-614Rb Ria R4c Rsb Gb Zc 88-61589-61590-61591-61592-615R Rya R4c Rsb Gb zc 88-61689-61690-61691-61692-616Ra Rib R4c Rsb Gb Zc 88-61789-61790-61791-61792-617Rb Rib R'~cRsb Gb Zc 8$-61889-61890-61891-61892-618R Rib R4c Rsb Gb Zc 88-61989-61990-61991-61992-619Ra Rtc R4c Rsb Gb zc 88-62089-62090-62091-62092-620Rb Rlc R4c Rsb Gb zc 88-62189-62190-62191-62192-621Rc Rlc Rc Rsb Gb Zc 88-62289-62290-62291-62292-622Ra Rla Rda Rsc Gb Zc 88-62389-62390-62391-62392-623Rb RIa R4a R5c ~b Zc 88-62489-62490-62491-62492-624Rc Rya R4a R5c Gb zc 88-62589-62590-62591-62592-625Ra Rlb R'~aR5c Gb zc 88-62689-62690-62691-62692-626Rb Rib R'~aR5c ~b zc 88-62789-62790-62791-62792-627R Rlb R'~aRsc Gb Zc 88-62889-628.90-62891-62892-628Ra Rlc R4a R5c Gb zc 88-62989-62990-62991-62992-629Rb R~ R4a Rsc Gb Zc 88-63089-63090-63091-63092-630R Roc R4a RSc Gb zc 88-63189-63190-63191-63I92-631Ra Rya R4b Rsc Gb zc 88-63289-63290-63291-63292-632Rb Rla R4b R5c ~b Zc 88-63389-63390-63391-63392-633R Rta R4b Rsc Gb Zc 88-63489-63490-63491-63492-634Ra R1b R4b Rsc Gb zc 88-63589-63590-63591-63592-635Rb Rlb Rib Rsc Gb Z

88-63689-63690-63691-63692-636Rc Rlb Rab R5c Gb zc 88-63789-63790-63791-63792-637Ra Roc R4b R5c Gb zc 88-63889-63890-63891-63892-638Rb R1c R4b Rsc Gb zc 88-63989-63990-63991-63992-639Rc Rlc R4b Rsc Gb zc 88-64089-64090-64091-64092-640Ra Rla R4c R5c Gb 2c 88-64189-64190-64191-64192-641Rb Rya R4c R5c Gb zc $8-64289-64290-64291-64292-642Rc Rya R4c Rsc Gb 88-64389-64390-64391-64392-643Ra Rib R4c R5c Gb Zc 88-64489-64490-64491-64492-644Rb Rib Rc Rsc Gb Zc 88-64589-64590-64591-64592-645Rc Rlb Rc Rsc Gb Z

88-64689-64690-64691-64692-646Ra Roc R4c R5c ~b Zc 88-64789-64790-64791-64792-647Rb Rlc R4c Rsc Gb Zc 88-64889-64890-64891-64892-648Rc Rlc R4c Rsc Gb Z

88-64989-64990-64991-64992-649Ra RIa R4a R5a ~c zc 88-65089-65090-65091-65092-650Rb Rla R4a R5a Gc zc 88-65189-65190-65191-65192-651Rc RIa R4a Rsa Gc Zc 88-65289-65290-65291-65292-652Ra Rlb R4a R5a Gc zc 88-65389-65390-65391-65392-653Rb RIb R4a R5a Gc Zc 88-65489-65490-65491-65492-654Rc Rlb R4a R5a ~c Zc 88-65589-65590-65591-65592-655Ra RIc R4a R5a Gc Zc 88-65689-65690-65691-65692-656Rb Rlc R4a R5a Gc Zc 88-65789-65790-65791-65792-657R R1c R4a RSa Gc zc 88-65889-65890-65891-65892-658Ra Rla R4b R5a ~c Zc 88-65989-65990-65991-65992-659Rb Rya R4b Rsa Gc Zc 88-66089-66090-66091-66092-660Rc Rla R4b R5a Gc Zc 88-66189-66190-66191-66192-661Ra RIb R4b Rsa Gc zc 88-66289-66290-66291-66292-662Rb Rtb R4b R5a Gc Zc 88-66389-66390-66391-66392-663Rc Rlb R4b Rsa Gc Zc 88-66489-66490-66491-66492-664Ra Rlc R4b R5a Gc zc 88-66589-66590-66591-66592-665Rb Rlc R4b R5a Gc 2c 88-66689-66690-66691-66692-666R R1c R4b R5a Gc zc 88-66789-66790-66791-66792-667Ra Rla R4c Rsa Gc Zc 88-66889-66890-66891-66892-668Rb Ria R4c R5a Gc zc 88-66989-66990-66991-66992-669R Ria R4c Rsa Gc zc 88-67089-67090-67091-67092-670Ra Rib R4c Rsa Gc Zc 88-67189-67I90-67191-67192-671Rb Rib R4c Rsa ~c zc $8-67289-67290-67291-67292-672Rc Rib R4c Rsa Gc ~c 88-67389-67390-67391-67392-673Ra Ric R4c R5a Gc ~c 88-67489-67490-67491-67492-674Rb Ric R4c R5a Gc zc 88-67589-67590-67591-67592-675Rc Ric R'icRSa Gc zc 88-67689-67690-67691-67692-676Ra Ria R4a R5b Gc ~c 88-67789-67790-67791-67792-677Rb Ria R4a R5b Gc zc 88-67889-67890-67891-67892-678Rc Ria R4a R5b Gc zc 88-67989-67990-67991-67992-679Ra Rib R4a R5b Gc ~c 88-68089-68090-68091-68092-680Rb Rib R4a R5b Gc zc 88-68189-68190-68191-68192-681Rc Rib R4a R5b Gc 2c 88-68289-68290-68291-68292-682Ra Ric R'laR5b Gc zc 8$-68389-68390-68391-68392-683Rb Ric R4a R5b Gc zc 88-68489-68490-68491-68492-684Rc Ric R4a R5b ~c zc 88-68589-68590-68591-68592-685Ra Ria R4b Rsb Gc 2c 88-68689-68690-68691-68692-686Rb Ria R4b Rsb ~c zc 88-68789-68790-68791-68792-687R Ria R4b Rsb Gc ~c 88-68889-68890-68891-68892-6$8Ra Rib R4b R5b Gc ~c 88-68989-68990-68991-68992-689Rb Rib Rb Rsb Gc Zc 88-69089-69090-69091-69092-690R Rib Rab Rsb G Z

88-69189-69190-69191-69192-691Ra Ric R4b Rsb Gc zc 88-69289-69290-69291-69292-692Rb Ric R4b Rsb G' Z

88-69389-69390-69391-69392-693Rc Ric R4b Rsb Ci Z

88-69489-69490-69491-69492-694Ra Ria R4c R5b Gc zc 88-69589-69590-69591-69592-695Rb Ria R4c R5b ~c zc 88-69689-69690-69691-69692-696Rc Ria R4c RSb Gc zc 88-69789-69790-69791-69792-697Ra Rib R4c R5b Gc zc 88-69889-69890-69891-69892-698Rb Rib R'icRsb G Z

88-69989-69990-69991-69992-699Rc Rib R4c Rsb G Z

88-70089-70090-70091-70092-700Ra Ric R4c Rsb Gc 2c 88-70189-70190-70191-70192-701Rb Ric R4c Rsb G Z

88-70289-70290-70291-70292-702Rc Ric R4c Rsb G Z

88-70389-70390-70391-70392-703Ra Ria R4a Rsc Gc zc 88-70489-70490-70491-70492-704Rb Ria R4a R5c Gc zc 88-70589-70590-70591-70592-705R Ria R4a R5c Gc zc 88-70689-70690-70691-70692-706Ra Rib R4a R5c Gc zc 88-70789-70790-70791-70792-707Rb Rib R4a Rsc Gc zc 88-70889-70890-70891-70892-708Rc Rib R4a Rsc Gc Zc 88-70989-70990-70991-70992-709Ra Ric R'laRsc ~c zc 88-71089-71090-71091-71092-710Rb Ric R4a Rsc Gc zc 88-71189-71190-71191-71192-71IR Ric R4a Rsc Gc Zc 88-71289-71290-71291-71292-712Ra Ria R4b Rsc Gc zc 88-71389-71390-71391-71392-713Rb Ria R4b Rsc Gc zc 88-71489-71490-71491-71492-714Rc Ria R4b RSc Gc zc 88-71589-71590-71591-71592-715Ra Rib Rab Rsc Gc zc 88-71689-71690-71691-71692-716Rb Rlb Rab Rsc Gc Zc 88-71789-71790-71791-71792-717Rc Rlb Rab Rsc G Zc 8$-71889-71890-71891-71892-718Ra R~ RaU Rsc G Z

88-71989-71990-71991-71992-719Rb Roc Rab Rsc Gc Zc 88-72089-72090-72091-72092-720Rc Rlc Rab Rsc G Zc 88-72189-72190-72191-72192-721Ra Rla Rac R5c Gc Zc 88-72289-72290-72291-72292-722Rb Rya Rac Rsc Gc Zc 88-72389-72390-72391-72392-723Rc RIa Rac RSc Gc zc 88-72489-72490-72491-72492-724Ra Rlb Rac Rsc Gc zc 88-72589-72590-72591-72S92-725Rb Rjb Rac Rsc Gc Z

88-72689-72690-72691-72692-726Rc Rlb Rac Rsc Gc Zc 88-72789-72790-7279I-72792-727Ra Roc Rac Rs Gc zc 88-72889-72890-72891-72892-728Rb Roc Rac Rsc Gc Zc 88-72989-72990-72991-72992-729R Roc Rac Rsc Gc Z

where all symbols are as defined above.
In one aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is H or GH3, Rs is -H, and all other symbols are as defined above in connection with formula (1).
In another aspect of any of formulae (88), (89), (90), (91), and (92) of the present to invention, R is -H or CH3; Rs is CH3; and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3; G is -(CH?)S , where s is an integer from 0-5; and alI other symbols are as defined above in connection with formula (I).
In a further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or -CH3; Rs is -H; G is -(CHZ)S , where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I).
In a further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3; Rs is CH3; G is -(CHZ)S , where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I).

In a further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, Z is -NR; and all other symbols are as defined above in connection with formula (I).
In a further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, RS is -H or CH3; Z is -NR; and all other symbols are as defined above in connection with formula (I).
In a still further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, G is -(CHZ)S , where s is an integer from 0-5; Z is -NR;
and all other symbols are as defined above in connection with formula (I).
l0 In a still further aspect of any of formulae (88), (89), (90), (9I), and (92) of the present invention, R is -H or CH3; RS is -H; G is -(CH2)S , where s is an integer from 0-5; Z
is -NR; and all other symbols are as defined above in connection with formula (I).
In a yet further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, Z is O; and all other symbols are as defined above in connection with formula (I).
In a yet further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3; R5 is CH3; G is -(CHZ)S , where s is an integer from 0-5; Z is -NR;
and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, RS is -H or CH3, Z is O, and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3; G is -(CH2)S , where s is an integer from 0-5; Z is O; and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3, G is -(CH?)S , where s is an integer from 0-5; Z is O; and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3; RS is -H; G is -(CHz)S , where s is an integer from 0-5; Z is O; and 3o all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH3; Rs is CH3; G is -(CH2)S-, where s is an integer from 0-5; Z is O;
and all other symbols are as defined above in connection with formula (I).
In yet another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, Rø is a substituted or unsubstituted aryl group; and all other symbols are as defined above in connection with formula (I).
The present invention also encompasses various compounds of general formula (IV) having a formula:
Ra N- G=
R O
(93), NY
N
N
to where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, R, R4, Rs, G, and Z of formula (93) are selected to produce compounds of formula (93-1) through (93-243) as follows:
Formula R R Rs G Z

93-1 Ra R a Rsa Ga Za 93-2 Rb R4a Rsa Ga Za 93-3 R~ R4a Rsa Ga Za 93-4 Ra R4b Rsa Ga Za 93-5 Rb R4b Rsa Ga Za 93-6 R~ R4U Rsa Ga Za 93-7 Ra IZ4 Rsa Ga Za 93-8 Rb R4 Rsa Ga Za 93-9 R R4~ Rsa Ga Za 93-10 Ra R4a Rsb Ga Za 93-11 Rb R'~a Rsb Ga Za 93-12 R~ R4a Rsb Ga Za 93-13 Ra R4b Rsb Ga Za 93-14 Rb R'~b Rsb Ga Za 93-15 R R4b Rsb Ga Za 93-16 Ra R'~ Rsb Ga Za 93-17 Rb R4 Rsb Ga Za 93-18 R~ R4 Rsb Ga Za 93-19 Ra R4a Rs~ Ga Za 93-20 Rb Raa IZs~ Ga Za 93-21 R R'~~ Rs~ Ga Za 93-22Ra R4b Rsc Ga Za 93-23Rb R4b Rsc Ga za 93-24R R4b Rsc Ga Za 93-25Ra R4c Rsc Ga Za 93-26Rb R4c Rsc ~a za 93-27Rc R4c Rsc Ga Za 93-28Ra Rda Rsa Gb Za 93-29Rb R4a Rsa Gb Za 93-30Rc R4a Rsa Gb za 93-31Ra R4b Rsa Gb za 93-32Rb R4b R5a Gb za 93-33Rc R4b Rsa Gb Za 93-34Ra R4c Rsa Gb Za 93-35Rb R4c Rsa Gb Za 93-36Rc R4c Rsa Gb za 93-37Ra R4a Rsb ~b Za 93-38Rb R4a Rsb ~b za 93-39Rc R4a Rsb ~b Za 93-40Ra R4b Rsb Gb za 93-41Rb 1Z'~b Rsb ~b za 93-42Rc R4b Rsb ~b za 93-43Ra R4c Rsb ~b za 93-44Rb R4c Rsb Gb za 93-45Rc R4c Rsb Gb Za 93-46Ra R4a Rsc Gb za 93-47Rb R4a Rsc ~b za 93-48Rc R4a Rsc Gb za 93-49Ra R4b Rsc ~b za 93-50Rb R4b Rsc Gb za 93-51R R4b Rsc Gb ~a 93-52Ra R4c Rsc Gb ~a 93-53Rb R4c Rsc ~b ~a 93-54Rc R4c Rsc Gb za 93-SSRa R4a R5a ~c ~a 93-56Rb R4a Rsa Gc za 93-57Rc R4a Rsa Gc Za 93-58Ra R4b Rsa ~c 2a 93-59Rb R4b Rsa Gc za 93-60Rc R4b Rsa Gc Za 93-61Ra R4c Rsa ~c za 93-62Rb R4c Rsa ~c za 93-63Rc R4c Rsa Gc Za 93-64Ra R4a Rsb Gc Za 93-65Rb R4a Rsb Gc za 93-66R R4a Rsb ~c ~a 93-67Ra R4b Rsb ~c za 93-68Rb R4b Rsb Gc za 93-69 Rc R4b Rsb Gc za 93-70 Ra R4c Rsb Gc za 93-71 Rb R4C Rsb Gc 2a 93-72 Rc R4c Rsb ~c za 93-73 Ra Rya R5c Gc Za 93-74 Rb R4a Rsc Gc za 93-75 Rc R4a Rsc ~c za 93-76 Ra R4b Rsc Gc za .

93-77 Rb R4b Rsc Gc Za 93-78 Rc R4b Rsc Gc za 93-79 Ra R4c Rsc Gc za 93-80 Rb R4c Rsc Gc Za 93-81 Rc R4 Rsc Gc ~a 93-82 Ra R4a Rsa Ga zb 93-83 Rb R4a Rsa Ga ~b 93-84 Rc R4a Rsa Ga zb 93-85 Ra R4b Rsa Ga zb 93-86 Rb R4b Rsa Ga 93-87 R R4b Rsa Ga zb 93-88 Ra R4c Rsa ~a ~b 93-89 Rb R4c Rsa Ga 2b 93-90 R R4c Rsa Ga zb 93-91 Ra R4a Rsb Ga ~b 93-92 Rb Rda Rsb Ga ~b 93-93 R R4a Rsb (sa Zb 93-94 Ra R4b Rsb Ga zb 93-95 Rb R4b Rsb Ga zb 93-96 Rc R4b Rsb Ga Zb 93-97 Ra R'~c Rsb Ga zb 93-98 Rb R4c Rsb Ga zb 93-99 Rc R4c Rsb Ga zb 93-100Ra R4a Rsc Ga 93-101Rb R'~a Rsc Ga Zb 93-102R R4a Rsc ~a 93-103Ra R4b Rsc Ga zb 93-104Rb R4b Rsc Ga Zb 93-105Rc R4b Rsc Ga Zb 93-106Ra R4c Rs Ga ~b 93-107Rb R4c Rsc Ga Zb 93-108Rc R'~ Rsc Ga Zb 93-109Ra R4a Rsa Gb Zb 93-110Rb R4a Rsa Gb zb 93-111Rc R4a Rsa Gb zb 93-112Ra R4b Rsa Gb zb 93-113Rb R4b Rsa Gb zb 93-114R R4b Rsa Gb Zb 93-115Ra R4c Rsa Gb zb 93-116Rb R4c Rsa Gb Zb 93-117Rc R4c Rsa Gb Zb 93-118Ra R4a Rsb Gb zb 93-119Rb R4a Rsb Gb zb 93-120Rc R4a R5b Gb zb 93-121Ra R4b Rsb Gb ~b _ 93-122Rb R'~b Rsb Gb Zb 93-123R R4b Rsb Gb zb 93-124Ra R4c Rsb Gb zb 93-125Rb R4c Rsb Gb ~b 93-126R R4c Rsb Gb zb 93-127Ra R4a Rsc Gb zb 93-128Rb R4a Rsc Gb Zb 93-129R R4a R5c ~b ~b 93-130Ra R4b Rsc Gb zb 93-131Rb R4b Rsc Gb Zb 93-132R R4b Rsc Gb Zb 93-133Ra R4c Rsc Gb Zb 93-134Rb R4c Rsc Gb zb 93-135Rc R4c Rsc Gb Zb 93-136Ra R4a Rsa Gc Zb 93-137Rb R4a Rsa Gc zb 93-138Rc R4a Rsa ~c Zb 93-139Ra R4b Rsa ~c zb 93-140Rb R4b Rsa ~c ~b 93-141Rc R'~b Rsa Gc Zb 93-142Ra R4c Rsa ~c zb 93-143Rb R4c R5a Gc ~b 93-144R R4c Rsa Gc zb 93-145Ra R4a Rsb ~c zb 93-146Rb R4a Rsb ~c ~b 93-147R R4a Rsb Gc Zb 93-148Ra R4b Rsb Gc zb 93-149Rb R4b Rsb Gc Zb 93-150Rc Rib Rsb Gc Zb 93-151Ra R4c Rsb Gc Zb 93-152Rb R4c Rsb Gc Zb 93-153Rc R4c Rsb G Zb 93-154Ra Ra Rsc Gc Zb 93-155Rb R4a R5c Gc Zb 93-156Rc R'~a Rsc Gc Zb 93-157Ra R4b Rsc Gc ~b 93-158Rb R4b Rsc Gc Zb 93-159Rc R4b Rsc GC Zb 93-160Ra R4c Rsc G Zb 93-161Rb R4c Rsc Gc Zb 93-162Rc R4c Rsc Gc Zb 93-163Ra R4a Rsa Ga Zc 93-164Rb R4a Rsa Ga zc 93-165R R4a Rsa Ga zc 93-166Ra R4b Rsa Ga zc 93-167Rb R4b Rsa Ga Zc 93-168Rc R4b Rsa Ga zc 93-169Ra R4c Rsa ~a zc 93-170Rb R4c Rsa Ga Zc 93-171Rc R4c Rsa Ga Zc 93-172Ra R4a Rsb Ga Zc 93-173Rb R4a Rsb Ga zc 93-174Rc R4a Rsb ~a zc 93-175Ra R4b Rsb ~a zc 93-176Rb R4b Rsb ~a zc 93-177R R4b Rsb ~a zc 93-178Ra R4 Rsb Ga Zc 93-179Rb R4c Rsb Ga Zc 93-180R R4c Rsb Va zc 93-181Ra R4a Rso Ga Zc 93-182Rb R4a Rsc Ga zc 93-183Rc R4a R5c Ga zc 93-184Ra R'~b Rsc Ga Z

93-185Rb R4b Rsc ~a Zc 93-186Rc R4b R5c Ga ~c 93-187Ra R4c Rsc ~a Zc 93-188Rb R4c Rsc Ga ~c 93-189Rc R4c Rsc Ga Zc 93-190Ra R4a Rsa Gb ~c 93-191Rb R4a Rsa Gb ~c 93-192Rc R4a Rsa Gb ~c 93-193Ra R4b R5a ~b Zc 93-194Rb R4b Rsa ~b ~c 93-195Rc R4b Rsa Gb zc 93-196Ra R4 Rsa Gb Zc 93-197Rb R4c Rsa Gb Zc 93-198R R4c Rsa Gb zc 93-199Ra R4a Rsb Gb zc 93-200Rb R4a R5b Gb Zc 93-201Rc R4a Rsb Gb Z

93-202Ra R4b Rsb Gb zc 93-203Rb R4b Rsb Gb Zc 93-204Rc R'~b Rsb Gb zc 93-205Ra R4c Rsb Gb Zc 93-206Rb R4c Rsb Gb Zc 93-207Rc R4c Rsb Gb Z

93-208Ra R4a Rsc Gb Zc 93-209Rb R4a Rsc Gb Zc 93-210Rc R'~a Rsc ~b zc 93-211Ra R4b Rsc Gb Zc 93-212Rb R4b Rsc Gb Z

93-213R R4b Rsc Gb Z

93-214Ra R4c Rsc Gb zc 93-215Rb R4c Rs Gb Zc 93-216Rc Roc Rsc Gb Zc 93-217Ra R4a Rsa Gc zc 93-218Rb R4a Rsa Gc zo 93-219R R4a Rsa Gc zc 93-220Ra R4b Rsa Gc Zc 93-221Rb R4b R5a Gc Zc 93-222Rc R4b Rsa Gc zc 93-223Ra R4c Rsa Gc zc 93-224Rb R4c Rsa Gc Zc 93-225Rc R4c Rsa G Zc 93-226Ra R4a Rsb ~c zc 93-227Rb R4a Rsb Gc zc 93-228Rc R4a Rsb ~c zc 93-229Ra R4 Rsb Gc zc 93-230Rv R4b Rsb Gc Zc 93-231R R'~b Rsb Gc Zc 93-232Ra R'~ Rsb Gc Zc 93-233Rb R4c Rsb (1c ~c 93-234R Roc Rsb G Zc 93-235Ra R4a Rsc Gc ~o 93-236Rb R4a Rsc ~c zc 93-237Rc R4a Rsc Gc ~c 93-238Ra R4b Rsc Gc Zc 93-239Rb R4b Rsc Gc Zc 93-240Rc R4b Rsc G Z

93-241Ra R4c Rsc Gc ~o 93-242Rb R4c Rsc Gc Zc 93-243R R4c Rsc Gc Zc where all symbols are as defined above.
In one aspect of any of formula (93) of the present invention, R is -H or CH3, and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formula (93) of the present invention, R4 is a substituted or unsubstituted aryl group; and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formula (93) of the present invention, RS is -H or CH3, and all other symbols are as defined above in connection with formula (I).

In yet another aspect of any of formula (93) of the present invention, G is -(CH2)s-, where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I).
In yet another aspect of formula (93) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R4 is an alkenyl group, a cycloallcenyl 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 l0 heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; RS is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an allcoxy group, an alkenyl group, or an alkoxyalkyl group; and all other symbols are as defined above in connection with formula (I).
In still another aspect of formula (93) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, or an alkyl group; R4 is a cycloalkenyl group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an arallcyl group, an aralkenyl group, an arallcynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; RS is hydrogen, a hydroxy group, a halogen, an alkyl group, or an alkoxy group; and all other symbols are as defined above in connection with formula (I).
In yet another aspect of formula (93) of the present invention, R is hydrogen or an alkyl group; R4 is a substituted or unsubstituted aryl group; G is f CH2~2, (CH~33, or (CH2~4; Z
is O, S, or NH; and RS is hydrogen or an alkyl group.
In still another aspect of formula (93) of the present invention, R is -H or CH3; R4 is a substituted or unsubstituted aryl group; G is f CHZj~, (CH2)3, or f CHZ)4; Z
is O, S, or NH; and RS is -H or CH3.
The present invention also encompasses various compounds of general formula (IV) as follows:

Rio O Rio ~--NR
R9 ~~ ' NR RW~ S O
I ° N ~
Nr I N~ w Ns I w ; Rs ~N~N G=Z ~ / N~N G O ~
tv~e ~o (94); tv~e IoI (95);

Rio °\~ R~o ~L--NR
RwGI ~N O R~~~I S O
I , N I
Nr ~(I N ~ Rs N/ ~ ~ ~ R5 N~N G-S ~ / N_ 1fN C' Me [°~ (96); and Me IoI (97);
where R9 and RI° 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(O=) group, a thio(S=) group, 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 amyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an arallcyl group, an alkylsulfonyl group, an to 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 piperzinyl 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 above in connection with formula (I).
According to various aspects of the present invention, R, R5, G, Z, R9, and Rl° of any of formulae (94), (95), (96), and (97) are selected to produce compounds of formulae (94-1), 2o (95-1), (96-1), and (97-1) through formulae (94-729), (95-729), (96-729), and (97-729) as follows:

Formulae R RS R R G Z

94-1 95-1 96-1 97-1 Ra RSa R RI Ga Za a a 94-2 95-2 96-2 97-2 Rb RSa R9a RlOa Ga Za 94-3 95-3 96-3 97-3 R Rsa R9a RlOa Ga za 94-4 95-4 96-4 97-4 Ra RSb R9a RlOa Ga za 94-5 95-5 96-5 97-5 Rb RSb R9a Rioa Ga Za 94-6 95-6 96-6 97-6 Rc RSb R9a Rloa Ga Za 94-7 95-7 96-7 97-7 Ra RSc R9a RlOa Ga ~a 94-8 95-8 96-8 97-$ Rb Rsc R9a RlOa Ga ~a 94-9 95-9 96-9 97-9 R R5c R9a RIOa Ga za 94-109S-10 96-10 97-10 Ra RSa R9b Rloa Ga Za 94-1195-11 96-11 97-11 Rb RSa R9b RIOa Ga ~a 94-1295-12 96-12 97-12 R RSa R9b RIOa Ga Za 94-1395-13 96-13 97-13 Ra RSb R9b RlOa Ga ~a 94-1495-14 96-14 97-14 Rb RSb R9b RlOa Ga Za 94-1595-15 96-15 97-15 Rc Rsb R9b RIOa Ga Za 94-1695-16 96-16 97-16 Ra Rsc R9b RlOa Ga za 94-1795-17 96-17 97-17 Rb RSc R9b RlOa Ga ~a 94-1895-18 96-18 97-18 R R5c R9b RlOa Ga Za 94-1995-19 96-19 97-19 Ra RSa R9c RlOa Ga ~a 94-2095-20 96-20 97-20 Rb R5a R9c RlOa Ga Za 94-2195-21 96-21 97-21 R R5a R9c RlOa Ga Za 94-2295-22 96-22 97-22 Ra RSb R9c RIOa Ga Za 94-2395-23 96-23 97-23 Rb RSb R9c RlOa Ga ~a 94-2495-24 96-24 97-24 Rc RSb R9c RIOa Ga Za 94-2595-25 96-25 97-25 Ra RSc R9c RlOa Ga Za 94-2695-26 96-26 97-26 Rb RSc R9c RlOa Ga Za 94-2795-27 96-27 97-27 R RSc R9c RlOa Ga za 94-2895-28 96-28 97-28 Ra RSa R9a RlOb Ga za 94-2995-29 96-29 97-29 Rb RSa R9a Rlob Ga za 94-3095-30 96-30 97-30 Rc Rsa R9a RlOb Ga ~a 94-3195-31 96-31 97-31 Ra R5b R9a RlOb Ga Za 94-3295-32 96-32 97-32 Rb RSb R9a RIOb Ga za 94-3395-33 96-33 97-33 Rc Rsb R9a RlOb Ga Za 94-3495-34 96-34 97-34 Ra RSc R9a RlOb Ga za 94-3595-35 96-35 97-35 Rb R5c R9a RlOb Ga Za 94-3695-36 96-36 97-36 RC RSc R9a RlOb Ga Za 94-3795-37 96-37 97-37 Ra RSa R9b RlOb Ga Za 94-3895-38 96-38 97-38 Rb RSa R9b RlOb Ga Za 94-3995-39 96-39 97-39 Rc Rsa R9b RlOb Ga za 94-4095-40 96-40 97-40 Ra RSb R9b Riob Ga Za 94-4I95-41 96-41 97-41 Rb R5b R9b Rrob Ga Za 94-4295-42 96-42 97-42 Rc Rsb R9b RlOb Ga za 94-4395-43 96-43 97-43 Ra Rsc R9b RlOb Ga Za 94-4495-44 96-44 97-44 Rb Rsc R9b RIOb Ga Za 94-4595-45 96-45 97-45 Rc RSc R9b RIOb Ga Za .

94-4695-46 96-46 97-46 Ra R5a R9c RlOb Ga za 94-4795-47 96-47 97-47 Rb RSa R9c RlOb Ga za 94-4895-48 96-48 97-48 Rc Rsa R9c RIOb Ga Za 94-4995-49 96-49 97-49 Ra Rsb R9c RlOb Ga Za 94-5095-50 96-50 97-50 Rb R5b R9c RlOb Ga Za 94-5195-51 96-51 97-51 Rc RSb R9c RlOb Ga Za 94-5295-52 96-52 97-52 Ra R5c R9c RIOb Ga za 94-5395-53 96-53 97-53 Rb Rsc R9c RlOb Ga za 94-5495-54 96-54 97-54 Rc RSc Rgc RlOb Ga za 94-5595-55 96-55 97-55 Ra RSa R9a RlOc Ga Za 94-5695-56 96-56 97-56 Rb RSa R9a RlOc Ga za 94-5795-57 96-57 97-57 Rc R5a R9a RlOc Ga ~a 94-5895-58 96-58 97-58 Ra R5b R9a RlOc Ga ~a 94-5995-59 96-59 97-59 Rb RSb R9a RlOc Ga za 94-6095-60 96-60 97-60 Rc R5b R9a RlOc Ga Za 94-6195-6I 96-61 97-61 Ra R5c R9a RlOc Ga za 94-6295-62 96-62 97-62 Rb RSc R9a RIOc Ga za 94-6395-63 96-63 97-63 R Rsc R9a RIOc Ga za 94-6495-64 96-64 97-64 Ra R5a R9b RlOc Ga ~a 94-6595-65 96-65 97-65 Rb RSa R9b RIOc Ga za 94-6695-66 96-66 97-66 Rc Rya R9b RlOc ~a za 94-6795-67 96-67 97-67 Ra R5b R9b RIOc Ga Za 94-6895-68 96-68 97-68 Rb R5b R9b RIOc Ga Za 94-6995-69 96-69 97-69 Rc R5b R9b RlOc Ga za 94-7095-70 96-70 97-70 Ra Rsc R9b RlOc Ga za 94-7I95-71 96-71 97-71 Rb Rsc R9b RIOc Ga ~a 94-7295-72 96-72 97-72 R Rsc R9b Rloc ~a za 94-7395-73 96-73 97-73 Ra R5a R9c RlOc ~a Za 94-7495-74 96-74 97-74 Rb RSa R9c RlOc ~a ~a 94-7595-75 96-75 97-75 Rc RSa R9c RlOc Ga Za 94-7695-76 96-76 97-76 Ra Rsb R9c RlOc Ga za 94-7795-77 96-77 97-77 Rb RSb R9c RlOc ~a za 94-7895-78 96-78 97-78 Rc R5b R9c RlOc Ga za 94-7995-79 96-79 97-79 Ra RSc R9c RIOc Ga Za 94-8095-80 96-80 97-80 Rb R5c R9c RlOc Ga Za 94-8195-81 96-81 97-81 R Rsc R9c RlOc Ga Za 94-8295-82 96-82 97-82 Ra Rsa R9a RlOa Gb Za 94-8395-83 96-83 97-83 Rb R5a R9a Rioa Gb Za 94-8495-84 96-84 97-84 Rc RSa R9a R~oa Gb za 94-8595-85 96-85 97-85 Ra R5b R9a RlOa Gb Za 94-8695-86 96-86 97-86 Rb Rsb R9a RIOa Gb Za 94-8795-87 96-87 97-87 R RSb R9a RlOa Gb Za 94-8895-88 96-88 97-8$ Ra RSc R9a RIOa Gb Za 94-8995-89 96-89 97-89 Rb RSc R9a RiOa Gb Za 94-9095-90 96-90 97-90 Rc RSc R9a RlOa Gb za 94-9195-91 96-91 97-91 Ra R5a R9b RlOa ~b Za 94-9295-92 96-92 97-92 Rb R5a R9b RlOa Gb Za 94-9395-93 96-93 97-93 R Rsa R9b RlOa Gb Za 94-9495-94 96-94 97-94 Ra RSb R9b RIOa Gb Za 94-9595-95 96-95 97-95 Rb RSb R9b RlOa Gb za 94-9695-96 96-96 97-96 Rc R5b R9b RlOa Gb za 94-9795-97 96-97 97-97 Ra Rsc R9b RIOa Gb Za 94-9895-98 96-98 97-98 Rb RSc R9b RIOa Gb ~a 94-9995-99 96-99 97-99 Rc R5c R9b Rloa Gb za 94-10095-10096-10097-100Ra RSa R9c RIOa Gb za 94-10195-10196-10197-101Rb Rsa R9c RlOa Gb za 94-10295-10296-10297-102Rc Rsa R9c RiOa Gb za 94-10395-10396-10397-103Ra RSb R9c RlOa Gb ~a 94-10495-10496-10497-104Rb RSb R9c RlOa ~b Za 94-10595-10596-10597-105Rc Rsb R9c RIOa Gb za 94-10695-10696-10697-106Ra Rsc R9c RlOa ~b ~a 94-10795-10796-10797-107Rb Rsc R9c RlOa ~b ~a 94-10895-10896-10897-108R RSc R9c RlOa Gb ~a 94-10995-10996-10997-109Ra RSa R9a RIOb Gb Za 94-11095-11096-11097-110Rb Rsa R9a RlOb Gb za 94-11195-11196-11197-111Rc RSa R9a RlOb Gb Za 94-11295-11296-11297-112Ra Rsb R9a RlOb Gb za 94-11395-11396-11397-113Rb Rsb R9a RlOb ~b ~a 94-11495-11496-11497-114Rc R5b R9a RlOb Gb za 94-11595-11596-11597-115Ra Rsc R9a RIOb Gb Za 94-11695-11696-11697-116Rb Rsc R9a RlOb Gb Za 94-11795-11796-11797-117Rc R5c R9a RlOb Gb ~a 94-11895-11896-11897-118Ra RSa R9b RIOb Gb ~a 94-11995-11996-11997-119Rb RSa R9b Rlob Gb za 94-12095-12096-12097-120R Rsa R9b RlOb Gb ~a 94-12195-12196-12197-121Ra Rsb R9b RlOb Gb Za 94-12295-12296-12297-122Rb RSb R9b RIOb ~b ~a 94-12395-12396-12397-123Rc RSb R9b RIOb ~b za 94-12495-12496-12497-124Ra RSc R9b RIOb Gb Za 94-12595-12596-12597-125Rb Rsc R9b RlOb Gb Za 94-12695-12696-12697-126Rc RSc R9b RlOb Gb za 94-12795-12796-12797-127Ra R5a R9c Rlob Gb Za 94-12895-12896-12897-128Rb Rsa R9c RlOb Gb Za 94-12995-12996-12997-129R Rsa R9c RlOb Gb Za 94-13095-13096-13097-130Ra RSb R9c RlOb Gb Za 94-13195-13196-13197-131Rb Rsb R9c RIOb Gb Za 94-13295-13296-13297-132R R5b R9c Rlob ~b Za 94-13395-13396-13397-133Ra Rsc R9c RlOb Gb Za 94-13495-13496-13497-134Rb Rsc R9c RlOb Gb za 94-13595-13596-13597-135Rc Rsc R9c RlOb Gb Za 94-13695-13696-13697-136Ra RSa R9a RlOc Gb Za 94-13795-I3796-13797-137Rb Rsa R9a RlOc Gb Za 94-13895-13896-13897-138Rc Rsa R9a RlOc Gb za 94-13995-13996-13997-139Ra RSb R9a RlOc Gb Za 94-14095-14096-14097-140Rb RSb R9a RlOc Gb za 94-14195-14196-14197-141Rc RSb R9a RlOc Gb Za 94-14295-14296-14297-142Ra R5c R9a RIOc Gb Za 94-14395-14396-14397-143Rb RSc R9a RlOc Gb ~a 94-14495-14496-14497-144R Rsc R9a RlOc Gb Za 94-14595-14596-14597-145Ra RSa R9b RlOc Gb za 94-14695-14696-14697-146Rb RSa R9b RlOc Gb Za 94-14795-14796-I4797-147R Rsa R9b RlOc ~b za 94-14895-14896-14897-148Ra RSb R9b RIOc Gb Za 94-I4995-I4996-14997-I49Rb RSb R9b RlOc Gb Za 94-15095-15096-15097-150Rc RSb R9b Rloc Gb za 94-15195-15196-ISI97-151Ra RSc R9b RlOc Gb za 94-15295-15296-15297-152Rb RSc R9b RIOc Gb za 94-15395-I5396-15397-153R RSc R9b RlOc Gb za 94-I5495-15496-15497-I54Ra RSa R9c Rloc Gb za 94-15595-I5596-I5597-I55Rb RSa R9c RIOc ~b za 94-15695-15696-15697-156Rc Rsa R9c RlOc Gb za 94-15795-15796-15797-157Ra RSb R9c RlOc Gb za 94-15895-I5896-15897-158Rb RSb R9c RlOc ~b za 94-15995-15996-15997-159Rc Rsb R9c RIOc Gb za 94-I6095-16096-16097-160Ra RSc R9c RlOc Gb za 94-16195-I6196-16197-I61Rb Rsc R9c RIOc Gb Za 94-16295-16296-16297-I62RC Rsc R9c RIOc Gb ~a 94-I6395-16396-16397-163Ra RSa R9a RiOa ~c Za 94-16495-16496-16497-164Rb RSa R9a RlOa Gc ~a 94-16595-16596-16597-I65Rc RSa R9a RIOa Gc za 94-16695-16696-16697-166Ra Rib R9a RIOa Gc za 94-I6795-16796-16797-167Rb Rsb R9a RlOa Gc Za 94-16895-16896-16897-168Rc RSb R9a Rloa Gc ~a 94-16995-16996-16997-I69Ra R5c R9a RIOa ~c za 94-17095-17096-17097-170Rb Rsc R9a RIOa Gc za 94-17195-17196-17197-I71R Rsc R9a RlOa Gc Za 94-17295-17296-17297-172Ra Rsa R9b RIOa Gc Za 94-17395-17396-17397-173Rb RSa R9b RIOa ~c Za 94-17495-17496-17497-174R Rsa R9b RlOa Gc Za 94-17595-I7596-17597-175Ra RSb R9b RlOa ~c Za 94-17695-17696-17697-176Rb Rsb R9b RlOa Gc ~a 94-17795-17796-17797-177R Rsb R9b RIOa Gc Za 94-17895-17896-17897-178Ra RSc R9b RlOa Gc za 94-17995-17996-17997-179Rb R5c R9b RlOa ~c Za 94-18095-18096-18097-180Rc RSc R9b RIOa Gc Za 94-18195-18196-18197-181Ra RSa R9c RlOa Gc za 94-18295-18296-18297-182Rb RSa R9c RlOa Gc Za 94-18395-18396-18397-183Rc RSa R9c RlOa Gc Za 94-18495-18496-18497-184Ra Rsb R9c RIOa ~c Za 94-18595-18596-18597-185Rb Rsb R9c R~oa Gc za 94-18695-18696-18697-186Rc Rsb R9c RlOa Gc Za 94-18795-18796-18797-187Ra RSc R9c RlOa Gc za 94-18895-18896-18897-188Rb RSc R9c RlOa Gc Za 94-18995-18996-18997-189Rc RSc R9c RlOa Gc za 94-19095-19096-19097-190Ra Rsa R9a RlOb Gc Za 94-19195-19196-19197-191Rb RSa R9a RlOb Gc za 94-19295-19296-19297-192Rc RSa Rga RlOb Gc Za 94-19395-19396-19397-193Ra R5b R9a RlOb Gc Za 94-19495-19496-19497-194Rb R5b R9a RIOb Gc Za 94-19595-19596-19597-195Rc Rsb R9a RIOb Gc za 94-19695-19696-19697-196Ra Rsc R9a RlOb Gc Za 94-19795-19796-19797-197Rb Rsc R9a RlOb Gc za 94-19895-19896-19897-198R Rsc R9a RlOb Gc Za 94-19995-19996-19997-199Ra RSa R9b RIOb Gc Za 94-20095-20096-20097-200Rb RSa R9b RlOb Gc za 94-20195-20196-20197-201R Rsa R9b RlOb Gc za 94-20295-20296-20297-202Ra R56 R9b RIOb ~c za 94-20395-20396-20397-203Rb RSb R9b RlOb Gc ~a 94-20495-20496-20497-204Rc R56 Rib RIOb Gc Za 94-20595-20596-20597-205Ra RSc R9b RIOb Gc Za 94-20695-20696-20697-206Rb Rsc R96 RlOb ~c za 94-20795-20796-20797-207Rc Rsc R9b RiOb Gc za 94-20895-20896-20897-208Ra R5a R9c RIOb Gc Za 94-20995-20996-20997-209Rb RSa R9c RlOb Gc za 94-21095-21096-21097-210Rc Rsa R9c RlOb Gc Za 94-21195-21196-21197-211Ra Rsb R9c RIOb ~c ~a 94-21295-21296-21297-212Rb R56 R9c RIOb Gc ~a 94-21395-21396-21397-213Rc RSb ROc RIOb ~c za 94-21495-21496-21497-214Ra RSc R9c RlOb ~c Za 94-21595-21596-21597-215Rb R5c R9c RIOb ~c Za 94-21695-21696-21697-216Rc R5c R9c RlOb Gc za 94-21795-21796-21797-217Ra RSa R9a RIOc Gc Za 94-21895-21896-21897-218Rb RSa R9a RIOc Gc Za 94-21995-21996-21997-219Rc RSa R9a RIOc ~c za 94-22095-22096-22097-220Ra RSb R9a RlOc ~c Za 94-22195-22196-22197-221Rb RSb R9a RlOc Gc za 94-22295-22296-22297-222Rc R56 R9a RIOc Gc Za 94-22395-22396-22397-223Ra R5c R9a RIOc Gc Za 94-22495-22496-22497-224Rb R5c R9a RlOc Gc Za 94-22595-22596-22597-225R Rsc R9a RIOc Gc za 94-22695-22696-22697-226Ra RSa R9b RlOc Gc Za 94-22795-22796-22797-227Rb RSa R9b RlOc Gc Za 94-22895-22896-22897-228Rc RSa R9b RlOc Gc Za 94-22995-22996-22997-229Ra RSb R9b RIOc Gc za 94-23095-23096-23097-230Rb R56 R9b RlOc Gc Za 94-23195-23196-23197-231R R5b R9b RlOc Gc Za 94-23295-23296-23297-232Ra Rsc R96 RlOc Gc Za 94-23395-23396-23397-233Rb RSc R9b Rtoc Gc Za 94-23495-23496-23497-234Rc RSc Rgb Rloc Gc 2a 94-23595-23596-23597-235Ra RSa R9c RlOc Gc Za 94-23695-23696-23697-236Rb R5a R9c RlOc Gc za 94-23795-23796-23797-237R RSa R9c RlOc Gc za 94-23895-23896-23897-238Ra R5b R9c RlOc ~c Za 94-23995-23996-23997-239Rb RSb R9c Rtoc Gc Za 94-24095-24096-24097-240R R~' R9c RlOc Gc za 94-24195-24196-24197-241Ra R5c R9c RlOc Gc za 94-24295-24296-24297-242Rb R5c R9c RlOc Gc za 94-24395-24396-24397-243Rc Rsc R9c RlOc Gc ~a 94-24495-24496-24497-244Ra RSa R9a RIOa Ga zb 94-24595-24596-24597-245Rb Rsa R9a Rloa Ga zb 94-24695-24696-24697-246Rc RSa R9a RlOa Ga zb 94-24795-24796-24797-247Ra R56 R9a RlOa Ga zb 94-24895-24896-24897-248Rb R56 R9a RlOa Ga Zb 94-24995-24996-24997-249Rc R5b R9a Rloa Ga Zb 94-25095-25096-25097-250Ra R5c Rga RlOa Ga ~b 94-25195-25196-25197-251Rb Rsc R9a RlOa Ga zb 94-25295-25296-25297-252Rc Rsc R9a RlOa Ga ~b 94-25395-25396-25397-253Ra R5a R9b RIOa ~a ~b 94-25495-25496-25497-254Rb R5a R9b RIOa Ga zb 94-25595-25596-25597-255R Rsa R9b RIOa Ga Zb 94-25695-25696-25697-256Ra R5b R9b RlOa Ga Zb 94-25795-25796-25797-257Rb RSb R9b RlOa Ga zb 94-25895-25$96-25897-258Rc RSb R9b RlOa Ga zb 94-25995-25996-25997-259Ra R5c R9b RlOa Ga zb 94-26095-26096-26097-260Rb RSc R96 RIOa Ga Zb 94-26195-26196-26197-261R Rsc R9b RlOa Ga Zb 94-26295-26296-26297-262Ra R5a R9c RlOa ~a ~b 94-26395-26396-26397-263Rb R5a R9c RlOa Ga ~b 94-26495-26496-26497-264Rc Rsa R9c RIDa Ga Zb 94-26595-26596-26597-265Ra R5b R9c Rloa Ga zb 94-26695-26696-26697-266Rb RSb R9c RlOa Ga zb 94-26795-26796-26797-267R Rsb R9c RlOa ~a zb 94-26895-26896-26897-268Ra Rsc R9c RlOa ~a zb 94-26995-26996-26997-269Rb R5c R9c RlOa ~a ~b 94-27095-27096-27097-270R Rsc R9c RlOa ~a ~b 94-27195-27196-27197-271Ra RSa R9a RIOb Ga Zb 94-27295-27296-27297-272Rb R5a R9a 8106 Ga zb 94-27395-27396-27397-273Rc Rsa R9a RlOb Ga ~b 94-27495-27496-27497-274Ra R56 R9a RlOb Ga Zb 94-27595-27596-27597-275Rb R5b R9a RIOb Ga ~b 94-27695-27696-27697-276Rc R5b R9a RIOb Ga zb 94-27795-27796-27797-277Ra Rsc R9a Rlob ~a ~b 94-27895-27896-27897-278Rb RSc R9a RIOb Ga zb 94-27995-27996-27997-279R Rsc R9a RlOb Ga ~b 94-28095-28096-28097-280Ra RSa R9b RlOb Ga Zb 94-28195-28196-28197-281Rb RSa R9b RlOb Ga Zb 94-28295-28296-28297-282Rc RSa R9b RlOb Ga Zb 94-28395-28396-28397-283Ra RSb R9b RlOb Ga Zb 94-28495-28496-28497-284Rb R~' Rgb RIOb Ga zb 94-28595-28596-28597-285RC R5b R9b RlOb Ga ~b 94-28695-28696-28697-286Ra RSc R9b Rlob Ga zb 94-28795-28796-28797-287Rb RSc R9b RlOb ~a zb 94-28895-28896-28897-288Rc RSc R9b RlOb ~a zb 94-28995-28996-28997-289Ra RSa jZ~ RlOb Ga zb 94-29095-29096-29097-290Rb R5a Rgc R~Ob Ga zb 94-29195-29196-29197-291Rc R5a R9c RIOb Ga zb 94-29295-29296-29297-292Ra RSb R9c RIOb Ga zb 94-29395-29396-29397-293Rb Rsb R9c RIOb Ga zb 94-29495-29496-29497-294R RSb R9c RlOb Ga zb 94-29595-29596-29597-295Ra Rsc R9c RlOb Ga zb 94-29695-29696-29697-296Rb Rsc R9c RlOb Ga zb 94-29795-29796-29797-297R Rsc R9c RlOb Ga Zb 94-29895-29896-29897-298Ra RSa R9a RlOc Ga ~b 94-29995-29996-29997-299Rb Rsa R9a RlOc Ga ~b 94-30095-30096-30097-300Rc RSa R9a RlOc Ga Zb 94-30195-30196-30197-301Ra R5b R9a RlOc Ga ~b 94-30295-30296-30297-302Rb RSb R9a RIOc Ga ~b 94-30395-30396-30397-303Rc RSb R9a RlOc ~a ~b 94-30495-30496-30497-304Ra R5c R9a RlOc Ga Zb 94-30595-30596-30597-305Rb RSc R9a RlOc Ga ~b 94-30695-30696-30697-306Rc Rsc R9a RlOc Ga Zb 94-30795-30796-30797-307Ra Rsa R9b RIOc Ga ~b 94-30895-30896-30897-308Rb RSa R9b RIOc Ga ~b 94-30995-30996-30997-309Rc Rsa R9b RlOc Ga zb 94-31095-31096-31097-310Ra Rsb R9b RlOc Ga Zb 94-31195-31196-31197-311Rb RSb R9b RIOc Ga zb 94-31295-31296-31297-312Rc Rsb R9b RlOc ~a ~b 94-31395-31396-31397-313Ra Rsc R9b RlOc ~a Zb 94-31495-31496-31497-314Rb Rsc R9b RIOc Ga Zb 94-31595-31596-31597-315Rc Rsc R9b RIOc Ga zb 94-31695-31696-31697-316Ra RSa R9c RIOc ~a zb 94-31795-31796-31797-317Rb Rsa R9c RlOc Ga ~b 94-31895-31896-31897-318Rc RSa R9c RIOc ~a Zb 94-31995-31996-31997-319Ra RSb R9c RIOc Ga ~b 94-32095-32096-32097-320Rb R5b R9c RlOc Ga ~b 94-32195-32196-32197-321Rc RSb Rgc RlOc Ga zb 94-32295-32296-32297-322Ra Rsc R9c RlOc Ga ~b 94-32395-32396-32397-323Rb RSc R9c RlOc Ga Zb 94-32495-32496-32497-324R RSc R9c RlOc Ga ~b 94-32595-32596-32597-325Ra RSa R9a RlOa ~b Zb 94-32695-32696-32697-326Rb R5a R9a RlOa Gb zb 94-32795-32796-32797-327R Rsa R9a RlOa Gb zb 94-32895-32896-32897-328Ra RSb R9a RlOa Gb zb 94-32995-32996-32997-329Rb Rsb R9a RlOa Gb zb 94-33095-33096-33097-330Rc RSb R9a RIOa Gb zb 94-33195-33196-33197-331Ra Rsc R9a RIOa Gb zb 94-33295-33296-33297-332Rb RSc R9a RIOa Gb Zb 94-33395-33396-33397-333Rc RSc R9a RlOa Gb zb 94-33495-33496-33497-334Ra R5a R9b Rloa Gb Zb 94-33595-33596-33597-335Rb Rsa R9b RIOa Gb Zb 94-33695-33696-33697-336Rc Rsa R9b RIOa Gb zb 94-33795-33796-33797-337Ra RSb R9b RlOa ~b Zb 94-33895-33896-33897-338Rb RSb R9b RlOa Gb zb 94-33995-33996-33997-339Rc RSb R9b RIOa Gb zb 94-34095-34096-34097-340Ra RSc R9b RiOa Gb Zb 94-34195-34196-34197-341Rb RSc R9b RlOa Gb ~b 94-34295-34296-34297-342Rc RSc R9b RIOa Gb ~b 94-34395-34396-34397-343Ra RSa R9c RiOa Gb zb 94-34495-34496-34497-344Rb R5a R9c RIOa Gb zb 94-34595-34596-34597-345Rc Rsa R9c RIOa Gb Zb 94-34695-34696-34697-346Ra Rsb R9c RlOa ~b Zb 94-34795-34796-34797-347Rb RSb R9c RIOa Gb Zb 94-34895-34896-34897-348Rc RSb R9c RlOa ~b Zb 94-34995-34996-34997-349Ra Rsc R9c RlOa ~b zb 94-35095-35096-35097-350Rb RSc R9c RiOa Gb Zb 94-35195-35196-35197-351Rc R5c R9c RlOa Gb Zb 94-35295-35296-35297-352Ra R5a R9a RIOb Gb zb 94-35395-35396-35397-353Rb Rsa R9a RiOb Gb Zb 94-35495-35496-35497-354Rc R5a R9a RlOb Gb Zb 94-35595-35596-35597-355Ra RSb R9a RlOb Gb ~b 94-35695-35696-35697-356Rb R5b R9a RiOb Gb Zb 94-35795-35796-35797-357Rc RSb R9a RlOb Gb Zb 94-35895-35896-35897-358Ra Rsc R9a Riob Gb zb 94-35995-35996-35997-359Rb Rsc R9a RlOb Gb zb 94-36095-36096-36097-360R RSc R9a RIOb Gb Zb 94-36195-36196-36197-361Ra RSa R9b RlOb ~b zb 94-36295-36296-36297-362Rb Rsa R9b RlOb ~b Zb 94-36395-36396-36397-363Rc Rsa R9b RlOb Gb Zb 94-36495-36496-36497-364Ra Rsb Rib RlOb Gb Zb 94-36595-36596-36597-365Rb Rsb R9b RIOb ~b zb 94-36695-36696-36697-366R RSb R9b Rlob Gb Zb 94-36795-36796-36797-367Ra RSc R9b RIOb Gb ~b 94-36895-36896-36897-368Rb R5c R9b RlOb Gb Zb 94-36995-36996-36997-369R RSc R9b Riob Gb ~b 94-37095-37096-37097-370Ra Rsa R9c RlOb Gb Zb 94-37195-37196-37197-371Rb RSa R9c RlOb Gb zb 94-37295-37296-37297-372R R5a R9c RiOb Gb Zb 94-37395-37396-37397-373Ra Rsb R9c RIOb Gb Zb 94-37495-37496-37497-374Rb Rsb R9c RIOb Gb Zb 94-37595-37596-37597-375Rc RSb R9c RiOb Gb Zb 94-37695-37696-37697-376Ra Rsc R9c RIOb Gb Zb 94-37795-37796-37797-377Rb Rsc R9c Rlob Gb zb 94-37895-37896-37897-378Rc RSc R9c RlOb Gb Zb 94-37995-37996-37997-379Ra RSa R9a RlOc Gb ~b 94-38095-38096-38097-380Rb Rsa R9a RlOc Gb zb 94-38195-38196-38197-381Rc R5a R9a RlOc Gb Zb 94-38295-38296-38297-382Ra RSb Rya RIOc Gb zb 94-38395-38396-38397-383Rb RSb R9a RlOc Gb zb 94-38495-38496-38497-384Rc RSb R9a R~o Gb zb 94-38595-38596-38597-385Ra RSc R9a RIOc Gb zb 94-38695-38696-38697-386Rb Rsc Rga RlOc ~b Zb 94-38795-38796-38797-387R RSc R9a RlOc Gb Zb 94-38895-38896-38897-388Ra Rsa R9b RlOc Gb zb 94-38995-38996-38997-389Rb RSa R9b RlOc ~b zb 94-39095-39096-39097-390Rc RSa R9b RIOc Gb zb 94-39195-39196-39I97-391Ra R5b R9b RIOc Gb Zb 94-39295-39296-39297-392Rb RSb R9b Rloc Gb Zb 94-39395-39396-39397-393Rc RSb R9b RlOc Gb Zb 94-39495-39496-39497-394Ra R5c Rob RIOc Gb ~b 94-3959S-39596-39597-395Rb Rsc R9b RIOc Gb zb 94-39695-39696-39697-396Rc Rsc R9b Rloc Gb Zb 94-39795-39796-39797-397Ra Rsa R9c RIOc Gb ~b 94-39895-39896-39897-398Rb RSa R9c Rloc Gb zb 94-39995-39996-39997-399R R5a R9c RlOc Gb zb 94-40095-40096-40097-400Ra RSb R9c RlOc Gb Zb 94-40195-40196-40197-401Rb RSb R9c R~o Gb Zb 94-40295-40296-40297-402Rc RSb R9c RlOc Gb zb 94-40395-40396-40397-403Ra Rsc R9c RlOc Gb ~b 94-40495-40496-40497-404Rb RSc R9c RlOc ~b Zb 94-40595-40596-40597-405Rc RSc R9c RlOc Gb zb 94-40695-40696-40697-406Ra RSa R9a RlOa ~c Zb 94-40795-40796-40797-407Rb RSa R9a RlOa ~c zb 94-40895-40896-40897-408R RSa R9a RlOa Gc Zb 94-40995-40996-40997-409Ra RSb R9a RIOa Gc Zb 94-41095-41096-41097-410Rb RSb R9a , Gc Zb RlOa 94-41195-41196-41197-411Rc Rsb R9a RlOa Gc zb 94-41295-41296-41297-412Ra Rsc R9a R~oa Gc zb 94-4I395-41396-41397-413Rb R5c R9a RlOa Gc zb 94-41495-41496-41497-414Rc R5c R9a RlOa Gc Zb 94-41595-41596-41597-415Ra Rsa R9b RlOa Gc Zb 94-41695-41696-41697-416Rb RSa R9b RiOa Gc zb 94-41795-41796-41797-417R RSa R9b RlOa Gc ~b 94-4I895-41896-41897-418Ra Rsb R9b R~oa Gc Zb 94-41995-41996-41997-419Rb RSb R9b RIOa Gc zb 94-42095-42096-42097-420RC RSb R9b RIOa Gc Zb 94-42195-42196-42197-421Ra RSc R9b RlOa Gc Zb 94-42295-42296-42297-422Rb RSc Rib RlOa Gc zb 94-42395-42396-42397-423Rc RSc R9b RlOa Gc zb 94-42495-42496-42497-424Ra Rsa R~ RlOa Gc zb 94-42595-42596-42597-425Rb R5a R9c RlOa Gc zb 94-42695-42696-42697-426R Rsa R9c RlOa ~c zb 94-42795-42796-42797-427Ra Rsb R9c RIOa Gc Zb 94-42895-42896-42897-428Rb RSb R9c Rtoa Gc zb 94-42995-42996-42997-429Rc Rsb R9c RIOa Gc zb 94-43095-43096-43097-430Ra RSc R9c RlOa Gc zb 94-43195-43196-43197-431Rb RSc R9c Rloa Gc Zb 94-43295-43296-43297-432Rc Rsc R9c RlOa Gc Zb 94-43395-43396-43397-433Ra RSa R9a RlOb Gc zb 94-43495-43496-43497-434Rb RSa Rya RlOb Gc ~b 94-43595-43596-43597-435Rc RSa R9a RlOb Gc zb 94-43695-43696-43697-436Ra R5b R9a RIOb ~c zb 94-43795-43796-43797-437Rb R5b R9a RIOb ~c ~b 94-43895-43896-43897-438Rc R5b R9a RlOb Gc Zb 94-43995-43996-43997-439Ra Rsc R9a RlOb ~c ~b 94-44095-44096-44097-440Rb RSc R9a RlOb Gc Zb 94-44195-44196-44197-441Rc Rsc R9a RIOb Gc zb 94-44295-44296-44297-442Ra RSa R9b RlOb Gc Zb 94-44395-44396-44397-443Rb RSa R9b RlOb Gc ~b 94-44495-44496-44497-444Rc Rsa R9b RIOb ~c ~b 94-44595-44596-44597-445Ra RSb R9b RIOb Gc Zb 94-44695-44696-44697-446Rb R5b R9b RlOb Gc zb 94-44795-44796-44797-447R RSb R9b RlOb Gc Zb 94-44895-44896-44897-448Ra RSc R9b Rob G~ Zb 94-44995-44996-44997-449Rb Rsc R9b RIOb ~o Zb 94-45095-45096-45097-450Rc RSc Rgb RlOb ~c ~b 94-45195-45196-45197-45IRa RSa R9c RlOb Gc zb 94-45295-45296-45297-452Rb RSa R9c RlOb Gc zb 94-45395-45396-45397-453Rc Rsa R9c RlOb Gc Zb 94-45495-45496-45497-454Ra R5b R9c RlOb Gc zb 94-45595-45596-45597-455Rb R5b R9c RI06 Gc zb 94-45695-45696-45697-456R R5b R9c RlOb Gc zb 94-45795-45796-45797-457Ra Rsc R9c Rlob Gc zb 94-45895-45896-45897-458Rb RSc R9c RlOb Gc zb 94-45995-45996-45997-459R RSc R9c Rlob ~c ~b 94-46095-46096-46097-460Ra R5a R9a RIOc ~c Zb 94-46195-46196-46197-461Rb Rsa R9a RlOc Gc zb 94-46295-46296-46297-462R Rsa R9a RlOc ~c zb 94-46395-46396-46397-463Ra Rsb R9a Rloc ~c Zb 94-46495-46496-46497-464Rb RSb R9a RIOc Gc zb 94-46595-46596-46597-465Rc Rsb R9a RIOc Gc Zb 94-46695-46696-46697-466Ra RSc R9a RlOc Gc Zb 94-46795-46796-46797-467Rb Rsc R9a RlOc Gc Zb 94-46895-46896-46897-468R Rsc R9a RlOc Gc zb 94-46995-46996-46997-469Ra RSa R9b RlOc Gc zb 94-47095-47096-47097-470Rb RSa R9b RlOc Gc Zb 94-47195-47196-47197-471R RSa R9b RIOc Gc Zb 94-47295-47296-47297-472Ra RSb R9b RIOc ~c zb 94-47395-47396-47397-473Rb RSb R9b RlOc ~c Zb 94-47495-47496-47497-474R RSb R9b RIOc Gc zb 94-47595-47596-47597-475Ra Rsc R9b Rloc Gc zb 94-47695-47696-47697-476Rb RSc R9b RlOc Gc zb 94-47795-47796-47797-477R Rsc R9b RlOc Gc zb 94-47895-47896-47897-478Ra Rsa R9c RlOc Gc Zb 94-47995-47996-47997-479Rb RSa R9c RIOc Gc Zb 94-48095-48096-48097-480Rc R5a R9c R30c Gc ~b 94-48195-48196-48197-481Ra Rsb R9c RIOc Gc ~b 94-48295-48296-48297-482Rb Rsb R9c RIOc ~c zb 94-48395-48396-48397-483Rc RSb R9c RlOc ~c ~b 94-48495-48496-48497-484Ra R5c R9c RIOc ~c zb 94-48595-48596-48597-485Rb Rsc R9c RlOc Gc zb 94-48695-48696-48697-486Rc Rsc R9c RlOc Gc Zb 94-48795-48796-48797-487Ra RSa R9a RlOa ~a zc 94-48895-48896-48897-488Rb RSa R9a RlOa Ga Zc 94-48995-48996-48997-489Rc Rsa R9a RlOa Ga ~c 94-49095-49096-49097-490Ra RSb R9a RlOa Ga zc 94-49195-49196-49197-491Rb RSb R9a RlOa Ga Zc 94-49295-49296-49297-492Rc RSb R9a RIOa ~a zc 94-49395-49396-49397-493Ra RSc R9a RlOa Ga ~c 94-49495-49496-49497-494Rb Rsc R9a RlOa ~a zc 94-49595-49596-49597-495Rc Rsc R9a RlOa Ga Zc 94-49695-49696-49697-496Ra RSa R9b RlOa Ga Zc 94-49795-49796-49797-497Rb Rsa R9b RlOa Ga zc 94-49895-49896-49897-498R Rsa R9b RlOa ~a Zc 94-49995-49996-49997-499Ra RSb R9b RlOa Ga ~c 94-50095-50096-50097-500Rb R5b R9b RlOa ~a ~c 94-50195-50196-50197-501Rc RSb R9b Rloa Ga 2c 94-50295-50296-50297-502Ra RSc R9b RlOa Ga zc 94-50395-50396-50397-503Rb Rsc R9b Rloa Ga Zc 94-50495-50496-50497-504Rc R5c R9b RIOa Ga Zc 94-50595-50596-50597-505Ra RSa R9c RlOa Ga ~c 94-50695-50696-50697-506Rb RSa R9c RIOa Ga zc 94-50795-50796-50797-507R Rsa R9c RlOa Ga zc 94-50895-50896-50897-508Ra RSb R9c RIOa Ga Zc 94-50995-50996-50997-509Rb RSb R9c RlOa Ga zc 94-51095-51096-51097-510R RSb R9c RIOa Ga zc 94-51195-51196-51197-511Ra RSc R9c RIOa Ga zc 94-51295-51296-51297-512Rb RSc R9c RlOa Ga ~c 94-51395-51396-51397-513R Rsc R9c RIOa Ga zc 94-51495-51496-51497-514Ra R5a R9a RIOb Ga zc 94-51595-51596-51597-515Rb RSa R9a RlOb Ga Zc 94-51695-51696-51697-516Rc Rsa R9a RlOb Ga zc 94-51795-51796-51797-517Ra R5b R9a RIOb Ga Zc 94-51895-51896-51897-518Rb RSb R9a RIOb Ga zc 94-51995-51996-51997-519R Rsb R9a RlOb Ga Zc 94-52095-52096-52097-520Ra Rsc R9a RlOb Ga Zc 94-52195-52196-52197-521Rb RSc R9a RlOb Ga zc 94-52295-52296-52297-522R Rsc R9a RlOb ~a ~c 94-52395-52396-52397-523Ra RSa R9b RlOb Ga zc 94-52495-52496-52497-524Rb RSa R9b RIOb ~a ~c 94-52595-52596-52597-525R Rsa R9b RIOb Ga Zc 94-52695-52696-52697-526Ra R5b R9b RiOb Ga Zc 94-52795-52796-52797-527Rb R5b R9b RlOb Ga ~c 94-52895-52896-52897-52$Rc Rsb R9b RlOb Ga Zc 94-52995-52996-52997-529Ra RSc R9b RIOb Ga Zc 94-53095-53096-53097-530Rb RSc R9b RIOb Ga Zc 94-53195-53196-53197-531Rc Rsc R9b RIOb Ga Zc 94-53295-53296-53297-532Ra R5a R9c RlOb ~a zc 94-53395-53396-53397-533Rb R5a R9c RiOb Ga zc 94-53495-53496-53497-534Rc RSa R9c RlOb ~a zc 94-53595-53596-53597-535Ra RSb R9c RIOb Ga zc 94-53695-53696-53697-536Rb Rsb R~ RIOb Ga ~c 94-53795-53796-53797-537Rc RSb jZ~ RlOb ~a zc 94-53895-53896-53897-538Ra RSc R9c RlOb Ga zc 94-53995-53996-53997-539Rb Rsc R9 RIOb Ga zc 94-54095-54096-54097-540Rc Rsc R9c RlOb Ga ~c 94-54195-54196-54197-541Ra R5a R9a Rloc Ga ~c 94-54295-54296-54297-542Rb RSa R9a RlOc Ga zc 94-54395-54396-54397-543R RSa R9a RlOc ~a Zc 94-54495-54496-54497-544Ra Rsb R9a RlOc ~a ~c 94-54595-54596-54597-545Rb RSb R9a Rtoc Ga Zc 94-54695-54696-54697-546Rc R5b R9a RlOc Ga Zc 94-54795-54796-54797-547Ra R5c R9a RlOc Ga zc 94-54895-54896-54897-548Rb RSc R9a RIOc Ga Zc 94-54995-54996-54997-549Rc R5c R9a RlOc Ga Zc 94-55095-55096-55097-550Ra R5a R9b RlOc ~a Zc 94-55195-55196-55197-551Rb Rsa R9b RlOc ~a Zc 94-55295-55296-55297-552Rc RSa R9b RIOc Ga Zc 94-55395-55396-55397-553Ra R~' R9b RIOc Ga ~c 94-55495-55496-55497-554Rb RSb Rgb RlOc Ga Zc 94-55595-55596-55597-555R Rsb R9b RlOc Ga ~c 94-55695-55696-55697-556Ra Rsc R9b Rloc Ga Zc 94-55795-55796-55797-557Rb Rsc R9b RlOc Ga Zc 94-55895-55896-55897-558R Rsc R9b RlOc Ga Zc 94-55995-55996-55997-559Ra R5a R9c RIOc Ga zc 94-56095-56096-56097-560Rb RSa R9c RlOc Ga zc 94-56195-56196-56197-561Rc R5a R9c RlOc Ga Zc 94-56295-56296-56297-562Ra RSb R9c Rloc Ga Zc 94-56395-56396-56397-563Rb RSb R9c RlOc Ga zc 94-56495-56496-56497-564Rc RSb R9c RlOc ~a zc 94-56595-56596-56597-565Ra RSc R9c RlOc Ga Zc 94-56695-56696-56697-566Rb RSc R9c Rloc Ga zc 94-56795-56796-56797-567Rc RSc R9c RlOc Ga Zc 94-56895-56896-56897-568Ra RSa R9a RlOa Gb zc 94-56995-56996-56997-569Rb RSa R9a RiOa Gb zc 94-57095-57096-57097-570Rc RSa R9a RlOa ~b zc .

94-57195-57196-57197-571Ra RSb R9a RIOa Gb zc 94-57295-57296-57297-572Rb Rsb R9a RIOa ~b Zc 94-57395-57396-57397-573R Rsb R9a RIOa Gb zc 94-57495-57496-57497-574Ra R5c R9a RlOa ~b Zc 94-57595-57596-57597-575Rb RSc R9a RIOa Gb Zc 94-57695-57696-57697-576Rc Rsc R9a RIOa Gb Zc 94-57795-57796-57797-577Ra RSa R9b RIOa ~b Zc 94-57895-57896-57897-578Rb Rsa R9b RlOa Gb zc 94-57995-57996-57997-579Rc RSa R9b RlOa Gb zc 94-58095-58096-58097-580Ra Rsb R9b RlOa Gb zc 94-58195-58196-58197-581Rb Rsb R9b RlOa Gb zc 94-58295-58296-58297-582Rc Rsb R9b RlOa Gb zc 94-58395-58396-58397-583Ra Rsc R9b RlOa Gb Zc 94-58495-58496-58497-584Rb R5c R9b RlOa Gb Zc 94-58595-58596-58597-585Rc Rsc R9b RIOa Gb zc 94-58695-58696-58697-586Ra R5a R9c RlOa Gb 2c 94-58795-58796-58797-587Rb RSa R9c RlOa Gb ~c 94-58895-58896-58897-588R Rsa R9c Rloa Gb Zc 94-58995-58996-58997-589Ra RSb R9c RIOa ~b Zc 94-59095-59096-59097-590Rb R5b R9c RIOa ~b Zc 94-59195-59196-59197-591Rc RSb R9c RlOa ~b Zc 94-59295-59296-59297-592Ra RSc R9c RIOa Gb Zc 94-59395-59396-59397-593Rb RSc R9c RIOa Gb Zc 94-59495-59496-59497-594Rc RSc R9c RlOa Gb Zc 94-59595-59596-59597-595Ra Rsa R9a RlOb Gb zc 94-59695-59696-59697-596Rb Rsa R9a RlOb Gb Zc 94-59795-59796-59797-597Rc Rsa R9a Rlob Ob Zc 94-59895-59896-59897-598Ra RSb R9a RlOb Gb Zc 94-59995-59996-59997-599Rb RSb R9a RlOb Gb zc 94-60095-60096-60097-600Rc Rsb R9a RlOb Gb zc 94-60195-60196-60197-601Ra RSc R9a RIOb Gb Zc 94-60295-60296-60297-602Rb Rsc R9a RlOb Gb Zc 94-60395-60396-60397-603Rc Rsc R9a RlOb ~b Zc 94-60495-60496-60497-604Ra RSa R9b RlOb Gb Zc 94-60595-60596-60597-605Rb RSa R9b Rlob Gb zc 94-60695-60696-60697-606Rc R5a R9b RlOb Gb Zc 94-60795-60796-60797-607Ra Rsb R9b Rlob Gb Zc 94-60895-60896-60897-608Rb R5b R9b RlOb Gb Zc 94-60995-60996-60997-609R Rsb R9b RiOb Gb Zc 94-61095-61096-61097-610Ra Rsc R9b RIOb Gb zc 94-61195-61196-61197-611Rb RSc R9b RlOb ~b zc 94-61295-61296-61297-612Rc Rsc R9b RIOb Gb Zc 94-61395-61396-61397-613Ra RSa R9c RIOb Gb Zc 94-61495-61496-61497-614Rb R5a R9c RlOb Gb zc 94-61595-61596-61597-615Rc RSa R9c RlOb Gb zc 94-61695-61696-61697-616Ra R5b R9c RlOb Gb ~c 94-61795-61796-61797-617Rb RSb R9c RlOb Gb zc 94-61895-61896-61897-618Rc RSb R9c Rlob Gb zc 94-61995-61996-61997-619Ra RSc R9c RIOb Gb Zc 94-62095-62096-62097-620Rb RSc R9c RlOb Gb Zc 94-62195-62196-62197-621Rc RSc R9c RlOb Gb zc 94-62295-62296-62297-622Ra R5a R9a RlOc Gb zc 94-62395-62396-62397-623Rb Rsa R9a RlOc Gb Zc 94-62495-62496-62497-624Rc RSa R9a RlOc Gb Zc 94-62595-62596-62597-625Ra RSb R9a RIOc Gb Zc 94-62695-62696-62697-626Rb R5b R9a RIOc Gb ~c 94-62795-62796-62797-627R R5b R9a R~Oc Gb Zc 94-62895-62896-62897-628Ra RSc R9a RlOc ~b Zc 94-62995-62996-62997-629Rb Rsc R9a RlOc Gb zc 94-63095-63096-63097-630R RSc h'~a RiOc Gb 2c 94-63195-63196-63197-631Ra RSa R9b RlOc Gb zc 94-63295-63296-63297-632Rb Rsa R9b RIOc Gb Zc 94-63395-63396-63397-633R R5a R9b RIOc Gb Zc 94-63495-63496-63497-634Ra RSb R9b RlOc Gb Zc 94-63595-63596-63597-635Rb Rsb R9b RlOc Gb Zc 94-63695-63696-63697-636Rc Rsb R9b RlOc Gb zc 94-63795-63796-63797-637Ra Rsc R9b RlOc Gb ~c 94-63895-63896-63897-638Rb Rsc R9b RIOc Gb Zc 94-63995-63996-63997-639R Rsc R9b RIOc Gb Zc 94-64095-64096-64097-640Ra R5a R9c RlOc ~b Zc 94-64195-64196-64197-641Rb R5a R9c RlOc Gb ~c 94-64295-64296-64297-642Rc RSa R9c RlOc Gb Zc 94-64395-64396-64397-643Ra R5b R9c RIOc ~b Zc 94-64495-64496-64497-644Rb Rsb R9c Rloc Gb zc 94-64595-64596-64597-645Rc RSb R9c R1 Gb Zc oc 94-64695-64696-64697-646Ra Rsc R9c RlOc Gb zc 94-64795-64796-64797-647Rb RSc R9c Rloc Gb Zc 94-64895-64896-64897-648Rc Rsc R9c RlOc Gb Zc 94-64995-64996-64997-649Ra R5a R9a RIOa Gc Zc 94-65095-65096-65097-650Rb RSa R9a R~oa Gc zc 94-65195-65196-65197-651R Rsa R9a RiOa Gc zc 94-65295-65296-65297-652Ra R5b R9a RlOa Gc zc 94-65395-65396-65397-653Rb RSb R9a RlOa Gc zc 94-65495-65496-65497-654R R5b R9a RlOa Gc zc 94-65595-65596-65597-655Ra RSc R9a RlOa Gc Zc 94-65695-65696-65697-656Rb RSc R9a RlOa Gc ~c 94-65795-65796-65797-657Rc RSc R9a RIOa ~c zc 94-65895-65896-65897-658Ra R5a R9b RIOa Gc Zc 94-65995-65996-65997-659Rb RSa R9b RlOa Gc Zc 94-66095-66096-66097-660Rc RSa R9b RlOa Gc zc 94-66195-66196-66197-661Ra RSb R9b RIOa Gc Zc 94-66295-66296-66297-662Rb Rsb R9b RlOa Gc Zc 94-66395-66396-66397-663Rc Rsb R9b Rloa ~c zc 94-66495-66496-66497-664Ra RSc R9b RlOa ~c zc 94-66595-66596-66597-665Rb RSc R9b RlOa ~c zc 94-66695-66696-66697-666Rc Rsc R9b RlOa Gc Zc 94-66795-66796-66797-667Ra R5a R9c RlOa Gc Zc 94-66895-66896-66897-668Rb R5a R9c Rloa Gc Zc 94-66995-66996-66997-669R Rsa R9c RlOa Gc zc 94-67095-67096-67097-670Ra RSb R9c Rloa Gc zc 94-67195-67196-67197-671Rb Rsb R9c RIOa Gc Zc 94-67295-67296-67297-672Rc RSb R9c RlOa Gc Zc 94-67395-67396-67397-673Ra R5c R9c RIOa Gc Zc 94-67495-67496-67497-674Rb Rsc R9c RlOa Gc zc 94-67595-67596-67597-675R RSc R9c RlOa Gc Zc 94-67695-67696-67697-676Ra RSa R9a RlOb ~c zc 94-67795-67796-67797-677Rb RSa Rya RIOb Gc Zc 94-67895-67896-67897-678Rc Rsa R9a RIOb Gc ~c 94-67995-67996-67997-679Ra RSb R9a RIOb Gc zc 94-68095-68096-68097-680Rb R5b R9a RIOb Gc ~c 94-68195-68196-68197-681Rc RSb R9a RlOb Gc zc 94-68295-68296-68297-682Ra RSc R9a RlOb ~c zc 94-68395-68396-68397-683Rb R5c R9a RIOb Gc zc 94-68495-68496-68497-684R R5c R9a RIOb Gc 2c 94-68595-68596-68597-685Ra RSa R9b RiOb Gc Zc 94-68695-68696-68697-686Rb RSa R9b RlOb Gc ~c 94-68795-68796-68797-687Rc Rsa R9b RIOb ~c ~c 94-68895-68896-68897-688Ra RSb R9b RlOb Gc zc 94-68995-68996-68997-689Rb RSb R9b RIOb Gc zc 94-69095-69096-69097-690Rc Rsb R9b RlOb Gc zc 94-69195-69196-69197-691Ra RSc R9b RlOb Gc zc 94-69295-69296-69297-692Rb RSc R9b RIOb Gc zc 94-69395-69396-69397-693Rc RSc Rgb Rlob Gc zc 94-69495-69496-69497-694Ra Rsa R9c RIOb Gc Zc 94-69595-69596-69597-695Rb RSa R9c RIOb Gc zc 94-69695-69696-69697-696Rc Rsa R9c RlOb Gc ~c 94-69795-69796-69797-697Ra R5b R9c RIOb Gc Zc 94-G9895-69896-69897-698Rb RSb R9c Blob Gc Zc 94-69995-69996-69997-699R Rsb R9c RIOb Gc zc 94-70095-70096-70097-700Ra RSc R9c RlOb Gc ~c 94-70195-70196-70197-701Rb R5c R9c RIOb ~c zc 94-70295-70296-70297-702R RSc R9c RIOb Gc Zc 94-70395-70396-70397-703Ra RSa R9a RlOc Gc Zc 94-70495-70496-70497-704Rb R5a R9a RIOc Gc zc 94-70595-70596-70597-705R Rsa R9a RlOc Gc zc 94-70695-70696-70697-706Ra R55 R9a RlOc Gc zc 94-70795-70796-70797-707Rb R5b R9a RIOc Gc Zc 94-70895-70896-70897-708Rc RSb Rya R~o Gc Z

94-70995-70996-70997-709Ra Rsc R9a RlOc Gc Zc 94-71095-71096-71097-710Rb Rsc R9a RIOc Gc Zc 94-71195-71196-71197-711Rc Rsc R9a RIOc Gc zc 94-71295-71296-71297-712Ra Rsa R9b RIOc Gc Zc 94-71395-71396-71397-713Rb Rsa R9b RlOc Gc Zc 94-71495-71496-71497-714R Rsa R9~'RIOc Gc Zc 94-71595-71596-71597-715Ra RSb R9b RIOc Gc ~o 94-71695-71696-71697-716Rb Rsb R9b Rloc Gc zc 94-71795-71796-71797-717Rc Rsb R9b Bloc Gc Z

94-71895-71896-71897-718Ra Rsc R9b RlOc Gc zc 94-71995-71996-71997-7I9Rb R5c Rsb Rloc Gc zc 94-72095-72096-72097-720Rc RSc R9b RlOc Gc zc 94-72195-72196-72197-721Ra R5a R9c RIOc Gc Zc 94-72295-72296-72297-722Rb RSa R9c RlOc Gc Zc 94-72395-72396-72397-723Rc RSa R9c RIOc Gc zc 94-72495-72496-72497-724Ra RSb R9c RlOc Gc Zc 94-72595-72596-72597-725Rb Rsb R9c Rloc Gc 2c 94-72695-72696-72697-726R R5b R9c Rloc Gc Zc 94-72795-72796-72797-727Ra R5c R9c RIOc Gc Zc 94-72895-72896-72897-728Rb RSc R9c RIOc Gc zc 94-72995-72996-72997-729Rc RSc R9c RlOc Gc zc where all symbols are as defined above.
In one aspect of any of formulae (94), (95), (96), and (97) of the present invention, R
is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; RS is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an allcoxyalkyl group;
R9 and R'°
independently are hydrogen, a halogen, a vitro group, an amino group, a mono-or di-substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, to an oxo(O=) group, or a thio(S=) group; G is f CHZ)z, fCH2)3, or f CHZ)4;
and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formulae (94), (95), (96), and (97) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amilio group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; RS

is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an allcoxy group, an allcenyl group, or an alkoxyalkyl group; R9 and Rl° independently are an alkyl group, a cycloalkyl group, an allcoxy group, a haloalleoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbanyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; and G is f CH232, f CHZ)3, or ~CH2)~; and all other symbols are as defined as above in connection with formula (I).
In yet another aspect of of formulae (94), (95), (96), and (97) the present invention, R
is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; RS is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R~
and R' °
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 heterocyclyl sulfonyl group, wluch is optionally substituted with a halogen, a hydroxyl group, a vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an allcoxy group, or an aryl group; and G is ~CHZ)Z, ECH2~3, or fCH2)~; and all other symbols are as defined as above in connection with formula (I).
In still another aspect of any of formulae (94), (95), (96), and (97) of the present invention, R is hydrogen or an alkyl group; R5 is hydrogen or an alkyl group;
R9 is hydrogen, O
-~-S-N~ 'Me an alkoxy group, or O ; Rl° is hydrogen or an alkoxy group; and G is f CHZ)2, ~CHZ)3, or f CHZ)4.
In still another aspect of any of formulae (94), (95), (96), and (97) of the present O
-~-S-N~ N'Me invention, R is -H or Me; RS is -H or Me; R9 is -H, -OMe, or O ; R'° is -H, -OMe, or -OEt; and G is f CHz32, fCH~j~, or f CHZj4.

The present invention further encompasses various compounds of general formula (IV) as follows:
OMe O O
R~ / OMe ~NR R~ /~OMe ~NR
I S O
Nw w _ I s0 ~~ Nw w I _ . s R
N~N~N G-Z ~ ~ R N~N~N G-Z
Me [°J (98); Me I°I ( °
R~ /OEt ~NR R~
'I °
R5 N~ I
N,N I N-G-Z ~ ~ ,N~
Me ° (100); and Me (101);
where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, R, R', R5, G, and Z of any of formulae (98), (99), (100), and (101) are selected to produce compounds of formulae (98-1), (99-1), (100-1), and (101-1) through formulae (98-243), (99-243), (100-243), and (101-243) as follows:
Formulae R R R5 G Z

98-1 99-1 100-1 101-1 Ra R Rsa Ga Za a 98-2 99-2 100-2 101-2 Rb Rta Rsa Ga za 98-3 99-3 100-3 101-3 R Rla Rsa Ga Za 98-4 99-4 100-4 101-4 Ra RIb Rsa Ga Za 98-5 99-5 100-5 101-5 Rb R1b Rsa Ga Za 98-6 99-6 100-6 101-6 R RIb Rsa Ga Za 98-7 99-7 100-7 101-7 Ra R~~ Rsa Ga Za 98-8 99-8 100-8 101-8 Rb Rl~ Rsa Ga Za 98-9 99-9 100-9 101-9 R RI Rsa Ga Za 98-10 99-10 100-10 101-10 Ra Rta Rsb Ga Za 98-11 99-11 100-11 141-11 Rb Rla R56 Ga Za 98-12 99-12 100-12 101-12 R Rla Rsb Ga Za 98-13 99-13 100-13 101-13 Ra Rlb Rsb Ga Za 98-14 99-14 100-14 101-14 Rb Rtb R56 Ga Za 98-15 99-15 100-15 101-15 R~ Rtb R56 Ga Za 98-16 99-16 100-16 101-16 Ra Rt R56 Ga Za 98-17 99-17 100-17 101-17 Rb Rl~ Rsb Ga Za 98-18 99-18 100-18 101-18 RC R~~ R56 Ga Za 98-19 99-19 100-19 101-19 Ra Rta Rsc Ga Za 98-20 99-20 100-20 101-20 Rb Rta Rsc Ga Za 98-2199-21 100-21 101-21 R Ria Rsc Ga Za 98-2299-22 100-22 101-22 Ra Rib Rsc Ga Za 9$-2399-23 100-23 101-23 Rb Rib R5c Ga za 98-2499-24 100-24 101-24 Rc Rib Rsc ~a za 98-2599-25 100-25 101-25 Ra Ric Rsc Ga ~a 98-2699-26 100-26 101-26 Rb Ric R5c Ga ~a 98-2799-27 100-27 101-27 R Ric Rsc Ga za 98-2899-28 100-28 101-28 Ra Ria Rsa ~b za 98-2999-29 100-29 101-29 Rb Ria Rsa Gb za 98-3099-30 100-30 101-30 Rc Ria Rsa Gb za 98-3199-31 100-31 101-31 Ra Rib Rsa Gb ~a 98-3299-32 100-32 101-32 Rb Rib Rsa Gb za 98-3399-33 100-33 101-33 Rc Rib Rsa ~b 2a 98-3499-34 100-34 101-34 Ra Ric Rsa Gb za 98-3599-35 100-35 101-35 Rb Ric Rsa ~b za 98-3699-36 100-36 101-36 R Ric Rsa Gb za 98-3799-37 100-37 101-37 Ra Ria Rsb ~b za 98-3899-38 100-38 101-38 Rb Ria Rsb Gb za 98-3999-39 100-39 101-39 Rc Ria Rsb Gb za 98-4099-40 100-40 101-40 Ra Rib R5b ~b ~a 9$-4199-41 100-41 101-41 Rb Rib Rsb Gb za 98-4299-42 100-42 101-42 Rc Rib Rsb Gb za 98-4399-43 100-43 101-43 Ra Ric Rsb Gb za 98-4499-44 100-44 101-44 Rb Ric Rsb Gb za 98-4599-45 100-45 101-45 Rc Ric Rsb Gb za 98-4699-46 100-46 101-46 Ra Ria Rsc Gb za 98-4799-47 100-47 101-47 Rb Rla Rsc ~b za 98-4899-48 100-48 101-48 Rc Ria Rsc ~b za 98-4999-49 100-49 101-49 Ra Rib Rsc Gb za 98-5099-50 100-50 101-50 Rb Rib Rsc Gb za 98-5199-51 100-51 101-51 Rc Rib Rsc ~b za 98-5299-52 100-52 101-52 Ra Ric Rsc Gb za 98-5399-53 100-53 101-53 Rb Ric Rsc (ib 2a 98-5499-54 100-54 101-54 Rc Roc Rsc ~b ~a 98-5599-55 100-55 101-55 Ra Rya R5a ~c Za 98-5699-56 100-56 101-56 Rb Ria R5a Gc 2a 98-5799-57 100-57 101-57 Rc Ria Rsa ~c 2a 98-5899-58 100-58 101-58 Ra Rib Rsa Gc ~a 98-5999-59 100-59 101-59 Rb Rib Rsa Gc Za 98-6099-60 100-60 101-60 Rc Rib Rsa ~c za 98-6199-61 100-61 101-6I Ra Ric Rsa Gc za 98-6299-62 100-62 101-62 Rb Ric Rsa ~ za 98-6399-63 100-63 101-63 Rc Roc Rsa Gc ~a 98-6499-64 100-64 101-64 Ra Rya Rsb Gc Za 98-6599-65 100-65 101-65 Rb Rya Rsb Gc Za 98-6699-66 100-66 101-66 R Rya Rsb ~c ~a 98-6799-67 100-67 101-67 Ra Rib Rsb ~c Za 98-6899-68 100-68 101-68 Rb R1b Rsb Gc 2a 98-6999-69 100-69 101-69 Rc RIb Rsb Gc ~a 98-7099-70 100-70 101-70 Ra Rlc Rsb Gc 2a 98-7199-71 100-71 10I-71 Rb Rlc Rsb Gc Za 98-7299-72 100-72 101-72 R RIc Rsb Gc Za 98-7399-73 100-73 101-73 Ra Rla Rsc Gc Za 98-7499-74 100-74 101-74 Rb R1a Rsc Gc Za 98-7599-75 100-75 101-75 Rc Rla Rsc Gc Za 98-7699-76 100-76 101-76 Ra Rib Rsc Gc Za 98-7799-77 100-77 101-77 Rb Rib Rsc G Za 98-7899-78 100-78 101-78 Rc Rib Rsc Gc Za 98-7999-79 100-79 101-79 Ra RIc Rsc Gc Za 98-8099-80 100-80 101-80 Rb R~ Rsc Gc ~a 98-8199-81 100-81 101-81 R Rlc Rsc Gc 2a 98-8299-82 100-82 101-82 Ra R1a Rsa Ga zb 98-8399-83 100-83 l0I-83 Rb Rla Rsa Ga Zb 98-8499-84 100-84 101-84 R Rya Rsa Ga 2b 98-8599-85 I00-85 101-$5 Ra Rlb Rsa Ga 2b 98-8699-86 100-86 101-86 Rb Rib Rsa Ga ~b 98-8799-87 100-87 101-87 R RIb Rsa Ga Zb 98-8899-88 100-88 101-88 Ra Rlc Rsa Ga Zb 9$-8999-89 100-89 101-89 Rb Roc Rsa Ga Zb 98-9099-90 100-90 101-90 R Rjc Rsa Ga ~b 98-9199-91 100-91 101-91 Ra R1a Rsb Ga Zb 98-9299-92 100-92 101-92 Rb Rla Rsb Ga ~b 98-9399-93 100-93 101-93 Rc Rla Rsb Ga ~b 98-9499-94 100-94 101-94 Ra Rlb Rsb Ga ~b 98-9599-95 100-95 101-95 Rb Rib Rsb Ga zb 98-9699-96 100-96 101-96 Rc RIb Rsb Ga Zb 98-9799-97 100-97 101-97 Ra Rlc Rsb Ga ~b 98-9899-98 100-98 101-98 Rb Rlc Rsb Ga Zb 98-9999-99 100-99 101-99 Rc Rlc Rsb Ga 2b 98-10099-100100-100101-100Ra Rla Rsc Ga Zb 98-10199-101100-101101-101Rb R1a Rsc Ga zb 98-10299-102100-102101-102R Rla Rsc Ga zb 98-10399-103100-103101-103Ra RIb Rsc Ga ~b 98-10499-104100-104101-104Rb RIb Rsc Ga zb 98-10599-105100-105101-105Rc Rlb Rsc Ga zb 98-10699-106100-106101-106Ra Rlc Rsc Ga 2b 98-10799-107100-107101-107Rb RIc R5c Ga ~b 98-10899-108100-108101-108R Rlc Rsc Ga Zb 98-10999-109100-109101-109Ra Rla Rsa Gb Zb 98-11099-110100-I10101-110Rb R1a Rsa Gb Zb 98-11199-111100-111101-111R Rla Rsa Gb Zb 98-11299-112100-112101-112Ra R1b Rsa Gb ~b 98-11399-113100-113101-113Rb Rlb Rsa Gb Zb 98-11499-114100-114101-114R RIb Rsa Gb 2b 98-11599-115 100-115101-115Ra Ric Rsa Gb Zb 98-lI699-116 100-116101-I16Rb Ric Rsa Gb Zb 98-11799-117 100-117101-117R Ric Rsa Gb Zb 98-11899-118 I00-II8I0I-118Ra Ria Rsb Gb Zb 9$-11999-119 100-119IOI-119Rb Ria Rsb Gb Zb 98-12099-120 100-120101-120R Ria Rsb Gb Zb 98-12199-121 100-121101-12IRa Rib Rsb Gb Zb 98-I2299-122 100-122101-122Rb Rib Rsb Gb Zb 98-12399-123 100-123101-123R Rib Rsb Gb Zb 98-12499-124 100-124l0l-124Ra Ric Rsb Gb Zb 98-12599-I25 100-I25101-I25Rb Ric Rsb Gb Zb 98-12699-126 100-I26101-126R Ric Rsb Gb Zb 98-I2799-127 100-127101-I27Ra Ria Rsc Gb Zb 98-12899-128 100-128101-I28Rb Ria Rsc Gb Zb 98-12999-129 100-129101-129Rc Ria Rsc Gb Zb 98-13099-130 100-130101-130Ra Rib Rsc Gb Zb 98-13199-131 100-131101-131Rb Rib Rsc Gb Zb 98-13299-132 100-132101-132R Rib Rsc Gb Zb 98-13399-133 100-133101-I33Ra Ric Rsc Gb Zb 98-13499-134 100-134101-134Rb Ric Rsc Gb Zb 98-13599-135 100-135101-135R Ric Rsc Gb Zb 98-13699-136 100-136101-136Ra Ria Rsa Gc Zb 98-13799-I37 100-137101-137Rb Ria Rsa Gc Zb 98-13899-138 100-138101-I38R Ria Rsa Gc Zb 98-13999-139 100-139101-139Ra Rib Rsa Gc Zb 98-14099-140 100-140101-140Rb Rib Rsa Gc Zb 98-14199-141 I00-141101-14IRc Rib Rsa Gc Zb 98-14299-142 100-142101-142Ra Ric Rsa Gc Zb 98-14399-143 100-143101-143Rb Ric Rsa Gc Zb 98-14499-144 100-144101-144R Ric Rsa Gc Zb 98-14599-145 100-145101-145Ra Ria Rsb G Zb 98-14699-146 100-146101-146Rb Ria Rsb Gc Zb 98-14799-147 100-147101-147Rc Ria Rsb Gc Zb 98-14899-148 I00-148101-148Ra Rib Rsb Gc Zb 98-14999-149 I00-149101-149Rb Rib Rsb Gc Zb 98-15099-150 100-150101-150R Rib Rsb Gc Zb 98-15199-151 100-151101-151Ra Ric Rsb Gc Zb 98-15299-I52 100-152101-152Rb R' Rsb G Zb 98-15399-153 100-153101-153Rc Ric Rsb G Zb 98-15499-154 100-154101-154Ra Ria Rsc Gc Zb 98-I5599-155 100-155I01-155Rb Ria Rsc Gc Zb 98-15699-156 100-156101-156Rc Ria Rsc Gc Zb 98-15799-157 100-157101-157Ra Rib Rsc Gc Zb 98-15899-158 100-158101-158Rb Rib Rsc G Zb 98-15999-I59 100-159101-159R Rib Rsc Gc Zb 98-16099-160 100-160101-160Ra Ric Rsc Gc Zb 98-16199-161 100-161101-161Rb Ric Rsc Gc Zb 98-16299-162 100-162101-162R Roc Rsc G Zb 98-I6399-163 100-163101-I63Ra R1a Rsa Ga Zc 98-I6499-I64 100-164101-164Rb R1a Rsa Ga Zc 98-16599-165 100-165101-165R Rla Rsa Ga Zc 98-16699-166 100-166101-166Ra R1b Rsa Ga Zc 98-16799-167 100-I67l0l-167Rb Rlb Rsa Ga Zc 98-16899-168 100-168101-16$Rc RIb Rsa Ga Zc 98-16999-169 100-169I01-169Ra Rlc Rsa Ga Zc 98-17099-170 100-170101-170Rb RIc Rsa Ga Zc 98-17199-171 100-17Il0l-171Rc Rlc Rsa Ga Zc 98-17299-I72 100-I72101-I72Ra Rla Rsb Ga Zc 98-17399-173 100-173101-173Rb Rla Rsb Ga Zc 98-17499-174 I00-174101-174R Rya Rsb Ga Zc 98-17599-175 100-175101-175Ra R1b Rsb Ga Zc 98-17699-I76 100-I76101-176Rb Rlb Rsb Ga Zc 98-I7799-177 100-177101-177Rc Rlb Rsb Ga Zc 98-17899-178 100-178101-178Ra R1c Rsb Ga Zc 98-17999-179 100-179101-179Rb Ric Rsb Ga Zc 98-18099-I80 100-180101-180Rc Roc Rsb Ga Zc 98-18199-I81 100-181101-181Ra Rya R5 Ga Zc 98-18299-182 100-182101-182Rb R1a Rsc Ga Zc 98-18399-I$3 100-183I01-183Rc Rla Rsc Ga Zc 98-18499-184 100-I84101-I84Ra RIb Rsc Ga Zc 98-18599-185 100-185101-I85Rb RIb Rsc Ga Zc 98-18699-I86 100-186101-186R RIb Rsc Ga Zc 98-18799-187 100-187101-187Ra Rlc Rsc Ga Zc 98-18899-188 100-188101-188Rb Rlc Rsc Ga Zc 98-18999-189 100-189101-189Rc Roc Rsc Ga Zc 98-19099-I90 100-190101-I90Ra Rla R5a Gb Zc 98-19199-19I 100-191101-191Rb R1a Rsa Gb Zc 98-I9299-192 100-192101-192Rc Rla Rsa Gb Zc 98-19399-193 100-I93101-193Ra Rlb Rsa Gb Zc 98-19499-194 100-194101-I94Rb j'yb Rsa Gb Zc 98-19599-195 100-195101-195Rc Rlb Rsa Gb Zc 98-19699-196 100-I96101-196Ra R1c Rsa Gb Zc 98-19799-197 100-197101-197Rb R~ Rsa Gb Zc 98-I9899-198 100-198101-198Rc RIc Rsa Gb Zc 98-19999-199 100-199101-199Ra R1a Rsb Gb Zc 98-20099-200 100-200101-200Rb Rla Rsb Gb Zc 98-20199-201 100-201101-201Rc Rya Rsb Gb Zc 98-20299-202 100-202IOI-202Ra Rib R'~' Gb Z

98-20399-203 100-203101-203Rb Rib Rsb Gb Z

98-20499-204 I00-204101-204R Rib Rsb Gb Zc 98-20599-205 I00-205101-205Ra RI Rsb Gb Zc 98-20699-206 100-206101-206Rb Roc Rsb Gb Zc 98-20799-207 100-207101-207R Rlc Rsb Gb Z

98-20899-208 100-208101-208Ra Rya Rsc Gb Zc 98-20999-209 I00-209101-209 Rb RIa Rsc Gb Z

98-21099-210 100-210101-210 Rc Rla Rsc Gb Zc 98-21199-211 100-211101-211 Ra R1b Rsc Gb Zc 98-21299-212 100-212101-212 Rb Rlb Rsc Gb Z

98-21399-213 100-213101-213 Rc Rib Rsc Gb Z

98-21499-214 100-214101-214 Ra Rlc Rsc Gb Zc 98-21599-215 100-215101-215 Rb Rlc Rsc Gb Z

98-21699-216 100-216101-216 R Rlc Rsc Gb Z

98-21799-217 100-217101-217 Ra Rya Rsa Gc Zc 98-21899-218 100-218101-218 Rb RIa Rsa Gc Zc 98-21999-219 100-219101-219 Rc Rla Rsa Gc Zc 98-22099-220 100-220101-220 Ra Rlb Rsa Gc Zc 98-22199-221 100-221101-221 Rb Rib Rsa G Zc 98-22299-222 100-222101-222 R RIb Rsa G Zc 98-22399-223 100-223101-223 Ra Rlc Rsa Gc Zc 98-22499-224 100-224101-224 Rb Ric Rsa Gc Zc 98-22599-225 100-225101-225 Rc Roc Rsa G Zc 98-22699-226 100-226101-226 Ra RIa Rsb Gc Zc 98-22799-227 100-227I01-227 Rb Rla Rsb Gc Zc 98-22899-228 100-228101-228 R Rla Rsb Gc Zc 98-22999-229 100-229101-229 Ra Rib Rsb G Zc 98-23099-230 100-230101-230 Rb Rib Rsb Gc Z

98-23199-231 100-231101-231 Rc RIb Rsb Gc Zc 98-23299-232 100-232101-232 Ra Rlc Rsb Gc Zc 98-23399-233 100-233101-233 Rb RIc Rsb Gc Zc 98-23499-234 100-234101-234 R Rlc Rsb Gc Zc 98-23599-235 100-235101-235 Ra RIa Rsc Gc Zc 98-23699-236 100-236101-236 Rb Rla Rsc Gc Zc 98-23799-237 100-237141-237 Rc Rla Rsc Gc Zc 98-23899-238 100-238101-238 Ra Rib Rsc Gc Z

98-23999-239 100-239101-239 Rb Rlb Rsc Gc Z

98-24099-240 100-240101-240 Rc RIb Rsc Gc Zc 98-24199-241 100-241101-241 Ra RIc Rsc Gc Zc 98-24299-242 100-242101-242 Rb RIc Rsc Gc Z

98-24399-243 100-243101-243 R Roc Rsc Gc Z

where all symbols are as defined above.
In one aspect of any of formulae (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 allcyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; RI is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an allcyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an allcenyloxy group, or a cycloalkenyloxy group; RS is is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alleoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an allcoxyalkyl group, an allcenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, G is -(CH2)S , where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I).
to In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, G is -(CHZ)S CH=CH-(CH~)S-, where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, G is -(CH2)5 C=C-(CHZ)S , where s is an integer from 0-5; and all other symbols are as defined above in cormection with formula (I).
In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, Z is O, and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, Z is NR, and all other symbols are as defined above in connection with formula (I).
In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, Z is fCH~)" or S(=O)", where a is an integer from 0-2; and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (98), (99), (100), and (101) of the present invention, E is O, and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (98), (99), (100), and (101) of the present invention, E is S, and all other symbols are as defined above in connection with formula (I).
In still another aspect of any of formulae (98), (99), (100), and (101) of the present invention, E is NR, and all other symbols are as defined above in connection with formula (I).
Examples of compounds having general formula (IV) include, but are not limited to:

d /~N
s o I ~ o N~o "~o OCHa \ OCHa N/ N~O \ O NH
O I / / _ ~O
N_N~
> >
~NiCHa OEt ~~ / N
I '\o N\ \
O N\
N~ II N V ' ~ ~O
O
O ~ ~ ~ S
and According to another aspect of the present invention, various compounds of general formula (I) having general formula (V) Rz B\A ~E~R4 X4 g~C~ W Ar K L-~CH~~ v -C-X~CH~~ ~C-O-R
X~ X

WO 2005/042712 , PCT/US2004/035939 its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates are provided. Except as otherwise provided herein, all symbols are as defined above in connection with formula (I).
Examples of compounds having the general formula (V' contemplated by the present invention include, but are not limited to:
R~

R~ B .p I ~E~R X4 g(C) W Ar D~ ~ J K-L-(CHa) v -C-X-(CH2) p \C-O-R
Rs ~ XZ X
(102);
R~

R2 B ;S~~E~R X4 S(p) W Ar I ~/
p/~~ \ 'K-L-(CH2)v-~-X-(CH2)p \Ii-C-R
R ~X ~ Xs (103);
R~

R~ B N i vE\ /R XQ S(C) w Ar D: ~~ ~ ~K(-L-(GH2)v -C-X-(CH2) p ~C-O-R
R~ ~ IX2 IX
(104);
R~
R~ B ;C ~E~R4 X4 S(p) W Ar p: ~~ ~ K-L-(CH2) v -C-X-(CH~)~C-O-R
R~ ~ X2 X
(105);
R~
R~ HB ~~cH2~%E~R4 ~X4 S(O),"r Ar K-L-(CH2)v- i-X-(CH2)p \C-C-R
Rs ~ Xz X
3 (106);
R~

R~ p A~~E~R X4 S(0) w Ar D~~~s' ~K-~--(CH2)v-IX-X-(CH2)p \Ii-O-R
R/ IXI ~ X3 (107);

R~ S A ~ ~E~R X4 S(C) w Ar D/~~ ~K-~ (CHa)v-X X-(CH~)~C-O-R
R IX' ~ Xs (108);

RZ N A I ~E~R4 X4 S(C) W Ar D: ~ ~ TK-~-(CHa)v-C-X-(CH2)~C_0_R
/ ~ II
Rs X X~ II
X3 (109);

RZ HC A~'E~R X4 S(C) w Ar ~J I ~./
D~~~~ ~K-L-(CH2)v-~ -X-(CH2)~I~-C_R
R IXI 2 Xs (110)i R~
~A ~E~R4 g(p) W Ar R2 cHzC>~ ~ I Xa DS~3: ~K-~-(CHZ)v-X X-(CH2 p--CII C R

(111);
R~
a _ R2 B p'~~E~R X4 g(C) w Ar o~,~: ~~~-~-(~H2)v-~ -X-(~H2)~~-o_R
IXI X~
X3 (112);

Ra g \A i ~E~R4 X4 S(C) w Ar I _ _ S/ J~ ~~-~ (CH2)v-i X (CH2)P I~ C R
R/ X ~ X3 (113);

R2 g~A~~E~R4 X4 S(C) w Ar HC~ J~' ~I'K-~'-(CH2)v-C-X-(CH~)~C_C_R
Rs IXI X~ II
X3 (114);

R~
\ 4 R~ g \A /E~R X4 S(O) w Ar ~H2C)n / 3 ~ K-L-(CH2) v -C-X-(CHI) p~C-O-R
Rs ~ X2 X
(115);
R~
Ra ~A 1 /E\ / X4 SAO) W Ar R2 B ,~
I _ _ _ \ 'K-L-(CH2)v (~ X (CHOP ~~ O R
R/a ~X X2 X
(116);
R~
4 X4 g(O) W Ar ~E~R
g~A
~
~

~ _ R i (CFi2)-p-C
~ I -X -O-f2 D~~S~
K-L-(CH2)v-~ i / I
I

X (117);

4 X4 g(O) W Ar sE~R
g~A
T

~
I -~-X-(CH~)p C_O-R
R
~
D/NJ
K-L (CHa)v ~
I
I

R ~ X3 (118);
X

R~
\ 4 X4 S(O) w Ar g~A
~E~R' ~ ~
R K-L-(CH~)v-C-X--O-R
~ I (CH~)~
p~C~ \ ' R H ~ i X X3 (119);

R~
4 X4 g(O) W Ar ~E~R
g~A
2 ' II

~ -C-X -(CH2)-p-R -O-R
K-L-(CH2)v i X lI (12U)i R~
a X4 g(O) W Ar ~O~R
g~A

~
R -X
~ X-(CHa)~
I -O-R
p/ ~ ~
K-L-(CHI) v ~ i R X ~ Xs (121);

R~
g~A X4 S(p) w Ar ~~~R4 a ~ ~/
R X-(CH2)~
D/~: -p-R
K-~ (CHZ)v -~ i I X
I

R Z X
X (122);

R~
R Ra X4 g(p) W Ar g~A ~N~

R I _ ~
D,/~ ~ K-L-(CH~)v -C-X (CH2) p 'C-p-R

/ ~

R X~ IX
(123);

R~
4 X4 g(p) W Ar g~A
~E~R

~ -C-X-(CH2)~C-O-R
R
D~ ~~
N-L-(CHZ) v ~

R X 2 X3 (124);

~E~R4 X4 S(p) w Ar g~'4 R~ -C-X-(CHa)p \C-O-R
i IC-L-(CH~)v D/~~

~

R X 2 X3 (125);

R~
4 X4 g(p) W Ar g~A
oE~R

R~ CH-L-(CHz) - i -X-(CH2) p \C-p-R
~ v D/ ~:

~
I
I

R3 X~ IX3 (126) X

R~
~A ~E~R 4 g(p) W Ar B ~ ~ X

R (CH2)v C-X-(CHZ) p ~C-p-R
p/~~
K-~-G-Z-Ar-\

~

R
X X3 (127);

R~
~A ,E /g(p) W Ar Ra X
B
~

~
~. ~/

(CH2)v IX-X-(CH~)~C-p-R
D~~~:
~K-Y-G-~

~ ~
R/ I
I X

x Xa (128);

R~
4 ~g(O) W Ar ~A
,E
R

R2D:
, ~
~
(CH~)t-(CHa) v C-X-(CHI) p a O
R
~

~ X
~

R ~ I ( (129);

R~
4 g(O) W Ar ,E
R X
B
~

R2~ 4 ~~~~~ (CH2)V
\ X (CH2) p~C-O-R
/K-L-~ O

R Xs X (130);

R~
4 og(O) W Ar ~A
,E
R

R2D: (CH2)v C-X-(CH2) p a ~ I
~ C-O-R
~
L-~
J

~ S

R X3 (131);

R~
4 ~g(O) W Ar /E~R
X

R2- ~
~ a I X-(CH2) p \C-O_R
p~ (CH~)v C
J~
\
/K-L-~ R

R X3 (132);
X

R~
B X4 S(O) W Ar A
/E~Ra R~~ \ /K-L -(CH~)v p~~J~~ i-X-(CH~)p C_O-R

~ I

R3 X~ O (133);
X

R~
4 g(O) W Ar ,E
R X
B
~

Rz~ 4 p~ (CH~)v yX-(CH2)~C-O_R
J~
~K-L-R 2 S (134);
X

R~

B S(O) W Ar A
~E~R

R~~ 4 ~~~Je' -(L'H2)V C-X-(CH~)~C-p-R
~K-~-/
I
I

R X2 NI R (135) X

R~ B A~~E~Ra O~S(O) W Ar D/~~ \/K-L-(CH~)v I I X (CH2) p~C-O-R
R3 fXI X2 X
(136);

R2 B A ~E~Ra S~S(O),N Ar K-L-(CHa)v C-X-(CH~)~C-O-R
R/ ~ x2 I I
X3 (137);

R2 B A~~E~R RN~g(O) W Ar K-L-(CH2)v C-X-(CH2)p \C-O-R
R/s ~ ?C~ X
(138);
R1 _ / R11 B A of Ra X~S(O) w \ ,R12 R2~ Ja p/~~: ~K-L-(CH~)v iI-X (CH2p-\C-O-R
Rs IXI X2 II
X3 (139); and R1 a B A~~E R X~S(O)w \ ~
R2 D:~ ~ ~ L-(CH~)v C-X-(CH2)-~a \R1~
R~.1 ~ X~ C-O-R
X3 (140), where all symbols are as defined above in connection with formula (I).
The present invention contemplates various compounds of general formula (V) having the formula:
Rts H HN o~~Rta CH2) ~ ~O~R
H2)p 0 0 (141), where RI1, Ri2, RI3, and R14 independently are hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an aryl group, an acyloxy group, an amyl group, an allcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, an aralkyl group, an alkylsulfonyl group, an alkylsulf'myl group, an arylsulfonyl group, an arylsulfmyl 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 l0 group, a vitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomoipholinyl group, or a piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an allcoxy group, or an aryl group; and all other symbols are defined as above in connection with formula (I).
In one aspect of formula (141) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group; and all other symbols are as defined in connection 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 connection with formula (I).
In another aspect of formula (141) of the present invention, Rl is hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an allcoxy 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 connection with formula (I).
In another aspect of formula (141) of the present invention, R'' is hydrogen, a hydroxy group, a halogen, a vitro 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 allcenyl group, a cycloallcenyl group, an alkoxyallcyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in connection with formula (I}.
In yet another aspect of formula (141) of the present invention, R' ~ is hydrogen, a halogen, a vitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an allcoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; and all other symbols are as defined in connection with formula (I).
In still another aspect of formula (141) of the present invention, RIl is an alkylsulfonyl group, an alkylsulfmyl group, an arylsulfonyl group, an arylsulfmyl 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 vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl l0 group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in connection with formula (I).
In yet another aspect of formula (141) of the present invention, R12 is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) is group; and all other symbols are as defined in connection with formula (I).
In still another aspect of formula (141) of the present invention, R'2 is an alkylsulfonyl group, an alkylsulfmyl group, an arylsulfonyl group, an arylsulfmyl 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 20 group, a vitro 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 piperzinyl group, wherein the substiiuent on the heterocyclyl group is a halogen, a vitro group, an amino group, an allcyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in connection with formula (I).
25 In a further aspect of fomnula (141) of the present invention, R13 is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group; and all other symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, R13 is an alleylsulfonyl 30 group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an arallcylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other s symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, R14 is hydrogen, a halogen, a vitro 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(O=) group, or a thio(S=) group; and all other symbols are as defined in connection with formula (I).
In yet another aspect of formula (141) of the present invention, RI4 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 vitro 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 piperzinyl group, wherein the substituent on the heterocyclyl group is a halogen, a vitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in connection with formula (I).
In yet another aspect of formula (141) of the present invention, R is hydrogen or an 2o alkyl group, and all other symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, R is -H, CH3, or CZHS, and all other symbols are as defined in connection with formula (I).
In still another aspect of formula (141) of the present invention, RI is hydrogen or an alkyl group, and all other symbols are as defined in connection with formula (I).
In yet another aspect of formula (141) of the present invention, R' is -H, CH3, or C2H5, and all other symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, RZ is hydrogen or an alleyl group, and all other symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, RZ is -H, CH3, or CZHS, 3o and all other symbols are as defined in connection with formula (I).

In yet another aspect of formula (141) of the present invention, Rll is hydrogen, a halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, R' 1 is -H, -Cl, -OGH3, or -SCH3, and all other symbols are as defined in connection with formula (I).
In a further aspect of formula (141) of the present invention, Rlz is hydrogen, a halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in connection with formula (I).
In a another aspect of formula (141) of the present invention, R~Z is H, Cl, -OCH3, or to -SCH3, and all other symbols are as defined in connection with formula (I).
In a further aspect of formula (141) of the present invention, RI3 is hydrogen, a halogen, or an allcyl group, and all other symbols are as defined in connection with formula (I).
In a still further aspect of formula (141) of the present invention, RI3 is -H, -F, or CH3, and all other symbols are as defined in connection with formula (I).
In yet another aspect of formula (141) of the present invention, R'4 is hydrogen, a halogen, or an alkyl group, and all other symbols are as defined in connection with formula (I).
In a further aspect of formula (141) of the present invention, R14 is -H, -F, or -CH3, and all other symbols are as defined in connection with formula (I).
In another aspect of formula (141) of the present invention, RI 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 alleenyl group, a cycloalkenyl group, an alkoxyallcyl group, an alkenyloxy group, or a cycloalkenyloxy group; RII, R'2, R'3, 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(O=) group, or a thio(S=) group, an alkyl group, or a cycloalkyl group, an alkoxy group; and all other symbols are as defined as above in connection with formula (I).
In another aspect of formula (141) of the present invention, Ri and R2 independently are hydrogen, a hydroxy group, a halogen, an allcoxy group; RI', RIZ, R13, and Rla independently are hydrogen, a halogen, a hydroxy group, an alkoxy group; and all other symbols are as defined as above in coimection with formula (I).
In yet another aspect of formula (141) of the present invention, RI and Rz independently are -H or -OCH3; Rl1 is -Cl, -OCH3, or -SCH3; RIZ is -Cl, -OCH3, or -H; R is H, CH3, or CZHS; R13 is F or CH3; RI4 1S F or CH3; v is 0 or 1; and all other symbols are as defined as above in connection with formula (I).
The present invention also contemplates various compounds of general formula (V) as follows:

R~~ I I N.H O
Rz/~ NR ~OR
SO H
(142), to where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, R, Rl, and R2 of formula (142) are selected to produce various compounds of formula (142-1) through formula (142-27) as follows:
Formula R R R

142-1 Ra Rla R a 142-2 Rb Rla Rza 142-3 R~ Rla Rza 142-4 Ra Rlb Rza 142-5 Rb Rib Rza 142-6 R~ Rlb Rza 142-7 Ra Rl~ Rza 142-8 Rb RI Rza 142-9 R Rl~ Rza 142-10 Ra Rla Rzb 142-11 Rb Rla Rzb 142-12 R Rla Rzb 142-13 Ra Rlb Rzb 142-14 Rb Rlb Rzb 142-15 R Rib Rzb 142-16 Ra RI Rzv 142-17 Rb R'~ Rzb 142-18 R Rl~ Rzb 142-19 Ra Rl~ Rz 142-20Rb Rla Rzc 142-21R Rla Rz 142-22Ra Rib Rzc 142-23RU Rib Rzc 142-24R RIb Rzc 142-25Ra Rlc Rzc 142-26Rb R' Rzc 142-27R R~ Rz where all symbols are as defined above.
In one aspect of formula (142) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, alkyl group, an alkoxy group, an allcenyl group, or an alkoxyalkyl group; and Rl and Rz independently are hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloallcoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group.
l0 In another aspect of formula (142) of the present invention, R' and Rz are independently a halogen or an alkyl group; and R is hydrogen, an allcyl NOz _ group, ~ ~ \ , or ~~ .
In still another aspect of formula ( 142) of the present invention, R' is -OCH3 or -F; Rz NOz _ is -OCH3 or -Cl; R is -H or CZHS, ~ / \ , or ~~ .
~s The present invention also contemplates various compounds of general formula (~
as follows:
R~ N (CHZ)v NH~(CH2)P COzR
~\ ~ /
1 ~ ~' RZ ~%/ NCO \ I O NH
O=S=O
O
/I
R1g\/~R14 (143) where all symbols are as defined above in connection with formula (I).
In one aspect of formula (143) of the present invention, Rl and Rz independently are 20 hydrogen, a hydroxy group, a halogen, a vitro 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 allcenyl group, a cycloalkenyl group, an allcoxyallcyl group, an alkenyloxy group, or a cycloalkenyloxy group; RI3 and R'4 independently are hydrogen, a halogen, a vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an allcoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an allcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; and all other symbols are as defined in connection with formula (I).
In another aspect of formula (143) of the present invention, RI 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 heteroaralkyl 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 vitro 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(O=) group, a thio(S=) group, an alkyl group, a cycloalkyl group, an allcoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an aryl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralleyl group; and all other symbols are as defined in connection with formula (I).
In another aspect of formula (143) of the present invention, RI and RZ
independently are hydrogen, an alkyl group, or an alkoxy group; R13 and RI4 independently are hydrogen, a halogen, an alkyl group, or an alkoxy group; and all other symbols are as defined in connection with formula (I).
In yet another aspect of formula (143) of the present invention, R' and RZ are -H or -OCH3; RI3 is CH3 or -F; RI4 is -H or -F; and all other symbols are as defined in connection with formula (I).
The present invention also contemplates various compounds of general formula (V) having the formula:

~(CH2)p CO~R
R ~\ N\ / (CH2)~~NH
RZ ~%/ \IN~O \ ~ ~O NH
O=S=O
O
cH3 (144), where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, R, R', Rz, v, and p of formula (144) are selected to produce various compounds of formula (144-1} through (144-243) as follows:
FormulaR R R v p 144-1 Ra Ria R a va pa 144-2 Rb Rla Rza va pa 144-3 R Rla Rza va pa .

144-4 Ra Rlb Rza va pa 144-5 Rb Rlb Rza va pa 144-6 R Rlv Rza va pa 144-7 Ra Rl Rza va pa 144-8 Rb RI R''a va pa 144-9 R~ Rl~ Rza va pa 144-10 Ra Rla Rzb va pa 144-11 Rb Rla Rzb va pa 144-12 R~ Rla Rzt, va pa 144-13 Ra Rtb Rzb va pa 144-14 Rb Rlb Rzb va pa 144-15 R Rlb R2b va pa I44-16 Ra RI~ Rzb va pa 144-17 Rb RI~ Rzb va pa 144-18 R Rl~ Rzb va pa 144-19 Ra R~ a Rz~ va pa 144-20 Rb R~ a Rz va pa 144-21 R Rla Rz va pa 144-22 Ra Rlb Rzo va pa 144-23 Rb Rlb R2~ va pa 144-24 R~ Rib Rz va pa 144-25 Ra Rye Rz~ va pa 144-26 Rb Rl~ R2~ va pa 144-27 R~ R1 Rz~ va pa 144-28 Ra Rla Rza vb pa 144-29 Rb R1a Rza vb pa 144-30 R~ Rya Rza vb pa 144-31 Ra RIb Rza vb pa 144-32Rb Rib Rza vb pa 144-33R Rib Rza vb pa I44-34Ra Ri Rza vb pa 144-35Rb Ric Rza vb pa 144-36R Ric Rza vb pa 144-37Ra Ria Rzb vb pa 144-38Rb Ria Rzb vb pa 144-39Rc Ria Rzb vb pa 144-40Ra Rib Rzb vb pa 144-41Rb Rib Rzb vb pa 144-42Rc Rib Rzb vb pa 144-43Ra Ric Rzb vb pa I44-44Rb Ri c Rzb vb pa 144-45Rc Ric Rzb vb pa 144-46Ra Ri a Rzc vb pa 144-47Rb Ria Rzc vb pa 144-48R Ria Rzc vb pa 144-49Ra Rib Rzc vb pa 144-50Rb Rib Rzc vb pa 144-51Rc Rib Rzc vb pa 144-52Ra RI c Rzc vb pa 144-53Rb Ric Rzc vb pa 144-54Rc Ri Rz vb pa 144-55Ra Ria Rza vc pa 144-56Rb Ria Rza vc pa 144-57R Ria Rza vc pa 144-58Ra Rib Rza vc pa 144-59Rb Rib Rza vc pa 144-60R Rib Rza v pa 144-61Ra Ri c Rza vc pa 144-62Rb Ric Rza vc pa 144-63Rc Ri c Rza vc pa 144-64Ra Ria Rzb vc pa 144-65Rb Ria Rzb v pa 144-66Rc Ria R2b vc pa 144-67Ra Rib R2b vc pa 144-68Rb Rib Rzb vc pa 144-69Rc Rib Rzb v pa 144-70Ra Ric Rzb vc pa 144-71Rb Ric R2b vc pa 144-72R Ri Rzb vc pa 144-73Ra Ria Rzc vc pa 144-74Rb Ria Rzc vc pa 144-75Rc Ria Rzc vc pa 144-76Ra Rib Rzc vc pa 144-77Rb Rib Rzc vc pa 144-78Rc Rib Rzc v pa 144-79Ra R'c Rzc vc pa 144-80Rb Rlc Rzc v pa 144-81Rc Rlc Rzc vc pa 144-82Ra R' Rza va pb a 144-83Rb R'a Rza va pb 144-84Rc R' Rza va pb a z b 'b 144-85Ra R R va p " a b z 144-86Rb R a va p ' R b " z 144-87R R R Va p ' a 144-88Ra Roc Rza va pb 144-89Rb R'c Rza va pb 144-90R R' Rza va pb c 144-91Ra R' Rzb va pb a b 144-92Rb R' Rzb va p a 144-93R R'a Rzb va pb 144-94Ra R'b Rzb va pb 144-95Rb R'b Rzb va pb 144-96Rc Rtb Rzb va pb 144-97Ra Roc Rzb pa pb 144-98Rb Rlc Rzb va pb 144-99Rc Rlc Rzb va pb 144-100Ra R'a Rzc va pb ' b 144-101Rb R Rzc va p a 144-102Rc R'a Rzc va pb b z b 144-103Ra R' R va p c 144-104Rb R'b Rzc va pb 144-105Rc Rib Rzc Va pb 144-106Ra Rlc Rzc Va pb b 144-107Rb Ric Rzc va p 144-108R R'c Rzc va b p b 144-109Ra R'a Rza vb p 144-110Rb R'a Rza vb pb 144-111R R'a Rza vb pb 144-112Ra R'b Rza vb pb 144-113Rb R'b Rza Vb pb b b 144-114R R'b Rza v p 144-115Ra R'c Rza vb pb 144-116Rb Rlc Rza Vb b p b 144-117Rc Rlc Rza vb p 144-118Ra R'a Rzb ~b pb 144-119Rb Rla Rzb Vb pb 144-120R R'a Rzb vb pb 144-121Ra R'b Rzb vb pb b b b b 144-122Rb R' Rz v p b b b b 144-123R R' Rz V p 144-124Ra R'c Rzb vb pb 144-125Rb R'c Rzb vb pb 144-126Rc Ric Rzb Vb b p i z b 144-127Ra R R v pb a c 144-128Rb Ria Rzc Vb b P
i z b 144-129R R c v b a R P
ib 144-130Ra R Rzc vb pb 144-131Rb Rib Rzc vb pb 144-132Rc Rib Rzc vb pb 144-133Ra Ric Rzc vb b P
b i z b 144-134R R R v pb c c 144-I35Rc Ric Rzc vb b P

144-136Ra Ria Rza vc b P

144-137Rb Ria Rza vc pb 144-138R Ria R2a vc pb 144-139Ra Rib Rza vc b P
b ib z 144-140R R a vc b R P
ib 144-141Rc R Rza vc pb 144-142Ra Ric Rza vc pb 144-I43Rb Ric Rza vc pb 144-144Rc Ric Rza vc b P

144-145Ra Ria Rzb v b P

144-146Rb Ria Rzb Vc b P

144-147Rc Ria Rzb vc b p ib zb 144-148Ra R R vc b P

144-149Rb Rib Rzb vc pb 144-150R Rib Rzb vc b P
i zb 144-151Ra c R vc pb R

144-152Rb Ric R2b vc pb 144-153R Ric Rzb vc pb 144-154Ra Ria Rzc vc pb 144-155Rb Ria Rzc vc pb 144-156R Ria Rzc ~c pb 144-157Ra Rib Rzc vc b P

144-I58Rb Rib Rzc vc pb 144-159R Rib Rzc v pb 144-160Ra Ric Rzc vc b h b i 144-161R R Rz vc pb c 144-162R Ric Rzc v pb 144-163Ra Ria Rza va pc 144-164Rb Ria Rza va pc 144-165Rc Ria Rza va pc 144-166Ra Rib Rza va pc 144-167Rb Rib Rza va pc 144-168R Rib Rza va pc 144-169Ra Ric Rza va pc 144-170Rb Ric Rza va pc 144-171R Ric Rza va pc 144-172Ra Ria Rzb va pc 144-I73Rb Rla Rzb va pc 144-174R Rya Rzb va ~c 144-175Ra Rlb Rzb va pc 144-176Rb R'b Rzb ',a pc 144-177R Rlb Rzb Va pc 144-178Ra R'c Rzb va pc 144-179Rb Rlc Rzb va ~o 144-180R Rlc Rzb va pc 144-181Ra R'a Rzc va pc 144-182Rb Rla Rzc va pc 144-183Rc Rla Rzc va pc 144-184Ra R"' Rzc va pc 144-185Rb Rlb Rzc va pc 144-186Rc Rlb Rzc va pc 144-187Ra Rlc Rzc va ~c 144-188Rb R'c Rzc va pc 144-189Rc R'c Rzc va pc 144-190Ra Rla Rza Vb pc 144-191Rb Rla Rza Vb pc 144-192R Rya Rza vb ~c 144-193Ra R"' Rza vb pc 144-194Rb R"' Rza vb pc 144-195R Rlb Rza vb pc 144-196Ra Rlc Rza vb pc 144-197Rb Rlc R2a vb pc 144-198Rc Rlc Rza vb pc 144-199Ra Rta Rzb vb pc 144-200Rb R'a Rzb vb pc 144-201Rc Rla Rzb Vb pc 144-202Ra Rlb Rzb vb ~c 144-203Rb Rlb Rzb vb pc 144-204R Rlb Rzb vb p 144-205Ra R' Rzb vb pc 144-206Rb R'c Rzb vb p 144-207Rc R' Rzb vb pc c I44-208Ra jZla R2c ~b pc 144-209Rb Rl Rzc vb pc a 144-210Rc R' Rzc Vb pc a 144-211Ra R"' Rzc Vb pc 144-212Rb R'b Rzc vb pc 144-213Rc R'b Rzc vb pc 144-214Ra R' Rz vb pc 144-215Rb R' Rzc vb pc 144-216R R'c Rzc vb pc 144-217Ra R' Rza uc pc a 144-218Rb R' Rza vc pc a 144-219Rc R' Rza vc pc a 144-220 Ra Rlb R2a vc pc 144-22I Rb Rib R2a vc pc 144-222 R RIb R2a vc pc 144-223 Ra RIc RZa vc pc 144-224 Rb RIc R2a vc pc 144-225 R Rtc R2a ~ pc 144-226 Ra Rja R2b vc pc 144-227 Rb RI R2b vc pc a 144-228 Rc Rla R2b vc pc 144-229 Ra RIb R2b vc pc 144-230 Rb RIb R2b vc pc 144-231 Rc Rib R2b vc pc 144-232 Ra Rlc R2b v pc 144-233 Rb Rlc R2b vc pc 144-234 Rc RI R2b vc pc 144-235 Ra Ria R?c vc pc 144-236 Rb Ria R2c vc pc 144-237 Rc Rla RZc vc pc 144-238 Ra Rlb R2c vc pc 144-239 Rb RIb Rzc vc p 144-240 Rc Rlb RZc v p 144-241 Ra Rlc R2c vc pc 144-242 Rb RIc R'' vc pc 144-243 R~ RI R2c vc pc c where all symbols are as defined above.
In one aspect of formula (144) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an allcyl group, an alkoxy group, an allcenyl group, or an alkoxyalkyl group; Rl and RZ
independently are hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalleyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an allcenyloxy group, or a cycloallcenyloxy group; and all other symbols are as defined in to connection with formula (I).
In another aspect of formula (144) of the present invention, Rl and RZ are independently hydrogen, an alkyl group, or an alkoxy group; and all other symbols are as defined in cormection with formula (I).
In yet another aspect of formula (144) of the present invention, RI and R2 are -OCH3;
and all other symbols are as defined W connection with formula (I).

The present invention further contemplates various compounds of general formula (V) having the formula:
R~~
~~/R1z / O
O W O~ N. H O
I ~ O ~OR
Ii Ra~~ Ov,N
z / I SO .H
(145), where all symbols are as defined above in connection with formula (I).
According to various aspects of the present invention, R, RI, R2, RI', and R12 of formula (145 are selected to provide various compounds of formula (145-1) through formula (145-243) as follows:
Formula R Rl R' R' R12 145-1 Ra Rla Rza R a RI2a 145-2 Rb RI a R2a RI 1 RI2a a 145-3 R~ RI a R2a Rt t Rt2a a 145-4 Ra Rlb R2a Rlla Rl2a 145-5 Rb RIb R2a Rna Rl2a 145-6 R~ Rlv Rza R~~a Rl2a 145-7 Ra RI~ R2a Rna Rt2a 145-8 Rb Rl~ R2a Rna Rl2a 145-9 R~ Rl~ R2a Rlla Rlza 145-10 Ra Rla R2b Rna R~za 145-11 Rb RIa R2t Rna R~2a 145-12 R~ Rl a R2b R> > Rl2a a 145-13 Ra R1b R2b Rlla R~2a 145-14 Rv Rib R2b Rlla R,~2a 145-15 R~ Rib Rzb R~~a R~2a 145-16 Ra R~~ R2b Rlla Rl2a 145-17 Rb Rm R2b Rna R~2a 145-18 R~ R'~ R2b Rtm Rl2a 145-19 Ra RIa R2c Rna Rt2a 145-?0 Rb Rla Rzc Rna Rt2a 145-21 R R~ a Rz RI t R~
a 2a 145-22 Ra R~ b R2~ R> > Rl2a a 145-23 Rb Rlb Rzc Rna Rt2a 145-24 R~ Rib R2~ Rtla R~2a 145-25 Ra RI Rzc Rna R~2a 145-26 Rb RI Rzc R> > Rl2a a 145-27R Rl Rzc Rlla Rl2a 145-28Ra Rla Rza Rllb Rl2a 145-29Rb Rla R2a Rllb Rl2a 145-30R Rla R2a Rllb Rl2a I45-31Ra Rlb R2a Rllb Rl2a 145-32Rb Rlb Rza Rl Rl2a ib 145-33Rc Rlb Rza Rllb Rl2a 145-34Ra Rlc R2a Rltb Rlza 145-35Rb Rlc R2a Rllb Rlza 145-36Rc Rlc R2a Rllb Rl2a 145-37Ra Rla R2b Rllb Rl2a 145-38Rb Rla Rzb Rllb Rl2a 145-39R Rla R2b Rllb Rl2a 145-40Ra Rlb Rzb Rilb RI2a 145-4IRb Rlb Rzb Rltb Rl2a 145-42Rc Rlb R2b Rllb Rl2a 145-43Ra Rlc R2b Rllb Rl2a 145-44Rb Rlc R2b Rllb Rl2a 145-45R Rl R2b Rllb Rl2a 145-46Ra Rla R2c Rllb Rl2a 145-47Rb Rla R2c Rllb Rl2a 145-48R Rla Rzc Rllb Rl2a 145-49Ra Rlb R2c Rllb Rlza 145-50Rb Rlb Rzc Rilb Rl2a 145-51Rc Rlb R2c Rllb Rl2a 145-52Ra Rl R2c Rllb Rl2a 145-53Rb Rlc R2c Rllb Rl2a 145-54Rc Rlc R2c Rllb Rl2a 145-55Ra Rla R2a Rilc Rl2a 145-56Rb Rla R2a Rllo Rl2a 145-57Rc Rla Rza Rllc Rlza 145-58Ra Rlb R2a Rllc Rl2a 145-59Rb Rlb R2a Rllc Rl2a 145-60R Rlb R2a Rllc Rlza 145-61Ra Rlc R2a Rllc Rl2a 145-62Rb Rlc Rza Rllc Rl2a 145-63Rc Rlc R2a Rllc Rl2a 145-64Ra Rla Rzb Rllc Rl2a 145-65Rb Rla R2b Rllc Rlza 145-66Rc Rla Rzb Rllc Rl2a 145-67Ra Rlb Rzb Rllc Rl2a 145-68Rb Rlb R2b Rllc Rl2a 145-69Rc Rlb R2b Rllc Rl2a 145-70Ra Rl Rzb Rl Rl2a 145-71Rb Rlc R2b Rlic Rlza 145-72Rc Rlc Rzb Rllc Rl2a 145-73Ra Rl R2o Rl Rl2a a l c I45-74Rb Rla R2c Rllc Rl2a 145-75Rc Rla R2c Rllc Rl2a I45-76Ra Rlb R2c Rllc Rl2a 145-77Rb Rlb R2c Rllc Rt2a 145-78R Rlb R2c Rllc Rl2a 145-79Ra Rlc R2c Rilc Rl2a 145-80Rb Rl R2c Rl t Rl2a c .

145-81R Rlc R2c Rllc Rl2a 145-82Ra Rla R2a Rlla Rl2b 145-83Rb Rla R2a Rlla Rl2b 145-84Rc Rla R2a Rlla Rl2b 145-85Ra Rlb R2a Rlla Rl2b 145-86Rb Rlb R2a Rlla Rl2b 145-87R Rlb Rza Rlia Rl2b 145-88Ra Rlc R2a Rlla Rl2b 145-89Rb Rlc Rza Rlla RI2b 145-90Rc Rl R2a Rl l Rl2b c a 145-91Ra Rl R2b Rl l Rt a a 2b 145-92Rb Rl R2b Rl l Rl2b a a 145-93Rc Rl R2b RI l Rl2b a a 145-94Ra Rlb R2b Rlla Rl2b 145-95Rb Rlb R2b Rlla Rl2b 145-96R Rlb R2b Rlla Rl2b 145-97Ra Rlc R2b Rlla Rl2b 145-98Rb Rl R2b Rl l Rl2b a 145-99Rc Rl R2b Rl l Rl2b c a I45-100Ra Rla Rzc Rlla Rl2b 145-101Rb Rla Rzc Rlla Rl2b 145-102Rc Rla R2c Rlla Rl2b 145-103Ra Rlb R2c Rlta Rlzb 145-104Rb Rlb R2c Rlla Rl2b 145-105Rc Rlb R2c Rlla RI2b 145-106Ra Rlc Rzc Rlla Rl2b 145-107Rb Rlc R2c Rlla Rl2b 145-108Rc Rl Rzc Rl l Rl2b a 145-109Ra Rla R2a Rllb Rl2b 145-110Rb Rla R2a Rllb Rl2b 145-111Rc Rla Rza Rllb Rlzb 145-112Ra Rlb R2a Rllb Rl2b 145-113Rb Rlb R2a Rllb Rl2b 145-114Rc Rlb R2a Rllb Rl2b 145-115Ra Rl R2a Rlib Rl2b 145-116Rb Rlc R2a Rllb Rl2b 145-117R Rlc R2a Rllb Rlzb 145-118Ra Rla R2b Rllb Rl2b 145-119Rb Rla Rzb Rllb Rl2b 145-120R Rla Rzb Rllb Rl2b 145-121Ra Rib R2b Ri 1b Ri2b 145-122Rb Rib Rzb Riib Ri2b 145-123R Rlb R2b Rllb Rl2b 145-124Ra Rlc Rzb Riib Rlzb 145-125Rb Ric Rzb Riib Rizb 145-126Rc Ric R2b Rlib Rizb 145-127Ra Ria R2c Rlib Rizb 145-128Rb Ria R2c Riib Rizb 145-129Rc Ria R2c Riib Ri2b 145-130Ra Rib Rzc Rlib Ri2b 145-131Rb Rib Rzc Rilb Rl2b 145-132Rc Rib Rzc Rnb Ri2b 145-133Ra Ric R2c Riib Rl2b 145-134Rb Ric R2c Riib Ri2b 145-135Rc Ric R2c Ri ib Rizb 145-136Ra ~la R2a Riic Ri2b 145-137Rb Ria R2a Rilc Rl2b 145-138R Ria R2a Rilc Rl2b 145-139Ra Rib R2a Rilc Ri2b 145-140Rb Rib R2a Rllc Rl2b 145-141Rc Rib R2a Rlic Ri2b 145-142Ra Ric R2a Rlic Ri2b 145-143Rb Rlc R2a Riic Rlzb 145-144Rc Ric Rza Riic Ri2b 145-145Ra Rla R2b Riic Rl2b 145-146Rb Ria R2b Rllc Rl2b 145-147R Ria R2b Riic Rlzb 145-148Ra Rib R2b Rllc Ri2b 145-149Rb Rlb Rzb Riic Ri2b 145-150R Rib R2b Rlic Ri2b 145-151Ra Rlc Rzb Riic Ri2b 145-152Rb Ric R2b Rilc Ri2b 145-153R Ric R2b Rllc RI2b 145-154Ra Ria R2c Riic Rl2b 145-155Rb Ria R2c Riic Rl2b 145-156R Ria R2c Rllc Ri2b 145-157Ra Rib R2c Rllc Rl2b 145-158Rb Rib Rzc Rllc RI2b 145-159R Rib R2c Riic Ri2b 145-160Ra Ric R2c Rllc Ri2b 145-161Rb Ric R2c Rllc Ri2b 145-162R Rlc Rzc Riic Rizb 145-163Ra Ria R2a Rila Rl2c 145-164Rb Rla R2a Rlia Ri2c 145-165R Ria R2a Rila Rl2c 145-166Ra Rib R2a Rlla Rl2c 145-167Rb Rib R2a Rila Ri2c 145-168R R"' R2a R"a Rl2c 145-169Ra R'c R2a Rlla Rt2c 145-170Rb RIc Rza Rtta Rl2c 145-171Rc Rlc Rza Rna Rl2c I45-172Ra Rla R2b Rna Rt2c 145-173Rb RIa R2b Rlla Rlzc I45-174Rc Rla R2b Rlla Rl2c 145-175Ra R1b R2b Rlla Rtzc 145-176Rb Rib R2b Rlla Rl2c 145-177R R"' R2b Ra Rl2c 145-178Ra RIc R2b Rtta Rl2c 145-179Rb Rlc R2b Rna Ri2c 145-180R Rlc R2b Rna Rl2c 145-181Ra R'a Rzc R"a R'2c 145-182Rb R'a R2c R"a R'2c I45-183R RIa R2c Rlta Rl2c I45-184Ra Rlb R2c Rna Rl2c 145-185Rb R"' R2c R"a R'2c 145-186R R"' R2c Rla Rl2c I45-187Ra Rtc R2c Rlta Ri2c 145-188Rb R'c R2c Rna Rt2c I45-189R Rlc Rzc Rlta Rl2c 145-190Ra Rta Rza Rllb Rl2c 145-191Rb R'a R2a Rnb Rlzc 145-192R Rla R2a Rllb Rl2c 145-193Ra R"' Rza R"'' R'2c 145-194Rb R'b R2a R"'' Rl2c 145-195R R"' R2a R> R~2o >b 145-196Ra Rtc R2a Rllb Rlzc 145-197Rb R'c R2a Rb R~2c 145-198R Rlc R2a Rllb Rlzc 145-199Ra RIa R2b Rnb Rl2c 145-200Rb Rla Rzb Rllb Rl2c 145-201R Rla R2b Rnb Rl2c 145-202Ra R"' R2b R"b R'2c 145-203Rb R'b Rzb R"b Rizc 145-204R R'b R2b R"b Rlzc I45-205Ra R'c Rzb Rnb Rlzc I45-206Rb Rlc R2b Rllb Rl2c 145-207Rc R'c Rzb R"b R'2c I45-208Ra RIa R2c Rnb Rlzc 145-209Rb Rla R2c Rnb Rl2c 145-210R R'a R2c R1b Rt2c 145-211Ra Rib Rzc Rt Rlzc tb I45-212Rb R'b R2c Rtlb Rl2c 145-213R R'b R2c R"b R'2c I45-214Ra R'c R2c Rllb Rl2c I45-215Rb Rlc Rzc Rub RI2c 145-216R RIc Rzc Rnb Rl2c 145-217Ra RI a R2a Rn c Rt2c 145-218Rb RI a R2a R11 Rl2c c 145-219R RIa R2a Rllc Rl2c 145-220Ra Rib R2a Rnc Rl2c 145-221Rb Rib Rza RI~c R~2c 145-222R Rib Rza Rllc R~2c 145-223Ra Rtc Rza Rilc R~2c 145-224Rb Rlc R2a Rnc Rl2c 145-225Rc Rlc Rza Rnc R~2o 145-226Ra Rla R2b R" Rl2c 145-227Rb RIa R2b Rllc Rl2c 145-228Rc Rta Rzb Rnc Rl2c 145-229Ra Rib R2b Rm Rl2c 145-230Rb Rib Rzb RI~c R~z 145-231R Rib Rzb Rnc R~zc 145-232Ra Rlc Rzb Rnc R~2c 145-233Rb Rlc R2b R~~ R~2c 145-234R Rlc Rzb Rnc R~zc 145-235Ra Rya Rzc Rl~ Rl2c 145-236Rb Rla Rzc Rt~o Rl2c 145-237R Rya Rzc Rnc R~2c 145-238Ra Rib Rzc RIIc Rizc 145-239Rb Rlb Rzc R~Ic R~z 145-240R Rlb R2c Rn RI2c 145-241Ra Rlc Rzc Rnc Rl2c 145-242Rb Rl Rzc Ro Rl2c 145-243Rc R' Rzc R11 Rlzc where all symbols are as defined above.
In one aspect of formula (145) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an allcyl group, an allcoxy group, ari alkenyl group, or an alkoxyallcyl group; Rl and R2 independently are hydrogen, a hydroxy group, a halogen, a vitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an allcoxy group, a cycloallcoxy group, an allcenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloallcenyloxy group; and R' 1 and RIZ independently are hydrogen, l0 a halogen, a vitro 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(O=) group, or a thio(S=) group, an alkyl group, or a cycloalkyl group, an allcoxy group.

In another aspect of formula (145) of the present invention, R is hydrogen or an alkyl group; RI and RZ independently are hydrogen, a hydroxy group, a halogen, an alkoxy group;
and R'1 and R~Z 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 CZHS; Rl and RZ are -OCH3; and Rl ~ and R12 independently are -H, -F, or CH3.
The present invention still further contemplates various compounds of general formula (V) having the formula:
(146), where R is as defined above in connection with formula (I).
In one aspect of formula (146) of the present invention, R is hydrogen, a hydroxy group, a halogen, a vitro group, or an optionally substituted amino group.
In another aspect of formula (146) of the present invention, R is an alkyl group, an allcoxy group, an alkenyl group, or an alkoxyallcyl group.
In yet another aspect of formula (146) of the present invention, R is a cycloalkenyloxy group, an acyl group, an aryl group, an arallcyl group, a heterocyclyl group, or a heteroaryl group.
In still another aspect of formula (146) of the present invention, R is -H or an alkyl group.
In still another aspect of formula (146) of the present invention, R is -H or CzHs.
Additional examples of compounds having general formula (V) include, but are not limited to:

Me0 ~ N' / NH~COzC2H5 C-O O \ II
H' I ~' I O CH' _ Me0 I / NCO \ I O tJH
~C O O-S-O
hl,C O O HN j~ \ ~ ~ /
O ~ ~ N~O~Cht~ \ I

> >

> ;

~N,H
N~ / ~ ~C02C2Hs MeO
%I ~~N~O HN ~O
5. H Me0 \ I O . O ~ ~ / F
F

OOHS
ocH, ~ N\
I \ ° I \ I o ' ~ ~ N,N ~ N~N~COOC2H5 .~ \
O O~O I / N H~OC2H5 / O O NH ~ ~ ~ CH3 II ii > >
ci s cl ~ ~ CHs \ ° \ I o / I
I O~O I \ I-I HN,S \
0 ~N~OCZHS
O [OI ~ N02 \ O \ I O / I
I / I Oi\r0 I \ H HN SO \
O ~N~OC2H5 > >
F / F
OS ~
H HN. .O
N~OC~HS ~ I s H
~O
> ;

O O
s SCH3 F ~H
~N O
o w ~
I ono ~ o o CI ' N OH
O ( / N~OCzHS
H w ,N.
HN. ~ S H
~ ; and H3C0 ~ O W I
O~O I ~ O O
OCH30 ~ [j N~OC2H5 H
HN. .O
~S I
O
It is contemplated that any compound shown or described herein, including compounds of the various formulae shown or described above, may be provided as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts forming 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-ethyhnorpholine, N-ethylpiperidine, to glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'-diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, or spermidine; chiral bases like alkylphenylamine, glycinol, or phenyl glycinol;
salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino 2o acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, allcyl, alkenyl, or alkynyl; ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates.
Pharmaceutically acceptable solvates may be hydrates or may comprise other solvents of crystallization such as alcohols.
Processes for Preparing the Compounds The compounds of the present invention can be prepared according to the following processes. However, it should be understood that other processes having other process l0 conditions may be used to form the compounds of the present invention.

According to one aspect of the present invention, a process for preparing a compound of general formula (II) z BMA E R4 F-'~/NR
- ~ I
Y-G =~-Ar~Y2 ~~ ~'R
where R' is attached to B; R~ is attached to J; R3 is -H; A, B, D and J
independently are -CH;
Rl and Rz independently are an alkoxy group or an aralkoxy group; R4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third position and/or fourth position respectively, X and E are each O, G is -(CHz)S ; ~CHz)S CH=CH-(CHz)S , or 2o f CHz)S CH=CH-(CHz)S , where s is an integer from 0-5; F is O, S or -NR; Y
and Z
independently are O, -NR, f CHz~", or S(=O)", where n is an integer from 0-2;
Yl and Yz independently are O or S; R and RS independently are hydrogen, a hydroxy group, a halogen, a vitro group, an optionally substituted amino group, an allcyl 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 'Ar' is an optionally substituted phenyl group or an optionally substituted naphthyl group is provided.
The process comprises first alkylating the Rutin hydrate of formula (IIa) R~
R2 B\ A E R4 p. , ; ~ (IIa) R J~ Y.Rut X
where 'Rut' is rutinose; RI is attached to B; R~ is attached to J; R3 is H; A, B, D and J
independently are -CH, Rl and RZ independently are a hydroxy group; R4 is a phenyl group optionally substituted with a hydroxy group at the third andlor fourth positions; X, Y, and E
are O; and '----' is an optional chemical bond;
to a compound of formula (IIa), where RI is attached to B; RZ is attached to J; R3 is H;
A, B, D and J independently are -CH; Rl and RZ independently are an allcoxy group or an aryloxy group; R4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third and fourth positions; X, Y, and E are O; and all other symbols are as defined above.
The alkylation is carried out using an alkyl halide alkylating or aralkylating agent.
Examples of agents that may be suitable include MeI, EtI, EtBr, n-PrI, n-PrBr, i-PrBr, i-PrI, n-BuCl, or s-BuBr; a dialkylsulphate such as dimethylsulphate or diethylsulphate; or an aralkyl halide such as benzyl halide. The reaction may be carried out in the presence of an alkali, for example, sodiumhydride (NaH), potassiumhydride (KH), potassium tertiary butoxide (t-BuOK), potassium acetate (KOAc), sodium acetate (NaOAc), n-butyl lithium (n-BuLi), sec-butyl lithium (s-BuLi), tert butyl lithium (t-BuLi), lithium diisopropyl amide (LDA), sodium carbonate (Na2C03), potassium carbonate (K2C03), sodium bicarbonate (NaHC03), potaasium 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 may 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 ~0 hours. The reaction may be carned out under an inert atmosphere of, for example, nitrogen (NZ), argon (Ar), or helium (He).
Next, the compound of formula (IIa) is hydrolysed to a compound of formula (IIb) R~
R2 B~ A ' E R4 (IIb) R~'J ~ YH

X
where Rl is attached to B; R2 is attached to J; R3 is H; A, B, D and J
independently are -CH;
R' and RZ independently are an alkoxy group or an aralkoxy group; R4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third and fourth positions; X, Y, and E are O; and all other symbols are as defined above.
The hydrolysis is optionally carried out using an inorganic acid, such as hydrochloric acid (HCl), sulfuric acid (H2S04), or a mixture thereof with water. The reaction temperature may be maintained at 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, l0 for example, from about 1 hour to about 50 hours.
Next, the compound of formula (IIb) is reacted with a compound of formula (IIc), O, ~'--Ar-Z-G-Hal (IIc) 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 formula (IId) R~
R~ B\ A E. R4 O
Dr ~ % I Y-G-Z-Ar' ( 5 (IId R3 R ) where R' is attached to B; R2 is attached to J; R3 is H; A, B, D, and J
independently are -CH;
RI and R2 independently are an allcoxy group or an aralkoxy group; R4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third and fourth positions; and all other symbols are as defined above.
2o This reaction is carried out in the presence of a base, for example, NaH, I~H, KOtBu, KOAc, NaOAc, NaOEt, KOEt, n-BuLi, s-BuLi, t-BuLi, LDA, Na2C03, I~ZC03, NaHC03, I~HG03, 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 may be maintained at from about -30°C to 150°C, for example, from about 30°C to about 100°C. The duration of the reaction may be from about 1 hour to about 50 hours, for example, from about 2 hours to about 25 hours. The reaction may be carried out under an inert atmosphere of N2, Ar, or He.
Lastly, the compound of formula (IId) is condensed with a compound of formula (IIe), H
't ~ 2 Y .~ Y (IIe) F
where F, YI, and YZ are as defined above, to obtain a compound of formula (II) Y~

2 B.\,A E R4 F~NR
R - ~ I -~ (II) D. . ~ Y-G-Z-Ar Y2 X
where all symbols are as defined above.
The condensation may be carned out using a base, for example, Et3N, diethylamine, 1o diisopropylethyl amine, diisopropyl amine, DBU, piperidine, or any mixture thereof. The reaction may be carried out in the presence of an acid, for example, benzoic acid, formic acid, acetic acid, or any mixture thereof. The reaction may be carried out in the presence of a solvent, for example, benzene, toluene, xylene, ethanol, i-propanol, bytanol, DMF, DMSO, 1,4-dioxane, or any mixture thereof. The reaction may be maintained at a temperature of is from about 30°C to about 300°C, for example, from about 50°C to about 200°C. The duration of the reaction may be from about 10 hours to about 150 hours, for example, from about 20 hours to about 80 hours. The reaction may be carried out under an inert atmosphere of NZ, Ar, or He.
2o PROCESS 2 According to another aspect of the present invention, a process for preparing a compound of formula (II) is provided. All symbols are as defined above, except that X and E
are O.
Y~
B A E R4 F~NR
I
R D. ~~ I Y-G-Z-Ar=~Y2 R
X

First, a compound of formula (IIf) R~
EH
R~ B

R 3' where X and E are O; and all other symbols are as defined above, is acylated to a compound of formula (IIg) R~
Ra B\'A Y~ E~ (IIg) Dj~~ X

The acylation may be carried out by using an acylating agent such as, for example, acetic anhydride. The reaction is optionally carried out in the presence of a base such as, for example, Na2CO3, K~C03, NaHC03, KHC03, NaOH, I~OH, or any mixture thereof. The reaction may be maintained at a temperature of from about -30°C to about 150°C, for l0 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 ea~ample, from about 20 minutes to about 2 hours.
The compound of formula (IIg) is then rearranged to a compound of formula (IIh}
R~
R2 B\A EH (I ) Ih R~J

X
where X and E are O; and all other symbols are as defined above. This reaction is optionally carned 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 may be carried out in the presence of a Lewis acid, such as alumizuum chloride (A1C13), zinc chloride (ZnCl2), or tin chloride (SnCI~,.), or in the presence of UV
light. The reaction temperature may be maintained at from about 50°C to about 300°C, for 2o 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 may be carried out under anhydrous reaction conditions.
The compound of formula (IIh) is then condensed to a compound of formula (IIi) R~
R~ B\ A E H R4 (Bi) D~ ' ~J

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, NaZC03, K2C03, NaHC03, KHCO3, NaOH, KOH, or any mixture thereof. The reaction temperature may be maintained at from s about -30°C to about 50°C, for example, from about 0°C
to about 20°C. The duration of the reaction may be from about 2 hours to about 50 hours, for example, from about 5 hours to about 20 hours.
The compound of formula (IIi) then undergoes a cyclization reaction to form a compound of formula (IIb) R~
R~ B\ A E R4 (IIb) RJ'J ~ YH

where all symbols are as defined above. This reaction is carried out using a base, for example, Na2C03, K~C03, NaHC03, KHC03, NaOH, KOH, or any mixture thereof. The reaction temperature may be maintained at 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 formula (IIb) is then reacted with a compound of formula (IIc) ~Ar -Z-G-Hal (IIc) where 'Hal' is a halogen; and all other symbols are as defined above, to obtain a compound of formula (IId) R~
R2 B\ A E R4 O
D~~~ ~ Y-G =-Z-Ar-~~ 5 (IId R3 R ) where all symbols are as defined above.
The compound of formula (IId) is then reacted with a compound of formula (IIe) H
Y1~~Y2 (IIe) F
where F is O, S, or -NR; YI and YZ independently are O or S, to obtain a compound of formula (II) 2 B\,A E R'~ F~NR
R D. ~J I Y-G-Z-Ar-~~,2 (II) R
X
where E and X are O; and all other symbols are as defined above.
The conversion of compound of formula (ITb) to compound of formula (II) is carned out as provided in Process 1.

l0 According to another aspect of the present invention, a process for preparing a compound of formula (II) is provided, 2 B\A E R'~ F~NR
R D~ ~ ~ [ Y-G-Z-Ar-=~~Y2 (II) R3 .I R
X
where X is O, E is -NR, and all other symbols are as defined above.
First a compound of formula (IIj) \A NHR
R2 B ~~ ~ ~IJ) D~':J- 'COOMe Rs where all symbols are as defined above, is converted to a compound of formula (IIk), R2 B.\,A NHR (Illz) D~ :1 ~COOH

where all symbols are as defined above. This reaction may be carried out using a base, for example, Na2C03, KZC03, NaHC03, KHCO3, NaOH, KOH, or any mixture thereof. The reaction may 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 may be maintained at 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 formula (IIIc) is then reacted with a compound of formula (IIm) Ra ~Hal (IIm) O
where 'Hal' is a halogen, and R4 is as defined above, to obtain a compound of formula (IIn) R~
B\A NHR
R ; (IIn) ~~;J- _COO R~

where all symbols are as defined above.
This reaction may occur in the presence of a brominating agent, for example, bromine, bromine water, N-bromosuccinamide, copper bromide, or any mixture thereof. The solvent is acetic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, dichlromethane (DCM), chloroform (CHCl3), 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, or any mixture thereof. The reaction may be carried out in the presence of catalytic amount of hydrobromic acid. The reaction temperature may 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, from about 1 hour to about 20 hours.
Alternatively, the reaction may be carried out in the presence of a solvent, for example, acetonitrile, DMF, DMSO, DCM, CHCl3a 1,2-dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, butanol, HMPA, 1,4-dioxane, acetone, dimethyl ether, diethyl ether, THF, water, or any mixture thereof. The reaction may be carned out in the presence of a base, for example, NaH, KH, KOtBu, KOAc, NaOAc, n-BuLi, s-BuLi, t-BuLi, LDA, Na2C03, K2CO3, NaHCO3, KHC03, NaOH, KOH, an amine base such as Et3N, diethyl amine, diisopropylethyl amine, diisopropyl amine, DBU, or any mixture thereof.
The reaction temperature may be from about -78°C to about 150°G, 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 may be carried out under an inert atmosphere maintained by N2, Ar, or He.
The compound of formula (IIn) is then converted to a compound of formula (IIb) R2 B\ A E R4 (IIb) R3J ~ YH
X
where X is O, E is -NR, and all other symbols are as defined above. This reaction may be carned out using polyphosphoric acid. Optionally, the reaction may 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, to from about 50°C to about 180°C. The duration of the reaction may be from about 10 minutes to about 72 hours, for example, from about 2 to I5 hours. The reaction may be carried out under an inert atmosphere maintained by NZ, Ar, or He.
The compound of formula (IIb) is then reacted with a compound of formula (IIc) ~'-Ar-Z---G--Hal (IIc) where all symbols are as defined above, to obtain a compound of formula (IId) B~AER4 R= ; O
Y-G-Z-Ar~R5 (IId) R X
where E is -NR, and all other symbols are as defined above.
The compound of formula (Ird) is then reacted with a compound of formula (IIe) H
Y1~~Y2 ~Ie) F
2o where all symbols are as defined above, to obtain a compound of formula (II) B\,A E R4 F ~NR
R D. ~: I Y-G =Z-Ar-=~Yz R
X

where X is O, E is NR, and all other symbols are as defined above.

According to another aspect of the present invention, a process for preparing a compound of formula (IV) is provided. The process comprises the following:

i 'I
/'/ EHz Ri E~Ra EYR
~ ~_~Iz KHz + R4COC1 ~p ~R~ ~ ~ ~z~ K'H
R z KHz R
X IVb X X IVd IVa IVc ~Ar -Z-G-Hal Rs IIC
i R CYRa O
O~~RzI K~G~Z-Ar-~(Rs X IVe H
Yi~~Yz F
/Y/t t E~Ra F~NH
O~~_~z~ K~G~Z-Ar--CR5 'yz R
X (IV) where all symbols are as defined above.
The conversion of a compound of formula (IVa) to a compound of formula of (IVc) may be carned out using an appropriate acylchloride of formula IVb in the presence of a to base, for example, Na?C03, KZCO3, NaHCO3, KHC03, NaOH, KOH, triethyl amine, diisopropylethylamine, or any mixture thereof. The reaction may be carried out in a solvent, for example, benzene, toluene, xylene, DMF, DMSO, 1,4-dioxane, dichloromethane, CHC13, 1,2-dichloroethane, carbon tetrachloride, or any mixture thereof. The reaction temperature may be maintained at 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 may be carned out under an inert atmosphere of N?, Ar, or He.
The conversion of a compound of formula (IVc) to a compound of (IVd) may be carried out using a base, for example, NaH, KH, KOtBu, KOAc, NaOAc, NaOEt, KOEt, n-2o BULi, s-BULi, t-BULi, LDA, NaZC03, KZC03, NaHC03, KHC03, NaOH, KOH, or any mixture thereof. The reaction may be carned out in a solvent, for example, benzene, toluene, xylene, methanol, ethanol, i-propanol, t-butanol, or any mixture thereof. The reaction temperature may be maintained at from about -70° C to about 250°
C, for example, from about -10° C to about 150 °C. The duration of reaction may be from about 5 hours to about 150 hours, for example, from about 20 to about 100 hours. The reaction may be carried out under an inert atmosphere of N2, Ar, or He.
The conversion of compound of formula (IVd) to a compound of formula (IV) may be carned out as provided in Process 1.

l0 According to another aspect of the present invention, a process for preparing a compound of formula (Va) is provided. The process comprises:
R~A~~ E RQ O RBA E R4 + ~'-Ar-Z= G-Hal ~ B~ ~~ ~ ~ O
0~3J YH R5 D~J~ Y-G-Z-Ar~ s R X
X
R (Ilc) R (Ild) W here R5 (IIb) represents alkoxy, cycloalkenyloxy XQ S(O)W Ar H2N_(CH2)P\C-O-F2 B A~ E R4 (Ilp) X3 D/ J~~ ~ Y-G-Z-A O

W here RS
R1A E Rq B~~ "~ I I O 4~S(O),"-Ar (Iid) represents hydroxy Y-G =Z-Ar--~ X group NH-(CHa)p ~C-O-R
Xa (V8) The conversion of a compound of formula (IIb) to a compound of formula (IId) may 1s be carried out as provided in Process 1.. The conversion of the compound of formula (IId) to a compound of formula (Va) may be carned out by reacting the compound of formula (IId) with compound of 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 temperature of the reaction may 20 be maintained at 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 may be carried out in a nitrogen atmosphere.

According to another aspect of the present invention, a process for preparing a compound of formula (Vb) is provided B A, N~
D/~ ~ I N-Y-G-Z-Ar--~O ~ S(O)W-Ar R2 R3X NH-(CH2)OC-O-R

(Vb) The process comprises:
B A, COOH RBA N
it D! ~ ~ ~ r R J NH2 D~~ ° NH

X
VIa VIb The conversion of a compound of formula (VIa) to a compound of formula (VIb) is carried out in the presence of formamide in a nitrogen atmosphere. The temperature of the reaction may be maintained at from about 10°C to about 70°C, for example, 25°C to about l0 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 formula (VIb) to a compound of formula (Vb) is carried out as provided in Process 5.
It should be understood that in any of the reactions presented herein, any reactive group on the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups include, for example, tertiarybutyldimethylsilyl, 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-fluorenyl methoxy carbonyl (-N-FMOC), benzophenoneimine, or propargyloxy carbonyl (POC) to protect an amino or anilino group; acetal protection for an aldehyde; and ketal protection for a ketone. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
The enantiomers of compound of formula (II) may be prepared by using reactants in their single enantiomeric form in the process wherever applicable or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form. The single enantiomers also may be prepared by resolving the racemic mixture by conventional methods.
The stereoisomers of the compounds of the present invention may be prepared by using reactants in their single enantiomeric form in the process, by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form, or by resolving 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 mandelic acid, camphorsulfonic acid, tartaric acid, or lactic acid, wherever applicable, or chiral bases such as brucine, cinchona allcaloids and their derivatives.
Commonly used methods are compiled by JAQUES, ENANTIOMERS, RACEMATES AND RESOLUTION (I981).
Where appropriate, the compounds of formula (I) may be resolved by: treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; employing conventional reaction conditions to convert the acid into an amide; separating the diastereomers by i5 fractional crystallization or chromatography; and preparing the stereoisomers of compound of formula (I) by hydrolyzing the pure diastereomeric amide.
The stereoisomers of the present invention also may include E and Z isomers or their mixtures in various rations.
Formulations and Pharmaceutical Compositions The present invention provides compounds of general formula (I), pharmaceutical compositions comprising one or more compound of 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 may be used for the treatment of bacterial infections. They also may be used for the tl-eatment of bacterial infections associated with multi-drug resistance. The pharmaceutical compositions of the present invention also may be used to modulate inflammatory responses, particularly those resulting from AGE and glycated protein accumulation. The pharmaceutical compositions of the present invention also may be used to modulate smooth muscle cell proliferation and the diseases or conditions related thereto. The compositions provided herein also may be used to treat vascular occlusive conditions, such as stenosis, restenosis and atherosclerosis; diseases mediated by inflammation, such as autoimrnune 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 therein. Such salts are commonly referred to as non-toxic, "pharmaceutically acceptable salts". Other salts, however, may be useful in the preparation of the compounds of the present invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts that may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, for example, hydrochloric acid, sulfuric acid, fumaric acid, malefic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, or any mixture thereof.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, 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, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, metlrylsulfate~ mutate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.
B. Alternative Forms of the Compounds Where the compounds of the present invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they additionally may exist as diastereomers. Where compounds of the present invention have geometrical isomers, it is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and are contemplated hereby.
In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed hereby. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.
Moreover, the compounds of the present invention may be prepared in racemic form.
Alternatively, individual enantiomers may be prepared either by enantiospecific synthesis or to by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation ~f diastereomeric pairs by salt formation with an optically active acid, for example, (+)di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds also may be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
Alternatively, the compounds may be resolved using a chiral HPLC column.
The compounds of the present invention optionally are formulated and administered as a prodrug. In general, prodrugs comprise functional derivatives of the claimed compounds that are capable of being enzymatically activated or converted into the more active parent form. Thus, in the treatment methods of the present invention, the term "administering"
encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but that converts to the specii~ied 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); Wihnan, 14 gIOCHEM. 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 by reference herein in its entirety.
The prodrugs of present invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, 3o peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, I3-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine, and other 5-fluorouridine prodrugs that may be converted into the more active drug.
Enzymes that may be used in the methods and compositions of the present invention include, but are not limited to, alkaline phosphatase for converting phosphate-containing prodrugs into free drugs; arylsulfatase for converting sulfate containing prodrugs into free drugs; cytosine deaminase for converting non-toxic S-fluorocytosine into the anti-cancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases, and cathepsins, such as cathepsins B and L, for converting peptide-containing prodrugs into free drugs; D-alanylcarboxypeptidases for converting prodrugs that l0 contain D-amino acid substituents; carbohydrate cleaving enzymes such as 13-galactosidase and neuraminidase for converting glycosylated prodr~gs into free drugs; J3-lactamase for converting drugs derivatized with 13-lactams into free drugs; and penicillin amidases, such as penicillin V amidase or penicillin G amidase, for converting drugs derivatized at their amine nitrogens with phenoxyacetyl or phenylacetyl groups, respectively, into free drugs.
Alternatively, antibodies with enzymatic activity, also known in the art as "abzymes", may be used to convert the prodrugs of the present invention into free active drugs. See for-exanzple, Massey, 328 NATURE 457-48 (1987).
C. Pharmaceutical Auxiliaries In addition to the compounds contemplated hereby, the pharmaceutical compositions 2o of the present invention optionally comprise at least one suitable auxiliary or carrier such as, but not limited to, a diluent, binder, stabilizer, buffer, salt, lipophilic solvent, preservative, adjuvant, or any combination thereof. Pharmaceutically acceptable auxiliaries typically are used. Examples and methods of preparing such sterile solutions are described in, for example, 1ZEMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990)), incorporated by reference herein in its entirety.
Pharmaceutically acceptable carriers routinely are selected to be suitable for the mode of administration, solubility, and/or stability of the compound.
Pharmaceutical excipients and additives useful in the present invention include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (for example, sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides;
derivatized sugars such as alditols, aldonic acids, esterified sugars; and polysaccharides), which can be present singly 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, which also can 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, l0 xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol.
The pharmaceutical compositions comprising the compounds of the present invention also can include a 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 salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris; tromethamine hydrochloride; phosphate buffers; or any combination thereof.
Additionally, pharmaceutical compositions of the invention optionally include polymeric excipients/additives, such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (for example, cyclodextrins, such as 2-hydroxypropyl-(3-cyclodextrin), polyethylene glycols, flavoring agents, anti-microbial agents, sweeteners, antioxidants, anti-static agents, surfactants (for example, polysorbates such as "TWEEN 20" and "TWEEN
SO"), lipids (for example, phospholipids, fatty acids), steroids (for example, cholesterol), chelating agents (for example, EDTA), and any combination thereof. Exemplary pharmaceutical excipients and/or additives are described in REM1NGTON: THE
SCIENCE &
PRACTICE OF PHARMACY (19th ed., Williams 8z 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 may be 3o combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, or any mixture thereof. Moreover, suitable binders, lubricants, disintegrating agents, and coloring agents also may be incorporated into the mixture.
Suitable binders include, without limitation, starch; gelatin; natural sugars such as glucose or beta-lactose;
corn sweeteners; natural and synthetic gums such as acacia, 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, sodium benzoate, sodium acetate, sodium chloride, or any combination thereof. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, or any combination thereof.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a to predetermined amount of the active ingredient; as a powder Qr granules; as a solution or a 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, ~ptionally with one or more auxiliary ingredients. Compressed tablets typically are prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets typically are made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets optionally are coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein.
The compositions of the present invention optionally are incorporated into a biodegradable polymer, thereby allowing for sustained release of the compound.
The polymer is implanted in the vicinity of where drug delivery is desired, for example, at the site of restenosis. Such biodegradable polymers are described, for example, in 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, which matrices are foamed into shaped articles, for example, films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S.
3o Patent No. 3,773,919, incorporated by reference herein in its entirety), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTS (Tap Pharmaceuticals, Inc., Chicago, IL) (injectable microspheres composed of lactic acid glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
2. Pharmaceutical Compositions for Parenteral Administration As used herein, "parenteral" includes subcutaneous injections, intravenous, intramuscular, intraperitoneal injections, or infusion techniques.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that optionally include suspending agents and thickening agents.
The formulations may be presented in unit-dose or mufti-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets, such as those described above.
For parenteral administration, sterile suspensions and solutions are desired.
Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The pharmaceutical compositions may be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Acceptable liquid carriers include, for example, vegetable oils such as peanut oil, cotton seed oil, sesame oil, and organic solvents such as solketal and glycerol formal. The formulations may be prepared by dissolving or suspending the active ingredient in the liquid Garner 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 basis or medium, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis or medium such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the compound to be administered in a suitable liquid carrier. The liquid forms rnay include suitably flavored suspending or dispersing agents, such as the synthetic and natural gums, for example, tragacanth, acacia, and methyl-cellulose.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tamports, creams, gels, pastes, foams, or spray formulations comprising the active ingredient s and an appropriate carrier.
The compounds also may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. REMINGTON'S PHARMACEUTICAL SCIENCES (A. Osol ed., 16th ed.
(1980)), incorporated by reference herein in its entirety.
The compounds contemplated hereby optionally are formulated as liposomes.
Liposomes may be prepared by any suitable method, such as those described in U.S. Patent is Nos. 5,013,556; 4,485,045; 4,544,545; WO 97/38731; Epstein et al., 82 PI20C. NATL. ACRD.
SCI. USA 3688 (1985); and Hwang et al., 77 PROC. NATL. ACAD. SCI. USA 4030 (1980), each of which is incorporated by reference herein in its entirety. The compounds of the present invention also can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes 2o can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phophatidylcholines.
Compounds of the present invention also may be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
The compounds of the present invention also may be coupled with soluble polymers as targetable 2s drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine optionally substituted with palmitoyl residue.
D. Pharmaceutically Acceptable Preservatives The present invention provides stable formulations, preserved solutions and 3o formulations containing a preservative, and mufti-use preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one compound contemplated hereby in a pharmaceutically acceptable formulation. Preserved formulations contain at least one known preservative comprising at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (for example, hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or any mixture thereof, in an aqueous diluent. Any suitable concentration or mixture can be used, such as 0.001-5%, or any range or value therein including, but not limited to, 0.001, 0.003, 0.005, 0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, l.l, 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, no preservative, 0.1-2% m-cresol (for example, 0.1, 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (for example, 0.5, 0.9, 1.1., 1 _5, 1.9, 2.0, 2.5%), 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% alkylparaben(s) (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%).
Other excipients, for example, isotonicity agents, buffers, antioxidants, preservative enhancers, optionally are added to the diluent. An isotonicity 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 range of pHs, such as from about pH 4 to about pH 10, specifically, a range from about pH 5 to about pH 9, more specifically, a range of about 6.0 to about 8Ø According to one aspect of the present invention, the formulations of the present invention have pH between about 6.8 and about 7.8. Suitable buffers include phosphate buffers, for example, sodi~un phosphate and phosphate buffered saline (PBS).
Other additives, such as a pharmaceutically acceptable solubilizers like Tween (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic~
polyls, other block co-polymers, and chelators such as EDTA and EGTA is optionally added to the pharmaceutical compositions to reduce aggregation. These additives are particularly useful if a pump or plastic container is used to administer the pharmaceutical composition.

The presence of pharmaceutically acceptable surfactant mitigates the propensity for the composition to aggregate.
During any of the processes of preparing of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may 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 SYNTHESIS (1991), each of which is incorporated by reference herein in its entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
E. Combination Therapy In addition, co-administration or sequential administration of the compounds of the present invention and other therapeutic agents may be desirable, such as chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, nucleolytic compounds, radioactive isotopes, receptors, and pro-drug activating enzymes, which may be naturally occurring or produced by recombinant methods. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, where there is a time period while both (or all) active therapeutic agents simultaneously exert their biological activities.
The compounds of this invention optionally are administered in combination with an antirheumatic (for example, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an anti-cancer, an antimicrobial (for example, aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an anti-psoriatic, a corticosteriod, an anabolic steroid, a diabetes-related agent, 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 laxative, an anticoagulant, an erythropieitin (for example, epoetin alpha), a filgrastim (for example, G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (for example, basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an anti-metabolite, a mitotic inhibitor, a radiopharmaceutical, an anti-depressant, anti-manic 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 analog thereof, dornase alpha (Pulmozyme), a cytokine, or any combination thereof.
Such anti-cancer or antimicrobial compounds also can include toxin molecules that are associated, bound, co-formulated, co-administered, or sequentially administered, in either order, with at least one of the compounds of the present invention. The term "toxin" includes to both endotoxins and exotoxins produced by any naturally occurring, mutant, or recombinant bacteria or viruses that may cause any pathological condition in humans and other mammals, including toxin shock, which can result in death. The toxin optionally can act to kill selectively the pathologic cell or tissue. The pathologic cell can be a cancer or other cell.
Such toxins can be, but are not limited to, purified or recombinant toxin or toxir~ fragment comprising at least one functional cytotoxic domain of toxin, for example, selected from at least one of ricin, diphtheria toxin, a venom toxin, or a bacterial toxin.
Such toxins may include, but are not limited to, enterotoxigenic E. coli heat-labile enterotoxin (LT), heat-stable enterotoxin (ST), Shigella cytotoxin, Aeromonas enterotoxins, toxic shock syndrome toxin-1 (TSST-1), Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcal enterotoxins. Such bacteria include, but are not limited to, 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 (for example, Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei), Salmonella species (for example, Salmonella typhi, Salmonella cholera-suis, Salmonella enteritidis), Clostridium species (for example, Clostridium per&ingens, Clostridium dificile, Clostridium botulinum), Camphlobacter species (for example, Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species, (for example, Heliobacter pylori), Aeromonas species (for example, Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae), Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (for example, Vibrios cholerae, Vibrios parahemolyticus), Klebsiella species, 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 (2d. ed. Plenum Medical Book Co., New York) (1991); MANDELL ET AL., PRINCIPLES AND PRACTICE OF
INFECTIOUS
DISEASES (3d. ed. Churchill Livingstone) (1990); BERKOW ET AL., THE MERCK
MANUAL
(16th ed. Merck and Go.) (1992); Wood et al., 76 FEMS MICROBIOLOGY IMMUNOLOGY

s 134 (1991); Marrack et al., 248 SCIENCE 705-711 (1990), each of which is incorporated 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 imrnunosuppressive 1o 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 may be administered simultaneously or sequentially, in either is order and at various times with a compound of the present invention that comprises 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 cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan;
aziridines such as benzodopa, carboquone, meturedopa, and uredopa;
ethylenimines and 2o methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiehin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitroureas such as cannustine, 25 chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromoinycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idambicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, 30 peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FI.J); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;
pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, rnepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;
bestrabucil;
bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine;
elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;
mitoguazone;
mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;
podophyllinic acid;
2-ethylhydrazide; procarbazine; PSK~; razoxane; sizofrran; spirogermanium;
tenuazonic acid; triaziquone; 2, 2',2"-trichlorotriethylamine; urethan; vindesine;
dacarbazine;
mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa; taxoids, for example, paclitaxel (TAXOL~, Bristol-Myers Squibb Oncology, Princeton, NJ) and doxetaxel (TAXOTERE~, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine;
methotrexate;
platinum analogs such as cisplatin and carboplatin; vinblastine; platinum;
etoposide (VP-16);
ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;
novantrone;
teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11;
topoisomerase inhibitor RFS 2000; difluoromethylornithine (I~MFO); retinoic acid; esperamicins;
capecitabine; and 2o pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4 hydroxytamoxifen, trioxifene, lceoxifene, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
The therapeutic agent may comprise a cytolcine. The term "cytokine" is a generic term for proteins released by one cell population which act on another cell as intercellular mediators. As used herein, the term "cytokine" includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone;
parathyroid hormone; thyroxine; insulin; proiiisulin; relaxin; prorelaxin;
glycoproteW
hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSIi~, and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor;
prolactin;
placental lactogen; tumor necrosis factor-a and -13; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor;
integrin; thrombopoietin (TPO); nerve growth factors such as NGF-13; platelet growth factor;
transforming growth factors (TGFs) such as TGF-a and TGF-13; insulin-like growth factor-I
and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-a, -13 and -?; colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF);
granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (GCSF); interleukins (ILs) such as IL-l, 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-a or TNF-13; and other polypeptide factors including LIF
and kit ligar~d (KL).
The compounds of the present invention may be administered in combination with an anti-inflammatory agent including, but not limited to, adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, i.e_, aspirin; para-aminophenol derivatives, i.e., acetominophen; indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and lcetoroIac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone}, nabumetone, gold compounds (auranof'm, aurothioglucose, gold sodium thiomalate). Commercially available nonsteroidal anti-inflammatory drugs 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~, Pulrnicort (AstranZeneca), and Vanceril (Schering), Asacol (Procter & Gamble), Colazal (Salix), Dipentum (Pharmacia & Upjohn), and Rowasa (Solvay).

The compounds of the present invention may be admistered in combination with an antirheumatic agent. Commercially available antirheumatic agents include, but are not limited to, Anaprox (Roche Labs.), Arava (Aventic), Arthrotec (Searle), Azulfidine (Pharmacia & Upjohn), Gataflam (Novartis), Celebrex (Pfizer), Gelestone (Schering), s 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).
Moreover, the compounds of the present invention may be used in combination with to any cardiovascular agent including, but not limited to, adrenergic blockers such as Cardura (Pfizer), Dibenzyline (WellSpring), 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 (GlaxoSmithI~line), and Normodyne (Schering);
15 angiotensin converting enzyme inhibitors, such as Accupril (Parke-Davis), Aceon (Solway), Altace (Monarch), Captopril (Mylan), Enalaprilat (Baxter Anesthesia), Lotensin (Novartis), Mavik (Abbott), Monopril (Bristol-Myers Squibb), Prinivil (Merck), Univasc (Schwarz), Vaotec (Merck), and Zestril (AstraZeneca); angiotenisin converting enzyme inhibitors such as Lexxel (AstraZeneca), Lotrel (Novartis), Tarka (Abbott), Accuretic (Parke-Davis), 20 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), antilipemic agents such as bile acid sequestrants, fibric acid derivatives, HMG-CoA reductase inhibitors, and 25 nicotinic acid; Beta adrenergic blocking agents; calcium channel blockers;
inotropic agents;
vasodilators including coronoary vasodilators, natriuretic peptides, and peripheral vasodilators; and vasopressors.
According to one aspect of the present invention, the therapeutic agent comprises a small molecule toxin, including maytansine, calicheamicin, trichothene, and CC
1065.
30 According to another aspect of the present invention, the therapeutic agent comprises one more calicheamicin molecules. Members of the calicheamicin family of antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations.

Structured analogues 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 such toxins include nonbinding active fragments of diphtheria toxin, diphtheria A chain, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, dianthin proteins, Phytolaca americana proteins (PAPI, PAPAII, and PAP-S), momordica charantia inhibitor, curcin, crotin sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictoein, phenomvcin, enomycin and the tricothecenes. See, for example, WO 93/21232, incorporated herein by reference in its entirety.
The present invention further contemplates therapeutic agents that have nucleolytic 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 Y9°, Atzzz, Ret86, Re186, Sm~53, Bizlz, psz and radioactive isotopes of Lu.
The compound of the present invention may be conjugated to a receptor, such as streptavidin, for utilization in tumor pretargeting. Briefly, the compound-receptor conjugate is administered to the patient and unbound conjugate is removed from circulation with a clearing agent. A ligand, such as biotin, which is conjugated to a cytotoxic agent, is then 2o administered.
1. Timing of Administration According to one aspect of the present invention, a compound described herein is administered before a second therapeutic agent. The administration of a compound may occur anytime from several minutes to several hours before the administration of the second therapeutic agent. The compound may alternatively be administered anytime from several hours to several days, possibly several weeks, and up to several months before the second therapeutic agent.
More specifically, a compound of the present invention may be administered at least about 1 minute, at least about minutes, at least about mW utes, at least about minutes, at 3o least about minutes, 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 about 24 minutes, at least about 25 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 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.
Furthermore, a compound of the present invention may 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.
Moreover, a compound of the present invention may 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 least 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 may be administered at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weelcs, at least about 5 weeks, at s 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 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.
1 o Further, a compound of the present invention may 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.
15 According to another aspect of the present invention, a compound of the present invention is administered after the therapeutic agent. The administration of a compound may occur anytime from several minutes to several hours after the administration of the therapeutic agent. A compound may alternatively be administered anytime from several hours to several days, possibly several weeks, and even up to several months after the second 20 therapeutic agent.
More specifically, a compound of the present invention may be administered at least about 1 minute, at least about minutes, at least about minutes, at least about minutes, at least about minutes, 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 25 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 about 24 minutes, at least about 25 minutes, at 30 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 Ieast 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 s minutes, at least about 51 minutes, at least about 52 minutes, 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 after the second therapeutic agent.
More specifically, a compound of the present invention may 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 after the second therapeutic agent.
Moreover, a compound of the present invention may 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 least about 29 days, at least about 30 days or at least about 31 days after the administration of the second therapeutic agent.
A compound of the present invention may 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 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 after the second therapeutic agent.
Further, a compound of the present invention may 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 after the second therapeutic agent.
The compound of formula (I) also may be administered in conjunction with other medications used in the treatments of cardiovascular diseases, including platelets aggregation to inhibitors such as aspirin, antithrombotic agents such as coumadin, calcium channel blockers such as dilteazem and nefidipine, angiotension converting enzyme (ACE) inhibitors such as captopril and enalopril and 13 Mockers such as propanalol. The compound also can be administered in combination with non steroid antiinflamatory agents such as ibuprofen, indomethacin, sulindac, or COX II inhibitors such as rofecoxib or celecoxib. A
therapeutic amount of the compound of formula (I) also can be administered with a carticosteroid. They also can be administered in combination with a TNF-a modulating agent for example etanercept or infliximab. A therapeutic amount of the compound of formula (I) also can be administered also can be administered with HMGCoA reductose inhibitors, PPAR-?
agonists, HDL elevators or retinoids.
Methods of Administration The compounds of the present invention may be administered by any suitable means, including, but not limited to, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdemnal means.
3o A. Pulmonary/Nasal Administration There are a several desirable features of an inhalation device for administering a compound of the present invention. For example, delivery by the inhalation device is advantageously reliable, reproducible, and accurate. For pulmonary administration, at least one pharmaceutical composition is delivered in a particle size effective for reaching the lower airways of the lung or sinuses. The inhalation device optionally delivers small dry particles, typically less than about 10 pm, for example, about 1-5 Vim, for good respirability.
The pharmaceutical composition of the present invention can be delivered by any suitable inhalation or nasal device. Devices capable of depositing aerosolized formulations in the sinus cavity or alveoli of a patient include, but are not limited to, metered dose inhalers, nebulizers, dry powder generators, and sprayers. Other devices suitable for directing pulmonary or nasal administration are also known in the art.
to All such devices may be used for the administration of a pharmaceutical composition in an aerosol. Such aerosols may comprise either solutions (both aqueous and non aqueous) or solid particles. Metered dose inhalers like the Ventolin~ metered dose inhaler, typically use a propellent gas and require actuation during inspiration. See, for example, WO
98/35888; WO 94/16970. Dry powder inhalers like Turbuhaler~ (Astray, Rotahaler~
(Glaxo), Diskus° (Glaxo), Spiros inhaler (Dura), devices marketed by Inhale Therapeutics, and the Spinhaler~ powder W baler (Fisons), use breath-actuation of a mixed powder. See U.S. Patent Nos. 5,458,135; 4,668,218; WO 97/25086; WO 94/08552; WO 94106498;
and EP
0 237 507, each of which is incorporated by reference herein in its entirety.
Nebulizers, for example, AERx~, Aradigm, the Ultravent~ nebulizer (Mallinckrodt), and the Acorn II~
nebulizer (Marquest Medical Products) produce aerosols from solutions, while metered dose inhalers, and dry powder inhalers generate small particle aerosols. These specific examples of commercially available inhalation devices are intended to be a representative of specific devices suitable for the practice of the invention, and are not intended as limiting the scope of the invention.
Where the earner is a solid, formulations suitable for nasal administration include a coarse powder having a particle size, for example, from about 20 to 500 microns that is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
Where the earner is a liquid, suitable formulations for administration as, for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
1. Administration as a Spray A spray comprising a pharmaceutical composition of the present invention can be produced by forcing a suspension or solution of a compound contemplated hereby through a nozzle under pressure. The nozzle size and configuration, the applied pressure, and the liquid feed rate are chosen to achieve the desired output and particle size.
An electrospray s can be produced, for example, by an electric field in connection with a capillary or nozzle feed. Typically, particles of at least one compound delivered by a sprayer have a particle size less than about 20 ~.m, less than about 19 Win, less than about 18 Nm, less than about 17 ~,rn, less than about 16 N,m, less than about 15 Vim, less than about 14 Nrn, less than about 13 Nrn, less than about 12 Etm, less than about 11 urn, less than about 10 fun, less than about 9 Eun, to less than about 8 Vim, less than about 7 ~.un, less than about 6 ~.m, less than about 5 qm, less than about 4 Vim, less than about 3 Vim, less than about 2 Nm, less than about 1 qm.
Pharmaceutical compositions according to the present invention suitable for use with a sprayer typically include a compound contemplated hereby in an aqueous solution at a concentration of about 0.1 mg to about 100 mg of a compound contemplated hereby per mL
is of solution or mg/gm, or any range or value therein including, but not hnited to, 0.1, 0.2., 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, l, 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 20 also can 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 pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose, or the like. The pharmaceutical composition also can include a surfactant, 2s which can reduce or prevent surface-induced aggregation of the pharmaceutical composition caused by atomization of the solution in forming an aerosol. Various conventional surfactants can be employed such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. Amounts will generally range between 0.001 and 10% by weight of the formulation. Suitable surfactants include, but are not limited to, 3o polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art also can 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 compressed air source is used to create a high-velocity air jet through an orifice. As the gas expands beyond the nozzle, a low-pressure region is created, which draws a solution of composition protein 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 range of configurations, flow rates, and baffle types can be employed to achieve the desired performance characteristics from a given jet nebulizer. In to an ultrasonic nebulizer, high-frequency electrical energy is used to create vibrational, mechanical energy, typically employing a piezoelectric transducer. This energy is transmitted to the formulation of composition protein either directly or through a coupling fluid, creating an aerosol including the composition protein. Advantageously, particles of the pharnlaceutical composition delivered by a nebulizer have a particle size less than about 20 Vim, less than about 19 E.im, less than about 18 Eam, less than about 17 Eun, less than about 16 Eim, less than about 15 Eun, less than about 14 Eim, less than about 13 Etm, less than about I2 E.un, less than about 11 Eim, less than about 10 E.im, less than about 9 Eim, less than about 8 E.un, less than about 7 qm, less than about 6 E rn, less than about 5 Eam, less than about 4 E.vm, less than about 3 E~m, less than about 2 E~m, less than about 1 E~m.
2o 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 hereby per mL of solution or mg/gm, or any range or value therein including, but not limited to, 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 also can 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 3o compositions suitable for use in a sprayer include albumin, protamine, or the like. Typical carbohydrates useful in pharmaceutical compositions include sucrose, mannitol, lactose, trehalose, glucose, or any combination thereof. The pharmaceutical composition also can include a surfactant, which can reduce or prevent surface-induced aggregation of the pharniaceutical composition caused by atomization of the solution in forming an aerosol.
Various conventional surfactants can be employed such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. Amounts will generally range s between 0.001 and 10% by weight of the formulation. Suitable surfactants for purposes of this invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art also can be included in the pharmaceutical composition.
3. Administration by a Metered Dose Inhaler l0 In a metered dose inhaler (MDI), a propellant, a compound of the present invention, and any excipients or other additives are contained in a cannister as a mixture including a liquefied, compressed gas. Actuation of the metering valve releases the mixture as an aerosol, typically containing particles in the size range of less than about 20 pm, less than about 19 Vim, less than about 18 Vim, less than about 17 Nrn, less than about 16 Vim, less than 1s about 15 Nm, less than about 14 Nxn, less than about 13 Nrn, less than about 12 Vim, less than about 11 pm, less than about 10 Vim, less than about 9 Vim, less than about 8 ~xn, less than about 7 Nrn, less than about 6 Vim, less than about 5 ~,m, less than about 4 Nm, less than about 3 Vim, less than about 2 l.un, less than about 1 Eun.
The desired aerosol particle size can be obtained by employing a formulation of a 20 compound of the present invention produced by various methods known to those of skill in the art including, but not limited to, jet-milling, spray drying, critical point condensation.
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 2s generally include a finely divided powder containing a compound contemplated hereby as a suspension in a non-aqueous medium, for example, suspended in a propellant with the aid of a surfactant. The propellant can be any conventional material employed for this purpose such as chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon including trichlorofluoromethane, dichlorodifluoromethane, 3o dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like. 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 trioleate, soya lecithin, oleic acid, or the like. In some cases solution aerosols are formed using solvents such as ethanol. One of ordinary skill in the art will recognize that the methods of the present invention can be achieved by pulmonary administration of a compound contemplated hereby via devices not described herein.
B. Mucosal Administration For absorption through mucosal surfaces, the compositions and methods of the present invention for administering a compound contemplated hereby include an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, a bioactive peptide, and an aqueous continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion of the emulsion particles. See, for exazyzple, U.S. Patent No. 5,514,670. Mucous surfaces suitable for application of the compositions of the present invention can include corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, abdominal, intestinal, and rectal routes of administration. Pharmaceutical compositions for vaginal or rectal administration, such as suppositories, can contain as excipients, for example, polyalkyleneglycols, vaseline, cocoa butter. Pharmaceutical compositions for intranasal administration can be solid and contain excipients, for example, lactose or can be aqueous or oily solutions of nasal drops. For buccal administration, excipients include sugars, calcium stearate, magnesium stearate, pregelinatined starch. See, for example, U.S.
Patent No.
5,849,695.
C. Transdermal Administration The pharmaceutical compositions of the present invention may be adminstered 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 (referred to collectively as "microparticles" unless otherwise stated). Any suitable delivery device may be used, for example, microparticles made of synthetic polymers, such as polyhydroxy acids, for example, polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyanhydrides, and polyphosphazenes, and natural polymers such as collagen, polyamino 3o acids, albumin and other proteins, alginate and other polysaccharides, and any combination thereof. See, foz~ example, U.S. Patent No. 5,814,599, incorporated by reference herein in its entirety. To be administered in the form of a transdermal delivery system, the dosage administration may be continuous rather than intermittent throughout the dosage regimen.
Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier. According to one aspect of the present invention, a transdermal patch is used as a topical delivery system.
Topical compositions may be admixed with a variety of Garner materials including, for example, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E
oils, mineral oil, PPG2 myristyl propionate, or any mixture thereof, to form, for example, alcoholic solutions, to topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. Examples of such carriers and methods of formulation may be found in 1ZEMINGTON'S PHARMACEUTICAL SCIENCES (1990), incorporated by reference herein in its entirety. Pharnaceutical 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 deliver the compounds of the present invention to the subject over prolonged periods of time, for example, for periods of one week to one year for a single adminstration. Certain medical devices may be employed to provide a continuous 2o intermittent or on demand dosing of a patient. The devices may include a pump or diffusion apparatus, or any other device containing a reservoir of drug and optionally diagnostic or monitoring components to regulate the delivery of the drug. Various slow-release, depot, or implant dosage forms can be utilized. For example, a dosage form can contain a pharnaceutically acceptable non-toxic salt of compound contemplated hereby that has 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, naphthalene mono- or di-sulfonic acids, 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 from for example, N,N'-dibenzyl-ethylenediamine or ethylenediamine; 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 just described, 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 tannate 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 slow degrading, non-toxic, non-antigenic polymer such as a polylactic acid/polyglycolic acid polymer, for example, as described in U.S. Patent No.
3,773,919. The compounds or relatively insoluble salts thereof also can be formulated in cholesterol matrix silastic pellets, particularly for use in animals. Additional slow-release, depot, or implant formulations, for example, gas or liquid liposomes are described in, for example, U.S. Patent NO. 5,770,222; SUSTAINED AND CONTROLLED RELEASE DRUG DELIVERY SYSTEMS (1978), incorporated by reference herein in its entirety.
Dosage Determination In general, the compounds contemplated hereby may be used alone or in concert with other therapeutic agents at appropriate dosages to obtain optimal efficacy while minimizing any potential toxicity. The dosage regimen utilizing a compound of the present invention may be selected in accordance with a variety of factors including type, species, age, weight, sex, medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
Optimal precision in achieving concentrations of drug within the range that yields maximum efficacy with minimal toxicity may require a regimen based. on the kinetics of the compound's availability to a target site(s). Distribution, equilibrium, and elimination of a drug may be considered when determiliing the optimal concentration for a treatment regimen.
The dosages of a compound contemplated hereby may be adjusted when combined to achieve desired effects. On the other hand, dosages of these various therapeutic agents may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone.
In particular, toxicity and therapeutic efficacy of a compound contemplated hereby may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LDSO (the dose lethal to 50% of the population) and the EDSO (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index and it may be expressed as the ratio LDSO/EDSO. Compounds exhibiting large therapeutic indices typically are used.
Although compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects. Generally, the compounds of the present invention may be administered in a manner that maximizes efficacy and minimizes toxicity.
Data obtained from cell culture assays and animal studies may be used in formulating a range of dosages for use in humans. The dosages of such compounds are generally within a range of circulating concentrations that include the EDSO with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods of the invention, the therapeutically effective dose may be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the ICSO (the concentration of the test compound that achieves a half maximal inhibition of symptoms) as determined in cell culture. Such information may be used to determine accurately useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
Moreover, the dosage administration of the pharmaceutical compositions of the present invention may be optimized using a pharmacokinetic/pharmacodynamic modeling system. For example, one or more dosage regimens may be chosen and a pharmacokinetic/pharmacodynamic model may be used to, determine the pharmacokinetic/pharmacodynamic profile of one or more dosage regimens. Next, one of the dosage regimens for administration may 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.
3o Methods are known in the art for determining effective doses for therapeutic and prophylactic purposes for the disclosed pharmaceutical compositions or the disclosed drug combinations, whether or not formulated in the same composition. For therapeutic purposes, the term "jointly effective amount", as used herein, means that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., inhibiting the onset or progression of a disorder), the term "jointly effective amount" refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician. Thus, the present invention provides combinations of two l0 or more therapeutic agents wherein, for example, (a) each therapeutic agent is administered in an independently therapeutically or prophylactically effective amount; (b) at least one therapeutic agent in the combination is administered in an amount that is sub-therapeutic or subprophylactic if administered alone, but is therapeutic or prophylactic when administered in combination with the second or additional therapeutic agents according to the invention; or (c) both therapeutic agents are administered in an amount that is subtherapeutic or sub-prophylactic if administered alone, but are therapeutic or prophylactic when administered together. Combinations of three or more therapeutic agents are analogously possible.
Methods of combination therapy W clude coadministration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation;
and administration of two or more active agents separately formulated.
Dosages The pharmaceutical compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. In the case of oral administration, the daily dosage of the compositions may be varied over a wide range from about 0.0001 to about 1,000 mg per patient, per day. The range may more particularly be 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 may be provided in a form of scored or unscored tablets containing about 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 dosage for the patient to be treated.
In the case of injections, it is usually convenient to give by an intravenous route in an amount of about 0.01-30 mg, about 0.1-20 mg or about 0.1-10 mg per day to adults (at about 60 kg). In the case of other animals, the dose calculated for 60 kg may be administered as well.
The daily dosage of the pharmaceutical compositions may be varied over a wide range from about 5 to about 1000 mg per adult human per day. For oral administration, the pharmaceutical compositions optionally are provided in the form of tablets containing, 5.0, l0 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 dosage to the patient to be treated. An effective amount of the drug typically is provided at a dosage level of 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 dosage 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 dosage level is from about 0.5 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of about 1 to about 10 times per day.
Doses of a compound of the present invention optionally can 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, 12.9, 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 ~g/mL serum concentration per single or multiple administration or any range, value or fraction thereof.

As a non-limiting example, treatment of humans or animals can be provided as a one-time or periodic dosage of a compound of the present invention 0.1 to 100 mg/kg such as 0.5, 0.9, 1.0, l.l, 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 mglleg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 l, 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 week l, 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, Sl, or 52, or alternatively or additionally, at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 l, 12, 13, 14, l0 15, 16, 17, 18, 19, or 20 years, or any combination thereof, using single, infusion or repeated doses.
Specifically, the pharmaceutical compositions of the present invention may be administered at least once a week over the course of several weeks. According to one aspect of the present invention, the pharmaceutical compositions are administered at least once a week over several weeks to several months. According to another aspect of the present invention, the pharmaceutical compositions are administered once a week over four to eight weeks. According to yet another aspect of the present invention, the pharmaceutical compositions are administered once a week over four weeks.
More specifically, the pharmaceutical compositions may 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 least once a day for about 10 days, at least once a day for about 11 days, at least once a day for about 12 days, at least once a day for about 13 days, at least once a day for about 14 days, at least once a day for about 15 days, at least once a day for about 16 days, at Least once a day for about 17 days, at least once a day for about 18 days, at least once a day for about 19 days, at least once a day for about 20 days, at least once a day for about 21 days, at least once a day for about 22 days, at least once a day for about 23 days, at least once a day for about 24 days, at least once a day for about 25 days, at least once a day for about 26 days, at least once 3o a day for about 27 days, at least once a day for about 28 days, at least once a day for about 29 days, at least once a day for about 30 days, or at least once a day for about 31 days.

Alternatively, the pharmaceutical compositions may be administered about once every day, about once every 2 days, about once every 3 days, about once every 4 days, about once every 5 days, about once every 6 days, about once every 7 days, about once every 8 days, about once every 9 days, about once every 10 days, about once every 11 days, about once every 12 days, about once every 13 days, about once every 14 days, about once every 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, about once every 22 days, about once every 23 days, about once every 24 days, about once every 25 days, about once every 26 days, about once every 27 days, about once every 28 days, about 10 once every 29 days, about once every 30 days, or about once every 31 days.
The pharmaceutical compositions of the present invention may alternatively be administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 15 weeks, about once every 11 weeks, about 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, about once every 20 weeks.
Alternatively, the pharmaceutical compositions of the present invention may be 2o administered about once every month, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, about once every 6 months, about once every 7 months, about once every 8 months, about once every 9 months, about once every 10 months, about once every 11 months, or about 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 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 about 10 weeks, at least once a week for about 11 weeks, at least once a week for about 12 weeks, at Ieast once a week for about 13 weeks, at least once a week for about 14 weeks, at least once a week for about 15 weeks, at least once a week for about 16 weeks, at least once a week for about 17 weeks, at least once a week for about 18 weeks, at least once a week for about 19 weeks, or at least once a week for about 20 weeks.
Alternatively the pharmaceutical compositions may be administered at least once a week for about 1 month, at least once a week for about 2 months, at least once a week for about 3 months, at least once a week for about 4 months, at least once a week for about 5 months, at least once a week for about 6 months, at least once a week for about 7 months, at least once a week for about 8 months, at least once a week for about 9 months, at least once a week for about 10 months, at least once a week for about 11 months, or at least once a week for about 12 months.
Methods of Using the Compounds A. Heparan Sulfate Proteoglycan Modulation The present invention comprises methods and compositions comprising the identification of compounds for the treatment and prevention of vascular, particularly cardiovascular diseases. More specifically, the present invention relates to methods and compositions for the treatment and prevention of smooth muscle cell proliferation, such as "anti-proliferative" compounds that effect synthesis of proteoglycans. Methods for screening for compounds or molecules that induce HSPG synthesis comprise the addition of such compounds to assays and measuring HSPG synthesis including, but not limited to, the 2o production of Syndecan, Glypican, and Perlecan. Methods for measuring the induction of Perlecan synthesis are also contemplated hereby. 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 HSPGs including Syndecan and Glypican. HSPG production is important in regulating SMC
proliferation and the methods and compositions described herein provide for high throughput screening of molecules that induce HSPG production and regulate SMC
proliferation.
Additionally, the present invention comprises methods and compositions for gene therapy, comprising administering compositions comprising nucleic acids that effect the synthesis or expression of HSPG, particularly Perlecan. For example, vectors comprising nucleic acids coding for Perlecan or active fragments of Perlecan are provided to cells, for example, circulatory tissue cells such as, for example, endothelial cells.
Such 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 comprises methods and compositions for inducing the synthesis or expression of HSPGs, including, but not limited to HSPGs such as Syndecan, Glypican and Perlecan, and also comprises induction and synthesis of active fragments of HSPGs, for example, active fragments of Perlecan. As used herein, when an HSPG
is referred to, the entire molecule or fragments are included therein. For example, Perlecan refers to the entire Perlecan molecule or fragments thereof. Fragments of Perlecan may have the same or different effects on cells. All of these fragments and activities are contemplated to in the present invention.
A major extracellular HSPG in the blood vessel matrix is Perlecan, a protein originally identified in basement membrane. It interacts with extracellular matrix proteins, growth factors and receptors. Perlecan also is present in basement 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 HS chains of Mr~70 kDa are attached to one end of the molecule. Perlecan core protein has a complex functional organization consisting of five consecutive domains with homologies to molecules involved in control of cell proliferation, lipoprotein binding and cell adhesion. The N-terminal domain I (aa ~l-195) contains attachment sites for HS chains. Domain II comprises four repeats homologous to the ligand-2o binding portion of the LDL receptor. Domain III has homology to domains IVa and IVb of laminin and is thought to mediate cell attachment.
SMC hyperplasia is a major event in the development of atherosclerosis and also is responsible for the significant number of failure rates following vascular procedures such as angioplasty and coronary artery bypass surgery, particularly due to restenosis. Proliferation of arterial wall SMC in response to local injury is a major feature of many vascular proliferative disorders. While not wishing to be bound by theory, it is generally thought that the endothelium regulates the growth of the underlying SMC. In the normal vessel, SMC are quiescent, but they proliferate when damage to the endothelium occurs.
Naturally occurnng growth modulators, many of which are derived from the endothelium, tightly control SMC
3o proliferation in vivo.
Though not wishing to be bound by any particular mechanism, it is believed that extracellular HSPGs mediate quiescence in SMCs. In serum-starved quiescent SMC, Perlecan synthesis is induced. For example, Perlecan inhibits DNA synthesis and SMC
proliferation, and blocking Perlecan results in stimulation of DNA synthesis even in the absence of serum and growth factors. Induction of Perlecan and other HSPGs is an important event for the inhibition of SMC growth. Known antiproliferative agents fail to inhibit SMC
proliferation when the effects of Perlecan are blocked. Thus, the present invention comprises methods and compositions for mediating Perlecan and other HSPG synthesis, expression and amounts are taught for the maintenance of SMC in a quiescent state. Such methods and compositions of the present invention also comprise treatment and prevention of vascular diseases, more specifically, pathologies related to SMC proliferation. In particular, such l0 pathologies include atherosclerosis and restenosis.
The present invention also comprises methods and compositions for the treatment and prevention of vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis. Such methods and compositions comprise methods for inhibition of smooth muscle cell (SMC) growth and proliferation, and for induction of quiescence in smooth muscle cells. The present invention further comprise methods and compositions for inducing HSPG synthesis and expression including, but not limited to, the induction of HSPGs 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 of the vein graft's response to harvest and surgical implantation into high-pressure arterial circulation. In neointimal hyperplasia, smooth muscle cells in the middle layer of the vessel wall become activated, divide, proliferate, and migrate into the inner layer.
The resulting abnormal neointimal cells express pro-inflammatory molecules, including cytokines, chemolcines, and adhesion molecules that further trigger a cascade of events that lead to occlusive neointimal disease and eventually graft failure.
Proliferation of SMC in response to local injury is a major feature of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. Though not wishing to be bound to any particular theory, it is generally believed that the endothelium regulates the growth of the underlying SMC. In normal vessels, SMC are quiescent, but they 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 cationic molecules and macromolecules, protecting the main structural component of the basement membrane, type IV collagen, from proteolytic attack, binding cytokines and growth factors including, but not limited to, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and transforming growth factor 13 (TGF-J3), functioning as storage for these cytokines, regulating mesodermal cell fate, positioning of the heart, acting in vasculogenesis and angiogenesis after ischemic injury, effecting interactions of cells with adhesive proteins and blood vessels, inducing proliferation of smooth muscle cells during atherogenesis, acting to increase cell spreading, inhibiting chemotaxis, and effecting the metabolism of lipoproteins and nonthrombogenic characteristics of endothelial cells. Additionally, it is believed that the 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 HSPG can inlubit cell growth.
Although it is currently believed that endothelial HSPGs inhibit SMC
proliferation, it is not known whether SMC synthesize antiproliferative HSPGs that act 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 blocking HSPGs results in stimulation of DNA synthesis even in the absence of serum and growth factors.
Indeed, known antiproliferative agents fail to inhibit SMC proliferation when the effects of HSPGs are blocked.
Examples of HSPGs include Syndecan, Glypican, and Perlecan, which are generated within the cardiovascular system. Vascular SMCs express Syndecans l, 2 and 4, Glypican-1 and Perlecan. The regulation of HSPG expression 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, to decrease Perlecan. In contrast, cellular antiproliferative agents, TGF-(3, apolipoprotein E and heparin stimulate HSPGs.
The present invention comprises methods and compositions for the treatment and prevention of smooth muscle cell proliferation, including vascular occlusive pathologies.
Such methods comprise administering compositions comprising therapeutic agents capable of inhibiting SMC proliferation. Administration of such therapeutic agents that are effective in inhibiting SMC proliferation, such as the aforementioned thizolidinedione compositions, are administered to humans and animals suspected of having or who have, for example, vasculopathy or who have undergone angioplasty or other procedures damaging to the endothelium. Effective amounts are administered to such humans and animals in dosages that are safe and effective. Routes of administration include, but are not limited to, intravenous, subcutaneous, transdermal, nasal, and inhalation therapies. Such therapeutic agents may 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 including, but not limited to, cardiac stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic ateriosclerotic disease, hypertension, arterial hypertension, renovascuIar hypertension, syncope, shock, syphilis of the cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrythmias, ventricular fibrillation, His bundle arrythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, coronary artery disease, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart diseases, endocarditis, pericardial disease, cardiac tumors, aordic and peripheral aneuryisms, aortic dissection, inflammation of the aorta, occulsion of the abdominal aorta and its branches, peripheral vascular disorders, occulsive arterial disorders, peripheral atherlosclerotic disease, thromboangitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperFusion injury, post pump syndrome, ischemia-reperfusion injury, and dyslipidemia. Such a method optionally comprises 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 such modulation, treatment, or therapy.

1. Assessing HSPG Activity The present invention comprises methods and compositions for determining therapeutic agents that are capable of effecting SMC proliferation. Such assays are taught herein and can be used as assays to determine agents that affect the amount or activity of HSPGs, for example, Perlecan, in such assays. For example, in one assay, Perlecan is induced in cells by certain inducers, and the response is measured. Potential therapeutic agents are then added to a replicate assay and the effect on Perlecan induction is determined.
Using such methods and compositions, therapeutic agents are determined that can either inhibit Perlecan, elevate induction of Perlecan, or that have no effect at all. Such therapeutic l0 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. Such compositions are formulated for use in methods of administration in an effective amount for treatment of conditions such as biological conditions including, but not limited to, vascular occlusive lesions including atherosclerosis, transplant vasculopathy, cardiac allograft vasculopathy, restenosis, and graft atherosclerosis after coronary transplantation. The compositions may comprise other compounds including compounds with activities and pharmaceutical adjuncts that are needed for administration of the compound or compounds with the desired activity. The 2o compositions may additionally be administered exclusively or in conjunction with other pharmaceutical compositions and surgical methods for treating smooth muscle cell proliferation and vascular occlusive diseases, including, but not limited to, before, during and after PTCA procedures.
In the assays of the present invention, the compound initially has unknown activity, effect, or effects. The activity of the compound is unknown, in that the compound's effects in the assays of the present invention are not yet determined. The compound may have many other known activities, and may be a compound that has other therapeutic uses.
Any agent that causes the cells or components of the assay to respond in a measurable manner is contemplated by the present invention.
3o The present invention comprises methods and compositions for measuring the activity of unknown compounds. Such methods comprise assays for specific activity of biological components involved 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 measurement of the effects of compounds on SMC
proliferation in response to an HSPG-inducing agent.
s According to one aspect of the present invention, a compound suspected of effecting HSPG synthesis is added to cells in an assay. The response of the cells can be measured by determining levels of HSPG synthesis measured by methods known to those skilled in the art and compared to the amount of HSPG synthesis in untreated cells. The compound may have a stimulating effect, an inhibitory effect, a stabilizing effect, or no effect at all.
l0 According to another aspect of the present invention, a composition suspected of effecting SMC proliferation is added 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 which are not treated with the compound. The composition may have a stimulating effect, an inhibitory effect, a stabilizing 15 effect, or no effect at all.
Compositions with HSPG stimulating effects, particularly Perhecan stimulating effects, are usefuh as anti-proliferative therapeutics, specifically, inhibiting SMC proliferation and thus, treating vascular occlusive conditions. These selective activators of, for example, Perlecan include small organic molecules, peptides, peptoids, or polynucleotides that act 20 directly upon Perlecan to modulate the biological activity or to increase the biological stability of the protein. In addition, the selective activators of Perlecan can increase the biosynthesis of Perlecan by increasing the transcription of the Perlecan gene, increasing the biological stability of the Perlecan mIRNA or increasing the translation of Perlecan mIRNA
into protein. Furthermore, the selective activators of Perhecan can block or decrease the 2s effects of agents or proteins that inhibit the activity of Perlecan.
The present invention also comprises methods and compositions for assays that may be used to identify such selective activators or inhibitors of Perlecan. These assays readily determine the activators that up-regulate and the inhibitors that down-regulate the amount of Perlecan and its biological activity. In general, such assays include, but are not limited to, 3o promoter-based assays to identify compounds that affect Perlecan and assays for Perlecan biological activity in recombinant, partially purified protein, or lysates from cells expressing Perlecan in the presence or absence of compounds of interest. Measurements of Perlecan include biological activity assays and quantitation of Perlecan protein, using ELISA or Western blot determinations, or quantitation of Perlecan RNA using RT-PCR, or Northern blots.
Both indirect and direct methods of measurement of changes in Perlecan are contemplated by the present invention. The assay methods contemplated hereby rely on indirect measurement of Perlecan through measurement of determinants of Perlecan activity or expression.
Additionally, direct determination of the change in the amount of Perlecan protein can be done using other immunological methods, such as Western blots, densitometric l0 measurements or ELISA methods. Alternatively, the direct determination of the change in the amount of Perlecan mRNA can be accomplished using RT-PCR or Northern analysis methods which are known to one skilled in the art. Measurements are also directly made using lysates of cells, and purified or partially purified Perlecan protein that is either a recombinant or natural form of the protein. The means for the measurement of biological activity are known to those skilled in the art.
Another method of identifying and determining compounds that affect Perlecan comprises identifying compounds that interact with the promoter regions of the Perlecan gene, or interact and effect 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 the regulatory sequences, such as an enzyme, in a promoter-reporter construct.
The protein product of the indicator region is referred to herein as a reporter enzyme or reporter protein. The regulatory region of the sequence of Perlecan comprises a range of nucleotides from approximately -4000 to +2000, where the transcription initiation site is -I-l, for example, from -2500 to +1200, for example, from -1500 to +800 relative to the transcription initiation site.
Cells are transfected with the vector and then treated with compounds of interest. For example, the transfected cells are treated with a compound suspected of effecting the transcription of Perlecan and the level of activity 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 are determined by measuring the amount of the reporter protein or determining the activity of the reporter enzyme controlled by the regulatory sequences. An increase in the amount of the reporter protein or the reporter enzyme activity shows a stimulatory effect on Perlecan, by positively affecting the promoter, whereas a decrease in the amount or the reporter protein or the reporter enzyme activity shows a negative effect on the promoter and thus, on Perlecan.
Additionally, the present invention comprises methods and compositions for identifying selective inhibitors of Perlecan protein or biological activity.
These selective inhibitors of Perlecan are small organic molecules, peptides, peptoids, or polynucleotides that act directly upon Perlecan or the promoter region of Perlecan to modulate expression or to decrease the biological stability of the protein. In addition, the selective inhibitors of Perlecan can decrease the biosynthesis of Perlecan by decreasing the transcription of the Perlecan gene, decreasing the biological stability of the Perlecan mRNA or decreasing the translation of Perlecan mRNA into protein. Furthermore, the selective inhibitors of Perlecan can block or decrease the effects of agents or proteins that increase the activity of Perlecan.
Table 1 presents exemplary that have been shown to induce HSPG.
Table 1.
S. No Compound Fold induced at 10 M
1 2.9 ° ~ I ~ S'~ o I ~ I °~.° ~ ° NH
N

F
2 2.8 ~ I ~ S~o ( °~° ~ ° NH
N

CI
3 1.181 ° ~ I ~ S~o I °~° ~ ° NH
N W F

F

4 , F 1.66 Me N ~ I F
~O
I / I O~O ~ s O I ~ s NH
CI
O
2.6 ° / I ~ S~o I o~H \ ° NH
N
CH3 ( F
B. Heparanase Modulation HSPGs are important components of the subendothelial extracellular matrix and the basement membrane of blood vessels. Rosenberg et al., 99 J. CLIN. INVEST. 2062-5 (1997). Basement membranes are continuous sheets of extracellular matrix composed of collagenous and noncollagenous proteins and proteoglycans that separate parenchyma) cells from underlying interstitial connective tissue. They have characteristic permeabilities and play a role in maintaining tissue architecture.
In addition to HSPGs, the basal lamina consists predominantly of a complex network to of adhesion proteins, fibronectin, laminin, collagen and vitronectin. Wight et al., 6 CURB.
OPIN. LIPIDOL. 326-334 (I995). Heparan sulfate (HS) is an important structural component of the basal lamina. Each of the adhesion proteins interacts with HS side chains of HSPGs within the matrix. Thus, HSPGs function as a barrier to the extravasation of metastatic and inflammatory cells. ~ Cleavage of HS by the endoglycosidase Heparanase produced by metastatic tumor cells and inflammatory cells destroys the filtering properties of the lamina.
In addition, the degradation of the HS may assist in the disassembly of the extracellular matrix and thereby facilitate cell migration by allowing blood home cells to escape into the bloodstream. Vlodavsky et al., 12 INVASION METASTASIS 112-127 (1992).
Heparanase activity has been described in a number of tissues and cell types 2o including liver, placenta, platelets, fibroblasts, neutrophils, activated T
and B-lymphocytes, monocytes, and endothelial cells (7-16). Nakajima et al., (31) CANCER LETT.

(1986); Nakajima et al., 36 J. CELL. BIOCIIEM. 157-167 (1988); Ricoveri et al., 46 CANCER

IZES. 3855-3861 (1986); Gallagher et al., 250 BIOCHBM. J. 719-726 (1988);
Dempsey et al., GLYCOBIOLOG1' 467 (2000); Goshen et aL, 2 MoL. HUM. IZEPROD. 679 (1996);
Parish et al., 76 IM1VILINOL CELL BIOL. 104-113 (1998); Gilat et al., 181 J. ExP. MED.

(1995); Graham, et al., 39 BIOCHEM. MoL. BIOL. INT. 56371 (1996); Pillarisetti et al., 270 5 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 invasiveness and tumor metastatic activity. An important process in tissue invasion by blood-borne tumor cells and white cells involves their passage through the vascular endothelial cell layer and 1o subsequent degradation of the underlying basal lamina or basement membranes and extracellular matrix with a battery of secreted proteases and glycosidases.
Nakajinia et al., 220 SCIENCE 611-613 (1983); Vlodavsky et a1.,12 INVASION METASTASIS 112-127 (1992).
Heparanase activity was shown to correlate with the metastatic potential of animal and human tumor cell lines. Nakajima et al., 31 CANCER LETT. 277-283 (1986);
Nakajima et al., 212 PROD CLIN BIOL 1ZES. 113-122 (1986); Freeman et al., 325 BIOCHEM. J.

(1997); Vlodavsky et al., 5 NAT. MED. 793-802 (1999); Hulett et al., 5 NAT
MED. 803-809 (1999). It also is known to regulate growth factor activity. 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 higher by more than an order of magnitude after injection of the rats with highly metastatic mammary adenocarcinoma cells. In addition, Heparanase activity in the sera of rats bearing MTLn3 tumors correlated well with the extent of the metastases. Moreover, serum/urine Heparanase activity in cancer patients was shown to be 2-4 fold increased in particular where tissue metastases were present.
Because the cleavage of HS appears to be essential for the passage of metastatic tumor cells and leukocytes through basement membranes, studies of Heparanase inhibitors provides the potential of developing a novel and highly selective class of anti-metastatic and anti-inflammatory drugs.
Thus, the present invention further relates to compounds that modulate Heparanase 3o activity. Such compounds are useful in treating and/or preventing cancer including, but not limited to, malignant and non-malignant cell growth, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, 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, sarcomas, malignant melanoma, hemangioma, metastatic disease, cancer related bone resorption, cancer related bone pain,.
According to another aspect of the present invention, the compounds contemplated hereby are useful in modulating heparanase activity as a means for treating and preventing autoimmune diseases.
By way of background, in the normal course of resolution of a disease in an infected tissue, local resting immune effector cells in the body become activated after recognizing antigens of the infecting organism as foreign. Upon activation these effector cells in the body synthesize and secrete signaling molecules (chemokines, lymphokines and cytokines), which attract additional immune effector cells to the site of infection, where they are also activated. Once activated, these immune effector cells become capable of exiting the vasculature and entering the infected tissue where they begin to attract and destroy the infectious agent and the infected tissue. This process continues until the infection is eradicated.
2o Occasionally, however, the immune system malfunctions or overreacts to the initial insult, wluch can lead to the initiation of debilitating and life threatening chronic and acute diseases. This can occur when (1) the immune system mistakenly identifies a cell surface molecule on normal tissue as a foreign molecule, (2) the synthesis arid secretion of chernokines, cytokines, and lymphokines is not shut down after the eradication of the disease, or (3) the immune system overreacts to the apparent infection and destroys vast quantities of surrounding normal tissue.
In normal activity, the 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 infected tissue. The process of exiting the circulation and entering the 3o inflamed tissue involves two distinct steps. First, the immune effector cells must bind to the luminal/apical surface of the blood vessel walls. This is accomplished through the interaction of adhesion molecules on the immune effector cells with their locally upregulated cognate receptors on the endothelial cells lining 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 breach the basement membrane (BM) and extracellular matrix (ECM) that surround the basal portion of the blood vessels and give the vessels their shape and strength. The BM and ECM consists of structural proteins embedded in a fiber meshwork consisting mainly of complex carbohydrate containing structures (glycosaminoglycans), of which the main constituent is heparin sulfate proteoglycan (HSPG).
In order to breach this barrier the immune effector cell must weaken or destroy it, which is to accomplished through the local secretion of proteases and heparanase(s).
Thus, the inhibition of heparanase using the compounds of the present invention finds utitlity 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 autoimmune-related disease in a cell, tissue, organ, animal, or patient including, but not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, Crolm's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney translplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, -meditated 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, 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, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, ankylosing spondylitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST
syndrome, cold agglutinin disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Cogan's syndrome, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis arid dermatomyositis, primary agammaglobulinemia, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, Sjogren's syndrome, stiff man syndrome, Talcayasu arteritis, temporal arteritis/giant cell arteritis, Wegener's 3o granulomatosis; okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (for example, including but not limited toasthenia, anemia, cachexia), chronic salicylate intoxication,.

1. Heparanase Assays The present invention further relates to methods for assaying Heparanase activity. In this regard, the effect of the compounds of the present invention may be evaluated using such assays. Future candidate compounds also useful in the treatment methods of the present invention also may be evaluated using the assays discussed herein.
Furthermore, the present invention also contemplates compositions and methods for assays measuring any glycosidase activity including, but not limited to, any enzymes with glycosaminoglycan-degrading activity, chondroitinase, heparan sulfate endoglycosidase, heparan sulfate exoglycosidase, polysaccharide lyases, keratanase, hyaluronidase, glucanase, amylase, and other glycosidases i 0 and enzymes.
Thus, in one aspect, the present invention comprises compositions and methods for the measurement of cellular and enzymatic activities. Such assays can be used to measure such activities, both qualitatively and quantitatively. Moreover, the assays described herein for determining the presence of such activities may be used in methods for diagnosing metastases, metastatic potential and inflammatory states. In addition, the assays of the present invention also can be used to screen for compounds that alter, either stimulate or inhibit, such cellular and enzymatic activities.
Existing Heparanase assays require preparation of the radiolabeled substrate and separation of degraded products from the uncleaved substrate. See Goshen et al., 2 Moi,.
2o Hunt. IZEPROD. 679-84 (1996); Nakajiina et al., 31 CANCER LETT. 277-83 (1986). Other Heparanase assays require the biosynthetic radiolabeling of matrix-associated HSPG and the detection of HS chain degradation by gel-filtration analysis of radiolabeled material released from the matrix. Vlodaslcy et al., 12 INVASION METASTASIS 112-27 ( 1992).
Solid-phase Heparanase assays have also been developed where chemically and biosynthetically radiolabeled heparin and HS chains were attached to a solid support, with release of radiolabel from the solid support being a measure of enzyme activity. Assays using such procedures are taught in U.S. Patent No. 4,859,581, which is entirely expressly herein incorporated by reference.
Previous studies have also radiolabeled both heparin and HS by iodination at naturally occurring glucosamine residues or by N-acetylation of the partially de-N-sulfated substrate. Such procedures require the use of radioactive iodine, which is a powerful ?
emitter and therefore extremely hazardous. For example, one sensitive radioactive assay for Heparanase requires affinity chromatography of the Heparanase-cleaved products on columns of histidine-rich glycoprotein Sepharose. Freeman and Parish, 325 BIOCHEM. J.
229-37 (1997).
There are also some non-radioactive assays available for Heparanase. One assay for Heparanase involves measuring the optical density (at 230 nm) of unsaturated uronic acids formed during degradation of heparin. A color-based assay for measuring Heparanase activity utilizes heparin's ability to interfere with color development during the interaction of protein with the dye Coomassie brilliant blue. 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, bodily fluid, or other fluid suspected of having Heparanase activity, to form a reaction mixture. Tlus sample may be pretreated to remove contaminating 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 is 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, from a known standard, indicates there was Heparanase activity in the sample. The biotin-binding plate comprises any means for binding biotin, for example, to a solid surface. See WO 02/23197, which is entirely expressly incorporated 2o herein by reference.
In general, a method for measuring Heparanase activity comprises attaching one of a binding partner to a substrate for the enzyme to be measured. Incubation with a sample comprising the enzyme to be measured allows for activity by the enzyme to be measured in a reaction mixture. A portion or the whole reaction mixture, depending on the amount needed, is then mixed with the complementary binding partner, so that the binding partners are bound together. This is the first binding reaction. After incubating to allow for binding, washings are performed. A complementary binding partner, complementary to the first binding partner attached to the substrate, is added. This complementary binding partner may or may not be the same as the first complementary binding partner. This is the second binding reaction.
The complementary binding partner in the second binding reaction is labeled in a manner that is detectable. For example, the complementary binding partner is labeled with an enzyme that causes a detectable color change when the appropriate reaction conditions exist.

Some methods comprise the use of binding partners including, but not limited to, biotin and Streptavidin. Other ways of binding one of the binding partners such as biotin, can be used at either biotin-binding step, either binding biotin to the plate or in detection of the 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 the binding partners, such as biotin and Streptavidin or an antibody and its antigen. The biotin is the complementary binding partner of Streptavidin;
Streptavidin is the complementary binding partner of biotin. An antibody that specifically binds biotin also is a complementary binding partner of biotin.
l0 In the above method, the labeled binding partner, i.e., the enzyme labeled-streptavidin, can be labeled with any detectable marker including but not limited to, enzymes, dyes, chemiluminescence, and other methods known in the art. One such method comprises labeling with an 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 enzyme activity. For example, a composition comprising the candidate compound is added to a known amount of Heparanase either before or during the incubation of the Heparanase and its substrate-binding parh~er. If the compound alters the activity of the Heparanase, the assay methods of the present invention will show a change in the amount of detectable label.
Such assays are used for high throughput determination of the activity of candidate compounds. See WO 02/23197, which is entirely expressly incorporated herein by reference.
C. Inflammation Modulation The present invention is directed to methods and compositions comprising compounds or molecules that have specific biological effects and are useful as therapeutic agents. In particular, the present invention is directed to methods and compositions comprising compounds or molecules that are effective in effecting inflammation. More particularly, the present invention is directed to methods and compositions comprising 3o compounds or molecules that are effective in inhibiting inflammation caused by the accumulation or presence of glycated proteins or AGE. The present invention also provides compositions for and methods of treatment of biological conditions including, but not limited to, vascular complications of type I and type II diabetic-induced vasculopathies, other vasculopathies, microangiopathies, renal insufficiency, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis.
The present invention has utility in inhibiting inflammation or cell activation by glycated proteins or AGE. Pharmacological inhibition of AGE-induced cell activation provides the basis for therapeutic intervention in many diseases, most notably in diabetic complications and Alzheimer's disease. Therapeutic approaches for inhibition of AGE-induced inflammation include, but are not limited to, blocking the glycation of proteins, blocking AGE interactions with receptors and blocking AGE-induced signaling or signaling-l0 associated inflammatory responses.
For example, a method of the present invention is to block AGE effects by inhibiting AGE induced signaling. The sequence of these signaling events leading to inflammation is not clear, but inhibition of these signaling events leads to reduced or no inflammatory results.
Compounds that block AGE-induced up-regulation of inflammatory molecules were determined using screening assays. The present invention comprises methods and compositions comprising compounds or molecules such as the thizolidinedione compounds provided herein.
Other aspects of the present invention comprise methods and compositions comprising compounds that block glycated protein-induced inflammation. Further aspects of the present invention comprise thizolidinedione compounds that are capable of inhibiting AGE effects. Still further aspects of the present invention employ compositions comprising the compounds of the formulae contemplated hereby that block glycated protein-induced inflammation.
Enhanced formation and accumulation of glycated proteins and AGE are thought to play a major role in the pathogenesis of diabetic complications, and atherosclerosis, leading to the development of a range of diabetic complications including nephropathy, retinopathy, and neuropathy. There is ample in vivo evidence that suggests that diabetes-related complications can be reduced by 1) preventing glycation of proteins, 2) by breaking the cross-links in glycated proteins, or 3) by blocking glycated protein interaction with receptors.
3o Despite the importance of AGE in the pathogenesis of diabetic microangiopathies, there are no currently available medications known to block AGE formation.

Aminoguanidine, which prevents AGE formation, is actively pursued as a therapy for diabetic vasculopathy. However it is not clear whether this drug would affect normal glucose metabolism or glycosylation of proteins. Moreover, some studies show that although aminoguanidine reduces AGE formation, it did not inhibit glomerular basement thickness in diabetic rats nor improved endothelial function. See, for example, Birrell et al., 43 DIABETOLOGIA 110-16 (2000); Wada et al., 42 DIABETOLOGIA 743-47 (1999); Soulis et al., 50 KIDNEY INT. 627-34 ( 1996).
In addition to the AGE formation inhibitors, AGE cross-link breakers are also actively pursued as a therapy for vasculopathy. N-Phenacylthiazolium bromide (PTB) is a to prototype AGE cross-link breaker that reacts with and cleaves covalent AGE-derived protein cross-links. Although PTB reduced AGE accumulation, it did not prevent vascular permeability. Cooper et al., 43 DIABETOLOGIA 660-64 (2000); ~turai et al., 49(8) METABOLISM 996-1000 (2000).
Inhibition of reactions with receptors of AGE is an alternative approach to treatment of related pathologies. RAGE, a known receptor for AGE, is a possible therapeutic target.
Blocking RAGE also inhibited AGE-induced inflammation. However, because of the multiple functions of RAGE and possible long teen side effects of accumulated AGE in plasma, this method is not currently pursued in humans. Using the methods and compositions of the present invention, more speciEc inhibitory compounds can be used for treatments.
Endothelium is the target organ of damage in diabetes. See Laight et al., 15 DIABETES METAB. RES. REV. 274-82 (1999); Stehouwer et al., 34 CARDIOVASC. 55-(1997). Up-regulation of molecules involved in endothelial inflammation, such as IL-6 and monocyte chemoattractant protein-1 (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 GLII~IICA. CHIMICA. ACTA. 31-52 (2000).
An overall approach to the understanding and treatment of diabetes and its complications is to interfere in the regulation of genes, such as those leading to the production of cytokines, and to inhibit AGE-induced inflammation.
The effectiveness of the compounds of the present invention in inhibiting glycated protein- and AGE-induced inflammation can be determined using the assays described herein and in U.S. Provisional Patent Application Serial No. 60/259,306, which is incorporated by reference in herein its entirety. Such assays comprise measurement of the specific activity of biological components involved 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 measurement of the effects of 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. The 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 to invention are then added to the assay and the production of cytokines is measured. From the comparison of the assay without the compound with the assay with the compound, the biological effect of the compound can be determined. The compound may have an inhibitory effect, a stimulatory effect, or no effect at all. Compounds for treatment of inflammation include those that have an inhibitory effect.
Assays comprise endothelial cells that are stimulated in an inflammatory response by the presence of the glycated protein, glycated human serum albumin. Such endothelial cells produce cytokines. A method in accordance with the present invention comprises measurement of the amount of the cytokine IL-6, and another aspect of the present invention comprises measurement of 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 methods known to those skilled in the art and later developed can be used to measure the amount of cytokines produced in response to the stimulating agent and to the compound having unknown activity.
IL-6 is a pro-inflammatory cytokine that is known to play a key role izi 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); Picleup et al., 8(67) LIFE SCI. 291-300 (2000).
IL-6 also promotes the growth of renal mesangial cells thus contributing to nephropathy.
See Kado et 3o al., 36 AcTa. DIABETOL. 67-72 (1999). The serum IL-6 level 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 the urinary IL-6 level is a good indicator of diabetic nephropathy. Serum IL-6 is useful in the evaluation of atherosclerosis and nephropathy.
MCP-l, another pro-inflammatory cytokine is found highly expressed in human atherosclerotic lesions and postulated to play a central in monocyte recruitment into the s arterial wall and developing lesions. See Libby, 247 J. INTERN. MED. 349-58 (2000).
Recent results show that MCP-1 also is a key pathogenic molecule in diabetic nephropathy.
See Eitner et al., 51 KIDNEY INT. 69-78 (1997); Banba et al. 58 KIDNEY INT.
684-90 (2000).
Glycated albumin stimulates endothelial production of IL-6 and MCP-1. The effects of glycated albumin on IL-6 production are comparable to that of TNFa, a known inducer of l0 IL-6. Because of the well established role of these cytokines in vascular diseases, screening for compounds that block AGE-induction of these cytokines provides a novel approach for identifying therapeutic agents that block AGE-induced inflammation in vivo.
Once the baseline response to the stimulating agent for the production of cytokines by the endothelial cells is established, thus comprising the control levels for the screening assay, 15 the methods comprise addition of compounds having unknown activities. The effect of the compound on the baseline response is determined by comparing the amount of 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 the cells in the presence of 20 glycated albumin are then used as therapeutic agents. One or more compounds may be added to the screening assay. Combinations or mixtures of compounds can be added.
Different amounts and formulations of the compounds are added to determine the effects on the screening assay. The screening assay also may be used to determine stimulatory compounds or compounds that have no effects in the assay.
25 Table 2 presents examples that have inhibited Proinflammatory cytokines IL-6 and MCP-1.
Table 2.
S. Compound 1'roinflammat% of Concentration No or c inhibitionin tokine M

1 IL-6 50 4.64 NH

N
~

F

2 S MCP-1 50 7.9 0 o I ~ ~o I \ I °~° \ ° NH
o N
cH3 I o F

I w ° I °~° ~ I °~NH
o N
CH3 I o CI
4 p o I ~ S~p MCP-1 44 5 I I O~O \ O NH
o N
CH3 I o Br MCP-1 50 4.4 ° o I ~ S~ o I ~ I °~° ~ ° NH
N W F
CH3 I ~ F
6 o I F MCP-1 61 5 Ne Iw I F
o O~O ~ S
O I o / NH
CI
O
'1 MCP-1 SO 6.5 ° o I ~ S'~ o I ~ I °~° ~ ° NH
I o F

° o ~ ~ S'~ o °~NH
I o N I I w F F
CH3 o F

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. Such compositions are formulated for administration in an effective amount for treatment of conditions such as biological conditions including, but not limited to, vascular complications of type I and type II diabetic induced vasculopathies, other vasculopathies, microangiopathies, renal insufficiency, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis. The compositions may comprise pharmacutical adjuncts that are needed for administration of the compound or compounds with the desired activity.
to Moreover, the compounds of the present invention are useful in the treatment or prophylaxis of at least one autoimmune-related disease in a cell, tissue, organ, animal, or patient including, but not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, traumalhemorrhage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney translplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft 3o rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, -meditated 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, post-MI cardiotomy syndrome, type IV hypersensitivity , contact dernlatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metaboIic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-1 o antitrypsin deEciency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular is nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, ankylosing spondylitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST
syndrome, cold agglutinin disease, discoid lupus, essential mixed cryoglobulinemia, 2o fibromyalgia-fibromyositis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Cogan's syndrome, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, 25 Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, Sjogren's syndrome, stiff man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, Wegener's granulomatosis; okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (for example, including but not limited toasthenia, anemia, cachexia), chronic salicylate intoxication,. See, for- example, The Merck Manual, 12th-17th Editions, Merck &
3o 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, malignant and non-malignant cell growth, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, HodgkW 's disease, a malignamt lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic io syndrome/hypercalcemia of malignancy, solid tumors, adenocarcinomas, sarcomas, malignant melanoma, hemangioma, metastatic disease, cancer related bone resorption, cancer related bone pain, or any combination thereof.
Drug-Coated Medical Devices The compounds of the present invention may be used alone or in combination with other agents along 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 utilized in the treatment of vascular disease may ultimately induce further complications. For example, balloon angioplasty is a procedure utilized to increase blood flow through an artery and is the predominant treatment for coronary vessel stenosis. As stated above, however, the procedure typically causes a certain degree of damage to the vessel wall, thereby potentially exacerbating the problem at a point later in time. Although other procedures and diseases may cause similar injury, exemplary compounds of the present invention will be described with respect to the treatment of restenosis and related complications following percutaneous transluminal coronary angioplasty and other similar arterial/venous procedures, including the joining of arteries, veins and other fluid carrying conduits in other organs or sites of the body, such as the liver, lung, bladder, kidney, brain, prostate, neck and legs.
The local delivery of a compound of the present invention and, optionally, other 3o therapeutic agents, from a stmt prevents vessel recoil and remodeling through the scaffolding action of the stmt. In addition, drug-coated stems can prevent multiple components of neointimal hyperplasia or restenosis as well as a reduce inflammation and thrombosis. Local administration of a compound of the present invention and other therapeutic agents to stented coronary arteries also may have additional therapeutic benefit. For example, higher tissue concentrations of the compounds of the present invention and other therapeutic agents may be achieved utilizing local delivery rather than systemic administration. In addition, reduced systemic toxicity may be achieved utilizing local delivery rather than systemic administration while maintaining higher tissue concentrations. In utilizing local delivery from a stmt rather than systemic administration, a single procedure may suffice with better patient compliance.
An additional benefit of combination therapeutic agent and/or compound therapy may be to reduce the dose of each of the therapeutic agents, thereby limiting their toxicity, while still to achieving a reduction in restenosis, inflammation and thrombosis. Local stmt-based therapy is therefore a means of improving the therapeutic ratio (efficacy/toxicity) of anti-restenosis, anti-inflammatory, and anti-thrombotic therapeutic agents.
Although 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 delivery of a compound of the present invention, alone or as part of a therapeutic agent combination, may be utilized to treat a wide variety of conditions utilizing any number of medical devices, or to enhance the function and/or life of the device. For example, intraocular lenses, placed to restore vision after cataract surgery is often compromised by the formation of a secondary cataract. The latter is often a result of cellular overgrowth on the lens surface and can be potentially minimized by combining a drug or drugs with the device. Other medical devices that often fail due to tissue in-growth or accumulation of proteinaceous material in, on and around the device, such as shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable defibrillators also can benefit from the device-drug/drug combination approach. Other surgical devices, sutures, staples, anastornosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings, bone substitutes, intraluminal devices, and vascular supports could also provide enhanced patient benefit using this drug-device combination approach. Any type of medical device may be coated in some fashion with a compound of the present invention, alone or as part of a therapeutic agent combination that enhances treatment over the singular use of the device or therapeutic agent.

In addition to various medical devices, the coatings may be used to deliver a compound of the present invention in combination with other therapeutic agents including antiproliferative/antimitotic agents including natural products such as vinca alkaloids (for example, vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (for example, etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP) IIb/IIIa inhibitors and vitronectin receptor antagonists; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylinelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BGNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)); platinum coordiilation complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (e.g. estrogen);
anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin);
fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory; antisecretory (breveldin); anti-inflammatory agents such as adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, i.e., aspirin; para-aminophenol derivatives, i.e., acetominophen; indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolinetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate);
immunosuppressives (Cyclosporine, 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 oligionucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors.
Although any number of stems may be utilized in accordance with the present invention, for simplicity, a limited number of stems will be described herein.
The skilled artisan will recognize that any number of stems may be utilized in connection with the present invention. In addition, as stated above, other medical devices may be utilized.
A stmt is commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction. Typically, stems are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ. A common 1o method of expansion occurs through the use of a catheter-mounted, angioplasty balloon that is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
A stmt may resemble an expandable cylinder and may comprise a fenestrated structure for placement in a blood vessel, duct or Iumen to hold the vessel, duct or lumen open, more particularly for protecting a segment of artery from restenosis after angioplasty.
The scent may be expanded circumferentially and maintained in an expanded configuration that is circumferentially or radially rigid. The stmt may be axially flexible and when flexed at a band, for example, the stmt avoids any externally protruding component parts.
2o The stmt may be fabricated utilizing any number of methods. For example, the stent may be fabricated from a hollow or formed stainless steel tube that may be machined using lasers, electric discharge milling, chemical etching or other means. The stmt is inserted into the body and placed at the desired site in an unexpanded form. Expansion may be effected in a blood vessel by a balloon catheter, where the final diameter of the stmt is a function of the diameter of the balloon catheter used. It should be appreciated that a stmt in accordance with the present invention may be embodied in a shape-memory material including, for example, an appropriate alloy of nickel and titanium or stainless steel.
Structures formed from stainless steel may be made self expanding by configuring the stainless steel in a predetermined manner, for example, by twisting it into a braided 3o configuration. After the stmt has been formed it may be compressed to occupy a space sufficiently small as to permit its insertion in a blood vessel or other tissue by insertion means, wherein the insertion means include a suitable catheter, or flexible rod. Upon emerging from the catheter, the stmt may be configured to expand into the desired configuration where the expansion is automatic or triggered by a change in pressure, temperature, or electrical stimulation.
Furthermore, a stmt may be modified to comprise one or more reservoirs. Each of the reservoirs may be opened or closed as desired. These reservoirs may be specifically designed to hold the therapeutic agent/therapeutic agent combination to be delivered.
Regardless of the design of the stmt, it is preferable to have the therapeutic agent/therapeutic agent combination dosage applied with enough specificity and a sufficient concentration to provide an effective dosage in the affected area. In this regard, the reservoir size in the bands is sized to apply adequately the therapeutic agent/therapeutic agent combination dosage at the desired location and in the desired amount.
Alternatively, the entire inner and outer surface of the stmt may be coated with therapeutic agent/therapeutic agent combination in therapeutic dosage amounts.
The coating techniques may vary depending on the therapeutic agent/therapeutic agent combination.
Also, the coating techniques may vary depending on the material comprising the stmt or other intraluminal medical device.
One or more compounds of the present invention and, in some instances, other therapeutic agents as a combination, may be incorporated onto or affixed to the stmt in a number of ways. For example, the compound may be directly incorporated into a polymeric 2o matrix and sprayed onto the outer surface of the stmt. The compound elutes from the polymeric matrix over time and enters the surrounding tissue. The compound typically remains on the stmt for at least three days up to approximately six months, for example, between seven and thirty days.
Any number of non-erodible polymers may be utilized in conjunction with the compound. According to one aspect of the present invention, the polymeric matrix comprises two layers. The base layer comprises a solution of polyethylene-covinylacetate) and polybutylmethacrylate. The compound is incorporated into 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 topcoat determines the rate at which the compound elutes from the matrix. Essentially, the compound elutes from the matrix by diffusion through the polymer matrix. Polymers are permeable, thereby allowing solids, liquids and gases to escape therefrom. The total thickness of the polymeric matrix is from about one micron to about twenty microns or greater. It is important to note that primer layers and metal surface treatments may be utilized before the polymeric matrix is affixed to the medical device. For example, acid cleaning, alkaline (base) cleaning, salinization and parylene deposition may be used as part of the overall process described above.
The polyethylene-co-vinylacetate), polybutylinethacrylate and compound solution may be incorporated into or onto the stmt in a number of ways. For example, the solution may be sprayed onto the stmt or the stmt may be dipped into the solution. The solution may be sprayed onto the stmt and then allowed to dry. The solution may be electrically charged to to one polarity and the stmt electrically charged to the opposite polarity.
In this manner, the solution and stmt will be attracted to one another. In using this type of spraying process, waste may be reduced and more precise control over the thickness of the coat may be achieved. Other methods include spin coating and plasma polymerization.
Drug-coated stems are manufactured by a number of companies including Johnson &
Johnson, Inc. (New Brunswick, 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 No. 6,273, 913; U.S. Patent Application No. 20020051730; WO 02/26271; and WO
02/26I 39, each expressly entirely incorporated herein by reference.
Expression Profiles and Microarray Methods of Use The present invention contemplates a variety of microarrays that may 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, for example, a specific organism or cell type, including human microarrays, vascular microarrays, inflammation microarrays, cancer microarrays, apoptosis microarrays, oncogene and tumor suppressor microarrays, cell-cell interaction microarrays, cytokine and cytokine receptor microarrays, blood microarrays, cell cycle microarrays, neuroarrays, mouse microarrays, and rat microarrays, or combinations thereof.
The 3o microarrays may represent diseases including cardiovascular diseases, vasculopathic conditions, inflammatory diseases, autoimmune diseases, neurological diseases, irmnunologicah diseases, various cancers, infectious diseases, endocrine disorders, and genetic diseases.
Alternatively, the microarrays useful in assessing the efficacy of the compounds of the present invention may represent a particular tissue type including, but not limited to, heart, liver, prostate, lung, nerve, muscle, or connective tissue; for example, coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascuhar endothelium, pulmonary artery endothelium, myometrium microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal ~broblast, neural progenitor cells, skeletal muscle, astrocytes, aortic smooth muscle, mesangial cells, coronary artery smooth muscle, bronchial smooth muscle, uterine smooth muscle, lung 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 including complementary and homologous sequences, wherein said gene expression profile is generated from a cell type treated with a compound of the present invention and is selected from the group comprising coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascular endothelium, pulmonary artery endothelium, myometrium microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibrobhast, pulmonary artery smooth muscle, dermal hbroblast, neural progenitor cells, skeletal muscle, astrocytes, aortic smooth muscle, mesangial cells, coronary artery smooth muscle, bronchial smooth muscle, uterine smooth muscle, lung fibroblast, osteobhasts, 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 3o a compound of the present invention and is selected from the group comprising coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascuhar endothelium, pulmonary artery endothelium, myometrium microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, 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, aortic smooth muscle, mesangial cells, coronary artery smooth muscle, bronchial smooth muscle, uterine smooth muscle, lung fibroblast, osteoblasts, and prostate stromal cells.
More specifically, the present invention contemplates methods for the reproducible measurement and assessment of the expression of specific mRNAs or proteins in, for to example, a specific set of cells. One method combines and utilizes the techniques of laser capture microdissection, T7-based RNA amplification, production of cDNA from amplified RNA, and DNA microarrays containing immobilized DNA molecules for a wide variety of specific genes, including HSPGs such as Perlecan, to produce a profile of gene expression analysis for very small numbers of specific cells. The desired cells are individually identified and attached to a substrate by the laser capture technique, and the captured cells are then separated from the remaining cells. RNA is then extracted from the captured cells and amplified about one million-fold using the T7-based amplification technique, and cDNA may be prepared from the amplified RNA. A wide variety of specific DNA molecules are prepared that hybridize with specific polynucleotides of the microarray, and the DNA
2o 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 the immobilized DNA on 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 specific immobilized DNA
molecules on the microarray. The hybridization results demonstrate, for example, which genes of those represented on the microarray as probes are hybridized to cDNA
from the captured cells, and/or the amount of specific gene expression. The hybridization results 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 of a different set of 3o captured cells. For example, gene expression profiles may be generated from cells treated (and not treated) with a compound of the present invention. The similarities and differences provide useful information for determining 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 gene expression analysis are likewise applicable in the contea~t of protein expression profiles. Total protein may be isolated from a cell sample and hybridized to a microarray comprising a plurality of protein-binding agents, which may include antibodies, receptor proteins, small molecules,. Using any of several assays known in the art, hybridization may be detected and analyzed as described above. In the case of fluorescent detection, algorithms may be used to extract a protein expression profile representative of the particular cell type. In this regard, the change in protein expression in l0 response to treatment of cells with a compound of the present invention may 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 tissue or cell type is used to detect changes in gene transcription 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. Thereafter, the gene transcripts, primarily mRNA, of 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 hybridize with a corresponding probe to form hybridization pairs. Thus, the microarray provides a model of the transcriptional responsiveness following exposure to a particular drug candidate. A hybridization signal may then be detected at each hybridization pair to obtain a gene expression profile.
Gene and/or protein expression profiles and microarrays also may be used to identify activating or non-activating compounds of a particular gene such as Perlecan or other HSPG.
Compounds that increase transcription rates or stimulate, maintain, or stabilize the activity of a protein are considered activating, and compounds that decrease rates or inhibit the activity of a protein are non-activating. Moreover, the biological effects of a compound may be reflected in the biological state of a cell. This state is characterized by the 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 amounts of the constituent RNA
species, especially mRNAs, in the cell under a given set of conditions. Thus, the gene expression profiles, microarrays, and algorithms discussed herein may be used to analyze and characterize the transcriptional state of a given cell or tissue following exposure to an activating or non-activating compound, specifically, a compound of the present invention.
Microarray techniques and methods for analyzing results are well known in the art.
See U.S. Patent Nos. 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; U.S. Patent Application Nos. 200110014461 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. ACRD. SCI. USA

(2000); Getz et al., 97 PROC. NATL. ACAD. SCI. USA 12079-84 (2000); Harrington et al., 3 CURRENT OPINION MICROBIOL 285-91 (2000); Hotter et al., 97 PROC. NATL. ACRD.
SCI. USA
l0 8409-14 (2000); MacBeath et al., 289 SCIENCE 1760-63 (2000); Duggan et al., 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); Hacia et al., 26 NUCLEIC ACIDS lZES. 3865-66 (1998); Lockhart et al., NUCLEIC ACIDS
SYMP. SER. 11-12 (1998); Schena et aL, 16 TRENDS BIOTECHNOL. 301-6 (1998);
Shalom 46 PATROL. BIOL. 107-9 (1998); Welford et al., 26 NUCLEIC ACID IZES. 3059-65 (1998);
Blanchard et al., 11 BIOSENSORS BIOELECTRONICS 687-90 (1996); Lockhart et al., NATURE BIOTECHNOL. 1675-80 (1996); Schena et al., 93 PROC. NATL. ACRD. SCI.
USA
10614-19 (1996); Tomayo et al., 96 PROC. NATL. ACRD. SCI. USA 2907-12 (1996);
Schena et al., 270 SCIENCE 467-70 (1995).
Database Creation Database Access and Associated Methods of Use The present invention comprises a variety of methods including methods for providing diagnostics and predictors relating to biomolecules including HSPGS, particularly, Perlecan. The present invention further comprises methods of providing diagnostics and predictors relating to the efficacy of the compounds of the present invention.
The present invention still further contemplates methods of providing expression profile databases, and methods for producing such databases, for normal and diseased tissues.
The expression profile database may be an internal database designed to include annotation information about the expression profiles generated to assess the effect of the 3o compounds of the present invention and through other sources and methods.
Such 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 tumor type or progression, information related to a compound of the present invention such as dosage and administration information, descriptive information about related cI~NAs associated with the sequence, tissue or cell source, sequence data obtained from external soaxces, expression profiles for a given gene and the related disease state or course of disease, for example whether the expression profile relates to or signii'ies a particular disease state, and preparation methods. The expression profiles may be based on protein and/or polynucleotide microarray data obtained from publicly available or proprietary sources. The database may be divided into two sections: one for storing the sequences and related expression profiles and the other for storing the associated information. This database may l0 be maintained as a private database with a firewall within the central computer facility.
However, this invention is not so limited and the expression profile database may be made available to the public.
The database may be a network system comiecting the network server with clients.
The network may be any one of a number of conventional network systems, including a local area network (LAN) or a wide area network (WAN), as is known in the art (for example, Ethernet). The server may include software to access database information for processing user requests, and to provide an interface for serving information to client machines. The server may support the World Wide Web and maintain a website and Web browser for client use _ Client/server environments, database servers, and networks are well documented in the 2o technical, trade, and patent literature.
Through the Web browser, clients may construct search requests for retrieving data from, for example, a microarray database and an expression profile database.
For example, the user may "point and click" to user interface elements such as buttons, pull down menus, and scroll bars. The client requests may be transmitted to a Web application that formats them to produce a query that may be used to gather information from the system database, based, for example, on microarray or expression data obtained by the client, and/or other phenotypic or genotypic information. Specifically, the client may submit expression data based on microarray expression profiles 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 system of the client expression data with the expression data contained in the database. By way of example, the system compares the expression profiles submitted by the client with expression profiles contained in the database and then provides the client with diagnostic information based on the best match of the client expression profiles with the database profiles. Thus, in one aspect, the comparison of expression profiles aids the clinician in determining the effectiveness of treatment with a compound of the present invention. Based on such a comparison, the clinician may alter or adjust the treatment regimen.
In addition, the website may provide hypertext links to public databases such as GenBank and associated databases maintained by the National Center for Biotechnology Information (NCBI), part of the National Library of Medicine as well as, any links providing relevant information for gene expression analysis, genetic disorders, and scientific literature.
to Information including, but not limited to, identifiers, identifier types, biomolecular sequences, common cluster identifiers (GenBank, Unigene, Incyte template identifiers, and so forth) and species names associated with each gene, is contemplated.
The present invention also provides a system for accessing and comparing bioinformation, specifically expression profiles and other information which 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 operatively coupled to the computer processor, and a computer process stored in the memory that executes in the computer processor and which comprises a means for matching an expression profile of a biomolecular sequence from a patient with expression profile and sequence identification information of 2o 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 expression profile and other information in a database.
Furthermore, the system for accessing and comparing information contained in biomolecular databases comprises a computer program comprising computer code providing an algorithm for matching an expression profile generated from a patient, for example, treated with a compound of the present invention, with expression profile and sequence identification information of biomolecular sequences in a biomolecular database.
The present invention contemplates, for example, the use of a Graphical User Interface ("GUI") for the access of expression profile information stored in a biomolecular 3o database. The GUI may be composed of two frames. A first frame may contain a selectable list of biomolecular databases accessible by the user. When a biomolecular database is selected in the first frame, a second frame may display information resulting from the pair-wise comparison of the expression profile database with the client-supplied expression profile as described above, along with any other phenotypic or genotypic information.
The second frame of the GUI may contain a listing of biomolecular sequence expression information and profiles contained in the selected database.
Furthermore, the second frame may allow the user to select a subset, including all of the biomolecular sequences, and to perform an operation on the list of biomolecular sequences.
The user may select the subset of biomolecular sequences by selecting a selection box associated with each biomolecular sequence. The operations that may be performed include, but are not limited to, downloading all listed biomolecular sequences to a database spreadsheet with classification information, saving the selected subset of biomolecular sequences to a user file, downloading all listed biomolecular sequences to a database spreadsheet without classification information, and displaying classification information on a selected subset of biomolecular sequences.
If the user chooses to display classification information on 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. Furthermore, 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 the one or more fields displayed in the second GUI. The GUI also may allow the user to select or deselect each of the one or more external databases.
The methods of the present application father relate to the commercial and other uses of the compositions and methodologies of the present invention. In one aspect, the methods include the marketing, sale, or licensing of the compositions and methodologies of the present invention in the context of providing consumers, i.e., patients, medical practitioners, medical service providers, researchers, and pharmaceutical distributors and manufacturers, with expression profile databases including, in particular, databases produced in accordance with 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 establishing a sales group for marketing the pharmaceutical composition.
The present invention provides a method of conducting target discovery comprising identifying, by one or more of the above drug discovery methods, a test compound, as described above, which modulates the level of expression of a gene or the activity of a gene product such as Perlecan; conducting therapeutic profiling of agents identified, or further analogs thereof, for efficacy and toxicity in animals; and optionally formulating a pharmaceutical composition including one or more of the agents identified as having an acceptable therapeutic profile; and optionally licensing or selling, the rights for further drug development of said identified agents.
The present invention is further illustrated by the following preparations and examples, which are not to be construed in any way as imposing limitations upon the scope thereof. It will be clear to one of skill in the art that various other modifications, i0 embodiments, and equivalents thereof exist that do not depart from the spirit of the present invention and/or the scope of the appended claims.

1-[4-(2-Bromo ethoxy) phenyl]-1-ethanone O
\ / O~s Br is A mixture of 4-hydroxyacetophenone (20 g, 147 mmol) and potassium carbonate (81 g, 588 mrnol) was placed into 2 L round bottomed flask and acetone (1 L) was added. To this reaction mixture dibromoethane (38 mL) was added in one portion, and then the reaction mixture was allowed to reflux for 36 hours, under nitrogen atmosphere. The reaction mixture 20 was cooled to room temp, and filtered off, residue was washed with acetone (2 ~ 100 mL), and the filtrates were combined and concentrated under reduced pressure. The crude was chromatographed over silica gel by using 10-15 % ethyl acetate / pet. ether (2 L), affording the title compound 7 g (20 %) as a white solid. Mp. 58-61°C.
IR: ? max (fir, cm 1): 1678, 1603;
25 1H NMR (200 MHz, CDC13): d 7.93 (d, J= 8.87 Hz, 2H), 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 (CI method, I-butane): 245 (MH+, 100), 243 (M'-, 100).

2-(3,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H 4-chromenone OMe OMe O
Step (i):
3-[(6-O-(deoxy-a-L-manopyranosyl)-13-glucopyranosyl)oxy)-2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-4H-1-benzopyran-4-one OMe O
A mixture of Rutin hydrate (1) (80 g, 120.5 mmol) and potassium carbonate (320 g, 2319 mmol) was placed into a 2 L three neck round bottom flask, fitted with a reflux condenser with nitrogen atmosphere and dropping funnel and acetone (1.5 L) was added. To this reaction mixture dimethyl sulfate (160 mL) was added dropwise. The reaction mixture was refluxed at 60°C for 68 hours. Then the reaction mixture was cooled to 25°C and the solid separated was filtered. The residue was washed with acetone (1 L) followed by methanol (500 mL), filtrates were combined and concentrated under reduced pressure affording 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 bottom flask and hydrochloric acid (20 %, 1 L) was added at 25 °C. The reaction 2o mixture was allowed to reflux at 100°C for 2 hours and then cooled to 25 °G. The solid that separated was filtered, washed with isopropanol (200 mL) and dried under vacuum to affording the title compound (27.5g, 70%) as a pale yellow solid. Mp. 192-194°C.
IR: ? max (fir, em ~): 3279, 2925, 1609, 1516;

1H NMR (200 MHz, CDC13): d 7.83-7.79 (m, 2H), 7.00 (d, J= 9.14 Hz, 1H), 6.56 (d, J
= 1.88 Hz, 1H), 6.36 (s, 1H), 3.99 (s, 6H), 3.96 (s, 3H), 3.93 (s, 3I~;
Mass (CI method, I-butane): 359 (M+, 100).
s PREPARATION 3 1-(4- { 2-[2-(3,4-Dimethoxyphenyl)-5,7-dimethoxy-4-oxo-4H-3-chromenyloxy]
ethoxy}
phenyl)-1-ethanone M
O
A mixture of compound obtained in Preparation 2 (25 g, 69.6 mmol), a compound io obtained in Preparation 1 (21.5 g, 88.4 mmol) and potassium carbonate (77 g, 557 mmol) was placed in a I L round bottomed flask 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). It was is triturated with methanol and filtered to afford the title compound (31.5 g, 87 %), as a pale brown solid, after drying under vacuum. Mp.143-I44 °C.
IR: ? maX (KBr, cW 1): 1668, 1624, 1600;
1H NMR (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, 1H), 6.36 (s, 1H), 4.47 (d, J= 4.40 Hz, 2H), 4.29 (t, J= 4.40 Hz, 20 2H), 3.97 (s, 3H), 3.90 (s, 9H), 2.54 (s, 3H);
Mass (CI method, I-butane): 521 (MH+, 30), 385 (100).

4-Fluorophenylacetate o~
F
4-Fluorophenol (20 g, 178.5 mmol) was placed into single neck 1 L round bottomed 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 to it 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, 60 mL) was added to it.
The mixture was extracted with chloroform (3 ~ 100 mL), combined extracts were dried over sodium sulphate and concentrated under reduced pressure to afford the title compound (26 g, 95 %) as a white solid.
IR: ? ",aX (I~Br, cm 0:1764;
IH NMR (200MHz, CDCI~): 7.05 (s, 2H), 7.01 (s, 2H), 2.27 (s, 3H);
Mass (CI method, I-butane): 155(M+', 100).

(2-Hydroxy-4-fluoro phenyl)-1-ethanone OH
FI/
O
A mixture of 4-fluorophenylacetate obtained in Preparation 4 (25 g, 223 mmol), aluminium chloride (89 g, 670 mmol), was placed into 1 L single neck round bottom flask, fitted with an air condenser and calcium chloride guard tube. The reaction mixture was slowly heated to 120-125°C over 30 minutes, and then to 165°C
(generation of HCl gas was observed). The mixture was stirred at the same temperature for 30 min and then cooled to room temp. Water (500 mL) was added to it followed by 6 N HCl (150 mL). The mixture was extracted with chloroform (3 ~ 200mL), combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (21 g, 84 %) as a white solid.
IR: ? maX (KBr, crri I): 3442, 1650;

1H NMR (200MHz, CDC13): 11.98 (s, H, D20 exchangeable), 7.43-7.37 (m, 1H), 7.27-7.17 (m, 1H), 6.98-6.9I (m, 1H), 2.62 (s, 3H);
Mass (CI method, I-butane): 155 (M+1, 47).
s PREPARATION 6 1-(5-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)-2-propen-1-one OMe OH
F
O
To a mixture of (2-hydroxy-4-fluoro phenyl)-1-ethanone (3 g, 19.7 mmol) obtained in Preparation s, and 4-fluorobenzaldehyde (4.37 g, 19.7 mmol) in methanol was slowly added to sodium hydroxide solution at 0 °C, under NZ atm. The reaction mixture was allowed to stir for 10 hours at 0-10 °C. Water (100 mL) was added to it followed by 6 N
HCl (ls mL).
Solid separated was filtered off and dried under vacuum to afford 3 g (41 %) of the title compound as a yellow solid.
IR: ? maX (KBr, crri 1): 3s00, 1642;
15 1H NMR (200MHz, CDCl3): 12.6 (s, 1H, D20 exchangeable), 7.92 (d, J=15.3 Hz, 2H), 7.76-7.SS (m, 3H), 7.41 (d, J=15.3 Hz, 2H), 7.0-6.94 (m, 2H), 3.87 (s, 3H);
Mass (CI method, I-butane): 272 (M+, 100%).

20 6-Fluoro-2-(4-rnethoxy phenyl)- 3-hydroxy - 4H 4-chromenone OMe O
F OH
O
The chalcon product (3.0 g, 11 mmol), obtained in Preparation 6, was dissolved in methanol (30 mL) and cooled to 0 °C. To this mixture was added sodium hydroxide solution (20 mL, 20%) and then the reaction mixture was stirred at the same temperature for s-10 2s min. Hydrogen peroxide was added to this mixture and stirring continued at 0-10°C for 1 hours. Water (100 mL) was added to it followed by 6 N HCl (30 mL). Separated solid was filtered off and dried under vacuum to afford 1.0 g (32 %) of the title compound as a yellow solid.
IR: ? max (I~Br, crri I):3261, 1602, 1559;
IH NMR (200MHz, CDC13): X8.23 (d, J=9.13 Hz, 2H), 7.90-7.85 (m, 1H),7.63-7.56 (m, 1H), 7.48 -7.38 (m, 1H), 7.06 (d, J=9.13 Hz, 2H), 3,91 (s, 3H);
Mass (CI method, I-butane):287(M+l, 100%}.

1-(4-{2-[6-Fluoro-2-(4-methoxyphenyl)-4-oxo-4H 3-chromenyloxy} phenyl)-1-ethanone s OMe O
O W
O
O
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 1 L round bottomed flask 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 yeas cooled to 25°C and poured slowly into ice-cold water (1 L). The solid that separated was filtered and washed with water (2 ~ 500 mL). It was triturated with methanol and filtered to afford the title compound (0.4 g, 85 %), as a pale brown solid, after drying under vacuum.
2o PREPARATION 9 N-Methyl anthranilic acid ~~OOH
NHMe To a solution of methyl-N-methyl anthranilate (20 g, 121 mmol) in methanol (100 mL), placed in a 250 mL single neck round bottomed flask, was added a solution of NaOH
(9.69 g, 242 mmol) in 25 mL of water at 0-10 °C. The reaction mixture was heated to 50°C
for 6 hours and then cooled to room temperature. Methanol was removed completely from the reaction mixture and water (100 mL) was added to it. The mixture was washed with ether (3 ~ 50 mL) and the aqueous layer was acidified (pH ~ 5-6) with ice cold 2 N HCI. The solid that separated was filtered, washed with water (2 ~ 50 mL) and dried under vacuum to afford the title compound 17.0 g (93 %) as a white color solid.mp-178-180 °C.
IH NMR (200MHz, CDCl3): 87.99 (dd, 1H, J = 1.34 Hz), 7.46-7.25 (m, 1H), 6.70-6.58 (m, 2H), 2.93 (s, 3H);
Mass (CI method): 152 (M+1, 100%).

2-Bromo-1-(4-methylphenyl)-1-ethanone O
Br Me 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 21.40g (134 mmol) of bromine dissolved in acetic acid (30 mL) dropwise at 10-15°C.
The reaction mixture was stirred at 25-35°C for 5 hrs, then poured into water (100 mL). The solid that separated was filtered to give the required product (20 g, 65%).
IH NMR (200MHz, CDCl3):87.88(d, J=8.3Hz, 2H), 7.29(d, BHz, 2H), 4.42(s, 2H), 2.41(s, 3H).
2o PREPARATION 11 2-(4-Methyl phenyl)-2-oxo ethyl -2-methylaminobenzoate Me COO
O
NHMe To a solution of N-methyl anthranilic acid (lO.Og, 66 mmol), obtained in Preparation 9, in 100 mL of dimethyl formamide, placed in a 250 mL single neck round bottomed flask was added a solution of KOH (3.89g, 69 mmol) in 10 mL of water and the mixture was stirred for 45 min at 25-35°C. The mixture was cooled to 10°C, and the bromoketone (16.9 g, 79 mmol), obtained in Preparation 10, was added to it. The reaction mixture was stirred for hours at room temperature and then poured in ice water (500 mL). The solid that separated out was filtered, washed with water (2 x 100 mL) and dried under vacuum to afford the title compound (11.0 g, 58 %) as a white color solid. Mp: 96-98°C.
IR (KBr, cm 1): 3382, 1684, 1674;
s 1H NMR (200MHz, DMSO-d6): 8 7.91-7.87 (m, 3H), 7.47-7.34 (m, 3H), 6.75-6.57 (m, 2H), 5.62 (s, 2H), 3.32 (s, NH), 2.83 (d, J=4.3 Hz, 3H), 2.38 (s, 3H};
Mass (CI method): 284 (M+l, 100%).

10 3-Hydroxy-1-methyl-2-(4-methylphenyl)-1,4-dihydro-4-quinolinone Me Me w N w I
I/ I
OH
O
Polyphosphoric acid (PPA, 80 g) was heated to 140°C under nitrogen atmosphere in a 250 mL single neck round bottom flask. 2-(4-Methyl phenyl)-2-oxo ethyl -2-methylamW obenzoate (10 g, 35 mmol) obtained in Preparation 11 was added in small is portions and the mixture was stirred at 140 °C for 6 hours. The mixture was cooled to 25-35°C and ice cooled water was added to the mixture and stirred for 30 min. Solids that separated were filtered, washed with water and dried under vacuum to afford the title compound (6.0 g, 73 %) as brown solid. Mp. 216-218°C.
IR (KBr, cm I): 3433, 1598;
2o IH NMR (200MHz, DMSO-d6): 8 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 (CI method): 266 (M+1, 100%).

25 4-(2-Bromoethoxy)benzaldehyde ~\
\ / o~Br A mixture of 4-hydroxybenzaldehyde (10.0 g, 82 mrnol) and potassium carbonate (46 g, 326 mmol) was placed into 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 hrs under a 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), combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography over silicagel by using 10-15% ethyl acetate / pet. ether to afford the title compound (8.50 g, 45 %) as a white solid.
IR(KBr, c~ i):3439, 1682, 1602, 1577;
1H NMR (200MHz, CDCl3):~9.88(s, 1H), 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(CI method):231(M+2, 231, 100%).

1-(3-f2-[1-Methyl-2-(4-methylphenyl)-4-oxo-1,4-dihydro-3-quinoliniloxyJethoxy) phenyl)-1 s 1-ethanone O
A mixture of hydroxy compound obtained in Preparation 12 (3.0 g, 11 mmol), bromoketo compound obtained in Preparation 1 (2.43 g, 10 mmol) and potassium carbonate (6.24 g, 45 mmol) was placed in a 1 L round bottomed flask and DMF (30 mL) was added.
2o The mixture was heated to 80°C with stirring and held at this temperature for 12 hours under a nitrogen atmosphere. The mixture was cooled to 25°C and poured slowly into ice-cold water (1 L). The solid that separated was filtered and washed with water (2 ~
500 mL). It was triturated with methanol and ftltered to afford the title compound (2.8 g, 64 %), as a pale brown solid, after drying under vacuum.
2s 'H NMR (200MHz, CDCl3): b 8.60 (d, J=7.8Hz, 1H), 7.74-7.21 (m, lOH), 6.93 (d, J=8.3Hz, 1H), 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 (CI method): 428 (M+l, 428, 100%).

4-(2-Bromo-ethoxy)-benzoic acid ethyl ester GO2Et Br~O
Step (i) To a solution of 4-hydroxybenzoic acid (15g, 108.6 mmol) in ethanol (200 mL) was added SOC12 (16 mL, 217.4 mmol) at 0 °C under anhydrous condition. The mixture was heated to reflux for 7 hours with stirnng. After completion of the reaction, the mixture was concentrated under vacuum and the residue was neutralized by using aqueous NaHCO3 to solution until the pH reached 7Ø The solid separated was filtered, washed with water (2 x 50 mL), and dried under vacuum to afford the desired compound in 89% yield ( 16 g).
Step (ii) A mixture of 4-hydroxybenzoic ester (5 g, 30.12. mmol) and anhydrous I~ZC03 (4.62 g, 33.51 inmol) 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 stirring continued for 6 hrs. 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).

4-{2-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H chromen-3-yloxy~
-ethoxy}-benzoic acid ethyl ester o~

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-Bromo-ethoxy)-benzoic acid ethyl ester (3.66 g, 13.40 mmol) obtained in Preparation 15 and KZC03 (4.62 g, 33.51 mmol) in DMF
(20 mL) was stirred at 80°C for 9 hrs 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).

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

2-(Toluene-4-sulfonylamino)-succinamic acid O _ O HN~S ~ ~ CHs O

O

To a stirred solution of L-Aspergine (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 mmol) at 0°C. After stirring for I min. additional quantity of NaOH
(4.4g, 110 mmol) in water (75 mL) was added to the reaction mixture at the same temperature.
Stirnng continued for 1 hr. and then dioxane was removed from the mixture under low vacuum. The residue was washed with ethylacetate (2 x 30 mL), aqueous layers collected, combined, and acidified with conc. HCl very slowly with stirring at 0°C. The solid separated was filtered and washed with cold water (2 x 30 mL) to afford the desired product in 59%
yield (17 g).
mp: 198-200°C.
to 3-Amino-2-(toluene-4-sulfonylamino)propionic acid ethyl ester Step (i):
3-Amino-2-(toluene-4-sulfonylamino)-propionic acid O _ NN~S
O
HZN~OH

To a cold (0°C) and stirring solution of NaOH (1.95 g, 48.95 mmol) in water (8.7 mL) was added bromine (0.36 mL, 6.99 mmol) slowly and drop wise. After 5 min.
a cold solution of Preparation 18 (2.0 g, 6.99 mmol) and NaOH (0.55 g) in water (6.4 mL) was added in one portion. The solution was stirred for 20 min. at 0 °C and then for 30 min. at 90°C. The mixture was cooled to 0 °C and the pH was adjusted to 7.0 by slow addition of cons. HCI. The solid separated was filtered, washed with cold EtOAc (2 x 25 mL) and dried under vacuum to afford the desired compound in 61 % yield (1.1 g). mp 225-226°C.
Step (ii) 3-Amino-2-(toluene-4-sulfonylamino)-propionic acid ethyl ester O _ HN~ ISI ~ ~ CHs O
HaN~O~CH3 O
To a cold (0°C) and stirring solution of the compound (2 g, 7.75 mmol), obtained in step (i), in ethanol (20 mL) was added SOCl2 (1.25 mL, 17.05 mmol) under anhydrous condition. The mixture was heated to reflux for 12 hrs with stirring. After completion of the reaction, the mixture was concentrated under vacuum to afford the hydrochloride salt of title compound in 90% yield (2.0 g). This was used for the next step without further purification.

4-(3,4-Dimethoxyphenylcarboxamido)-1-methyl-3-propyl-1H-5-pyrazolecarboxamide N- O
-N
'H
O NH2 ~ OMe OMe A mixture of 4-amino-1-methyl-3-propyl-1H-5-pyrazolecarboxmide (19.57g, 107.5 mmol} and triethylamine (54.4g, 134.38 mmol) in dichloromethane (300 mL) were taken in a 1 liter 3 neck round bottom flask fitted with a nitrogen balloon, pressure equalizing addition funnel and a septum. To the mixture was added a solution of 3,4-dimethoxy-1-benzenecarbonylchloride (21.5g, 107.5mmol) in dichloromethane (100mL) at 0°C through a pressure equalizing addition funnel over a period of 0.5 hours under nitrogen atmosphere.
The reaction temperature was raised to 25°C after addition and the contents were stirred for another 12 hours. 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 2o under vacuum to get the title compound 33g, (89 %) as a white solid. Mp:
176-178°C.
IR: v maX (KBr, crri 1): 3370, 3243, 2960, 16$2, 1631;
IH NMR (200 MHz, CDCl3): 8 7.81 (s, 1H), 7.49 (d, J = 6.45Hz, 2H), 6.94 (d, J
=
~.86Hz, 1H), 3.99-3.96 (m, 9H), 2.53 (t, J = 7.22Hz, 2H), 1.68-1.57 (m, 2H), 0.92 (t, J = 7.SlHz, 3H);

Mass (CI method, I-butane): 347(MH+, 100).

5-(3,4-Dimethoxyphenyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one O
N NH
N \ I ~ OMe ~N
OMe 4-(3,4-dimethoxyphenylcarboxamido)-1-methyl-3-propyl-1 H-5-pyrazolecarboxamide, obtained in Preparation 20 (17g, 49.13 mmol) in tert-butanol (350 mL) was taken in a one liter single neck round bottom flask fitted with a reflux condenser and to it potassium tertiary butoxide (16.55g, 147.38 mmol) was added carefully and the contents were refluxed for 63 hours under nitrogen atmosphere. The reaction mixture was cooled to 25-35°C and tent-butanol was completely removed under vacuum. To the residue cold water (200 mL) was added followed by addition of dilute hydrochloric acid (3N) under stirring until the pH was constant at 7. The solid formed was filtered off and dried under vacuum to afford the title compound 13g (81%) as a white solid. Mp: 210-212°C.
IR: v maX : (KBr, cm ~): 3438, 3204, 1670;
IH NMR (200 MHz, DMSO-d6): 8 12.3 (bs, DZO exchangeable, 1H), 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 (CI method, i-butane): 329(M+~, 100).

1-[4-(2-Bromoethylamino) phenyl]-1-ethanone i N s~ Br H
To a suspension of 60% NaH (5.93g, 247.08 mmol) in DMF (80 mL) taken in a one liter 2 neck round bottom flask fitted with a pressure equalizing addition funnel and a septum was added a solution of p-aminoacetophenone (208, 148.1 mmol) in DMF (60 mL) in drops through the pressure equalizing addition funnel under nitrogen atmosphere at 0°C and the contents were stirred for 2 hours at 25°C. Then to the stirred solution was added 1,2-dibromoethane (97.488, 518.5 mmol) in drops and the contents were further stirred for another 18 hours at 90°C. The reaction mixture was cooled to 25-35°C and was carefully added to cold water (650 mL) while stirring. The organics were extracted with ethylacetate (3 x 200 mL) and combined organics were washed with water (2 x 100 mL) followed by a brine wash. The separated organics were dried over Na2S04 and concentrated under reduced pressure. The crude was chromatographed over silicagel by using 15-20% ethyl acetate / pet.
l0 ether (3 Lit), affording the title compound S.lg (14 %) as a pale yellow solid.
Mp: 92-94°C.
IR: v max : (I~Br, ciri 1): 3360, 2927, 1650;
'H NMR (200 MHz, CDCI3): ~ 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 (CI method, I-butane): 244(M+2, 10), 162 (100).

1-(4-{2-[5-(3,4-Dimethoxyphenyl)-1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-6-yl]ethylamino}phenyl)-1-ethanone \ O H
N ~N
N\ ~ i ~ \
N
\ ~ O
OMe OMe A mixture of 5-(3,4-dimethoxyphenyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one obtained in Preparation 21 ( 2g, 6.09 mmol), 1-[4-(2-bromoethylamino) phenyl]-1-ethanone obtained in Preparation 22 (1.558, 6.405 mmol) and potassium carbonate (4.2138, 3.5 mmol) were taken in 100 mL round bottom flask and DMF
(20 mL) was added to this. The reaction mixture was stirred at 25°C for 16 hours under nitrogen atmosphere. The reaction mixture was slowly poured into ice-cold water (100 mL).
The solid separated was filtered, washed with water (2 x 5 mL) and dried under vacuum to afford the title compound 2.6 g (87%), as a pale yellow solid. Mp: 182-184°C.

IR: v max (KBr, cW ~): 3381, 2927, 1660, 1599;
IH NMR (200 MHz, DMSO-d6): 8 7.93 (d, J = 5.68 Hz, 2H), 7.71 (d, J = 8.31 Hz, 2H), 7.03 (d, J = 8.79 Hz, 1H), 6.91 (s, 1H), 6.69 (d, J = 8.79 Hz, 2H), 4.84 (m, 2H), 4.10 (s, 3I~, 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 (CI method, I-butane): 490 (M+1, 100).

6,7-Dimethoxyquinazolin-4(3H)-one O
Me0 I ~ ~ H
Me0 ~ N
A mixture of 2-amino-4,5-dimethoxybenzoic acid (29.6g, 0.15 mol) and formamide (0.6 mol, 24 mL) was stirred vigorously under nitrogen atmosphere. The mixture was heated to 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 l2.Sg of the desired product in 40% yield. Mp. 295-296°C (lit 296-297°C).
~HNMR (DMSO-d6, 200 MHz) 12.0 (bs, D20 exchangeable, lI~, 7.97 (s, 1H), 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.
2o F.; Baruth, H. W.; Yaremko, B. J. Med. Chem. 1983, 26, 420.

5-[-1-(4-~2-[2-(3,4-Dimethoxy phenyl)-5,7-dimethoxy-4-oxo-4h-3-chromenyloxy]ethoxy}
phenyl)ethylidene]-1,3-thiazolane-2,4-dione A mixture of compound (31 g, 59.6 mmol), obtained in Preparation 3, thiazolidene-1,3-dione (40 g, 341 mrnol), benzoic acid (14.5 g, 118.8 rmnol) and piperidine (10.1 g, 118.8 mmol) were placed into 1 L single neck round bottomed flask, to this toluene (600 mL) was added. The round bottomed flask was fitted with 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 was allowed to pass through a silica geI column. The product was eluted by using 0.5-1 % MeOH / CHCl3 (5 L) to afford the title compound, 22 g (60 %) as off white solid. Mp: 205-206°G.
IR: ? "~~ (KBr, cm ~): 3220, 1735, 1698, 1627, 1604;
IH NMR (200 MHz, CDCl3): d 9.07 (bs, 1H, exchangeable with DSO), 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 was prepared according to the methodology provided in Example 1.
/ OMe O N~H
Me0 O \ I d'O
OMe / ~S
O
OMe O /
1H NMR (200 MHz, CDCl3): d 12 (s, DSO exchangable), 7.68-7.44 (m, 4H), 7.10-6.84 (m, 4H), 6.51 (s, 1H), 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). Mp: 120-124°C.

Example 3 was prepared according to the methodology provided in Example 1.
OMe O
/ ~-NFi MeO I \ O ~ \ I OMe S I O
/ O~O /
OMe O \ I

1H NMR (200 MHz, CDCl3): d 8.65 (s, D20 exchangeable), 7.75-7.71 (m, 2H), 7.28-7.23 (m, 2H), 6.90-6.79 (m, 2I~, 6.70 (s, 1H), 6.53 (s, 1H), 6.37 (s, 1H), 4.49 (s, 2H), 4.25 (s, 2H), 3.97 (s, 3H), 3.91 (s, 9H), 2.68 (s, 3H). Mp: 210-214°G.

Example 4 was piepared according to the methodology provided in Example 1.
OMe Me0 ~ O ~ I OMe OMe ~~O
I O~O ~ S
OMe O Me0 I ~ ~ NH
O
'H NMR (200 MHz, CDCl3): d 9.18 (s, D20 exchangeable, 1H), 7.92 (s, 1H), 7.91-7.81 (m, 1H), 7.69 (s, 1H), 6.95 (d, J=8.79 Hz, 1H), 6.65 (s, 2H), 6.54 (s, 1H), 6.34 (s, 1H), 4.42 (s, l0 4H), 3.95 (s, 6H), 3.93 (s, 3H), 3.91 (s, 3H), 3.80 (s, 6H). Mp: 207-210°C.

Example 5 was prepared according to the methodology provided in Example 1.
OMe Me0 ~ O ~ I pMe ~~~O~sS ~ S
OI Me IOI ( , / NH
O
IH NMR (200 MHz, CDCI3}: 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, 1H), 6-5 (s, 1H), 6.36 (s, 1H), 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).
Mp: 138-142°C.

Example 6 was prepared according to the methodology provided in Example 1.
,_O
~!/~S
OMe O I / / NH
T

OMe Me0 ~ O ~ I OMe ~~~O~O

IH 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), 2.5I (s, 3H). Mp: 126-130°C.

Example 7 was prepared according to the methodology provided in Example 1.
OMe s OMe Me0 \ O \
H
'~O~N \ S
OMe O I / / NH
O
IH NMR (200 MHz, CDCl3): d 8.31 (s, D20 exchangeable, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.64 (s, 1H), 7.36 (d, J=10.2 Hz, 2H), 7.28 (m, 2H), 7.01 (d, J=8.79 Hz, 1H), 6.58 (s, 1H), 6.43 (s, io 1H), 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).
Mp: 192-195°C.

Example 8 was prepared according to the methodology provided in Example 1.
1H NMR (200 MHz, CDC13): d 8.17 (s, D20 exchangeable, 1H), 7.76 (d, J=8.3 Hz, IH), 7.68 (s, 1H), 7.28 (s, 1H), 7.11 (m, 1H), 6.98-6.89 (m, 2H), 6.52 (s, 1H), 6.37 (s, 1H), 4.48 (bs, 2H), 4.4I (bs, ZH), 3.97 (s, 3H), 3.91 (s, 9H), 3.13 (t, J= 7.3 Hz, 2H), 1.6-1.4 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). Mp: 204-208°C.

Example 9 was prepared according to the methodology provided in Example 1.
/ OMe Me0 \ O \
OMe O
~O°\r0 \ S
OMe O C~ I / /
b IH NMR (200 MHz, CDCI3): d 8.27 (s, D20 exchangeable, 1H), 7.76 (d, J=8.53 Hz, 1H), s 7.67 (s, 1H), 7.34 (s, 1H), 7.17 (m, 1H), 6.97-6.89 (m, 2H), 6.53 (s, 1H), 6.37 (s, 1H), 4.5 (s, 2H), 4.4 (s, 2H), 3.98 (s, 3H), 3.92 (s, 9H), 2.68 (s, 3H). Mp: 230-233°C.

Example 10 was prepared according to the methodology provided in Example 1.
/ OMe Me0 \ O \
OMe O
~O O I S~ H
OMe O B~ / /
p IH NMR (200 MHz, CDC13): d 8.25 (s, D20 exchangeable, 1H), 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).
Mp: 235-236 °C.
is Example 11 was prepared according to the methodology provided in Example 1.
/ OMe Me0 \ O \ I
~OMe O
O \ S
OMe O I / / NNa O
IH NMR (200 MHz, CDCl3): d 7.74 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 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). Mp: 225-228°C.

Example 12 was prepared according to the methodology provided in Example 1.
/ OMe MeO ~ O
OMe O
I O~rO ~ S
OMe O I / /
b 'H 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, 1H), 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). Mp: 195-198°C.

5-[-1-(4- f 2-[6-Fluoro-2-(4-methoxyphenyl)-4-oxo-4H-3-chromenyloxy]ethoxy}phenyl) lo. efliylidene]-1,3-thiazolane-2,4-dione A mixture of compound obtained in Preparation 8 (0.35 g, 0.72 mmol), thiazolidene-1,3-dione (0.54 g, 4.68 mmol), benzoic acid (0.19 g, 1.56 mmol) and piperidine (0.13 g, 1.56 is mol) were placed into a 50 mL single neck round bottomed flask, to this toluene (15 mL) was added. The round bottomed flask was fitted with Dean-Starlc 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 was allowed to pass through a silica gel column. The product was eluted by using 0.5-1 % MeQH
/ CHCl3 20 (5 L) to afford the title compound, 0.32 g (75 %) as off white solid. Mp:
210-212 °C.
IH NMR (200 MI3z, CDC13): d 12.2 (s, D20 exchangeable, H), 8.14 (d, J=8.87 Hz, 2H), 7.91-7.77 (m, 1H), 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).

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

/ ~-NH
O \ I S O
I
F / O~O
o \I
IH NMR (200 MHz, CDC13): d 12.2 (s, DZO exchangeable, 1H), 8.14 (d, J=8.87 Hz, 2H), s 7.91-7.784 (m, 1H), 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). Mp:
227-230°C.

l0 This compound was prepared according to the procedure provided in Example 13.

\ O \
H O
s ~N \
F O O ~ / / ~ H
O
IH NMR (200 MHz, CDCl3): d 12.21 (s, DSO exchangeable, 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, DSO
exchangeable, 1H), 4.14 (s, 2H), 3.82 (s, 3H), 3.35 (s, 2H), 2.5 (s, 3H).
15 Mp:182-185°C.

This compound was prepared according to the procedure provided in Example 13.
s o \

I ~ I ~o \ ~/C/
O O I a es~ H
O
20 IH NMR (200 MHz, CDCl3): d 12.2 (s, DZO exchangeable, 1H), 8.13 (d, J=3.23 Hz, 1H), 7.99 (d, J=5.1 Hz 1H), 7.71 (m, 1H), 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). Mp: 238-240 °C.

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

S ~ ~-NH
O \ S O
F / O~O \
O I
1H NMR (200 MHz, CDC13): d 12.31 (s, D20 exchangeable, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.96 (d, J=5.1 Hz, 1H), 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, 1H), 4.62 (s, 2H), 4.4 (s, 2H), 2.5 (s, 3H). Mp:
2I8-220 °C.

This compound was prepared according to the procedure provided in Example 13.
s H o s ~N ~/C/
F O o ' s /s~ H
O
'H NMR (200 MHz, CDCl3): d 12.1 (s, D20 exchangeable, 1H), 8.08 (d, J=2.95 Hz, 1H), 7.99 (d, J=4.83 Hz 2H), 7.91-7.78 (m, IH), 7.72 (d, J=8.06 Hz, 2H), 7.3-7.23 (m, 2H), 6.65 (d, J=8.59 Hz, 2H), 6.56 (m, DZO exchangeable, 1H), 4.33 (t, J=5.36 Hz, 2H), 3.59 (t, J=5.64 Hz, 2H), 2.62 (s, 3H). Mp: 218-219 °C.

This compound was prepared according to the procedure provided in Example 13.
/ F
\ O
O
~O J~
F O O I / /S
O
1H NMR (200 MHz, CDCl3): d 8.21-8.14 (m, 1H), 7.87-7.85 (m, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.36-7.26 (m, 4H), 6.88 (d, J=8.8 Hz, 3H), 4.46 (s, 2H), 4.21 (s, 2H), 2.5 (s, 3H). Mp: 262-265 °C.

This compound was prepared according to flee procedure provided in Example 13.
N
O \
°
~O \ J.J~~
O ° I / /S~ H
1H NMR (200 MHz, CDCl3): d 12.27 (s, DSO exchangeable, 1H), 9.35 (s, 1H), 8.67 (d, 5 J=4.57 Hz, 1H), 8.48 (d, J=8.33 Hz, 1H), 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). Mp: 251-254 °C.

l0 This compound was prepared according to the procedure provided in Example 13.
i ono \ s O I ~ s ~ H
O
'H NMR (200 MHz, CDC13): d 10.4 (bs, D20 exchangeable, 1H), 8.06-8.00 (m, 1H), 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, 1H) 6.84 (d, J=8.06 Hz, 2H), 6.04 (s, 2H), 4.44 (s, 2H), 4.18 (s, 2H). Mp: 198 200°C.

This compound was prepared according to the procedure provided in Example 13.
s o \
r ono \ s O I s ~ NH
O
IH NMR (200 MHz, CDC13): d 10.43 (bs, D20 exchangeable, 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, 1H), 7.32-7.28 (m, 1H), 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). Mp: 166-168°C.

This compound was prepared according to the procedure provided in Example 13.
/ s~

I~o~°° ~ s O I / / ~ H
O
IH NMR (200 MHz, CDCl3): 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). Mp: 220-222°C.

5-[ 1-(4- {2-[ 1-Methyl-4-oxo-2-(4-methylphenyl)-1,4-dihydro-3-quinolinyloxyJ
ethoxy) l0 phenyl}methylideneJ-1,3-thiazolane-2,4-dione ,O
O ~ , os NH
O
Me Ne W
~O
A mixture of compound obtained irr Preparation 14 (150 mg, 0.36 mmol), thiazolidene-1,3-dione (64 mg, 0.54 mmol), benzoic acid (88 mg, 0.72 mmol) and piperidine (61 mg, 0.72 mmol) were placed into 1 L single neck round bottomed flask, to this toluene i5 (600 mL) was added. The round bottomed flask was fitted with 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 was allowed to pass through a silica gel column. The product was eluted by using 0.5-1 % MeOH
/ CHCl3 (5 L) to afford the title compound, 100 mg (54 %) as brown solid. Mp: 250-252 °C.
2o IH NMR (200 MHz, CDCl3): 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).

This compound was prepared according to the procedure provided in Example 24.
o / ~ \ S

°\/~o \ o NH
N
CHs 1H NMR (200 MHz, CDCl3): d 12.5 (s, NH), 8.34 (d, 1H, J=7.8 Hz), 7.78-7.47 (m, 11H), s 6.90 (d, 2H, J=8.4 Hz), 4.23 (s, 2H), 3.99 (s, 2H), 3.47 (s, 3H). Mp: 250-252 °C.

This compound was prepared according to the procedure provided in Example 24.
CHs ° ~ I \ S~o \ o NH
N
CHs I /
F
io 1H NMR (200 MHz, CDCl3): 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). Mp:
196-198°C.

This compound was prepared according to the procedure provided in Example 24.
CHs ~ ~ \ S~o \ I °~o \ o NH
N \
CHs is CHs 1H NMR (200 MHz, CDCl3): d 12.25 (bs, NH), 8.34 (d, 1H, 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). Mp: 228-232°C.

This compound was prepared according to the procedure provided in Example 24.
,,o o H3C -'~S
\ - N
- ~ °~\ - II
N / o o \
H3C ~ \

IH NMR (200 MHz, CDC13): d 12.3 (NH, 1H), 8.33 (d, 1H, J=8.2 Hz), 7.77 (d, 2H, J=3.2 s Hz), 7.46-7.27 (m, 6H), 6.95 (d, 1H, 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). Mp: 210-212 °C.

3-(4- {2-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3 -yloxy]-ethoxy} -benzoylamino)-2-(toluene-4-sulfonylamino~-propionic acid ethyl ester To a solution of 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 EDCI (1.64 g, 8.61 mmol), HOBt (1 g, 7.46 mmol) and N-methyl morpholine (2.0 g, 20.09 rnmol) at 25-35°C under Nitrogen atmosphere. The mixture was stirred at the same temperature for 12 hrs. After completion of the reaction the mixture was poured into water (60 mL) and stirred for 30 min.
The separated solid was Bltered, washed with water (2 x 20 mL) and dried under vacuum. The crude product was purified further by crystallization from ethanol to give the desired product in 51 yield (2.3 g).

~HNMR (CDCl3, 200 MHz) 7.73-7.65 (m, SH), 7.25 (d, J = 8.8Hz, 2H), 6.88-6.73 (rn, 4H), 6.52(d, J = 2Hz, 1H), 6.36 (d, J = 2Hz, 1H), 5.91 (d, J = 7.8Hz, D20 exchangeable, 1H), 4.47 (m, 2H), 4.23 (m, 2H), 4.10-3.91 (m, 16H), 3.8 (m, 1H), 2.37 (s, 3H), 1 _14 (t, J = 7.3Hz, 3H).

This compound was prepared according to the procedure provided in Example 29.
c HI NMR (CDCl3, 200 MHz) 10.06 (m, DZO exchangeable, 1H), 8.82(s, 1H), 8.17-8.06 (m, to 2H), 7.74 (d, J = 8.3Hz, 2H), 7.27-7.19 (m, 3H), 6.24 (d, J = 7.8Hz, DZQ
exchangeable, 1H), 4.15-4.01 (m, 3H), 3.84-3.70 (m, 2H), 3.77-3.51 (m, 1H), 2.31 (s, 3H), 1.41 (d, J = 6.3Hz, 1H), 1.25-1.13 (m, SH).

This compound was prepared according to the procedure provided in Example 29.
N~H O
~OC~HS
~~ .N.
I SO H
Hl NMR (CDC13, 200 MHz) 9.30 (bs, DSO exchangeable, 1H), 7.76 (d, J = 8.lHz, 2H), 7.60 (d, J = 6Hz, 1H), 7.47 (s, 1H), 7.21 (d, J = 8.lHz, 2H), 6.99 (d, J = 7.SHz, 1H), 6. 76 (d, J =
9.OHz, DZO exchangeable, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 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.OHz, 3H).

This compound was prepared according to the procedure provided in Example 29.
o, ~ I
H HN.SO
N~OC2H5 - ~O
Hl NMR (DMSO-d6, 200 MHz), 8.32 (d, J = 8.8Hz, 2H), 8.10 (d, J = B.OHz, 1H), 7.80-7.50 (m, 7H), 7.28 (d, J = 7.8Hz, 2H), 7.03 (d, J = 8.60Hz, l I~, 6.85 (d, J =
8.3Hz, 2H), 4.43 (m, 2H), 4.37-4.26 (m, 2H), 4.07-4.03 (rn, 2H), 3.79 (m, 8H), 3.47(m, 1H), 2.30(s, 3H), 0.95 (t, J
= 7.3Hz, 3H).

to This compound was prepared according to the procedure provided in Example 29.
ci ~ ci I
o, a 1 I O~O ~ H HN~So O I i N~OCZHS
O _ [~O
Hl NMR (DMSO-d6, 200 MHz), 8.32 (d, J = 8.OHz, 2H), 8.17 (d, J = 8.OHz, 1H), 7.83 (d, J =
7.OHz, 1H), 7.69-7.47 (m, 7H), 7.28 (d, J = 8.OHz, 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.OHz, 3H).

This compound was prepared according to the procedure provided in Example 29.
a SCH3 o ~I o ~I
.~
I / I O~O ~ HN.S.
O I / N~OCzHg O _ ~O
2o Hl NMR (CDCl3, 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, 1H), 7.40 (t, J = 7.OHz, 1H), 7.24- 7.18 (m, 4H), 6.74 (d, J
= 8.6 Hz, 2H), 6.64 (m, D20 exchangeable, 1H), 5.69 (d, J = 7.3 Hz, D20 exchangeable, 1H), 4.52 (m, 2H), 4.22 (m, 2H), 4.10 - 3.99 (m, 3H), 3.95 - 3.85 (m, 1F3', 3.69 -3.59 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.13 (t, J = 7.0Hz, 3H).

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

H3C0 ~ O ~ ~ OF , ~ F
r I O~O I ~ H H ,SO w OCH30 ~N~OCZHS
O - [~O
Hl NMR (CDCl3, 200 MHz), 7.87 - 7.84 (m, 1H), 7.70 - 7.64 (m, 3H), 6.93 - 6.72 (m, SH), 6.53 (d, J = 3.0 Hz, 1H), 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.OHz, 3H).
to This compound was prepared according to the procedure provided in Example 29.
HI NMR (CDCl3, 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, 1H), 7.41 (t, J = 7.3 Hz, 1H), 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, D20 exchangeable), 5.65 (d, J = 8.4 Hz, 1H, D20 exchangeable), 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).
2o EXAMPLE 37 This compound was prepared according to the procedure provided in Example 29.

Hl 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, 1H), 6.36 (s, 1H), 5.99 (m, D20 exchangeable, 1H), 5.62 (d, J = 7.7 Hz, D20 exchangeable, 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).

This compound was prepared according to the procedure provided in Example 29.
Me0 \ N1 / NH~COzC2Fis Me0 I / IN~p \ I O I~JH
O=S=O
O
/I

Hl NMR (CDC13, 200 MHz) 7.67-7.59 (m, 3H), 7.26 - 7.23 (m, 3H), 7.15 - 7.10 (m, 3H), io 6.84 (d, J =8.6 Hz, 2H), 6.01 (bs, D20 exchangeable, 1H), 5.78 (bs, D20 exchangeable, 1H), 4.39 -4.30 (m, 4H), 3.98 - 3.88 (m, lOH), 3.60 - 3.36 (m, 3H), 2.38 (s, 3H), 1.06 (t, J =
7.OHz, 3H).

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

Me0\~/Nl ~N~COaC2H5 MeO~II ''''/°~~~''' INFO ['\~I H NIH
O O-S=O
/

Hl NMR (CDC13, 200 MHz) 8.30 (s, DZO exchangeable, 1H), 8.26 (s, 1H), 7.69 -7.57 (m, 4H), 7.47 (s, 1H), 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, 1H), 3.92-3.87 (m, 9H), 3.33 (m, 1H), 2.27 (s, 3H), 0.93 (t, J =
7.3Hz, 3H).

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

NH
Me0 w N1 \ 1 ~COZCzHs ~ NCO HN~S
Me0 O 0 ~F
F

Hi NMR (CDCl3, 200 MHz) 8.13 (s, 1H), 7.89 - 7.78 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.12 (s, 1H), 6.96 - 6.74 (m, 4H), 6.35 (d, J = 8.1 Hz, 1H), 4.41-4.31 (rn, 4H), 4.21 - 4.17 (rn, 1H), 4.13 - 4.02 (m, 2H), 3.99 (s, 6H), 3.86 - 3.84 (m, 1H), 3.78 -3 _ 68 (m, 1H), 1.15 (t, J = 7.3Hz, 3H).

This compound was prepared according to the procedure provided in Example 29 _ N
N~~\
N N~N~COOCaHs O O NH.~ CH

H' NMR NMR (CDCl3, 200MHz): d 8.09(d, 2H, J=8.8Hz), 7.58(d, 2H, J=8.3I3z), 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(m, 6H).

This compound was prepared according to the procedure provided in Example 29_ HO
N.S ~ / CHa O
)OGzHS
Hl NMR (CDCl3, 200MHz):d 12.0(bs, 1H), 8.43(m, 3H), 7.9(m, 1H), 7.75(m, 2H), 7.55-7.10(m, SH), 6.05(s, 1H), 5.39(s, 1H), 4.2(m, 2H), 4.0-3.6(m, 8H), 2.4(s, 3H), 1.3-0.9(m, 3H).

3-(4-{2-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy]-ethoxy] -benzoylamino)-2-(toluene-4-sulfonylamino)-propionic acid H3C-O \ O \ I

OS ~ ~ CH' H3C-O O ~ _ HN~II
O ~ ~ N~OH
O '' ~O
To a solution of ethyl ester of 3-(4-{2-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy]-ethoxy]-benzoylamino)-2-(toluene-4-sulfonylamino)-propionic acid (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 KZC03 (300 mg, 2.19 mmol) in water (5 mL) at 25-35°C and .the mixture was stirred at the same temperature for 24 hrs.
Then solvent was removed from the mixture under vacuum and the residue was acidified with cold HCI. The solid separated was filtered, washed with cold water (2 x 5 mL) and dried under vacuum to give the desired acid in 52 % yield (250 rng).
jHNMR (DMSO-d6, 200 MHz) 12.9 (bs, D20 exchangeable, 1H), 8.32 (s, D20 exchangeable, 1H}, 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, 1H), 6.86 (s, 1H}, 6.52 (s, 1H), 4.26 (s, 2H), 3.90-3.82 (m, 15H), 2.33 (s, 3H).

This compound was prepared according to the procedure provided in Example 43.
_H
H' NMR (DMSO-d6, 200 MHz) d 12.9 (bs, D20 exchangeable, 1H), 8.32 (s, D20 exchangeable, 1H), 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, 1H), 6.86 (s, 1H), 6.52 (s, 1H), 4.26 (s, 2H), 3.90-3.82 (m, 15H), 2.33 (s, 3H).

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

I I N.H o CI N Y -OH
~~ . IN
/ I SO .H
Hl NMR (DMSO-d6, 200 MHz): d 9.72 (bs, DZO exchangeable, 1H), 8.59 (s, 1H), 8.37(d, J
= 6.2 Hz, 1H), 8.14 (d, J = 9.4Hz, 1H), 7.60 (d, J = BHz, 2H), 7.19 (d, J =
8.OHz, 2H), 3.76-3.43 (m, 4H), 2.49 (s, 3H), 1.31 (d, J = 6.OHz, 2H), 1.11 (s, 2H).

5-[(E,Z)-1-(4-{2-[5-(3,4-Dimethoxyphenyl)-1-methyl-7-oxo-3-propyl-6,7-dihydro-pyrazolo[4,3-d]pyrimidin-6-yl]ethylamino)phenyl) ethylidene]1,3-thiazolane-2,4-dione N.N~
N~O
N
HN ~ \ \ O
Me0 S~NH
Me0 O
A mixture of 1-(4-{2-[5-(3,4-dimethoxyphenyl)-1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-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 (1.20g, 9.81 mmol) and piperidine (0.848, 9.81 mmol) was taken into 100 mL
single neck round bottom flask, to this toluene (60 mL) was added. The round bottomed flask (RBF) was fitted with dean stark, which was connected to a reflux condenser. The reaction mixture was heated to reflux for 35 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and stirred for an hour. The solid product formed was filtered off. The pure product was obtained by triturating the solid with isopropanol (5 mL), filtered off and dried under vacuum to afford the title compound as a pale green solid (l.Slg, 2.56 mmol).
Mp: 215-218 °C.
IR: V m~ (KBr, cm ~): 3380, 2956, 1679;

'H NMR (200 MHz, DMSO-d6): ~ 12.1(bs, DZO exchangeable, 1H), 7.95 (d, J = 6.98 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 7.86 Hz, 1H), 6.70 (d, J =
8.59 Hz, 2H), 6.53 (bs, D20 exchangeable, 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, 2H), 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 %.

This compound was prepared according to the procedure provided in Example 43.
HI NMR: d 12.5(bs, D20 exchangeable, 1H), 8.40-8.42 (m, 2H), 7.75 (s, 1H), 7.59-7.50 (m, SH), 7.19 (d, J = 8.3Hz, 2H), 5.07 (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) This compound was prepared according to the procedure provided in Example 46.
H~ NMR: d 12.4 (bs, D20 exchangeable, 1H), 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, 3 = 6.84Hz, 3H) This compound was prepared according to the procedure provided in Example 46.
H,CO
Hl NMR: d 12.28 (bs, D20 exchangeable, 1H), 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).

This compound was prepared according to the procedure provided in Example 46.
to HI NMR: d 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).

This compound was prepared according to the procedure provided in Example 46.
N ~ ~N~
O
N_N\

H' NMR: 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).

This compound was prepared according to the procedure provided in Example 46.
N-N~
Hl NMR: d 12.5 (bs, D20 exchangeable, 1H) 7.98 (d, J = 7.53Hz, 2H), 7.72 (s, 1H), 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).

This compound was prepared according to the procedure provided in Example 46.
~o s NH
~ O
O
N N
N~ I N / OCH3 Hl NMR: d 12.52 (bs, DZO exchangeable, 1H), 8.01-7.96 (m, 2H), 7.72 (s, 1H), 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).
'o EXAMPLE 54 This compound was prepared according to the procedure provided in Example 46.

i N ~ N~O I w O NH
O i i Ss~O
N-N, HI NMR: d 12.25 (bs, D20 exchangeable, 1H), 8.01-7.96 (m, 2H), 7.42-6.97 (m, SH), 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 = 7.25Hz, 3H).
s This compound was prepared according to the procedure provided in Example 46.

I ~ ~
NH
O
O /O
J\
N N
N ~ I ~ , OCH3 N
I\ OCH3 H' NMR: d 8.52 (bs, D20 exchangeable, 1H), 8.07 (d, J = 6.72Hz, 2H), 7.41-7.33 (m, 2H), l0 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).

5-[1-(3-Fluoro-4-{2-[2-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-15 3-yloxy]-ethoxy~ -phenyl)-ethylidene]-thiazolidine-2,4-dione ° / I ~ S~o W ~ °~° ~ °~NH
N \ F
i F
A mixture of compound 3-[2-(4-Acetyl-2-fluoro-phenoxy)-ethoxy]-2-(4-fluoro-phenyl)-1-methyl-1H-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 into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs 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 afford the title compound 209 mg (38%) as white solid.
1H NMR (200 MHz, DMSO-d6): d 12.31 (bs, D20 exchangeable, NH), 8.32 (d, J =
8.0 Hz, 1H), 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).
1o Mp: 220-222 °C

5-[ 1-(3-Ghloro-4- {2-[2-(2-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]
ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione A mixture of compovmd 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-2-(2-fluoro-phenyl)-1-methyl-1H-quinolin-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 into 50 mL single neck round bottom flask, to this toluene (50 mL) was added. The 2o RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under vacuum. The residue was purified by column chromatography followed by washing with ether to afford the title compound 200 mg (41 %) as off white solid.
2s 1H NMR (200 MHz, DMSO-d6): d12.39 (s, NH], 8.43 (d, J=8.0 Hz, 1H), 7.89 (d, J=3.0 Hz, 2H), 7.54 (s, 4H), 7.41-7.27 (m, 3H), 7.12 (d, J=8.6Hz, 1H), 4.41 (s, 2H), 4.16 (s, 2H), 3.59 (s, 3H), 2.71 (s, 3H).
Mp: 220-222 °C

5-[ 1-(4-{2-[2-(4-Fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy]-phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ I w S~°
I ~ I °~° ~ o NH
/ N

F
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(4-fluoro-phenyl)-1-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 into a single neck round bottom flask, to this toluene (500 mL) was added. The RBF was fitted with dean stark, to which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under vacuum. The residue was purified by column chromatography using 0-1% MeOH-CHC13 to afford the title compound 24 g (50%) as light brown solid.
1H NMR (200 MHz, DMSO-d6): d12.09 (bs,D20 exchangeble, 1H), 8.34 (d, J=7.8Hz, 1H), 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

5-[1-(3-{2-[2-(3,4-Dimethoxy-phenyl)-6-fluoro-4-oxo-4H-chromen-3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione OMe O
-NH
I
O I \ OMe S ( O
F / O~O
O I /
A mixture of 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 into a single neck round bottom flask, to this toluene (35 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25 °C, stirred for 6h at room temperature and filtered. The solid was triturated with i-PrOH (20 mL) and filtered to s afford the title compound 0.38 g (63%) as off white solid.
IH NMR (200 MHz, DMSO-d6): d 12.88 (bs, DSO exchangeable, 1H), 7.89-7.71 (m, SH), 7.28 (s, 1H), 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, 1H), 4.43 (s, 2H), 4.20 (s, 2H), 3.76 (s, 3H), 2.6 (s, 3H).
Mp: 228-230 °C
to 5-[1-(4- f 2-[2-(4-Chloro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy] -phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ I ~ S~ o °' NH
N

CI
15 A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(4-chloro-phenyl)-1-methyl-1H-quinolin-4-one (1.19 g, 2.45 mmol), 2,4-thiazolidenedione (1.72 g, 14.70 mmol), benzoic acid (0.59 g, 4.83 mmol), and piperidine (0.415 g, 4.82 mrnol) was taken into a single neck round bottom flask, to this toluene (100 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to 2o reflux for 72 hrs under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated under vacuum. The residue was purified by column chromatography using 6%
MeOH-CHC13 to afford the title compound 0.73 g (30%) as light brown solid.
1H NMR (200 MHz, DMSO-d6): 8.32 (d, J = 7.5 Hz, 1H), 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).
2s Mp: 238-240 °C

5-[ 1-(3-{2-[2-(3,4-Difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}
phenyl)-ethylidene]-thiazolidine-2,4-dione A mixture of compound 3-[2-(3-Acetyl-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-methyl-1H-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 into a single neck round bottom flask, to this toluene (30 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs undei nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography to afford the title compound 488 mg (40 %) as light brown solid.
'H NMR (200 MHz, DMSO-d6}: d 12.31 (NH, 1H), 8.32 (d, 1H, J=7.SHz), 7.81 (s, 2H), 7.62-7.30 (m, SH), 6.95 (d, 1H, J = 7.8 Hz), 6.77 (d, 2H, J = 9.7Hz), 4.26 (s, is 2H), 3.95 (s, 2H), 3.49 (s, 3H), 2.64 (s, 3H).
Mp: 236-240 °C

5-[I-(4- f 2-[1-Ethyl-2-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ I ~ S~o ° NH
F
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-1-ethyl-2-(4-fluoro-phenyl)-1H-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 into a single neck round bottom flask, to this toluene (30 mL) was added. The RBF was fitted with dean stark, which is connected to reflex condenser. The reaction mixture was heated to reflex for 72 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using MeOH-CHCl3 to afford the title compound 333 mg (45 %) as light brown solid.
IH NMR (200 MHz, DMSO-db~: d 12.09((bs, 1H, d20 exchangeble), 8.35(d, J=7.8Hz, 1H}, 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

5-[1-(4- f 2-[2-(3,4-Difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ I ~ S~o ° NH
N W F

F
is A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-1-methyl-1H-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) was taken into a single neck round bottom flask, to this toluene (30 mL) was added. The RBF was fitted with dean stark, which is connected to reflex condenser. The reaction mixture was heated to reflex for 72 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using MeOH-CHCl3 to afford the title compound 830 mg (39 %) as light brown solid.
'H NMR (200 MHz, DMSO-d~: d 12.24 (bs, NH, DZO exchangeable), 8.32 (d, J =
8.0 Hz, 1H), 7.81 (s, 2H), 7.66-7.32 (m, 6H), 6.80 (d, 3 = 8.6 Hz, 2H), 4.25 (s, 2H), 3.97 (s, 2H), 3.49 (s, 3H), 2.64 (s, 3H).
Mp: 248-250°C

5-[1-(4-{2-[7-Chloro-2-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione ° / I ~ S~o °~° ~ ° NH
CI
CH/3\ iI ~ F
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-7-chloro-2-(4-fluoro-phenyl)-1-methyl-1H-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 into a single neck round bottom flaslc, to this toluene (50 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was l0 heated to reflux for 48 hrs 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 afford the title compound 200 mg (41 %) as white solid.
'H NMR (200 MHz, DMSO-d6~: d 12.10 (bs, D20 exchangeble, 1H), 8.32 (d, J =
7.SHz, 1H), 7.89 (s, 1H), 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).
Mp: 292-296°C

5-[1-(4-{2-[2-(4-Fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethylamino}-phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ ~ \ S~o ° NH
N

F
A mixture of compound 3-[2-(4-Acetyl-phenylamino)-ethoxy]-2-(4-fluoro-phenyl)-methyl-1H-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 into a single neck round bottom flask, to this toluene (100 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using 0-2%
MeOH-CHG13 to afford the title compound 200 mg (41 %) as yellow solid.
1H NMR (200 MHz, DMSO-db7: 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).
l0 Mp: 130-132 °C

5-(4- f 2-[2-(4-Fluoro phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}-benzylidene)-thiazolidine-2,4-dione o ° I ~ Sao I ~ I ono ~ o NH
° N

A mixture of compound 4- f 2-[2-(4-Fluoro-phenyl)-1-methyl-4-oxo-1,4-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 into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF
2o was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 12 hrs under nitrogen atmosphere. The reaction mixture was cooled to 50°C and filtered. The residue was washed with hot MeOH and dried under vacuum to afford the title compound 200 mg (54%) as brown solid.
1H NMR (200 MHz, DMSO-dc~: d 12.5 (s, NH, D20 exchangeble), 8.35 (d, J=8.lHz, 1H), 7.81 (d, J = 3.2 Hz, 2H), 7.72 (s, 1H), 7.51-7.47 (m, SH), 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).
Mp: 225-228 °C

5-(4- {2-[2-(4-Bromo-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} -s A mixture of compound 4-{2-[2-(4-Bromo-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-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 into a single neck rowed bottom flask, to this toluene (50 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was to heated to reflux for 12 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The solid separated was filtered, washed with diethyl ether and dried under vacuum to afford the title compound 80 mg (53%) as light brown solid.
1H NMR (200 MHz, DMSO-cl~: d 8.35 (d, J = 8.8 Hz, 1H), 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).
1s Mp: 151-I54 °C

5-[ 1-(4-{2-[2-(5-Fluoro-2-methyl-phenyl)-1-methyl-4-oxo-I,4-dihydro-quinolin-3-yloxy]
ethoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione S
O
NH
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(5-fluoro-2-methyl-phenyl)-1-methyl-1H-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 into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF

benzylidene)-thiazolidine-2,4-dione was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under 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 afford the title compound 80 mg (26%) as brown solid.
'H NMR (200 MHz, DMSO-dc~: d 12.30 (s, D20 exchangeble, 1H), 8.35 (d, J=7.8Hz, 1H), 7.80 (s, 2H), 7.47-7.16 (m, SH), 6.96 (d, J = 7.8 Hz, 1H), 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).
Mp: I92-296 °C
io EXAMPLE 69 5-[ 1-(3-{2-[2-(4-Fluoro-2-methyl-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]
ethoxy}-phenyl)-ethylideneJ-thiazolidine-2,4-dione A mixture of compound 3-[2-(3-Acetyl-phenoxy)-ethoxy]-2-(4-fluoro-2-methyl-is phenyl)-1-methyl-IH-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 into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 20 25°C and concentrated. The residue was purified by column chromatography using 3-20%
EtOAc-CHCl3 to afford the title compound 120 mg (39%) as brown solid.
'H NMR (200 MHz, DMSO-dG): d 11.22 (bs, 1H), 8.59 (d, J = 7.2 Hz, 1H), 7.76-6.63 (m, lOH), 4.45-4.26 (m, 2H), 4.0-3.98 (m, 2H), 3.58 (s, 3H), 2.67 (s, 3H), 2.I5 (s, 3H).
2s Mp: 225-226 °C

5-[ I-(4-~3-[2-(4-Fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-propoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione w I ono I w N ~ s F o ~S
HN--A mixture of compound 3-[3-(4-Acetyl-phenoxy)-propoxy]-2-(4-fluoro-phenyl)-1-methyl-1H-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 into a single neck round bottom flask, to this toluene (30 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by colunm chromatography using 1 MeOH-CHCl3 to afford the title compound 130 mg (27 %) as white solid.
IH NMR (200 MHz, DMSO-d~: d 12.27 (bs, NH, DSO exchangeable), 8.30 (d, J =
7.8 Hz, 1H), 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).
Mp: 262-264 °C

5-[ 1-(3- { 3-[2-(4-Fluro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-propoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione I w I oho I w w S~o N ~ ~ o NH

F
A mixture of compound 3-[3-(3-Acetyl-phenoxy)-propoxy]-2-(4-fluoro-phenyl)-1-methyl-1H-quinolin-4-one (0.45 g, 1.011 mmol), 2,4-thiazolidenedione (0.710 g, 6.06 mmol), benzoic acid (300 mg, 2.46 mmol), and piperidine (300 mg, 3.52 mmol) was taken into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using 0.3%
MeOH-CHC13 to afford the title compound 187 mg (34 %) as light brown solid.
IH NMR (200 MHz, DMSO-d~: d 12.29 (NH, 1H), 8.31 (d, 1H, J = 7.8 Hz), 7.78 (s, 2H), 7.56-7.22 (m, 6H), 6.97 (d, 1H, J = 7.SHz), 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).
Mp: 168-170 °C

5-[ 1-(3-Chloro-4-{3-[2-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy)-propoxy) -phenyl)-ethylidene]-thiazolidine-2,4-dione ~ I ono I ~
N \ CI
cH3 I~~ I
S
H N-A mixture of compound 3-[3-(4-Acetyl-2-chloro-phenoxy)-propoxy]-2-(4-fluoro-phenyl)-1-methyl-1H-quinolin-4-one (0.40 g, 0.86 nnnol), 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 into a single neck round bottom flask, to this toluene (SO mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using 2%
MeOH-CHC13 to afford the title compound 140 mg (30 %) as light brown solid.
'H NMR (200 MHz, DMSO-d~: d 12.31 (NH, 1H), 8.32 (d, 1H, J = 7.8Hz), 7.80 (d, 2H, J = 2.9 Hz), 7.48-7.13 (m, 7H), 7.02 (d, 1 H, J = 8.3 Hz), 4.29 (s, 2I~, 4.07 (s, 2H), 3.47 (s, 3H), 2.64 (s, 3H), 1.82 (s, 2H).
Mp: 232-234 °C

5-[ 1-(4- f 2-[7-Fluoro-2-(4-fluoro-phenyl)-I-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione F ~ N w I
I ~ I O'~O .~ s O I / / NH

A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-7-fluoro-2-(4-fluoro-phenyl)-1-methyl-1H-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 into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using 0.5-I
MeOH-CHCI3 to afford the title compound 100 mg (21 %) as brown solid.
1H NMR (200 MHz, DMSO-d~: d 12.24 (bs, 1H), 8.39 (t, J = 7.30 Hz, 1H), 7.67 (d, J = 11.8 Hz, 1H), 7.52 (t, J = 8.30 Hz, 2H), 7.36 (t, J = 8.80 Hz, SH), 6.82 (d, J = 8.8 is Hz, 2H), 4.22 (s, 2H), 3.95 (s, 2H), 3.33 (s, 3H), 2.63 (s, 3H).
Mp: 276-278 °C

5-[ 1-(4-{2-[2-(3,4-Difluoro-phenyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ I ~ S'~o ° NH
F I / N I ~ F

F
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-fluoro-1-methyl-IH-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 into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 50 °G, 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 afford the title compound 125 mg (26%) as white solid.
1H NMR (200 MHz, DMSO-d~: d 12.23 (s, 1H), 8.39 (t, J = 8.6 Hz, 1H), 7.68-7.32 (m, 7H), 6.8I (d, J = 8.6 Hz, 2H), 4.25 (s, 2H), 3.97 (s, 2H), 3.43 (s, 3H), 2.64 (s, 3H).
Mp: 270-272 °C

5-[ 1-(4- ~2-[2-(3,4-Difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}
3-fluoro phenyl)-ethylidene]-thiazolidine-2,4-dione \ S~ o °~o ~ o NH
N ( W F F
CH3 I ~ F
A mixture of compound 3-[2-(4-Acetyl-2-fluoro-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-I-methyl-1H-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 into a single neck round bottom flask, to this toluene (30 mL) was added. The RBF
2o was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using 1-2%
MeOH-CHCl3 to afford the title compound 170 mg (35 %) as light brown solid.
1H NMR (200 MHz, DMSO-d~: d 12.29 (NH, 1H), 8.32 (d, 1H, 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

5-[1-(4-{2-[7-Chloro-2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy]-phenyl)-ethylidene]-thiazolidine-2,4-dione ° ~ I ~ S~o o~° W ° NH
CI ° N' \ F
CH~3\ iI\~/
F
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-7-chloro-2-(3,4-difluoro-phenyl)-1-methyl-1H-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 into a single neck round bottom flask, to this toluene (20 mL) was added. The RBF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using MeOH-CHCl3 to afford the title compound 150 mg (21 %) as white solid.
1H NMR (200 MHz, DMSO-db~: d 12.21 (bs, D2O exchangeable, NH), 8.30 (d, J =
8.8 Hz, 1H), 7.89 (s, 1H), 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

5-[1-(3-Chloro-4-{2-[7-chloro-2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione =o CI
A mixture of compound 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-7-chloro-2-(3,4-difluoro-phenyl)-1-methyl-1H-quinolin-4-one (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) was taken into a single neck round bottom flask, to this toluene (20 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under nitrogen atmosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using MeOH-CHCl3 to afford the title compound 120 mg (20%) as white solid.
1H NMR (200 MHz, DMSO-d~: d 12.25 (bs, D20 exchangeable, 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, IH), 4.20 (s, 2H), 4.02 (s, ZH), 3.39 (s, 3H), 2.57 (s, 3H).
Mp: 140-142 °C

5-[ 1-(4- {2-[ 6-Fluoro-2-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]
ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione ° / I ~ S~o F I ~ I °~° ~ ° NH
N

F
A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-6-fluoro-2-(4-fluoro-phenyl)-1-methyl-1H-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 into a single neck round bottom flask, to this toluene (30 mL) was added. The RSF
was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 72 hrs under 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 afford the title compound 80 mg (16 %) as light brown solid.
'H NMR (400 MHz, DMSO-d6): d12.27 (bs, D20 exchangeable, NH), 8.35 (dd, J =
8.9, 7.0 Hz, 1H), 7.64 (d, J = 12 Hz, 1H), 7.55-7.47 (m, 3H), 7.39-7.23 (rn, 3H), 7.04 (d, J = 8.6 Hz, 1H), 4.28-4.26 (m, 2H), 4.07-4.06 (m, 2H), 3.42 (s, 3H), 2.63 (s, 3H).
Mp: 245-248 °C

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 ~ I ~ S~o F ~ °~o ~ o NH
N I ~ Cl F
F
A mixture of compound 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-6-fluoro-1-methyl-1H-quinolin-4-one (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 into a single neck round bottom flask, to this toluene (30 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction l0 mixture was heated to reflux for 72 hrs under nitrogen afimosphere. The reaction mixture was cooled to 25°C and concentrated. The residue was purified by column chromatography using 0.5-1 % MeOH-CHCl3 to afford the title compound 40 mg (8 %) as light brown solid.
IH NMR (400 MHz, DMSO): d12.27 (bs, D20 exchangeable, NH), 8.40-8.33 (m, 1H), 7.64 (d, J =12.0 Hz, 1H), 7.55-7.47 (m, 3H), 7.39-7.23 (m, 3H), 7.04 (d, J = 8.6 Hz, 1H), 4.30 (m, 2H), 4.08 (m, 2H), 3.42 (s, 3H), 2.63 (s, 3H).
Mp: 215-218 °C

5-[1-(3-Chloro-4- f 2-[2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione r 'NH
A mixture of compound 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-1-methyl-1H-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, 4I 1.7 mmol) were taken a single neck round bottomed flask, to this toluene (1000 mL) was added. The round-bottomed flask was fitted with dean stark apparatus, 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 allowed to pass through a silica gel column. The product was eluted by using 0.3-0.9 % MeOH / CHC13 to afford the title compound, 37 g (32%) as off white solid.
IH NMR (200 MHz, CDCI3) ~ 12.30 (s, 1H), 8.32 (m, 1H), 7.77 (m, 2H), 7.52 (ddd, J
= 8.0, 2.0, 0.8 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.45 (m, 1 H), 7.25 (m, 1 H), 7.3 5 (dd, J = 10.0, 2.4 Hz, 1 H), 7.31 (dd, J = 8.4, 2.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 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

5-[1-(4-{3-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy]-propoxy] -phenyl)-ethylidene]-thiazolidine-2,4-dione / OMe Me0 I ~ O I ~ ( OMe O~O ~ S NH
OMe O
O
A mixture of 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 50 mL single neck round bottom flask, to this toluene (15 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was heated to reflux for 48 hrs under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and was filtered. The solid was dried to afford the title compound 189 mg (34%) as white solid.
'H NMR (200 MHz, CDCl3): d 8.38 (s, 1H), 7.68-7.65 (m, 2H), 7.3-7.25 (m, 2H), 6.91-6.85 (m, 3H), 6.51 (s, 1H), 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) Mp: 198-200 °C

The following compounds are readily prepared by one of skill in the art using the processes set forth above:
Exam Com ound le 82 5-[1-(3-Chloro-4-{2-[2-(3,4-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)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yl]-propoxy]-phenyl)-ethylidene]-thiazolidine-2,4-dione 86 5-[1-(3-Chloro-4-{3-[2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-propyl}
-phenyl)-ethylidene]-thiazolidine-2,4-dione 87 5-[1-(3-Chloro-4-{2-[5-(3,4-difluoro-phenyl)-1,3-dimethyl-7-oxo-1,7-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-difluoro-phenyl)-1,3-dimethyl-7-oxo-1,7-dihydro-pyrazolo[4,3-d]pyrimidin-6-yl]-propoxy}-phenyl)-eth lidene]-thiazolidine-2,4-dione 89 3-[2-(3-Chloro-4-{2-[2-(3,4-difluoro-phenyl)-4-oxo-4H-chromen-3-yloxy]-ethoxy]-phenyl)-acetylamino]-2-(toluene-4-sulfonylamino)-propionic acid ethyl ester 90 3-[2-(3-Chloro-4-{2-[2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy}-phenyl)-acetylamino]-2-(toluene-4-sulfonylamino)- ro ionic acid ethyl ester 91 3-(4-{2-[2-(3,4-Difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy] -benzoylamino)-2-(toluene-4-sulfonylamino)-pro ionic acid ethyl ester Similarly, 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 bromolcetone see (a) J. MED. CHEM. 1996(39), 2939-2952; (b) J.
HET.
CHEM., 1972(9) 887; (b) INDIAN 3. 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 formula (I) wherever applicable with 1 to 4 equivalents of a base, for example, sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, 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, diethanolamiiie, choline, tromethamine, guanidine, or any derivative or mixture thereof, also may be used.
Alternatively, acid addition salts wherever applicable are prepared by treatment with acids, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-l0 toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, malefic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palinitic 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 amino acid groups and other groups may be prepared by reacting the compounds of formula (I) with the respective groups in the presence of a solvent, for example, alcohols and ketones, or any mixture thereof.
Various polymorphs of a compound of general formula (I) according to the present invention may be prepared by crystallization of compound of formula (I) under different conditions, for example, by using different solvents or their mixtures for recrystallization; by performing crystallizations at different temperatures; or by using various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compound followed by gradual or fast cooling also may obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
Pharmaceutically acceptable solvates of compound of formula (I) forming part of this invention may be prepared by conventional mefliods such as dissolving the compounds of formula (I) in the presence of a solvent, for example, water, methanol, ethanol etc., for example, water and recrystallizing by using different crystallization techniques.
The regioisomers of a compound of formula (I) may be prepared by modifying the reaction conditions, for example, by using reagents, for example, acid to base or base to acid, or by reaction with free base hydrazine instead of its salt with diketone. The molar proportion also can change the regioisomer formation.

Claims (59)

1. A compound of general formula (I) its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein wherein L is ~Y~G=Z~Ar~ or -(CH2)t -;
wherein Q is wherein R1, R2, and R3 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, 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, 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-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S, or N;
wherein 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, 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 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 O, S, N, > CH, or ~CH2~n;
wherein '----' is an optional chemical bond;
wherein E is O, S, or -NR;
wherein K is N, C, or CH;
wherein Y and Z independently are O, -NR, ~CH2~u, or S(=O)u;
wherein G is ~(CH2)s-, -(CH2)s-CH=CH-(CH2)s-, or ~(CH2)s-C=C-(CH2)s-;
wherein X, X1, X2, X3, and X4 independently are O, S, or -NR;
wherein F is O, S, or -NR;

wherein Y1 and Y2 independently are O or S;
wherein n, w, u independently are an integer from 0-2;
wherein p, t, m, s, v independently are and integer from 0-5;
wherein R and R5 independently are hydrogen, potassium, sodium, 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, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group; and wherein 'Ar' is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl group.

2. ~The compound of claim 1, wherein any of R1, R2, R3, and R4 independently are 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(O=) group, a thio(S=) group, 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 piperzinyl 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.

3. ~A compound of general formula (II) its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R1, R2 and R3 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, 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, 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-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S, or N;
wherein 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, 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 aralalkynyl 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 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 O, S, N, >CH, or (CH2)n;

wherein '----' is an optional chemical bond;
wherein E is O, S, or -NR;
wherein Y and Z independently are O, -NR, (CH2)", or S(=O)u;
wherein G is -(CH2)s-, -(CH2)s-CH=CH-(CH2)s-, or -(CH2)s -C=C-(CH2)s-;
wherein X is O, S, or -NR;
wherein F is O, S, or -NR;
wherein Y1 and Y2 independently are O or S;
wherein n and u independently are an integer from 0-2;
wherein s is an integer from 0-5;
wherein R and R5 independently are hydrogen, potassium, sodium, 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, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group; and wherein 'Ar' is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl group.

4. ~The compound of claim 3, wherein any of R1, R2, R3, and R4 independently are 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(O=) group, a thio(S=) group, 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 amyl 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 piperzinyl 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.

5. ~A compound of general formula (III) its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R1, R2, and R3 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, 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, 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-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S, or N;
wherein 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, 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 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 '----' is an optional chemical bond;
wherein E is O, S, or -NR;
wherein Z is O, -NR, (CH2)u, or S(=O)u;~
wherein G is -(CH2)s, -(CH2)s-CH=CH-(CH2)s-, or -(CH2)s -C=C-(CH2)s-;
wherein u is an integer from 0-2;
wherein s is an integer from 0-5;
wherein R and R5 independently are hydrogen, potassium, sodium, 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, 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 amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, a thio(S=) group, 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.

6. ~The compound of claim 5, wherein any of R1, R2, R3, and R4 independently are 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(O=) group, a thio(S=) group, 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 heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl 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.

7. ~The compound of claim 5, wherein one or both of R' and R" independently are substituted with a halogen, a hydroxyl group, a nitro group, an amino group, or an alkyloxy group.

8. ~The compound of claim 5, wherein one or both of R' and R" independently are substituted with a heterocyclyl group comprising a morphonyl group, a thiomorphoine, or a piperzine.

9. ~The compound of formula (III) as claimed in claim 5, wherein the compound is:

10. A compound of general formula (IV) its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein 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, 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, 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-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S, or N;
wherein 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, 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 alralkynyl 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 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 D and J independently are O, S, N, >CH, or CH2;
wherein '----' is an optional chemical bond;
wherein E is O, S, or -NR;
wherein K is N, C, or CH;
wherein Z is O, -NR, (CH2)u, or S(=O)u;
wherein G is -(CH2)s-, -(CH2)s -CH=CH-(CH2)s-, or -(CH2)s -C=C-(CH2)s-;
wherein X is O, S, or -NR;
wherein F is O, S, or -NR;
wherein Y1 and Y2 independently are O or S;~
wherein u is an integer from 0-2;
wherein s is an integer from 0-5;
wherein R and R5 independently are hydrogen, potassium, sodium, 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, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group; and wherein 'Ar' is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl group.

11. The compound of claim 10, wherein any of R1, R2, R3, and R4 independently are 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(O=) group, a thio(S=) group, 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 heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl 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.

12. The compound of formula (IV) as claimed in claim 10, wherein the compound is:

13. ~A compound of general formula (V) its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R1, R2, and R3 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, 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, 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-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are O, S, or N;
wherein 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, 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 alralkynyl 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 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 O, S, N, >CH, or (CH2)n;
wherein E is O, 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 O, -NR, (CH2)u, or S(=O)";
wherein G is -(CH2)s-, -(CH2)s -CH=CH-(CH2)s-, or -(CH2)s-C=C-(CH2)s-;
wherein X1, X2, X3, and X4 independently are O, S, or -NR;
wherein X is O, S, or -NR;
wherein n and w independently are an integer from 0-2;
wherein p, t, and v independently are an integer from 0-5;
wherein R is hydrogen, potassium, sodium, 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, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group; and wherein 'Ar' is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl group.

14. ~The compound of claim 13, wherein any of R1, R2, R3, and R4 independently are 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(O=) group, a thio(S=) group, 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 heterocyclyl group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl 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. ~The compound of formula (V) as claimed in claim 13, wherein the compound is:

16. ~A method of treatment or prophylaxis of a disease that is mediated by an inflammation response or smooth muscle cell proliferation in a human or animal, comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

17. The method of claim 16, wherein the inflammation response includes a diabetic vascular complication, wherein the diabetic vascular complication comprises diabetic retinopathy, microangiopathies, renal insufficiency, or Alzheimer's disease.

18. The method of claim 16, wherein the inflammation response results from a glycated protein or an advanced glycation end product accumulation.

19. The method of claim 18, wherein the glycated protein or the advanced glycation end product accumulation is mediated by a pro-inflammatory cytokine.

20. The method of claim 19, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-.alpha., or MCP-1.

21. The method of claim 16, wherein the smooth muscle cell proliferation is inhibited by inducing the expression of perlecan.

22. The method of claim 16, wherein the smooth muscle cell proliferation is mediated by a pro-inflammatory cytokine.

23. The method of claim 22, wherein the pro-inflammatory cytokine comprises IL-6, IL-1, TNF-.alpha., or MCP-1.

24. A method of treatment or prophylaxis of undesired inflammation in a human or animal comprising administering to the human or animal with the undesired inflammation a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

25. A method of treatment or prophylaxis of undesired smooth muscle cell proliferation in a human or animal comprising administering to the human or animal with the undesired smooth muscle cell proliferation a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

26. A method for treatment or prophylaxis of a disease or disorder mediated by a cell adhesion molecule, comprising administering to a patient in need thereof a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

27. The method of claim 26, wherein the disease or disorder mediated by cell adhesion molecules is an inflammatory disorder or a cardiovascular disease.

28. The method of claim 27, wherein the inflammatory disorder is rheumatoid arthritis, osteoarthrites, asthama, dermatitis, psoriasis, organ transplantation or allograft rejection, autoimmune diabetes, or multiple sclerosis.

29. The method of claim 27, wherein the cardiovascular disease is athresclerosis, restenosis, coronary artery disease, angina, dyslipidemia, small artery disease, diabetes mellitus, diabetic nepropathy, or diabetic retinopathy.

30. The method of claim 26, wherein the cell adhesion molecule is VCAM-1.

31. The method of claim 26, further comprising administering a therapeutically or prophylactically effective amount of at least one other medication comprising a platelet aggregation inhibitor, an antithrombotic agent, a, calcium channel blocker, an angiotension converting enzyme inhibitor, a .beta. blocker, a non-steroid antiinflamatory agent, a COX II
inhibitor, a corticosteroid, a TNF-.alpha. modulating agent, a HMGCoA
reductose inhibitor, a PPAR-? agonist, an HDL elevator, or a retinoid.

32. ~The method of claim 31, wherein the at least one other medication is aspirin, dilteazem, nefidipine, captopril, enalopril, propanalol, ibuprofen, indomethacin, sulindac, rofecoxib, celecoxib, etanercept, or infliximab.

33. ~A method of treatment or prophylaxis of cancer in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

34. ~A method according to claim 33, wherein the cancer comprises melanoma, prostate cancer, leukemia, lymphoma, non-small lung cancer, cancer of the central nervous system, breast cancer, colon cancer, ovarian cancer, or renal cancer.

35. ~A method for inhibiting smooth muscle cell proliferation in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

36. ~A method for inhibiting an inflammatory response in an endothelial cell in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

37. ~A method for treating or preventing organ transplant vasculopathy in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

38. ~The method of claim 37, wherein the organ is a liver, a kidney, a heart, a lung, a pancreas, a pancreatic islet, and skin.

39. ~The method of claim 37, further comprising administering a therapeutically or prophylactically effective amount of an immunosuppressive agent.

40. The method of claim 39, wherein the immunosuppressive agent is CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, Zenapax.

41. The method of claim 39, wherein the administering is oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.

42. The method of claim 39, wherein the immunosuppressive agent is administered before the composition.

43. The method of claim 39, wherein the immunosuppressive agent is administered after the composition.

44. The method of claim 39, wherein the immunosuppressive agent is administered simultaneously with the composition.

45. A method for treating or preventing restenosis in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

46. A method for treating or preventing atherosclerosis in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

47. A method for treating a disease mediated by inflammation in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

48. The method of claim 47, wherein the disease mediated by inflammation is an autoimmune disease.

49. The method of claim 48, wherein the autoimmune disease is alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinn disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-Ebromyositis, Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritis 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, Sjogren's syndrome, stiff man syndrome, systematic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, or Wegener's granulomatosis.

50. A method for treating or preventing metastases in a human or animal comprising administering to the human or animal a composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1.

51. A method of modulating Perlecan activity in a human or animal comprising administering to the human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1.

52. A method for modulating Heparanase in a human or animal comprising administering to the human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1.

53. A stent coated with a composition comprising a compound according to claim 1.

54. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier, diluent, excipient, or solvate.

55. The pharmaceutical composition of claim 54, in the form of a tablet, capsule, powder, syrup, solution, suspension.

56. A medical device coated with a composition comprising a compound according to claim 1.

57. The medical device of claim 56, wherein the medical device is a shunt, a colostomy bag attachment device, an ear drainage tube, a lead for a pace maker and implantable defibrillator, a suture, a staple, an anastornosis device, a vertebral disk, a bone pin, a suture anchor, a hemostatic barrier, a clamp, a screw, a plate, a clip, a vascular implant, a tissue adhesive or sealant, a tissue scaffold, a bone substitute, an intraluminal device, and a vascular support.

58. A method for treatment or prophylaxis of cardiovascular disease in a human or animal comprising administering to the human or animal a composition comprising a therapeutically effective amount of a compound according to claim 1.

59. The method of claim 58, wherein the cardiovascular disease is athresclerosis, restenosis, coronary artery disease, angina, dyslipidemia, small artery disease, diabetes mellitus, diabetic nepropathy, or diabetic retinopathy.