AU2004286277A1 - Heterocyclic compounds and methods of making and using thereof - Google Patents

Heterocyclic compounds and methods of making and using thereof Download PDF

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AU2004286277A1
AU2004286277A1 AU2004286277A AU2004286277A AU2004286277A1 AU 2004286277 A1 AU2004286277 A1 AU 2004286277A1 AU 2004286277 A AU2004286277 A AU 2004286277A AU 2004286277 A AU2004286277 A AU 2004286277A AU 2004286277 A1 AU2004286277 A1 AU 2004286277A1
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group
rib
ria
halogen
heterocyclyl
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Srinivas Padakanti
Manojit Pal
Ram Pillarisetti
Kalleda Srinivasa Rao
Yeleswarapu Koteswar Rao
Vedula Manohar Sharma
Akella Venkateswarlu
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Reddy US Therapeutics Inc
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Reddy US Therapeutics Inc
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Assigned to REDDY US THERAPEUTICS, INC. reassignment REDDY US THERAPEUTICS, INC. Request for Assignment Assignors: PAL, MANOJIT, PILLARISETTI, RAM, Rao, Yeleswarapu, REDDY US THERAPEUTICS, INC., Sharma, Veudla, VENKATESWARLU, AKELLA
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Description

WO 2005/042712 PCT/US2004/035939 5 10 HETEROCYCLIC COMPOUNDS AND METHODS OF MAKING AND USING THEREOF 15 FIELD OF THE INVENTION The present invention relates to compounds, pharmaceutical compositions, and methods of making and use thereof. 20 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 fonnation of protein cross 25 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-1, 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 30 etiological factor include, but are not limited to, vascular complications of diabetes, microangiopathies, renal insufficiency, and Alzheimer's disease.
WO 2005/042712 PCT/US2004/035939 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 linked to microangiopathies is through the process of non-enzymatic glycation of critical proteins. Non-enzymatic glycation of critical proteins is discussed in 5 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. Nati. Acad. Sci. U S A., 1994 (91)9436-40; Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease, J Am. Soc. Nephrol., 2000 (11)1656-66; and 10 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 15 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 20 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 25 proteins in the pathogenesis of diabetic nephropathy., J. Axn. 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 30 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 2 WO 2005/042712 PCT/US2004/035939 progression of type II diabetes: a study with aminoguanidine in C57/BLKsJ 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 5 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 10 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-i (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; 15 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 20 central cell surface receptor for S100/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 25 RAGE could lead to accumulation of AGE in circulation, the long-term 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 30 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 3 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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 15 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-l lH; and Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 100:S87-9. Many humans and animals have limited lifespans and lifestyles because of such conditions. Currently there are no known effective 20 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 25 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 30 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 4 WO 2005/042712 PCT/US2004/035939 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 (SMC) hyperplasia is a major event in the development of 5 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 10 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 15 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 20 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 25 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 30 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 5 WO 2005/042712 PCT/US2004/035939 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 5 accumulation. Further, the present invention provides compounds and compositions that inhibit smooth muscle cell proliferation, which may be mediated by pro-inflammatory cytokines like IL-6, IL-1, TNF-a, MCP-1, or by inducing the expression of perlecan, a heparin sulfate proteoglycan (HSPG). Ri B\A R- (I) R2D/.K R 3L-Q 10 The present invention provides novel compounds of formula (1), 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 15 thereof. The present invention also provides novel compounds of formula (II), their phannaceutically acceptable salts, and pharmaceutical compositions containing one or more of such compounds, optionally in combination with other active ingredients. Y1 R 4 K \A E RF NR R _=Y-GZ-Ar '2
R
3 R 5 x 20 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 25 containing them, or their mixtures, or in combination with other active ingredients. 6 WO 2005/042712 PCT/US2004/035939 \NR Ri ~ S 0 \~ E R 4 R R2( I O-G-Z O 0 O R" The present invention also provides a process for preparing compounds of the formula (III) as defined above, their salts, and pharmaceutically acce-ptable compositions thereof 5 The present invention also provides novel compounds of formula (IV), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of such compounds, optionally in combination with other active ingredients. 1Y ER R FA NR D I (IV) 2 -GZ-Ar 2 x The present invention also provides a process for preparing compounds of the 10 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. RA E R 4 XTS(O) wAr R2-P\~ R2 K-L CH 2 )v--~X
CH
2 )p OR 15 X X3 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 20 formula (I) comprises treatment and/or prophylaxis of inflammatory conditions, such as those mediated by AGE or glycated protein accumulation. Such inflammatory conditions include 7 WO 2005/042712 PCT/US2004/035939 diabetic vascular complications, including diabetic retinopathy, microangiopathies, 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 5 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 inhibiting thrombosis comprising administering an effective amount of a compound contemplated hereby. 10 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 15 an immunosuppressive agent. The immunosuppressive agent may include, but is not limited to, CeIlCept, 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 20 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 25 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 imnune dysfunction 30 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, 8 WO 2005/042712 PCT/US2004/035939 Graves' disease, Guillain-Barr6, 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, 5 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, Sj6gren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, 10 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 15 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 20 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). 25 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-1, 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, 30 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. 9 WO 2005/042712 PCT/US2004/035939 Still another aspect of the present invention provides treatment and/or prophylaxis of of a disease by delivering the compound(s) of formula (I) at the site of the disease by using a compound(s) of formula (I) coated stents. The present invention further provides pharmaceutical compositions containing 5 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, 10 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, 15 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, 20 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 carrier(s) or excipient(s). In general, the formulations are prepared by unifonnly and intimately bringing into associate the active ingredient with liquid carriers or 25 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. 30 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 10 WO 2005/042712 PCT/US2004/035939 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" 5 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 10 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 15 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 20 assays of the present invention and combinations, fragments, analogs or derivatives of such entities. The term "glycated protein", as used herein, includes proteins linked 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, 25 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 ifn a measurable manner is contemplated by the present invention. Enhanced formation and 30 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 I1 WO 2005/042712 PCT/US2004/035939 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 5 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 phenylaminee" refers to a primary or secondary benzeneamine, more commonly known as aniline. The amino group on the aniline may be optionally substituted 10 with hydrogen, alkyl (C-C 12 , straight chain or branched), cycloalkyl (C 3
-C
10 ), 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, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl anriino, acyl, carboxyl, 15 amido, sulfonamido, 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 fonns used in standard organic synthesis. The term "naphthylamine" refers to a primary or secondary a- or B-naphthylamine. 20 The ring substructure in the naphthylamine 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, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, 25 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 B naphthylalkyl amine (for example, 2-a-naphthylethyl amine). The tern "benzalkyl amine" refers to a primary or secondary benzylalkyl amine (for example, phenylethyl amine). These 30 aryl ailcyl 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, 12 WO 2005/042712 PCT/US2004/035939 benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carbolyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate. If applicable these groups can be represented in 5 protected or unprotected forns 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, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, 10 alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate. These groups can be represented in protected or unprotected forms used in standard organic synthesis. 15 The tenn "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, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, 20 morpholino, thiomorpholino, piperazinyl, phosphate, phosphonic acid, or phosphonate. These groups can be represented in protected or unprotected forms used in standard organic synthesis. The term "polynucleotide" refers generally to polymeric forms of nucleotides of any length, either ribonucleotides or deoxynucleotides. Thus, this term includes, but is not 25 limited to, single-stranded, double-stranded, or multi-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 30 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 13 WO 2005/042712 PCT/US2004/035939 components. Furthermore, a polynucleotide may be modified after polymerization to facilitate its attachment to other polynucleotides, proteins, metal ions, labeling components, or a solid support. The backbone of the polynucleotide may comprise modified or optionally substituted 5 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., NUCL. ACIDS RES. (1996) 24:1841-1848, and Chaturvedi et al., NuCL. ACIDS RES. (1996) 24:2318-2323. 10 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 15 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 20 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. 25 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 30 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 14 WO 2005/042712 PCT/US2004/035939 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, 5 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. 10 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 15 of the present invention. Furthermore, 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 20 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 nxay 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", 25 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 30 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 15 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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 long 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 15 polypeptide may be a single molecule or may be a multi-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 20 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 25 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 protein 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 30 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". 16 WO 2005/042712 PCT/US2004/035939 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. 5 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 10 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 15 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 20 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 inhibit 25 the binding of the parent monoclonal antibody to its antigen. A functional equivalent may comprise F(ab') 2 fragments, F(ab) 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 30 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. 17 WO 2005/042712 PCT/US2004/035939 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 least about 75% free, at least about 80% free, at least about 83% free, at least about 85% free, at least about 88% free, at least about 90% free, at least about 91% free, 5 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 10 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 15 (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 20 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 25 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, 30 horses, dogs, cats, guinea pigs, rabbits, rats, primates, and mice. The terns "treatment", "treating", "treat", are used herein to refer generally to obtaining a desired pharmacological and/or physiologic effect. The effect may be 18 WO 2005/042712 PCT/US2004/035939 prophylactic in that it may completely or partially prevent a disease or symptom thereof and/or may be therapeutic in that it may 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 tle 5 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 symptoin, 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 10 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, phospholipics 15 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 polynucleoticle 20 sequence binds to a complementary sequence through base pairing. Hybridization conditions 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 25 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. 30 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 19 WO 2005/042712 PCT/US2004/035939 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. 5 The term "oligonucleotide" as used herein refers to a polynucleotide sequence comprising, for example, from about 10 nucleotides (nt) to about 1000 nt. Oligonucleotides for use in the present invention are, for example, from about 15 nt to about 150 nt, or from about 150 nt to about 1000 nt in length. The oligonucleotide may be a naturally occurring oligonucleotide or a synthetic oligonucleotide. Oligonucleotides may be prepared by the 10 phosphoramidite method (Beaucage and Carruthers, TETRAHEDRON LETr. (1981) 22:1859 1862), orby the triester method (Matteucci et al., J. AM. CHEM. SOC. (1981) 103:3185), or by other chemical methods known in the art. The term "microarray" refers generally to the type of genes or proteins represented on a microarray by oligonucleotides (polynucleotide sequences) or protein-binding agents, and 15 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 oligonucleotides 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 20 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 microarray" in which each of the microarray oligonucleotides or protein-binding agents correspond to a gene or protein 25 associated with a cancer. An "epithelial microarray" may be a microarray of oligonucleotides 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. 30 The term "detectable" refers to a polynucleotide expression pattern which is detectable via the standard techniques of polymerase chain reaction (PCR), reverse transcriptase-(RT) PCR, differential display, and Northern analyses, which are well known to 20 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 20 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 tenn "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. 30 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 21 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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, 15 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 20 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 25 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, 30 the intra-organismal and intra-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 22 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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. 15 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 20 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 25 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 30 Information (NCBI), which is part of the National Library of Medicine. 23 WO 2005/042712 PCT/US2004/035939 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 5 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, 10 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. 15 Compounds of General Formula (1) The present invention is related to compounds of formula (I), 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 20 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) R1 R (I) D Ks 25 R L-Q its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, and its pharmaceutically acceptable solvates are provided. According to this aspect, 24 WO 2005/042712 PCT/US2004/035939 Ri R 3L-Q is \A E R 4 A E R 4 X; or X
-Y-G-C
|| 5 In this and other aspects, L is -Y-G=Z-Ar- , X1, or -(CH 2 )t -, and Q is YiY F NRXTS(O)w-Ar NR -CH 2 )v-C-X-(CH 2 )pK 2R2O-R
R
5 or or R', R 2 , and R 3 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 10 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 15 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 1 21 two of RI, R2, and R 3 in combination optionally form a 5-member or 6-member saturated 20 cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are 0, S, or N. The cyclic ring formed by any two of R', R 2 , or R 3 may be oxlanyl, 1,3-dioalanyl, or 1,4 dioxalanyl. 25 WO 2005/042712 PCT/US2004/035939
R
4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy 5 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 10 group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfmyl group, an aralkylsulfmyl 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 15 sulfonic acid or a derivative thereof. Any of R', R 2 , R 3 , and R 4 independently optionally 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 20 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 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 25 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 alloxy group, or an aryl group. 30 According to this and other aspects, A, B, D, and J independently are 0, S, N, >CH, or (CH 2 )n; '----' is an optional chemical bond; E is 0, S, or -NR; K is N, C, or CH; Y and Z independently are 0, -NR, (CH 2 )u, or S(=O),; G is -(CH 2 ),-, -(CH 2 )s-CH=CH-(CH 2 )s-, or 26 WO 2005/042712 PCT/US2004/035939
(CH
2 )s-C=C-(CH 2 )s-; X, X 1 , X 2 , X 3 , and X 4 independently are 0, S, or -NR; F is 0, S, or NR; Y 1 and Y 2 independently are 0 or S; n, w, u 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. 5 R and R 5 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: 10 'Halogen' is fluorine, chlorine, bromine, or iodine; 'Alkyl' group is a linear or branched (CI-Cio)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 (C 3
-C
7 ) cycloalkyl group which may be mon or polycyclic. 15 Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. 'Alkoxy' is (C-CIO)alkyl-O-, wherein the (CI-C 1 o)alkyl group is as defined above. Exemplary alkyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy. 'Cycloalkoxy' is a (C 3
-C
6 )cycloalkoxy group. Exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. 20 'Alkenyl' is a (C 2
-C
6 )alkenyl group. Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl. 'Cycloalkenyl' is (C 3
-C
7 )cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. 'Alkoxyalkyl' is a (CI-C 6 )alkoxy(C-C1o)alkyl group, where alkoxy and alkyl groups 25 are as defined above. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl. 'Alkenyloxy' is (C 2
-C
6 )alkenyl-O-, where the (C 2
-C
6 )alkenyl group is as defined above. Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy. 30 'Cycloalkenyloxy' is a (C 3
-C
7 )cycloalkenyl-O-, where the (C 3
-C
7 )cycloalkenyl group is as defined above. Exemplary cycloalkenyloxy groups include cycloethenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy. 27 WO 2005/042712 PCT/US2004/035939 'Acyl' is H-CO- or (CI-Cjo)alkyl-CO-, where (Ci-Cio)alkyl group is as defined above. Exemplary acyl groups include acetyl, propionyl. 'Acyloxy' is (C-C 6 )acyl-O-, where acyl group is as defined above. Exemplary acyloxy groups include acetyloxy, propionyloxy. 5 '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 10 aroyl groups include benzoyl, 1 -naphthoyl. 'Aroyloxy' is the aroyl-O- group, wherein the aroyl group is as defined above. Exemplary aroyloxy groups include benzoyloxy, 1 -naphthoyloxy. 'Aralkyl' is the aryl-(CI-Cio)alkyl group, wherein aryl and (CI-C1o)alkyl groups are as defined above. Exemplary aralkyl groups include benzyl, 2-phenylethyl. 15 'Aralkenyl' is aryl-(C 2
-C
6 )alkenyl group, wherein aryl and (C 2
-C
6 )alkenyl groups are as defined above. 'Aralkynyl' is aryl-(C 2
-C
6 )alkynyl group, wherein the aryl and group is as defined above. 'Aralkoxy' is aralkyl-O- group, wherein the aralkyl group as defined above. 20 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 0, S or N. Exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl. 25 'Heterocyclenyl' is a non-aromatic monocyclic or polycyclic hydrocarbon ring system of about 5 to 10 carbon atoms, having at least one hetero atom selected from 0, 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-tetrahycropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl. 30 'Heteroaryl' is an aromatic monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from 0, S or N. Exemplary heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, 28 WO 2005/042712 PCT/US2004/035939 pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxole, 1,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl. 'Heteroaralkyl' is a heteroaryl-(Ci-Cio)alkyl group, wherein the heteroaryl and (Cl Clo)alkyl groups are as defined above. Exemplary heteroaralkyl groups include 5 thienylmethyl, pyridyhnethyl, 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 10 above. Exemplary heteroaralkoxy groups include thienylmethyloxy, pyridylmethyloxy. 'Alkylcarbonyl' or 'acyl' is (CI-Cio)alkyl-CO-, wherein the (C-Cio)alkyl group is as defined above. Exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl. 'Alkoxycarbonyl' is (C-C 10 )alkyl-O-CO-, wherein the (CrCio)alkyl group is as 15 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. 20 Exemplary aryloxycarbonyl groups include phenoxycarbonyl, naphthyloxycarbonyl. 'Aralkoxycarbonyl' is aryl-(C-C 6 )alkoxy-CO-, where aryl and (C-C 6 )alkoxy are as defined above. Exemplary aralkoxycarbonyl groups include benzyloxycarbonyl, 2 phenethyloxycarbonyl. 'Heteroarylcarbonyl' is heteroaryl-CO-, wherein heteroaryl is as defined above. 25 Exemplary heteroarylcarbonyl groups include pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl. 'Alkylsulfonyl' is (C-Cio)alkyl-S0 2 -, wherein the (CI-Cio)alkyl group is as defined above. Exemplary alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, 30 propylsulfonyl. 'Arylsulfonyl' is aryl-S0 2 -, wherein the aryl group is as defined above. Exemplary arylsulfonyl groups include benzenesulfonyl. 29 WO 2005/042712 PCT/US2004/035939 'Heteroarylsulfonyl' is heteroaryl-SO,- wherein heteroaryl is as defined above. Exemplary heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolylsulfonyl, pyrazolylsulfonyl, pyrrolylsulfonyl, pyridazinylsulfonyl, phlithalazinylsulfonyl, quinazolinylsulfonyl, pyridylsulfonyl, thienylsulfonyl. 5 'Alkylsulfinyl' is (CI-Cio)alkyl-SO-, where (C-Clo)alkyl is as defined above. Exemplary alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl. 'Arylsulfinyl' 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. 10 Exemplary heteroarylsulfmyl groups include pyrazinylsulfinyl, isothiazolylsulfinyl, oxazolylsulfinyl, pyrazolylsulfinyl, pyrrolylsulfinyl, pyridazinylsulfmyl, phthalazinylsulfinyl, quinazolinylsulfinyl, pyridylsulfinyl, and thienylsulfinyl. 'Aralkylsulfinyl' is aryl-(Cj-Cio)alkyl-SO- group, where in aryl and (C-Cio)alkyl groups are as defined above. Exemplary aralkylsulfmyl groups include benzylsulfinyl, 2 15 phenethylsulfinyl. 'Alkylthio' is (CI-Cio)alkyl-S-, wherein (C-CIO)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. 20 '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-(CI-Cio)alkyl-S- group, wherein aryl and (CI-C1o)alkyl groups are as defined above. Exemplary aralkylthio groups include benzylthio, and 2-phenethylthio. 25 'Aryloxyalkyl' is aryl-O-(C-C 10 )alkyl, where aryl and (C-C 1 o)alkyl groups are as defined above. Exemplary aryloxyalkyl groups include phenoxymethyl, phenoxyethyl, and phenoxypropyl. 'Aralkoxyalkyl' is aryl-(C-Cio)alkyl-O--(C-CIo)alkyl, where (C-CIo)alkyl and aryl groups are as defined above. Exemplary aralkoxyalkyl groups include benzyloxymethyl, 30 benzyloxyethyl, and benzyloxypropyl. 'Fused heteroarylcycloalkyl' is fused heteroaryl and cyclo(C 3
-C
6 )alkyl, wherein heteroaryl and cyclo(C 3
-C
6 )alkyl groups are as defined herein. Exemplary fused 30 WO 2005/042712 PCT/US2004/035939 heteroarylcycloalkyl groups include 5,6,7,8-tetrahydroquinolinyl, and 5,6,7,8 tetrahydroisoquinolyl. 'Fused heteroarylcycloalkenyl' is fused heteroaryl and cyclo(C 3
-C
6 )alkenyl, wherein heteroaryl and cyclo(C 3
-C
6 )alkenyl groups are as defined herein. Exemplary fused 5 heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6 dihydroquinoxalinyl. 'Fused heteroaryiheterocyclenyl' 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 10 dihydro[2,7]naphthyridinyl. 'Carboxylic acid or its derivatives' may be amides or esters. Exemplary carboxylic acid groups include CONTH 2 , CONHMe, CONMe 2 , CONHEt, CONEt 2 , CONHPh, COOCH 3 ,
COOC
2
H
5 or COOC 3
H
7 . 'Sulfonic acid or its derivatives' may be amides or esters. Exemplary sulfonic acid 15 groups include SO 2
NH
2 , SO 2 NHMe, SO 2 NMe 2 , SO 2
NHCF
3 , COOCH 3 , COOC 2
H
5 , or C00C 3
H
7 . As used herein: Ra is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group; 20 Rb is an alkyl 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; R" is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl 25 group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; Rib is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an 30 alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group; R] is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl 31 WO 2005/042712 PCT/US2004/035939 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;
R
2 a is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a 5 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; Rb is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a 10 heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group; R2 is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfmyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, 15 an aralkylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof;
R
3 a is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an 20 alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group;
R
3 b is an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, or a heteroarylcarbonyl group; 25 R is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl 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; 30 R 4 a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy 32 WO 2005/042712 PCT/US2004/035939 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 5 group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralcyl group, a heteroaryloxy group, or a heteroaralkoxy group; R' is an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, or an aralkylsulfinyl 10 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;
R
5 a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally 15 substituted amino group; Rb is an alkyl 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; Ra is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted 20 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 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 25 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 nitro group, an amino group, a mono- or di- substituted 30 amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; 33 WO 2005/042712 PCT/US2004/035939 R"b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; 5 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
9 ' is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) 10 group, or a thio(S=) group;
R
9 ' is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; 15 R 9 ' 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 nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted 20 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;
R
1 0 ' is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) 25 group, or a thio(S=) group; R'Ob is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; 30 R1OC 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 34 WO 2005/042712 PCT/US2004/035939 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 5 alkoxy group, or an aryl group. RIa is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; R ii is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a 10 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; R" is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an 15 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 20 alkoxy group, or an aryl group; R1 2 a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; R12b is an allcyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a 25 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; R 12 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an 30 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 35 WO 2005/042712 PCT/US2004/035939 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;
R
13 a is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted 5 amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; R13b is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a 10 heterocyclyl group, an aralkyl group; R 13 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 nitro group, an amino group, an alkyloxy group, or any 15 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; R14, is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted 20 amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; R 14 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 25 heterocyclyl group, an aralkyl group; R 14 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any 30 combination thereof, and wherein the heterocycle group is optionally a substituted morpholinyl group, a thiomorpholinyl group, or a piperzinyl group, wherein the substituent 36 WO 2005/042712 PCT/US2004/035939 on the heterocyclyl group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group;
R
20 ' is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) 5 group, or a thio(S=) group; R20s is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; 10 R20c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted 15 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; R la is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) 20 group, or a thio(S=) group; R21I is an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; 25 R1 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 nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted 30 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. 37 WO 2005/042712 PCT/US2004/035939 G' is -(CH 2 )s-, where s is an integer from 0-5; G' is -(CH 2
),-CH=CH-(CH
2 ),-, where s is an integer from 0-5; G' is -(CH 2 )s-C=C-(CH 2 ),-, where s is an integer from 0-5; Za is 0; Zb is NR; Z' is (CH 2 )u or S(=O)n, where u is an integer from 0-2; 5 Ea is 0; E 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; v4 is 4-5; wa is 0; wb is 1; w" is 2; Xa is 0; Xb is S; and Xc is -NR. 10 According to another aspect of the present invention, various compounds of general formula (I) having general formula (II) Y1 R 2 A E R 4 F NR D. Y-G=Z-Ar 2 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 (1) having general formula (III) -NR \ E R 4 0 R2+ V R 0-G-Z O O R" its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, 20 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 cycloalkyl group, an 38 WO 2005/042712 PCT/US2004/035939 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 5 arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group. In one aspect of the present invention, R', R2, R, and R 5 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 0 or -NR, where R is as defined above; G is -(CH2)- or -(CH2)-CH=CH-(CH2)s-; s is an integer from 1-3; and R' and R" 10 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 15 encompassed by this invention, as provided below. 2 R 1 2r NR R O-G-Z R (2) R 2 ZNR O R2 o-G-Z O OG-Z R() RS ( ); R2 O-G-ZNR RO-ZO
R
3 R0 NR R R4 R'R 5 N " ('); 0 (); E R 4 R' I - E 1 S_ NR0 ~I - 0 R
R
3 03 0 R 5 N 02 (7); 0 (); R' 0 ' 43R WO 2005/042712 PCT/US2004/035939 R_ -I- q R2 0 RO G Z O0 O-G-Z O R" R' N R
N
2 ~ R NR o (9); 0 (10); E R 4 R' E R 4 R O-G-ZO o G-Z NR RR0RR"NR o (11); 0 (12); E R 4 R R O-G-Z 0 R2 0 T R" NR and 0 (13); where all symbols are as defined above in connection with formula (I). Thus, by way of 5 example, and not by way of limitation, the present invention contemplates the following exemplary compounds:
R
4 R'. S R 4 R R O-G-Z R Ro O-G-Z 03S 0 1NR oNR ' NR o (14); 0 (15); R R R 4 O N R 4 R-~ E R (16); 0 (17); R ~~5 (CH2s-C==CH(CH)s R2 0-(CH 2
)-CC-(CH
2 )s-Z 0 0 N, R" 5R" R 5 R 10 0 (19); 40 WO 2005/042712 PCT/US2004/035939 R G- R R 0 (20); O (21); RRt MeO O R 4 RMeOw E R O-G-Z- O 0 MeOeGN II I MeQ OR'eO R' IO O-G-Z O O-G-Z so 0~e 0 RN 0 (28); 0 (27); MMe O Oe M e O 0 R 4 M e M e R " 0 O-G-ZS P. -G -- \ eOMe0 o (28); and 0 (2); NR' 10where all symbols are as defined above in connection with formula (I). Accordin o furher eapeto the present invention, conempate RvRandiou comuds avin thfollonggeerlfomua 4Me MeOq N.
0 R N. O~e0 0m (30) 10 ~ ~ ~ ~ ~ R whrrl ybl r sdfndaov ncneto ihfrua() Accordi0 to6) va0u aset(fte2rsn7nenin),;, . n Eo oml (30 ar seectd t prde vroscmonso oml3-)truhfrua(023 as O follows:Me O R 41O~ WO 2005/042712 PCT/US2004/035939 Formula R RR E 30-1 R" Rsa R'" R"la Ea 30-2 R, R 5 a Ra R"a Ea 30-3 Rc Rsa R'a Rita Ea 30-4 Ra R 5 b Ria Rta Ea 30-5 Rb Rlb R'a R t a Ea 30-6 Rc R5 R t a Ry t a Ea 30-7 Ra R 5 c R'a Rta Ea 30-8 Rb RC Rta Rita Ea 30-9 Rc R 5 C Ra Rta Ea 30-10 Ra Rsa R'b Ria Ea 30-11 Rb R 5 a R'" R"a Ea 30-12 Rc R 5 a Rib R
T
a Ea 30-13 Ra R 5 b Rib Ra Ea 30-14 R R 5 b R'b Ria E" 30-15 Rc Rb Rb Ra Ea 30-16 Re R5c Rb Ria Ea 30-17 Rb R5c Rb Rya Ea 30-18 Rc R 5 C Rib Rlya Ea 30-19 Ra Ra R'c Ria Ea 30-20 Rb R 5 a R'c Rita Ea 30-21 RC Ra R'c Rita Ea 30-22 Ra Rab R'c Rvia Ea 30-23 Rb R 5 b R'c Riia Ea 30-24 RC R5b R'c Rla Ea . 30-25 R R 5 c R'' Ra Ea 30-26 R R 5 c R'C Ra Ea 30-27 Rc R 5 c R'c Rita Ea 30-28 Ra Ra R a Rb Ea 30-29 R Rsa Ra R"b Ea 30-30 Rc R 5 . R'a R"b Ea 30-31 Ra Rab Ria Rb Ea 30-32 Rb Rib Ra R"b Ea 30-33 Rc R 5 T Ra Rth Ea 30-34 Ra R 5 C Ria R"b Ea 30-35 Rb R 5 c Ra R"b Ea 30-36 R' Rc R'a Rh Ea 30-37 Ra R 5 a Rb R"b Ea 30-38 Rb Re Rib Rh Ea 30-39 Re Ra Rib Rut Ea 30-40 Ra Rb Rb R"b Ea 30-41 Rb R 5 b Rb R"b Ea 30-42 Re Rib Rb RuT Ea 30-43 Re Rc Ri R" Ea 30-44 R RWC Rb Rb Ea 30-45 Re R'C Rb R"b Ea 42 WO 2005/042712 PCT/US2004/035939 30-46 Ra Rsa Rc Rub Ea 30-47 R Rsa R' R"b Ea 30-48 Re Rsa RC Rb Ea 30-49 R R5b R'e R"b Ea 30-50 R Rb R'e Rb Ea 30-51 Re Rib Rtc Rb Ea 30-52 Ra Rc R'e R"b Ea 30-53 Rb R 5 c Rc Rub Ea 30-54 Re R 5 c R'C Rb Ea 30-55 Ra R 5 a Ra RIC Ea 30-56 Rb Rsa Ria Ric Ea 30-57 Rc R 5 a R a R" Ea 30-58 Ra Rsb Ra Re Ea 30-59 R Rsb Ra R"yC Ea 30-60 Re Rib Ra Rl' Ea 30-61 Ra R 5 R'a R' Ea 30-62 R R 5 c R'a R"e Ea 30-63 Re Rsc Ra RvIc Ea 30-64 Ra R 5 R'b Rle Ea 30-65 Rb R 5 a R'b Rl Ea 30-66 Re R 5 a Rib Ri' Ea 30-67 Ra Rib Rb R"e Ea 30-68 R Rb Rib R" Ea 30-69 Re R 5 b Rb Re Ea 30-70 Ra Re Rib R"e Ea 30-71 R Rsc Rb Rie Ea 30-72 Re Rs' Rb R" Ea 30-73 Ra Ria R'' Ri' Ea 30-74 Rb R 5 a R'e R" Ea 30-75 Re Rsa R'e Rl Ea 30-76 Ra Rib Rc R"c Ea 30-77 Rb R 5 b Re R' Ea 30-78 Re Rb Re Re Ea 30-79 Ra Rse Re Re Ea 30-80 Rb R' Re R" Ea 30-81 Re R 5 . R'e Re E 30-82 R R 5 Ra Ria Eb 30-83 R R 5 a Ra Rta Eb 30-84 Re Rsa R'a Rfua Eb 30-85 Ra R5b Ria Rla Eb 30-86 Rb R 5 b Ra Rla E b 30-87 Re R 5 b R'a R"a E b 30-88 Ra Re Rla R"a Eb 30-89 R R R'a R"a Eb 30-90 Re Rse Ra Rula Eb 30-91 Ra R 5 a Rb Ria E 30-92 Rb Rsa Rb Rula Eb 43 WO 2005/042712 PCT/US2004/035939 30-93 Re Rsa R'" Ria Eb 30-94 Ra Rb Rib Ria Eb 30-95 Rb R5b Rib Ra Eb 30-96 R' Rab R'b Rla Eb 30-97 R R Rb Rita E 30-98 Rb R R" Ria Eb 30-99 Re Rsc Rb R t a Eb 30-100 Ra Rsa Rie Rita Eb 30-101 Rb R5a R' Ra Eb 30-102 Re R 5 a RI R"a Eb 30-103 Ra Rib R'' R"a Eb 30-104 Rb REb R'e R"a Eb 30-105 Re Rib Ri" Rla Eb 30-106 Ra R5c R'e Riia Eb 30-107 R Rc R'C R t a Eb 30-108 Re R 5 R'e R"a Eb 30-109 Ra Rsa Ra R"b Eb 30-110 R Rsa Ra R"b Eb 30-111 Re Rsa R"b Eb 30-112 Ra Rib R'a R"b Eb 30-113 R Rab R'a R"b Eb 30-114 Re Rab R'a Rib Eb 30-115 Ra Rc R'a R"b Eb 30-116 Rb Re R'a Rub Eb 30-117 Re R Ra R"b Eb 30-118 Ra Rsa Rb R"b Eb 30-119 R Ra Rb R"b Eb 30-120 Re R 5 a Rib R"b Eb 30-121 Ra R5b Rb Rib Eb 30-122 Rb R5b Rib R''b Eb 30-123 Re R5b Rb R"b Eb 30-124 Ra R5c Rib Rib Eb 30-125 Rb Rc Rb R'b Eb 30-126 Re Rc Rb Rib Eb 30-127 Ra R 5 a R Rib Eb 30-128 R R R'e R"b Eb 30-129 Re R 5 R'' Rib Eb 30-130 Ra RSb RIc R"b Eb 30-131 R Rab Rc R"b Eb 30-132 Re R5b Rc Rib Eb 30-133 Ra R Re R'ib Eb 30-134 Rb Ri' Re R''b Eb 30-135 Re R 5 Re Rib Eb 30-136 Ra Rsa R'a R"e Eb 30-137 R Rsa Ra R"c Eb 30-138 Re Ri5 R'a R'e' Eb 30-139 Ra Rib Ra Rle Eb 44 WO 2005/042712 PCT/US2004/035939 30-140 Rb Ra Ra Re Eb 30-141 Re R Rb R"c Eb 30-142 Ra R' R'a R"e Eb 30-143 Rb R 5 R'a R"e Eb 30-144 Re Rsc Ra Rlc Eb 30-145 Ra R 5 a R'b R"e Eb 30-146 Rb R 5 a Rib R" Eb 30-147 RR Ra R' lR ER 30-148 Ra REb Rb R"e Eb 30-149 Rb R5b Rib Rle Eb 30-150 Re R3b Rb Rble Eb 30-151 Ra RSc Rb R''e Eb 30-152 Rb R R'b R" Eb 30-153 Re R5c R'b R"e E 30-154 Ra Rsa R' R"e Eb 30-155 Rb Rsa R' Rile Eb 30-156 Re RSa Rc R"e Eb 30-157 R" R5b R'e R" Eb 30-158 Rb R5b Rc Rl 30-158 R R R'e R"e Eb 30-159 Re R 5 Ric R" Eb 30-160 Ra Ra R' R" 0 Eb 30-161 Rb Ra R'' R" 0 Eb 30-162 Re Ra R'e Rie Eb 30-163 Ra Rsa R'a RIa Ec 30-164 Rb RSa Ria Rlia E' 30-165 Re R 5 R'a R"a Ee 30-166 Ra Rsb R'a Rfia Ee 30-167 Rb Rsb R'a Rfta EC 30-168 Re Rb R'" R 1 a E' 30-169 Ra Rs R'a Rria E 30-170 Rb RC R'a Rla E' 30-171 Re RS' R'a R"a Ee 30-172 Ra Rsa Rib Rlva Ee 30-176 b R.5ba l la B 30-173 Re Rsa Rb R"a Ec 30-174 Re Rs Rib R"a E' 30-175 Ra R'c R'b R"a Ec 30-176 Rb R5- Rb Rl 1 a Ec 30-177 Re R.b Rib R"a E' 30-178 Ra Rie Rib R"a Ec 30-179 Rb R5e R' Ra E 30-180 Re Rsc R'b R 1 a FE 30-181 Ra Rsa Rue Ria E 30-182 Rb Rsa Rue R 1 ~a E 30-183 R Rsa Rc Rila Ec 30-184 Ra Rib Rc Ria E' 30-185 Rb R3b Re R'la Ec 30-186 Re REb Re Rlta Ec 45 WO 2005/042712 PCT/US2004/035939 30-187 Ra R R' Rita E 30-188 Rb R R'C Rla E 30-189 Rc Rsc R'C Rta Ec 30-190 Ra R5a R'a R"b EC 30-191 Rb Rsa R'a Rib Ec 30-192 RC R 5 a Ria R"b EC 30-193 Ra REb R'a R"b Ec 30-194 R Rlb R'a Rub EC 30-195 RC REb R'a R"b EC 30-196 Ra R5c R'a R"b EC 30-197 Rb Rsc R'a R"b EC 30-198 R' R 5 c R'a Rib Ec 30-199 Ra Rsa R'b R"b EC 30-200 Re Rsa Rb R"b EC 30-201 R' Rsa Rib Rib Ec 30-202 Ra R 5 b Rib R"b Ec 30-203 Rb Rib Rib R"b EC 30-204 Rc Rib Rb R"b Ec 30-205 Ra Rsc Rb Rib Ec 30-206 Ra Rsc R'b Rib EC 30-207 Re Ra R'b R"b Ec 30-208 Re Ra R'e Rib Ec 30-209 Ra Rsa R'' R"b EC 30-210 Rc R 5 a R'c Rub EC 30-211 Ra Rib R'c R"b EC 30-212 Ra Rib R' R"b EC 30-213 R' Rib R'" R"b EC 30-214 Ra R5c R'c Rib EC 30-215 Rb R' R'a R"b EC 30-216 RC Ra' R'C R"b EC 30-217 Ra R 5 a R'a Riic E' 30-218 Rb Rsa Ria RiC EC 30-219 Rc R a R'a R" EC 30-220 Ra Rb R'a R"ic EC 30-221 Rb R5 R'a R"' Ec 30-222 R Rb R a R"C EC 30-223 Ra R 5 . R'a Rc EC 30-224 Ra Ric Ra R c EC 30-225 Re Rsc R'a R"' EC 30-226 Ra Rsa Rib R"" EC 30-227 R Rsa Rib Ri"" EC 30-228 Re R 5 " Rib Ri"e B' 30-229 Ra Rib Rib R"e E 30-230 Rb Rb Rb Re Ec 30-231 Rc Rib Rib R"e E' 30-232 Ra R5C Rb Ri' EC 30-233 Rb Rsc R'b Re Ec 46 WO 2005/042712 PCT/US2004/035939 30-234 Re R'C Rb Rle E 30-235 Ra R'e R" E 30-236 Rb R 5 a R'' Re E 30-237 Re R 5 R'e R"le E 30-238 Ra Rb R'e R"e E 30-239 Rb Rib RG Rie Ee 30-240 Re Rb R'e R* Ee 30-241 Ra se R'e Ri"" E' 30-242 R R R'' Ri"' E' 30-243 Re R' Re Rile 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 nitro group, or an optionally substituted amino group; R5 is hydrogen, a 5 hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R' and R" independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, or a benzyloxy group; and E is 0, S, or NH. 10 In another aspect of formula (30) of the present invention, R is hydrogen, an alkyl group, potassium, or sodium; R5 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 0, S, or NH; R' and R? independently are -H, -Cl, -Br, or -CH 3 ; R5 is -H, -CH 3 , or -CH 2
CH
2
CH
3 ; and R is -H, K, or 15 Na. Examples of compounds of formula (30) include, but are not limited to: OMe OMe OMe OMe MeO 0 MeO 0 O H 0 0 N OMe O / NH OMe O / NH oMe NH OMe NH MeO O OMe M OMe 0O o 0KM e 0~- NH o' e0 OMeO . OMe N 47 WO 2005/042712 PCT/US2004/035939 OMe OMe MeO O 0Me OMe MWO O 0 Oe O M MeNH O 0 NH MeOeOMe oM Me O O 0 ~ 0 OON H OMeOe Om 0 O-I S ee 0 O OH ;0 MeON 0 e NOMe MeO O OMe 0 Me OMe 0 OS O O S-- eO I .NH O~e 0 c0 0H 0 O O OMe OMe 0 ~ N MeO 0 W 0 and O . 5 The present invention also contemplates various compounds of general formula (III) having the formula: N E R R2/D R NH 0 Me O (31 where all symbols are as defined above in connection with formula (I). According to various aspects of the present invention, R', R2, R , E, R', and R" of 10 fo nula (31) are selected to produce various compounds of formula (31-1) to (31-729) as follows: Formula R R E R' R" 31-1 Rila Rt2a RWa ESa R'a R' a 31-2 Ri Rb a R a E a R ra Rta 31-3 RNc Ra R 4. E a R'ta R"a 31-4 Rl" R"b Raa Ea R'a R"a 31-5 RIb Rzb RW. Ea RMa R"a 31-6 R, b RE4a ERa Rana R"a 31-7 R ]a Re Ra. E a R a Rvia 48 WO 2005/042712 PCT/US2004/035939 31-8 RIb R 2 e Ra a R'a Ria 31-9 Rc R 2 e Ra E a R'a Ra 31-10 RIa R2a 4b Ea R a Rla 31-11 Rib R~a R4b Ea R'a Rva 31-12 Rc R~a R4O Ea Ra R"a 31-13 R ] R2b R 4 Ea R'a R"a 31-14 b I R R 4 b Ea R'a Rla 31-15 RI' R2b R4b Ea R a Rla 31-16 R]a R R Ea R'a Ra 31-17 RIb R 2 c R4b Ea R'a Rita 31-18 Rl' R~e R4b Ea R'a Rla 31-19 RIa 2a Ra E a R'a Ra 31-20 R l R~a Rc Ea R'a R 1 a 31-21 Rl" R~a R 4" E a R ta Rlia 31-22 R2ca R b R4 Ea R'a R"a 31-23 R Rlb R4 Ea R' Ra 31-24 RIc R 2 b R c Ea R'a R"a 31-25 R ia R2a R c Ea Ra Rla 31-26 R l R2e R 4 C Ea Ria Rva 31-27 Rlc R~e R4" Ea R'a R t a 31-28 RI" R2a R4a Eb R'a Ra 31-29 R l R~a R4a Ea R'a Rva 31-30 Rl R R" E R'a R t a 31-31 R R 2 b R 4 a R a R a 31-32 RIC R 2 b R 4 a Ea R a Rta 31-33 Ric R2b R4a Eb R'a Ra 31-34 Rla Re Ra Ea Ra RUa 31-35 Rlb R2c R4a e Ria R"a 31-36 Rl R~c R4a Eb R t a Ra 31-37 R R a R Ea R"a 31-38 RIa R 2 a R 4 a Eb R'a R"a 31-39 RO R 2 a R 4 Eb R'a Rla 31-40 RIa R2b 4b e R'a R"" 31-41 Rib Rb R4b Eb R'a Ra 31-42 R R2b R4 E R'a Ra 31-43 R]a R2c R4 Eb Ra R"a 31-44 RIb R 2 e Rb 4 Eb R'a R"a 31-45 RTh R2c R4 Eh R'a R"a 31-46 Rla Ra R E Ra R"a 31-47 R Ra R4 Eb R'a Ra 31-48 R R R4 Eb R'a Rla 31-49 Rl Rb R4. Eh R'a R4aa 31-50 R l R2b R Eb R"a 31-51 Rc R 2 R4" Eb R'" Rla 31-52 Rla R 2 c R4c E Ra R"a 31-53 R lb R 2 c Rb Eb R a Rita 31-53 Rlc Rc Rc Eb R'a Rila 31-54 RI R 2 e Ri" Eb R'" Ria 31-43 R~' R 2 C 4 b R~ Rt WO 2005/042712 PCT/US2004/035939 31-55 RIa R2a R4a E R'a Rva 31-56 R l R Ra EC R'a Rita 31-57 Rl R2a R4a E' R'a Ra 31-58 Ria R2b Ra Ec Ria R"a 31-59 Rlb R2b R4 EC R'a Ria 31-60 Ric R 2 b Ra E Ra R1a 31-61 Rla R e R4a E R'a Ria 31-62 R R Ra EC Ra Rita 31-63 R R2b R4a E' R'a Rla 31-64 Rl" R2a R4b EC R'a Ria 31-65 Ri R2a R4a E R'a Ria 31-66 Ric Ra R EC Raa 31-67 Ria R2b R4b EC R'a Rla 31-68 R l R 2 b R BC R' Ra 31-69 Rc R R 4 b Ec R'a R"a 31-70 Rla R R 4 b Ec R'a Rta 31-71 R lb R 2e R4O Ec R a Rvia 31-72 RIC R2c R 4 b EC R'a Rita 31-73 RIa 2a Re Eb R'a R4a 31-74 R l R2a R EC Ria Ra 31-75 Rl" RWa R' E' Rla Rvia 31-76 Ria R 2b R4' Eb Rla Rla 31-77 R Rb R4c EC Ria Rita 31-78 RIC R 2 b R EC Ra Rla 31-79 Ria R 2 e R4c EC Rta R 1 a 31-80 R2c R2e R4c Ec Rla R"a 31-81 RI' R e R4c EC Ra R"" 31-82 Ria Ra Ra Ea R Rla 31-83 R Rza R4a Ea R' Rva 31-84 Rlc R ~a R4a Ea R'a R"a 31-85 Ria R2b R EC Rta 31-86 R l R2b R4a Ea R'b R 1 a 31-87 RI' R 2 b R 4 a Ea R' R"a 31-88 Rla R 2 ' R4a Ea R'a Rta 31-89 R lb R2' R 4a Ea R' Rb Wa 31-90 RIC R 2 e R 4 " Ba Ri Ria 31-91 RIa R2a R4 EC a R'i R"" 31-92 Ri R2. R4 EBa R'v Ria 31-93 Rlc R2a R 4 EBa R'a R"a 31-94 Ria R2b R4b Ea R' Rb W 31-95 R lb R2b Re Ea R'ib R"" 31-96 Rl' R2b R4C Ea R'i Rla 31-97 Rla R2' R E R' Rlta 31-98 Rb Re R4e Ea R' Rya 31-99 Rc R ~ R4 Ea R'b Ra 31-100 R]a Ra R4' Ea Rb Rlta 31-101 R l R ~ R' Ea Rb R"" 50 WO 2005/042712 PCT/US2004/035939 31-102 Ric R2. R4c Ea Rib Rita 31-103 RIa R 2 b R 4 c Ea Rib Rita 3114 Rlb R2b R4c Ea RIb it 31-104 Rlc R2b R4" Ea Rib Rla 31-105 RIC R2c R4 Ea Rib R"t 31-106 Rlb R 2 c R 4 c Ea Rib Ria 31-107 RIb R 2 c R 4 c E Rib R~ 31-108 R0 R 2 c R 4 C Ea Rib Ria 31-109 RIa R2a 4a Eb R'b Ria 31-110 RI Rb a Rea Eb R'b R"a 31-111 Rc R Ra E Rib Rita 31-112 RIa R 2 b R 4 a Eb Rib Ria 31-113 RIo R2b R 4 a Eb Rib Rita 31-114 R 1 c R2b R 4 a Eb Rb Rla 3115 Rlb 2b 4a Eb Rb Rt 31-113 Ria R Ra Eb Rib Rla 3117 Ic R2b 4a Eb R b lt 31-114 R l R~c R4a Eb Rib R'a 31-1 I 2c R4a Eb R'b Ria 31-118 Rla R2a R4b Eb R'b Rfa lb10 i R2a R4a Eb R" 31-121 Ria R2b Rob Eb Rib Rva 31-122 R R2c R4W Ea R' Ria 31-123 R l R R Eb Rib Ra 31-124 Ria R 2 c R 4 b Eb Rb Ria 31-125 Rlb R2 R4b Eb R'f Ria 31-126 Ric R2c R Eb Rib Rita 31-127 RIa R2a R4C E R' Ra 31-128 Rlc R~a RWc Eb R'b Rlia 31-120 R " R2a R4c Eb Rb R"a 31-13 Ia R2b R4 Eb R' R"a 31-131 Rlc R ~ R4' Eb Rb Rita lb12 I R2b R4 Eb R" ~ 31-133 Ria R ~c Rc Eb Rib Ra 31-134 Rb R~e R4 Eb R' Ra 31-135 RI" R R" Eb Rib Ria 31-136 Rla R 2 a R 4 a Eb Rib R"a 31-137 Rl R ~ R4a E' Rib Rila 31-138 Rl' Ra Ra Ec Ri Ria 31-139 RIa R2b R4a Ec R' Ria 31-140 R l R2b Ra Ec Rib Rita 31-141 Rl* Rb Ra E Rb Riia 31-142 Rla R2c R4a Eb R' Rva 31-143 R l R2" Ra E' Rib R'a 31-144 R3" R R 4 a Eb Rib Rfa 31-145 Rla R 2 a Rb Eb Rb R"a 3 1-132 RIo R 2 a R 4 C Eb Rib Riia 31-147 Rla R 2 a R 4 C Eb Rb Rita 3 1-145 Rlc Re R 4 C Eb R ib Rita 31-148 RIa R 2 b R 4 O E Rib Rita 51 WO 2005/042712 PCT/US2004/035939 31-149 R b R 2 b R 4 b Ec Rib Rla 31-150 R*c R2b 4b Ec Rtb Rla 31-151 R la R~c Rb Ec R'b Rlya 31-152 R b R ~ Rb E' Rib R"a 31-153
R
1 R Rc R Rib Rla 31-154 R la R2. RWc Ec R' R',a 31-155 R b R2a R4 Eb R'? Rva 31-156 R R4' ER R'b Ria 31-157 R la R2 R 4 Ec R' Ra 31-158 R R2b R 4 Ec Rib Ria 31-159 Rlc R2b R4" Ec R'b Rtia 31-160 RIa R2c R4c E Rib Rila 31-161 R 4 Rc Re Ec R'b Ra 31-162 R Rc R E Rb Ria 31-163 R ]a R2a R4a E" R'" Ra 31-164 R R Ra Ea Rb Riia 31-165 Rlc R 2 a R 4 a Ea Rba 31-166 R ]a R~b RWa Ea R'c Rlva 31-167 R lb R2b RWa E a R'c Rlia 31-168 Rib R 2 b R 4 a Ea Rb Rla 31-169 R a R 2 b R 4 a Ea Rib Riia 31-170 R b R 2 e R 4 a Ea R' Riia 31-171 R ' R Ra Ea Rb Riia 31-172 R a R2a R Ea Rc Rlia 31-173 R a R2a R4 Ea R'c Ra 31-174 R R R4 Ea R'c Ra 31-175 R ba Rb R 4 Ea R' R a 31-176 RIl R 2 b R 4 Ea R'" Riia 31-177 Ra R 2 b R 4 EBa Ro Ria 31-178 R la R 2e R 4b Ea R'c R"a 31-179 R R R4 Ea R'c Ria 31-180 R Rc R4 Ea Rc Ria 31-181 R a R2a R4c Ea R' Rla 31-182 R R2a R4c Ea R'" Ria 31-183 Rl R 2 a R 4 ' Ea Ro Ria 31-184 R la REb R 4' E a R'' R"a 31-185 R lb REb R4 E a R'c R la 31-186 RO R 2 C R4c Ea R'c Ria 31-187 R a R 2 e R 4 c Ea Ro Ria 31-188 Rib R 2 . R 4 v Ea R' Ra 31-189 R R R 4 Ea R'c Riia 31-190 R a R2a R 4 a Bt Rc Ria 31-191 R l R2a R4a Eb R'" Ra 31-192 Rle R2a Rja EB Ro Rla 31-193 R a R 2 b R 4 a Eb Rc Riia 31-194 R l R2b R4a Eb Rc Rlia 31-195 Rl* R2b R4a Eb R'" Ria 52 WO 2005/042712 PCT/US2004/035939 3116 a We 4a RIbW 31-196 Ria R ~c R E R'C Rta 311b I R2c R4a Eb R ~ 31-198 Rc Re R E R'C R t a 31-199 RIa R 2 a R 4 b Eb RIC Rla 31-200 RIb R 2 a R 4 Eb Ric Ra 31-201 R Ra R4b E' R' Ra 31-202 Ria R2b Rb E RIC Ra 31-203 R2ab Rb Rb e R' R"" 31-204 R' Rb R4b e R Rta 31-205 Ria R 2 b R 4 b Eb RIC Rita 31-206 Rb R2c R4 e R'" R4ba 31-207 R' Re R4 e RIC Ra 31-208 Ri]a R~a RA 4C e R'C R"a 31-209 R4b R~a Re e R' Ra 31-210 R' R R E RIC Ra 31-11 R a 2c b be e RI ~ 31-211 RI" R? R4c E RIC Rta 31-lb3 R c 4b , b RC Rl 31-212 R] Rz2 R4c E RIC Rita 31-213 RIC R 2 C Rb Eb RIC Rita 31-214 RIa R2a R4c Eb R' R"a 31-215 Rla Re R' EC Ri' Ra 31-216 R' R~c R E RIC Rita 31-210 RIC R 2 a 4" E' Ric R"p 31-218 R Ia Rb Ra Ec R'c Ra 31-211 R l R-a Ra Ec RIC Rla 31-220 Ria RWb Ra Ec R'G Rvia 31-221 RIb R 2 b R 4 a Eb R'* Ria 31-222 RIC R 2 b R 4 a Ec RIC R"a 31-223 RIa R4 Ra Eb R'G Rva 31-224 R R2' R4a Ec R Rita 31-225 R' R2a R4" E R Ra 31-226 RIC R 2 a R 4 Eb Ric Rla 31-227 Rib R 2 a R 4 b EC Ri Ra 31-218 Rl R2a Rb EC RIC Ria 31-219 Ric R 2 a R 4 b EC Ri Ria 31-230 RIa R2b R 4 EC Ric Rita 31-231 Rl Rl2b R4b E' R Rla 31-232 RI R2C R4 Ec R Rita 31-233 RIC R 2 b R 4 a E R R"a 31-234 R l R 2 C R 4 Ec R' R t a 31-235 RIb R 2 a R EC RIC R"a 31-236 RIC R 2 a R 4 Ec Ric Rta 3 1-237 RI' R 2 a R 4 b EC R' R 0 31-227 Rlb R 2 a R 4 b EC R' 0 Rita 31-239 RIC R 2 b R 4 EC R Rta 31-240 Ric R2b Rb Ec RIC Rla 31-241 RIa R 2 b Rb B R Ra 31-242 RIb R 2 c R 4 c EC R Ra 53 WO 2005/042712 PCT/US2004/035939 31-243 Ric R 2 c R 4 c Ec RIc Ria 31-244 RIa R2a R4a Ea Ra R" 31-245 R l Ra Ra Ea R'a Rib 31-246 R Ra R4a Ea R'a R" 31-247 Rla R2b Ra Ea R'a Rub 31-248 RI a E a R'a R" 31-249 Rlc R~b RWa Ea R'" R"ib 31-250 R]a Rc R 4 a E a R'a R"b 31-251 Rib R 2 c R4a Ea R'a R"b 31-252 RIC R 2 e R 4 a Ea R'a R"b 31-253 Ria R R Ea R'a Rib 31-254 Rlb R2a R4 Ea R" Rib 31-255 R Ra Ra b Ea R'a Rib 31-256 Rla Rb R4b E a R'a R' 31-257 R Rb R4 Ea R'a R"b 31-258 R R2b R4b Ea R'a R"b 31-259 R2a R2e R Ea Ra Rlb 31-260 R l R2e R4b Ea R'a R"b 31-261 Rlc 2b Re W Ea R'a R" 31-262 Ria Ra R" Ea R'a Rub 31-263 R l R2a R4e E" R'a R"b 31-264 RIc R 2 a R 4 ' Ea R'a Rib 31-265 RIa Rb2b R4 Ea R'a R" 31-266 Rl R 2 b R Ea R'a R"b 31-267 RIb R2b R 4 " Ea R'a R"b 31-268 Rla R2c R4c Ea R'a R" 31-269 R l R2c R' Ea R'a Rib 31-270 Rl" R2" RW" E a R'" Rv 31-271 R]a R2a R4a E b R'" R" 31-272 Rib R ~a Ra Eb R'a R"b 31-273 Rlb R2a R4a Eb Ra Rib 31-274 Rla R2b Ra Eb R'a R"b 31-275 Rl R2b Ra Eb R'a R"b 31-276 RcI R2b R4a E R'a Rtv 31-277 Rla Re Ra E R'a Rub 31-278 Rb R c R4a Eb R'a R" 31-279 Rlc R~c R 4a E b R'a R"tb 31-280 R Ra R B R'a R"b 31-281 R lb R~a R 4b E b R a R"t 31-282 Rl* R ~a R Ea Ria R"b 31-283 RIa R2b R4b E b Ra R" 31-284 R l R2b R Ba Ria R"b 31 -2b85 R' Rb R4c Eb R'a R" 31-286 Ria Rc R4 Eb Ra R"b 31-287 R l R~e R4b Et R'a Rib 31-288 RI' Re RO Eb Ra R"b 31-289 RI R2a R Eb R'a R"b 54 WO 2005/042712 PCT/US2004/035939 31-290 R Ra R 4 c Eb Ra Rub 31-291 RR R EW R'a Rub 31-292 RI a R2b R Eb Rta R 31-293 R Rlb R4' E R'a R"b 31-294 RIc R 2 b R 4 c Eb R'a Rib 31-295 R I a R~c R 4c Eh R'a R"b 31-296 Rib R2c R 4 'C Eb R'a Rib 31-297 RIc R R 4 c Eb Ra Rib 31-298 Ria R 2 a R4a Eb R'a Rib 31-299 RIb R 2 a R4a Eb Ra Rib 31-300 RIc R 2 a R 4 a Eb R'a R"b 31-301 RIa R2 R 4 a EC R 'a Rb 31-302 Rib R 2 b R 4 a Ec R'a R'ib 31-303 R2c R b R4a E' R'a R''b 31-304 Rla R Ra Ec R'a Rib 31-305 R l R2c R4a E' R'a R" 31-306 Rlc R 2c RWa Ec R'ra R''b 31-307 Rla R ~a R4 Ec R'a Rib 31-308 Rb R a Rb E' R a R,,b 31-309 Rc Ra R EC Ra R''b 31-310 Rla R2b R4 E' R'a R' 31-311 R l R2b R4b EC Rya Rb 31-312 Rc R 2 b R 4 l Ec R'" R"b 31-313 Rl" Rwc RWb Ec R ta R"l 31-314 Rl R 2 C R 4 EC R'a R'b 31-315 RIc R 2 C R 4 EC Ria R"b 31-316 Ria R2a R4 E R'a R'' 31-317 R l R ~a R EC R'a Rib 31-318 Rl' Ra R EC R'a R'b 31-319 R a R 2 a R4c EC Rta R''b 31-320 R 1 l R 2 b RC E' Ra R'b 31-321 Rlc R 2b R 4c E' Rta R' r 31-322 Ria R~c Rw' E' R'a Rlvb 31-323 Rib R 2 e R4b EC Ra R"b 31-324 R' R R4' EC R'a R"b 31-325 Ria R2a Ra ECa R' R'' 31-326 Rl Rb a R4a E" R'a R''b 31-327 Rlc R2a RWa E a R' b Rl'' 31-328 Ria R 2b R4a E a R'b R''" 31-329 R' R2b R4a Ea R' R''b 31-330 Rlc R2b R4a Ea R' Rib 31-331 Rla R2e 4a Ea R'b R" 31-332 Rl R~e Ra Ea Ri Rib 31-333 Ric R2e R4 Eaa R' R" 31-334 Ria R ~ R4 EBa R' Rib 31-335 R l R a R 4 C E" R' R"b 31-336 RIC R2a RO Ea R'b R',b 55 WO 2005/042712 PCT/US2004/035939 31-337 R Ia R2b R4b Ea R'b R"b 31-338 Ri Rb b RWb E a R'b Ryr 31-339 RIC R2b R4 Ea Rib R"b 31-340 ba Re R4b Ea R' R" 31-341 Riz Re R Ea R'b R"b 31-342 RIc R 2 c R 4 b Ea Rib R"b 31-343 Ria R 2 a R 4 " Ea R'b R"b 31-344 R Ra R Ea Rb R"b 31-345 RIC Ra R4C Ea Rb R"b 31-346 Ria R 2
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4 a Rib R"b 3137 Rlb R2a E Rr R 31-344 RIC Rb R4 Ea Rib R"b 3 1-345 RIC R 2 b R 4 " E Rib R"b 31-349 Ria R2e R 4 c Ea Rb R"b 31-350 RIa b e R 2 E a Rb R"b 31-351 RIC R 2 b R 4 " Ea Rb R"b 31-352 RIa R2a R4a Ea Rb R"b 31-353 R l R2a Raa E Rb R"b 31-354 Ric R 2 a R 4 a Eb Rb R"b 31-355 Ria Reb Ra Eb Rb R"b 31-356 Rb R Ra Eb R'b R"b 31-357 RIC R 2 b Ra Eb Rb R"b ?]a b R4a bb o 31-358 R R R E Rb R"b 31-359 R Re Ra E Rb R"b 31-360 RIc R2 R4a Eb R'b R"i 31-361 RW R R4 Eb Rb R"b 31-362 R R Rb Eb Rb Rb 31-363 R R2ca Rb e R' R" 31-364 Ria R2b R4 Eb R'b R"b 31-365 RIC R 2 b R 4 b Eb Rib R"b 31-366 R]iC R2b R4b e R'ib R"v 31-367 RIa R 2 c R 4 b Eb Rb R"b 31-368 Rlb R2e R4W Eh R' Rtv 31-369 R R e R Eb Rib Rb 31-370 R2a R a R4 Eb R' R"i 31-371 Rb R2a R" Eb Rib Rub 31-372 RI R 2 a R 4 Eb Rb R"b 31-373 Ria R2b R4 e R' R"i 31-374 Ra R R4 Eb Rib R"b 31-375 RI R 2 b R 4 b Eb Rib Rub 31-376 1 R 2" Re Ee 0 b R'" R"b 31-377 iT Re R4c e R'b Ri 31-378 Ra Re R4" Eb Rb R"b 338 alb 2c W. bc R b Ri 31-38 R Ra R4a Ec Rib R"b 31-360 Ri Ra Ra Ec Rib R"b 31-382 Ria R 2 b R 4 " Ec Rib R"b 31-383 R 1 l R 2 b R 4 a Eb Rb R"b 56 WO 2005/042712 PCT/US2004/035939 31-384 RIC R 2 b R 4 . EC R'b R''b 31-385 Ra R 2 e R 4 a EC R'b R''b 31-386 Rlb R Ra Ec R'b R''l 31-387 RR2c R4aR' R'b 31-388 Rl Ra Rb EC R'b R''b 31-389 RIb R 2 a Rb EC R'b R''b 31-390 R R2a R4b E R'b R"v 31-391 Rl R2b R4 Ec R'b R''b 31-392 RiG R 2 R4b Ec Rb R''b 31-393 Re R2 R4b E R' R'' 31-394 RIa Re Rb EC Rib R'b 31-395 R1b R~c R 4b EG R' R'' 31-396 RIb Re Rb Ec Rib R''b 31-397 RC R 2 a R 4 b EC Ri R''b 31-398 R2I Ra R4. Ec R' R''l 31-399 Rlc R ~ R4" EC Rb Rib 31-400 Ra R2b R EC Rb R''b 31-401 RIC R 2 b R4b EC Rb Rub 31-402 RI" R 2 b R 4 c EC Rb Rub 31-403 Rla R 2e Re E R'it Rli 31-404 RIb R 2 c R 4 . EC Rib Rib 31-405 RIC R 2 c R 4 EC Rb Rb 31-406 R 1 R~a R4a E a R'c R" t 31-407 R2Ib Ra R4a E a R' R 31-408 R Ra R4a Ea Rb Rb 31-409 R R2b R4a Ea R'" R 31-410 Rlb Rb Ra Ea Rb Rib 31-411 RIC Rib R 4 a Ea Rb Rub 31-412 RI R~c RWa E a R'c Rli 31-413 RIb R 2 c Ra Ea Rb Rib 31-414 Rl R 2 c R 4 a Ea Rb R'b 31-415 R Ra R Ea Rb R'b 31-416 RIa R 2 a R 4 Ea R'" Ril 31-417 Ric R2a R4 Ea Ryc Rib 31-418 RC R 2 b R4 Ea Rc Rib 31-419 R I R 2 b R 4 Ea Rc Rib 31-420 RIc R 2 b R 4 Ea R'c Rib 31-421 RI R R Ea R'" Rlb 31-422 RR2c R4 Ea R' R 31-423 RI R2c R4 Ba R' Rib 31-424 Rlb R 2 a Ra Ea R' Rib 31-425 RIb R 2 a Rc Ea R' Rib 31-426 R" R 2 a Rb Ea R'e R'lb 31-427 RIa R 2 b Re Ea R' Rib 31-428 RIb R 2 b Rb Ea R" R"b 31-429 RIb R 2 b R 4 " Ea R' R''b 31-430 R Re R4c Ea R' R''b 57 WO 2005/042712 PCT/US2004/035939 31-431 RIb R 2 c Rac Ea R' Rub 31-432 RI R 2 c Rac Ea R' R" 31-433 Ria Wa R 4 a Eb R' R"b 31-434 RIb R2a R4a E b R"b 31-435 RIo R 2 a R 4 a Eb R' R"b 31-436 Ria R 2 b R 4 a E R"b 31-437 Rib R 2 b Raa Eb R' R"b 31-438 R 2b R4" E ' R'e Rub 31-439 RIa R2c Ra Eb R' 0 R"b 31-440 RIb R 2 c R4a Eb R' R"b 31-441 RI Re 0 Raa Eb R' 0 R"b 31-442 Ria R 2 a R 4 b E R' R"b 31-443 R l R2a 4b Eb R'e R"f 31-444 Rl R ~a Rob Eb R' R"b 31-445 Ria R2a R4b e R'b R"b 31-446 R l R2b R4b Eb R'o R"b 31-447 Rl" R2b R4 Eb R' R"t 31-448 Ria R~e R 4 b Eb R' 0 R"b 31-449 Rl R2e R 4 b Eb R' R"b 31-450 RI" R2c Rab Eb R'" R" 31-451 Rla R2a R4b Eb R'" R" 31-452 Ril R ~a R4c Eb R' R"b 31-453 R R2" RI' Eb R'e R" 31-454 R]a R2b Re Eb R' R"b 31-456 Rl" R2b R4c Eb R' R" 31-457 Rla R2c R E R' R"b 3145a l 2ca 4c by Ri 31-451 R'c R~e R4 E R'' R"b 31-452 RIb R R 4 " Eb R'' R"b 31-460 RIa R2a R 4 a Eb R'e R"b 31-461 Rlc R a R4a E" R'e Rib 31-462 Rib R 2 b R4a Eb R'o R"b 31-463 Ria R2b R4a Eb R' R"l 31-464 Rlc R2b Ra E" R' 0 R"b 31-465 Rl" R26 Raa E" R'e R"i 31-466 RIIIa R2a Ec R'e R" 31-467 Rle R Ra Ec R'e R"b 31-458 Ri R 2 c Raa Eb R' 0 R"b 31-469 RIa R 2 a R 4 Eb R'" Rib 31-470 RIb R 2 a R 4 O E" RI R"b 31-471 RI R a R 4 " E R' 0 R"b 31-472 RIa R 2 b R 4 a Ec R' R"b 31-473 RIb R 2 b R 4 , E 0 R'e R"b 31-474 RIb R 2 b R4a E R' R"b 31-475 RIa R 2 c R 4 E R'c R"b 31-476 Rlb R 2 e R 4 b Ec R'" R"b 31-477 RI" R 2 e R 4 b E R' R"b 58 WO 2005/042712 PCT/US2004/035939 Ia Ra 4c ER 31-478 R R 2 a R EC R' R"b lb R2a R4 31-479 R R R E RIC R"b 31-480 Rlc R2b R4' Ec R'G R"b 31-481 Ra R 2 b R Ec R'C R"b 31-482 Rib R 2 b R 4 c E' R'C R"b 31-483 RiG R 2 b R 4 " E R'C R"b 31-48 RI R 2c R4" E R' Rl 31-484 R R a 4a E Rc Rb 31-488 Rlc R2a R4" Ea R'a Rb 31-486 R ' R2a Ra Ea Ra Rc 31-487 Ria R 2 a R 4 a Ea R'a R" 31-489 RIb R 2 a R 4 a Ea Ra RC 31-492 R* R R4 Ea Ria R"e 31-493 RbIa 2b R4a Ea Ra R"" 31-490 Rc Re R4a Ea R'a R"lC 31-495 Rl R2e R 4a Ea Ria R"c 31-491 Ria R R4 Ea Rla R"t 31-497 Rc R 2a R4 EIa Ra RWe 31-492 Ric Ra R4b Ea Ria Rl 31-493 RIa R 2 Re Ea Ria Rle 31-494 RIb R 2 a R 4 b Ea R'a Rle 31-495 RI R 2 b R 4 b Ea Ria R"G 31-502 Ria R2c R4 Ea R'a R"c 31-503 Rlc R2c R4 Ea Ria R""c 31-504 Rla Rlc R4 Ea Ra R"" 31-505 Ria R2 R4 Ea Rta R"l 31-50 RIc 2a R4 Ea R'a R" 31-507 R R a R4 Ea Ria R"le 31-508 Ria R2a R4 Ea R'a Rl 31-500 Rlc R2 R4 Ea R'a R"G 31-50 R2aRb 4b Ra Rr 31-501 Ric R2b R4 Ea Rla Re 31-511 RIa R2e R4 Ea R'a R" 31-512 R l R2c R4 Ea Ra R"G 3151 Rlb R2c W4 Eabi Rt 31-513 Rlc R2e R Ea Ria Ri"e 31-514 Ria R R4" Ea Ria Rle 31-515 RIa R 2 a R 4 Ea Ria R"le 31-516 Ric R2a Ra Eb Rta R" 31-517 RIa R 2 b R 4 a Eb Ria Rle 31-518 R 1 l R 2 b R 4 a Ea Ria RIl 31-519 Rl" R ~ Ria Eb Ria Rle 31-520 Ria R2c Ra Ea R 1 a Ri"e 31-521 Rib R 2 c R4. Ea R 1 a Ri"e 31-522 RIc R 2 e R 4 a E R'a R" 31-517 RIa R 2 a R 4 a Eb R'" R"G 31-518 R la R- Rb E b Ica Rie 31-524 Rib R 2 a R 4 b Eb R'a Rle 59 WO 2005/042712 PCT/US2004/035939 31-525 R Ra R4b Eb R'a R" 31-526 Ria R R Eb R'a R" 31-527 R4b R2b Rb4 e R a R" 31-528 Rlc R2b R4 Eh R'a R" 31-529 R" R 2 c R4 Eh R'a Rc 31-530 R Rwc R4b Eb R'a R"4b 31-531 RIC R 2 c Rb Eb R'a R"C 31-532 Ria R 2 a R 4 b Eb R'a R"c 31-533 RIb R 2 a R' E R'a R"c 31-534 Ri R2a R4 Eb Ra R"c 31-535 Rla R2b R4c Eb R'a R'' 31-536 Rlb R2b R Eb R a R" 31-537 Rl" RWb Rw E I R~a R""c 31-538 a 2 R 4 Eb R'a R"c 31-539 RIc R 2 e R e Ra R"c 31-540 Rlc R R' E R'a R" 31-541 R R2a Ra Ec Ra Rfc 31-542 RIt Ra Raa Ec R'a Rvc 31-543 RIC R 2 a a Ec R'a Rc 31-544 Ria R2b R4a E R'a R" 31-545 R l R2b Ra Ec R'a R"c 31-546 RIb R 2 b R 4 a Eb R'a R"vc 31-547 Ria R 2 c R4a E' R a R" 31-548 R l Rc R4a EC R'a R" 31-549 Rlc R-e R4a Ec R a Rlc 31-550 Rla R 2a R4b E R'a R" 31-551 R l R ~a R Ec Ra R"c 31-552 RIC R2a R4 E' R'a R" 31-553 R R R Ec Ra R"c 31-554 R R2b R4 Ea R'a R"c 31-555 RlC R ~ R4b Ec R'a Rc 31-556 Rla R 2 e R 4 Ec R'a R"c 31-557 RIc R 2 e R 4 b EC R'a R"c 31-558 Rlc R2c R4a Ec R'a R" 31-559 Ria Ra R4' Ec R'a R"c 31-560 Rlb R R4 E' Ra Rac 31-561 Ric Ra Rc Ec Ra R"c 31-562 RIa R 2 b R 4 c EC R'a R"c 31-563 R l R2b R4" E R'a R" 31-564 R4b Rb Re E" R'a R" 31-565 Rla R2' R4 Ec R'a R"c 31-566 Rlb R~e RW' E' R'a R"c 31-567 Rlc R~e R4' Ec R'a R"lc 31-568 Rila R 2a R4a Ea R' Rc 31-569 RI Ra Ra Ea R' RIc 31-570 R" Ra Ra Ea R' Rc 31-571 Ria R2b Ra Ea R' R"C 60 WO 2005/042712 PCT/US2004/035939 31-572 R l R R 4 a Ea R'b R"v 31-573 R ' R2b R4a Ea R'b R" 31-574 RIa R 2 e Ra Ea R'b R"l 31-575 R lb R2c R4" Ea R' R" 31-576 R' We R WRa E a R'tb R,,c 31-577 R R2a R 4 Ea R'b Rc 31-578 Rlc R ~a R 4 b Ea Rib R"le 31-579 Rc R2a R 4 b Ea R'b Rlc 31-580 a ib b R 4 b Ea R'b R" 31-581 R l R 2 b R 4 b Ea R'b Ri"e 31-582 Ric R 2 b R 4 b Ea R'b R" 31-583 Rl " R2c Re E a R'"b R" 31-584 R b R2c R 4 b Ea Rib Ri 31-585 R' R 2 b 4 b Ea Rb R'e 31-586 R ia 2a R4 E" R'i R" 31-587 Rlb R R 4 ' Ea Rib R" 31-588 Rlc R 2 a R 4 ' Ea Rb R" 31-589 RG R 2 b R 4 b Ea Rb R'e 31-590 R b R 2 b R 4 . Ea Rib Ri"c 31-591 Rl* R 2 b R 4 Ea Rb Ri"c 31-592 Ria R 2 e R 4 ' Ea Rb Ri"e 31-593 R l 2b R4c Ea R'i R" 31-594 R 4 R R 4 Ea Rb Rl 31-595 R]a R ~a R 4 a Eb Rib Rc 31-596 Rl b Ra R4a E b R'b Rttc 31-597 Rlc R2a R 4 a Eb Rb R" 31-598 RIa R 2 b R 4 a Eb Rb R" 31-599 R R R 4 a EB Rib Ri"e 31-600 R Rb Ra Eb R't R"c 31-601 Ria R R 4 a EB Rib R" 31-602 R l R 2 c 4 a Eb Rib R"c 31-603 Rlb 2c R4a Eb R'b R" 31-604 R Ra Rlb e Rb R'' 31-605 R R 2 a R 4 a Eb R'b Rle 31-606 R 2a R4 Eb R' R" 31-607 Rla R2b Rb Eb Rib R" 31-608 R R R 4 Bb Rib R',c 31-609 Ic R2b 4 n R" R 31-600 R R R 4 Eb Rb Ri"e 31-611 R 1 l R 2 e R 4 b Eb Rb Ri"e 31-612 R b R 2 e R 4 b Eb Rib Ri"e 3162 RIc R2c 4ab b l y 31-613 Rla R2a R4c E Rib Rl 31-614 R Ra R 4 ' C EB Rib R" 31-615 R R ~ R4c Eb Rib Rl 31-616 RIa R 2 b R 4 Eb Rib Rle 3 1-607 RIlb R~ b BcEb R ib Rile 31-618 R~b R 2 b R 4 c Eb Rb Rl 31-610 R R Rc EB R'b Ril 31-63 R R RG Bb Rib Ril WO 2005/042712 PCT/US2004/035939 31-619 Ria R 2 c R 4 C Eb R'b R" 31-620 R l R2c Re E R'b R" 31-621 RIC R 2 c R 4 c Eb R'b Rl 31-622 RI R-a R4a E' Rtb R"c 31-623 R R2a Ra Ec R'b Re 31-624 Ric R a R4" Ec R'sb R"' 31-625 Ria R R 4 a E' Rib R"e 31-626 Rib R2b R 4 E' Rib R"l 31-627 R R2b R 4 a E' Rib Rl 31-628 RIa R 2 e R4a Ee Rb Rle 31-629 Rl R-e R 4 a Ec Rib Rle 31-630 Ric R 2 c R 4 a Ee Rb Rlc 31-631 R R R 4 a Ee Rb Rle 31-632 RIC R 2 a R 4 Ec R'b Rc 31-633 R' R 2 a R4b Ec Rib Rle 31-634 Ria R 2 b R 4 b E' Rib Ri"e 31-635 R Rb b R4b Ec R' R" 31-636 Rl' R2b R 4 b Ee R'b Ri" 31-637 Ria R 2 e R4b E' Rb Rle 31-638 R l Re Rb Ec Rb R"e 31-639 RIe R 2 e R 4 b Ee Rib Ri"e 31-640 Rla R 2 a R 4 ' E' Rib RIe 31-641 R R R 4 b E' Rb Ri" 31-642 RIe R 2 a Rc E Rb Rl 31-643 Rla R2 R 4 ' Ec Rib Rle 31-644 Rl R2b R 4 c Ee Rb R"e 31-645 RI R 2 b R 4 E Rb Rle 31-646 Ia R2e 4b' R" R 31-643 Rl R2c R 4 c Ee Rib R"e 31-647 Rlb R2bc c Rib R~ 31-648 Rl' R2e R 4 c Ec Rb R" 31-649 R" Ra R 4 a Ea Rc Rle 31-650 Rb RWa RWa E a R'' Rlfc 31-651 Rl' RWa RWa Ea R'" R"c 31-652 Ri]a R2b R 4a Ea R'c R"c 31-653 R lb R2b RW. E a R'' R"c 31-654 Rl' R2b R4" Ea R'c R"l 31-655 Ri]a R 2e R" Ea R'c R" 31-656 R l R 2 c Raa Ea Rb Rle 31-657 R R 2 e R. Ea Rb Rie 31-658 Ria R 2 a R 4 e Ea R' RI 31-659 R 1 l R 2 a Ra Ea R'' R" 31-660 Rlc R2a Rb Ea R'' R" 31-661 Rla R2b R 4 Ea R' Rile 31-662 R lb R2b R4b Ea Rlc R"1 31-663 Ric R2b R 4 Ea R'c Rle 31-664 Ria R~e R 4 a Ea R' R"e 31-665 Rl Re R 4 Ea Ric Rle 62 WO 2005/042712 PCT/US2004/035939 3166 RIc R2c R4b F e R 31-666 R R"' R Ea R'e R"C 31-667 R l R a R4' Ea R'c R 31-669 R R 2a R 4 , Ba R'' R" 31-670 R l R 2 b R 4 Ba R'' Rftc 31-671 Rib R 2 b R4 Ba R R"?c 31-672 R Rb R Ea R'' R"c 31-673 Ria R 2 c R 4 ' Ea R' R"e 31-674 R R c R4' Ea R'' R"Y 31-675 RU R 2 c R 4 ' E" R'' Ri 31-676 RIa R2a R4a Eb R'' R!'c 31-677 R R a R4a Eb R'' R" 31-678 Rl R2a R4a Eb Rc R"e 31-679 R]a R2b R4a Eb R'' R" 31-680 R R 2 b R 4 a Eb R'' RI" 31-681 Rla R 2 b R 4 a Eb R"V 31-682 a R 2 R4a Eb R' R" 31-683 RO R 2 e R4a Eb R'U Ric 31-684 Rla R 2 e R 4 a Eb R'U R" 31-685 R ]a
R
4 b Eb R'' R 31-686 R I R2a R 4 b Eb R' RI"e 31-687 R 1 l R 2 a R 4 b Eb R' Re 31-688 RIba R2 R 4 b Eb RU RIC 31-689 R R2b R 4 b En R'U RIc 31-690 Rc R 2 b R 4 b E RU R"e 31-691 RIa R 2 e R 4 b Eb RU R"" 31-692 R R 2 ' R 4 Bb RU RIc 31-693 Rc R 2 e R 4 b Eb R' RI"e 31-694 RIa R2a R 4 ' Eb R' Ric 31-695 RO R 2 a R 4 ' Eb R' RIU 31-696 R R2a R4c Eb R' Re 31-697 R b R 2 a R4c Eb RU R" 31-698 R R2b R4c EB R' R" 31-699 R I R 2 b R 4 ' Eb RU R" 31-700 RIa R 2 e R 4 U Eb RU R" 31-701 R lb R2e R4' Eb R'c R"? 31-702 RI R 2 e R4c Eb R'U R 3 1-700 R 1 a R 2 a R 4 a Eb Rc RIc 31-701 R R 2 a R 4 a Bb R' R" 31-702 RIl R2a R 4 a E RU RC 31-706 RcIa 2a R4a E' R' R" 31-703 R ] R2b Ra EU R'' Ri 31-704 ' b R 2 a Ra E R'' Ri 31-709 R R R EU R'U Rc 31-710 R U R 2
R
4 a Ec R' RIc 31-710 R~b R 2 e R 4 a EU R' 31-711 RO R 2 ca B Rtc RIU 31-712 Ria R 2 a R 4 b E R'U RPc 63 WO 2005/042712 PCT/US2004/035939 31-713 R b e R 4 b E R' R" 31-714 R1 R2a R4b Ec R'' R" 31-715 R R2b R4b EC RIC R" 31-716 R R2b R4b E' R'C R" 31-717 R R ~ R4 Ec RIC RIc 31-718 R1a R 2 c R 4 b EC RIC R"C 31-719 R' b R2- 4b E I t 31-719 RC R 2 e Rb Ec RIC R"c 31-720 Ra R2c R4b E' R' R" 31-721 R R ~a R4 Ec RIC R"C 31-722 RG R2a Re Ec R'' R"1 31-723 R]a R2a R E c R I" 31-725 R ) R2 R' E' RIC R 31-726 Rc Rb R4 Ec RIC R"c 31-727 Ria R R 4 C Ec RIC RIc 31-728 RIb Rc R 4 C EC RIC RIc 31-729 R 1 c R 2 b R 4 c Ec RIC Rc where all symbols are as defined above. In one aspect of formula (31) of the present invention, R and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or 5 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 hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalk:enyl group, an alkoxyalkyl 10 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 heteroaralkcyl group, a heteroaryloxy group, or a heteroaralkoxy group; R' and R" independently are hydrogen, a halogen, a nitro group, an 15 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 haloalkcoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkcoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; and 20 all other symbols are as defined above in connection with formula (I). 64 WO 2005/042712 PCT/US2004/035939 In another aspect of formula (31) of the present invention, R1 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group; R 2 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or 5 an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group;
R
4 is a substituted or unsubstituted aryl group, R' is hydrogen, a halogen, or an alkyl group; and R" is hydrogen, a halogen, or an alkyl group; and all other symbols are as defined above in connection with fonnula (I). In yet another aspect of formula (31) of the present invention, R' is hydrogen or an 10 alkoxy group; R 2 is hydrogen or an alkoxy group; R 4 is a substituted or unsubstituted aryl group, R' is hydrogen, a halogen, or an alkyl group; R" is hydrogen, a halogen, or an alkyl group; and E is O, S, or NH. In still another aspect of formula (31) of the present invention, R' is -H or -OCH 3 ; R 2 is -H or -OCH 3 ; R 4 is a substituted aryl group, R' is -H, -Cl, -Br, or -CH 3 ; and R" is -H, -Cl, 15 Br, or -CH 3 ; and E is 0, S, or NH. The present invention further contemplates various compounds of general formula (III) having the general formula: 0
R
4 I 0) F F ERNH Me 0 (32), where all symbols are as defined above in connection with formula (I). 20 According to various aspects the present invention, R 4 , R', and R' of formula (32) are selected to produce various compounds of formula (32-1) through formula (32-27) as follows: Formula R4 R' R" 32-1 Raa R'a Ra 32-2 R 4 Ra Rita 32-3 RaC R'a R"a 32-4 R R'b Ria 32-5 R4b R'b R"a 32-6 R 4 c R'b Rita 32-7 Ra R'" Rlia 32-8 R4b R' Rta 65 WO 2005/042712 PCT/US2004/035939 32-9 R 4 c R'e RiTa 32-10 R 4 a R'a R"b 32-11 R 4 b Rb 32-12 R 4 e R'a R"b 32-13 R 4 a Rb R'rb 32-14 Rb R'b R''b 32-15 R 4 " Rb R''b 32-16 R4a R'" R''b 32-17 R R'e R''b 32-18 R 4 c Ric R''b 32-19 R 4 a Ria R"e 32-20 R, R 1 a R"r 32-21 R 4 R'a R"IC 32-22 R 4 a R'b RI" 32-23 R R'b R' 32-24 R 4 C R'b Ri' 32-25 R 4 a R'e RTc 32-26 R R'e R" 32-27
R
4 R' Rl where all symbols are as defined above. In one aspect of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an 5 alkoxy group, or a cycloalkoxy group; R' is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(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 nitro group, an amino group, a mono- or di 10 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, R4 is an alkenyl group, a cycloalkenyl 15 group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, or an aralkoxy group; R' is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, a thio(S=) 66 WO 2005/042712 PCT/US2004/035939 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 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 5 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 one aspect of the present invention, E is 0 or -NR; R 4 is optionally N substituted with an alkyl group or an alkoxy group, - , or ; and R' and R? 10 are defined as above. Examples of such compounds include, but are not limited to: OMe 0 o R 4 O O NH F0 0R OMe O IY S I o NH F O ~ Me 0. 0 oMe
OCH
3 O NH 0 N 0o 0 - S 0 F O r'' NH_' FI 1- I~ 0 5- (I)---NHF a 0 0 ~. OCH 3 S I H 0 0 F ONN S F O O - o - o - 0* 0 0 F S i-NH 0r 0 S 0 0 15F O O F NH 67 WO 2005/042712 PCT/US2004/035939 N S\
N
0 0 O I H 0 F S F O N F NH I NH 0 ;and . The present invention still further contemplates various compounds having the general formula: 0 R 4 o I0 0 NH 0 (33), 5 where R 4 is as defined above in connection with formula (I). In one aspect of formula (33) of the present invention, R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group. 10 In another aspect of formula (33) of the present invention, R 4 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 heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group. 15 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 aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an arallcylthio group, a fused 20 heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof. 68 WO 2005/042712 PCT/US2004/035939 In still another aspect of formula (33) of the present invention, Ri is , -0 SMe o uh1 u r o iie o , or Examples of such compounds include, but are not limited to: 1 0> 0 10> 0il j ~ ~ jii 0 0 ONH O7 NH 0 ;*and S ~0 0O NH 5 0 The present invention further still contemplates various compounds having the general formula: R' R 5 o , NH R" N ~ R20 R2 R21 (34), where all symbols are as defined above in connection with formula (I). 10 where R 20 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 aroyl group, an alkoxycarbonyl group, an 15 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 69 WO 2005/042712 PCT/US2004/035939 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 5 group; and all other symbols are as defined above. According to various aspects of the present invention, R, R, R 20 , R 21 , IR and R" of formula (34) are selected to produce various compounds of formula (34-1) through formula (34-729) as follows: Formula R R' R R' R' R" 34-1 Ra R 5 a R 20 a R 2 1 R'a R!a 34-2 Rb Rsa R 2 Oa R 2 1a Rta R"a 34-3 Rc RSa R 2 oa Ra R'a R"a 34-4 Ra Rab 2Oa R21a R'a Ria 34-5 Rb Rb R2-a RR'" R"a 34-6 RW RE ROa R21a R'a R"a 34-7 Ra RSb R 2 0a R 2 1a R'a R"a 34-8 R Re R 2 0 a RnIa R'a Ra 34-9 R Re R20a R a Ra R"a 34-10 Ra Rsa R2b Ra Ria R"a 34-11 R Rsa R 2 Gb R 2 1a Ria R"a 34-12 Rc Rsa R20b Rna R'a R'ya 34-13 Ra Rba R 2 Ob R 2 1a RIa R"a 34-14 R R5b R20b Raa R'a R"a 34-15 Rb R5b R 2 0b R 2 1a Ra Rita 34-16 Ra R R2Gb R2a R a R"a 34-17 R R R R2a Rta R"a 34-18 Rc R5 R20b Raa R'a R"a 34-19 Ra Rsa R20e R 21 a R'a Ra 34-20 Re Rs5a R20c R?'a R ta R"a 34-21 Re RSa R 2 0C Rr2a Ria R"a 34-22 Ra R R 2 oc RIa R'a Rita 34-23 Rb Rb R 2 0c RnIa Ra Ria 34-24 Re RC R 2 c R 2 ia R'a Rita 34-25 Ra Ra' R 20 c R 2 1a Ra R"a 34-26 Re RSa R2c R2a R'a Ra 34-27 R' RS R 20C R 2a R',a R'la 34-28 Ra Rsa Ra R 2 1 b R'a R t a 34-29 Re R 5 a R 20 a R 21 b RIa R"a 34-30 R Rsa R 2 oa R 2 lb R a R"a 34-31 Ra Rsb R20a R 21 Ria R"a 34-32 R, Rsb R 20 a R21b Ra Rita 34-33 Rc REb R 2 Oa R 2 Ib Rta Rita 70 WO 2005/042712 PCT/US2004/035939 34-34 Ra Rsc R20a R 2 1b R a R"a 34-35 R, RS' R20a R 2 1b R a Rita 34-36 R R5 R20a R 2 1b R a R"a 34-37 Ra R 5 a R20b R 2 1b Rla R"a 34-38 Rb R 5 a R 2 0b R 2 1b R'" R"t 34-39 Re R 5 a R2b R21b Ra Rita 34-40 Ra R 5 b R 2 0b R 2 lb R'a R'ta 34-41 Rb R 5b R2b R21b R'a R"a 34-42 Re R R20b R 2 1b R a R"a 34-43 Ra Rw' R 2 0b R 2 lb R'a Rla 34-44 Rb Rs5c R20b R21b R'a R"a 34-45 Rc Rsc R20s R21b R'a R"a 34-46 R a Rsa R20e R21b R'a R"a 34-47 R Rsa R 20' R21 b R'Ia Rfla 34-48 Re R 5 a R20e R 2 1b R'a Rla 34-49 Ra R 5 C R20e R21b R'a R"a 34-50 Rb RC R 2 o R 2 1b R'a R"a 34-51 Re R 5b R20c R21 b R'a R"a 34-52 Ra R5 R20c R21b Ria R" 34-53 R R5 R20' R 2 1b Ria Rta 34-54 Rc R 5 R20C R 2 1b Ra Ria 34-55 Ra R5a R2Ga R21e Ria R"a 34-56 RC R5a R R Ra Ra 34-57 Re Rsa R 2 Oa R 2 1 Ra Rita 34-58 R R 5 b R 2 0a R 2 1e RIa Rita 34-59 R, R3b R20a Rgoc R'ia R"a 34-60 Re R3b R 20a RMl R'ia R"ta 34-61 Ra R 5 c R 2 Ga R 2 lb RIa Rta 34-62 Ra Re R 20 a R7Ib Ria Rita 34-63 Rb Rsc R20a R2 R'a R" 34-64 R a Rsa R20b R 21 Rta R'ja 34-65 R R R20 R 2 Ria Ria 34-66 Re R 5 a R 20 b R 2 1 R'" Rita 34-67 Ra R 5 b R20b R 21 C Ra R"a 34-68 Rb Rla R 2 0b Rlc Ra Rta 34-69 RC R 5 b R 2 0a R' 21 R'a Rita 34-70 Ra R5 R20b RIc RGa Raa 34-71 Ra Rc R20b R 21 R'a Rla 34-72 Rb R 5 b R 2 Ob Re Ria Rita 34-73 R a Rsa R2oe R1" R'" Rlfa 34-74 RC R 5 a R 2 o R 21 c R'a Rita 34-75 R' Ra R 20 c R 1 C R'a R"a 34-76 Ra R 5 b R 20 C R 21 R'a R"a 34-77 Re R 5 C R 2 O R 2 1 c R'a Rtta 34-78 Rc RS R20c R 2 1C RIa Ria 34-79 Ra R.
5
R
2 0b R 2 1 C RIa Rtta 34-80 R R 5 R20 R 2 Ic R'a Rita 71 WO 2005/042712 PCT/US2004/035939 34-81 RC Rsc R 2 0c RIc R'a Rla 34-82 Ra RSa R 2 Ga Rnta R'b Rla 3483 R Rsa R20a Rla R' Ra 34-83 R, Rsa R20a Raa Rib Rla 34-84 Re R 5
R
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2 I R 1
RI
WO 2005/042712 PCT/US2004/035939 34-551 R R5 R 2 Ob R]c R'a Rle 34-552 Re R 5 a R 2 Ob R 2 1 C R'a R''' 34-553 Ra R R2b RIc R a R"C 34-554 R R3b R20b R3l R'a R"e 34-555 R' Rab R20b Rle R'a R"C 34-556 Ra R 5 c R 2 0b R 2 e R'a Rlc 34-557 Rb R 2 We R 2 1e R4 R"e 34-558 Re R 5 c R 2 Db R 2 1 Ra Ri"e 34-559 R a Rsa R2" R2 R4 R" 34-560 R, R R20 R 2 C R Ril 34-561 Re R5 R20C Rec R R" 34-562 Ra R 5 b R RIc Ra Ric 34-563 Rb R3b R 20c RIC R a R"I 34-566 Re R 5 ' R Rc Ra R"e 34-567 R R 5 R RIC Ra R"rC 34-563 Ra Rsa R R 1 a R'a R"c 34-564 Re R 5
R
2 0a R]a R t Rc 34-565 Ra Ra R 2 Da Rna Ria R" e 34-571 a R5 R20a R2a R' R" 34-572 Rc R R Ra R' R"lC 34-573 R' RC R 2 Da Rie R'b Rie 34-574 Ra Rsc ROa R 2 1a Rib Re 34-575 e Rc R 20a Ra Rib Rle 34-576 R a Rs5c R~oa Rnla R'b Rltc 34-570 Ra Rsa R20a R 2 la R'b R"e 34-578 Re Rsa R2 R 21a R' R" 34-579 Ra Ra R2b Ra R Ri"e 34-58 Ra R b R2b R'b R" 34-572 Rc Ra R20b R2a Rib Rlc 34-583 Ra Rb R 20 b Rna Rib Rle 34-584 R R 5 c Rb R 21 a Rib R"e 3452 R R5b 2Da 21a R R 34-585 Ra Rsc R20b Ra Rb R"e 34-586 Re Rbe R 20 c Ra Rib R"e 34-587 Re Rsa R2 R 2 la Rib R"e 34-588 Rb Rsa R 2 c R 2 a Rib R"e 34-589 Re R 5
R
2 o R 2 1 a Rb R"e 34-580 Re Rab R 2 oe RIa Rb R"e 34-581 Ra Rb R20c Ra Rb R"e 34-592 Re Rb R 2 Dc RIa R'b R"e 34-593 Ra R5 R20c Rna Rb R"e 34-594 Rb Rsc R 2 o RIa Rib R"le 34-595 Re RM R 2 Da R 21 a Rib R"e 34-596 Rb R 5
R
20 a R 21 b Rb Ri"e 34-597 Re Ra R20a R 2 1b Rib R"e 82 WO 2005/042712 PCT/US2004/035939 34-598 Ra R5b R 20 a R 2 1b R'b Re 34-599 Rb Rab R 2 0a R 2 1b Rb R"lC 34-600 Re Rab R 2 0a R 2 1b Rib Ri"e 34-601 R5c R2Ca R 2 1b Rib Re 34-602 Rn Re Ra R21b R' R" 34-603 RS Re R20a R21b R'b R" 34-604 Ra Ra R20b R2b Rib Rte 34-605 Re Rsa R 2 Ob R 2 1b Rib Rie 34-606 R Rsa R 2 b R 2 1b Rib R"e 34-607 Ra R~a R 2 0b R 2 1b Rib R"e 34-608 R Rsa R 2 0b R 2 1b Rib Re 34-609 R REb R2Gb R 2 1b Rib Re 34-610 Ra R5' R20b R21b R'b R" 34-611 Rb RSc R2Gb R21b R R" 34-612 R Rsc R2b R21b Rib R" 34-613 Ra Rsa R 2 0c R 2 1b Rib Rie 34-614 R, R 5 a R20c R 2 1b Rib Re 34-615 R R 5 a R 2 0b R 2 lb Rib Rile 34-616 R RC R20' R 2 1b Rib Rie 34-617 Rb Rab R20e R21b R'i R" 34-618 R" Rab R2c R21b Rib R" 34-619 Ra Rsc R2Cc R21b R'b Re 34-620 Rb Rsc R2c R21b Rib Rt 34-621 Re Ra' R 2 Oc R 2 1b Rib Re 34-622 Ra Rsa R2a R Rib Ri 34-623 R Rsa R 20a RE' R'b R"l 34-624 Rb Ra R 2 Ca R2- Rib R" 34-625 Ra REb R20a R? I R'b RWc 34-626 RS Rb 2Ca R 2 1b Rib Rte 34-627 Re Rab R20a Rl R'b Rvc 34-628 Ra Rsc R20a RI Rib Ri 34-629 R Rc R20a R 21 R' R" 34-630 R R 5 R20a R' Rib R"e 34-631 Re RSa R 2 e R 2 le Rb R" 34-632 R Ra R 2 0b R 2 1c Rib Rile 34-633 Rb Rsa R 2 0 s R 1 Rib Rie 34-634 Ra Rob R 20 b R 1 c Rib Rle 34-635 Ra R 5 R20b R21 Rib R" 34-636 RS R5 R20b R " R' R" 34-637 R R' R20b R Rib R"e 34-638 Rb Rsc R20b RIC R' R" 34-639 Re Rsc R20b Rc Rib Re 34-640 Rn Rsa R 2 c RlIc Rib Ric 34-641 Rb Rsa R 2 oc RIe Rb Rle 34-642 R Rsa R20b Re Rib R"e 34-643 Ra R5 R R 2 e Rb R"e 34-634 R b R 2 Cb Ro W R ib Rie 34-634 R Rs R2 R' Rib R 34-36 e Rb Rob 21 ' RibR3 WO 2005/042712 PCT/US2004/035939 34-645 Re Rab R 2 oc R 2 1C Ri R"c 34-646 Ra R' R 2 0 c R21e R'b R"c 34-647 Rb RC R 2 Oc R 2 1e Ri R" 34-648 R Rsc R20c R21C R'b R" 34-649 Ra Ra R~oa R2a R'" R" 34-650 R5 Ra R20a R21a R'e R" 34-651 R Rsa R2o R2a R'' R" 34-652 Ra Rb R20a R21a R' R"e 34-653 Rb R5b R2a Ra Ryc R" 34-654 Re R 5 a R 2 0a Raa R'e R"le 34-655 Ra Rib R 20 a Raa Re R" 34-656 Rb R' R 2 Ga Ra Rc R"e 34-657 R' Re R2oa 21a R'e Ri 34-658 Re Ra a R20 R2a R'' R" 34-659 Ra Rsa R 2 0Q R 2 1a Re R"e 34-660 Rb RSa R 2 0G R 2 1a Re Rie 34-661 Ra R 5 R20b R21a R'' Rle 34-662 Re RC R20b Rla R'' R" 34-663 R' R 5 b R 2 0b Raa Re R"e 34-664 Ra Ra R20b Rla R'' R" 34-665 R Ra' R20b Ra R'e Rle 34-666 Re R5. R2b R 2 1a R'c RIc 34-667 Ra RSa R 2 0b R Ia R'e R'' 34-668 Rb RSa R 2 oc R 2 1a R'e R" 34-669 Re R5a Re R21a R'e Ri"e 34-670 Ra Rab R20e R2a R'' R" 34-671 R RC R 2 0e Raa Re R"e 34-672 R Rc R 2 oe R 2 1a R' R"e 34-673 Ra Rsc R20e RIa Rc Ri"e 34-674 Ra R5' R 2 c R 2 1a Re R'e 34-675 Rb R R 2 0e R Ia R'e RIe 34-676 Ra Ra R20a R21b R'e Rie 34-677 R a R RR21 R Rile 34-678 Re Rba R20a R21b R' R" 34-679 Ra Rb R2a R 21 b Re R"e 34-680 Q R Rb R21a R'c R" 34-681 Re R R20a R21b R'' R" 34-682 Ra R' R20a R21b R'* R"t 34-683 Ra R5c R 2 a R 2 1b R'c Ri"e 34-684 Rb R5c R 20 a R 2 lb we R" 34-685 Ra RSa R 20 b R 2 1a R'' Rl 34-686 R Rsa R 2 0b R 2 1b Rc R1" 34-687 Rb R'a R 2 0 t R 2 1b R' R"e 34-688 Ra Rob R20b R 2 1b R'c Ri"e 34-689 Rb R5b R 2 Gb R 2 1b R' R"e 34-690 Rb Rb R 2 0a R 2 1b R'c Ri 34-691 Ra R 5 R20t R 2 1b Re R"e 84 WO 2005/042712 PCT/US2004/035939 34-692 Rb RR: R 2 0b R 2 1b R'e Rc 34-693 R' R' R 2 ab R 2 1b R' R' 34-694 Ra R 5 a R 2 0c R 2 1b R' RI" 34-695 Rb RSa R 2 0c R 2 1b RC R"e 34-69 Rc Ra R2Cc R2 '4 '' 34-696 Ra Rst R ~c R 2 1b Re RI 34-69 W Rb 2 C R1 e W 34-698 R R 5 R20c R 2 1b R'* R" 34-699 R' Rab ROc R 2 1b R'' R" 34-700 Ra Ra' R 2 ac R 2 1b R'' RC 34-701 Rb Rac R 2 0c R 2 1b R'e R,,c 34-702 Re Rsc R2ac R21b R' RWc 34-703 R a Ra" R 20a RM R'" R" W 34-704 R Rsa R 20a R 21e R'" R"1 34-705 R Rsa R20a R21e R'' R" 34-706 R a Ra R20W a R'e R'' RWc 34-707 RG Ra R20a R 2 1c R'c R" 34-708 Re R5 R2a R21C R'e R"" 34-709 Ra R R20a R 2 1C R'e R 34-710 R R" R 2 0 a R 2 1C RG R"G 34-711 R' Rab R 2 0a R 2 1 RG R" 34-712 Ra Ra R2Ob RC R'' RI" 34-713 R RSa R 2 0 b R21c R'e Rc 34-715 Ra Rsb R2 R R'G R" 34-716 Rc Rb R20b R R'c R" 34-717 R' R5b R20b R21C R'e R" 34-718 Ra R R20b R 2 1 c RG R" 34-719 Rb R 5 c R20b R21C R'e R" 34-721 Ra R 5 a R20c R 2 1 c Rc R" 34-722 RW Rsa R20c Rle R' R" 34-723 R' Rsa R20c R21e R'c R" 34-724 Ra R5 R20c R 2 C RG R"c 34-725 Ra Rab R20' R 2 1 C R'e R" 34-726 R' R 5 R20' R 21 c R'c R" 34-727 Ra Rsc R20c R 2 1c RG R" 34-728 R Rsc R 2 0c R21C RI' R" 34-729 Rb R 5 c R20C R 2 1C R'' R" 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 5alkoxy 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 85 WO 2005/042712 PCT/US2004/035939 group, an alkenyl group, or an alloxyalkyl group; R' and R? independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group; a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, a thio(S=) group; an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkoxy group, a cycloalkyl 5 group, an aryl group, or a benzyloxy group; and R and Ra 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 10 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; R5 is hydrogen or an alkyl group; R' and R? independently are hydrogen or a halogen;
R
20 is hydrogen or a halogen; and R is hydrogen or a halogen. 15 In yet another aspect of formula (34) of the present invention, R is -H, CH 3 , or
CH
2
CH
3 ; R5 is -H or CH 3 ; R' and R? independently are -H, -F, or -Cl; R2' is -H, -F, -Cl, or -Br; and RM is -H, CH 3 , or -F. Exemplary compounds include, but are not limited to: 00 1:O 0 NH N H 3 c /\ CH F CH, NH I NH 0 0 0 0 N ~ F NCI NH N F a
OH
3 FCH 3 FH 0 S 00 0 20 0 N0 N ~ F o S 20 O 3 Ci 0 " 86 WO 2005/042712 PCT/US2004/035939 0NH o--, ' NHr N N F 3 F H 0 NN NF F F F Me o Me F O' O N HO I oNH 0 O N ~NH 56 H3 0; a d0 F 0 NH f 00 JO"O O- -- NH s
N
3 F NN a z HR1 Br H C 0 Me I M 0 N0 N 0 NH
H,
3 0 F HN4( 0NH 5H 3 C 0; and 0 The present invention also contemplates various compounds having the general formula: NH 0 R O H 3 'I
R
21 (35), 10 where all symbols are as defined above in connection with formula (1). 87 WO 2005/042712 PCT/US2004/035939 where R 20 and R 2 ' 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 5 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 10 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 R' is defined above. 15 According to some variations of the present invention, R', R 20 , and R 21 of formula (35) are selected to produce various compounds of formula (35-1) to formula (35-27) as follows: Formula RI R 2 0 RE 35-1 Rla R20a Ra 35-2 R1 R20a Ra 35-3 R R2a R2a 35-4 Ria R20b R2a l55 b Gb R21 a 35-5 Rih R0 Ra 35-6 R R 2 Gb Ra 35-7 Rla R20c Rna 35-8 RIb R 20 c R2a 35-9 R R 2 c Rla 35-10 RIa 2oa 21b 35-11 RIb R2a R21b 35-12 RI R20a R21b 35-13 Rla R20 R21b 35-14 RIa Rb R21b 35-15 Ric R20b RE1 35-16 RIa R20c R21b 35-17 R I R2 R21b 35-18 Re R2c R21b 35-19 RIa R2 R 35-20 RIa R20a Ri 35-21 R R20a Rnc Ic288 ~ 1 WO 2005/042712 PCT/US2004/035939 35-22 RIa R 2 Ob R21C 35-23 R b R 2 0b R 2 1 35-24 RiC R 2 Ob ReC 35-25 R R2 Rc 35-26 RIb R 2
R
2 c 35-27 RI'c R 2 0 c R 2 1C 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 nitro group, a carboxy group, a carbamoyl group, an optionally 5 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 allenyloxy group, or a cycloalkenyloxy group; R 20 is hydrogen, a halogen, a nitro group, an amino group, a mono or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; and R2 is hydrogen, a halogen, a nitro group, 10 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, R1 is a halogen, R 2 0 is hydrogen or a halogen, and R 2 1 is hydrogen or a halogen. In yet another aspect of of formula (35) of the present invention, R 1 is C1 or F, R 20 is 15 H or -F, and R 2 1 is -F. Exemplary compounds of formula (35) include, but are not limited to: CH3 F 0S FI, N 0 0 _' NS> I NNH CI NN 0N CH F
CH
3 0 oo e 0 0 N N~ 0 N 0 NHN1 F F F NH F
OH
3 F F F 89 WO 2005/042712 PCT/US2004/035939 -S> 00 0 o- NH / NH Cl N F Ci N FN C
CH
3 F CH 3 F F o NH and CH 3 F The present invention further contemplates various compounds having the general formula: 0 I R R o HN-$ 5 0 (36), where all symbols are as defined above in connection with formula (I). According to some variations of the present invention, R, R 4 , R' and R" of formula (36) are selected to produce compounds of formula (36-1) through formula (36-81) as follows: 10 Formula R R 4 R' R" Formula R R 4 R' R" 36-1 Ra R 4 a R'a R"a 36-42 Rc R 4 b R'b R'' 36-2 Re R 4 a Ra R"a 36-43 Ra R 4 c Rb R'b 36-3 Rc R 4 a R'a R"a 36-44 Rb R 4 c R'b Rib 36-4 Ra R 4 b Ra Ria 36-45 Rc R 4 c R'b Rib 36-5 R' R 4 ' R'a R"a 36-46 Ra R 4 a R'" R" 36-6 Rc R 4 b Ra R"a 36-47 Rb R 4 a R'c Rib 36-7 Ra R 4 c R a R' a 36-48 Rc R 4 a R'c Rib 36-8 Rb R 4 R a R"a 36-49 Ra R 4 R'c R"b 36-9 Rc R 4 C R'a Rita 36-50 Rb R 4 " R'C Rib 36-10 Ra R 4 a Rb Rita 36-51 RC R 4 b R'c Rib 36-11 Rb R 4 a R'" Ra 36-52 Ra R 4 c R'c R"b 36-12 RC R 4 a Rb Rita 36-53 Rb R 4 c R'c Rib 36-13 Ra Rb Rb R a 36-54 Rc R 4 0 R'c Rib 36-14 Rb Rb Rb R'a 36-55 R" R 4 a Ra R"c 36-15 Rc R 4 b Rb R a 36-56 R R 4 a Ra Ri 36-16 Ra Rc Rb R"a 36-57 Rc R 4 a Ra R"c 90 WO 2005/042712 PCT/US2004/035939 36-17 Rb R 4 R'b R"a 36-58 Ra Rb Ra R"e 36-18 Re R 4 R'b R!,a 36-59 Rb Rib R'a R"e 36-19 Ra R 4 a R' R"a 36-60 Rc Rb R'a R"e 36-20 R R 4 a R' R"a 36-61 Ra Rie R'a Re 36-21 Rc R 4 a R'c R 1 a 36-62 Rb R 4 C Ra R"e 36-22 Ra R 4 R'e Ria 36-63 Re R 4 c Ra R"e 36-23 Rb R 4 b R'" R'ia 36-64 Ra R 4 a Rb R"e 36-24 Re R 4 b R'C R'a 36-65 Rb R 4 a R'b R"e 36-25 Ra Re R'e R"a 36-66 Re R 4 a R'b R"e 36-26 Re R 4 R'c R"a 36-67 Ra Rib Rb R"e 36-27 Re R 4 c R'c R'a 36-68 Rb Rib Rib Re 36-28 Ra R 4 a R'a Rib 36-69 R Rib Rb Rie 36-29 Rb R 4 a Ra Rib 36-70 Ra R 4 e Rb Re 36-30 Re R 4 a R a Rub 36-71 Rb R 4 Rb R"e 36-31 Ra R 4 b R a R"b 36-72 Re R 4 c Rib R" 36-32 Rb Rb Ra Rib 36-73 Ra R 4 a R'e Re 36-33 Re R 4 Ra R"b 36-74 Rb R4a Re R"e 36-34 Ra R 4 e Ra R"b 36-75 Re R 4 " R' R"e 36-35 R' R 4 c Ra R"b 36-76 Ra R 4 b R" Rie 36-36 Re R 4 c Rya Rib 36-77 Rb RIb R' Re 36-37 RD R 4 a Rb Rib 36-78 Re Rib R' Re 36-38 Rb R 4 a R b R"b 36-79 Ra R 4 e Rc Rue 36-39 Re R 4 a Rb R"b 36-80 Rb R4i Re Rie 36-40 Ra R 4 b Rb R"b 36-81 Re R 4 Re Re 36-41 Rb Rib Rb Rib 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 nitro group, an optionally substituted amino group, an alkyl group, an 5 alkoxy group, an alkenyl group, or an alkoxyalkyl group; R is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a 10 heteroaryloxy group, or a heteroaralkoxy group; and 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, or a benzyloxy group. 91 WO 2005/042712 PCT/US2004/035939 In another aspect of formula (36) of the present invention, R is hydrogen or an alkyl group; R 4 is a cycloalkenyl group, a cycloalkenyloxy group, an acyl group 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 5 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 CH 3 ; R is a halogen substituted aryl group; and R' and R" independently are -H or -Cl; and all other symbols are as defined above in connection with formula (I). 10 Examples of compounds of formula (36) include, but are not limited to: 0 0 N C-'N ~- ci CH3 F
CH
3 FHcF HN- HN 0; 0; 0 o o and FH 3 F The present invention also contemplates various compounds having the general formula: R0 H N N o R 4 0 s H N 15 0 (37), where all symbols are as defined above in connection with formula (I). According to some variations of the present invention, E, R', and R 4 of formula (37) are selected to produce compounds of formula (37-1) through formula (37-27): Formula E R I R 37-1 Ea Ria R4a 37-2 Eb RIa R4a 37-3 Ec RIa Ra 92 WO 2005/042712 PCT/US2004/035939 37-4 Ea Ri 37-5 Eb Rl R4a 37-6 E" R R a 37-7 Ea RI' R4a 37-8 Ec Rc Ra 379 EI' R4a 37-10 Ea R R 37-11 E b Ri]a R4O 37-12 E Ria R4 37-13 E a R ]b R4b 37-14 E b R lb RO 37-15 E' RI R4 37-16 Ea Rlc
R
4 b 37-17 Eb Re R4b 37-18 Ec Rc R40 37-19 Ea
R
1 3 R 4F 37-20 eh Rla RW" 37-21 Ec Rla R44 37-23 Ea R ] R4C 3-3 1b Rlb R4c 37-24 E' R' R4c 37-25 Ea Rlc R4c 37-26 Eb RIC Rle 37-27 Eb RI' R 4" where all symbols are as defined above. In one 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 5 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 aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl 10 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 another aspect of formula (3 7) of the present invention, R' is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally 15 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 93 WO 2005/042712 PCT/US2004/035939 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). 5 In yet another aspect of formula (37) of the present invention, R' is hydrogen, a halogen, or an alkoxy group; R 4 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 10 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 R22 halogen, or an alkoxy group; E is 0 or -NR; and R 4 is R 23 or ,where R? 2 and R 3 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di 15 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 20 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, 25 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 fonnula (I). In still another aspect of formula (37) of the present invention, R' is hydrogen or a halogen; E is 0 or NMe; R 4 is a substituted aryl group or a heterocycyl group; R2 is 94 WO 2005/042712 PCT/US2004/035939 hydrogen or an alkoxy group; R 2 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, R1 is -H, -F, or MeO; R 22 S E is O or NMe; R is R23 or ,where R 22 is -H or OMe; and R? 3 is -F or 5 OMe. An exemplary compound includes, but is not limited to: OMe MOo 0 OMe 0 S NH TO O OMeO O 0 According to another aspect of the present invention, various compounds of general formula (I) having general formula (IV) Y1 RE 4 FAN E NR D R-GZ-Ar 2RV 10 X 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). A multitude of compounds having the general formula (IV) are contemplated by the 15 present invention. Examples of such compounds include, but are not limited to:
Y
1
Y
1
R
0
R
4 F NR R 1 S R 4 FA NR -G=Z-Ar 2 K-yZ-Ar
R
2 ' R 5 RR X (38); X (39);
Y
1
Y
1 N R NR RE R 4 FNR K=-Ar . ~G=Z-Ar-- y
R
2
R
5 X (40); X (41); 95 WO 2005/042712 PCT/US2004/035939
Y
1
Y
1 RER4 FA NR R 1 2 r: 4 FA NR -2K G=Z-Ar R', , 2 R y XR (42); X R (43); Y1 RIY 1
R
1 E R 4 FA NR 4E R 4 Fk NR 11K-Gr-Z-Ar- D' I' =-A~ (4) R5 R 5 x(4; WX (45); E R 4 FA 4NR RE,_R 4 FrA vsI K-G=Z-Ar N -~-A j2XR (46); R 2 X Rs(47);
Y
1 Y1 R4 R' > E R 4 FA NR E R 4 FA NR KG=Z-Ar G-ZK-G=Z--Ar
R
5 H IR R(48); R 2 X(49);
Y
1 y 1 R4 FA 1 4F F R NR ,,9 E R 4 NR DIYD -j K- G=(CH 2 )6,-Ar y2- K- GS(=O),-Ar 5 RX(50); R 2 x (51);
Y
1 R E R 4 FA NR DI '] I
\~IK-CH
2 )-Z-Ar( -', X (52);
Y
1 R E R 4 FA NR K-(0 22 c ~~CH 2
)
2 -Ar Y
R
2
R
5 X (53);
Y
1 R' E R 4 FA NR IIK- (CH 2 )-C (CHA)-Are RZ2
R
5 X (54); 96 WO 2005/042712 PCT/US2004/035939
Y
1
Y
1 R' R4F l 4F D 1 YF NR E R 4 NR KDZ- D/ G=-I-' y K-G=Z-K y2Z-AI 0 2
R
5 (55); R 2 s R 5 (56);
Y
1 EDRI 4 F NR R 4 R G=~ ~~~~KGZ-Ar-( ly /-Z-Ar-q R s R5 (57); R 2 x Rs (58);
Y
1 Y1 ER R S NR E R 4 R NR D'YGZA- K-G=Z-Ar y x R-9 (59); R 2 x
R
5 (60); 2 Rs ER R F NR E R 4 F N K-G=Z-Ar G=- D2 Rx R 5 (61); R 2 x R 5 (62);
Y
1
Y
1 114EyR4 F NR D E -R 4 F NR K-G=Z-Ar D s o~ bj KG=Z-A 5 x R 5 (63); R x R 5 (64); E R4F <NR E R 4 F 'NR N-R 2 N- (C \jj~l -GZA -I NC 2 )-Z-Ar Y Rx
R
5 (65); R x
R
5 (66);
Y
1
Y
1 Rl A R4 E 4F NR E R' FA NR \jj N(CH 2 X -O-Ar DjI N(CH 2 X.-S-A
R
2 x Rs (67); j 2 x FR 5 (68); Yl 0
R
1 F>NR 1 EN R4 F>4NR Nj. (CH 2 ),-N-Ar />- N (CH 2 )1-0-Ar ( 0 R,2 0
R
2
R
5 (69); R 0 R 5 (70); RiJ R' > F NR E -R' F NR DCH)SSIYI- R xR 5 (71); R 2 0 (72); 97 WO 2005/042712 PCT/US2004/035939 R1 R1 /7E R 4 NR 4E YR' 0 NR D N-CH 2 )s-O-Ar NRN- (CH 2 )s-S-Ar - - CH2)s -Ar- NRD -c2 o Ar N R 0 R 5 (73); R X R 5 (74); NR R D, R R D/ R'SN N- (CH 2 ),-N-Ar- NR N- (CH 2 )O-Ar NR 0 R (76) 0 R (75); R R RI R R4'I NRA R 4 NR jD N-(CH 2 )2-Z-Ar D (CH2)R-r N
R
2 X 5 (7) R 2 X (8); RNR Dj N-(CH 2
)
2 O-Ar NR f N-(CH 2
)
2 -S-Ar
R
2 X R 5 (7) R 2 X R 5 (8);
R
1 R R1 E R 4 0A NR 'NR E R4 0 NR N- (CH 2
)
2 -- Ar R D N 2)R-A a "1- N-C,)--( R X R6 (8 1); R 2 X R5 (8); 09 NRN RR1 N OI
/-IIETR
4 N R E RN \j N-(CH 2
)
2 -S-Ar \D.j _-C 2 2 S-R 5 2 X 5 (83) R 2 X (8); 0 0 E 's NR Ej F4s NR b~I R- 0 --- 2 -(CH 2
)
2 - -Ar \j N (CH 2 )2 - ( X(8); (86);hr l S 01 N, ~ ~ E, R4 4 R (87), 98 WO 2005/042712 PCT/US2004/035939 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: 0 R1 NR R0 N -G=Z N N-G=Z NR 0 (88); R (89); R1
R
1 N N R 4 y~R 0 N NGZ / 'N N-G Z S NR O R 5 S 0 0 5
R
5 (90); R (91); R N 0 R1 S R5 NN R 4 Ni N N-G=Z and R (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', R4 , G, and Z of 10 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 4 R' G Z 88-1 89-1 90-1 91-1 92-1 Ra Ri" R 4 " Rsa Ga Za 88-2 89-2 90-2 91-2 92-2 R, Rla R4a Ra Ga Za 88-3 89-3 90-3 91-3 92-3 Rc Ria R4a Rsa Ga Za 88-4 89-4 90-4 91-4 92-4 Ra Rib R 4 a Ra Ga Za 88-5 89-5 90-5 91-5 92-5 R R R a Rsa Ga Za 88-6 89-6 90-6 91-6 92-6 R' Rl R 4
R
5 a Ga za 88-7 89-7 90-7 91-7 92-7 Ra RIc Ra Rsa Ga za 88-8 89-8 90-8 91-8 92-8 R Re R4" Rsa Ga Za 88-9 89-9 90-9 91-9 92-9 R4 RIC R 4 a R 5 a Ga za 99 WO 2005/042712 PCT/US2004/035939 88-10 89-10 90-10 91-10 92-10 Ra Ria R 4 b R5a Ga Za 88-11 89-11 90-11 91-11 92-11 Rb Ria R 4 b R G" Za 88-12 89-12 90-12 91-12 92-12 Rc Ria R 4 b R5a Ga Za 88-13 89-13 90-13 91-13 92-13 Ra R R 4 b Ra Ga Za 88-14 89-14 90-14 91-14 92-14 R b R R4 R5 G" Za 88-15 89-15 90-15 91-15 92-15 R R R' R G Za 88-16 89-16 90-16 91-16 92-16 Ra Ric R 4 b Ra Ga Za 88-17 89-17 90-17 91-17 92-17 R' RIC R 4 b Ra Ga Za 88-18 89-18 90-18 91-18 92-18 R Rc R Ra Ga Za 88-19 89-19 90-19 91-19 92-19 Ra Re R 4 4 Ra Ga Za 88-20 89-20 90-20 91-20 92-20 Re Rla Rac RMa Ga Za 88-21 89-21 90-21 91-21 92-21 R" RI Re Ra Ga Za 88-22 89-22 90-22 91-22 92-22 Ra R" R4 Ra Ga Za 88-23 89-23 90-23 91-23 92-23 Re RI" R 4 c Ra Ga Za 88-24 89-24 90-24 91-24 92-24 Rc Rlb R 4 c R 5 a Ga Za 88-25 89-25 90-25 91-25 92-25 Ra Ric R4c Rl G a Za 88-26 89-26 90-26 91-26 92-26 R Rb" Rc R5 Ga Za 88-27 89-27 90-27 91-27 92-27 R R'c R4 Ra Ga Za 88-28 89-28 90-28 91-28 92-28 Ra R R4a R5a Ga Za 88-29 89-29 90-29 91-29 92-29 Rb Ria Ra REb Ga Za 88-30 89-30 90-30 91-30 92-30 Rc Ria R~a R 5b G" Za 88-31 89-31 90-31 91-31 92-31 Ra R lb R~a R3b G"a Za 88-32 89-32 90-32 91-32 92-32 Ra RIb R 4 a Ra Ga Za 88-33 89-33 90-33 91-33 92-33 R Rlb R4a R3b Ga Za 88-34 89-34 90-34 91-34 92-34 Ra Ri'c R 4 a R Ga Za 88-35 89-35 90-35 91-35 92-35 R' R'c R 4 a R5b Ga Za 88-36 89-36 90-36 91-36 92-36 Rc R' R4a R Ga Za 88-37 89-37 90-37 91-37 92-37 Ra Ria R 4 O R5b Ga Za 88-38 89-38 90-38 91-38 92-38 Re Ra R4 Rb Ga Za 88-39 89-39 90-39 91-39 92-39 Rc R R REb Ga Za 88-40 89-40 90-40 91-40 92-40 Ra R lb R4 Sb Ga Z. 88-41 89-41 90-41 91-41 92-41 R' R lb R4b REb G a Za 88-42 89-42 90-42 91-42 92-42 Rc R l RO Rsb Ga Za 88-43 89-43 90-43 91-43 92-43 R a R'" R4b RSb G a Za 88-44 89-44 90-44 91-44 92-44 R' Ric R4 REb G a Za 88-45 89-45 90-45 91-45 92-45 RW R'c R4b REb Ga Za 88-46 89-46 90-46 91-46 92-46 R a R a Rlc Rsb G a Za lb 4a 5b C 88-47 89-47 90-47 91-47 92-47 Re R R R Ga Za 88-48 89-48 90-48 91-48 92-48 c Ra R4 Rb Ga Za 88-49 89-49 90-49 91-49 92-49 Ra Ric R 4 e Rb Ga Za 88-50 89-50 90-50 91-50 92-50 Re R lb R4" R5b G a Za 88-51 89-51 90-51 91-51 92-51 R' R"E Rc R 5b Ga Za 88-52 89-52 90-52 91-52 92-52 Ra Ric Ric Rs5b G a Za 88-53 89-53 90-53 91-53 92-53 Re Ri" R Rsb Ga Za 88-54 89-54 90-54 91-54 92-54 R Ria R 4 " Rsb Ga Za 88-55 89-55 90-55 91-55 92-55 Ra Rl R4a Rc Ga Za 88-56 89-56 90-56 91-56 92-56 Rb RIa R 4 a Rb Ga Za 100 WO 2005/042712 PCT/US2004/035939 88-57 89-57 90-57 91-57 92-57 R' Ria R 4 a Rc Ga Za 88-58 89-58 90-58 91-58 92-58 Ra Rib R 4 a R 5 ( Ga za 88-59 89-59 90-59 91-59 92-59 R R" Ra R' Ga Za 88-60 89-60 90-60 91-60 92-60 R R" R R Ga Za 88-61 89-61 90-61 91-61 92-61 Ra Rl' R 4 a Rsc Ga Za 88-62 89-62 90-62 91-62 92-62 R RI'c R4a sc Ga Za 88-63 89-63 90-63 91-63 92-63 Rc Rlc R4a Ra' Ga Za 88-64 89-64 90-64 91-64 92-64 R Ri R4a Rc' Ga Za 88-65 89-65 90-65 91-65 92-65 R' Ria R 4 Rsc Ga Za 88-66 89-66 90-66 91-66 92-66 R' R a R, Rc Ga Za 88-67 89-67 90-67 91-67 92-67 Ra Ra R 4 b R Ga Za 88-68 89-68 90-68 91-68 92-68 R4 R Rb Rsc Ga Za 88-69 89-69 90-69 91-69 92-69 R' R" Rlb R Ga Za 88-70 89-70 90-70 91-70 92-70 Ra Rc R4 Rc Ga Za 88-71 89-71 90-71 91-71 92-71 R R' R4b Rc Ga Za 88-72 89-72 90-72 91-72 92-72 Rc R' R4 R5c Ga Za 88-73 89-73 90-73 91-73 92-73 R Ria R 4 c RSc Ga Za 88-74 89-74 90-74 91-74 92-74 Rb Ria R4 Rc Ga Za 88-75 89-75 90-75 91-75 92-75 Rc Ria R 4 b Rsc Ga Za 88-76 89-76 90-76 91-76 92-76 Ra Rlb R 4 c Rac Ga Za 88-77 89-77 90-77 91-77 92-77 R R l R4c R Ga Za 88-78 89-78 90-78 91-78 92-78 Rc RIa R 4 C Rc' Ga za 88-79 89-79 90-79 91-79 92-79 Ra Rlc R4c R Ga Za 88-80 89-80 90-80 91-80 92-80 Rb Ric R 4 c Rc Ga za 88-81 89-81 90-81 91-81 92-81 Rc Rlc R' R5' Ga Za 88-82 89-82 90-82 91-82 92-82 Ra Ria R 4 a Rsa Gb Za 88-83 89-83 90-83 91-83 92-83 R c Ra Ra R a G b Za 88-84 89-84 90-84 91-84 92-84 R Ria R4a Rsa Gb Za 88-85 89-85 90-85 91-85 92-85 Ra R R 4 a RE" Ga Za 88-86 89-86 90-86 91-86 92-86 R' R R R " Gb Za 88-87 89-87 90-87 91-87 92-87 R4 R R a RSa Gb Za 88-88 89-88 90-88 91-88 92-88 Ra R 1 Rla Rsa Gb Za 88-89 89-89 90-89 91-89 92-89 RC R' R 4 a R 5 a Gb Za 88-90 89-90 90-90 91-90 92-90 R' R R4a Rsa eb Za 88-91 89-91 90-91 91-91 92-91 Ra R Ia Rb Rs5a (jt Za 88-92 89-92 90-92 91-92 92-92 R' Ria R4b Rsa Gb Za 88-93 89-93 90-93 91-93 92-93 R Ra Rb Rs a Gb Za 88-94 89-94 90-94 91-94 92-94 Ra Ri Rb W Rs5a ( b Za 88-95 89-95 90-95 91-95 92-95 R R lb R4b Rsa GE Za 88-96 89-96 90-96 91-96 92-96 R R l R4 Rsa GE Za 88-97 89-97 90-97 91-97 92-97 Ra RI' Rl RSa eb Za 88-98 89-98 90-98 91-98 92-98 Rc Rc R R5a Gb Za 88-99 89-99 90-99 91-99 92-99 R Rl" R4b Rsa GE Za 88-100 89-100 90-100 91-100 92-100 Ra Ria R4c Rsa Gb Za 88-101 89-101 90-101 91-101 92-101 R Rla R 4 c RSa Gb Za 88-102 89-102 90-102 91-102 92-102 Rb RIa Rc Rsa GE Za 88-103 89-103 90-103 91-103 92-103 Ra R 1 R Rsa Gb Za 101 WO 2005/042712 PCT/US2004/035939 88-104 89-104 90-104 91-104 92-104 R l Rb R4 R5a Gb Za 88-105 89-105 90-105 91-105 92-105 Re R R " R5a Gb Za 88-106 89-106 90-106 91-106 92-106 Ra Rib R4 Rsa Gb Za 88-107 89-107 90-107 91-107 92-107 R' RIc R 4
R
5 a Gb Za 88-108 89-108 90-108 91-108 92-108 Rc R R4e R5a Gb Za 88-109 89-109 90-109 91-109 92-109 Ra R R a RI, G Za 88-110 89-110 90-110 91-110 92-110 R4 R a a Rab G3 Za 88-111. 89-111 90-111 91-111 92-111 R" Ra Ra R l G Za 88-112 89-112 90-112 91-112 92-112 R4a R Gb Za 88-113 89-113 90-113 91-113 92-113 Ra R R " Rab GE Za 88-114 89-114 90-114 91-114 92-114 Rc Ri R b WE Ra Gb 3: Za 88-115 89-115 90-115 91-115 92-115 Ra RIa 4a R5b Gj Za 88-116 89-116 90-116 91-116 92-116 Rb Rc Ra REb Gb Za 88-117 89-117 90-117 91-117 92-117 Re Rl R Wa Rab Gb Za 88-118 89-118 90-118 91-118 92-118 Ra Ria R 4 Rab Gb Za 88-119 89-119 90-119 91-119 92-119 Re Rib R 4 R5b Gb za 88-120 89-120 90-120 91-120 92-120 R" R Ia R4b R3b Gb Za 88-121 89-121 90-121 91-121 92-121 R a R Ib RWb Rab G b Za 88-122 89-122 90-122 91-122 92-122 Rb RIb 4 R5b Gb Za 88-123 89-123 90-123 91-123 92-123 R4 R l R4b REb Gb Za 88-124 89-124 90-124 91-124 92-124 Ra R" R Rab Gb Za 88-125 89-125 90-125 91-125 92-125 Ra Rc R Rab G Za 88-126 89-126 90-126 91-126 92-126 Re R" R R l G Za 88-127 89-127 90-127 91-127 92-127 Ra R Ia Re R3b Gb Za 88-128 89-128 90-128 91-128 92-128 R Ria R 4 b R5b Gb Za 88-129 89-129 90-129 91-129 92-129 R Ri R 4 R5b Gb Za 88-130 89-130 90-130 91-130 92-130 Ra RIb Re R5b Gb Z. 88-131 89-131 90-131 91-131 92-131 R R R " Rab Gb Za 88-132 89-132 90-132 91-132 92-132 Rc R R " Rab Gb Za 88-133 89-133 90-133 91-133 92-133 Ra Ric R4 Rlb Gb Za 88-134 89-134 90-134 91-134 92-134 R RIc R 4 b Rb Gb Za 88-135 89-135 90-135 91-135 92-135 R" Ri" R R3 Gb Za 88-136 89-136 90-136 91-136 92-136 Re Ri Ra Rc Gb Za 88-137 89-137 90-137 91-137 92-137 Ra Ra R" R G Za 88-138 89-138 90-138 91-138 92-138 Re R R a R5e Gb Za 88-139 89-139 90-139 91-139 92-139 Ra R R a RSe Gb Za 88-140 89-140 90-140 91-140 92-140 Rb R Ra Rsc Gb za 88-141 89-141 90-141 91-141 92-141 Rb Rib Rb Re Gb Za 88-142 89-142 90-142 91-142 92-142 Ra Rl" Ra Rsc Gb Za 88-143 89-143 90-143 91-143 92-143 Re RI R 4 a RSb G Za 88-144 89-144 90-144 91-144 92-144 R4 R c a RSc Gb Za 88-145 89-145 90-145 91-145 92-145 Ra R R Rl G Za 88-146 89-146 90-146 91-146 92-146 Rb R R Re Gb Za 88-147 89-147 90-147 91-147 92-147 Re R 4Ia S blc Gb Za 88-148 89-148 90-148 91-148 92-148 Ra Rb R Rl4 G Za 88-149 89-149 90-149 91-149 92-149 R R R R3" Gb Za 88-150 89-150 90-150 91-150 92-150 Re Rlb R RSc Gb Za 102 WO 2005/042712 PCT/US2004/035939 88-151 89-151 90-151 91-151 92-151 Ra R' R R G' Za 88-152 89-152 90-152 91-152 92-152 Rb R R b RR Gb Za 88-153 89-153 90-153 91-153 92-153 Re Ri' R4b Rc Gb Za 88-154 89-154 90-154 91-154 92-154 Ra Ria R 4 c Rc Gb za 88-155 89-155 90-155 91-155 92-155 R Ria PR. R3 G Za 88-156 89-156 90-156 91-156 92-156 Rc Ria R 4 c Rc Gb Za 88-157 89-157 90-157 91-157 92-157 Ra R l R4' R Gb Za 88-158 89-158 90-158 91-158 92-158 Rb R l R4c Rc G Za 88-159 89-159 90-159 91-159 92-159 Re R R 4 c Rsc G Za 88-160 89-160 90-160 91-160 92-160 Ra RIC R R Gb Za 88-161 89-161 90-161 91-161 92-161 R R RI R4 c Gb Za 88-162 89-162 90-162 91-162 92-162 Re Rl R4c R Gb Za 88-163 89-163 90-163 91-163 92-163 Ra Rla Ra Ria Ge Za 88-164 89-164 90-164 91-164 92-164 Re R a R4a R Gc Za 88-165 89-165 90-165 91-165 92-165 R' Ria R 4 a Rsa Ge Za 88-166 89-166 90-166 91-166 92-166 Ra Rlb R4a R5a G Za 88-167 89-167 90-167 91-167 92-167 R R l R4a R Ge Za 88-168 89-168 90-168 91-168 92-168 Re R 1 l R 4 a R 5 Ge Za 88-169 89-169 90-169 91-169 92-169 R Ribc Raa Ra Ge Za 88-170 89-170 90-170 91-170 92-170 R Rib Ra Rsa G Za 88-171 89-171 90-171 91-171 92-171 R Ri' R 4 a Rsa Ge Za 88-172 89-172 90-172 91-172 92-172 Ra RIC R 4 Rsa Ge Za 88-173 89-173 90-173 91-173 92-173 R a e a Gc Za 88-174 89-174 90-174 91-174 92-174 Re Ra R Ra Ge Za 88-175 89-175 90-175 91-175 92-175 a Rib Ri RW a Ge Za 88-176 89-176 90-176 91-176 92-176 R R Ria R 4 b R5a G Za 88-177 89-177 90-177 91-177 92-177 R "R R sa Gc Za 88-178 89-178 90-178 91-178 92-178 Ra Ri' R4b R G Za 88-179 89-179 90-179 91-179 92-179 Re Rl R 4 b Rsa G Za 88-180 89-180 90-180 91-180 92-180 Rc Rlb R4b 5a Gc Za 88-181 89-181 90-181 91-181 92-181 Ra Ra Rc R" G Za 88-182 89-182 90-182 91-182 92-182 R b a R4c b a G Za 88-183 89-183 90-183 91-183 92-183 Re Ria R4 R Ge Za 88-184 89-184 90-184 91-184 92-184 Ra Ri Rl ' Rs a Ge Za 88-185 89-185 90-185 91-185 92-185 R R R4 R G Za 88-186 89-186 90-186 91-186 92-186 Rc Rie R 4 b RW Ge Za 88-187 89-187 90-187 91-187 92-187 Ra Ric RWc RW Gc Za 88-188 89-188 90-188 91-188 92-188 Rb Ric R4c R a Gc Za 88-189 89-189 90-189 91-189 92-189 Re Ri'c R Ra G Za 88-190 89-190 90-190 91-190 92-190 Ra R R 4 a Ra G Za 88-191 89-191 90-191 91-191 92-191 Ra Ra R 4 a R ja Ge Za 88-192 89-192 90-192 91-192 92-192 Rc R" Rja Rb G Za 88-193 89-193 90-193 91-193 92-193 Ra Ria R 4 ea Ra G Za 88-194 89-194 90-194 91-194 92-194 R' Rlb R4a R Ge Za 88-195 89-195 90-195 91-195 92-195 R Rl R 4 a R 5 b Ge Za 88-196 89-196 90-196 91-196 92-196 Ra Rlc Rja R. G Za 88-197 89-197 90-197 91-197 92-197 R RI'c R 4 a Rla G Za 103 WO 2005/042712 PCT/US2004/035939 88-198 89-198 90-198 91-198 92-198 Re RIC R 4 a Rab Ge Za 88-199 89-199 90-199 91-199 92-199 Ra Ria R4b Rb Gc Za 88-200 89-200 90-200 91-200 92-200 R Ria R 4 b R5' Ge Za 88-201 89-201 90-201 91-201 92-201 Re Ria RIb Rib Ge Za 88-202 89-202 90-202 91-202 92-202 Ra R R 4 R"b G Za 88-203 89-203 90-203 91-203 92-203 R Rb R4b R 5 b Gc Za 88-204 89-204 90-204 91-204 92-204 R' R lb R4 Rab G Za 88-205 89-205 90-205 91-205 92-205 Re R R4b Rb Ge Za 88-206 89-206 90-206 91-206 92-206 Ra RIc R4b R5b Ge Za 88-207 89-207 90-207 91-207 92-207 R' Rc Rb Rib Ge Za 88-208 89-208 90-208 91-208 92-208 Re RIC R 4 b Rab Ge Za 88-209 89-209 90-209 91-209 92-209 Ra Ria R 4 e R5b Ge Za 88-210 89-210 90-210 91-210 92-210 R Rla R 4 c Rab Gc Za 88-211 89-211 90-211 91-211 92-211 a R R 4 e Rab Ge Za 88-212 89-212 90-212 91-212 92-212 Rb R b R4c Rab G Za 88-213 89-213 90-213 91-213 92-213 Ra Rl R 4 c Rab Ge Za 88-214 89-214 90-214 91-214 92-214 Ra Rc RW' Rab G' Za b4 lbcc Z 88-215 89-215 90-215 91-215 92-215 R R R 4 c Rib Ge Za 88-216 89-216 90-216 91-216 92-216 Re Re Rc Rab Gc Za 88-217 89-217 90-217 91-217 92-217 Ra Ri' R 4 a Rc Ge Za 88-218 89-218 90-218 91-218 92-218 Rb RIa Ria Rib G Za 88-219 89-219 90-219 91-219 92-219 Re Ria R 4 a R5e Ge Za 88-220 89-220 90-220 91-220 92-220 Ra Ra R 4 a R5" Ge Za 88-221 89-221 90-221 91-221 92-221 R Ia R4a R5' G Za 88-222 89-222 90-222 91-222 92-222 Re R l R4a R Gc Za 88-223 89-223 90-223 91-223 92-223 RE Rc R 4 a R5c Ge Za 88-224 89-224 90-224 91-224 92-224 R' Ric R~ s e Za 88-225 89-225 90-225 91-225 92-225 R Rlc R4a R5' Gc Za 88-226 89-226 90-226 91-226 92-226 Ra R Ra Rc Ge Za 88-227 89-227 90-227 91-227 92-227 b Ra Rb Ra' G' Za 88-228 89-228 90-228 91-228 92-228 R Ria R4 Ra' Ge Za 88-229 89-229 90-229 91-229 92-229 Ra Rib R R5 Ge Za 88-230 89-230 90-230 91-230 92-230 R R 1 l R 4 a Rc Ge Za 88-231 89-231 90-231 91-231 92-231 Rc RIb R4 Re G Za 88-232 89-232 90-232 91-232 92-232 Ra R' R R G Za 88-233 89-233 90-233 91-233 92-233 Re R R a Rsc Ge Za 88-234 89-234 90-234 91-234 92-234 Re Rlc Rob Rsc Gc Za, 88-235 89-235 90-235 91-235 92-235 Ra Ria R4' R3c G' Za 88-236 89-236 90-236 91-236 92-236 Rb RIa R 4 b Re Ge Za 88-237 89-237 90-237 91-237 92-237 R Ria Rc R Gc Za 88-238 89-238 90-238 91-238 92-238 Re R b R 4 b R 5 Ge Za 88-239 89-239 90-239 91-239 92-239 R RIb Rb R Ge Za 88-240 89-240 90-240 91-240 92-240 R Rib R' RG" Ge Za 88-241 89-241 90-241 91-241 92-241 RE Rl R4' R5' Ge Za 88-242 89-242 90-242 91-242 92-242 Ra Re R 4 b Rsc Ge Za 88-243 89-243 90-243 91-243 92-243 R Re R4 R5e Ge Za 88-244 89-244 90-244 91-244 92-244 Ra Ra R" Rsa GE Za 104 WO 2005/042712 PCT/US2004/035939 88-245 89-245 90-245 91-245 92-245 R' Ria R 4 a R3" G Z 88-246 89-246 90-246 91-246 92-246 Rc Ria 4a Ra Ga Zb 88-247 89-247 90-247 91-247 92-247 Ra R l Rla Ra Ga Zb 88-248 89-248 90-248 91-248 92-248 R R" R4a Ra Ga Zb 88-249 89-249 90-249 91-249 92-249 Ra R l Rja Ra Ga Z b b a Wa Ca b 88-250 89-250 90-250 91-250 92-250 Ra Rc R R G Z 88-251 89-251 90-251 91-251 92-251 R4a R Ga Zb 88-252 89-252 90-252 91-252 92-252 Re R' Ra R G Z 88-253 89-253 90-253 91-253 92-253 Ra Ria R 4 Rsa Ga Ze b9a R 4 a Ga Z 88-251 89-255 90-251 91-251 92-255 R R R R G Z 88-256 89-256 90-256 91-256 92-256 a R R4 R4 G a Zb 88-252 89-252 90-252 91-252 92-252 Re R R R G Z 88-258 89-258 90-258 91-258 92-258 R4 Ri R4 W RMa G a Zt 88-259 89-259 90-259 91-259 92-259 Ra R S R4b Ra Ga Zb 88-25 89-253 90-25 91-25 92-253 Ra R'c R4b R G Z 88-261 89-261 90-261 91-261 92-261 R' Rlc R4b Ra Ga Zb 88-262 89-262 90-262 91-262 92-262 Ra Rla R4' Ra G Z 88-263 89-263 90-263 91-263 92-26 R R Rla R 4 c R[a Ga Zb 88-264 89-264 90-264 91-264 92-264 RC Ra R4 Ra Ga Zb 88-265 89-265 90-265 91-265 92-265 Ra Ra Rc Ra Ga Zb 88-266 89-266 90-266 91-266 92-266 Ra R l R4 Ra Ga Zb 88-267 89-267 90-267 91-267 92-267 R' R l R4 R Ga Z lb Wb S~a Ca b 88-268 89-268 90-268 91-268 92-268 Ra Rc Rc R G Z 88-269 89-269 90-269 91-269 92-269 Ra R" R4 Ra Ga Zb 88-270 89-270 90-270 91-270 92-270 Re Rc Rae Rsa Ga Z 88-271 89-271 90-271 91-271 92-271 Ra Ria R4a R5b G Z 88-272 89-272 90-272 91-272 92-272 Ra RWaRaa R 5 b Ga Zb 88-273 89-273 90-273 91-273 92-273 R" Ria R R Ga Ze 88-274 89-274 90-274 91-274 92-274 Ra R R a Rab G Z 88-275 89-275 90-275 91-275 92-275 Ra R R4 R Ga Z 88-276 89-276 90-276 91-276 92-276 Rc R Rea R5b Ga Zb 88-277 89-277 90-277 91-277 92-277 Ra Rc R R5 G Z 88-278 89-278 90-278 91-278 92-278 R4 R cc a R5a Ga e 88-279 89-279 90-279 91-279 92-279 Re Rc R" Rb Ga Ze 88-280 89-280 90-280 91-280 92-280 R4a R a Rb REb Ga Zb 88-281 89-281 90-281 91-281 92-281 R' Ria R4b R5b G Z 88-282 89-282 90-282 91-282 92-282 Rc RIa R Rb Ga b 88-283 89-283 90-283 91-283 92-283 Rb R R Rab Ga Zb 88-284 89-284 90-284 91-284 92-284 R' RbI R4 RSa Ga b 88-285 89-285 90-285 91-285 92-285 Re R R Rb Ga Ze 88-286 89-286 90-286 91-286 92-286 Ra RIc R 4 a Rb Ga Zb 88-287 89-287 90-287 91-287 92-287 RS R R4b Rab Ga b 88-288 89-288 90-288 91-288 92-288 R' Rl' R R5 G Z 1 a 5a b Ca b 88-289 89-289 90-289 91-289 92-289 Ra R R R G Z 88-290 89-290 90-290 91-290 92-290 Ra RIa Rlc R Ga Z 88-291 89-291 90-291 91-291 92-291 R RIa R R Ga Z 105 WO 2005/042712 PCT/US2004/035939 88-292 89-292 90-292 91-292 92-292 Ra R l R R Ga Zb 88-293 89-293 90-293 91-293 92-293 R R l Rb " Rs Ga Ze 88-294 89-294 90-294 91-294 92-294 Re R lb R4 Rlb G Ze 88-295 89-295 90-295 91-295 92-295 Ra R R 4 R5b Ga Z 88-296 89-296 90-296 91-296 92-296 R RIC R4 R 5 G Z 88-297 89-297 90-297 91-297 92-297 Rc Ric Re R G Ze 88-298 89-298 90-298 91-298 92-298 Ra Ra Ra R Ga Ze 88-299 89-299 90-299 91-299 92-299 Rb R Ra Re Ga Ze 88-300 89-300 90-300 91-300 92-300 R' Ra Ra R Ga Zb 88-301 89-301 90-301 91-301 92-301 Ra Rib R 4 a Rsc Ga Zb 88-302 89-302 90-302 91-302 92-302 Rb Rib R 4 a Rse Ga Zb 88-303 89-303 90-303 91-303 92-303 Rc R R a R G Ze 88-304 89-304 90-304 91-304 92-304 Ra Ric Ra R Ga e 88-305 89-305 90-305 91-305 92-305 R' RI" Ra Rs Ga e 88-306 89-306 90-306 91-306 92-306 Rc RI" Ra R Ga Ze 88-307 89-307 90-307 91-307 92-307 Ra Ra R R5 Ga e ]a 4b Se Ca b 88-308 89-308 90-308 91-308 92-308 R R' R R G e 88-309 89-309 90-309 91-309 92-309 Rc Rla R4 R Ga Z 88-310 89-310 90-310 91-310 92-310 Ra R b R4 Rc Ga zb 88-311 89-311 90-311 91-311 92-311 R R b R c Ga e 88-312 89-312 90-312 91-312 92-312 Re R b R4 R Ga e 88-313 89-313 90-313 91-313 92-313 Ra RI Re RW" Ga e 88-314 89-314 90-314 91-314 92-314 Rb RIl b Sc Ga Zb 88-315 89-315 90-315 91-315 92-315 Rc RC R R Ga 7 88-316 89-316 90-316 91-316 92-316 Ra R R Sc Ga e 88-317 89-317 90-317 91-317 92-317 Rb Rl R4 Re Ga Ze 88-318 89-318 90-318 91-318 92-318 Re Rl R4 Re Ga e 88-319 89-319 90-319 91-319 92-319 Ra R l R Rsc G Ze 88-320 89-320 90-320 91-320 92-320 Ra R l Rb " R Ga e lb Ra RIc 5C a b 88-321 89-321 90-321 91-321 92-321 Re R R" R" G e 88-322 89-322 90-322 91-322 92-322 Ra R R4 Re Ga Z7 88-323 89-323 90-323 91-323 92-323 Rb R I 4c Rc Ga ;b 88-324 89-324 90-324 91-324 92-324 Re R Rc Re Ga Z 88-325 89-325 90-325 91-325 92-325 Ra R R4a a Rs G a e 88-326 89-326 90-326 91-326 92-326 Ra R R R " GW 7e 88-327 89-327 90-327 91-327 92-327 Re Ri RI a Rsa G Ze 88-328 89-328 90-328 91-328 92-328 Ra Rib R 4 a sa Ga e 88-329 89-329 90-329 91-329 92-329 R R I Rb a R5a G Z 88-330 89-330 90-330 91-330 92-330 Re RIb Ra Ra b e 88-331 89-331 90-331 91-331 92-331 Ra RC Ra Rsa G Ze 88-332 89-332 90-332 91-332 92-332 Rc R I RC R " G Z 88-333 89-333 90-333 91-333 92-333 R4 R Ra RSa Gb Zb 88-334 89-334 90-334 91-334 92-334 Ra RI R4 Rsa G Z7 88-335 89-335 90-335 91-335 92-335 Re RIa R4 Ra Gb Zb 88-336 89-336 90-336 91-336 92-336 Rb RI R Ra G Z 88-337 89-337 90-337 91-337 92-337 Ra R I R4 Re a Gb Ze 88-338 89-338 90-338 91-338 92-338 Rb Ri R4b Rsa Gb Zb 106 WO 2005/042712 PCT/US2004/035939 88-339 89-339 90-339 91-339 92-339 Re Rib R4b R5 G Z 88-340 89-340 90-340 91-340 92-340 Ra Rle R4b Ra G Z 88-341 89-341 90-341 91-341 92-341 R R'c R4 Ra G Z 88-342 89-342 90-342 91-342 92-342 Re RI'c R 4 Ra Gb Zb 88-343 89-343 90-343 91-343 92-343 Ra Ria R4 Rsa G Ze 88-344 89-344 90-344 91-344 92-344 R Ria R 4 ; Ra G Z 88-345 89-345 90-345 91-345 92-345 Re Ria R 4 c RMa Gb Zb 88-346. 89-346 90-346 91-346 92-346 Ra Rib R4 Ra Gb Z 88-347 89-347 90-347 91-347 92-347 Rb R R4' Ra G Zb 88-348 89-348 90-348 91-348 92-348 Re Rlb R4' sa b Zb 88-349 89-349 90-349 91-349 92-349 Ra R' R4' Rsa Gb ZE 88-350 89-350 90-350 91-350 92-350 R RIC R4' R GU Zb 88-351 89-351 90-351 91-351 92-351 Rc Ric R4c Ra G:? Zo 88-352 89-352 90-352 91-352 92-352 R a Rila R~a R 5b Gb Ze 88-353 89-353 90-353 91-353 92-353 Rb RIa Ra Rb Gb Zb 88-354 89-354 90-354 91-354 92-354 R' Ria Raa Rsh b b Zb 88-355 89-355 90-355 91-355 92-355 Ra R l R4a R G Ze 88-356 89-356 90-356 91-356 92-356 R R lb R4a Rb Gb Zb 88-357 89-357 90-357 91-357 92-357 Ra R a Rja R, G Z 88-358 89-358 90-358 91-358 92-358 Ra R Ra 5b Gb Zb 88-359 89-359 90-359 91-359 92-359 R R' Rla R ' G Z 88-360 89-360 90-360 91-360 92-360 R* R Ra R Gb Zd 88-361 89-361 90-361 91-361 92-361 Ra Ria R4' R5b G b e 88-362 89-362 90-362 91-362 92-362 R R R Rsb Ub Z 88-363 89-363 90-363 91-363 92-363 R Ria R4b RII Gb Zb 88-364 89-364 90-364 91-364 92-364 Ra R" R Rlb Go Ze 88-365 89-365 90-365 91-365 92-365 R R1 Rb4 Rb Gb e 88-366 89-366 90-366 91-366 92-366 Re R lb R4b Rab GB b Zb 88-367 89-367 90-367 91-367 92-367 Ra Rib Rlb R5' G Ze 88-368 89-368 90-368 91-368 92-368 Ra Rc R4 R G Ze 88-369 89-369 90-369 91-369 92-369 R" Rc R4b Rb G Ze ,a 4ac Sb Cb b 88-370 89-370 90-370 91-370 92-370 Ra R R R G Z 88-371 89-371 90-371 91-371 92-371 Ra Ria R 4 b Rlb Gb Zb 88-372 89-372 90-372 91-372 92-372 Rb R R4 REb GU Z 88-373 89-373 90-373 91-373 92-373 Ra Ria R' Rsb Gb Zb 88-374 89-374 90-374 91-374 92-374 Ra Rib R 4 Rsb Gb Zb 88-375 89-375 90-375 91-375 92-375 R R Re Rab G Ze 88-376 89-376 90-376 91-376 92-376 Ra R" We R;RbGE Z 88-377 89-377 90-377 91-377 92-377 R4 R b Rb Rsb Gb Zb 88-378 89-378 90-378 91-378 92-378 Re Ric R Rlb G Z 88-379 89-379 90-379 91-379 92-379 Ra Ria R~a RM G Z 88-380 89-380 90-380 91-380 92-380 R R R a Rc G Ze 88-381 89-381 90-381 91-381 92-381 Re Ri" Ra Rsc Gb Ze 88-382 89-382 90-382 91-382 92-382 Ra R l R4a R b Gb Ze 88-383 89-383 90-383 91-383 92-383 R R l R4a Rc G Z 88-384 89-384 90-384 91-384 92-384 Re R l Rb a Rsc Gb Z 88-385 89-385 90-385 91-385 92-385 Ra Rib Ra R GE Zb 107 WO 2005/042712 PCT/US2004/035939 88-386 89-386 90-386 91-386 92-386 Rb R]' Ra R G Ze 88-387 89-387 90-387 91-387 92-387 Re RIc 4a 5c Gb Zb 88-388 89-388 90-388 91-388 92-388 Ra Ria R4 Rsc G Z 88-389 89-389 90-389 91-389 92-389 Ra R R4 Re ' GE Z 88-390 89-390 90-390 91-390 92-390 R' R a Re Rc G3: Ze 88-391 89-391 90-391 91-391 92-391 Ra Rlb R4b Rc Gb b 88-392 89-392 90-392 91-392 92-392 R Rb R4l RI G Z 88-393 89-393 90-393 91-393 92-393 Re Rb Rb Re G Z2 88-394 89-394 90-394 91-394 92-394 Ra RI' R4 R G Z 88-395 89-395 90-395 91-395 92-395 Ra RIC R 4 R Gb Zb 88-396 89-396 90-396 91-396 92-396 Rb RI' R4b Re GE ZE 88-397 89-397 90-397 91-397 92-397 Ra Ria R4c R G Zb 88-398 89-398 90-398 91-398 92-398 Re Ria R R G Ze 88-399 89-399 90-399 91-399 92-399 R Ria R4 R G Ze 88-400 89-400 90-400 91-400 92-400 R a Ri R4 Re W GE Z 2 88-401 89-401 90-401 91-401 92-401 Rb Rb RW G e 88-402 89-402 90-402 91-402 92-402 R' Rib R4' R G Z 88-403 89-403 90-403 91-403 92-403 Ra RIC R 4 ' R Gb Zb 88-404 89-404 90-404 91-404 92-404 R5 Ric R4' Rc Gb Zb 88-405 89-405 90-405 91-405 92-405 R' R' Re RN Gc ( Zb 88-406 89-406 90-406 91-406 92-406 Ra Ria Rza R Ge Zb 88-407 89-407 90-407 91-407 92-407 Rb R" R4a Ra Gc ZE 88-408 89-408 90-408 91-408 92-408 Re Ri R 4 a R G Ze 88-409 89-409 90-409 91-409 92-409 Ra RIa R 4 a R G Zb 88-410 89-410 90-410 91-410 92-410 R Rh Rb a Rsa Ge Z 88-411 89-411 90-411 91-411 92-411 Rc RS R G b ZE 88-412 89-412 90-412 91-412 92-412 Ra Ric R4a R Gc Zb 88-413 89-413 90-413 91-413 92-413 R RIC R4a Ra Ge Zb 88-414 89-414 90-414 91-414 92-414 R4 RI" RWa Rsa Ge Z' 88-415 89-415 90-415 91-415 92-415 Ra Ria R R G Ze 88-416 89-416 90-416 91-416 92-416 RC Rib R R G Z 88-417 89-417 90-417 91-417 92-417 Rc Rba b G e 88-418 89-418 90-418 91-418 92-418 Ra RI R4b Ra G Ze 88-419 89-419 90-419 91-419 92-419 R R l R 4 C Rsa G Z 88-420 89-420 90-420 91-420 92-420 R' R l R4b Rsa G Z7 88-421 89-421 90-421 91-421 92-421 Ra RIC R4 Ra Gc e 88-422 89-422 90-422 91-422 92-422 R RIC R4b R G Zb 88-423 89-423 90-423 91-423 92-423 R' RIC R4b R5 G Zb 88-424 89-424 90-424 91424 92-424 Ra Ria R4a Ra Gc Zb 88-425 89-425 90-425 91-425 92-425 R' R.ia Rac Ra G' Zt 88-426 89-426 90-426 91-426 92-426 R Ria RI Rsa G Ze 88-427 89-427 90-427 91-427 92-427 Ra Rl R4a R5a G e 88-428 89-428 90-428 91-428 92-428 Rb R lb R4 RsWa Ge Zb 88-429 89-429 90-429 91-429 92-429 R R R4 R G Z 88-430 89-430 90-430 91-430 92-430 Ra RIC R 4 Ra G' Ze 88-431 89-431 90-431 91-431 92-431 R Ric R4 R GC Z 88-432 89-432 90-432 91-432 92-432 R RIC R4 R G Z7 108 WO 2005/042712 PCT/US2004/035939 88-433 89-433 90-433 91-433 92-433 Ra RE Ra Rab Gc Zb 88-434 89-434 90-434 91-434 92-434 e4a R Gc Zb 88-435 89-435 90-435 91-435 92-435 RC Ra Ra R G' Zb 88-436 89-436 90-436 91-436 92-436 Ra Ra Rb4a Rsb Gc e 88-437 89-437 90-437 91-437 92-437 Re Rib Ra Rlb Gc Z 88-438 89-438 90-438 91-438 92-438 Re Rib R 4 a R b Gc Z 88-439 89-439 90-439 91-439 92-439 R4a Rl Ra R5b Ge Zb 88-440 89-440 90-440 91-440 92-440 Rb Rib Ra Rb Gc Zb 88-441 89-441 90-441 91-441 92-441 Re Rib Ra Rab G Ze 88-442 89-442 90-442 91-442 92-442 Ra Ria R4b R G4 Zb 88-443 89-443 90-443 91-443 92-443 R R a R Rb G Ze 88-444 89-444 90-444 91-444 92-444 R Rla R4a 5b Ge b 88-445 89-445 90-445 91-445 92-445 Ra RI R4b Rs b Ge Zo 88-446 89-446 90-446 91-446 92-446 Re R R4 RW W G Ze 88-447 89-447 90-447 91-447 92-447 Re R 1 l Rb R Ge Zb 88-448 89-448 90-448 91-448 92-448 R5a R R4W Rsb Ge b 88-449 89-449 90-449 91-449 92-449 Rb Rc R Rlb G' Z 88-450 89-450 90-450 91-450 92-450 RS Re' Rb Rb Gc Zb 88-451 89-451 90-451 91-451 92-451 Ra Ra Re R Gc Zb 88-452 89-452 90-452 91-452 92-452 Rb R Re R 5 Ge Zb 88-453 89-453 90-453 91-453 92-453 R4 RN Ra c R5b Gc e 88-454 89-454 90-454 91-454 92-454 Ra Rib Rc Rlb G Ze 88-455 89-455 90-455 91-455 92-455 Rb RIE Rb RSb Gc e 88-456 89-456 90-456 91-456 92-456 R' Rib R Rsb Ge Zb 88-457 89-457 90-457 91-457 92-457 Re Rc Re R3b Gc Z 88-458 89-458 90-458 91-458 92-458 Ra Ric R R5 Gc Zb 88-459 89-459 90-459 91-459 92-459 Re Rc Rac R Gc Z 88-460 89-460 90-460 91-460 92-460 Ra Ri Ra Rse G Zb 88-461 89-461 90-461 91-461 92-461 Ra Rl R4a R5 G e 88-462 89-462 90-462 91-462 92-462 Re R R4" Rc G Zb 88-463 89-463 90-463 91-463 92-463 Ra R R a Rc G Z7 88-464 89-464 90-464 91-464 92-464 Ra R R a R3 G Zb 88-465 89-465 90-465 91-465 92-465 Re Rl R Rc G Z7 88-466 89-466 90-466 91-466 92-466 Ra R" Ra Re G e 88-467 89-467 90-467 91-467 92-467 Ra RM Ra Rc G Z 88-468 89-468 90-468 91-468 92-468 R Rc Ra Rc G e 88-469 89-469 90-469 91-469 92-469 Ra Rl R4 Rs' G' Z 88-470 89-470 90-470 91-470 92-470 Ra RI Ra R ' G' Zb 88-471 89-471 90-471 91-471 92-471 R' R R Rsc G Ze 88-472 89-472 90-472 91-472 92-472 Ra R 1 l R4b Ra' G Zb 88-473 89-473 90-473 91-473 92-473 Ra Rib Rlb REc Ge Ze 88-474 89-474 90-474 91-474 92-474 R' R R 4 RC Ge Ze 88-475 89-475 90-475 91-475 92-475 Ra R" R4 R' G' Z 88-476 89-476 90-476 91-476 92-476 Ra Rc R4 R' G' e 88-477 89-477 90-477 91-477 92-477 Re R R4o R' G Z 88-478 89-478 90-478 91-478 92-478 Re RI RI c Rsc G* Z 88-479 89-479 90-479 91-479 92-479 Ra Rl RE ' Rsc Ge Zb 109 WO 2005/042712 PCT/US2004/035939 88-480 89-480 90-480 91-480 92-480 R" Ra RE ' Ra' Go Zb 88-481 89-481 90-481 91-481 92-481 Ra R" Re R G Ze 88-482 89-482 90-482 91-482 92-482 R R R 4 ' Rc G Ze 88-483 89-483 90-483 91-483 92-483 R' R R 4 RSW Gc Zb 88-484 89-484 90-484 91-484 92-484 Ra Ric R 4 0 RSO G 0 Zb 88-485 89-485 90-485 91-485 92-485 Rb RIc 4 Rsc Ge e 88-486 89-486 90-486 91-486 92-486 R' Rl" R R5e G' Zb 88-487 89-487 90-487 91-487 92-487 Ra R Ia Ra Rsa Ga Ze 88-488 89-488 90-488 91-488 92-488 R 0 RI R a R Ga Z' 88-489 89-489 90-489 91-489 92-489 R RIa R 4 a Rsa Ga Z' 88-490 89-490 90-490 91-490 92-490 Ra R ib Ra R 5 a Ga zc 88-491 89-491 90-491 91-491 92-491 b R RIa R 4 a Rsa Ga Z' 88-492 89-492 90-492 91-492 92-492 Re R"n Ra RMa G a Ze 88-493 89-493 90-493 91-493 92-493 R Rl 4a R5a G" Z' 88-494 89-494 90-494 91-494 92-494 Ra R' Ra Rsa Ga Ze 88-495 89-495 90-495 91-495 92-495 R' Rb l 4a R5a G9 Z 88-496 89-496 90-496 91-496 92-496 Ra Rla R R Ga Z t 88-497 89-497 90-497 91-497 92-497 R' Ri]a R R5a Ga Zc 88-498 89-498 90-498 91-498 92-498 Re Ria R4 R Ga Zc 88-499 89-499 90-499 91-499 92-499 Ra Rb R 4 a R5a Ga Ze 88-500 89-500 90-500 91-500 92-500 Rb R4 R5a Ga Ze 88-501 89-501 90-501 91-501 92-501 Re RIl R4b Ra Ga Z' 88-502 89-502 90-502 91-502 92-502 Ra Rlc R4b Rsa Ga Zc 88-503 89-503 90-503 91-503 92-503 Rb RIO R 4
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5 " Ga Ze 88-504 89-504 90-504 91-504 92-504 Re RI' R4b Rl G a Zc 88-505 89-505 90-505 91-505 92-505 Ra Ria RWe R" Ga Ze 88-506 89-506 90-506 91-506 92-506 Ra Ria R 4 RNa Ga Zc 88-507 89-507 90-507 91-507 92-507 R Ria R4 Ra Ga Zc 88-508 89-508 90-508 91-508 92-508 Ra Ria R 4 Ra Ga Ze 88-509 89-509 90-509 91-509 92-509 Re Ri R 4 Rsa Ga Z 88-510 89-510 90-510 91-510 92-510 Re Rl R4 R5' Ga Ze 88-511 89-511 90-511 91-511 92-511 Ra Rib R 4 Ra Ga Zc 88-512 89-512 90-512 91-512 92-512 Ra Ri' R 4 Rla Ga Zc 88-513 89-513 90-513 91-513 92-513 Re Rc R' Ra Ga Z' 88-514 89-514 90-514 91-514 92-514 Ra Ra R 4 a Rla Ga Z 88-515 89-515 90-515 91-515 92-515 Re Rla R 4 a Ra Ga Zc 88-516 89-516 90-516 91-516 92-516 Re R R a R Ga Z' 88-517 89-517 90-517 91-517 92-517 Ra Rh R 4 a Rba Ga Zc 88-518 89-518 90-518 91-518 92-518 Ra R R a Rab Ga Ze 88-519 89-519 90-519 91-519 92-519 R R R a R5b Ga Z' 88-520 89-520 90-520 91-520 92-520 Ra Re Ra R Ga Z' 88-521 89-521 90-521 91-521 92-521 R Ri'c R 4 a Rla Ga Zc 88-522 89-522 90-522 91-522 92-522 Re Rc Ra Rob Ga Z 88-523 89-523 90-523 91-523 92-523 Re Ra R 4 0 R a Ga Ze 88-524 89-524 90-524 91-524 92-524 R Ra R4e R5b Ga Zc 88-525 89-525 90-525 91-525 92-525 R' Ra R4 Rab Ga Zc 88-526 89-526 90-526 91-526 92-526 Re Rl R 4 a R 5 1 Ga Zc 110 WO 2005/042712 PCT/US2004/035939 88-527 89-527 90-527 91-527 92-527 Rb Rb R4b Rlb Ga Zc 88-528 89-528 90-528 91-528 92-528 R b 4 b Z 88-529 89-529 90-529 91-529 92-529 Ra R" R4b R 5 Ga Zc 88-29 9-29 0-59 1-29 2-29 ~ Ic RWb R5b Ga z 88-530 89-530 90-530 91-530 92-530 Rb Ric R4b Rb Ga Zc 88-531 89-531 90-531 91-531 92-531 Re Ric R4b Rb Ga Ze 88-532 89-532 90-532 91-532 92-532 Ra Ria R 4 c R* Ga Ze 88-533 89-533 90-533 91-533 92-533 R' R R4 Rlb Ga Z' 88-534 89-534 90-534 91-534 92-534 R Ria R 4 C Rb Ga Z" 88-535 89-535 90-535 91-535 92-535 Ra Rib R 4 R5b Ga Z' 88-536 89-536 90-536 91-536 92-536 R 4 R Ga Z 88-537 89-537 90-537 91-537 92-537 R RI R 4 c Rb Ga Ze 88-538 89-538 90-538 91-538 92-538 Ra R' R4l R4c Ga Z 88-539 89-539 90-539 91-539 92-539 Re RI" R4e R3b Ga Ze 88-540 89-540 90-540 91-540 92-540 Re R1c 4 R0 G Z' 88-541 89-541 90-541 91-541 92-541 Ra Ria R 4 a R5b Ga Z' 88-542 89-542 90-542 91-542 92-542 R Ra R4a R' Ga Ze 88-543 89-543 90-543 91-543 92-543 Re RIa R 4 a R5e Ga Ze 88-544 89-544 90-544 91-544 92-544 Ra RIa R 4 a R 5 c Ga Zc 88-545 89-545 90-545 91-545 92-545 R a RIb 4a RSc G" Z 88-546 89-546 90-546 91-546 92-546 R RIb Rja R' Ga Zc 88-547 89-547 90-547 91-547 92-547 Ra Ri' R 4 a Ric Ga Zc 88-548 89-548 90-548 91-548 92-548 R' Rib R 4 a Rc Ga Zc 88-549 89-549 90-549 91-549 92-549 R R R4a Se Ga Z' 88-550 89-550 90-550 91-550 92-550 Ra R R1 Ra' Ga Zc 88-551 89-551 90-551 91-551 92-551 Rb R Ia R4 Rsc Ga Zc 88-552 89-552 90-552 91-552 92-552 Re R Ia Re R5e Ga Ze lb 4a SC a 88-553 89-553 90-553 91-553 92-553 Ra R R R Ga Ze 88-554 89-554 90-554 91-554 92-554 Re R Ib R4 Ra' G a Zc 88-555 89-555 90-555 91-555 92-555 Re R Ib R4O Rc Ga Z' 88-556 89-556 90-556 91-556 92-556 Ra R'O R4 Ra' G a Z4 88-557 89-557 90-557 91-557 92-557 Rb Ric R4 Rie Ga Zc 88-558 89-558 90-558 91-558 92-558 Rc Ric R 4 REc Ga Z 88-559 89-559 90-559 91-559 92-559 Ra Ria R 4 a REc Ga Ze 88-560 89-560 90-560 91-560 92-560 Re Ria R4b Re Ga Ze 88-561 89-561 90-561 91-561 92-561 Re Ria R R5 G Z 88-562 89-562 90-562 91-562 92-562 R Ria R 4 Rac Ga Z 88-563 89-563 90-563 91-563 92-563 Ra RIb R4 RS' Ga Zc 88-564 89-564 90-564 91-564 92-564 Re RIb R4 R 5 Ga Z 88-565 89-565 90-565 91-565 92-565 Re R' Ric RN Ga Zc 88-566 89-566 90-566 91-566 92-566 Rb Ric R 4 b RC Ga Z" 88-567 89-567 90-567 91-567 92-567 R R' R4 R Ga Z" 88-568 89-568 90-568 91-568 92-568 Ra Rie R4b RCa Gb Ze 88-569 89-569 90-569 91-569 92-569 Re Ria R4" RMc Gb Zc 88-570 89-570 90-570 91-570 92-570 Rc Ra Re R5c Ga Ze 88-571 89-571 90-571 91-571 92-571 R RIa R4a RC Gb Zc 88-572 89-572 90-572 91-572 92-572 Rb R I a Rc Ga Ze 88-573 89-573 90-573 91-573 92-573 R RIb R4a R Ga Z 111 WO 2005/042712 PCT/US2004/035939 88-574 89-574 90-574 91-574 92-574 Ra Ric R 4 a Ra G b z 88-575 89-575 90-575 91-575 92-575 R' Rc Ra Rsa G Ze 88-576 89-576 90-576 91-576 92-576 Re Rl Rc " R Gb Zc 88-577 89-577 90-577 91-577 92-577 Ra RIa R 4 b R 5 a Gb Zc 88-578 89-578 90-578 91-578 92-578 Rb RIa R4, Ra Gp Zc 88-579 89-579 90-579 91-579 92-579 Re R R4 Rsa Gb Ze 88-580 89-580 90-580 91-580 92-580 Ra RI R R Gb Zc 88-581 89-581 90-581 91-581 92-581 b R R W Ra G Ze 88-582 89-582 90-582 91-582 92-582 R R" R Ra Gb Z" 88-583 89-583 90-583 91-583 92-583 Ra RS R4 Rsa Gb Zc 88-584 89-584 90-584 91-584 92-584 Re RO R Ra Gp Ze 88-585 89-585 90-585 91-585 92-585 Re Rle Re Ra Gb Zc 88-586 89-586 90-586 91-586 92-586 Ra Ria Re Ra Gb Ze 88-587 89-587 90-587 91-587 92-587 R RIa Ric R G Zc 88-588 89-588 90-588 91-588 92-588 Re Ri R" W R G Ze 88-589 89-589 90-589 91-589 92-589 Ra R R4" R5a Gb Zc 88-590 89-590 90-590 91-590 92-590 Re R R " Ra GE ZO 88-591 89-591 90-591 91-591 92-591 R R Re R Gb Zc 88-592 89-592 90-592 91-592 92-592 Ra R 4 Re Ra Gb Ze 88-593 89-593 90-593 91-593 92-593 Re R R " Rsa Gb Ze 88-594 89-594 90-594 91-594 92-594 R' Rb R 4 e Rsa Gb Ze 88-595 89-595 90-595 91-595 92-595 Ra Ria Ra Rab Gb Z 88-596 89-596 90-596 91-596 92-596 Re Ria Ra R- GE Z 88-597 89-597 90-597 91-597 92-597 R R R a Rsh G Zc 88-598 89-598 90-598 91-598 92-598 Rb Rib R 4 a Rsb Gb Ze 88-599 89-599 90-599 91-599 92-599 Rb R R a R 5 G Ze 88-600 89-600 90-600 91-600 92-600 Re R 1 l Ra R* G Z" 88-601 89-601 90-601 91-601 92-601 Ra Rc 4a Rsb Gb Ze 88-602 89-602 90-602 91-602 92-602 Rb Ric Ra Rb G Z 88-603 89-603 90-603 91-603 92-603 Re Ri R 4 a Rlb Gb Ze 88-604 89-604 90-604 91-604 92-604 Ra Rib R 4 a Rab Gb Ze 88-605 89-605 90-605 91-605 92-605 Rb R R4 Rab Gb Ze 88-606 89-606 90-606 91-606 92-606 R4 RIa R Rb Gb Ze 88-607 89-607 90-607 91-607 92-607 Ra R R b Rlb GE Ze 88-608 89-608 90-608 91-608 92-608 Re Rlb R4a Rb Gb Ze 88-609 89-609 90-609 91-609 92-609 Ra R R4 Rlb Gb Z 88-610 89-610 90-610 91-610 92-610 Ra R R4a Rb Gb Ze 88-611 89-611 90-611 91-611 92-611 Rb Ric R4b Rlb G b Ze 88-612 89-612 90-612 91-612 92-612 R Ri" R4 R G Zc 88-613 89-613 90-613 91-613 92-613 Ra RIa R R5 Gb Ze 88-614 89-614 90-614 91-614 92-614 Ra Ria R 4 b R5b G b z 88-615 89-615 90-615 91-615 92-615 R RIa R4 Rsb Gb Ze 88-616 89-616 90-616 91-616 92-616 Ra R R " Rab Gb ZO 88-617 89-617 90-617 91-617 92-617 4e RIb R4 Rb Gb ZO 88-618 89-618 90-618 91-618 92-618 Re R R c Rab Gb Z 88-619 89-619 90-619 91-619 92-619 Ra Rc Re Rab Gb Z 88-620 89-620 90-620 91-620 92-620 Ra RIc R Rab Gb Z 112 WO 2005/042712 PCT/US2004/035939 88-621 89-621 90-621 91-621 92-621 Re Rc R 4 " Rlb Gb Z" 88-622 89-622 90-622 91-622 92-622 R" R R 4 a Rc Gb Z" 88-623 89-623 90-623 91-623 92-623 Rb Ra R 4 a Rc Gb Z" 88-624 89-624 90-624 91-624 92-624 Re R" R 4 RC Gb Ze 88-625 89-625 90-625 91-625 92-625 Rd Rib R 4 a R5c Gb Ze 88-626 89-626 90-626 91-626 92-626 Rb Rib R 4 a R' Gb Z" 88-627 89-627 90-627 91-627 92-627 R' Rlb Ra RS5 Gb Z" 88-628 89-628. 90-628 91-628 92-628 Ra RO R 4 a R Gb Z" 88-629 89-629 90-629 91-629 92-629 Rb RO R 4 a Rc Gb Zo 88-630 89-630 90-630 91-630 92-630 R RIO R 4 a Re Gb Z 88-631 89-631 90-631 91-631 92-631 R Ra R 4 b R Gb Z" 88-632 89-632 90-632 91-632 92-632 R Ra R4 R G Z" 88-633 89-633 90-633 91-633 92-633 Re R R4 Rc Gb Z" 88-634 89-634 90-634 91-634 92-634 R " R4' Rc G Zc 88-635 89-635 90-635 91-635 92-635 R R lb R4b RNr Gb Zo 88-636 89-636 90-636 91-636 92-636 R' Rid R4b Rl GE Zc 88-637 89-637 90-637 91-637 92-637 Rd R R Ra' G' ZO 88-638 89-638 90-638 91-638 92-638 Rb Rib R 4 b RS5 G b z 88-639 89-639 90-639 91-639 92-639 Re Rb R 4 b Rc Gb Z" 88-640 89-640 90-640 91-640 92-640 Ra RI R 4 RS Gb Zc 88-641 89-641 90-641 91-641 92-641 R R a R4 RN G ZO, 88-642 89-642 90-642 91-642 92-642 R R" R 4 b RSO Gb Z" 88-643 89-643 90-643 91-643 92-643 Ra R l R4" Rl G Z" 88-644 89-644 90-644 91-644 92-644 Rb R R4c Rsc W b Za 88-645 89-645 90-645 91-645 92-645 Re R R Rc Gb ZO 88-646 89-646 90-646 91-646 92-646 Ra Rc Rc Re Gb ZO 88-647 89-647 90-647 91-647 92-647 R Rc R 4 ' Rc G' ZO 88-648 89-648 90-648 91-648 92-648 Re Ri R 4 ' RO Gb Z" 88-649 89-649 90-649 91-649 92-649 Ra Ri R R5 G' ZO 88-650 89-650 90-650 91-650 92-650 Rb Ra R~a Ra Ge Zc 88-651 89-651 90-651 91-651 92-651 Rc Ra Rja Ra Gc Z 88-652 89-652 90-652 91-652 92-652 RW Ri Rb a Ra Gc Z 88-653 89-653 90-653 91-653 92-653 R Ri Rb a Rsa Ge Z" 88-654 89-654 90-654 91-654 92-654 RW Ri Rb a Rla G' Z" 88-655 89-655 90-655 91-655 92-655 Ra Rlc R4a R~a G' Z" 88-656 89-656 90-656 91-656 92-656 R Rc R R G' Zc 88-657 89-657 90-657 91-657 92-657 R Rc R4a Ra Gc Zc 88-658 89-658 90-658 91-658 92-658 Ra R R4 Ra G' Z" 88-659 89-659 90-659 91-659 92-659 R Ria a Rld G' Ze 88-660 89-660 90-660 91-660 92-660 R' Rl Rb Ra G4 Z" 88-661 89-661 90-661 91-661 92-661 Ra Rb R 4 b R5" G4 Z" 88-662 89-662 90-662 91-662 92-662 R' Rib R 4 a Rsa G' Ze 88-663 89-663 90-663 91-663 92-663 R Rb R R5 Ge Zc 88-664 89-664 90-664 91-664 92-664 Ra Rb R 4 b RMa Ge Zc 88-665 89-665 90-665 91-665 92-665 Rb R R 4 d Rsa G' ZC 88-666 89-666 90-666 91-666 92-666 R RO R Ra Gc Z" 88-667 89-667 90-667 91-667 92-667 Ra RIO R 4 ' Ra Gc Zc 113 WO 2005/042712 PCT/US2004/035939 88-668 89-668 90-668 91-668 92-668 Rb Ra R 4 Rsa Ge Z' 88-669 89-669 90-669 91-669 92-669 Re Ril R 4 c Rsa Ge Ze 88-670 89-670 90-670 91-670 92-670 Ra Rib R 4 e R 5 a Ge Zc 88-671 89-671 90-671 91-671 92-671 4e R c R4' Rc Gc Z 88-672 89-672 90-672 91-672 92-672 R' Rib R4 Rsa Ge Z' 88-673 89-673 90-673 91-673 92-673 R4a R5 Re Ra Gc Z' 88-674 89-674 90-674 91-674 92-674 Re R' R4' Rsa Ge Z' 88-675 89-675 90-675 91-675 92-675 R' Ric R 4 e Rsa Ge Ze 88-676 89-676 90-676 91-676 92-676 Ra Ria R 4 a R5b Ge Zc 88-677 89-677 90-677 91-677 92-677 Re Ria R 4 a R 5 " Ge Ze 88-678 89-678 90-678 91-678 92-678 Re Ria R 4 a REb Ge Z 88-679 89-679 90-679 91-679 92-679 Ra R b R 4 a Rib Ge Ze 88-680 89-680 90-680 91-680 92-680 Re R R 4 a R5b Ge Z 88-681 89-681 90-681 91-681 92-681 R R lb 4a R5b G' Z' 88-682 89-682 90-682 91-682 92-682 Ra R' Ra R3b Ge Z 88-683 89-683 90-63 91-683 92-683 R R l 4a R5b Ge Zc 88-684 89-684 90-684 91-684 92-684 R R R R5 Ge Zc 88-685 89-685 90-685 91-685 92-685 Re Ria R 4 R3b Ge Z 88-686 89-686 90-686 91-686 92-686 Rb Ria R 4 R"b Ge Z 88-687 89-687 90-687 91-687 92-687 R Ria R4 Rab Ge Ze 88-688 89-688 90-688 91-688 92-688 Ra Rl R4 R3b Ge Zc 88-689 89-689 90-689 91-689 92-689 Ra R R 4 b R"b Ge Ze 88-690 89-690 90-690 91-690 92-690 R R R 5b R Gc Ze 88-691 89-691 90-691 91-691 92-691 Ra R Rb R3b Ge Zr 88-692 89-692 90-692 91-692 92-692 Re R' R 4 b Rsb Gc Zc 88-693 89-693 90-693 91-693 92-693 R Rib R 4 b RSb Gc Z 88-694 89-694 90-694 91-694 92-694 R a Ria R4' R3b Gc Z' 88-695 89-695 90-695 91-695 92-695 R' R R4 R3b Ge Zc 88-696 89-696 90-696 91-696 92-696 Re Ria R R5 Gc Z' 88-697 89-697 90-697 91-697 92-697 Ra R R Rsb Ge Zc 88-698 89-698 90-698 91-698 92-698 Rb Rae R 4 b Reb Ge Z' 88-699 89-699 90-699 91-699 92-699 Re Rl R Rb Ge Z' 88-700 89-700 90-700 91-700 92-700 Ra R' R 4 ' Rb Ge Z' 88-701 89-701 90-701 91-701 92-701 Rb R 1 ' R4 R3b Ge Z' 88-702 89-702 90-702 91-702 92-702 R" Re Re REb Gc Zge 88-703 89-703 90-703 91-703 92-703 Ra Ria RW Rsc G' Z'c 88-704 89-704 90-704 91-704 92-704 e Ria RWa Rsc G'c z'c 88-705 89-705 90-705 91-705 92-705 Re Ria R 4 " Rab Ge Z' 88-706 89-706 90-706 91-706 92-706 Ra Rib Ra R Ge Z' 88-707 89-707 90-707 91-707 92-707 R Rb R a R4eG' ZS 88-708 89-708 90-708 91-708 92-708 R" R R a R3 Ge E' 88-709 89-709 90-709 91-709 92-709 Ra Rl R' a R5D Ge Zc 88-710 89-710 90-710 91-710 92-710 R' Ric RWa Rc Gc Zc 88-711 89-711 90-711 91-711 92-711 Re Rl' R R5 Ge 7c 88-712 89-712 90-712 91-712 92-712 Ra R R Rc Ge ZC 88-713 89-713 90-713 91-713 92-713 Ra Ra R 4 R3c Ge Zc b la 4a SeC c Z 88-714 89-714 90-714 91-714 92-714 R' R R R Ge Z 114 WO 2005/042712 PCT/US2004/035939 88-715 89-715 90-715 91-715 92-715 Ra Rib R 4 b R' G Z' 88-716 89-716 90-716 91-716 92-716 Rb Rib R 4 b Rsc Ge Ze 88-717 89-717 90-717 91-717 92-717 R' R" R Rc Gc Zc 88-718 89-718 90-718 91-718 92-718 Ra R' R" Ra' G Z 88-719 89-719 90-719 91-719 92-719 Ra RI'c R 4 RSc Gc Ze 88-720 89-720 90-720 91-720 92-720 Re R R4b R' G5 Z' 88-721 89-721 90-721 91-721 92-721 Ra Ria R Rc G Z' 88-722 89-722 90-722 91-722 92-722 Rb Ria R 4 b R' Ge Z 88-723 89-723 90-723 91-723 92-723 Ra Ria R 4 c Rc Ge Zc 88-724 89-724 90-724 91-724 92-724 Ra R b R4 Ra G4 Z 88-725 89-725 90-725 91-725 92-725 R R R4 R ' Ge Ze 88-726 89-726 90-726 91-726 92-726 Re R ] R 4 e R5e Ge Z' 88-727 89-727 90-727 91-727 92-727 Ra R' Ri G Z' 88-728 89-728 90-728 91-728 92-728 Rb R R4 R Ge Ze 88-729 89-729 90-729 91-729 92-729 Rc R' R4' Rc Gc Ze 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 CH 3 , and all other symbols are as defined above in connectioni with 5 formula (I). In another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is H or CH 3 , R 5 is -H, and all other symbols are as defined above in connection with formula (I). In another aspect of any of fonnulae (88), (89), (90), (91), and (92) of the present 10 invention, R is -H or CH 3 ; RW is CH 3 ; 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 CH 3 ; G is -(CH 2 )s-, where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I). 15 In a further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or -CH 3 ; R is -H; G is -(CH 2 )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 CH 3 ; RW is CH 3 ; G is -(CH 2 ),-, where s is an integer from 0-5; and all 20 other symbols are as defined above in connection with formula (I). 115 WO 2005/042712 PCT/US2004/035939 In a further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH 3 , 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 5 invention, R is -H or CH 3 , Rs is -H or CH 3 ; 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 CH 3 , G is -(CH 2 )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). 10 In a still further aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH 3 ; R5 is -H; G is -(CH 2 )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 CH 3 , Z is 0; and all other symbols are as defined above in connection 15 with formula (I). In a yet further aspect of any of fornulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH 3 ; R is CH 3 ; G is -(CH 2 )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 20 invention, R is -H or CH 3 , R 5 is -H or CH 3 , Z is 0, 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 CH 3 ; G is -(CI-I 2 )s-, where s is an integer from 0-5; Z is 0; and all other symbols are as defined above in connection with formula (I). 25 In still another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH 3 , G is -(CH 2 )s-, where s is an integer from 0-5; Z is 0; 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 CH 3 ; Ri is -H; G is -(CH 2 )s-, where s is an integer from 0-5; Z is 0; and 30 all other symbols are as defined above in connection with formula (I). 116 WO 2005/042712 PCT/US2004/035939 In yet another aspect of any of formulae (88), (89), (90), (91), and (92) of the present invention, R is -H or CH 3 ; R 5 is CH 3 ; G is -(CH 2 )s-, where s is an integer from 0-5; Z is 0; 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 5 invention, R 4 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: NR S 0 N
R
4
R
5 N N-G Z 0 R (93), 10 where all symbols are as defined above in connection with formula (I). According to various aspects of the present invention, R, R 4 , R 5 , G, and Z of formula (93) are selected to produce compounds of formula (93-1) through (93-243) as follows: Formula R R 4 R G Z 93-1 R R 4 a Rsa Ga Za 93-2 R Ra Rsa Ga Za 93-3 R" R 4 a Rsa Ga Za 93-4 Ra R 4 Rsa Ga Za 93-5 Rb R 4 b R 5 a Ga za 93-6 Re R 4 Rsa Ga Za 93-7 Ra R 4 c Rsa Ga Za 93-8 R Rc Rsa Ga Za 93-9 Re R 4 e Rsa Ga Za 93-10 Ra R 4 a Rb Ga Za 93-11 Rb R 4 a R5b Ga Za 93-12 Re R 4 a Rsb Ga Za 93-13 Ra R 4 b Rab Ga Za 93-14 Rb R 4 b Rsb Ga Za 93-15 R" R 4 b Rsb Ga Za 93-16 Ra R 4 " REb Ga Za 93-17 R R4 Rsb Ga Za 93-18 Re R 4 e Rb Ga za 93-19 R a Rsc Ga za 93-20 Rb R 4 a RS" Ga za 93-21 Re R 4 a Rsc Ga Za 117 WO 2005/042712 PCT/US2004/035939 93-22 Ra R 4 b RSc Ga za 93-23 R4b Re Ga Za 93-24 Re R R' Ga Za 93-25 Ra Rb R Ga Za 93-265 E 4 Rsc Ga Za 93-26 R' R4 R Ga Za 93-27 Ra R 4 c Rsa Ga za 93-28 Ra R 4 a Rsa Gb Za 9330 R R4a Rsa Gb Z 93-29 Ra R4 Rla Gb Za 93-30 Re R 4 Rsa Gb za 93-31 Ra R 4 b Rsa Gb Za 93-3 Rb 4 sa 3b Za 93-35 R R Ra Ge Za 93-36 RC R 4 b Rsa Gb Za 93-34 Ra R 4 c Ra Gb Za 93-35 Rb R 4 a Ra Gb za 93-36 Rc R 0 Ra Gb za 93-37 Ra R4a Rsb Gb Za 93-38 R R4a Rsb GE Za 93-39 Re R 4 a Rsb Gb Za 93-40 Ra R 4 ' Rlb Gb Za 934 b R4' Rb Gb Z 93-41 R Ra R G Za 93-42 Ra R 4 b Rib Gb Za 93-43 Ra R 4 a Rb Gb Za 9348 R R4a Rb G Z 93-44 Ra R4c R G za 93-45 R R 4 R5b Gb Za 93-46 Ra R 4 a Rc Gb Za 9352 R R4 Rsc b Z 93-47 R R4a R4 G Za 93-48 R R 4 . Ra Gb Za 93-49 Ra R 4 b Rs Gb Za 93-50 Rb R 4 a Rsc Gb za 93-51 Re R 4 b Rsc Gb Za 93-52 Ra R 4 C Rsa Gb Za 935 b 4e c Sc Z 93-59 Re R Ra Gb Za 93-5 R R 4 a Rsa Gb Za 93-56 Ra R 4 a Rsa Gc Za 93-56 Rb R 4 ' R 5 Gc Za 9363 R R 4 ' Rsa' Ge Za 93-58 Ra R 4 Rsa Ge Za 93-59 Rb R Ra Gc Za 93-60 Rc R 4 RSa Gc Za 93-61 Ra R 4
R
5 a Ge Za 93-62 R0 Rc Rl Ge Za 93-63 Ra R 4 C R 5 b Ge Za 93-65 R R~ R G Za 93-66 Rc R 4 a R~b Gc Za 93-67 R a ei RWb Ge Za 93-68 Rb R R GbC Za 118 WO 2005/042712 PCT/US2004/035939 93-69 Re R 4 " Rb Gc za 93-70 Ra R 4 c Rb Gc Za 93-71 Rb R 4 " R3b G" Za 93-72 Re R 4 c Rib Ge Za 93-73 Ra R 4 a Rsc G' Za 93-74 Rb R 4 a RS G4 Za 93-75 Re R 4 a RSe Ge Za 93-76 Ra R 1 Rc Ge Za 93-77 R, R R Ge Za 93-78 Re R 4 R5 Ge Za 93-79 Ra R 4 R G Za 93-80 R R' R Ge Za 93-81 Re R 4 e R5 Ge Za 93-82 Ra R 4 a Rsa Ga Z' 93-83 Rb 4a sa Ga e 93-8 R Ra Ra Ga Z 93-84 Re R 4 R Ga Ze 93-85 R R 4 b Rsa Ga Zb 9388 R R4c Rsa ba Z 93-86 R R4 Rsa Ga Z 93-87 Re RSa Ga Zb 93-88 Ra R 4 a R5a Ga Zb 93-89 R Ra R5b Ga Ze 93-90 Re R 4 e Ra Ga Zb 93-91 Ra R 4 a Rib Ga Ze 9395 R R4a Rs G Z 93-92 R R4a Rib Ga Z 93-93 Re R 4 a Rsb Ga Zb 93-94 Ra R4 Rib Ga ZE 93-95 R R R Ga Z 93-96 Re R 4 a RSb Ga Zb 93-97 Ra R 4 a Rib Ga Zb b RSb Ga 93-98 R R R Ga Z 93-99 Re R 4 e R5b Ga 93-100 R R 4 a Rse Ga Zb 9310 R R4c Rsc Ga Z 93-101 Rb R4 Rsc Ga Zb 93-102 Re R 4 " R3e Ga Zb 93-103 R" R 4 RSa Ga Zb 910 kb 4e RSc Gb 93-104 R Ra Rsa Ga Z 93-10 R R 4 b R c G Z 93-106 Ra R 4 e Re Ga Zb 93-107 Re ' R Rc G a Z 93-108 Re R 4 Rsa Ga Z 93-110 Ra Ra R~a G 1, 93-110 Re R4a Rsa G Z 93-112 R R' Gj Zb 93-113 Rb e 41 RWa Gb Z 93-114 Re ei 1 Ra Gb Zb 93-115 Ra R 4 * RSa G 1 Z' 119 WO 2005/042712 PCT/US2004/035939 93-116 R4 R5a Gjb Z 93-117 Re R Rsa G ZE 93-118 R5a Ra Rbb GE Zb 93-119 R Ra Rab G Zb 93-120 Re 4a 5b Cb Zb 93-121 R" . R4 RWb G3: Z 93-122 Rb R4 Rlb G ZEb 93-123 Re R4 Rab G Z 93-124 Ra R54 Rb Gb Z 93-125 R R4 R G Z 93-126 Re R 4 a R Gb Zb 93-127 R Ra Re Gb Zb 93-128 R R4a Rsc G Z 93-129 Rb R 4 a R3b Gb Z 93-130 R5a R Rb5 G Zb 93-131 R R Rc G Z 93-132 Re R 4 R b Gb Zb 93-133 R R 4 e Rsc Gb Z 93-134 RS R Rs G Z 93-135 Re R4 R" GQb Z 93-136 Ra 4a RSa Ge b 93-137 Re Ra Ra Gb Z w a Sc cc b 93-138 R R R G Z 93-139 R a R4b R5a Ge Zb 93-140 S c Ra Gb Z 93-141 Re R4 Ra Ge Z 4b Sc bcb 93-142 Ra R R G Z 93-143 R R4 RSa G Z 93-144 Re R 4 " Rsa G Z 93-145 Ra R 4 " RC G Zb 93-146 e Ra Rab Gc Zb 93-147 R4e RSc Ge b 93-148 Ra R R5 G Z 93-149 R
R
4 R5b Gb Zb 93-150 Re R4b RW Gc Z 93-151 Ra R 4 c Ra Gc Zb 93-152 Re R. Rb Ge Z 93-153 R R4 RS5 Ge Z 93-154 Ra R 4 a RSc Ge Zb 93-155 Ra R4a Rb G Z 93-156 Re R4a R5 Ge Z 93-157 R4b Re Gb 93-158 R R R5 Gc Z 93-159 Re R 4 b Ra G Z 93-160 Ra R Rsc Ge Z 93-161 R R R5c G Z 93-162 Re R R5 G Z 120 WO 2005/042712 PCT/US2004/035939 93-163 Ra R 4 a Rsa Ga ze 93-164 Rb 4a Rsa Ga Z 93-165 R Ra Rsa Ga Z 93-166 Ra Re Ra Ga Zc 93-167 R R 4 Ra Ga Zc 93-168 Ra Rb Rsa Ga z 0 93-169 Rb Rb Rsa Ga zc 93-170 Rb R' Rsa Ga zc 93-171 Ra
R
4 Rsa Ga Z 93-172 Ra R4a REb Ga Z' 93-173 Rb R 4 a R 5 b Ga Z' 93-174 R R 4 a Rib Ga Ze 93-175 R a R4 R3b G a Z' 93-176 Rb R 4 Rsb Ga ZC 93-177 Re R 4 b R b Ga Z 93-178 Ra R 4 b R3b Ga ZC 93-179 R R4c R Ga ZC 93-180 Re Rc Rib G a Z 93-181 R R 4 a Rib Ga ZC 93-182 Rb R 4 a Rb Ga Z 93-183 R' Ra Rl Ga Z' 93-184 Ra R4b RS' Ga Zc 93-185 R4a Rsc Ga Z 93-186 R R R Ga Ze 93-187 Ra R 4 c Rsc Ga Zc 93-188 Ra R 4 c R5c Ga Z 93-189 R R' R * Ga Zc 93-190 Ra Ria Rb a Gb Zc 93-191 Ra R 4 a Rs5a ab Z 93-192 Re Ra Ra Gb Zc 93-193 Ra Re Rla Gb Ze 93-194 R. R 4 Rsa Ga Z 93-195 Re R 4 b Rsa Gb Ze 93-196 R4a Re' Rsa Gb Z 93-197 Rb R4' Ra Gb Z' 93-198 R' R 4 a Rsa Gb Zc 93-199 Ra R 4 a R Ge Zc 93-200 R 4a Ra Gb Ze 93-201 Re R4a REb G Ze 93-202 Ra R4b Rla Gb Z' 93-203 Ra R 4 0 R5a Gb Z' 93-204 Rb R 4 b Rsb Gb Z' 93-205 Ra R 4 5b Gb Z' 93-206 Ra R 4 RSb Gb Zc 93-207 Rc R R G Ze 93-208 Ra R 4 a R 5 Gb Ze 93-209 R Rja Rl' GE Z' 121 WO 2005/042712 PCT/US2004/035939 93-210 R R 4 a R 5 Gb ze 93-211 Ra Rb R5 Gb Zc 93-212 R R R' G, Z 93-213 Re R e Rsc Gb ze 93-214 Ra R 4 c Rsc Gb ze 93-215 Rb R4 R5c Gb Z' 93-216 R R e R' GZc 93-217 Ra R4a Rsa Ge Z 93-218 R Ra Ra G Z 93-219 R R 4 a R Ge Z 93-220 Ra Rb Rsa Ge Ze 93-221 R Rb Ra Ge Zc 93-222 Re Rb Rsa G Z 93-223 Ra R4C Rsa Ge Z 93-224 Rb R4' R G7Z 93-225 Re R(4' Ra' Ge Z a 4a Rc 93-227 R R R G Zc 93-227 Rb R4 Rb Ge Z 93-228 R a R4a Rb G Ze 93-229 Ra R 4 a R5b Gc Ze 93-228 W 4b b Ge 93-230 R R4b Rib Ge Ze 93-231 Re Rb Rsb Ge Z 93-232 Ra R 4 e Rib Gc 93-233 R R4 Rb GZc 93-234 Ra R 4 a Rb Gc ZC 93-236 Ra R4a R" G Z 93-237 Rb R4a R G Ze 93-237 R R 4 R G Z' 93-238 R R 4 b Re G Z 93-23 R R4 R Gc ZC 93-240 Re0 Rb Rie Ge z 93-241 Ra R4c Rs Ge Ze 93-242 R R' Rsc G Ze 93-243 R Re4 R5 G Z where all symbols are as defined above. In one aspect of any of formula (93) of the present invention, R is -H or CH 3 , and all other symbols are as defined above in connection with formula (I). 5 In another aspect of any of formula (93) of the present invention, R 4 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, R is -H or CH 3 , and all other symbols are as defined above in connection with formula (1). 122 WO 2005/042712 PCT/US2004/035939 In yet another aspect of any of formula (93) of the present invention, G is -(CH 2 )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 5 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 4 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a 10 heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; R 5 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; and all other symbols are as defined above in connection with formula (I). 15 In still another aspect of formula (93) 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; R 4 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, 20 a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; R 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 25 alkyl group; R is a substituted or unsubstituted aryl group; G is (CH 2
)
2 , (CH 2
)
3 , or (CH 2
)
4 ; Z is 0, S, or NH; and R is hydrogen or an alkyl group. In still another aspect of formula (93) of the present invention, R is -H or CH 3 ; R is a substituted or unsubstituted aryl group; G is (CH 2
)
2 , (CH 2
)
3 , or (CH 2
)
4 ; Z is 0, S, or NH; and
R
5 is -H or CH 3 . 30 The present invention also encompasses various compounds of general formula (IV) as follows: 123 WO 2005/042712 PCT/US2004/035939 R -NRo R0 0 N N N O N/ N SO N NGZN- O R - N0 R i R 6 N N O NWN N N-G=Z g / N N- G=O 10 (4;0 Me M(9); a e (97); R00
R
10 ?-NR SH N W N W'- 5 W5 'N N-G=S / N N-G=N Me (96); R M (97); where R 9 and R 10 independently are hydrogen, a halogen, a nitro group, an amino group, a 5 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 10 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, 15 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, Rs, G, Z, R 9 , and RO of any of formulae (94), (95), (96), and (97) are selected to produce compounds of formulae (94-1), 20 (95-1), (96-1), and (97-1) through formulae (94-729), (95-729), (96-729), and (97-729) as follows: 124 WO 2005/042712 PCT/US2004/035939 Formulae R R ' R 9
R'
0 G Z 94-1 95-1 96-1 97-1 Ra Rsa R 9 a RiOa Ga Za 94-2 95-2 96-2 97-2 R Ra R9a R10a Ga Za 94-3 95-3 96-3 97-3 R R 5 a R 9 a RlOa Ga Za 94-4 95-4 96-4 97-4 Ra R 5 1
R
9 a RiOa Ga Za 94-5 95-5 96-5 97-5 R Rsb R9a R1Oa Ga Za 94-6 95-6 96-6 97-6 R4 R 5 b R 9 a RiOa Ga Za 94-7 95-7 96-7 97-7 Ra Rc R 9 a RiOa Ga Za 94-8 95-8 96-8 97-8 Rb R5: R9a R10a Ga Za 94-9 95-9 96-9 97-9 R Rsc R 9 a R10a Ga Za 94-10 95-10 96-10 97-10 Ra Rsa R 9 1 R'Oa Ga Za 94-11 95-11 96-11 97-11 Rb R 5 a R 9 b oR 1 a Ga za 94-12 95-12 96-12 97-12 Re Rsa R 9 ' R'1Oa Ga Za 94-13 95-13 96-13 97-13 Ra R5b R 9 RlOa Ga Za 94-14 95-14 96-14 97-14 R, R R b RiOa Ga Za 94-15 95-15 96-15 97-15 Re R ,
R
9 Rioa Ga Za 94-16 95-16 96-16 97-16 R RS' Rb RiOa Ga Za 94-17 95-17 96-17 97-17 R Rc R R10 G a Za 94-18 95-18 96-18 97-18 R' Rc R 9 R10a Ga Za 94-19 95-19 96-19 97-19 Ra R 5 a R 9 ' RiOa Ga Za 94-20 95-20 96-20 97-20 R Rsa R9' RiOa Ga Za 94-21 95-21 96-21 97-21 R R 5 a R 9 c Rica Ga Za 94-22 95-22 96-22 97-22 Ra R 5 b R 9 c RiOa Ga za 94-23 95-23 96-23 97-23 Rb Rlb R 9 ' R' Oa Ga Za 94-24 95-24 96-24 97-24 Rc Rb R 9 e RiOa Ga Za 94-25 95-25 96-25 97-25 Ra R" R9 R"o Ga Za 94-26 95-26 96-26 97-26 R 5 Re R9' RiOa Ga Za 94-27 95-27 96-27 97-27 R' Rs Rc RiOa Ga Za 94-28 95-28 96-28 97-28 Ra Rsa R9a R lo Ga Za 94-29 95-29 96-29 97-29 Ra Rsa R 9 a R Ob Ga Za 94-30 95-30 96-30 97-30 sa R9a R lOb Ga Za 94-31 95-31 96-31 97-31 Ra R3b R9a R lob Ga Za 94-32 95-32 96-32 97-32 Rb RWb R9a R lob Ga Za 94-33 95-33 96-33 97-33 Re Rb R 9a R l Ga Za 94-34 95-34 96-34 97-34 Ra R R 9 a R lob Ga Za 94-35 95-35 96-35 97-35 Rb R 5 c R 9 a Rl Ob Ga Za 94-36 95-36 96-36 97-36 R R 5 c ,
R
9 a R Ob Ga Za 94-37 95-37 96-37 97-37 Ra Rsa R 9 b R lb Ga Za 94-38 95-38 96-38 97-38 Sc Ra R9 R lob Ga Za 94-39 95-39 96-39 97-39 R' Rsa R R lo Ga Za 94-40 95-40 96-40 97-40 Ra RC R 9 R lb Ga Za 94-41 95-41 96-41 97-41 R R Rsb R 9 b R ob GE Za 94-42 95-42 96-42 97-42 R R R9b R Ob Ga Za 94-43 95-43 96-43 97-43 Ra R 5 c R 9 b R'iOb Ga Za 94-44 95-44 96-44 97-44 Rb R' R 9 1 R lb Ga Za 94-45 95-45 96-45 97-45 Rc RsC R 9 " R Ob G" Za 125 WO 2005/042712 PCT/US2004/035939 94-46 95-46 96-46 97-46 R R R9c ROb Ga Za 94-47 95-47 96-47 97-47 Re Ra R9" R 10 Ga Za 94-48 95-48 96-48 97-48 RC Ra R R10 Ga Za 94-49 95-49 96-49 97-49 Ra Rb R 9 c Rl Ob Ga Za 94-50 95-50 96-50 97-50 R R R9" RIOb Ga Za 94-51 95-51 96-51 97-51 Rc Rib R 9 c ROb Ga Za 94-52 95-52 96-52 97-52 R Rc R9c RiOb Ga Za 94-53 95-53 96-53 97-53 Rb Re R9 RIOb Ga Za 94-54 95-54 96-54 97-54 Re R R9 R10b Ga Za 94-55 95-55 96-55 97-55 Ra R5a R9a Rioc Ga Za 94-56 95-56 96-56 97-56 Rb R ~a R 9 a RiO Ga Za 94-57 95-57 96-57 97-57 Re R5a R9 ROC Ga Za 94-58 95-58 96-58 97-58 Ra R5b R9a Rloe Ga Za 94-59 95-59 96-59 97-59 R REb R9a RO Ga Za 94-60 95-60 96-60 97-60 R S Rb R9a Rioc Ga Za 94-61 95-61 96-61 97-61 Ra R5e R9a Rlo" Ga Za 94-62 95-62 96-62 97-62 R Rsc R9a RlOc Ga Za 94-63 95-63 96-63 97-63 Rc R5c R9a Rioc Ga Za 94-64 95-64 96-64 97-64 Ra R5a R9b Rioc Ga Za 94-65 95-65 96-65 97-65 R R5a REb Rl0c Ga Za 94-66 95-66 96-66 97-66 R S R5a R9a R10 Ga Za 94-67 95-67 96-67 97-67 Ra Rb RSb RIOc Ga Za 94-68 95-68 96-68 97-68 Rc R R 9 a RIOC Ga Za 94-69 95-69 96-69 97-69 R Rab R9b ROC Ga Za 94-70 95-70 96-70 97-70 Ra Re Re Rioc G"a Za 94-71 95-71 96-71 97-71 Rb R e R9b Ric Ga Za 94-72 95-72 96-72 97-72 Re Re R Rioc Ga Za 94-73 95-73 96-73 97-73 Ra R5a R9b ROc Ga Za 94-74 95-74 96-74 97-74 R Rb R'c R1c Ga Za 94-75 95-75 96-75 97-75 Rb Ra R9b ROc Ga Za 94-76 95-76 96-76 97-76 Ra REb R9c ROC Ga Za 94-77 95-77 96-77 97-77 R Rcb R9 Rioc Ga Za 94-78 95-78 96-78 97-78 R" R R9 ROC Ga Za 94-79 95-79 96-79 97-79 R R'" Rc Roc Ga Za 94-80 95-80 96-80 97-80 Rc Rsc R R"oc Ga Za 94-81 95-81 96-81 97-81 R" RWe R9c Rlo" Ga Za 94-82 95-82 96-82 97-82 R Wa R9a RlOa Gb Za 94-83 95-83 96-83 97-83 R, R5a R9a R10" Ga Za 94-84 95-84 96-84 97-84 R Ra R 9 a R1Oa Gb Za 94-85 95-85 96-85 97-85 Ra REb R ~a ROa G Za 94-86 95-86 96-86 97-86 eb 5b R9a lOa Gb Za 94-87 95-87 96-87 97-87 RO R R9a ROa Ga za 94-88 95-88 96-88 97-88 Ra Sb R9a R Oa G Za 94-89 95-89 96-89 97-89 R R R RIOa ab Za 94-90 95-90 96-90 97-90 R R R ROa Gab Za 94-91 95-91 96-91 97-91 Ra Ra R9b Rioa ab Za 94-92 95-92 96-92 97-92 R Ra R ROa b za 126 WO 2005/042712 PCT/US2004/035939 94-93 95-93 96-93 97-93 Re Ra R" Rica Gb Za 94-94 95-94 96-94 97-94 Ra Rlb R9b RiOa Gb Za 94-95 95-95 96-95 97-95 R Rab R 9 R10a Gb Za 94-96 95-96 96-96 97-96 Re Rsb R 9 b RlOa Gb Za 94-97 95-97 96-97 97-97 Ra R' R9b R 10 a Gb Za 94-98 95-98 96-98 97-98 Rb RC R 9 b R10a Gb Za 94-99 95-99 96-99 97-99 Re Rc Rib R'0a (b Za 94-100 95-100 96-100 97-100 Ra Ra R9c Rioa Gb Za 94-101 95-101 96-101 97-101 R R R9 Rlo" GE Za 94-102 95-102 96-102 97-102 R Rsa R R10a Gb Za 94-103 95-103 96-103 97-103 Ra Rab R 9 c ROa Gb Za 94-104 95-104 96-104 97-104 R R Rb R RIN 0 Gb Za 94-105 95-105 96-105 97-105 Re Rab R 9 c R10a Gb Za 94-106 95-106 96-106 97-106 Ra R R 9 c RiOa Gb Za 94-107 95-107 96-107 97-107 R' Rc R'" Rioa Gb Za 94-108 95-108 96-108 97-108 Re Rc R 9 c Ria Gb Za 94-109 95-109 96-109 97-109 Ra R5a R 9 a R Ob Gb Za 94-110 95-110 96-110 97-110 R' Ra R9a R 10 Gi Za 94-111 95-111 96-111 97-111 Re R R9a R Ob Gb Za 94-112 95-112 96-112 97-112 R a R R 9a R 0 G3 Za 94-113 95-113 96-113 97-113 Rb Rlb R9a R 1b Gb Za 94-114 95-114 96-114 97-114 Ra b R9a R Ob G Za 94-115 95-115 96-115 97-115 Ra R R9a R 1b Gb Za 94-116 95-116 96-1Sb6 97-116 Rk Re R9a Rl Ob b Za 94-117 95-117 96-117 97-117 Rc Re R9a R 0 Gb Za 94-118 95-118 96-118 97-118 R Rb R9b R Ob Gb Za 94-119 95-119 96-119 97-119 Re Rsa R" R Ob Gb Za 94-120 95-120 96-120 97-120 Re Rsa R9a R' Ob G Za 94-121 95-121 96-121 97-121 RRSb R 10 Gb Za 94-122 95-122 96-122 97-122 R R5b R9a ROb Gb Za 94-123 95-123 96-123 97-123 R R a Rb R 1b Gb Za 94-124 95-124 96-124 97-124 Ra Ra R9b R Ob Gb Za 94-125 95-125 96-125 97-125 R Rla Rlb R Ob Gb Za 94-126 95-126 96-126 97-126 Re Rb Rb R Ob Gb Za 94-127 95-127 96-127 97-127 Ra Rs R9" R Ob Gb Za 94-128 95-128 96-128 97-128 R Ra R R 10Gb Za 94-129 95-129 96-129 97-129 Re R b R9 R Ob Gb za 94-130 95-130 96-130 97-130 Ra R5b RSc Rl Ob Gb Za 94-131 95-131 96-131 97-131 Rb REb R9' R Ob Gb Za 94-132 95-132 96-132 97-132 Rb RC RSc R Ob Gb Za 94-133 95-133 96-133 97-133 Ra b R94 R b Gb Za 94-134 95-134 96-134 97-134 R Rsc R 9 Rio0b G b Za 94-135 95-135 96-135 97-135 R' R 5 R9" R 10b GE Za 94-136 95-136 96-136 97-136 R R Ra R 9 R Gb Za 94-137 95-137 96-137 97-137 Ra RMa R9a ROb Gb Za 94-138 95-138 96-138 97-138 Re R R 9 R Gb Za 94-139 95-139 96-139 97-139 Ra R R~a R Gb Za 127 WO 2005/042712 PCT/US2004/035939 94-140 95-140 96-140 97-140 R R"n R a Rl0' G1 Za 94-141 95-141 96-141 97-141 Rc Rsb R9a R'oc Gb za 94-142 95-142 96-142 97-142 Ra Rc R9a R1Cc G: Za 94-143 95-143 96-143 97-143 R R R9a R G Za 94-144 95-144 96-144 97-144 R' R' R 9 a RiOc Gb Za ba ac R9a b 94-145 95-145 96-145 97-145 R R R Rice G Za 94-146 95-146 96-146 97-146 RC Rsa R 9 ' RIOC Gb Za 94-147 95-147 96-147 97-147 Ra Rsa R 9 b RO' Gb Za 94-148 95-148 96-148 97-148 R Rb R9b Riac Gb Za 94-149 95-149 96-149 97-149 R R REb R Gb Za 94-150 95-150 96-150 97-150 Rb Rb R9b Rlo' G Za 94-151 95-151 96-151 97-151 Ra R5c R9b Rl0' G Za 94-152 95-152 96-152 97-152 Rb R5e R9b Rioc Gb Za 94-153 95-153 96-153 97-153 R4 R5c R9b R lo Gb Za 94-154 95-154 96-154 97-154 Rba Rsa R9' R Gb Za 94-155 95-155 96-155 97-155 R Rsa R9' R10c Gb Za 94-156 95-156 96-156 97-156 Rc Rsa R9' Rlo' G3E Za 94-157 95-157 96-157 97-157 a R5b Rle R10c gb Za 94-158 95-158 96-158 97-158 R R R 9 Roc G Za 94-159 95-159 96-159 97-159 R Rab R9" R'oc Gb Za 94-160 95-160 96-160 97-160 5c R R9' Rbo' GE Za 94-161 95-161 96-161 97-161 R w Rs R9' R lo' GE Za 94-162 95-162 96-162 97-162 R R R9' RoC G Za 94-163 95-163 96-163 97-163 Ra Ra R9a Rioa Gb Za 94-164 95-164 96-164 97-164 R Rsa R9a Ri0a Ge Za 94-165 95-165 96-165 97-165 Rc Rsa R9c 1a Ge Za 94-166 95-166 96-166 97-166 Ra R R RiOa Gc Za 94-167 95-167 96-167 97-167 Rb Rka Ri1a Gc Za 94-168 95-168 96-168 97-168 R Rlb R9a R 10 a G' Za 94-169 95-169 96-169 97-169 Ra Ra' R9a Ri Oa Ge Za 9 a b Za 94-170 95-170 96-170 97-170 R Rc R Ria G1 Za 94-171 95-171 96-171 97-171 Rc Sb R9a Rba Ge Za 94-172 95-172 96-172 97-172 Ra Ra Rb R1oa Gc Za 94-173 95-173 96-173 97-173 R Rsa R9b Roa Ge Za 94-174 95-174 96-174 97-174 Rc Rsa R9b Ri1o0a Ge Za a Scb 9b 0 I C b Za 94-175 95-175 96-175 97-175 R R R R G Z 94-176 95-176 96-176 97-176 R R R' RiOa G' Za 94-177 95-177 96-177 97-177 Rc Rc R9b ROa Gb Za 94-178 95-178 96-178 97-178 Ra Rs R R10a Ge Za 94-179 95-179 96-179 97-179 Rb R' R 9 ' ROa Gc Za 94-160 95-180 96-180 97-180 Rc R" R' R0a Ge Za 94-181 95-181 96-181 97-181 Rc Ra RSc R10a Gc Za 94-182 95-182 96-182 97-182 Ra RSa R"' R0a Ge Za 94-183 95-183 96-183 97-183 R Ra R9' Rioa Ge Za 94-184 95-184 96-184 97-184 R R R9 R G Za 94-185 95-185 96-185 97-185 R Rab R9 R10a Gc Za 94-186 95-186 96-186 97-186 R' RC R 9 ' R 10 a Gc za 128 WO 2005/042712 PCT/US2004/035939 94-187 95-187 96-187 97-187 Ra Rse R 9 e Rioa Ge Za 94-188 95-188 96-188 97-188 R' Re R R1a Ge Za 94-189 95-189 96-189 97-189 Re RWe R"e RiOa Gc Za 94-190 95-190 96-190 97-190 Ra R R 9 a R Ob Gc Za 94-191 95-191 96-191 97-191 Rb R 5 a R 9 3 Rlob Ge za 94-192 95-192 96-192 97-192 Re Ra R 9 a R1Ob Gc Za 94-193 95-193 96-193 97-193 Ra Rb R 9 a RIOb Ge Za 94-194 95-194 96-194 97-194 R R' R9a RiOb Ge Za 94-195 95-195 96-195 97-195 Re Rsb R 9 a R10b G" Za 94-196 95-196 96-196 97-196 Ra RC R 9 a RIOb Ge Za 94-197 95-197 96-197 97-197 R Re R9a RiOb Gc Za 94-198 95-198 96-198 97-198 Re RS R 9 " R10b Ge Za 94-199 95-199 96-199 97-199 Ra RSa R"b ROb Ge Z" 94-200 95-200 96-200 97-200 R Rsa R9b R'0O Ge Za 94-201 95-201 96-201 97-201 Re Ra R 9 b RiOb Ge Z" 94-202 95-202 96-202 97-202 Ra Rb RSb R' Ob Ge Za 94-203 95-203 96-203 97-203 R, R R9b ROb Ge Za 94-204 95-204 96-204 97-204 Re R R9b R10b Ge Za 94-205 95-205 96-205 97-205 Ra Re R9b R Ob Ge Za 94-206 95-206 96-206 97-206 R Rsc R9b Rob Gc Za 94-207 95-207 96-207 97-207 Re R 5 R 9 ROb Ge Za 94-208 95-208 96-208 97-208 Ra Ra R9' R] Ob Gc Za 94-209 95-209 96-209 97-209 Rb Rsa R9' R 10 Ge Za 94-210 95-210 96-210 97-210 Re Rsa R9e Riob Ge za 94-211 95-211 96-211 97-211 Ra Ra R9e R10O Ge Za 94-212 95-212 96-212 97-212 R R R R10 Gc Za 94-213 95-213 96-213 97-213 Re Rsb R RJo Ge Za 94-214 95-214 96-214 97-214 Ra RS R9e RiOb Ge Za 94-215 95-215 96-215 97-215 Rb R5b R9e R Ob Ge Za 94-216 95-216 96-216 97-216 Re R b R9' ROb Ge Za 94-217 95-217 96-217 97-217 Ra Ra R9a RlOb Ge Za 94-218 95-218 96-218 97-218 Rb R R 9 a Rioc Ge Za 94-219 95-219 96-219 97-219 Re Rsa R9a Rioc Ge Za a a 9a lOc 94-220 95-220 96-220 97-220 R R9a R G Za 94-221 95-221 96-221 97-221 Rb Ra Roa Rc Ge Za 94-222 95-222 96-222 97-222 Re Rab R9a Ric Ge Za 94-223 95-223 96-223 97-223 Ra Rb R 9 a Ric Ge Za 94-224 95-224 96-224 97-224 Rb R c R 9 a Ric Ge Za 94-225 95-225 96-225 97-225 Re R R9a Ric Ge Za 94-226 95-226 96-226 97-226 Ra RC R"a Ric Ge Za 94-227 95-227 96-227 97-227 R S Ra R9b Rloc G Za 94-228 95-228 96-228 97-228 R Rsa Rb Riac Ge Za 94-229 95-229 96-229 97-229 Ra Rb RSa Ric Ge Za 94-230 95-230 96-230 97-230 Ra Ra R9b Ric Ge Za 94-231 95-231 96-231 97-231 Re R R9 Ric Ge Za 94-232 95-232 96-232 97-232 Ra Rb R9b Rice Ge Za 94-233 95-233 96-233 97-233 R R R9' Ric Ge Za 129 WO 2005/042712 PCT/US2004/035939 94-234 95-234 96-234 97-234 R' Rsc R 9 b R e Gc Za 94-235 95-235 96-235 97-235 Ra Rsa R 9 c ROC Ge Za 94-236 95-236 96-236 97-236 Rb 5a R9c R c G' Za 94-237 95-237 96-237 97-237 Rc Rsa RS' R 0 Gc Za 94-238 95-238 96-238 97-238 Ra Rst R 9 c Roc Ge za 94-239 95-239 96-239 97-239 Ra Rab R 9 c Rioc Gc Za 94-240 95-240 96-240 97-240 Rc Rb R9' Rioc G9 Za 94-241 95-241 96-241 97-241 Ra R Rc R 9 Roc Gc Za 94-242 95-242 96-242 97-242 Re R' R9c Rc Ge Za 94-243 95-243 96-243 97-243 Ra Rac R 9 c Ric Ge Za 94-244 95-244 96-244 97-244 R c5a R9a ROa Ga b 94-245 95-245 96-245 97-245 R R5a R9a RiOa Ga Ze 94-246 95-246 96-246 97-246 R Rsa R 9 ' Rioa Ga Ze 94-247 95-247 96-247 97-247 Ra Rb R 9a R10a Ga Ze 94-248 95-248 96-248 97-248 Rb Rb R 9a R10a Ga Z 94-249 95-249 96-249 97-249 Rb Ra R9a R1a Ga Ze 94-250 95-250 96-250 97-250 Ra Ra R 9 " Rica Ga Zb 94-251 95-251 96-251 97-251 Ra R ' R9a Rica Ga Zb 94-252 95-252 96-252 97-252 R' R 5 Ra ROa Ga Zb 94-253 95-253 96-253 97-253 R Rsa R9b R10a G Ze 94-254 95-254 96-254 97-254 Re a s R9b Rica Ga Zb 94-255 95-255 96-255 97-255 R' Rsa R9b RiOa Ga Ze 94-256 95-256 96-256 97-256 R a Rb RSb Rica G a e kb Sc 9b 0 Cab 94-257 95-257 96-257 97-257 R R R Rica Ga Z 94-252 95-258 96-258 97-258 Re RSC R9a Rica Ga Zb 94-259 95-259 96-259 97-259 Ra R~a Rb R'ca Ga Z 94-260 95-260 96-260 97-260 R b Rb RiOa Ga e 94-261 95-261 96-261 97-261 R Rsc R R1a G Ze 94-262 95-262 96-262 97-262 a Rsa R9 Ria Ga e 94-263 95-263 96-263 97-263 Re Rsa R9 Rica Ga Zb 94-264 95-264 96-264 97-264 Rc Rsa R9' R1ca Ga Zb 94-265 95-265 96-265 97-265 Rba Rab R Ra G a ZE 94-266 95-266 96-266 97-266 Rb R5' R9' Rica G a Zb 94-267 95-267 96-267 97-267 R Rs' R" RiOa Ga Ze 94-268 95-268 96-268 97-268 Ra Rb R9' Rica Ga Zb 94-269 95-269 96-269 97-269 Ra Rc R9b Rica Ga Zb 94-270 95-270 96-270 97-270 R Rsc R9' R10a Ga Zb 94-271 95-271 96-271 97-271 Re RWa R9a R10 Ga Zb 94-272 95-272 96-272 97-272 Rb Rsa Ra Rlb Ga Z2 94-273 95-273 96-273 97-273 Rb sa R"a Rica Ga Zb 94-274 95-274 96-274 97-274 Ra Ra R9a Rica Ga Zb 94-275 95-275 96-275 97-275 Ra Rsb R9a R lea Ga Zb 94-276 95-276 96-276 97-276 R R5b R9a RiOb Ga Z 94-277 95-277 96-277 97-277 Re Re R9a RIca Ga Zb 94-278 95-278 96-278 97-278 Rb RSC R9a Rlob Ga Zb 94-279 95-279 96-279 97-279 Rb R 5 c R9a RiO Ga Zo 94-280 95-280 96-280 97-280 Ra RSa RSe Rica Ga Zb 130 WO 2005/042712 PCT/US2004/035939 94-281 95-281 96-281 97-281 R Ra R' R" Ga Zb 94-282 95-282 96-282 97-282 Re Rsa R 9 b RlOb Ga Zb 94-283 95-283 96-283 97-283 Ra R 5 R9b Rl O Ga ZE 94-284 95-284 96-284 97-284 Rb R Re R' O Ga Z2 94-285 95-285 96-285 97-285 Re R3 R 9 b RIGb Ga Zb 94-286 95-286 96-286 97-286 Ra R5c R9b RIOb Ga Zb 94-287 95-287 96-287 97-287 Rb R3 R' R1 O G Z 94-288 95-288 96-288 97-288 Re Rie R 1 R Ob Ga Zb 94-289 95-289 96-289 97-289 R Rsa R9" Rlob G" Z 94-290 95-290 96-290 97-290 R Rsa Rc R10b G Zb 94-291 95-291 96-291 97-291 R' Ra R9 R G Z 94-292 95-292 96-292 97-292 Ra Rb R9C ROb Ga Z 94-293 95-293 96-293 97-293 e Rb R9c RlIb Ga e 94-294 95-294 96-294 97-294 R* Rab R9 RlDE G Ze 94-295 95-295 96-295 97-295 R R b R9e RIOb Ga Ze 94-296 95-296 96-296 97-296 Ra R R9c RIOb Ga Ze 94-297 95-297 96-297 97-297 R' R5 R9' RI O Ga Ze 94-298 95-298 96-298 97-298 Re R R9a ROb Ga Zb 94-299 95-299 96-299 97-299 Rb R R9a Rloc Ga Zb 94-300 95-300 96-300 97-300 R' Ra Ra Rloc Ga Zb 94-301 95-301 96-301 97-301 Ra R R9a Rloc Ga b 94-302 95-302 96-302 97-302 Rb Rsb R9a R1 " Ga Z 94-303 95-303 96-303 97-303 Re R a R9a RiOC Ga Ze 94-304 95-304 96-304 97-304 Ra R 5 ' R9a Ro' Ga Zb 94-305 95-305 96-305 97-305 Rb R R9a Rloc Ga Zb 94-306 95-306 96-306 97-306 R' R R Roc G Ze 94-307 95-307 96-307 97-307 Re Ra Re ROe Ga Zb 94-308 95-308 96-308 97-308 Ra Rsa Re R 0; Ga Z 94-309 95-309 96-309 97-309 Rc Rb Rb R G a Zb 94-310 95-310 96-310 97-310 Ra R R 9 ROC Ga Z 94-311 95-311 96-311 97-311 Re R3b R 9 ROt Ga Ze 94-312 95-312 96-312 97-312 Ra Ria R9b ROt Ga Zb 94-313 95-313 96-313 97-313 Ra Rc R9b Rioc Ga Zb 94-314 95-314 96-314 97-314 Rb Rs R R Ga Z 94-315 95-315 96-315 97-315 Re Rca Rb RlO Ga Ze 94-316 95-316 96-316 97-316 Ra RMb R9b R Ga Zt 94-317 95-317 96-317 97-317 Rb R 1 R9c R o Ga Ze 94-318 95-318 96-318 97-318 Rc Ra RSc RiO Ga Ze 94-319 95-319 96-319 97-319 Ra R 5 R9b RIOc Ga Zb 94-320 95-320 96-320 97-320 Rb R" RSc R 0 a Z 94-321 95-321 96-321 97-321 R R R9b R G Z 94-322 95-322 96-322 97-322 Re R" Roc Ri o Ga Ze 94-323 95-323 96-323 97-323 Rb Wse R9e RlO Ga Zb 94-324 95-324 96-324 97-324 R' R 5 c R9e R c Ga Z 94-325 95-325 96-325 97-325 Ra Rb R9a ROta ab Ze 94-326 95-326 96-326 97-326 Rb Ra R9a Rioa Gb Zb 94-327 95-327 96-327 97-327 Rc Ria R 9 " RlOa G b Z b 131 WO 2005/042712 PCT/US2004/035939 94-328 95-328 96-328 97-328 Ra R5b R 9 a RiOa Gb Zb 94-329 95-329 96-329 97-329 R' Rsb R9a RiOa G Z 94-330 95-330 96-330 97-330 R' Rsb R 9 a Ri0a Gb Zb 94-331 95-331 96-331 97-331 Ra RSC 9a ROa Gb Ze 94-332 95-332 96-332 97-332 R R R9a RIOa Gb Zb 94-333 95-333 96-333 97-333 Rc Rlc R 9 a R'Oa Gb Zb 94-334 95-334 96-334 97-334 Ra Rsa R 9 b Rloa Gb Zb 94-335 95-335 96-335 97-335 Rb Rsa R9b Rica Gb Zb 94-336 95-336 96-336 97-336 Re RWa R 9 b R'la Gb Zb 94-337 95-337 96-337 97-337 Ra Rab R 9 b RiOa Gb Zb 94-338 95-338 96-338 97-338 R Rb RSb Rloa Gb Z 94-339 95-339 96-339 97-339 Rc Rab R 9 b R1 a Gb Ze 94-340 95-340 96-340 97-340 Ra Rse R' Rioa Gb Zb 94-341 95-341 96-341 97-341 Rb R R9b RiOa G Z 94-342 95-342 96-342 97-342 Re Re R 9 b RiOa Gb Ze 94-343 95-343 96-343 97-343 Ra R 5 a R 9 c R Oa Gb Zb 94-344 95-344 96-344 97-344 Rb Rsa R9' Rioa Qh Zb 94-345 95-345 96-345 97-345 Re R5a R9c R10a Gb Zi 94-346 95-346 96-346 97-346 Ra Rb R9c R10a G Ze 94-347 95-347 96-347 97-347 Rb Rab R9' R0a Gb Zb 94-348 95-348 96-348 97-348 Re Rsb R'c RiOE' Gb Zb 94-349 95-349 96-349 97-349 R 9 Rloa Gb Zb 94-350 95-350 96-350 97-350 R RC R9' R 10 a Gb Zb 94-351 95-351 96-351 97-351 Re Rsc R9c R10a Gb Zb 94-352 95-352 96-352 97-352 Ra Rsa R9a RI O GE Z 94-353 95-353 96-353 97-353 Re Rsa R9" R.
0 Gb Zb 94-354 95-354 96-354 97-354 Ra Rsa R9a Rib Gb Zb 94-355 95-355 96-355 97-355 Ra Rb R9a RIb Gb Ze 94-356 95-356 96-356 97-356 Re R a R9a RiOb Gb Zb 94-357 95-357 96-357 97-357 R' Ri R9a R 10 G Ze b435 9538 9-5 738 W Rc Ra R]Ob Gb b 94-356 95-356 96-356 97-356 Rb Rc R'a RI O G Z 94-357 95-357 96-357 97-357 RE Rib R 9 " RIDb Gb Zb 94-360 95-360 96-360 97-360 Ra R5' R9a RI h Gb Zb 94-361 95-361 96-361 97-361 Ra Rsa REb Rio0b G e 94-362 95-362 96-362 97-362 R R a R a R0h Gb Ze 94-363 95-363 96-363 97-363 Re Rsa R9b RIOb Gb Zb 94-365 95-361 96-361 97-365 Ra Rla Rlb RIOb Gb Zb 9435 9-6 635 9-6 b bS Rl RlOb Gb e 94-366 95-366 96-366 97-366 R' R a R9b Rl0b G Z 94-367 95-367 96-367 97-367 Ra R 5 ' R9b RIOb Gb Zb 94-368 95-368 96-368 97-368 Ra R b R9b RIb Gb Ze 94-369 95-369 96-369 97-369 Re Ra' RSb R10b G Z 94-370 95-370 96-370 97-370 Ra Rsa RSc RIOb Gb Zb 94-371 95-371 96-371 97-371 Ra Rsa R9e RIOb Gb Ze 94-372 95-372 96-372 97-372 Rc Rsa R'" R" G' Z 94-373 95-373 96-373 97-373 Ra RSb R9e Rl0O G Z 94-374 95-374 96-374 97-374 R' Rsb R9' R'Ob G Zb 132 WO 2005/042712 PCT/US2004/035939 94-375 95-375 96-375 97-375 Re Rb RN R Jo G Z 94-376 95-376 96-376 97-376 Ra RS5 R9' Riob Gb Ze 94-377 95-377 96-377 97-377 Rb R RN R Jo G Z 94-378 95-378 96-378 97-378 Re R5c RC RIOb Gb Zb 94-379 95-379 96-379 97-379 Ra Ra Ra R' G Z 94-380 95-380 96-380 97-380 RI Ra R a Rioc Gb Zb 94-381 95-381 96-381 97-381 R Rsa R9a R 0' G Z 94-382 95-382 96-382 97-382 RIa Rb R9a Rlc G Zb 94-383 95-383 96-383 97-383 R R R9a Rloc G Z 94-384 95-384 96-384 97-384 R' Rb R9a Rloc Gb Zb 94-385 95-385 96-385 97-385 Ra R R9 Rloc Gb Z 94-386 95-386 96-386 97-386 Rb We R9a Rioc Gb Zb 94-387 95-387 96-387 97-387 R Rsc Ra R30 Gb Zb 94-388 95-388 96-388 97-388 Ra Rsa R9b RC Gb Ze 94-389 95-389 96-389 97-389 Ra RS R9b RO Gb Zb 94-390 95-390 96-390 97-390 Re R5a R 9b Rlo' G3: Zb 94-391 95-391 96-391 97-391 Ra b R9b Rloc Gb Zb 94-392 95-392 96-392 97-392 R R" R l R10' G Z 94-393 95-393 96-393 97-393 Re RsC Rla RC' Gb Zb 94-394 95-394 96-394 97-394 Ra R R9 Rloc G Z 94-395 95-395 96-395 97-395 Rb we R9b R1Ic Gb b 94-396 95-396 96-396 97-396 R R R9b R' G Z 94-397 95-397 96-397 97-397 Ra R' R9' ROC Gb Zb 94-398 95-398 96-398 97-398 Rb Ra R9b Rioc G Zb 94-399 95-399 96-399 97-399 R R R' Rce G Z 94-400 95-400 96-400 97-400 Ra Rb R9c R0c' Gb zb 94-401 95-401 96-401 97-401 Ra RC R9" RIGC Gb Zb 94-402 95-402 96-402 97-402 R Rb R9' Rlo' G Ze 94-403 95-403 96-403 97-403 Re R5c Rb Rc Gb Zb 94-404 95-404 96-404 97-404 Rb We R9c Rloc b ;tb 94-405 95-405 96-405 97-405 Ra Ra R9e Roc Gb Zb 94-406 95-406 96-406 97-406 r R9a R ROa Gb Zb 94-407 95-407 96-407 97-407 Rb Rsa R Ra Ge Ze 94-408 95-408 96-408 97-408 Re Ra R9 RiOa Gb Ze 94-409 95-409 96-409 97-409 Ra RSb R9 Roa Gb Zb 94-410 95-410 96-410 97-410 S sb 9a , Oa Gb 2b 94-411 95-411 96-411 97-411 Rc R R9a RiOa Ge Zb 94-412 95-412 96-412 97-412 Ra R RC ROa G Zb 94-413 95-413 96-413 97-413 R R5C R9 RIOa Gb Zb 94-414 95-414 96-414 97-414 R' R R9 Rile G4 Z 94-415 95-415 96-415 97-415 Ra Ra R9b Roa Gb Zb 94-416 95-416 96-416 97-416 Ra Ra RSa RIOa Gc Ze 94-417 95-417 96-417 97-417 R Rsa R9b RiOa Ge Zb 94-418 95-418 96-418 97-418 R Ra R a RIOa Ge Zb 94-419 95-419 96-419 97-419 Rb Rlb Rlb Rioa Ge Zb 94-420 95-420 96-420 97-420 Rb Rb R 9 b ROa Ge Zb 94-421 95-421 96-421 97-421 Ra Re Rla RIOa Ge Zb 133 WO 2005/042712 PCT/US2004/035939 94-422 95-422 96-422 97-422 R' R' R" Rica Gc Z' 94-423 95-423 96-423 97-423 Rc R'o R9b Ria Gc Zb 94-424 95-424 96-424 97-424 Ra Ra R9c Rica G* Zb 94-425 95-425 96-425 97-425 R R5 Rc Rica GC Z 94-426 95-426 96-426 97-426 RC Rsa Rc Rca Ge Zb 94-427 95-427 96-427 97-427 R REb R9' Ra Gc Z 94-428 95-428 96-428 97-428 R' R Rc R1 a G Z 94-429 95-429 96-429 97-429 R R R9' Rica Ge Z 94-430 95-430 96-430 97-430 Ra Rb R9C Rica Ge Zb 94-431 95-431 96-431 97-431 Ra R'c R9 Rica Ge Zb b R5 9c cc 94-432 95-432 96-432 97-432 R R Rc Ria Ge Z 94-433 95-433 96-433 97-433 Re R" R9 Rica Gb Zb 94-434 95-434 96-434 97-434 Ra Ra R a R10 Gc Zb 94-435 95-435 96-435 97-435 Rb Rsa R9a Riob Ge Z 94-436 95-436 96-436 97-436 Ra RSb R9a R10 Ge Zb 94-437 95-437 96-437 97-437 Ra Rsb R9a Ric0 Ge Ze 94-438 95-438 96-438 97-438 R R5b R 9 a RiOb G Ze 94-439 95-439 96-439 97-439 Ra R" R9a R10b G' Zb 94-440 95-440 96-440 97-440 Ra RSc Rba Rl0O G' e 94-441 95-441 96-441 97-441 R" R3" R 9 a Rich Ge Z 94-442 95-442 96-442 97-442 Ra R" R9b Rih Gc Ze 94-443 95-443 96-443 97-443 Re RSa R9a Rich Ge Zb 94-444 95-444 96-444 97-444 Ra R 5 a R9b Rihb Ge Zb 94-445 95-445 96-445 97-445 Ra Ra R9b RiOb Ge Zb 94-446 95-446 96-446 97-446 R R R9b Riob Gc Zb 94-447 95-447 96-447 97-447 Rc Ra R9b R cO Ge Zb 94-448 95-448 96-448 97-448 Ra Rb R b R h Ge Zb 94-449 95-449 96-449 97-449 R R' R 9 R 10 G Z 94-450 95-450 96-450 97-450 Re Rib R9b Rich Ge Zb 94-451 95-451 96-451 97-451 Ra RSa R9b RiOb Ge Zb 94-452 95-452 96-452 97-452 Rb R' R'" R 0b Gc Z 94-453 95-453 96-453 97-453 Re RC R9b R b Ge Zb 94-454 95-454 96-454 97-454 Ra RSb R9c Rihb Ge Zb 94-455 95-455 96-455 97-455 Re Rab R9 R ic Ge Z 94-456 95-456 96-456 97-456 Re Ra R9c R ic Ge Zb 94-457 95-457 96-457 97-457 Ra RS' R94 R 0 Ge Zb 94-458 95-458 96-458 97-458 Re R. R9h R b G" Z 94-459 95-459 96-459 97-459 R Rc R9 R Ob GC Z 94-460 95-460 96-460 97-460 Ra RMb R9' Roc Ge Zb 94-461 95-461 96-461 97-461 R R R R9 Rc Gc Zb 94-462 95-462 96-462 97-462 R4 R' R9 RE" Gc Zb 94-463 95-463 96-463 97-463 Ra RC R9a Rc Ge Ze 94-464 95-464 96-464 97-464 Rb R5b R7% Roc Gce g 94-465 95-465 96-465 97-465 Ra R~a Ra Ric Ge Zb 94-466 95-466 96-466 97-466 Ra Re Ra R4 Gc Ze 94-467 95-467 96-467 97-467 Rb RS" Rla Rloc Gc Zb 94-468 95-468 96-468 97-468 R" R'4 Ra Rloc Gc Z 134 WO 2005/042712 PCT/US2004/035939 94-469 95-469 96-469 97-469 Ra Rla R"b R'O G" Zb 9440 9-7 640 9-7 b 5a Pb Rioc e gb 94-470 95-470 96-470 97-470 R Ra RSb R 0' G' Zb 94-471 95-471 96-471 97-471 Ra Ra R9b R 10 ' Ge Zb 94-472 95-472 96-472 97-472 R Rib R9b R1c Gc Zb 94-473 95-473 96-473 97-473 R R R9b Rl0' Gc Zb 94-474 95-474 96-474 97-474 Ra R5b R9b Ro' Gc Ze 94-475 95-475 96-475 97-475 R Rc R9b Rice Ge Zb 9447 9-7b6-7 747 R Se P9b gloc G Zb 94-476 95-476 96-476 97-476 Ra R Rb Rlo' Gc Z 94-477 95-477 96-477 97-477 Rc Rc RSb ROc Ge Zb 9440 540 648 748 c9MRc Roc Gc Zb 94-478 95-478 96-478 97-478 Ra R 5 R9c R1c G Ze 94-479 95-479 96-479 97-479 Rb Ra R9 Rlo Gc Zb 94-480 95-480 96-480 97-480 Re Rsa R9c Rioc Ge b 94-481 95-481 96-481 97-481 Ra Rb R9c Rioe Ge Zb 94-486 95-486 96-486 97-486 Rc RP R9c Rloc Ge Zb 94-482 95-482 96-482 97-482 Ra Rb R9c R10a Ga Zc 94-483 95-483 96-483 97-483 Re Rsa R9c Rioa Ge Zb 94-484 95-484 96-484 97-484 R RSa RS" Rioc Ge Zb b448 9548 9646 9P8 e Wc Rc Rc e tb 94-485 95-48 96-485 97-48 Ra Ra R" RiOa Ga Zc 94-48 95-486 96-486 97-486 R' R 5 R9a RiOa Ga Z' 94-489 95-489 96-489 97-489 Ra R5 R9a RiOa Ga Z 94-495 95-495 96-495 97-495 R RS R9a Rioa Ga Ze 94-496 95-496 96-496 97-496 Ra Rsa R9a RiOa Ga Zc 94-497 95-497 96-497 97-497 R RMa RP2 RiOa Ga Ze 94-490 95-498 96-490 97-498 R4 Ri R9" R10a Ga Z' 94-499 95-499 96-491 97-499 Ra R RSa R 10 a Ga Ze 94-500 95-500 96-500 97-500 RW RE Re R1la G a Ze 94-492 95-492 96-492 97-492 Ra R R9 Rica Ga Z 94-493 95-493 96-493 97-493 Ra R~a Ra RiOa Ga ze 94-494 95-494 96-494 97-494 Rb RS R9a Rica Ga Ze 94-505 95-505 96-505 97-505 Re R R"a Rica Ga Ze 94-506 95-506 96-506 97-506 Ra RMa R9b Rioa Ga Ze 94-507 95-507 96-507 97-507 Re Ra R9b RiOa Ga Ze 94-508 95-508 96-508 97-508 Re R 5 a R9b Rioa Ga Zc 94-509 95-509 96-509 97-509 R' Rsb R9' R G a Zc 94-510 95-510 96-510 97-510 Ra Rsb R9' Rioa G a Zc 94-511 95-511 96-511 97-511 Ra Rl R9' R0a Ga Z' 94-497 95-497 96-409 97-507 R Ra Rc Rica G a Ze 94-500 95-500 96-500 97-500 Rb Rsc R9' R10a Ga Z' 94-513 95-513 96-513 97-513 Rc R5' R9c R10a Ga Ze 9451 9-11 9651 7-11 Ra RSc Pb Ri1a a Z 94-502 95-502 96-502 97-502 Rb R~ R9 Rlo Ga zc 94-503 95-503 96-503 97-503 Rb RWe RWb RicOa Ga Ze 94-514 95-514 96-514 97-514 Re R R9a Rica Ga Ze 94-515 95-515 96-515 97-515 Rb Ra R9a Rica G a Z 135 WO 2005/042712 PCT/US2004/035939 94-516 95-516 96-516 97-516 Re Rsa R9a R 1b Ga Ze 94-517 95-517 96-517 97-517 Ra Rab R 9 a R"'b Ga Z' 94-518 95-518 96-518 97-518 Rb Rlb R9a R 0b Ga Zc 94-519 95-519 96-519 97-519 Re Rab R 9 a R' Ob Ga zc 94-520 95-520 96-520 97-520 Ra R R9a R Ob Ga zC 94-521 95-521 96-521 97-521 Rb RC R9a R"b Ga Ze 94-522 95-522 96-522 97-522 Rc R4 R 9 a Rob Ga Ze 94-523 95-523 96-523 97-523 Ra Ra RSe R' b Ga Z' 94-524 95-524 96-524 97-524 Rb Rsa Ri R Ob Ga Z' 94-525 95-525 96-525 97-525 R Rsa RSb R' Ob Ga Z' 94-526 95-526 96-526 97-526 Ra Rsb R9b R Ob Ga Z4 94-527 95-527 96-527 97-527 Rb Sb R9b R 10 Ga Z 94-528 95-528 96-528 97-528 R Rlb Rlb R O Ga Ze 94-529 95-529 96-529 97-529 Ra Rb R 9 b R Ob Ga Ze 94-530 95-530 96-530 97-530 Ra R' R 9 b Riob Ga Ze 94-531 95-531 96-531 97-531 R S Rc R9b R lOb Ga Z 94-532 95-532 96-532 97-532 Ra Ra R9e R O Ga Ze 94-533 95-533 96-533 97-533 Re RC R9b R Ob Ga Ze 94-534 95-534 96-534 97-534 Ra Ra R9c R Ob Ga ze 94-535 95-535 96-535 97-535 Raa RE R9' R 0b Ga Zc 94-536 95-536 96-536 97-536 Rb Rsb R9' R 10 Ga Ze 94-537 95-537 96-537 97-537 Re Ra R 9 c R Ob Ga Ze 94-538 95-538 96-538 97-538 Ra R Roe R0b Ga Z' 94-539 95-539 96-539 97-539 R R5c R9c RiOb Ga Zc 94-540 95-540 96-540 97-540 Re R5b R9e R b Ga Ze 94-541 95-541 96-541 97-541 Ra Re Re R b a Z 94-542 95-542 96-542 97-542 R Ra R9a R 0 Ga Z4 94-543 95-543 96-543 97-543 R S Ra R9a RlO a Z 94-544 95-544 96-544 97-544 Ra Rab R9a R 0 Ga Ze 94-545 95-545 96-545 97-545 Re RSb R9a R Ob Ga Ze 94-546 95-546 96-546 97-546 Ra R~a R9a R Oc Ga Ze 94-547 95-547 96-547 97-547 a R' R 9a RlO Ga Zc 94-548 95-548 96-548 97-548 R' Re R'a R " Ga Z' 94-549 95-549 96-549 97-549 Re R 5 ' R"' R 0 Ga Ze 94-550 95-550 96-550 97-550 Ra Rsa R9a Roe Ga Zc 94-551 95-551 96-551 97-551 R S R5a R9b Ra 0 Ga Z' 94-552 95-552 96-552 97-552 Rc Ra R9b R Ga Zc 94-553 95-553 96-553 97-553 Re Rb R9a Ro" Ga Ze 94-554 95-554 96-554 97-554 R RSb Roa ROC Ga Ze 94-555 95-555 96-555 97-555 R" Rab REb Rlo" Ga Z" 94-556 95-556 96-556 97-556 Ra RS R9a R e Ga Ze 94-557 95-557 96-557 97-557 R Ra' Rlb ROC Ga Zc 94-558 95-558 96-558 97-558 Rb R 5 R9b R e Ga Zc 94-559 95-559 96-559 97-559 Ra RSa R9b Roe Ga ze 94-560 95-560 96-560 97-560 Ra RMb R9b Roe Ga Ze 94-561 95-561 96-561 97-561 Re Rsa R94 Rioc Ga Ze 94-562 95-562 96-562 97-562 Ra R 5 b Roe Ric Ga Z' 136 WO 2005/042712 PCT/US2004/035939 94-563 95-563 96-563 97-563 Rb R5b R" R10C Ga Zc 94-564 95-564 96-564 97-564 R R5' R9 Rc Ga Z 94-565 95-565 96-565 97-565 Ra Rc Rc ROc Ga Z' 94-566 95-566 96-566 97-566 R R5c R 9 c Rc Ga Z' 94-567 95-567 96-567 97-567 R Rsc R9' Rioc Ga Z" 94-568 95-568 96-568 97-568 Ra Rsa Rca Rica Gb Ze 94-569 95-569 96-569 97-569 R Rsa Rla R10a Gb Ze 94-570 95-570 96-570 97-570 R Rsa Ra Rica Gb Ze 94-571 95-571 96-571 97-571 Ra R5b R 9a Rl Oa GE Z' a b ba c 94-572 95-572 96-572 97-572 Rb R~ 9a Rla -b ze 94-573 95-573 96-573 97-573 R R R9a RiOa Gb Zc 94-574 95-572 96-574 97-57 R Re R9a Rica Gb ze 94-575 95-575 96-575 97-5756 R Rs' R 9a RiOa G Ze 94-576 95-573 96-573 97-576 R R' Ra Rica Gb Ze 94-577 95-577 96-577 97-577 Ra Rsa Rc RiOa G9 b Z 94-578 95-578 96-578 97-578 R Ra R9b Rica Gb Z' 94-579 95-579 96-579 97-579 Re Rsa R9a RiOa Gb Z' 94-580 95-580 96-580 97-580 Ra REb R' R1 GO Z 94-581 95-581 96-581 97-581 Re Rsh R9a Rioa Gb Z' 94-582 95-582 96-582 97-582 R' Rsb R9b Rla Gb Ze 94-583 95-583 96-583 97-583 Ra R 5 c R9b Ra GO Z' 94-584 95-584 96-584 97-584 Rb R 5 ' Re RiOa Gb Zc 94-575 95-585 96-585 97-585 Re Ra R 9 b Rica Gb ZC 94-586 95-586 96-586 97-586 Ra Rsa R 9 c Rica Gb Ze 94-587 95-587 96-587 97-587 R b Ra R9' Rioa o Zc 94-588 95-588 96-588 97-588 R' Rsa R' Rioa Gb Ze 94-589 95-589 96-589 97-589 Ra RSb R 9 ' RiOa Gb Ze 94-590 95-590 96-590 97-590 R R5' R 9 c Rioa Gb Ze 94-591 95-591 96-591 97-591 Rb R 5 b RNc RiOa Gb Z' 94-592 95-592 96-592 97-592 Ra Rc R 9 b Rioa Gb Zc 94-593 95-593 96-593 97-593 Ra R Re Rioa Gb Ze 94-594 95-594 96-594 97-594 R' R' R' Rioa Gb Ze 94-595 95-595 96-595 97-595 Ra Rsa R9 Rica G Z' 94-596 95-596 96-596 97-596 Re Rsa R9a Rica Gb z' 94-597 95-597 96-597 97-597 Rc Rsa R9a RlD GbEj Zc 94-598 95-598 96-598 97-598 Ra R3b R9" Rica Gb Z' 94-599 95-599 96-599 97-599 R' Rab R9 RI O G Z' 94-600 95-600 96-600 97-600 Re Rb R Rl0b G e Zc 94-601 95-601 96-601 97-601 Ra Rsc Ra Rica Gb Zc 94-602 95-602 96-602 97-602 R RC R9a Rica GE Zc 94-603 95-603 96-603 97-603 R RSc R Rica Gb Ze 94-604 95-604 96-604 97-604 Ra Rsa Reb Rica Gb Ze 94-605 95-605 96-605 97-605 Ra Rsa Rca Riob Gb Zc 94-606 95-606 96-606 97-606 Rb Ra Rlb R1 Gb Zc 94-607 95-607 96-607 97-607 Ra R 5 b Rb RiOb GE Z' 94-608 95-608 96-608 97-608 Re Rlb Rca ROb Gb Ze 94-609 95-609 96-609 97-609 R R R9b Riob G Z' 137 WO 2005/042712 PCT/US2004/035939 94-610 95-610 96-610 97-610 Ra R R9b R 0 G ZC 94-611 95-611 96-611 97-611 Rb R R9 R' Gb Zc 94-612 95-612 96-612 97-612 R' Rsc R 9 b R Ob Gb Zc a R5a 10cC 94-613 95-613 96-613 97-613 R R R R*b Gb Zc 94-614 95-614 96-614 97-614 Rb RSa R 9 ROb 0 Gb Zc 94-615 95-615 96-615 97-615 Rc Rsa R 9 e R Ob Gb zc 94-616 95-616 96-616 97-616 Ra Rsb R 9 " R Ob Gb Zc 94-617 95-617 96-617 97-617 Rb RSb Rc ROb Gb zc 94-618 95-618 96-618 97-618 Rc Rsb R R' b Gb z 94-619 95-619 96-619 97-619 R" R R94 RiOb Gb Zc 94-620 95-620 96-620 97-620 R Re R R O G Zc 94-621 95-621 96-621 97-621 Re Re Rc R 0b Gb Zc 94-622 95-622 96-622 97-622 R Rsa R9a R 0 GE Zc 94-623 95-623 96-623 97-623 Rb R 5 a R 9 a R Ic Gb Zc 94-624 95-624 96-624 97-624 R R 5 a R 9 a ROC Gb z' 94-625 95-625 96-625 97-625 Ra Rb R 9 a Roc G b z 94-626 95-626 96-626 97-626 R R3b R9a R l Gb Zc 94-627 95-627 96-627 97-627 R Rab R 9 a ROc Gb Zc 94-628 95-628 96-628 97-628 Ra Rsc R9a R 0 G Zc 94-629 95-629 96-629 97-629 R R 5 R9a R I Gb Ze 94-630 95-630 96-630 97-630 Re RC R 9 a ROc Gb Zc 94-631 95-631 96-631 97-631 Ra R R9 Roc Gb Z' 94-632 95-632 96-632 97-632 R Rsa R9b R10" Gb Zc 94-633 95-633 96-633 97-633 Rc Rsa R 9 b RlOc Gb Zc 94-634 95-634 96-634 97-634 Ra RSb R 9 b ROc Gb Zc 94-635 95-635 96-635 97-635 Rb Rb R9b R Oc Gb ze 94-636 95-636 96-636 97-636 R' REb R9b ROc Gb Zc 94-637 95-637 96-637 97-637 Ra R'C R9b ROC Gb zC 94-638 95-638 96-638 97-638 R R R 9b R 0 ' Gb zC 94-639 95-639 96-639 97-639 Re R5c R9b Rioc G ZC 94-640 95-640 96-640 97-640 Ra RSa R9c Rioc Gb Zc 94-641 95-641 96-641 97-641 R Rsa R9c Rioc Gb Zc 94-642 95-642 96-642 97-642 Rc Ra R 9
R
1 0 c Gb Ze 94-643 95-643 96-643 97-643 Ra Rab R 9 Roc Gb Zc 94-644 95-644 96-644 97-644 Rb RWb R 9 e RlOc Gb Ze 94-645 95-645 96-645 97-645 Re R5b R9C R 1 0 ' Gb zc 94-646 95-646 96-646 97-646 Ra Rc Rc RiOc Gb Zc 94-647 95-647 96-647 97-647 R R R9e RIce G Ze 94-648 95-648 96-648 97-648 R RSc R9c R 1 0 Gb Zc 94-649 95-649 96-649 97-649 R Ra R9a R0" G Zc 94-650 95-650 96-650 97-650 R Rsa R9a Ria Gc Zc 94-651 95-651 96-651 97-651 R R R9a Rca G Zc 94-652 95-652 96-652 97-652 R R5b R9a Rica G Ze 94-653 95-653 96-653 97-653 Rb Rb 9a o 10 a Ge e 94-654 95-654 96-654 97-654 R' RSb Ra RiOa Gc Zc 94-655 95-655 96-655 97-655 Ra Rsc R9a Ria Gc Zc 94-656 95-656 96-656 97-656 R R' Ra Rica Gc Zc 138 WO 2005/042712 PCT/US2004/035939 94-657 95-657 96-657 97-657 Re R'* R 9 a R1a Gc Z 94-658 95-658 96-658 97-658 Ra Rsa R 9 R1Oa Ge Ze 94-659 95-659 96-659 97-659 Rb Rsa R"b RiOa Ge Z' 94-660 95-660 96-660 97-660 Re Rsa REb RiOa Ge Z' 94-661 95-661 96-661 97-661 Ra Rb R 9 b Ri0a Ge Ze 94-662 95-662 96-662 97-662 Rb Rib R"b Rl a Ge Zc 94-663 95-663 96-663 97-663 Re Rib R 9 ' R 1 ' Ge Ze 94-664 95-664 96-664 97-664 Ra RS R b R1Oa Ge Ze 94-665 95-665 96-665 97-665 Re Ri R 9 b RlOa Ge Z' 94-666 95-666 96-666 97-666 Re Rie Rb R 10 a Ge Zc 94-667 95-667 96-667 97-667 Ra Rsa R 9 e Ri0a Ge Ze 94-668 95-668 96-668 97-668 Rb Rsa R 9 e Rica Ge Z' 94-669 95-669 96-669 97-669 Re Rsa R 9 R10a Ge Ze 94-670 95-670 96-670 97-670 Ra R R 9 e R10a Ge zc 94-671 95-671 96-671 97-671 Rb Rib R 9 ' R 10 a Ge Z' 94-672 95-672 96-672 97-672 R 0 Rib R 9 c R 10 a Ge Z' 94-673 95-673 96-673 97-673 Ra R 5 e R 9 c RiOa Ge Ze 94-674 95-674 96-674 97-674 Rb R3" R 9 RiOa Ge Ze 94-675 95-675 96-675 97-675 Re Rsc R 9 e R10a Ge Z4 94-676 95-676 96-676 97-676 Ra Rsa R9a RiOb Ge Ze 94-677 95-677 96-677 97-677 R Ra R 9 a R'Ob Gc Ze 94-678 95-678 96-678 97-678 c Rsa a RiOb Ge Ze 94-679 95-679 96-679 97-679 Ra Rlb R9a Riob Ge Z' 94-680 95-680 96-680 97-680 R Rsb R 9a Rio0b Ge Z' b 5b 9a Ob ec 94-681 95-681 96-681 97-681 R R R R0 G Ze 94-682 95-682 96-682 97-682 Re R5e R9a RIlb Ge Ze a 5. 9a lOb cc 94-683 95-683 96-683 97-683 R R R Rl G Z' 94-684 95-684 96-684 97-684 R' Ra' R9a RlOb G Z' 94-685 95-685 96-685 97-685 Ra Rsa RSb Rich Gc Ze 94-686 95-686 96-686 97-686 Re Rsa R 9 ' R'Ob Ge Ze 94-687 95-687 96-687 97-687 R' Rsa R 9 b ROb G' Ze 94-688 95-688 96-688 97-688 Ra R5a R9' RGb Ge Ze 94-689 95-689 96-689 97-689 R' Rlb R9' RiOb Ge Ze 94-690 95-690 96-690 97-690 Re R*a R 9 b RIOb Ge Ze 94-691 95-691 96-691 97-691 Ra Rb R 9 b RiOb Ge Ze 94-692 95-692 96-692 97-692 e Sc R9b RlOb Ge Z' 94-693 95-693 96-693 97-693 R Rsc R9b R10O Gc Ze 94-694 95-694 96-694 97-694 Ra Rsa R'" Rl0b G' Ze 94-695 95-695 96-695 97-695 Re Rsa Rib Rib Ge Zc 94-696 95-696 96-696 97-696 Ra R5' R" ROb Ge Ze 94-697 95-697 96-697 97-697 Ra Rt Rc R'b Gc Z 94-698 95-698 96-698 97-698 Rb Rab R9 RIOb Ge Z' 94-699 95-699 96-699 97-699 Re R5b R 9 e RlOb Ge ze 94-700 95-700 96-700 97-700 Ra RSc R9c R"'b Ge Ze 94-701 95-701 96-701 97-701 R Rsc R9 RIO G" Zc 94-702 95-702 96-702 97-702 Re R. RWe R10b Ge Ze 94-703 95-703 96-703 97-703 Ra Rsa R9a Riob Ge Ze 139 WO 2005/042712 PCT/US2004/035939 94-704 95-704 96-704 97-704 R Rsa R9a R 1C G Zc 94-705 95-705 96-705 97-705 Rc Rsa R 9 a RiOc Ge Ze 94-706 95-706 96-706 97-706 Ra Rib R 9 a R10c Ge Zc 94-707 95-707 96-707 97-707 Rb Rb R9a R10C G zC 94-708 95-708 96-708 97-708 Re Rb R 9 a R10c GC zc 94-709 95-709 96-709 97-709 Ra R' R 9 a Rice Ge Zc 94-710 95-710 96-710 97-710 R R Ra R10c G Ze 94-711 95-711 96-711 97-711 Re Re R 9 a Ro' Ge Ze 94-712 95-712 96-712 97-712 Ra R 5 a R 9 b RO G Ze 94-713 95-713 96-713 97-713 Rb R 5 " R 9 b Rice Ge Zc 94-714 95-714 96-714 97-714 Rc Ra R9h R10C Ge Ze 94-715 95-715 96-715 97-715 5b Rb R9b Rioc G9 Zc 94-716 95-716 96-716 97-716 R' R R Rice Ge Ze 94-717 95-717 96-717 97-717 Rb Rb R 9 b Ric Ge Ze 94-717 95-718 96-718 97-718 Ra Rib R 9 b Ric Ge Ze 94-719 95-719 96-719 97-719 R Rie R 9 b RiC Ge Ze 94-720 95-720 96-720 97-720 Rb Ri' R 9 b R10c Ge ze 94-721 95-721 96-721 97-721 Ra Rsa R 9 b Rie Ge Ze 94-722 95-722 96-722 97-722 Ra R R 9 " R10c Ge Z' 94-723 95-723 96-723 97-723 R' Ra R9e R10C G Z 94-724 95-724 96-724 97-724 Ra R R9 R3c Gc Ze 94-725 95-725 96-725 97-725 Re Ria R 9 c R10c Ge Ze 94-726 95-726 96-726 97-726 R' R b R9 R10c Ge Ze 94-727 95-727 96-727 97-727 Ra R" R 9 ' Ric Ge Ze 94-728 95-728 96-728 97-728 R R R9c R10c Ge Ze 94-729 95-729 96-729 97-729 Re R5' R' R10e Gc Ze 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 nitro group, an optionally substituted amino 5 group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R 5 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 9 and Ric 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, 10 an oxo(O=) group, or a thio(S=) group; G is (CH 2
)
2 , (CH 2
)
3 , or (CH 2
)
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 nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R 5 140 WO 2005/042712 PCT/US2004/035939 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 9 and
R
1 0 independently are an alkyl group, a cycloalkyl group, an alloxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy 5 group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, a heterocyclyl group, or an aralkyl group; and G is (Cl 2
)
2 , (CH 2
)
3 , or (CH 2
)
4 ; 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 nitro group, an optionally substituted amino 10 group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R 5 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 9 and R1 0 independently are an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an 15 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 20 alkoxy group, or an aryl group; and G is (CH 2
)
2 , (CH 2
)
3 , or (CH 2
)
4 ; 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; R is hydrogen or an alkyl group; R 9 is hydrogen, -S-N N-Me an alkoxy group, or 0 R 10 is hydrogen or an alkoxy group; and G is (CH 2
)
2 , 25 (CH 2
)
3 , or (CH 2
)
4 . In still another aspect of any of formulae (94), (95), (96), and (97) of the present 0 - -S-N N-Me I I \ -I invention, R is -H or Me; R5 is -H or Me; R9 is -H, -OMe, or ; R is -H, OMe, or -OEt; and G is (CH 2
)
2 , (CIH 2
)
3 , or (CH 2
)
4 . 141 WO 2005/042712 PCT/US2004/035939 The present invention further encompasses various compounds of general formula (IV) as follows: OMe 0 0
R
1 OMe o NR OMe ?NR N O NO 'N N-G=Z N N-G=Z Me (98); Me O N'Me 0 OEt OBt ?NR s N N O N I -= NN NGZ\ N N-G=Z S N Me (100); and 0 (101); 5 where all symbols are as defined above in connection with formula (I). According to various aspects of the present invention, R, R', R, 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: 10 Formulae R R. RI G Z 98-1 99-1 100-1 101-1 Ra Ria Rsa Ga Za 98-2 99-2 100-2 101-2 Rb Ria Rsa Ga Za 98-3 99-3 100-3 101-3 Re Ria Rsa Ga Za 98-4 99-4 100-4 101-4 Ra RIb Rsa Ga Za 98-5 99-5 100-5 101-5 R Rlb Rsa Ga Za 98-6 99-6 100-6 101-6 Re R ] R 5 a Ga Za 98-7 99-7 100-7 101-7 Ra Rc R 5 a Ga Za 98-8 99-8 100-8 101-8 R R Rsa Ga Za 98-9 99-9 100-9 101-9 Re RIc Rsa Ga Za 98-10 99-10 100-10 101-10 Ra R 1 8 Rsb Ga za 98-11 99-11 100-11 101-11 Re Rb a R G" Za 98-12 99-12 100-12 101-12 Rc Ria RIb Ga Za 98-13 99-13 100-13 101-13 Ra R ib Rsb Ga Za 98-14 99-14 100-14 101-14 Rb R Ib REb G a Za 98-15 99-15 100-15 101-15 Re Ra Rsb Ga Za 98-16 99-16 100-16 101-16 Ra RI' Rab Ga Za 98-17 99-17 100-17 101-17 Rb R' Rsb Ga Za 98-18 99-18 100-18 101-18 Re RI' Rab Ga Za 98-19 99-19 100-19 101-19 Re Ri R Ga Za 98-20 99-20 100-20 101-20 R Ria e Ga Za 142 WO 2005/042712 PCT/US2004/035939 98-21 99-21 100-21 101-21 Re Ria Rl' Ga Za 98-22 99-22 100-22 101-22 Ra Rib Rc Ga Za 98-23 99-23 100-23 101-23 Rb Rib RS' Ga Za 98-24 99-24 100-24 101-24 Rc Rib RSc Ga Za 98-25 99-25 100-25 101-25 Ra RC Rc Ga Za 98-26 99-26 100-26 101-26 R Rc Rsc Ga Za 98-27 99-27 100-27 101-27 Rc R R' Ga Za 98-28 99-28 100-28 101-28 R R Ra Rsa Gb Za 98-29 99-29 100-29 101-29 Rb Ria Ra Gb Za 98-30 99-30 100-30 101-30 Rc Rla Rsa Gb Za 98-31 99-31 100-31 101-31 Ra R l Ra G Za 98-32 99-32 100-32 101-32 R R S Ra Gb Za 98-33 99-33 100-33 101-33 R R Rs G Za 98-34 99-34 100-34 101-34 Ra R5 Ra Za 98-35 99-35 100-35 101-35 Rc R' Ra G Za 98-36 99-36 100-36 101-36 R' Ric Ra G Za 98-37 99-37 100-37 101-37 Ra R R5a Gb Za 98-38 99-38 100-38 101-38 Rc Rl Rab Gb Za 98-39 99-39 100-39 101-39 R R R Gb Za 98-40 99-40 100-40 101-40 Ra R5 Rb Gb Za 98-41 99-41 100-41 101-41 R R l Rb GE Za 98-42 99-42 100-42 101-42 Rc R lb RWb G3 Za 98-43 99-43 100-43 101-43 Ra Ric Rb e Za 98-44 99-44 100-44 101-44 Rb R Rsb GE Za 98-45 99-45 100-45 101-45 Ra R Rlb GE Za 98-46 99-46 100-46 101-46 Ra R l Rsc (:b Za 98-47 99-47 100-47 101-47 R' Rb R' Gb Za 98-48 99-48 100-48 101-48 Rc Rl R5c Gb Za 98-49 99-49 100-49 101-49 Ra R l R5' G Za 98-50 99-50 100-50 101-50 e Rlb Ra' G b Za 98-51 99-51 100-51 101-51 R Rb R 5 Gb Za 98-52 99-52 100-52 101-52 Ra RSb Rc G' Za 98-53 99-53 100-53 101-53 R Rl" Rsc G Za 98-54 99-54 100-54 101-54 R' Rl' R' GcE3 Za 98-55 99-55 100-55 101-55 Ra Rla Sa Gb Za 98-56 99-56 100-56 101-56 Rb Ra Rsa Ge Za 98-57 99-57 100-57 101-57 R' Ria Rsa Ge Za 98-58 99-58 100-58 101-58 Ra R 1 l Rsa Ge Za 98-59 99-59 100-59 101-59 R' R l Rsa Ge Za 98-60 99-60 100-60 101-60 R R'b R5a G' Za 98-61 99-61 100-61 101-61 Rc R' Rsa Ge Za 98-62 99-62 100-62 101-62 Re Rc Rsa Ge Za 98-63 99-63 100-63 101-63 Re Re Rsa Go Za 98-64 99-64 100-64 101-64 Ra Ria Rsb Ge Za 98-65 99-65 100-65 101-65 R' RIa R 5 b G Za 98-66 99-66 100-66 101-66 Re R Rsb Gc Za 98-67 99-67 100-67 101-67 Ra Ria R a G' Za 143 WO 2005/042712 PCT/US2004/035939 98-68 99-68 100-68 101-68 R R l Rlb Ge 7a 98-69 99-69 100-69 101-69 Re R R b Ge Za 98-70 99-70 100-70 101-70 Ra RiC Rb Ge 7a 98-71 99-71 100-71 101-71 Rb Ri' Rsb Ge Za 98-72 99-72 100-72 101-72 Re Ric Rsb Ge Za 98-73 99-73 100-73 101-73 Ra Ra RS Ge Za 98-74 99-74 100-74 101-74 R' Ria R G Za 98-75 99-75 100-75 101-75 Re Ria Re Ge Za 98-76 99-76 100-76 101-76 Ra R lb R G 7a 98-77 99-77 100-77 101-77 R R l R e Ge Za 98-78 99-78 100-78 101-78 Re R l R e Gc Za 98-79 99-79 100-79 101-79 Ra Re Re Ge Za 98-80 99-80 100-80 101-80 Rb R ic Re Ge Za 98-81 99-81 100-81 101-81 Re Rie Re Ge Za 98-82 99-82 100-82 101-82 Ra Rla Rsa Ga eb 98-83 99-83 100-83 101-83 R R " R a Ga e 98-84 99-84 100-84 101-84 Re RIa Rsa Ga eb 98-85 99-85 100-85 101-85 Ra R. Rs Ga Zb 98-86 99-86 100-86 101-86 R5 R Ra Ga Z 98-87 99-87 100-87 101-87 R' R" Rsa Ga 98-88 99-88 100-88 101-88 Ra Rlb sa Ga b 98-89 99-89 100-89 101-89 Re R' Ra Ga e 98-90 99-90 100-90 101-90 Re Rc a Ga b 98-91 99-91 100-91 101-91 Ra R.a Rsb Ga b 98-92 99-92 100-92 101-92 R R Rsb Ga Zb 98-93 99-93 100-93 101-93 Re RIa Rsa Ga zb 98-94 99-94 100-94 101-94 R Rlb R5b Ga b 98-95 99-95 100-95 101-95 Rb R R Ga e 98-96 99-96 100-96 101-96 R' Rlb Rlb Ga Zb 98-97 99-97 100-97 101-97 Ra Rlc Rb Ga b 98-98 99-98 100-98 101-98 Re R' R Go e 98-99 99-99 100-99 101-99 Ra RIb Rb Ga zb 98-100 99-100 100-100 101-100 Ra Ra R] b Ga Z 98-101 99-101 100-101 101-101 Re Ria Ri Ga Zb 98-102 99-102 100-102 101-102 R Ria R Ga eb 98-103 99-103 100-103 101-103 Ra Rb W R a 7t 98-104 99-104 100-104 101-104 Rb R. Rsc Ga Zb 98-105 99-105 100-105 101-105 Re R] Re Ga 7b 98-106 99-106 100-106 101-106 Ra Rla Rse Ga zb 98-107 99-107 100-107 101-107 R R' Re Ga Zb 98-108 99-108 100-108 101-108 Re Rlc R Ga Zb 98-109 99-109 100-109 101-109 Ra RIa Rsa Ga Zb 98-110 99-110 100-110 101-110 Rb Rla Rsa Ga Zb 98-111 99-111 100-111 101-111 Re Rla Rsa Ga Zb 98-112 99-112 100-112 101-112 Ra R ia Ga Zb 98-113 99-113 100-113 101-113 R' R"* R" Gb Zb 98-114 99-114 100-114 101-114 Re R l R Gb Zb 144 WO 2005/042712 PCT/US2004/035939 98-115 99-115 100-115 101-115 Ra R Rsa G( Z 98-116 99-116 100-116 101-116 R R Rsa Gb Z 98-117 99-117 100-117 101-117 Rc Rl Rsa G Z 98-118 99-118 100-118 101-118 Ra Rla Rb G Zb 98-119 99-119 100-119 101-119 Rb Ra Rlb G Ze 98-120 99-120 100-120 101-120 Rc Rla Rb Gb Z 98-121 99-121 100-121 101-121 Ra R Rlb (b e 98-122 99-122 100-122 101-122 Ra R R G Ze 98-123 99-123 100-123 101-123 Rc R l Rlb G Z 98-124 99-124 100-124 101-124 R Rlb R5b Gb Zb 98-125 99-125 100-125 101-125 RC R' Rl G Z 98-126 99-126 100-126 101-126 Rc RO Rb Gb Zb 98-127 99-127 100-127 101-127 R Ra R G' Z 98-128 99-128 100-128 101-128 Rb R R5 Gb Zb 98-129 99-129 100-129 101-129 Rc R] R Gb Z 98-130 99-130 100-130 101-130 Ra Rlb R5i Gb Ze 98-131 99-131 100-131 101-131 Rb R lb Z 98-132 99-132 100-132 101-132 R R' R5' G Z 98-133 99-133 100-133 101-133 Ra Ric Ra' Gb Z 98-134 99-134 100-134 101-134 Rb R' Rc G Ze 98-135 99-135 100-135 101-135 R' Rl' R. G5 Z 98-136 99-136 100-136 101-136 R Rlb Ra Gc Zb 98-137 99-137 100-137 101-137 Rb Rl Ra Gb zb 98-138 99-138 100-138 101-138 Re Ria Rsa Ge Z 98-139 99-139 100-139 101-139 R Rb Rsa G4 Z 98-140 99-140 100-140 101-140 Rb R b R G Z 98-141 99-141 100-141 101-141 Rc R l Rsa Ge Zb 98-142 99-142 100-142 101-142 Ra R S Ra Gc Zb 98-143 99-143 100-143 101-143 Rb R Rsa G4 Z 98-144 99-144 100-144 101-144 R' Rla Ra Ge Zb 98-145 99-145 100-145 101-145 Raa Rl R G' Z 98-146 99-146 100-146 101-146 Rb Ra Rs, Gc Zb 98-147 99-147 100-147 101-147 Rc Ra Rb G e 98-148 99-148 100-148 101-148 Ra Rib Rlb G4 Z 98-149 99-149 100-149 101-149 R Rb Ria G' Z 98-150 99-150 100-150 101-150 Rc R lb R 5b Gc ZE 98-151 99-151 100-151 101-151 Raa Rc b Go Zb 98-152 99-152 100-152 101-152 R R' Rl Ge Z7 98-153 99-153 100-153 101-153 R' Ric R" G' Zb 98-154 99-154 100-154 101-154 Ra Ril R G4 Ze 98-155 99-155 100-155 101-155 R R RE G' Z 98-156 99-156 100-156 101-156 R R Rib G' Z 98-157 99-157 100-157 101-157 Ra R R3 G' Zb 98-158 99-158 100-158 101-158 Ra R R Ge Z 98-159 99-159 100-159 101-159 R Rb R' Gc Z 98-160 99-160 100-160 101-160 Ra Ric R G4 Z 98-161 99-161 100-161 101-161 Rb Ric R* G' 145 WO 2005/042712 PCT/US2004/035939 98-162 99-162 100-162 101-162 Rc R Rsc G Zb 98-163 99-163 100-163 101-163 Ra Ria Rsa Ga Z 98-164 99-164 100-164 101-164 Rb Ria RSa Ga zo 98-165 99-165 100-165 101-165 R Ria Rsa Ga Z' 98-166 99-166 100-166 101-166 Ra Rlb sa Ga Ze 98-167 99-167 100-167 101-167 Ra R" Rsa G zc 98-168 99-168 100-168 101-168 R R5 Rsa Ga Ze 98-169 99-169 100-169 101-169 Ra RI Rsa Ga Z 98-170 99-170 100-170 101-170 Re R' Ra Ga Zc Ic a Ca 98-171 99-171 100-171 101-171 Ra Rc R G Z 98-172 99-172 100-172 101-172 Ra Rila Rsb Ga ZC 98-173 99-173 100-173 101-173 R' Ria Ra, Ga Ze 98-174 99-174 100-174 101-174 R Ra Rsa Ga Zo Ib Rsb Ga 98-172 99-172 100-172 101-172 Ra R R G Z' 9817 9-76 10-7 11-7 bR la Rb Ga z 98-177 99-177 100-177 101-177 R' R R Ga Z 98-178 99-178 100-178 101-178 Ra RSb R Ga Ze 98-179 99-179 100-179 101-179 Re RI Rlb Ga Zc 98-180 99-180 100-180 101-180 Rb R Rb Ga Zc 98-181 99-181 100-181 101-181 Ra Ria Rc G" Ze 98-182 99-182 100-182 101-182 R Ra R' Ga Z 98-183 99-183 100-183 101-183 Re Ria Rb Ga Z 98-184 99-184 100-184 101-184 Ra RI Rcb Ga Z 98-185 99-185 100-185 101-185 Rb RIC R' Ga Zc 98-186 99-186 100-186 101-186 Re R R Ga Z" 98-187 99-187 100-187 101-187 Ra Ria Rc Ga Ze 98-188 99-188 100-182 101-188 Rb Rlc Rsc Ga Z 98-189 99-189 100-189 101-189 R' Rl' Rc Ga Zc 98-190 99-190 100-190 101-190 Ra Ria Rsa Gb Z 98-191 99-191 100-191 101-191 R R Ria Rsa Gt Zc 98-192 99-192 100-192 101-192 Rc R]a Rsa (:t Zc 98-193 99-193 100-193 101-193 R" Ri Rs a GEb Ze 98-194 99-194 100-194 101-194 R R"a Rsa (b Zc 98-195 99-195 100-195 101-195 R R l Rsa Ga Ze 98-196 99-196 100-196 101-196 Re R' Ra Ga Ze 98-197 99-197 100-197 101-197 R RIc RSa Ga Ze 98-198 99-198 100-198 101-198 R Ric RC G Ze 98-199 99-199 100-199 101-199 Ra Ra RSb Ga Ze 98-200 99-200 100-200 101-200 R' Ria Rlb Gb Ze 98-201 99-201 100-201 101-201 R R]a R 5 l Gb Ze 98-202 99-202 100-202 101-202 R Rlb R 5 l G Ze 98-203 99-203 100-203 101-203 Ra R l Rlb Gb Ze 98-204 99-204 100-204 101-204 R' R l Rb GE Z 98-205 99-205 100-205 101-205 Re Rlc Rlb Gb Ze 98-206 99-206 100-206 101-206 R Rie Rlb Gb Zc 98-207 99-207 100-207 101-207 R* Ric Rlb Gb Zc 98-208 99-208 100-208 101-208 Ra Ria R'b G Z 146 WO 2005/042712 PCT/US2004/035939 98-209 99-209 100-209 101-209 R Rla R5. Gb ZO 98-210 99-210 100-210 101-210 Re Rla R 4 Gb Zc 98-211 99-211 100-211 101-211 Ra Rib R 5 G Z" 98-212 99-212 100-212 101-212 Rb Rib R3" Gb Zc 98-213 99-213 100-213 101-213 Re Rib R5C Gb Ze 98-214 99-214 100-214 101-214 Ra RIc R5c Gb ze 98-215 99-215 100-215 101-215 Rc R' RcCG Zc 98-216 99-216 100-216 101-216 Rc Rc Rc G Ze 98-217 99-217 100-217 101-217 Ra R]a Rba Gc Zc 98-218 99-218 100-218 101-218 Re Rl" Rsa Ge Z" 98-219 99-219 100-219 101-219 R Ra Rsa Ge ze 98-220 99-220 100-220 101-220 Rb R 1 l R 5 a Ge Zc 98-221 99-221 100-221 101-221 Re RIa Rsa Ge Ze 98-222 99-222 100-222 101-222 R Rlb Rsa G Z 98-223 99-223 100-223 101-223 Ra R Rsa Ge ZC 98-224 99-224 100-224 101-224 lb R' R5a Gc Z 98-225 99-225 100-225 101-225 R' RIc Rsa Ge Z' 98-226 99-226 100-226 101-226 Ra R]a R Gc Zc 98-227 99-227 100-227 101-227 Ra RIa Ra Gce Ze 98-228 99-228 100-228 101-228 Rb R1e R 5 b Ge Z' 98-229 99-229 100-229 101-229 Ra RIb R 5 b Ge Ze 98-230 99-230 100-230 101-230 Ra RIb Rb Ge Z 98-231 99-231 100-231 101-231 Rb Rla Rab Ge Ze 98-232 99-232 100-232 101-232 Re RI' REb Ge Ze 98-233 99-233 100-233 101-233 Ra Ric Rlb Ge Ze 98-234 99-234 100-234 101-234 Rc RI' Rab Gc ZC 98-235 99-235 100-235 101-235 Ra Rila RW" G' Z 98-236 99-236 100-236 101-236 l R5a Rb Gb Z' 98-237 99-237 100-237 101-237 R Ria R5 Ge Zc 98-238 99-238 100-238 101-238 Re Rib R5e Ge Z 98-239 99-239 100-239 101-239 Ra Ri RS' Ge Ze 98-240 99-240 100-240 101-240 R R l Rsc Ge ZC 98-241 99-241 100-241 101-241 Ra Rlc R5b Ge zC 98-242 99-242 100-242 101-242 Ra Rla R5 Ge Ze 98-243 99-243 100-243 101-243 R R'O Rc G" 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 5 group, an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group; R1 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an 147 WO 2005/042712 PCT/US2004/035939 alkenyloxy group, or a cycloalkenyloxy group; R5 is is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a 5 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 -(CH 2 )s-, where s is an integer from 0-5; and all other symbols are as defined above in connection with formula (I). 10 In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, G is -(CH 2 )s-CH=CH-(CH 2 )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 -(CH 2 )s-C=C-(CH 2 )s-, where s is an integer from 0-5; and all other symbols 15 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 0, 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 20 (I). In another aspect of any of formulae (98), (99), (100), and (101) of the present invention, Z is (CH2)u or S(=O)u, where u is an integer from 0-2; and all other symbols are as defined above in connection with fonnula (I). In still another aspect of any of formulae (98), (99), (100), and (101) of the present 25 invention, E is 0, 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 30 (I). Examples of compounds having general formula (IV) include, but are not limited to: 148 WO 2005/042712 PCT/US2004/035939 N\ N O0 / N N /0N N N NH MeO S NH 0 I . 0 OCH, NH OCH, 'N OCH 0 3N 0 O N\CH C H OCH3 CN NH2 N N ocH, OCHN h,(CH
N-
aOCd N"N 'N NHi -~O S R1 N 5 ; and According to another aspect of the present invention, various compounds of general formula (1) having general formula (V) 2 A E R 4 XS()wAr D. KL CH 2 ) v-C-XCH 2 ) -O-R () x X3 149 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 5 invention include, but are not limited to: RI O EIR XRS(O) NWAr R D K-L-(CH 2 )v -C-X-(CH 2 ) p IJ C-O-R R3 X X2II X3 (102); R1 _S E R4 XS(O) -Ar DR K-L-(CH 2 )v-C-X-(CH2) C-0-R R3 X X2 1 X3 (103); RIR N E R XS(O) WAr R ' i K -L-(CH 2 )v -- 0-X-(CH 2 ) - - R I I C-O-R
R
3 X X2II X3 (104); R2 C X-S(O)WAr 6/ K-L(CH2)v -C-x-(CH 2 ) C DJ,2 ,.K-L-2 1V P C-O-R
R
3 X X2 X3 (105);
R
1 2 H- (_H2)y E R4 X-S(O) j-Ar So KL-(CH 2 )v XCH 2 ) D 7 'Y I I P C-O-R R3 X X2II 10 X3 (106); R1 \A R4 S(O) Ar R D/ K-L-(CH 2 )v-C-X-(CH2)p J C-O-R R3 X X2 1 X3 (107); 150 WO 2005/042712 PCT/US2004/035939
R
1 E\A R XS(O) \WAr R2/, 4
,K-L-(CH
2 )V -C-X-(CH 2 ) pif11 C-O-R R3 xX 1 X3 (108);
R
1 \A R4 X-S(O) \WA, D_)- -K-L(CH 2 )V-C-X(CH2) -OR X3 (109);
R
2 . ' -- 'O-L(H2)-C-X-CH2) P
D
7 ~ ~ ~ 1 CK~ J I CO-R R3 xX 1 X3 (110); 04M \A 1E, X-S(O) wAr 0 ,K-L(CH 2 )V -c-x(CH2) p IXI2 C-O-R X3 (11); R"R
R
2 ~ K-L-H 2 )V -c-x-(CH 2 x-Po)/\ A 0/ifI I P C-O-R P3X 2 11
R
3 3 (11); R2_ X4-S(O) wAr
K-L-(CH
2 ) V-c-X-(CH2)p /-i >r I I PC-O-R
R
3 x (114); X3(13) WO 2005/042712 PCT/US2004/035939 \l-A E R4 4 S(O) WAr
(H
2 C)n- . L I GC2V c--C2 - O R3 xX 2 (15) -\ EyR X-S(O) WA, D.2 K -L(CH 2 ) V c-x(CH2) _ -bOY f p C-O-R X x3 (116); E2B X-S(O) wAr .' , y K -L (C H 2 )V C IX (C H 2) p--(\ _ R3 x C2O11 X3 (117); \lA E
R
4 0 A 2-__- X-S(O)w r D yK-L-(CH 2 )V -CX(CH 2 )-\ /'N' 11I P C-O-R R3 x X2 1 X3 (118); Rl B\A>E
R
4 -~S(o) -Ar D ~K-L-CH 2 )V 0XI<7CH 2 ) p _\ 'yII C-O-R R X3x (119); 2B-AE INx -S(O) w Ar D/ KL0 2 )VC-X(CH2)--/ DH yK I I P C-O-R X3 (120); R\A ,oy R 4 x~-O -Ar
R
2 B * )ICH -c-x-(CH 2 w
D~
4 ~.~.L~ I I C-O-R
R
3 (121); 152 WO 2005/042712 PCT/US2004/035939 \lA ,s R 4 X -S(O) WAr
KL-(CH
2 ) VG-X(CH2) p _\ I I C-OR R3 x X2I I X3 (122); D J -L-(CH 2 )v-c-x(CH2)p _ I~ I C-OR R3 x X2 1
R
3 3 (123); ,\A - XS(o) WAr R2,.- N--L-(CH 2 )V-C-X-(CH)p 0 J,~ 11 2) C-O-R R3 x X2 1 X3 (124); l\AE
R
4 -S(o) W-Ar R3 j C-L(CH2 )V -C1(C 2 ) -P-/ C-O-R x X2 11 X3 (125); \lA ,E R4X-S(o) WAr D y~j CH -L-(CH 2 )V C-x(CH2) I ~ I P C0OR 5 X3 (126); 2BA IE x S(O) W-Ar B/_ - K- Y-G=Z-Ar-(CH 2
)V-C-X(CH
2 ) OCR\ I I _- R~ IX 3 (127); A\ A
R
4 zSO WA D,- K--Y-G-C(CH 2 )V 0-X-CH 2 ) p-\ X, 1 C-O-R R X 12 11 X3 (128); 153 WO 2005/042712 PCT/US2004/035939 Rl 4 S(o) VTAr "D/y2 -- K-(CH 2 )t-(CH 2 )V-C-X(CH2) p-/ 11 C-O-R
R
3 x X2 1 X3 (129); -\ A ES(o) Ar R2 4 I f I D_A -L H)V-C-X-CH)p J- KL-C2 )-P' C-O-R R3 I I X3 (130); AR E 4S(o) W-A D/_j K-L-(CH 2 )V-C-X(CH2)-p _ 11 C-O-R X3 (131); -\A) ES(o
R
2 I Dj~ ~K-L-(CH2)Vwjf X-(CH 2 ) -O-R
R
3 X3N (132); \A R4 S(O) WAr 2b I .K-L-(CH 2 )V C'X-(CH 2 )p-O-R 50 (133); AE R4(0)-Ar -A E- ,S(o) wr D/,j ,K L(CH 2
)VCXCH
2
)-P
II 1 C-O-R
R
3 N (135); Rl 4 So) 154 WO 2005/042712 PCT/US2004/035939 RA E R 4 S(O) Ar R D K--L-(CH 2
)V-CX-(CH
2 ) pC YI I C-O-R R3XX X2 X3 (136); R1 AX E AR4 .S(O) WAr
R
2 B' S D K -L--(CH2)- X -(CH2) - O-R
R
3 X X2 X3 (137); R' XA ET R4 S(O),WAr R2__B RN DR K-L-(CH 2 )V- X-(CH 2 )- O-R 7- rI I P C-0-R
R
3 x X2 X3 (138); __ x~~o~w \ 7~ 12 R2 A E R4S(0)W R R2 I X 6/_j K-L-(CH 2
)V--C-X-(CH
2
)-O
I I p C-O-R R3 X X2 X3 (139); and RRR A E RS(O)V R1 R2 BRX 12 D K-L-(CH 2 )V-( X-(CH 2 ) PC--R R3 X X2 1 5 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:
-
R R i0 R O R12 R O OHN- R 0 /(CH2) !H2) OR 10 0 0 (141), 155 WO 2005/042712 PCT/US2004/035939 where R , R , 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 5 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 10 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 defined as above in connection with formula (I). 15 In one aspect of formula (141) of the present invention, R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group; and all other symbols are as defined in 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 20 defined in connection with formula (I). In another aspect of formula (141) of the present invention, R 1 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or 25 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 2 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, or an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or 30 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 1 1 is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy 156 WO 2005/042712 PCT/US2004/035939 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 still another aspect of formula (141) of the present invention, R" is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an 5 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 10 group is a halogen, a nitro group, an amino group, an alkyl group, an alkoxy group, or an aryl group; and all other symbols are as defined in connection with formula (I). In yet another aspect of formula (141) of the present invention, R is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) 15 group; and all other symbols are as defined in connection with formula (I). In still another aspect of formula (141) of the present invention, R2 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 20 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 in connection with formula (I). 25 In a further aspect of formula (141) of the present invention, R is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(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, R 13 is an alkylsulfonyl 30 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 157 WO 2005/042712 PCT/US2004/035939 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 5 symbols are as defined in connection with formula (I). In another aspect of formula (141) of the present invention, R 14 is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, a carboxy group, a cyano group, an oxo(O=) group, or a thio(S=) group; and all other symbols are as defined in connection with formula (I). 10 In yet another aspect of formula (141) of the present invention, R 1 4 is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the 15 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 in connection with formula (I). In yet another aspect of formula (141) of the present invention, R is hydrogen or an 20 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, CH 3 , or C 2
H
5 , and all other symbols are as defined in connection with formula (I). In still another aspect of formula (141) of the present invention, R' is hydrogen or an alkyl group, and all other symbols are as defined in connection with formula (I). 25 In yet another aspect of formula (141) of the present invention, R' is -H, CH 3 , or
C
2
H
5 , and all other symbols are as defined in connection with formula (I). In another aspect of formula (141) of the present invention, R 2 is hydrogen or an alkyl group, and all other symbols are as defined in connection with formula (I). In another aspect of formula (141) of the present invention, R 2 is -H, CH 3 , or C2H1, 30 and all other symbols are as defined in connection with formula (I). 158 WO 2005/042712 PCT/US2004/035939 In yet another aspect of formula (141) of the present invention, R" is hydrogen, a halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in connection with formula (1). In another aspect of formula (141) of the present invention, R" is -H, -Cl, -OCH 3 , or 5 SCH 3 , and all other symbols are as defined in connection with formula (I). In a further aspect of formula (141) of the present invention, R 12 is hydrogen, a halogen, an alkoxy group, or an alkylthio group; and all other symbols are as defined in connection with formula (I). In a another aspect of formula (141) of the present invention, R1 2 is H, Cl, -OCH 3 , or 10 -SCH 3 , and all other symbols are as defined in connection with formula (I). In a further aspect of formula (141) of the present invention, R 13 is hydrogen, a halogen, or an alkyl 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, R 3 is -H, -F, or 15 CH 3 , 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, R1 4 is -H, -F, or -CH 3 , 20 and all other symbols are as defined in connection with formula (I). In another aspect of formula (141) of the present invention, R' 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, 11 12 131 25 an alkenyloxy group, or a cycloalkenyloxy group; R", R , R , and R' 4 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). 30 In another aspect of formula (141) of the present invention, R' and R2 independently are hydrogen, a hydroxy group, a halogen, an alkoxy group; R", R , R , and R 14 159 WO 2005/042712 PCT/US2004/035939 independently are hydrogen, a halogen, a hydroxy group, an alkoxy group; and all other symbols are as defined as above in connection with formula (I). In yet another aspect of formula (141) of the present invention, R' and R2 independently are -H or -OCH 3 ; R1 1 is -Cl, -OCH 3 , or -SCH 3 ; R 12 is -Cl, -OCH 3 , or -H; R is 5 H, CH 3 , or C 2
H
5 ; R13 is F or CH 3 ; R 1 4 is F or CH 3 ; 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: 0 0
R
1 H R2: N OR O\ NH S H (142), 10 where all symbols are as defined above in connection with formula (I). According to various aspects of the present invention, R, R1, and R2 of formula (142) are selected to produce various compounds of formula (142-1) through formula (142-27) as follows: Formula R R R2 142-1 R R2a 142-2 R RIa R~d 142-3 R Rla R2a 142-4 Ra Rib R2a 142-5 R, R l Ra 142-6 R Rlb R2a 142-7 R a RC Ra 142-8 Rb RIO R2a 142-9 R R(e R2a 142-10 R a Rla R2b 142-11 R, Ria Rb 142-12 R Rla R2b 142-13 R Re ~ 142-14 Rb Rlb R2b 142-15 R RIb R2b 142-16 R a R1c R2b 142-17 Rb Ric R2b 142-18 Rc RWe R2b 142-19 Ra R1a 2e 160 WO 2005/042712 PCT/US2004/035939 142-20 Re Rla R 2 c 142-21 R Rl Rc 142-22 Ra Rib R 2 C 142-23 R, R b R~e 142-24 Rc Rib R 2 c 142-25 Ra R1c R 2 e 142-26 Re RIC R 2 c 142-27 R Ric R~e 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 nitro group, an optionally substituted amino group, alkyl group, an 5 alkoxy group, an alkenyl group, or an alkoxyalkyl group; and R 1 and R 2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group. 10 In another aspect of formula (142) of the present invention, R 1 and R2 are independently a halogen or an alkyl group; and R is hydrogen, an alkyl 40
-NO
2 group, , or In still another aspect of formula (142) of the present invention, R 1 is -OCH 3 or -F; R2 -1-0 - N 2 is -OCH 3 or -Cl; R is -H or C 2
H
5 , , or 15 The present invention also contemplates various compounds of general formula (V) as follows: R NI
(CH
2 )v NH-(CH2)p CO 2 R R2~> ~NH 0 R13' RI4 (143), where all symbols are as defined above in connection with formula (I). In one aspect of formula (143) of the present invention, R 1 and R2 independently are 20 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 161 WO 2005/042712 PCT/US2004/035939 cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyallyl group, an alkenyloxy group, or a cycloalkenyloxy group; R 13 and R1 4 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=) 5 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, 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, R' and R 2 independently 10 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; R 13 and R14 independently are hydrogen, a halogen, a nitro group, an amino group, a mono- or di 15 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 ailcoxy group, a haloalkoxy group, a cycloalkyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a heteroaryl group, or a heterocyclyl group, an aralkyl group; and all other symbols are as 20 defined in connection with formula (I). In another aspect of formula (143) of the present invention, R1 and R 2 independently are hydrogen, an alkyl group, or an alkoxy group; R 13 and R1 4 independently are hydrogen, a halogen, an alkyl group, or an alkoxy group; and all other symbols are as defined in connection with formula (I). 25 In yet another aspect of formula (143) of the present invention, R, and R 2 are -H or OCH 3 ; R1 3 is CH 3 or -F; R 1 4 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: 162 WO 2005/042712 PCT/US2004/035939 R12 O (CH 2 ), NH (CH2)P COO 2 R R2~> N~-0 NH 0
CH
3 (144), where all symbols are as defined above in connection with formula (I). According to various aspects of the present invention, R, R1, R 2 , v, and p of formula (144) are selected to produce various compounds of formula (144-1) through (144-243) as 5 follows: Formula R RI R 2 v p 144-1 Ra RIa R 2 a va pa 144-2 R Rla R2a va pa 144-3 Rc Ria R 2 a va . a 144-4 Ra Rib R 2 a va pa 14-5 R Rlb R2a ya pa 144-5 R, RIb R ~a va pa 144-6 Ra RIb R 2 a va pa 144-8 R R iC R2a a a 144-7 R, Ric R2a va pa 144-1 Rb Ric
R
2 va pa 14-1 Wc R ~ l ea pa 144-11 R Ra R2b v pa 144-12 R Ria
R
2 b va pa 144-13 Ra RIb R2b Va pa 144-14 R R R va pa 144-15 R Ria R 2 b va pa 144-16 Ra Ric
R
2 b va pa 144-17 R" RIC Rb va pa 144-18 Rb R I R2b Va pa 144-19 Ra Ria
R
2 c Va pa 144-20 Ra Ria
R
2 e Va pa 144-21 ' Ria R2c Va pa 144-22 Ra RIb R e a pa 144-23 Re Rb
R
2 e va pa 144-24 Ra R
R
2 c Va pa 144-25 Rb Ria
R
2 c Va pa 144-26 Rb R I R 2 c va pa 144-27 Rc Rib
R
2 c va pa 144-28 Ra Ria
R
2 a vb pa 144-29 R Ria R2a va pa 144-30 Ra Ria R 2 a va pa 144-31 Ra Rlb R2a vb pa 163 WO 2005/042712 PCT/US2004/035939 144-32 Rb R b R 2 a vb pa 144-33 Rc R l Ra vb pa 144-34 Ra Ric R 2 a v pa 144-35 R Rc Ra vb pa 144-36 R4 R ic R 2 a vb pa 144-37 Ra Ri a R 2 b vb pa 144-38 Rb Ri a R 2 b pa 144-39 Rc Ria R 2 b vb pa 144-40 Ra Rib R 2 b vb p a 144-41 Rb R b R 2 b v pa 144-42 R Rb 2 b v pa 144-43 Ra Rio R 2 b pa 144-44 R R c R 2 b vb pa 144-45 R4 Rio R 2 b vb pa 144-46 Ra R a R 2 e vb pa 144-47 R Ria R 2 e v pa 144-48 R4 Ria R 2 c vb pa 144-49 Ra RIb R 2 0 b pa 144-50 Rb R'l R 2 vb pa 144-51 R R E 2b ' vb pa 144-52 Ra Ri R 2 e v0 pa 144-53 Rb Rio R 2 c vb pa 144-54 R4 Rio R 2 e vb pa 144-55 Ra Ria R2a vC p a 144-56 R Ra R 2 a v pa 144-57 Rc Ria R 2 a v pa 144-58 Ra R b R 2 a V pa 144-59 R Rlb R 2 a v' pa 144-60 R' R'l R 2 a VC pa 144-61 Ra R R 2 a vc pa 144-62 R R* Ra v' pa 144-63 R' Ro R 2 a v' pa 144-64 R a Rla R 2 b v' pa 144-65 Rb Ria R 2 b v p a 144-66 R4 Ria R 2 b vc pa 144-67 Ra Rib R 2 b vO pa 144-68 Rb R l Rb v" pa 144-69 Rc Rib R 2 b pe pa 144-70 Ra Rio R 2 b vC pa 144-71 Rb Rio R 2 e ve pa 144-72 R Rio R 2 b v pa 144-73 R a Ria R 2 c Ve pa 144-74 Rb Ria R 2 e e p a 144-75 R Ri a
R
2 ' v4 p a 144-76 Ra Rib R2c v4 p a 144-77 Rb Rib R 2 e v' pa 144-78 R' Rib R 2 e v' pa 164 WO 2005/042712 PCT/US2004/035939 144-79 Ra RIc R 2 v p 144-80 Rb RIC R 2 C vC pa 144-81 R RIG R 2 e vc pa 144-82 Ra Ri]a R 2 a va pb 144-83 Rb Ri a R 2 a va pb 144-84 Rc Rla R 2 a va pb 144-85 Ra Rib R 2 a va pb 144-86 Rb Rib R 2 a va pb 144-87 Re Rib R 2 a va pb 144-88 Ra R I R 2 a Va pb 144-89 R Rec R 2 a va pb 144-90 Rc RiG R 2 a va pb 144-91 Ra Ria R 2 b va pb 144-92 R R a R 2 b va pb 144-93 Re Ria R 2 b va pb 144-94 Ra Rib R 2 b va b 144-95 Rb R R 2 b a p 14-5 k b RTh a pb 144-96 Re R'l R2b va pb 144-97 Ra RG R 2 b va pb 144-98 Re Rl R2b va pb 144-99 Re RIC R 2 b va pb 144-100 Ra Ria R 2 C va p 144-101 RI Ra R2e a b 144-102 Rc Rla Re va pb 144-103 Ra Ri R 2 e va pb 144-104 Ra Rib R 2 c va pb 144-105 R Rb 2e a pb 144-106 R R R c va pb 144-107 Re R
R
2 e a pb 144-108 R Ri R 2 c a pb 144-109 Ra Rla R2a vb p 144-110 Rb Ria R 2 a vb pb 144-111 Re Ria R 2 a vb pb 144-112 Ra Rib R 2 a vb pb 144-113 R R Ra vb pb 144-114 R Rlb R 2 a vb pb 144-115 Ra RIG Ra vb pb 144-116 Rb RIc R 2 a vb p 144-117 Re RG R 2 a vb pb 144-118 R Rla 2b b pb 144-119 Rb Rila R ba p b 144-120 R Ra R2b vb pb 144-121 Ra R R2b b pb 144-122 R Rl R2b vb pb 144-123 R' Ria R 2 b Vb pb 144-124 Ra Rl R ~ vb pb 144-125 Rb RI R 2 b v p 165 WO 2005/042712 PCT/US2004/035939 144-126 Rc RIC R 2 b vb pb 144-127 Ra Rla 2c vb pb 144-128 Rb R Re vb pb 144-129 Rb Ra R 2 C vb pb 144-130 Ra R R2e v pb 144-131 Re R l R2e vb pb 144-132 Rc2e vb pb 144-133 Ra R Re b pb 144-134 R Rc R2 vb pb 144-135 Rc R R vb pb 144-136 Rca Rba Ra v pb 144-137 Re R]a Ra v" pb 144-138 Rc Ria R 2 a vb pb 14-39 R Re R2a ve b 144-134 Ra R l R2a v" pb 14I40 k R 2. b b 144-141 Re Rb Ra v pb 144-142 Ra Rl R2a v pb 144-143 Ra RO R. v" pb 144-144 R" Rlc REa vc p b 144-145 Ra Ria R2b ve pb 144-146 R Ra R2b v" pb 144-147 R RIa R2a e p b 144-148 Re R Rb v" pb 144-149 Ra Rlb R2b v p b 144-150 b R 2 v p b 144-151 R R" Rb v pb 144-152 a R R~b vc pb 144-153 R5 Rc Rb v" pb 144-154 R2a Ra Rc v pb 144-155 Rb R Re v pb 144-156 R Ria R 2 c v p 144-157 R2a R Rc v p 144-158 Re R Re v pb 144-159 R2 RR e p 144-160 Ra Rc RC v pb 144-161 Rb R Re v" pb 144-162 R R I R 2 b e pb 144-163 Ra Rla Ra va p c 144-164 Rb Rla R 2 a va pc 144-165 R Ria R 2 a va pc 144-166 Ra Rib R 2 a va pc 144-167 REb Rlb R 2a va pe 144-168 Re Rb R2a Va pb 144-169 R Rl Ra va pc 144-170 Re RIC R 2 a va pc 144-171 R Rlc R2a va pc 144-172 Ra Ria R 2 b va pc 166 WO 2005/042712 PCT/US2004/035939 144-173 Rb Ria R 2 b va pc 144-174 RC Ria R 2 b va pe 144-175 Ra Rib R 2 b Va pc 144-176 Rb Rib R 2 b va pc 144-177 RC Rib R 2 b Va pC 144-178 Ra RIC R 2 b a c 144-179 Rb Rl R 2 b va pc 144-180 R' RIO R 2 b va pc 144-181 R a Ria R 2 c va pe 144-182 R Ra R2e Va pC 144-183 Rc R R va pe 144-184 RC Ria R 2 c a pc 144-1 84 Rh Rib R 2 e va p 0 144-185 R Rib R 2 c va pc 144-186 Rc Rib R 2 C a pc 144-187 R Ric R 2 C va pc 144-188 Rb Ri R 2 c Va p 0 144-189 Rc RIC R 2 C Va pC 144-190 Ra Ria R 2 a vb pC 144-191 Rb R 2 a vb p 0 144-192 Rc R a R 2 a vb pc 144-193 Ra Rib R 2 a vb pc 144-19 b R l R2a Vb pc 144-194 Ra R lb R-a vb pe 144-197 RC Rl'
R
2 a vb p 144-19 a R RIC 2a vb pC 144-196 Ra Ria Ra v p' 144-197 Rb RiCa Rb vb pc 144-201 Rb Ria
R
2 vb pc 144-201 Ra R a R 2 b vb pc 144-200 Rb Ri
R
2 b vb pc 144-201
R
0 Ri
R
2 eb Vb pc 144-202 Ra Rlb
R
2 b Vb pC 144-206 Rb Rl
R
2 b vb pC 144-207 R Rib
R
2 b vb pc 144-208 Ra RIa
R
2 e vb pc 144-209 Rb Ria
R
2 e b pc 144-210 Rc Ria R2e Vb pc 144-211 Ra Rlb Re vb pc 144-212 Ra Rib
R
2 C Vb pc 144-213 Rc Rb R e vb p' 144-214 Ra Ric
R
2 c vb pc 144-215 R Ri
R
2 e Vb pc 144-216 Rb RIb
R
2 C Vb pC 144-217 Ra Rib
R
2 Ca p 144-218 Rb Ria
R
2 Ca v pc 144-219 Re Ria R 2 a VC pc 167 WO 2005/042712 PCT/US2004/035939 144-220 Ra Rib R2a VC pC 14-2 l R b 2a VC pC 144-221 R Rlb R2a v' p' 144-222 R Rib R 2 a v' p' 144-223 Ra RIc R 2 a VC pC 144-224 Rc R' Ra vC pc 144-225 R Ric R 2 a VC pC 144-226 Ra R la R 2 b VC pC 144-227 Rb RIa Rb vC pC 144-228 R R Ra R 2 b v' pC 144-229 Ra Rib R 2 VC pC b4-3 lc R b 2b VC pC 144-230 Ra Rc Rb v' p' 144-231 R Rib R 2 b VC pC 144-232 R RI'C R 2 b vC pC 144-233 R R12 R 2 b VC p 144-234 Rc RIC R 2 b vC p' 144-235 Ra R 1 " R 2 C VC pC 144-236 Rb Ria R 2 C VC pC 144-237 RC Ri" R 2 . VC pC 144-238 Ra Rib R 2 e ye pC b l 2CC C 144-239 Rh Ri R2 v p' 144-240 RC Rib R 2 C vC p' 144-241 Ra RI'C R 2 e v' pc 144-242 Rb RiC R 2 C vC pC 144-243 RC RIC R 2 e v4 P 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 nitro group, an optionally substituted amino group, an alkyl group, an 5 alkoxy group, an alkenyl group, or an alkoxyalkyl group; R' and R 2 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and all other symbols are as defined in 10 connection with formula (I). In another aspect of formula (144) of the present invention, R 1 and R2 are independently hydrogen, an alkyl group, or an alkoxy group; and all other symbols are as defined in connection with fonnula (I). In yet another aspect of formula (144) of the present invention, R' and R2 are -OCH 3 ; 15 and all other symbols are as defined in connection with formula (I). 168 WO 2005/042712 PCT/US2004/035939 The present invention further contemplates various compounds of general formula (V) having the formula: R" 0 O O N-H O 0 OR R
R
2 S NH (145), where all synibols are as defined above in connection with formula (I). 5 According to various aspects of the present invention, R, R', R 2 , R", and R1 2 of formula (145) are selected to provide various compounds of fonnula (145-1) through formula (145-243) as follows: Formula R RI R2 R" R1 145-1 Ra Ria R 2 a Rla R 12 a 145-2 Rb Rla R2a Rla R12a 145-3 R Ra R ~a R R1a 145-4 Ra Ria
R
2 a RIla R1 2 a 145-5 Ra Rib
R
2 a RIla Ru12a 145-6 R R 2a R]a R12a 145-7 Ra Rlc R2 R R1a 145-8 e Rib
R
2 a Ra 12a 145-9 Ra Ric R2a Rla R1 2 a 145-10 R Ri R 2 RIla Rl2a 145-11 Re Ria R2 RIla Ru12a 145-12 Ra Ria R2b RIa Ru12a 145-13 Ra Ria
R
2 b R1la R12a 145-14 Re Ri
R
2 b RIla R1 2 a 145-15 Rc Rib R2b RIa Rl2a 145-1 R Rlc R 2 b RIla Rl2a 145-17 Re Rb R2b RIla R2a 145-16 Ra R R2b RIla R 2 a 145-19 Ra Rla RC R]a R2a 145-21 Rc Ria Re Rla Rua 145-1 Re Ria R 2 e Ruia Ruia 145-22 R b R2c RIla Ru12a 145-23 Rb Rlb R2c Rlla Ra 145-24 Rb Ri b R2e RIla R1 2 a 145-25 Ra Rio R 2e RIla R1 2 a 145-26 Rb R1 R2e R]u]a Ru12a 169 WO 2005/042712 PCT/US2004/035939 145-27 Re Ri R 2 e Rlla R1 2 a 145-28 Ra Ria R 2 a RIlb R 2 a 145-29 R Rila R2a Rilb R12a 145-30 Rb Ra R2a Rilb Rua 145-31 Ra Rlb R2a Rib R12a 145-32 Re Rl R Ra R R1a 145-33 Ra Rib R2a Rb Ru1 2 a 145-34 Ra RI R2a RIlb Rl2a 145-35 R R
R
2 a R11b Rua 145-36 Re Rib
R
2 a R11b R1 2 a 145-37 Ra Ria
R
2 Rlb R1 2 a 145-38 RI Ra R2 R lb R12a 145-39 R Rla R Rb Rua 145-40 Ra Re
R
2 b R b R 2 a 145-41 2 R R) b Rib R12a 145-42 R Rl Rb RIb Rua 145-43 Ra Ra
R
2 b Rb Ra 145-44 Re Ra
R
2 b Ru b R1 2 a 145-45 R Rib
R
2 b R b R 2 a 145-46 Ra Ria
R
2 c R b R1 2 a 145-47 R Ria
R
2 e RIb
R
2 a 145-48 Re Ria
R
2 e Rib R1 2 a 145-49 Rb Re
R
2 e Rlb R12a 145-50 Re Rib
R
2 e RIb R1 2 a 145-51 Re Rb
R
2 e R Ib R1 2 a 145-52 Ra R2Ic Re Rl Rb ua 145-53 Rb R Re R] l Rua 145-54 Re Ri
R
2 ' RIb
R
2 a 145-55 Ra Ria
R
2 a R"b
R
2 a 145-56 1 Ra Ra Rlb R12a 145-57 R Rba
R
2 a R Rua 145-58 Ra Rib
R
2 a Rub" Rua 145-59 Re R b R 2 a Ruc
R
2 a 145-60 R R Ra R2 Il Ru~a 145-61 R RI R2a R Rua 145-62 Re Ri
R
2 a R"b
R
2 a 145-63 Re Rlc RWa R11c Ru1a 145-64 Ra Ra
R
2 b Rl R1 2 a 145-65 Rb Ri a 2" Rl
R
2 a 145-66 Re Ria RWb Rn1c Rula 145-57 Ra Ria R 2 b Rle Ru 145-68 Ra Rib
R
2 b Rl" Ra 12 156 kb Rlb Wa Ile R12a 145-69 R' Rb Rb R44 Rua 145-70 R R
R
2 b Rc Ru 2 a 145-71 Ra Re
R
2 b Ri
R
2 a 145-72 R Ric
R
2 b Rle Ru 2 a 145-63 R We R Ile l2a 145-6 Ra Ra R R R 145-6 R Ria R~b Rile70~ WO 2005/042712 PCT/US2004/035939 145-74 R Ria R 2 e RDl R1a 145-75 Re Ria R 2 c Rl Rua 145-76 Ra Rib R 2 c Rlc R1a 145-77 Rb Rib R 2 c Rl R1a 145-78 Rc Rib R 2 c Rile R 2 a 145-79 Ra Rie R 2 c Rlec R 2 a 145-80 Rb RIc R 2 c Ril' Rua 145-81 R 0 Rie R 2 e Rilc R12a 145-82 Ra Ra R2a Rla R1 2 b 145-83 R0 Ria R2a Rla R12b 145-84 R Ria R a Rua R12b 145-85 Ra
R
1 b R 2 a Rlla R 2 b 145-85 Ra Rib R 2 a R 11 a R1 2 b 145-86 Rb R lb R 2 a Rila R1 2 b 145-87 Re Rib R 2 a Rla Rl 2 b 145-88 Ra Ric R 2 a Rla R1 2 b b4-0 R RIC R2a Rh" R2b 145-89 R RIa R~b Rla R12b 145-90 Re Rie R 2 a Rla R1 2 b 145-91 Ra Ria R 2 b Rlla R1 2 b 145-92 Rb Ria R 2 b Rua R 12b 145-93 Re R ]a R 2 b Rula Rl 2 b 145-94 Ra Rib R 2 b Rula R1 2 b 145-95 Ra Ric R2b Rua R12b 145-96 Re Rib R 2 b RUa R1 2 b 145-97 Ra RIc R 2 b RIla R1 2 b 145-98 Rb Ria R 2 b Ria R1 2 b 145-99 Re Ric R 2 b Rula R 2 b 145-100 Ra Ra R 2 c Rla R1 2 b 145-101 Rb Ria R 2 c RIa R1 2 b 145-102 Re R 1 l R 2 c Rla R1 2 b 145-103 Ra Rib R 2 c Ruia R12b 145-10 Rb Rl 2e Ra R12b 145-104 R R Rc Rl R2b 145-105 Re Rib
R
2 e Rla R12b 145-106 Ra Rc
R
2 a RIla R1 2 b 145-107 Rb Rie
R
2 a Rla R1 2 b 145-108 Re Ria
R
2 a RIla R1 2 b 145-110 Ra Ria R2a R Ib R1 2 b 145-110 Rb RI a R 2 a R1b R1 2 b 145-111 R Ria Ra Rlub R1 2 b 145-112 Ra Rib
R
2 a Rulb R12b 145-113 Rb RIb
R
2 a RIlb R1 2 b 145-117 R Rib
R
2 a R Ib R1 2 b 145-118 Ra Ria R 2 b RIlb R12b 145-119 R R]a R2b Ri l R12b 145-120 Rc Ria R 2 b R"b R1 2 b 171 WO 2005/042712 PCT/US2004/035939 145-121 Ra Rib R 2 b Ru b R 2 b 145-122 R R l R2b R' b R1 2 b 145-123 R4 Rib R 2 b R Ib R1 2 b 145-124 Ra RI* R 2 b RIlb R1 2 b 145-125 R Rl' R2b Ruib R1 2 b 145-126 Re Ri" R 2 b R1ib R1 2 b 145-127 Ra Ria R 2 e Ru b R1 2 b 145-128 RI Ra R2e Ri l R12b 145-129 R4 Rla R~e R Ib R12b 145-130 Ra Ria R 2 Ru b R1 2 b 145-131 R Rib R 2 c Ruib R1 2 b 145-132 Rb Rib R 2 c Ru b R1 2 b 145-133 Ra Rib R 2 c Ruib R1 2 b 145-134 R RIO R 2 c Ruib R1 2 b 145-135 R' Rl" R2' R R1 2 b 145-136 Ra Ria R 2 a Rub R1 2 b 145-137 Ra ia R 2 a Rile R1 2 b 145-138 RI Ra R2a Rlic R12b 145-139 Ra Rlb Ra R R12b 145-140 Re Ria R~a Ril R12b 145-141 R' Rib Ra Rho Ri 2 b 145-142 Rla Rl4 Ra Rle R12b 145-143 R Rl4 R2a R"" R12b 145-144 Re Rib R2a Rile R1 2 b 145-145 Ra Ria R 2 b Rle R1 2 b 145-146 RI RIa R2 Rl R12b 145-147 R Ria R2b R"" R12b 145-148 Ra R e R 2 b Rile Ri 2 b 145-149 Ra R l R 2 b Rle R1 2 b 145-150 R Ra R2b Rl R12b 145-151 Ra R ' R2b RDl R12b 145-152 Re R' R 2 b Rle R1 2 b 145-153 Re Rb R 2 b Ril R1 2 b 145-154 Ra R2ba Re Rle R12b 145-155 R, Ria R RI" R12b 145-156 Re Ria R 2 " R R1 2 b 145-157 Ra RI R 2 e Rile R2b 145-158 R Rb R2. R R12b 145-159 Re R R2c R"" Rl12b 145-160 Ra Ric Rc R RI 2 b 145-161 Ra Ria R 2 e Rile R1 2 b 145-162 Re R R2e Rle R12b 145-163 Ra Ria R2a Rla R 145-164 Re Rla 2a Rlea R 2 b 145-165 Re Ria R2a Rla R12c 145-166 Ra Ri R2a RIa R2 145-167 RW R RI R R12c 172 WO 2005/042712 PCT/US2004/035939 145-168 R' R b R 2 a Ra R 2 c 145-169 Ra RO R 2 a Ra R 2 c 145-170 Rb RO R 2 a Ru 1 a R 2 c 145-171 R R R 2 a Rula R 12 c 145-172 Ra Ria R 2 b Rua R12c 145-173 Rb Rla R2b Rua R12c 145-174 R' R Rl Ra Rc 145-175 Ra Ria R 2 b RIla R1 2 c 145-176 Ra Rib R 2 b Rl]a R1 2 c 145-177 R Rlb R 2 b Rua R1 2 c 145-178 Ra RiC R 2 b Rua R1 2 c 145-179 Ra RC R 2 b Rula R1 2 c 145-180 R' RI R2b Rua R12c 145-181 R R R Ra R 145-182 R Rila R2b R]a R1c 145-183 Rc Ria R2e Rla R1 145-184 Ra Rlb R 2 e Rula R12c 145-185 R R R2c 145-186 R R R2e Rua R1 2 c 145-187 Ra Rlc R 2 c R 1 a R1 2 c 145-188 Rb Rib R 2 c Ru 1 a R1 2 c 145-189 R' Rl" R ~ Rla R1 145-190 Ra Rla R 2 a Rlb R1 2 c 145-191 Re Ra R 2 a RIla Rl 2 c 145-192 Rh Ra R2a RIla R12c 145-193 Ra R l R2a Ri l R1 145-194 Rb R l R 2 a RIlb R 2 c 145-195 R R b R2a R b R1 2 c 145-196 Rb Ra R 2 a RIIb R 2 c 145-197 R RIC R 2 a Ru b R1 2 c 145-198 Ra Rb R2a RIlb R1 2 c 145-199 Ra Rla R2b Ri l R1 145-200 Rb Rla R2b RI R12c 145-201 R Ra R R11b R1 145-202 Ra RO R 2 b R1 b R1 145-203 he R l R2b R1lb R12c 145-204 R' R R Rlb R1 2 c 145-205 Ra RO R 2 b R Ib R12c 145-206 R R R 2 b RIlb R1 2 c 145-207 R I R2b RIlIb R12c 145-208 Ra Rla R~e RIlb R1 145-209 R RIa R2c RIlb R1 2 c 145-210 Rc Ria R 2 b RIlb R1 2 c 145-211 Ra R b R 2 c R b R1 2 c 145-204 R 0 Rib R 2 c Rhib R 12c 145-212 Ra RO R 2 c R b R 2 c 145-203 R' R Re Ri RD 145-209 Ra R R 2 e R11 R 145-211 R a Rb R 2 c RIb R 2 c 173 WO 2005/042712 PCT/US2004/035939 145-215 Rb RI' R2' R11b R1 145-216 R' RIc R 2 c R11b RI1C 145-217 Ra Rla R2a R' R1 2 e 145-218 Rb RIa R 2 a Re R12c 145-219 R Ria R a Rle R1 2 c 145-220 Ra Rib R 2 a Rle R1 2 c 145-221 R R ] R2a R" R 145-222 R' Rib R2a Rle R 2 c 145-223 Ra R 1 c R 2 a Rile R1 2 c 145-224 R RI' R ~a Ruc R 145-225 Re Rc R 2 a Rle R1 2 c 145-226 Ra RIa R 2 b Rle R12c 145-227 e RIa R2b Ri R12 145-228 Rc RIa R2b R" R 145-229 Ra R l R2b Ri R12c 145-230 Re Rl R2b R1 R12c 145-231 Rc Rib R 2 b Rile R12c 145-232 R a RI' R~b R11 R 12c 145-233 R RI' Rb Rle R1 2 c 145-234 R' Rib R 2 b Rue R 2 c 145-235 Ra Ria R 2 b Rle R1 2 c 145-236 e Ria R2e R1c R 12c 145-237 R' Ria Ra C R R1e 145-238 Re Rib R 2 e Rle R1 2 c 145-239 R R 1 l R 2 e Rle R1 2 c 145-240 R' Ra R 2 e Rle R 2 c 145-241 Ra Ria R 2 C Rle R1 2 c 145-242 Ra Rib R 2 e; R2c 145-243 R' R' R2 R1 R 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 nitro group, an optionally substituted amino group, an alkyl group, an 5 alkoxy group, an alkenyl group, or an alkoxyalkyl group; 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 alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group; and R 1 and R 12 independently are hydrogen, 10 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. 174 WO 2005/042712 PCT/US2004/035939 In another aspect of formula (145) of the present invention, R is hydrogen or an alkyl group; R 1 and R2 independently are hydrogen, a hydroxy group, a halogen, an alkoxy group; and R"1 and R1 2 independently are hydrogen, a halogen, a hydroxy group, or an alkoxy group. 5 In yet another aspect of formula (145) of the present invention, R is -H or C 2
H
5 ; R, and R2 are -OCH 3 ; and R 1 and R1 2 independently are -H, -F, or CH 3 . The present invention still further contemplates various compounds of general formula (V) having the formula: MeO MeOMe 0 0 01 N H 0 O O N 0 0 OR OM'0 s\ H a s (146), io 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 nitro group, or an optionally substituted amino group. In another aspect of formula (146) of the present invention, R is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group. 15 In yet another aspect of formula (146) of the present invention, R is a cycloalkenyloxy group, an acyl group, an aryl group, an arallkyl 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. 20 In still another aspect of formula (146) of the present invention, R is -H or C 2
H
5 . Additional examples of compounds having general formula (V) include, but are not limited to: o-CC MeO N NH CO2C2H5 HOc o-6 Me o' 0 'O " Ne- o H O HC-0 0 _ HN' osW 0 NI ' o ~ 0 C CH, 175 WO 2005/042712 PCT/US2004/035939 0 F H MoN N 0CH N I N C0C 2 H cl N OCH, 0MeO= 10 OMe OMe 0 A N, o~H 0 N NH 0CH N C0 2
H
5 MeO-w N -CH C, HN 0 0 F F OCH, OC H 3 OCH N N N 0" 2 3 0 -q~l 0 0 0 NH HO
N
0 N H 3 00 N N HN~COOC2H 5 0 H 0b 0 N 0J C 2 H5 0 0
NO
2 ,, O0-CH
SCH
3
H
3 -0 N 0 N 0 I Y ~ CH, "N HC-0 0 HI HHNO H 10 0 ,' N 0C2H 5 0 N _ OH 50 0 0 0 3 3e OMe
DCH
3
SOCH
3 0
H
3 0 0~F F 0N OIKN'H 0 HC 0 1-N 0 OH HN "::DrI--O 0 0 Mao OMe "',
OCH
3 0 ,- N C 2
H
5 : S H I0 0 0 176 WO 2005/042712 PCT/US2004/035939 0 0
SCH
3 I 0- 0 0 N1 N OH 0C3 OC2H HN O IN 0 0 ;and OCHO SOCH3I 0'- -'-'00 0 OCH,O U N 0-C 2
H
5 H NH. P HN 0 It is contemplated that any compound shown or described herein, including 5 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, 10 glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, NN' diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, 15 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, seine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino 20 acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl; ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, 177 WO 2005/042712 PCT/US2004/035939 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 5 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 io conditions may be used to form the compounds of the present invention. PROCESS ] According to one aspect of the present invention, a process for preparing a compound of general formula (1I) Y1 Ri 4F \A E RF NR D Y-G=Z-Ar 2 15 x where R' is attached to B; R 2 is attached to J; R 3 is -H; A, B, D and J independently are -CH; R' and R2 independently are an alkoxy group or an aralkoxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third position and/or fourth position respectively; X and E are each 0, G is -(CH 2 )s-, (CH 2 )s-CH=CH-(CH 2 )s-, or 20 (CH 2 )s-CH=CH-(CH 2 )s-, where s is an integer from 0-5; F is 0, S or -NR; Y and Z independently are 0, -NR, (CH 2 ),, or S(=0),, where n is an integer from 0-2; Y' and Y 2 independently are 0 or S; R and R independently are hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, an alkoxy group, an alkenyl group, an alkoxyalkyl group, a cycloalkenyloxy group, an acyl group, an aryl group, 25 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 (Ila) 178 WO 2005/042712 PCT/US2004/035939
R
1 4 \A E R D7,~ (H1a) R J, Y.Rut R 3 x where 'Rut' is rutinose; R 1 is attached to B; R 2 is attached to J; R 3 is H; A, B, D and J independently are -CH, R' and R2 independently are a hydroxy group; R4 is a phenyl group optionally substituted with a hydroxy group at the third and/or fourth positions; X, Y, and E 5 are 0; and '----' is an optional chemical bond; to a compound of formula (Ila), where R1 is attached to B; R2 is attached to J; R3 is H; A, B, D and J independently are -CH; R1 and R independently are an alkoxy group or an aryloxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third and fourth positions; X, Y, and E are 0; and all other symbols are 10 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 15 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 (Na 2
CO
3 ), potassium carbonate (K 2
CO
3 ), sodium bicarbonate (NaHCO 3 ), potaasium bicarbonate (KHCO 3 ), sodium hydroxide (NaOH), potassium 20 hydroxide (KOH), or any mixture thereof. The solvent used is, for example, dimethylfomamide (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 25 -30'C to about 250'C, for example, from about 30'C to about 100'C. The duration of the reaction may be from about 0.5 hours to about 100 hours, for example, from about 20 hours to about 80 hours. The reaction may be carried out under an inert atmosphere of, for example, nitrogen (N 2 ), argon (Ar), or helium (He). Next, the compound of formula (Ila) is hydrolysed to a compound of formula (Ib) 179 WO 2005/042712 PCT/US2004/035939 \A E R 4 D YH (Ub)
R
3 X where R' is attached to B; R2 is attached to J; R3 is H; A, B, D and J independently are -CH; R1 and R2 independently are an alkoxy group or an aralkoxy group; R 4 is a phenyl group optionally substituted with an alkoxy group or an aralkoxy group at the third and fourth 5 positions; X, Y, and E are 0; 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 (H 2 SO4), 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, 10 for example, from about 1 hour to about 50 hours. Next, the compound of formula (Ib) is reacted with a compound of formula (lIc), 0 Ar-Z~--G-Hal (c R5 where 'Hal' is a halogen; 'Ar', G, Z and RW are as defined above; and '----' is an optional chemical bond, to obtain a compound of formula (Id) Ri BAA E R 4 R2-. 0 D-, , - Y-G=Z-Ar R (Hd) 15 R X where R1 is attached to B; R2 is attached to J; R3 is H; A, B, D, and J independently are -CH; R1 and R2 independently are an alkoxy group or an aralkoxy group; R 4 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. 20 This reaction is carried out in the presence of a base, for example, NaH, KH, KOtBu, KOAc, NaOAc, NaOEt, KOEt, n-BuLi, s-BuLi, t-BuLi, LDA, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 ,
KHCO
3 , 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 25 30'C to 150'C, for example, from about 30 0 C to about 100*C. The duration of the reaction 180 WO 2005/042712 PCT/US2004/035939 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 N 2 , Ar, or He. Lastly, the compound of formula (lId) is condensed with a compound of formula (Ie), H 5 F where F, Y', and Y 2 are as defined above, to obtain a compound of formula (II) Y1 R4 \A E R 4 F NR R2 Y-G=Z-Ar y2 where all symbols are as defined above. The condensation may be carried out using a base, for example, Et 3 N, diethylamine, 10 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, fonnic 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 15 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 N 2 , Ar, or He. 20 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 0. Y1 Ri \A E R 4 F NR Y-GZ-Ar 2 X 181 WO 2005/042712 PCT/US2004/035939 First, a compound of formula (IIf) RI A EH
R
3 where X and E are 0; and all other symbols are as defined above, is acylated to a compound of formula (1Ig) Ri RB\ A E R 2- (11g) D/ X 5
R
3 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, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, or any mixture thereof. The reaction may be maintained at a temperature of from about -30'C to about 150'C, for 10 example, from about 10 0 C to about 50'C. The duration of the reaction may be from about 10 minutes to about 5 hours, for example, from about 20 minutes to about 2 hours. The compound of formula (I1g) is then rearranged to a compound of formula (IIh) RI \A EH R2 ; (llh) D.< R3 X where X and E are 0; and all other symbols are as defined above. This reaction is optionally 15 carried out in the presence of a solvent, for example, DCM, CHC1 3 , 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 aluminium chloride (AlCl 3 ), zinc chloride (ZnCl 2 ), or tin chloride (SnCl4), or in the presence of UV light. The reaction temperature may be maintained at from about 50'C to about 300'C, for 20 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 (TIh) is then condensed to a compound of formula (IIi) 182 WO 2005/042712 PCT/US2004/035939 Ri 4 \A EH R R D(li)
R
3 X where X and E represent 0 and all other symbols are as defined above. The reaction is carried out in the presence of a base, for example, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, or any mixture thereof. The reaction temperature may be maintained at from 5 about -30'C to about 50'C, for example, froin about 0 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 (1Ib) R1 \A E R 4 R D.J YH (Ib) 10 X where all symbols are as defined above. This reaction is carried out using a base, for example, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , 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 15 about 10 hours, for example, from about 0.2 hours to about 5 hours. The compound of formula (Ilb) is then reacted with a compound of formula (Ic) 0 Ar -Z-- Hal (I1c) R5 where 'Hal' is a halogen; and all other symbols are as defined above, to obtain a compound of formula (1Id) \A E R 4
R
3 R - Y-=Z-Ar4 (IHd) 20 X where all symbols are as defined above. The compound of formula (Ild) is then reacted with a compound of formula (Ile) 183 WO 2005/042712 PCT/US2004/035939 H Y1i-N 2 (Ie) F where F is 0, S, or -NR; Y' and"Y 2 independently are 0 or S, to obtain a compound of formula (II) YR \A E R 4 F NR D Y-G=Z-Ar 2 x 5 where E and X are 0; and all other symbols are as defined above. The conversion of compound of formula (Ib) to compound of formula (II) is carried out as provided in Process 1. PROCESS 3 10 According to another aspect of the present invention, a process for preparing a compound of formula (II) is provided, YR Ri 4 F \A E R F NR
R
2 B R Y-G=Z-Ar y2 R3 R x where X is 0, E is -NR, and all other symbols are as defined above. First a compound of formula (Ij) Ri \A NHR R(lIj) 15 DJ COOMe where all symbols are as defined above, is converted to a compound of formula (Ilk),
R
1 \A NHR R2_B (ilk) JCOOH where all symbols are as defined above. This reaction may be carried out using a base, for example, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, or any mixture thereof. The 184 WO 2005/042712 PCT/US2004/035939 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 5 0.5 hours to about 20 hours, for example, from about 2 hours to about 10 hours. The compound of formula (Ilk) is then reacted with a compound of formula (I1m) R4' 'Hal (U1m) 0 where 'Hal' is a halogen, and R 4 is as defined above, to obtain a compound of formula (Iln) Ri \A NHR R2 B :(11,) D7R JZ COO R 10 R 3 0 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, 15 dichlromethane (DCM), chloroform (CHCl 3 ), 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 0 C to about 40 0 C. The duration of the reaction may be from about 1 hour to about 72 hours, for example, from about 20 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, CHCl 3 , 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 carried out in the presence of 25 a base, for example, NaH, KH, KO'Bu, KOAc, NaOAc, n-BuLi, s-BuLi, t-BuLi, LDA, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, an amine base such as Et 3 N, diethyl amine, diisopropylethyl amine, diisopropyl amine, DBU, or any mixture thereof. The reaction temperature may be from about -78 0 C to about 150'C, for example, from about 185 WO 2005/042712 PCT/US2004/035939 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 N 2 , Ar, or He. The compound of formula (Iln) is then converted to a compound of formula (I1b) \A E R4 R (Ib) YH R 3 'IV 5 RX where X is 0, E is -NR, and all other symbols are as defined above. This reaction may be carried 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 0 C to 300'C, for example, 10 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 15 hours. The reaction may be carried out under an inert atmosphere maintained by N 2 , Ar, or He. The compound of formula (Ilb) is then reacted with a compound of formula (Ilc) 0 Y-Ar -Z=--Hal (Ic)
R
5 15 where all symbols are as defined above, to obtain a compound of formula (Ild) \A E R 4
RR
5 R O D. Y-=Z-Ar4 5Id where E is -NR, and all other symbols are as defined above. The compound of formula (Ild) is then reacted with a compound of formula (Ile) H (lIe) F 20 where all symbols are as defined above, to obtain a compound of formula (II) Y1 R4 4 \A ,E R 4 F NR D Y-G=Z-Ar 2 R 3 R 5 X 186 WO 2005/042712 PCT/US2004/035939 where X is 0, E is -NR, and all other symbols are as defined above. PROCESS 4 According to another aspect of the present invention, a process for preparing a 5 compound of formula (IV) is provided. The process comprises the following: 0 R' E H, R' R1L RE R 4 D HH+ R4COGi 0D R 0 D R RR!] R X IVb x X IVd IVa IVc Ar-Z:-G-Hal R5 IlC R E R 4 D 11 G-:.Z-Ar- D" I N/2 F x Ie Y Y R1 E R 4 FNH D, GZ-Ar y 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 carried out using an appropriate acylchloride of formula IVb in the presence of a 10 base, for example, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, triethyl amine, diisopropylethylamine, or any mixture thereof. The reaction may be carried out in a solvent, for example, benzene, toluene, xylene, DMT, DMSO, 1,4-dioxane, dichloromethane, CHCl 3 , 1,2-dichloroethane, carbon tetrachloride, or any mixture thereof. The reaction temperature may be maintained at from about -30 0 C to about 150*C, for example, from about 20*C to 15 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 carried out under an inert atmosphere of N 2 , 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 20 BULi, s-BULi, t-BULi, LDA, Na 2
CO
3 , K 2 C0 3 , NaHCO 3 , KHCO 3 , NaOH, KOH, or any mixture thereof. The reaction may be carried out in a solvent, for example, benzene, toluene, 187 WO 2005/042712 PCT/US2004/035939 xylene, methanol, ethanol, i-propanol, t-butanol, or any mixture thereof. The reaction temperature may be maintained at from about -700 C to about 250" C, for example, from about -100 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 5 under an inert atmosphere of N 2 , Ar, or He. The conversion of compound of formula (IVd) to a compound of formula (IV) may be carried out as provided in Process 1. PROCESS 5 10 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 R 4 0, 'iA E R + Ar-Z=-G-Ha Y-G hZ YH 5 D< Y-G-Z-Ar-( R X (ic) X (lid) Where R 5 (Jib) represents alkoxy, cycloalkenyloxy X4-S(O),-Ar H2N-(CH2) eC-o-R BA , Y - G = Z - A r - R 5 2 R~XR 1 Where R 5 BA E R0 X 4 'S(O)-Ar (lid) represents hydroxy D Y-G=Z-Ar e group R R X <
NH-(CH
2 ) ' -V CO-R
X
3 (Va) The conversion of a compound of formula (IIb) to a compound of formula (I1d) may 15 be carried out as provided in Process 1. The conversion of the compound of formula (I1d) to a compound of formula (Va) may be carried out by reacting the compound of formula (Ild) with compound of formula (Ilp) 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. 188 WO 2005/042712 PCT/US2004/035939 PROCESS 6 According to another aspect of the present invention, a process for preparing a compound of formula (Vb) is provided. RA N BA - ~ G-Z-Ar X-S(O)w-Ar 2 R3 NH-(CH2)p (Vb) x 3 5 The process comprises: R A COOH RA AN ,'-J NH 2 D NH k33 R 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 10 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 15 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 20 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 25 their single enantiomeric form in the process wherever applicable or by conducting the 189 WO 2005/042712 PCT/US2004/035939 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 stercoisomers of the compounds of the present invention may be prepared by 5 using reactants in their single enantiomeric formi 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 diastercomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, or lactic acid, wherever applicable, or 10 chiral bases such as brucine, cinchona alkaloids and their derivatives. Commonly used methods are compiled by JAQUES, ENANTIOMERS, RACEMATES AND RESOLUTION (1981). Where appropriate, the compounds of formula (I) may be resolved by: treating with chiral amines, aniinoacids, aminoalcohols derived from aminoacids; employing conventional reaction conditions to convert the acid into an amide; separating the diastereomers by 15 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. 20 Fonnulations 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. 25 The pharmaceutical compositions of the present invention may be used for the treatment of bacterial infections. They also may be used for the treatment 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 30 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 190 WO 2005/042712 PCT/US2004/035939 mediated by inflammation, such as autoinimune 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 5 compounds of the present invention contained therein. Such salts are commonly referred to as non-toxic, pharmaceuticallyy 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 10 of the compound with a solution of a pharmaceutically acceptable acid, for example, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, or any mixture thereof. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example, sodium 15 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 20 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, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine 25 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 30 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 191 WO 2005/042712 PCT/US2004/035939 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 5 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 10 by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, for example, (+)di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyltartaric 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 15 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 20 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 specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in 25 DESIGN OF PRODRUGS (1985); Wihnan, 14 BIOCHEM. Soc. TRANS. 375-82 (1986); STELLA ET AL., Prodrugs: A Chemical Approach to Targeted Drug Delivery in DIRECTED DRUG DELIVERY 247-67 (1985), each of which is incorporated 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, 30 peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, B lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or 192 WO 2005/042712 PCT/US2004/035939 optionally substituted phenylacetamide-containing prodrugs, 5-fluorocytosine, and other 5 fluorouridine prodrugs that may be converted into the naore 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 5 prodrugs into free drugs; arylsulfatase for converting sulfate containing prodrugs into free drugs; cytosine deaminase for converting non-toxic 5-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 10 contain D-amino acid substituents; carbohydrate cleaving enzymes such as B-galactosidase and neuraminidase for converting glycosylated prodrugs into free drugs; B-lactamase for converting drugs derivatized with B-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. 15 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. Seefor example, Massey, 328 NATURE 457-48 (1987). C. Pharmaceutical Auxiliaries In addition to the compounds contemplated hereby, the pharmaceutical compositions 20 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, REMINGTON'S PHARMACEUTICAL SCIENCES (Gennaro, Ed., 18th Edition, Mack 25 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, 30 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 193 WO 2005/042712 PCT/US2004/035939 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, 5 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, 10 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, 15 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-p-cyclodextrin), 20 polyethylene glycols, flavoring agents, anti-microbial agents, sweeteners, antioxidants, anti static agents, surfactants (for example, polysorbates such as "TWEEN 20" and "TWEEN 80"), 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 REMINGTON: THE SCIENCE & 25 PRACTICE OF PHARMACY (19th ed., Williams & Williams (1995)) and PHYSICIAN'S DESK REFERENCE ( 52 "nd 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 30 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 194 WO 2005/042712 PCT/US2004/035939 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, 5 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 10 predetermined amount of the active ingredient; as a powder or 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, optionally with one or more auxiliary ingredients. Compressed tablets typically are prepared by compressing, in a 15 suitable machine, the active ingredient in a free-flowing forn 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 20 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. 25 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 formed 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. 30 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 DEPOT® (Tap Pharmaceuticals, 195 WO 2005/042712 PCT/US2004/035939 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, 5 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 10 formulations may be presented in unit-dose or multi-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. 15 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 20 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 carrier such that the final formulation contains from about 0.005% to 30% by weight of the active ingredient, for example, a compound of the present invention. 3. Pharmaceutical Compositions for Other Routes of Administration 25 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 may include suitably flavored 30 suspending or dispersing agents, such as the synthetic and natural gums, for example, tragacanth, acacia, and methyl-cellulose. 196 WO 2005/042712 PCT/US2004/035939 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 5 and an appropriate carrier. The compounds also may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyleellulose or gelatin-microcapsules and poly(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, 10 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 15 Nos. 5,013,556; 4,485,045; 4,544,545; WO 97/38731; Epstein et al., 82 PROC. NATL. ACAD. Sci. USA 3688 (1985); and Hwang et al., 77 PROc. NATL. ACAD. SC. 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 20 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 25 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 30 formulations containing a preservative, and multi-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 197 WO 2005/042712 PCT/US2004/035939 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 5 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 thereirt 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, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9. Non 10 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, 15 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, 20 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 8.0. 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, sodium phosphate and phosphate buffered saline (PBS). 25 Other additives, such as a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic@ 30 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. 198 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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 15 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 20 antirheumatic (for example, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid anti-inflanunatory 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 25 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 30 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 199 WO 2005/042712 PCT/US2004/035939 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 methylxianthine, a 5 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 10 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 toxin fragment 15 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-i (TSST-1), Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcal 20 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 25 cholera-suis, Salmonella enteritidis), Clostridium species (for example, Clostridium perfringens, 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 30 species (for example, Vibrios cholerae, Vibrios parahemolyticus), Klebsiella species, Pseudomonas aeruginosa, and Streptococci. See, for example, Stein, ed., IN'TERNAL MEDICINE 1-13 (3rd ed. Little, Brown and Co., Boston) (1990); EVANS ET AL., BACTERIAL 200 WO 2005/042712 PCT/US2004/035939 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 l\/ERCK MANUAL (16th ed. Merck and Co.) (1992); Wood et al., 76 FEMS MICROBIOLOGY IMMUNOLOGY 121 5 134 (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 immunosuppressive 10 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 15 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 20 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-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, 201 WO 2005/042712 PCT/US2004/035939 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, mepitiostane, testolactone; anti-adrenals such as 5 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; 10 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, 15 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 (DMFO); retinoic acid; esperamicins; capecitabine; and 20 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, keoxifene, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, 25 leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. The therapeutic agent may comprise a cytosine. 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 30 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 202 WO 2005/042712 PCT/US2004/035939 growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSI), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; 5 placental lactogen; tumor necrosis factor-a and -B; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-B; platelet growth factor; transforming growth factors (TGFs) such as TGF-a and TGF-B; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-a, -B and 10 -?; colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte macrophage-CSF (GM-CSF); and granulocyte-CSF (GCSF); interleukins (ILs) such as IL-i, 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-B; and other polypeptide factors including LIF and kit ligand (KL). 15 The compounds of the present invention may be administered in combination with an anti-inflammatory agent including, but not limited to, adrenocortical steroids cortisoli, 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 20 (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate). Commercially available nonsteroidal anti-inflammatory drugs include, but are 25 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), Naprosym (Roche Labs.), Orudis (Wyeth-Ayerst), Oruvail (Wyeth-Ayerst), Ponstel (First Horizon), Relafen (GlaxoSmithKline), Tolectin (Ortho-McNeil), Toradol (Roche Labs., Inc.), Vioxx 30 (Merck), Voltaren (Novartis), Advair (GlaxonSmithKline), Flovent (GlaxoSmithKline), Puhnicort (AstranZeneca), and Vanceril (Schering), Asacol (Procter & Gamble), Colazal (Salix), Dipentum (Pharmacia & Upjohn), and Rowasa (Solvay). 203 WO 2005/042712 PCT/US2004/035939 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), Cataflam (Novartis), Celebrex (Pfizer), Celestone (Schering), 5 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 10 any cardiovascular agent including, but not limited to, adrenergic blockers such as Cardura (Pfizer), Dibenzyline (WellSpring), Hytrin (Abbott), Minipress (Pfizer), and Mfinizide (Pfizer); adrenergic stimulants such as Aldoclor (Merck), Aldomet (Merck), Aldoril (Merck), Catapres (Boehringer Ingelheim), Clorpres (Bertek), and Tenex (Robins); alpha/beta adrenergic blockers such as Coreg (GlaxoSmithKline), and Normodyne (Schering); 15 angiotensin converting enzyme inhibitors, such as Accupril (Parke-Davis), Aceon (Solvay), Altace (Monarch), Captopril (Mylan), Enalaprilat (Baxter Anesthesia), Lotensin (Novartis), Mavik (Abbott), Monopril (Bristol-Myers Squibb), Prinivil (Merck), Univasc (Schwarz), Vaotec (Merck), and Zestril (AstraZeneca); 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. 204 WO 2005/042712 PCT/US2004/035939 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 5 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, 10 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 15 include Y 90 , At 222 , Ret 86 , Re186, Sm 5 , Bi 1 2 , p 32 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 20 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 25 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 minutes, at least about minutes, at 30 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, 205 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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 20 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 25 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 30 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 206 WO 2005/042712 PCT/US2004/035939 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 weeks, at least about 5 weeks, at 5 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. 10 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 36 207 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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, 15 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 20 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 25 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 30 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 208 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 B blockers 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 15 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. 20 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, 25 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 transdernal means. 30 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 209 WO 2005/042712 PCT/US2004/035939 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 pm, for good respirability. 5 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. 10 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* (Astra), Rotahaler* 15 (Glaxo), Diskus® (Glaxo), Spiros* inhaler (Dura), devices marketed by Inhale Therapeutics, and the Spinhaler® powder inhaler (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 94/06498; 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* 20 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. 25 Where the carrier 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 carrier is a liquid, suitable formulations for administration as, for example, a nasal spray or as nasal 30 drops, include aqueous or oily solutions of the active ingredient. 1. Administration as a Spray 210 WO 2005/042712 PCT/US2004/035939 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 5 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 pm, less than about 19 pim, less than about 18 pm, less than about 17 pm, less than about 16 pm, less than about 15 gm, less than about 14 pm, less than about 13 pm, less than about 12 pm, less than about 11 pm, less than about 10 pm, less than about 9 pm, 10 less than about 8 pm, less than about 7 pm, less than about 6 pm, less than about 5 pm, less than about 4 pm, less than about 3 pm, less than about 2 Pm, less than about 1 pm. Phannaceutical 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 ing to about 100 mg of a compound contemplated hereby per mL 15 of solution or mg/gm, or any range or value therein including, but not united 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 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, 25 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, 30 polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art also can be included in the pharmaceutical composition. 211 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 pharmaceutical composition delivered by a nebulizer have a particle size less than about 20 15 Vtm, less than about 19 im, less than about 18 im, less than about 17 pum, less than about 16 pm, less than about 15 pm, less than about 14 pm, less than about 13 im, less than about 12 pm, less than about 11 pm, less than about 10 pim, less than about 9 pim, less than about 8 pm, less than about 7 im, less than about 6 pm, less than about 5 im, less than about 4 pm, less than about 3 im, less than about 2 jim, less than about 1 pm. 20 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 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 30 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 212 WO 2005/042712 PCT/US2004/035939 include a surfactant, 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 5 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 10 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 pm, less than about 18 pm, less than about 17 pm, less than about 16 pm, less than 15 about 15 pm, less than about 14 pum, less than about 13 pm, less than about 12 pm, less than about 11 pm, less than about 10 pm, less than about 9 pm, less than about 8 pm, less than about 7 pm, less than about 6 ptm, less than about 5 pm, less than about 4 pm, less than about 3 pm, less than about 2 pm, less than about 1 pm. 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 25 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, 30 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 213 WO 2005/042712 PCT/US2004/035939 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 5 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 10 peptide, and an aqueous continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion of the emulsion particles. See, for example, 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 15 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. 20 5,849,695. C. Transdermal Administration The pharmaceutical compositions of the present invention may be administered via transdermal routes using forms of transdermal skin patches. For transdermal administration, a compound of the present invention is encapsulated in a delivery device such as a liposome 25 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 30 acids, albumin and other proteins, alginate and other polysaccharides, and any combination thereof. See, for example, U.S. Patent No. 5,814,599, incorporated by reference herein in its 214 WO 2005/042712 PCT/US2004/035939 entirety. To be administered in the form of a transdermal delivery system, the dosage administration may be continuous rather than intennittent 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 5 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 carrier 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, 10 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 REMINGTON'S PHARMACEUTICAL SCIENCES (1990), incorporated by reference herein in its entirety. Pharmaceutical formulations may contain from about 0.005% to about 10% by weight of the active ingredient, for example, from about 0.0 1% to 5% by weight of the active 15 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 administration. Certain medical devices may be employed to provide a continuous 20 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 pharmaceutically acceptable non-toxic salt of compound contemplated hereby that has a low 25 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 30 thereof, or with an organic cation formed from for example, NN'-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 215 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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 20 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 25 compound's availability to a target site(s). Distribution, equilibrium, and elimination of a drug may be considered when determining 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 30 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 216 WO 2005/042712 PCT/US2004/035939 animals, for example, for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (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 LD 5 0
/ED
50 . Compounds exhibiting large therapeutic indices typically are used. 5 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. 10 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 ED 5 0 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 15 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 IC 50 (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 20 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 25 pharmacokinetic/phannacodynamic 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. 30 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, 217 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 (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 include coadministration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation; 20 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, 25 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). 30 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, 218 WO 2005/042712 PCT/US2004/035939 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 5 (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, 10 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 15 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, 20 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, 25 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, 30 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and/or 5000 pg/mL serum concentration per single or multiple administration or any range, value or fraction thereof. 219 WO 2005/042712 PCT/US2004/035939 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, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of day 5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively or additionally, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, or alternatively or additionally, at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 10 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 15 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 20 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 25 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 30 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. 220 WO 2005/042712 PCT/US2004/035939 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 5 once every 12 days, about once every 13 days, about once every 14 days, about once every 15 days, about once every 16 days, about once every 17 days, about once every 18 days, about once every 19 days, about once every 20 days, about once every 21 days, 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 phannaceutical 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 20 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 25 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 least once a week for 30 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 221 WO 2005/042712 PCT/US2004/035939 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 I month, at least once a week for about 2 months, at least once a week for 5 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. 10 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 15 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 20 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 25 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 30 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 222 WO 2005/042712 PCT/US2004/035939 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, 5 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 10 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 15 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 -1-195) contains attachment sites for HS chains. Domain II comprises four repeats homologous to the ligand 20 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 25 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 occurring growth modulators, many of which are derived from the endothelium, tightly control SMC 30 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, 223 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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. 20 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 25 cytokines, chemokines, 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 30 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 224 WO 2005/042712 PCT/US2004/035939 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, 5 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 B (TGF-B), 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, 10 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 15 HSPG can inhibit 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 20 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 1, 2 and 4, Glypican-1 25 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-p, apolipoprotein E and heparin stimulate HSPGs. 30 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 225 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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, renovascular 15 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 20 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 25 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 30 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. 226 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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 20 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, 25 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. 30 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 227 WO 2005/042712 PCT/US2004/035939 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. 5 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. 10 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 Perlecan stimulating effects, are useful 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 mRNA or increasing the translation of Perlecan mRNA into protein. Furthermore, the selective activators of Perlecan can block or decrease the 25 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, 30 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 228 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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 20 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 +1, 25 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 30 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 229 WO 2005/042712 PCT/US2004/035939 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. 5 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 10 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 I presents exemplary that have been shown to induce HSPG. 15 Table 1. Fold induced at 10 S. No CompoundM 1 2.9 NH
N
CH
3 F 2 2.8 o ~ S NH N
CH
3 C CI 3 1.181 NH N F
CH
3 F 230 WO 2005/042712 PCT/US2004/035939 4 F 1.66 Me N F 0 o Cl NH CI 0 5 2.6 o N 0 NH H N
CH
3 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. 2062-70 5 (1997). Basement membranes are continuous sheets of extracellular matrix composed of collagenous and noncollagenous proteins and proteoglycans that separate parenchymal 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 10 of adhesion proteins, fibronectin, laminin, collagen and vitronectin. Wight et al., 6 CURR. OPIN. LIPIDOL. 326-334 (1995). Heparan sulfate (HS) is an important structural component of the basal lamina. Each of the adhesion proteins interacts with 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 15 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 bome 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 20 including liver, placenta, platelets, fibroblasts, neutrophils, activated T and B-lymphocytes, monocytes, and endothelial cells (7-16). Nakajima et al., (31) CANCER LETT. 277-283 (1986); Nakajima et al., 36 J. CELL. BIOCHEM. 157-167 (1988); Ricoveri et al., 46 CANCER 231 WO 2005/042712 PCT/US2004/035939 RES. 3855-3861 (1986); Gallagher et al., 250 BIOCHEM. J. 719-726 (1988); Dempsey et al., 10 GLYCOBIOLOGY 467 (2000); Goshen et al., 2 MOL. HUM. REPROD. 679 (1996); Parish et al., 76 IMMUNOL CELL BIoL. 104-113 (1998); Gilat et al., 181 J. EXP. MED. 1929-1934 (1995); Graham, et al., 39 BIOCHEM. MOL. BIOL. INT. 56371 (1996); Pillarisetti et al., 270 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 10 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 al.,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 15 al., 212 PROG CLIN BIoL RES. 113-122 (1986); Freeman et al., 325 BIOCHEM. J. 229-237 (1997); Vlodavsky et al., 5 NAT. MED. 793-802 (1999); Hulett et al., 5 NAT MED. 803-809 (1999). It 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. 20 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. 25 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 30 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), 232 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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), 15 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. 20 Occasionally, however, the immune system malfunctions or overreacts to the initial insult, which 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 and secretion of chemokines, cytokines, and lymphokines is not shut down after the eradication of the disease, 25 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 30 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 233 WO 2005/042712 PCT/US2004/035939 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 5 (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 10 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 15 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, 20 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, 25 trauma/hemorrhage, bums, 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, 30 hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney transIplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft 234 WO 2005/042712 PCT/US2004/035939 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, astluna, myasthenia gravis, -meditated 5 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, 10 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-l antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, 15 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, 20 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-Barr6, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, 25 juvenile arthritis, lichen planus, m6nibre's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Cogan's syndrome, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, Sjgren's syndrome, stiff-man syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, Wegener's 30 granulomatosis; okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (for example, including but not limited toasthenia, anemia, cachexia), chronic salicylate intoxication,. 235 WO 2005/042712 PCT/US2004/035939 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 5 invention also may be evaluated using the assays discussed herein. Furthenrore, 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 10 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 15 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 MOL. 20 HuM. REPROD. 679-84 (1996); Nakajima 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. Vlodasky et al., 12 INVASION METASTASIS 112-27 (1992). Solid-phase Heparanase assays have also been developed where chemically and 25 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 30 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 236 WO 2005/042712 PCT/US2004/035939 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 5 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). 10 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. This 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. 15 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 20 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, 25 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. 30 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. 237 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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 15 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 20 and its substrate-binding partner. 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 25 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 30 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 238 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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 20 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 25 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. 30 Despite the importance of AGE in the pathogenesis of diabetic microangiopathies, there are no currently available medications known to block AGE formation. 239 WO 2005/042712 PCT/US2004/035939 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 5 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 TNT. 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 10 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); Oturai et al., 49(8) METABOLISM 996-1000 (2000). Inhibition of reactions with receptors of AGE is an alternative approach to treatment 15 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 term 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 specific inhibitory compounds can be used for 20 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. 55-68 (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 25 vasculopathy. See Stehouwer et al., 34 CARDIOVASC. 55-68 (1997); Libby, 247 J. INTERN. MED. 349-58 (2000); Van Lente, 293 CLINICA. 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. 30 The effectiveness of the compounds of the present invention in inhibiting glycated protein- and AGE-induced inflanunation can be determined using the assays described herein and in U.S. Provisional Patent Application Serial No. 60/259,306, which is incorporated by 240 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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. 15 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 20 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. 25 IL-6 is a pro-inflammatory cytokine that is known to play a key role in the pathogenesis of diabetes and atherosclerosis. See Horii et al., 39 KIDNEY INT. SuPPL. 71-5 (1993); Huber et al., 19 ARTERIOSCLER THROMB. VAsc. BIOL. 2364-67 (1999); Shikano et al., 85 NEPHRON 81-5 (2000); Pickup et al., 8(67) LIFE SC. 291-300 (2000). IL-6 also promotes the growth of renal mesangial cells thus contributing to nephropathy. See Kado et 30 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 +/- 0.90 241 WO 2005/042712 PCT/US2004/035939 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-1, another pro-inflammatory cytokine is found highly expressed in human atherosclerotic lesions and postulated to play a central in monocyte recruitment into the 5 arterial wall and developing lesions. See Libby, 247 J. INTERN. MED. 349-58 (2000). Recent results show that MCP-l 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 10 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-L. Table 2. S. No Compound Proinflammat % of Concentration in ory cytokine inhibition PM IL-6 50 4.64 oor_ NH I I S F 242 WO 2005/042712 PCT/US2004/035939 2 MCP-1 50 7.9 NH N
CH
3 F 3 s IL-6 49 5 J: I 0 6NH
CH
3
C
4 0 e MCP-1 44 5 O NH 1 0
CH
3 Br 5 MCP-1 50 4.4 NH N F
CH
3 F 6 Me F MCP-1 61 5 F O C N H C, 0 7 MCP-1 50 6.5 o 0 N. F 8 MCP-1 50 7 ,,N-- NH N FF
OH
3 F 243 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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 15 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 20 inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, bums, 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, 25 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 transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft 30 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, 244 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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, 20 fibromyalgia-fibromyositis, Graves' disease, Guillain-Barr6, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen planus, m6niere'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, Sj6gren'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 & 30 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 245 WO 2005/042712 PCT/US2004/035939 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 5 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 malignamt lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic 10 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 15 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 20 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 25 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 30 therapeutic agents, from a stent prevents vessel recoil and remodeling through the scaffolding action of the stent. In addition, drug-coated stents can prevent multiple components of neointimal hyperplasia or restenosis as well as a reduce inflammation and thrombosis. Local 246 WO 2005/042712 PCT/US2004/035939 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 5 systemic toxicity may be achieved utilizing local delivery rather than systemic administration while maintaining higher tissue concentrations. In utilizing local delivery from a stent 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 10 achieving a reduction in restenosis, inflammation and thrombosis. Local stent-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 15 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 20 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 25 combination approach. Other surgical devices, sutures, staples, anastomosis 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 30 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. 247 WO 2005/042712 PCT/US2004/035939 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/antirnitotic agents including natural products such as vinca alkaloids (for example, vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (for 5 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/IIla inhibitors and vitronectin receptor 10 antagonists; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs, streptozocin), trazenes-dacarbazinine (DTIC); antiproliferative/antimnitotic antimetabolites such as folic acid analogs (methotrexate), 15 pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine)); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (e.g. estrogen); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as 20 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., 25 acetominophen; indole and indene acetic acids (indomethacin, sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate); immunosuppressives 30 (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 248 WO 2005/042712 PCT/US2004/035939 and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors. Although any number of stents may be utilized in accordance with the present invention, for simplicity, a limited number of stents will be described herein. The skilled 5 artisan will recognize that any number of stents may be utilized in connection with the present invention. In addition, as stated above, other medical devices may be utilized. A stent is commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction. Typically, stents 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 10 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 stent may resemble an expandable cylinder and may comprise a fenestrated 15 structure for placement in a blood vessel, duct or lumen to hold the vessel, duct or lumen open, more particularly for protecting a segment of artery from restenosis after angioplasty. The stent may be expanded circumferentially and maintained in an expanded configuration that is circumferentially or radially rigid. The stent may be axially flexible and when flexed at a band, for example, the stent avoids any externally protruding component parts. 20 The stent 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 stent 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 stent is a function of the 25 diameter of the balloon catheter used. It should be appreciated that a stent 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 30 configuration. After the stent 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 249 WO 2005/042712 PCT/US2004/035939 emerging from the catheter, the stent 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 stent may be modified to comprise one or more reservoirs. Each of 5 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 stent, 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 10 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 stent 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. 15 Also, the coating techniques may vary depending on the material comprising the stent 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 stent in a number of ways. For example, the compound may be directly incorporated into a polymeric 20 matrix and sprayed onto the outer surface of the stent. The compound elutes from the polymeric matrix over time and enters the surrounding tissue. The compound typically remains on the stent 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 25 compound. According to one aspect of the present invention, the polymeric matrix comprises two layers. The base layer comprises a solution of poly(ethylene-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 30 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 250 WO 2005/042712 PCT/US2004/035939 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 5 above. The poly(ethylene-co-vinylacetate), polybutylnethacrylate and compound solution may be incorporated into or onto the stent in a number of ways. For example, the solution may be sprayed onto the stent or the stent may be dipped into the solution. The solution may be sprayed onto the stent and then allowed to dry. The solution may be electrically charged 10 to one polarity and the stent electrically charged to the opposite polarity. In this manner, the solution and stent 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 stents are manufactured by a number of companies including Johnson & 15 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 02/26 139, each expressly entirely incorporated herein by reference. 20 Expression Profiles and Microaray 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 25 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 30 microarrays may represent diseases including cardiovascular diseases, vasculopathic conditions, inflammatory diseases, autoimmune diseases, neurological diseases, 251 WO 2005/042712 PCT/US2004/035939 immunological 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, 5 heart, liver, prostate, lung, nerve, muscle, or connective tissue; for example, coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, dermal microvascular endothelium, pulmonary artery endothelium, myometrium microvascular endothelium, keratinocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, 10 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, prostate stromal cells, or combinations thereof. 15 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, 20 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 fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural 25 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. 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 30 a compound of the present invention and is selected from the group comprising coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, denral microvascular endothelium, pulmonary artery endothelium, 252 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 15 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 20 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 ininobilized 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 25 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 30 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 253 WO 2005/042712 PCT/US2004/035939 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 context of protein expression profiles. Total protein may be isolated from a cell sample and 5 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 10 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 15 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 20 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. 25 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 30 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 254 WO 2005/042712 PCT/US2004/035939 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 5,837,832; 5,700,637; 5,445,934; U.S. Patent Application Nos. 2001/0014461 Al; 2001/0039016 Al; 2001/0034023 Al; WO 01/94946; and WO 01/77668. See also, Haab et al., 2 GENOME BIOLOGY 1-12 (2001); Brown et al., 97 PROC. NATL. ACAD. SC. USA 262-7 (2000); Getz et al., 97 PROC. NATL. ACAD. SC. USA 12079-84 (2000); Harrington et al., 3 CURRENT OPINION MICROBIOL 285-91 (2000); Holter et al., 97 PROC. NATL. ACAD. SC. USA 10 8409-14 (2000); MacBeath et al., 289 SCIENCE 1760-63 (2000); Duggan et al., 21 NATURE GENET 10-14 (1999); Lipshutz et al., 21 NATURE GENET 5-9 (1999); Eisen et al., 95 PROC. NATL. ACAD. SCI USA 14863-68 (1998); Ermolaeva et al., 20 NATURE GENET. 19-23 (1998); Hacia et al., 26 NUCLEIC ACIDS RES. 3865-66 (1998); Lockhart et al., NUCLEIC ACIDS SYMP. SER. 11-12 (1998); Schena et al., 16 TRENDS BIOTECHNOL. 301-6 (1998); Shalon, 46 15 PATHOL. BIOL. 107-9 (1998); Welford et al., 26 NUCLEIC ACID RES. 3059-65 (1998); Blanchard et al., II BIOSENSORS BIOELECTRONICS 687-90 (1996); Lockhart et al., 14 NATURE BIOTECHNOL. 1675-80 (1996); Schena et al., 93 PROC. NATL. ACAD. SCI. USA 10614-19 (1996); Tomayo et al., 96 PROC. NATL. ACAD. SCI. USA 2907-12 (1996); Schena et al., 270 SCIENCE 467-70 (1995). 20 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 25 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 30 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 255 WO 2005/042712 PCT/US2004/035939 tumor type or progression, information related to a compound of the present invention such as dosage and administration information, descriptive information about related cDNAs associated with the sequence, tissue or cell source, sequence data obtained from external sources, expression profiles for a given gene and the related disease state or course of 5 disease, for example whether the expression profile relates to or signifies 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 10 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 connecting the network server with clients. The network may be any one of a number of conventional network systems, including a local 15 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 20 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 25 then 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 30 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 256 WO 2005/042712 PCT/US2004/035939 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 5 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. 10 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 15 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 20 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 25 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 30 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 257 WO 2005/042712 PCT/US2004/035939 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 5 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 10 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 infonnation on a selected subset of biomolecular sequences. If the user chooses to display classification information on a selected subset of 15 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 20 GUI also may allow the user to select or deselect each of the one or more external databases. The methods of the present application futher 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, 25 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 30 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 258 WO 2005/042712 PCT/US2004/035939 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 5 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, 10 embodiments, and equivalents thereof exist that do not depart from the spirit of the present invention and/or the scope of the appended claims. PREPARATION 1 1-[4-(2-Bromo ethoxy) phenyl]-1-ethanone 15
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r A mixture of 4-hydroxyacetophenone (20 g, 147 mmol) and potassium carbonate (81 g, 588 mmol) 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 x 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 (KBr, cm-): 1678, 1603; 25 'H NMR (200 MHz, CDCl 3 ): 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). 259 WO 2005/042712 PCT/US2004/035939 PREPARATION 2 2-(3,4-Dimethoxyphenyl)-3-hydroxy-5,7-dimethoxy-4H-4-chromenone OMe OMe MeO O OH OMe 0 Step (i): 5 3-[(6-O-(deoxy-a-L-manopyranosyl)-B-glucopyranosyl)oxy]-2-(3,4-dimethoxyphenyl)-5,7 dimethoxy-4H- 1 -benzopyran-4-one OMe OMe MeO 0 ORut OMe 0 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 10 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 15 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 20 mixture was allowed to reflux at 100"C for 2 hours and then cooled to 25 *C. 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 0 C. IR: ? max (KBr, cm'1): 3279, 2925, 1609, 1516; 260 WO 2005/042712 PCT/US2004/035939 'H NMR (200 MHz, CDC 3 ): d 7.83-7.79 (in, 2H), 7.00 (d, J= 9.14 Hz, 1H), 6.56 (d, J = 1.88 Hz, 1H), 6.36 (s, IH), 3.99 (s, 6H), 3.96 (s, 3H), 3.93 (s, 3H); Mass (CI method, I-butane): 359 (M', 100). 5 PREPARATION 3 1-(4-{2-[2-(3,4-Dimethoxyphenyl)-5,7-dimethoxy-4-oxo-4H-3-chromenyloxy]ethoxy} phenyl)-1-ethanone OMe OMe MeO 0 OMe Oa 0 A mixture of compound obtained in Preparation 2 (25 g, 69.6 mmol), a compound 10 obtained in Preparation 1 (21.5 g, 88.4 inmol) and potassium carbonate (77 g, 557 minol) was placed in a 1 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 15 triturated with methanol and filtered to afford the title compound (31.5 g, 87 %), as a pale brown solid, after drying under vacuum. Mp. 143-144 C. IR: ? max (KBr, cm-'): 1668, 1624, 1600; 'H NMR (200 MHz, CDCl 3 ): d 7.87 (d, J= 8.79 Hz, 2H), 7.71-7.67 (in, 2H), 6.87 6.76 (in, 31H), 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). 261 WO 2005/042712 PCT/US2004/035939 PREPARATION 4 4-Fluorophenylacetate F 0 4-Fluorophenol (20 g, 178.5 mmol) was placed into single neck 1 L round bottomed 5 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 x 100 mL), combined extracts were dried over 10 sodium sulphate and concentrated under reduced pressure to afford the title compound (26 g, 95 %) as a white solid. IR: ? max (KBr, em):1764; 1H NMR (200MHz, CDCl 3 ): 7.05 (s, 2H), 7.01 (s, 2H), 2.27 (s, 3H); Mass (CI method, I-butane): 155(M', 100). 15 PREPARATION 5 (2-Hydroxy-4-fluoro phenyl)-l-ethanone FaOH F 0 A mixture of 4-fluorophenylacetate obtained in Preparation 4 (25 g, 223 mmol), 20 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 HC1 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 25 was extracted with chloroform (3 x 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, cm- 1 ): 3442, 1650; 262 WO 2005/042712 PCT/US2004/035939 'H NMR (200MHz, CDCl 3 ): 11.98 (s, H, D 2 0 exchangeable), 7.43-7.37 (m, 1H), 7.27-7.17 (m, 1H), 6.98-6.91 (m, 1H), 2.62 (s, 3H); Mass (CI method, I-butane): 155 (M+1, 47). 5 PREPARATION 6 1-(5-Fluoro-2-hydroxyphenyl)-3-(4-methoxyphenyl)-2-propen-1 -one F OMe OH We FO 0 To a mixture of (2-hydroxy-4-fluoro phenyl)- I -ethanone (3 g, 19.7 mmol) obtained in Preparation 5, and 4-fluorobenzaldehyde (4.37 g, 19.7 mmol) in methanol was slowly added 10 sodium hydroxide solution at 0 *C, under N 2 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 (15 mL). Solid separated was filtered off and dried under vacuum to afford 3 g (41 %) of the title compound as a yellow solid. IR: ? ,,x (KBr, cn): 3500, 1642; 15 'H NMR (200MHz, CDC1 3 ): 12.6 (s, 1H, D 2 0 exchangeable), 7.92 (d, J=15.3 Hz, 2H), 7.76-7.55 (m, 3H), 7.41 (d, J=15.3 Hz, 211), 7.0-6.94 (m, 2H), 3.87 (s, 3H); Mass (CI method, I-butane): 272 (M+, 100%). PREPARATION 7 20 6-Fluoro-2-(4-methoxy phenyl)- 3-hydroxy - 4H-4-chromenone OMe 0 Ns K I F OH 0 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 5-10 25 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 263 WO 2005/042712 PCT/US2004/035939 filtered off and dried under vacuum to afford 1.0 g (32 %) of the title compound as a yellow solid. IR: ? ma (KBr, cm):3261, 1602, 1559; 'H NMR (200MHz, CDC1 3 ): 68.23 (d, J=9.13 Hz, 2H), 7.90-7.85 (in, 1H),7.63-7.56 5 (in, 1H), 7.48 -7.38 (in, 1H), 7.06 (d, J=9.13 Hz, 2H), 3,91 (s, 3H); Mass (CI method, I-butane):287(M+1, 100%). PREPARATION 8 1-(4-{ 2 -[6-Fluoro-2-(4-methoxyphenyl)-4-oxo-4H-3-chromenyloxy} phenyl)-1-ethanone OMe O F O 10 0 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 15 reaction 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 x 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. 20 PREPARATION 9 N-Methyl anthranilic acid COOH 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 25 (9.69 g, 242 nmol) in 25 mL of water at 0-10 *C. The reaction mixture was heated to 50 0 C for 6 hours and then cooled to room temperature. Methanol was removed completely from 264 WO 2005/042712 PCT/US2004/035939 the reaction mixture and water (100 mL) was added to it. The mixture was washed with ether (3 x 50 mL) and the aqueous layer was acidified (pH ~ 5-6) with ice cold 2 N HCl. The solid that separated was filtered, washed with water (2 x 50 mL) and dried under vacuum to afford the title compound 17.0 g (93 %) as a white color solid.mp-l 78-180 "C. 5 1H NMR (200MEz, CDC1 3 ): 67.99 (dd, 1H, J= 1.34 Hz), 7.46-7.25 (in, 1H), 6.70 6.58 (in, 2H), 2.93 (s, 3H); Mass (CI method): 152 (M+1, 100%). PREPARATION 10 10 2-Bromo-l-(4-methylphenyl)-1-ethanone 0 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 15 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%). 'H NMR (200MHz, CDCl 3 ):57.88(d, J=8.3Hz, 2H), 7.29(d, 8Hz, 2H), 4.42(s, 2H), 2.41 (s, 3H). 20 PREPARATION 11 2-(4-Methyl phenyl)-2-oxo ethyl -2-methylaminobenzoate Me NHMe To a solution of N-methyl anthranilic acid (10.0g, 66 mmol), obtained in Preparation 9, in 100 mL of dimethyl formamide, placed in a 250 mL single neck round bottomed flask 25 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 265 WO 2005/042712 PCT/US2004/035939 10 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. JR (KBr, cm'): 3382, 1684, 1674; 5 'H NMR (200MHz, DMSO-d 6 ): 6 7.91-7.87 (in, 3H), 7.47-7.34 (in, 3H), 6.75-6.57 (n, 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+1, 100%). PREPARATION 12 10 3-Hydroxy-1-methyl-2-(4-methylphenyl)-1,4-dihydro-4-quinolinone Me 1OH 0 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 methylaminobenzoate (10 g, 35 mmol) obtained in Preparation 11 was added in small 15 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, cn'): 3433, 1598; 20 'H NMR (200MHz, DMSO-d 6 ): 8 8.44 (d, J=8.3 Hz, 111), 8.06-7.91 (m, 2H), 7.75 7.61 (in, 1H), 7.48-7.35 (in, 4H), 5.21 (bs, OH), 3.70 (s, 3H), 2.43 (s, 3H); Mass (CI method): 266 (M+1, 100%). PREPARATION 13 25 4 -(2-Bromoethoxy)benzaldehyde 0 o~ Br A mixture of 4-hydroxybenzaldehyde (10.0 g, 82 mmol) and potassium carbonate (46 g, 326 mmol) was placed into 2L round bottom flask, and DMF (150 mL) was added. The 266 WO 2005/042712 PCT/US2004/035939 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 5 Na 2
SO
4 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, cm- 1 ):3439, 1682, 1602, 1577; H NMR (200MHz, CDC1 3 ):89.88(s, 1H), 7.86(d, J=8.8Hz ,2H), 7.03(d, J=8.8Hz 10 ,2H), 4.40(t, 2H, J=6.2Hz), 3.69(t, J=5.9Hz ,2H); Mass(CI method):231(M-' 231, 100%). PREPARATION 14 1-(3-{2-[1-Methyl-2-(4-methylphenyl)-4-oxo-1, 4 -dihydro-3-quinoliniloxy]ethoxy} phenyl) 15 1 -ethanone Me Me N 0 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. 20 The mixture was heated to 80 0 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 x 500 mL). It was triturated with methanol and filtered to afford the title compound (2.8 g, 64 %), as a pale brown solid, after drying under vacuum. 25 'H NMR (200MHz, CDCI 3 ): 5 8.60 (d, J=7.8Hz, IH), 7.74-7.21 (in, 1OH), 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+1, 428, 100%). 267 WO 2005/042712 PCT/US2004/035939 PREPARATION 15 4 -(2-Bromo-ethoxy)-benzoic acid ethyl ester CO2 Et BrO 5 Step (i) To a solution of 4-hydroxybenzoic acid (15g, 108.6 mmol) in ethanol (200 mL) was added SOC1 2 (16 niL, 217.4 mmol) at 0 *C under anhydrous condition. The mixture was heated to reflux for 7 hours with stirring. After completion of the reaction, the mixture was concentrated under vacuum and the residue was neutralized by using aqueous NaHCO 3 10 solution until the pH reached 7.0. 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 K 2 C0 3 (4.62 g, 33.51 mol) in acetone (50 mL) was stirred at 50 'C for 30 min. under Nitrogen 15 atmosphere. 1,2-Dibrornoethane (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). 20 PREPARATION 16 4-{ 2
-[
2
-(
3
,
4 -Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] -ethoxy}-benzoic acid ethyl ester o I I 268 WO 2005/042712 PCT/US2004/035939 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 K 2 C0 3 (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 5 into water (60 mL) and stirred for 30 min. The separated solid was filtered, washed with water (2 x 20 mL) and dried under vacuum to give the desired product in 68 % yield (4.2 g). PREPARATION 17 4-{2-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy] 10 -ethoxy)-benzoic acid O- CH 3
H
3
C--
0 O-CH,
HC
0 0 o OH To a solution of 4-{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, 15 36.36 mmol) in water (10 mL) at 25-35'C and the mixture was stirred at 60'C for 6 brs. Then solvent was removed from the mixture under vacuum and the residue was acidified with cold HCL. 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). 20 PREPARATION 18 2-(Toluene-4-sulfonylamino)-succinamic acid 0 0 H i / CH 3
H
2 N OH 0 269 WO 2005/042712 PCT/US2004/035939 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 0 C. After stirring for 1 min. additional quantity of NaOH (4.4g, 110 mmol) in water (75 mL) was added to the reaction mixture at the same temperature. Stirring 5 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 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. 10 PREPARATION 19 3-Amino-2-(toluene-4-sulfonylamino)propionic acid ethyl ester Step (i): 3-Amino-2-(toluene-4-sulfonylamino)-propionic acid 0 II o HNH \ / -0CH 3
H
2 N OH 15 0 To a cold (OC) 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 20 90'C. The mixture was cooled to 0 'C and the pH was adjusted to 7.0 by slow addition of conc. HCl. 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) 25 3-Amino-2-(toluene-4-sulfonylamino)-propionic acid ethyl ester 270 WO 2005/042712 PCT/US2004/035939 0
HOCH
3 0 To a cold (0*C) and stirring solution of the compound (2 g, 7.75 mmol), obtained in step (i), in ethanol (20 nL) was added SOCL 2 (1.25 mL, 17.05 mmol) under anhydrous condition. The mixture was heated to reflux for 12 hrs with stirring. After completion of the 5 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. PREPARATION 20 4-(3,4-Dimethoxyphenylcarboxamido)-l-methyl-3-propyl-1H-5-pyrazolecarboxamide -- N N HI O NH 2 OMe 10 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 15 benzenecarbonylchloride (21.5g, 107.5mmol) in dichloromethane (100mL) at 0 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 20 under vacuum to get the title compound 33g, (89 %) as a white solid. Mp: 176-178'C. IR: v ma (KBr, em-): 3370, 3243, 2960, 1682, 1631; 'H NMR (200 MHz, CDCl 3 ): 6 7.81 (s, 1H), 7.49 (d, J = 6.45Hz, 2H), 6.94 (d, J = 8.86Hz, 1H), 3.99-3.96 (m, 9H), 2.53 (t, J = 7.22Hz, 2H), 1.68-1.57 (in, 2H), 0.92 (t, J = 7.51Hz, 3H); 271 WO 2005/042712 PCT/US2004/035939 Mass (CI method, I-butane): 347(MH, 100). PREPARATION 21 5-(3,4-Dimethoxyphenyl)-1 -methyl-3-propyl-6,7-dihydro-IH-pyrazolo[4,3-d]pyrimidin-7 5 one 0 N' NH N N OMe 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 10 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 0 C and tert-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 15 afford the title compound 13g (81%) as a white solid. Mp: 210-212*C. IR: v ma: (KBr, cnf'): 3438, 3204, 1670; 'H NMR (200 MHz, DMSO-d 6 ): 5 12.3 (bs, D 2 0 exchangeable, 1H), 7.73 (in, 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 (in, 2H), 0.96 (t, J = 7.24 Hz, 3H); 20 Mass (CI method, i-butane): 329(M+', 100). PREPARATION 22 1-[4-(2-Bromoethylamino) phenyl]-1-ethanone 0 NBr H 25 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 272 WO 2005/042712 PCT/US2004/035939 was added a solution of p-aminoacetophenone (20g, 148.1 mmol) in DMF (60 mL) in drops through the pressure equalizing addition funnel under nitrogen atmosphere at 0 0 C and the contents were stirred for 2 hours at 25 0 C. Then to the stirred solution was added 1,2 dibromoethane (97.48g, 518.5 mmol) in drops and the contents were further stirred for 5 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 Na 2
SO
4 and concentrated under reduced pressure. The crude was chromatographed over silicagel by using 15-20% ethyl acetate / pet. 10 ether (3 Lit), affording the title compound 5.1 g (14 %) as a pale yellow solid. Mp: 92-94'C. IR: V max : (KBr, cm-'): 3360, 2927, 1650; 'H NMR (200 MHz, CDC1 3 ): 8 7.84 (d, J = 8.89 Hz, 2H), 7.48 (d, J = 8.58 Hz, 2H), 3.68-3.52 (m, 411), 2.51 (s, 3H); 15 Mass (CI method, I-butane): 244(M+2, 10), 162 (100). PREPARATION 23 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 0 H N N N /~ OMe 20 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 (1.55g, 6.405 mmol) and potassium carbonate (4.213g, 3.5 mmol) were taken in 100 mL round bottom flask and DMF 25 (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. 273 WO 2005/042712 PCT/US2004/035939 IR: v max (KBr, cm7 ): 3381, 2927, 1660, 1599; 'H NMR (200 MHz, DMSO-d 6 ): 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, 111), 6.69 (d, J = 8.79 Hz, 2H), 4.84 (in, 2H), 4.10 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.72 (t, J = 4.5 Hz, 2H), 2.91 (t, J = 7.33 Hz, 5 2H), 2.40 (s, 3H), 1.89-1.78 (in, 2H), 0.93 (t, J= 7.32 Hz, 3H); Mass (CI method, I-butane): 490 (Me, 100). PREPARATION 24 6,7-Dimethoxyquinazolin-4(3H)-one 0 MeO NH 10 MeO 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 15 (2 x 20 mL) to give 12.5g of the desired product in 40% yield. Mp. 295-296 0 C (lit 296 297*C). 'HNIM4R (DMSO-d6, 200 MHz) 12.0 (bs, D20 exchangeable, 1H), 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. 20 F.; Baruth, H. W.; Yaremko, B. J. Med. Chem. 1983, 26, 420. EXAMPLE 1 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 OMe oMe MeO 0 OMeO NH 25 0 274 WO 2005/042712 PCT/US2004/035939 A mixture of compound (31 g, 59.6 mmol), obtained in Preparation 3, thiazolidene 1,3-dione (40 g, 341 mmol), benzoic acid (14.5 g, 118.8 nmol) 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 5 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 / CHC1 3 (5 L) to afford the title compound, 22 g (60 %) as off white solid. Mp: 205-206*C. IR: ? m (KBr, cm-'): 3220, 1735, 1698, 1627, 1604; 10 1H NMR (200 MHz, CDCl 3 ): d 9.07 (bs, IH, exchangeable with D 2 0), 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). 15 EXAMPLE 2 Example 2 was prepared according to the methodology provided in Example 1. OMe O NH MeO 0 O s OMe O 'H NMR (200 MHz, CDCl 3 ): d 12 (s, D 2 0 exchangable), 7.68-7.44 (m, 4H), 7.10-6.84 (m, 20 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 Example 3 was prepared according to the methodology provided in Example 1. 0Me NH MeO O O~ S o o O 25 OMe0 275 WO 2005/042712 PCT/US2004/035939 H NMR (200 MHz, CDC1 3 ): d 8.65 (s, D 2 0 exchangeable), 7.75-7.71 (m, 2H), 7.28-7.23 (m, 2H), 6.90-6.79 (m, 2H), 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'C. 5 EXAMPLE 4 Example 4 was prepared according to the methodology provided in Example 1. OMe MeO O OMe OMe OMe O O NH MeO 'H NMR (200 MHz, CDC1 3 ): d 9.18 (s, D 2 0 exchangeable, 1H), 7.92 (s, IH), 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, io 4H), 3.95 (s, 6H), 3.93 (s, 3H), 3.91 (s, 3H), 3.80 (s, 6H). Mp: 207-210*C. EXAMPLE 5 Example 5 was prepared according to the methodology provided in Example 1. OMe MeO O OMe OMe 0 NH 0 15 'IH NMR (200 MHz, CDC1 3 ): 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 0 C. EXAMPLE 6 20 Example 6 was prepared according to the methodology provided in Example 1. oMe MeO 0 OMe OMe O NH cH 3 0 276 WO 2005/042712 PCT/US2004/035939 'H NMR (200 MHz, CDCl 3 ): d 7.72-7.67 (d, J=10.78, 3H), 6.86 (d, J=8.36 Hz, LH), 6.64 6.52 (m, 3H), 6.37 (s, 1H), 4.47 (s, 2H), 4.27 (s, 2H), 3.98 (s, 3H), 3.91 (s, 9H), 2.53 (s, 3H), 2.51 (s, 3H). Mp: 126-130'C. 5 EXAMPLE 7 Example 7 was prepared according to the methodology provided in Example 1. OMe OMe MeO O.0 N H 0
-
N . OMeO NH 0 t H NMR (200 MHz, CDC1 3 ): d 8.31 (s, D 2 0 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, 10 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 Example 8 was prepared according to the methodology provided in Example 1. OMe Meo O OMe 11 .N OMe O I H 0 15 'H NMR (200 MHz, CDCl 3 ): d 8.17 (s, D 2 0 exchangeable, 1H), 7.76 (d, J=8.3 Hz, 1H), 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), 4.41 (bs, 2H), 3.97 (s, 3H), 3.91 (s, 9H), 3.13 (t, J= 7.3 Hz, 2H), 1.6-1.4 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). Mp: 204-208*C. 20 277 WO 2005/042712 PCT/US2004/035939 EXAMPLE 9 Example 9 was prepared according to the methodology provided in Example 1. OMe MeO 0 O1 O s OMeO c1 NH 0 H NMR (200 MHz, CDC1 3 ): d 8.27 (s, D 2 0 exchangeable, 1H), 7.76 (d, J=8.53 Hz, 1H), 5 7.67 (s, 1H), 7.34 (s, 1H), 7.17 (m, 1H), 6.97-6.89 (m, 2H), 6.53 (s, lH), 6.37 (s, 111), 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 Example 10 was prepared according to the methodology provided in Example 1. OMe MeO 0 O4 OMe O NH Br 10 0 'H NMR (200 MHz, CDCl 3 ): d 8.25 (s, D 2 0 exchangeable, 111), 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, 211), 6.52 (s, 111), 6.37 (s, 1H), 4.5 (bs, 2H), 4.39 (bs, 2H), 3.98 (s, 3H), 3.91 (s, 6H), 3.90 (s 311), 2.69 (s, 3H). Mp: 235-236 "C. 15 EXAMPLE 11 Example 11 was prepared according to the methodology provided in Example 1. OMe MeO O. O e O O 0 OMeo O NNa 'H NMR (200 MHz, CDC 3 ): d 7.74 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.24 (d, J = 7.9 Hz, 20 2H), 7.00 (d, J = 8.0 Hz, 11H), 6.83 (d, J = 6.10 Hz, 2 H), 6.76 (s, 111), 6.5 (s, 111), 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 0 C. 278 WO 2005/042712 PCT/US2004/035939 EXAMPLE 12 Example 12 was prepared according to the methodology provided in Example 1. OMe MeG . 0 o-.. Me O OMe 0 0 OMe O NK 0 H NMR (200 MHz, CDCl 3 ): d 7.76-7.69 (m, 2H), 7.3 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 5 Hz, 111), 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, 311). Mp: 195-198'C. EXAMPLE 13 5-[-1-(4- {2-[6-Fluoro-2-(4-methoxypheny)-4-oxo-4H-3-chromenyloxy]ethoxy}phenyl) 10 ethylidene]- 1,3-thiazolane-2,4-dione OMe
N
0 I N 0 F O 0 NH 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 15 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-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 / CHC13 20 (5 L) to afford the title compound, 0.32 g (75 %) as off white solid. Mp: 210-212 'C. 1H NMR (200 MHz, CDC1 3 ): d 12.2 (s, D 2 0 exchangeable, H), 8.14 (d, J=8.87 Hz, 211), 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). 25 279 WO 2005/042712 PCT/US2004/035939 EXAMPLE 14 This compound was prepared according to the procedure provided in Example 13. OCH, 3 N F O 0 N H NMR (200 MHz, CDC1 3 ): d 12.2 (s, D20 exchangeable, 1H), 8.14 (d, J=8.87 Hz, 2H), 5 7.91-7.784 (m, 111), 7.75 (d, J= 8.6 JHz, 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 0 C. EXAMPLE 15 10 This compound was prepared according to the procedure provided in Example 13. OCHa | H O F o N O _ NH 0 1H NMR (200 MHz, CDCl 3 ): d 12.21 (s, D 2 0 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, 211), 6.44 (s, D20 exchangeable, 1H), 4.14 (s, 211), 3.82 (s, 3H), 3.35 (s, 2H), 2.5 (s, 3H). 15 Mp: 182-185 0 C. EXAMPLE 16 This compound was prepared according to the procedure provided in Example 13. S
N
0 N 0 0 0 20 'H NMR (200 MHz, CDC1 3 ): d 12.2 (s, D20 exchangeable, 1H), 8.13 (d, J=3.23 Hz, 11H), 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. 280 WO 2005/042712 PCT/US2004/035939 EXAMPLE 17 This compound was prepared according to the procedure provided in Example 13. S NH F O O~ 0 0 5 'H NMR (200 MHz, CDC1 3 ): d 12.31 (s, D 2 0 exchangeable, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.96 (d, J=5.1 Hz, IH), 7.85-7.77 (m, 11H), 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: 218-220 "C. EXAMPLE 18 10 This compound was prepared according to the procedure provided in Example 13. S 0 H 0 F O NH 0 - N 0 'H NMR (200 MHz, CDC1 3 ): d 12.1 (s, D 2 0 exchangeable, 1H), 8.08 (d, J=2.95 Hz, 111), 7.99 (d, J=4.83 Hz 2H), 7.91-7.78 (m, 111), 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, D 2 0 exchangeable, 1H), 4.33 (t, J=5.36 Hz, 2H), 3.59 (t, J=5.64 15 Hz, 2H), 2.62 (s, 3H). Mp: 218-219 *C. EXAMPLE 19 This compound was prepared according to the procedure provided in Example 13. F
N
0 1 F 0 -- SN O NH 20 'H NMR (200 MHz, CDCl 3 ): 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, 31H), 4.46 (s, 211), 4.21 (s, 211), 2.5 (s, 311). Mp: 262 265 OC. 281 WO 2005/042712 PCT/US2004/035939 EXAMPLE 20 This compound was prepared according to the procedure provided in Example 13. N F O S4 O NH 00 H NMR (200 MHz, CDC1 3 ): d 12.27 (s, D 2 0 exchangeable, 1H), 9.35 (s, 1H), 8.67 (d, 5 J=4.57 Hz, 1H), 8.48 (d, J=8.33 Hz, IH), 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. EXAMPLE 21 10 This compound was prepared according to the procedure provided in Example 13. O0NH 0 H NMR (200 MHz, CDC1 3 ): d 10.4 (bs, D 2 0 exchangeable, 1H), 8.06-8.00 (m, lH), 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. 15 EXAMPLE 22 This compound was prepared according to the procedure provided in Example 13. s o0 0 O NH 0 H NMR (200 MHz, CDC1 3 ): d 10.43 (bs, D 2 0 exchangeable, 1H), 8.15-8.07 (m, 2H), 7.96 20 (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. 282 WO 2005/042712 PCT/US2004/035939 EXAMPLE 23 This compound was prepared according to the procedure provided in Example 13. s o 0 o 1, ~. NH 0-0 'H NMR (200 MHz, CDCl 3 ): d 8.12 (bs, D 2 0 exch), 8.08-8.04 (in, 3H), 7.83-7.74 (in, 3H), 5 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 (in, 2H), 2.48 (s, 3H). Mp: 220-222*C. EXAMPLE 24 5-[1-(4-{2-[1-Methyl-4-oxo-2-(4-methylphenyl)-1,4-dihydro-3-quinolinyloxy]ethoxy) 10 phenyl)methylidene]-1,3-thiazolane-2,4-dione Me Me N o NH 0 A mixture of compound obtained in 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 15 (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 / CHC1 3 (5 L) to afford the title compound, 100 mg (54 /) as brown solid. Mp: 250-252 0 C. 20 'H NMR (200 MHz, CDC 3 ): d 12.5 (s, NH), 8.33 (d, 1H, J=8.2 Hz), 7.78 (in, 2H), 7.52-7.22 (in, 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). 283 WO 2005/042712 PCT/US2004/035939 EXAMPLE 25 This compound was prepared according to the procedure provided in Example 24. oO JO NH I 0 N
CH
3 'H NMR (200 MHz, CDC1 3 ): d 12.5 (s, NH), 8.34 (d, 1H, J=7.8 Hz), 7.78-7.47 (m, 11H), 5 6.90 (d, 2H, J=8.4 Hz), 4.23 (s, 2H), 3.99 (s, 2H), 3.47 (s, 311). Mp: 250-252 "C. EXAMPLE 26 This compound was prepared according to the procedure provided in Example 24.
CH
3 0 NH 0 0 N
CH
3 F 10 'H NMR (200 MHz, CDC1 3 ): 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 0 C. EXAMPLE 27 This compound was prepared according to the procedure provided in Example 24.
CH
3 o oS N 15 CH3 CH 3 H NMR (200 MHz, CDC1 3 ): d 12.25 (bs, NH), 8.34 (d, II, 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. 20 284 WO 2005/042712 PCT/US2004/035939 EXAMPLE 28 This compound was prepared according to the procedure provided in Example 24. 0 o
H
3 a N
H
3 C /\
HOH
3 CH3 'H NMR (200 MHz, CDC1 3 ): d 12.3 (NH, 1H), 8.33 (d, 1H, J=8.2 Hz), 7.77 (d, 2H, J=3.2 5 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. EXAMPLE 29 3-(4-{2-[2-(3,4-Dimethoxy-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-3-yloxy]-ethoxy} 10 benzoylamino)-2-(toluene-4-sulfonylamino)-propionic acid ethyl ester
O-CH
3
H
3 -0 N 0 O-CH, O 9
CH
3
H
3 C-O 0 HNSI 0 N 0OCH 3 0 0 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 15 (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 inmol) at 25-35 0 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 filtered, washed with water (2 x 20 mL) and dried under vacuum. The crude 20 product was purified further by crystallization from ethanol to give the desired product in 51 % yield (2.3 g). 285 WO 2005/042712 PCT/US2004/035939 'HNMR (CDC1 3 , 200 MHz) 7.73-7.65 (m, 5H), 7.25 (d, J= 8.8Hz, 2H), 6.88-6.73 (m, 4H), 6.52(d, J = 2Hz, 1H), 6.36 (d, J = 2Hz, 1H), 5.91 (d, J = 7.8Hz, D 2 0 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). 5 EXAMPLE 30 This compound was prepared according to the procedure provided in Example 29. 0 0 F NH 0 C . N OC 2
H
5 S' H HI NMR (CDC1 3 , 200 MHz) 10.06 (m, D 2 0 exchangeable, 1H), 8.82(s, 1H), 8.17-8.06 (m, 10 2H), 7.74 (d, J= 8.3Hz, 2H), 7.27-7.19 (m, 3H), 6.24 (d, J = 7.8Hz, D 2 0 exchangeable, 1H), 4.15-4.01 (m, 3H), 3.84-3.70 (m, 2H), 3.77-3.51 (m, IH), 2.31 (s, 3H), 1.41 (d, J= 6.3Hz, 1H), 1.25-1.13 (m, 5H). EXAMPLE 31 15 This compound was prepared according to the procedure provided in Example 29. OMe OMe C 0 0 o.NH 0 O OC 2 H6 MeO OMe N, O 'H H NMR (CDCl 3 , 200 MHz) 9.30 (bs, D 2 0 exchangeable, 1H), 7.76 (d, J 8.1Hz, 2H), 7.60 (d, J = 6Hz, 1H), 7.47 (s, 1H), 7.21 (d, J = 8.1Hz, 2H), 6.99 (d, J= 7.5Hz, 1H), 6. 76 (d, J= 9.0Hz, D 2 0 exchangeable, 1H), 6.53 (s, 11), 6.41 (s, 1H), 4.17 (m, 2H), 4.02-3.86 (m, 15H), 20 3.46-3.39 (m, 2H), 2.35 (s, 3H), 1.06 (t, J= 7.0Hz, 3H). 286 WO 2005/042712 PCT/US2004/035939 EXAMPLE 32 This compound was prepared according to the procedure provided in Example 29. OCH3 OCHa
N
0 o o cc O'- 1 H HNO, a K-r N CH 5 0 0 H' NMR (DMSO-d, 200 MHz), 8.32 (d, J 8.8Hz, 2H), 8.10 (d, J = 8.0Hz, IH), 7.80-7.50 5 (m, 7H), 7.28 (d, J = 7.8Hz, 2H), 7.03 (d, J 8.60Hz, 111), 6.85 (d, J= 8.3Hz, 2H), 4.43 (m, 2H), 4.37-4.26 (m, 2H), 4.07-4.03 (m, 2H), 3.79 (m, 8H), 3.47(m, 1H), 2.30(s, 3H), 0.95 (t, J = 7.3Hz, 3H). EXAMPLE 33 10 This compound was prepared according to the procedure provided in Example 29. cl c1
N
0 N o HN0 0 0 2
H
5 0 0 H' NMR (DMSO-d 6 , 200 MHz), 8.32 (d, J = 8.0Hz, 2H), 8.17 (d, J = 8.0Hz, 1H), 7.83 (d, J= 7.0Hz, 1H), 7.69-7.47 (m, 7H), 7.28 (d, J = 8.0Hz, 2H), 6.73 (d, J = 8.9Hz, 2H), 4.39 (bs, 2H), 4.07 (bs, 2H), 3.82-3.75 (m, 2H), 3.34 (m, 3H), 2.30 (s, 3H), 0.95 (t, J = 7.0Hz, 3H). 15 EXAMPLE 34 This compound was prepared according to the procedure provided in Example 29. SCH3 oHN 0 N H oc2H 0 0 20 H' NMR (CDCl 3 , 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, IH), 7.40 (t, J = 7.0Hz, 1H), 7.24 - 7.18 (m, 4H), 6.74 (d, J = 8.6 Hz, 2H), 6.64 (m, D 2 0 exchangeable, 1H), 5.69 (d, J = 7.3 Hz, D 2 0 exchangeable, 1H), 287 WO 2005/042712 PCT/US2004/035939 4.52 (m, 2H), 4.22 (i, 2H), 4.10 - 3.99 (m, 3H), 3.95 - 3.85 (m, 1H), 3.69 - 3.59 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.13 (t, J = 7.0Hz, 3H). EXAMPLE 35 5 This compound was prepared according to the procedure provided in Example 29. OCH3 OCHa H3CO 0 F F O O H HN'" OCH30 N OC 2 H5 0 0
H
1 NMR (CDC1 3 , 200 MHz), 7.87 - 7.84 (m, 1H), 7.70 - 7.64 (m, 3H), 6.93 - 6.72 (m, 5H), 6.53 (d, J = 3.0 Hz, 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= 7.0Hz, 3H). 10 EXAMPLE 36 This compound was prepared according to the procedure provided in Example 29. SCH, 0N ON OC2Hs N HI NMR (CDC1 3 , 200 MHz), 8.25 (d, J = 7.81 Hz, 1H), 8.13 (d, J = 8.8 Hz, 2H), 7.70 15 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, D 2 0 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). 20 EXAMPLE 37 This compound was prepared according to the procedure provided in Example 29. OCCo H2H H 0CM0 OCH310 N C,H, HN -, S 288 WO 2005/042712 PCT/US2004/035939 H' NMR (CDCl 3 , 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, IH), 6.36 (s, 1H), 5.99 (m, D 2 0 exchangeable, 1H), 5.62 (d, J = 7.7 Hz, D 2 0 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). 5 EXAMPLE 38 This compound was prepared according to the procedure provided in Example 29. MeD N NH COCH, ~ NN0 Meo))ND0 n ~~ 00o CH, H' NMR (CDCl 3 , 200 MHz) 7.67-7.59 (m, 3H), 7.26 - 7.23 (m, 3H), 7.15 - 7.10 (m, 3H), 10 6.84 (d, J =8.6 Hz, 2H), 6.01 (bs, D 2 0 exchangeable, 1H), 5.78 (bs, D 2 0 exchangeable, 1H), 4.39 - 4.30 (m, 4H), 3.98 - 3.88 (m, 10H), 3.60 - 3.36 (m, 3H), 2.38 (s, 3H), 1.06 (t, J = 7.0Hz, 3H). EXAMPLE 39 15 This compound was prepared according to the procedure provided in Example 29. 0 MeD N N O H OO2C 2 H, H NH CH, H' NMR (CDC 3 , 200 MHz) 8.30 (s, D 2 0 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). 20 EXAMPLE 40 This compound was prepared according to the procedure provided in Example 29. 0 Me NN CO2C2H MeO HN F 289 WO 2005/042712 PCT/US2004/035939 H' NMR (CDCI 3 , 200 MHz) 8.13 (s, IH), 7.89 - 7.78 (m, 1H), 7.69 (d, J = 8.0 1hz, 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 (ria, 4H), 4.21 - 4.17 (m, 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). 5 EXAMPLE 41 This compound was prepared according to the procedure provided in Example 29
OCH
3 OCH3 / N " ' NI H 'N N N 0COC 2
H
5 0 NH S / CH 3 H' NMR NMR (CDC13, 200MHz): d 8.09(d, 2H, J=8.8Hz), 7.58(d, 2H, J=8.3-1z), 7.26(m, 10 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). EXAMPLE 42 15 This compound was prepared according to the procedure provided in Example 29.
H
3 00, 0 0 HNH H C N_ \/ - CH 3 HCO N0 0 I COOC 2
H
5
NO
2 H' NMR (CDC13, 200MHz):d 12.0(bs, 1H), 8.
4 3(m, 3H), 7.9(m, 1H), 7.75(m, 2H), 7.55 7.10(m, 5H), 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). 20 290 WO 2005/042712 PCT/US2004/035939 EXAMPLE 43 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 Hac-OHO O-cH, H, c-O 0 HN H 00HO0 O N OH 0 0 5 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 K 2 C0 3 (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 10 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 mg). 'IHNMR (DMSO-d 6 , 200 MHz) 12.9 (bs, D 2 0 exchangeable, IH), 8.32 (s, D 2 0 exchangeable, 1H), 8.13 (d, J = 8.3Hz, 1H), 7.72-7.63 (m, 4H), 7.32 (d, J = 7.3Hz, 15 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). EXAMPLE 44 This compound was prepared according to the procedure provided in Example 43. OMe OMe O O O O0 A N'H O O OH MeO OMe 0,% N 20 S ' H' NMR (DMSO-d 6 , 200 MHz) d 12.9 (bs, D 2 0 exchangeable, 111), 8.32 (s, D 2 0 exchangeable, 1H), 8.13 (d, J = 8.3Hz, 1H), 7.72-7.63 (in, 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). 291 WO 2005/042712 PCT/US2004/035939 EXAMPLE 45 This compound was prepared according to the procedure provided in Example 43. 0 0 F N..,H 0H ci N TI OH N, 5 H'NMR (DMSO-d, 200 MHz): d 9.72 (bs, D 2 0 exchangeable, 111), 8.59 (s, 1H), 8.37(d, J = 6.2 Hz, 1H), 8.14 (d, J = 9.4Hz, 1H), 7.60 (d, J = 8Hz, 2H), 7.19 (d, J - 8.0Hz, 2H), 3.76 3.43 (in, 4H), 2.49 (s, 3H), 1.31(d, J= 6.Hz, 2H), 1.11 (s, 2H). EXAMPLE 46 10 5-[(E,Z)-1-(4-f{2-[5-(3,4-Dimethoxyphenyl)-1-methyl-7-oxo-3-propyl-6,7-dihydro-1H pyrazolo[4,3-d]pyrimidin-6-y]ethylamino}phenyl) ethylidene]1,3-thiazolane-2,4-dione N N\ N 0 MeO __ C) \ S NH MeO 0 A mixture of 1-(4-{2-[5-(3,4-dimethoxypheny)-1-methyl-7-oxo-3-propyl-6,7 dihydro-1IH-pyrazolo[4,3-d]pyrimidin-6-yl]ethylamino}phenyl)-1-ethanone obtained in 15 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 (0.84g, 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 brs under nitrogen atmosphere. The reaction mixture was cooled to 20 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 (1.51g, 2.56 mmol). Mp: 215-218 oC. IR: v max (KBr, cm-): 3380, 2956, 1679; 292 WO 2005/042712 PCT/US2004/035939 'H NMR (200 MHz, DMSO-d 6 ): 5 12.1(bs, D 2 0 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, 111), 6.70 (d, J= 8.59 Hz, 211), 6.53 (bs, D 2 0 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, 5 J= 7.25 Hz, 3H); Mass (ESMS): 589 (MH+, 100), Purity = 94.5 %. EXAMPLE 47 This compound was prepared according to the procedure provided in Example 43. NNH NNNH 10 H NMR: d 12.5(bs, D 2 0 exchangeable, 1H), 8.40-8.42 (m, 211), 7.75 (s, 1H), 7.59-7.50 (m, 5H), 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) 15 EXAMPLE 48 This compound was prepared according to the procedure provided in Example 46. N / N NS H' NMR: d 12.4 (bs, D 2 0 exchangeable, 111), 8.36 (m, 211), 7.48-7.31 (m, 7H), 4.94 (m, 211), 4.05 (s, 3H), 3.64 (m, 2H), 2.91 (m, 2H), 2.60 (s, 311), 1.85-1.82 (m, 2H), 0.98 (t, J = 6.84Hz, 20 3H) 293 WO 2005/042712 PCT/US2004/035939 EXAMPLE 49 This compound was prepared according to the procedure provided in Example 46. N NS OCR, HCO H' NMR: d 12.28 (bs, D 2 0 exchangeable, 1H), 7.93 (m, 211), 7.49-7.29 (m, 4H), 7.04 (d, J = 5 8.86Hz, 111), 4.93 (m, 2H), 4.04 (s, 31), 3.83 (s, 3H), 3.82 (s, 3H), 3.64 (m, 211), 2.90 (t, J = 7.52Hz, 2H), 2.59 (s, 3H), 1.89-1.78 (m, 2H), 0.96 (t, J =7.25Iz, 3H). EXAMPLE 50 This compound was prepared according to the procedure provided in Example 46. OEt o N N N 10 01NNO:O H NMR: d 7.95-7.90 (m, 211), 7.67 (s, 1H), 7.44-7.33 (m, 3H), 6.95 (d, J 8.63Hz, 2H), 4.65- 4.59 (m, 211), 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, 211), 1.30 (t, J = 6.99Hz, 311), 0.95 (t, J = 7.25Hz, 3H). 15 EXAMPLE 51 This compound was prepared according to the procedure provided in Example 46. N- N-'- 0 0 NH 0 _0 N-N 294 WO 2005/042712 PCT/US2004/035939 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, 311), 2.84 (t, J = 7.33Hz, 2H), 2.63 (s, 3H), 1.83-1.72 (m, 2H), 0.93 (t, J = 7.32Hz, 3H). EXAMPLE 52 5 This compound was prepared according to the procedure provided in Example 46. OCHa OCH3 0 0 N 0 (CHSNO N-N, H1 NMR: d 12.5 (bs, D 2 0 exchangeable, 111) 7.98 (d, J = 7.53Hz, 211), 7.72 (s, 111), 7.51 (d, J = 8.59Hz, 211), 7.08-7.01 (m, 311), 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 = 10 7.25Hz, 3H). EXAMPLE 53 This compound was prepared according to the procedure provided in Example 46. - NH 0 0 0 OCH N N | NCH
OCH
3 15 H NMR: d 12.52 (bs, D 2 0 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). 20 EXAMPLE 54 This compound was prepared according to the procedure provided in Example 46. 295 WO 2005/042712 PCT/US2004/035939
OCH
3
OCH
3 0 S 0 N-N. H' NMR: d 12.25 (bs, D 2 0 exchangeable, 1H), 8.01-7.96 (m, 2H), 7.42-6.97 (m, 5H), 5.02 (m, 2H), 4.56 (m, 2H), 4.07 (s, 31), 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). 5 EXAMPLE 55 This compound was prepared according to the procedure provided in Example 46. 00 0 0 f ,N N N' I N O s OcH 3 H' NMR: d 8.52 (bs, D 2 0 exchangeable, 111), 8.07 (d, J = 6.72Hz, 2H), 7.41-7.33 (m, 2H), 10 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, 311), 1.98-1.86 (m, 2H), 1.04 (t, J = 7.25Hz, 3H). EXAMPLE 56 5-[i-(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 0~ S,0 NH N K F
CH
3 F A mixture of compound 3-[2-(4-Acetyl-2-fluoro-phenoxy)-ethoxy]-2-(4-fluoro phenyl)-1-methyl-IH-quinolin-4-one (0.45 g, 1.0 mmol), 2,4-thiazolidenedione (0.703 g, 296 WO 2005/042712 PCT/US2004/035939 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 5 25*C and concentrated. The residue was purified by column chromatography using 1% MeOH-CHCl 3 to afford the title compound 209 mg (38%) as white solid. H NMR (200 MHz, DMSO-d): d 12.31 (bs, D 2 0 exchangeable, NH), 8.32 (d, J= 8.0 Hz, 1H), 7.79 (d, J = 3.2 Hz, 2H), 7.50-6.99 (in, 8H), 4.27 (s, 2H), 4.06 (s, 2H), 3.47 (s, 3H), 2.64 (s, 3H). 10 Mp: 220-222 'C EXAMPLE 57 5-[1-(3-Chloro-4-{2-[2-(2-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione 0 O~-~ NH N Ci
CH
3 15 F A mixture of compound 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 20 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. 25 'H NMR (200 MHz, DMSO-d 6 ): 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 (in, 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 297 WO 2005/042712 PCT/US2004/035939 EXAMPLE 58 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 0 0 ~ N 5
CH
3 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, 10 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 25oC and concentrated under vacuum. The residue was purified by column chromatography using 0-1% MeOH-CHC 3 to afford the title compound 24 g (50%) as light brown solid. 'H NMR (200 MHz, DMSO-d 6 ): d12.09 (bs,D 2 0 exchangeble, 1H), 8.34 (d, J=7.8Hz, 15 1H), 7.80 (d, J=3.4Hz, 2H), 7.53-7.22 (in, 7H), 6.82(d, J=8.2Hz, 2H), 4.23(s, 2H), 3.96(s, 2H), 3.48(s, 3H), 2.64 (s, 3H). Mp: 228-230'C EXAMPLE 59 20 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 NH e S o F OMe O0 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), 25 benzoic acid (0.27 g, 2.2 mmol), and piperidine (0.19 g, 2.23 mmol) was taken into a single 298 WO 2005/042712 PCT/US2004/035939 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 5 afford the title compound 0.38 g (63%) as off white solid. 'H NMR (200 MHz, DMSO-d 6 ): d 12.88 (bs, D 2 0 exchangeable, 1H), 7.89-7.71 (in, 5H), 7.28 (s, 1H), 7.06 (d, J = 8.6 Hz, IH), 6.96 (d, J = 7.5 Hz, 1H), 6.87 (d, J= 8.32 Hz, 1H), 6.75 (s, lH), 4.43 (s, 2H), 4.20 (s, 2H), 3.76 (s, 3H), 2.6 (s, 3H). Mp: 228-230 'C 10 EXAMPLE 60 5-[i-(4-{2-[2-(4-Chloro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] ethoxy)-phenyl)-ethylidene]-thiazolidine-2,4-dione 0 S 0 NH N
CH
3 C1 CICH3 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 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 20 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-CHC 3 to afford the title compound 0.73 g (30%) as light brown solid. 'H NMR (200 MHz, DMSO-d 6 ): 8.32 (d, J= 7.5 Hz, 1H), 7.79 (s, 2H), 7.97-7.32 (in, 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). 25 Mp: 238-240 "C 299 WO 2005/042712 PCT/US2004/035939 EXAMPLE 61 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 0 O0 N F o
CH
3 ' F HN-4\ 0 5 A mixture of compound 3-[2-(3-Acetyl-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-1 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 10 reflux for 72 hrs under 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=7.8Hz), 7.81 (s, 2H), 7.62-7.30 (in, 51), 6.95 (d, 1H, J = 7.8 Hz), 6.77 (d, 2H, J = 9.7Hz), 4.26 (s, 15 2H), 3.95 (s, 2H), 3.49 (s, 311), 2.64 (s, 3H). Mp: 236-240 'C EXAMPLE 62 5-[1-(4-{2-[1-Ethyl-2-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} 20 phenyl)-ethylidene]-thiazolidine-2,4-dione o 's -' ', N NH 0 o N F A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-l-ethyl-2-(4-fluoro phenyl)-H-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 300 WO 2005/042712 PCT/US2004/035939 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 column chromatography using MeOH-CHCl 3 to 5 afford the title compound 333 mg (45 %) as light brown solid. 'H NMR (200 MHz, DMSO-d6): d 12.09((bs, 1H, d20 exchangeble), 8.35(d, J=7.8Hz, 1H), 7.87-7.77 (in, 2H), 7.55-7.23 (in, 7H), 6.83 (d, J=8.7Hz, 2H), 4.23(s, 2H), 4.02-3.98(m, 411), 2.64(s, 3H), 1.16(t, J=6.8Hz, 311). Mp: 214-216 *C 10 EXAMPLE 63 5-[1-(4-{2-[2-(3,4-Difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} phenyl)-ethylidene]-thiazolidine-2,4-dione NN N F
CH
3 F 15 A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-l 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 reflux condenser. The reaction mixture was heated to 20 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 MeOH-CHCl 3 to afford the title compound 830 mg (39 %) as light brown solid. 'H NMR (200 MHz, DMSO-d6): d 12.24 (bs, NH, D 2 0 exchangeable), 8.32 (d, J = 8.0 Hz, 111), 7.81 (s, 211), 7.66-7.32 (in, 6H), 6.80 (d, J = 8.6 Hz, 211), 4.25 (s, 2H), 25 3.97 (s, 2H), 3.49 (s, 3H), 2.64 (s, 311). Mp: 248-250'C 301 WO 2005/042712 PCT/US2004/035939 EXAMPLE 64 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 0 S )= NH C1 N
CH
3 F 5 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 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 10 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, D 2 0 exchangeble, 1H), 8.32 (d, J = 15 7.5Hz, 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 EXAMPLE 65 20 5-[1-(4-{2-[2-(4-Fluoro-phenyl)-l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] ethylamino} -phenyl)-ethylidene]-thiazolidine-2,4-dione 0 0,- 0 N 0 NH H N
CH
3 / F A mixture of compound 3-[2-(4-Acetyl-phenylamino)-ethoxy]-2-(4-fluoro-phenyl)-1 methyl-1H-quinolin-4-one (0.4 g, 0.93 mmol), 2,4-thiazolidenedione (0.65 g, 5.6 mmol), 302 WO 2005/042712 PCT/US2004/035939 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 0 C and 5 concentrated. The residue was purified by column chromatography using 0-2% MeOH CHC1 3 to afford the title compound 200 mg (41%) as yellow solid. 'H NMR (200 MHz, DMSO-d6): d 8.61 (d, J = 8.3 Hz, 2H), 7.77 (t, J = 8.2 Hz, 2H), 7.56-7.19 (in, 6H), 6.56 (d, J = 8.3 Hz, 211), 5.99 (bs, NH), 3.94-3.92 (in, 2H), 3.53 3.41 (in, 4H), 3.18 (s, 2H), 2.68 (s, 3H). 10 Mp: 130-132 "C EXAMPLE 66 5-(4-{2-[2-(4-Fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} benzylidene)-thiazolidine-2,4-dione o - NH N 15
CH
3 F A mixture of compound 4-{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 20 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. 'H NMR (200 MHz, DMSO-d6): d 12.5 (s, NH, D 2 0 exchangeble), 8.35 (d, J=8.lHz, 25 1H), 7.81 (d, J = 3.2 Hz, 2H), 7.72 (s, 111), 7.51-7.47 (in, 511), 7.29-7.25 (in, 2 H), 6.88 (d, J= 8.6 Hz, 2H), 4.20 (s, 2H), 3.99 (s, 211), 3.50 (s, 3H). Mp: 225-228 *C 303 WO 2005/042712 PCT/US2004/035939 EXAMPLE 67 5-(4-{2-[2-(4-Bromo-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-ethoxy} benzylidene)-tbiazolidine-2,4-dione N " O NH N
CH
3 Br 5 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 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 10 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. H NMR (200 MHz, DMSO-d6): d 8.35 (d, J= 8.8 Hz, 1H), 7.87-7.39 (in, 1 LH), 6.89 (d, J= 8.7 Hz, 2H), 4.24 (bs, 2H), 4.01(bs, 4H), 1.16 (t, J= 6.8Hz, 3H). 15 Mp: 151-154 *C EXAMPLE 68 5-[1-(4-{2-[2-(5-Fluoro-2-methyl-phenyl)-l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] ethoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione 0 0~ I I N N F
H
3 C 20 H 3 C A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(5-fluoro-2-methyl phenyl)-l-methyl-lH-quinolin-4-one (0.25 g, 0.56 mmol), 2,4-thiazolidenedione (0.394 g, 3.37 mmol), benzoic acid (142 mg, 1.16 mmol), and piperidine (100 mg, 1.17 mmol) was taken into a single neck round bottom flask, to this toluene (50 mL) was added. The RBF 304 WO 2005/042712 PCT/US2004/035939 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-CHC 3 to afford the title compound 80 mg (26%) as brown solid. 5 'H NMR (200 MHz, DMSO-d6): d 12.30 (s, D 2 0 exchangeble, IH), 8.35 (d, J=7.8Hz, 1H), 7.80 (s, 2H), 7.47-7.16 (in, 5H), 6.96 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 9.1 Hz, 2H), 4.31-4.26 (in, 2H), 3.95 (in, 2H), 3.52 (s, 3H), 2.62 (s, 3H), 2.21 (s, 3H). Mp: 192-196 'C 10 EXAMPLE 69 5-[1-(3-{2-[2-(4-Fluoro-2-methyl-phenyl)-l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione 0 0 N O S
H
3 C F HN
H
3 C O A mixture of compound 3-[2-(3-Acetyl-phenoxy)-ethoxy]-2-(4-fluoro-2-methyl 15 phenyl)-l-methyl-1H-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-CHC 3 to afford the title compound 120 mg (39%) as brown solid. 'H NMR (200 MHz, DMSO-d6): d 11.22 (bs, 1H), 8.59 (d, J= 7.2 Hz, 1H), 7.76-6.63 (in, 10H), 4.45-4.26 (in, 211), 4.0-3.98 (in, 2H), 3.58 (s, 3H), 2.67 (s, 3H), 2.15 (s, 3H). 25 Mp: 225-226 *C 305 WO 2005/042712 PCT/US2004/035939 EXAMPLE 70 5-[1-(4-{3-[2-(4-Fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-propoxy) phenyl)-ethylidene]-thiazolidine-2,4-dione 0 I I N N I H3 F 0 s HN-\ 5 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 10 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-CHC 3 to afford the title compound 130 mg (27 %) as white solid. 'H NMR (200 MHz, DMSO-d6): d 12.27 (bs, NH, D 2 0 exchangeable), 8.30 (d, J 7.8 Hz, 1H), 7.81 (s, 2H), 7.55-7.3 (in, 7H), 6.88 (d, J = 7.8 Hz, 2H), 4.01 (s, 2H), 15 3.62 (s, 2H), 3.49 (s, 3H), 2.68 (s, 3H), 1.82 (s, 2H). Mp: 262-264 "C EXAMPLE 71 5-[1-(3-{3-[2-(4-Fluro-phenyl)-1 -methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy]-propoxy} 20 phenyl)-ethylidene]-thiazolidine-2,4-dione 0 0 0 S C I0
CH
3
-
F A mixture of compound 3-[3-(3-Acetyl-phenoxy)-propoxyj-2-(4-fluoro-phenyl)-1 methyl-IH-quinolin-4-one (0.45 g, 1.011 mmol), 2,4-thiazolidenedione (0.710 g, 6.06 25 mmol), benzoic acid (300 mg, 2.46 mmol), and piperidine (300 mg, 3.52 iniol) was taken 306 WO 2005/042712 PCT/US2004/035939 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% 5 MeOH-CHCl 3 to afford the title compound 187 mg (34 %) as light brown solid. 'H NMR (200 MHz, DMSO-d6): d 12.29 (NH, 1H), 8.31 (d, 1H, J = 7.8 Hz), 7.78 (s, 2H), 7.56-7.22 (in, 6H), 6.97 (d, 1H, J = 7.5Hz), 6.80 (d, 2H, J = 6.7 Hz), 3.99 (s, 2H), 3.58-3.55 (in, 2H), 3.46 (s, 3H), 2.66 (s, 3H), 1.79 (s, 2H). Mp: 168-170 *C 10 EXAMPLE 72 5-[1-(3-Chloro-4-f{3-[2-(4-fluoro-phenyl)-l-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] propoxy} -phenyl)-ethylidene]-thiazolidine-2,4-dione 0 N C1 CI C CH3 F 0 s HN-K 15 A mixture of compound 3-[3-(4-Acetyl-2-chloro-phenoxy)-propoxy]-2-(4-fluoro phenyl)-l-methyl-1H-quinolin-4-one (0.40 g, 0.86 mnnol), 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 (50 mL) was added. The RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was 20 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-CHC 3 to afford the title compound 140 mg (30 %) as light brown solid. IH NMR (200 MHz, DMSO-d6): d 12.31 (NH, IH), 8.32 (d, 1H, J= 7.8Hz), 7.80 (d, 2H, J = 2.9 Hz), 7.48-7.13 (in, 7H), 7.02 (d, 1H, J = 8.3 Hz), 4.29 (s, 2H), 4.07 (s, 25 2H), 3.47 (s, 3H), 2.64 (s, 3H), 1.82 (s, 2H). Mp: 232-234 C 307 WO 2005/042712 PCT/US2004/035939 EXAMPLE 73 5-[1-(4-{2-[7-Fluoro-2-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3-yloxy] ethoxy)-phenyl)-ethylidene]-thiazolidine-2,4-dione
CH
3 F F N O NH
CH
3 0 5 A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-7-fluoro-2-(4-fluoro phenyl)-1-methyl-IH-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 10 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 0.5-1% MeOH-CHCl 3 to afford the title compound 100 mg (21%) as brown solid. H NMR (200 MHz, DMSO-d6): d 12.24 (bs, 1H), 8.39 (t, J = 7.30 Hz, 1H), 7.67 (d, J= 11.8 Hz, IH), 7.52 (t, J= 8.30 Hz, 2H), 7.36 (t, J = 8.80 Hz, 5H), 6.82 (d, J = 8.8 15 Hz, 2H), 4.22 (s, 2H), 3.95 (s, 2H), 3.33 (s, 3H), 2.63 (s, 3H). Mp: 276-278 "C EXAMPLE 74 5-[1-(4-{2-[2-(3,4-Difluoro-phenyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinolin 20 3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione NH 0 0 F F N
CH
3 F A mixture of compound 3-[2-(4-Acetyl-phenoxy)-ethoxy]-2-(3,4-difluoro-phenyl)-7 fluoro-1-methyl-1H-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 308 WO 2005/042712 PCT/US2004/035939 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 C, filtered and washed with hot toluene. The solid was treated with toluene under reflux 5 for 10 hours, filtered, washed with hot MeOH and dried to afford the title compound 125 mg (26%) as white solid. 'H NMR (200 MHz, DMSO-d6): d 12.23 (s, 1H), 8.39 (t, J = 8.6 Hz, 1H), 7.68-7.32 (m, 7H), 6.81 (d, J= 8.6 Hz, 2H), 4.25 (s, 2H), 3.97 (s, 2H), 3.43 (s, 3H), 2.64 (s, 3H). 10 Mp: 270-272 C EXAMPLE 75 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 NH K I 0 N F F 15 FH 3 F A mixture of compound 3-[2-(4-Acetyl-2-fluoro-phenoxy)-ethoxy]-2-(3,4-difluoro phenyl)-l-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 20 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-CHCl 3 to afford the title compound 170 mg (35 %) as light brown solid. 'H NMR (200 MHz, DMSO-d6): d 12.29 (NH, 1H), 8.32 (d, 1H, J= 7.8 Hz), 7.80 (d, 25 2H, J - 2.9 Hz), 7.62-6.99 (in, 7H), 4.28 (s, 2H), 4.07 (s, 2H), 3.48 (s, 3H), 2.64 (s, 3H). Mp: 204-206 'C 309 WO 2005/042712 PCT/US2004/035939 EXAMPLE 76 5-[i-(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 0 Ci 0 0 NNH Ci' N 'sF
CH
3 F 5 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 10 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-CHC 3 to afford the title compound 150 mg (21%) as white solid. 1H NMR (200 MHz, DMSO-d6): d 12.21 (bs, D 2 0 exchangeable, NH), 8.30 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 7.62-7.30 (in, 611), 6.79 (d, J = 8.8 Hz, 2H), 4.24 (s, 2H), 15 3.94 (s, 2H), 3.45 (s, 3H), 2.62 (s, 3H). Mp: 296-298 *C EXAMPLE 77 5-[i-(3-Chloro-4-{2-[7-chloro-2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin 20 3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione -S NH C1 CIaNN F H3 /F A mixture of compound 3-[2-(4-Acetyl-2-chloro-phenoxy)-ethoxy]-7-chloro-2-(3,4 difluoro-phenyl)-1-methyl-lH-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) 310 WO 2005/042712 PCT/US2004/035939 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 5 MeOH-CHC 3 to afford the title compound 120 mg (20%) as white solid. IH NMR (200 MHz, DMSO-d6): d 12.25 (bs, D 2 0 exchangeable, NH), 8.26 (d, J 8.3 Hz, 1H), 7.86 (s, 1H), 7.46-7.19 (in, 6H), 6.99 (d, J = 8.8 Hz, LH), 4.20 (s, 2H), 4.02 (s, 2H), 3.39 (s, 3H), 2.57 (s, 3H). Mp: 140-142 'C 10 EXAMPLE 78 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 0 0~~N F o e NH F 0 N
CH
3 F 15 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 RBF was fitted with dean stark, which is connected to reflux condenser. The reaction mixture was 20 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-CHC 3 to afford the title compound 80 ing (16 %) as light brown solid. 'H NMR (400 MHz, DMSO-d): d12.27 (bs, D 2 0 exchangeable, NH), 8.35 (dd, J = 8.9, 7.0 Hz, 1H), 7.64 (d, J = 12 Hz, 1H), 7.55-7.47 (in, 3H), 7.39-7.23 (in, 3H), 7.04 25 (d, J= 8.6 Hz, 1H), 4.28-4.26 (in, 2H), 4.07-4.06 (in, 2H), 3.42 (s, 3H), 2.63 (s, 3H). Mp: 245-248 "C 311 WO 2005/042712 PCT/US2004/035939 EXAMPLE 79 5-[1-(3-Chloro-4-{2-[2-(3,4-difluoro-phenyl)-6-fluoro-1-methyl-4-oxo-1,4-dihydro-quinolin 3-yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione F NH Ct N
CH
3 F F 5 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 mmnol), 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 10 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-CHC 3 to afford the title compound 40 mg (8 %) as light brown solid. 'H NMR (400 MHz, DMSO): d12.27 (bs, D 2 0 exchangeable, NH), 8.40-8.33 (in, 111), 7.64 (d, J =12.0 Hz, 1H), 7.55-7.47 (in, 3H), 7.39-7.23 (in, 3H), 7.04 (d, J= 8.6 15 Hz, 1H), 4.30 (in, 2H), 4.08 (in, 2H), 3.42 (s, 3H), 2.63 (s, 3H). Mp: 215-218 *C EXAMPLE 80 5-[l-(3-Chloro-4-{2-[2-(3,4-difluoro-phenyl)-1-methyl-4-oxo-1,4-dihydro-quinolin-3 20 yloxy]-ethoxy}-phenyl)-ethylidene]-thiazolidine-2,4-dione F Me N F.. N' 0 0 S N O 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 imol), thiazolidine-2,4-dione (141 g, 1200 312 WO 2005/042712 PCT/US2004/035939 mmol), benzoic acid (44 g, 361 mmol) and piperidine (35 g, 411.7 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 5 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 / CHCl 3 to afford the title compound, 37 g (32%) as off white solid. 'H NMR (200 MHz, CDCI 3 ) 8 12.30 (s, 1H), 8.32 (m, 1H), 7.77 (in, 2H), 7.52 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H), 7.48 (d, J= 2.0 Hz, IH), 7.45 (in, 1H), 7.25 (in, 1H), 7.35 10 (dd, J= 10.0, 2.4 Hz, IH), 7.31 (dd, J= 8.4, 2.4 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 4.31 (dd, J= 3.4, 6.8 Hz, 2H), 4.09 (dd, J= 3.4, 6.8 Hz, 2H), 3.47 (s, 3H), 2.63 (s, 3H). Mp: 212-214"C EXAMPLE 81 15 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 MOO 0 We 0 Me O OMe I SA NH OMeO / N We 0 0 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 20 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 25 mg (34%) as white solid. 'H NMR (200 MHz, CDCl 3 ): d 8.38 (s, IH), 7.68-7.65 (in, 2H), 7.3-7.25 (in, 2H), 6.91-6.85 (in, 3H), 6.51 (s, 1H), 6.37 (s, 1H), 4.25-4.13 (in, 4H), 3.97-3.91 (in, 12H), 2.7 (s, 1H), 2.25-2.19 (in, 2H) Mp: 198-200'C 313 WO 2005/042712 PCT/US2004/035939 EXAMPLES 82-91 The following compounds are readily prepared by one of skill in the art using the processes set forth above: Example Compound 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-[L-(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)-ethylidene]-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)-propionic 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)-propionic acid ethyl ester 5 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 bromoketone see (a) J. MED. CHEM. 1996(39), 2939-2952; (b) J. HET. CHEM., 1972(9) 887; (b) INDIAN J. CHEM. SECT., 1990(29) 77; (c) TETRAHEDRON LETT., 10 1997(38) 3581; (d) CHEM. PHARM. BULL. 1992(40)1170). 314 WO 2005/042712 PCT/US2004/035939 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, 5 ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol, or any mixture thereof. Organic bases, for example, lysine, arginine, diethanolamine, choline, tromethamine, guanidine, or any derivative or mixture thereof, 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 10 toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, or any mixture thereof, in the presence of a solvent, for example, ethyl acetate, ether, alcohols, acetone, THF, dioxane, or any mixture thereof. The salts of amino acid groups and other groups may be prepared by reacting the compounds of 15 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 20 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. 25 Pharmaceutically acceptable solvates of compound of formula (I) forming part of this invention may be prepared by conventional methods 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 30 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. 315

Claims (48)

1. A compound of general formula (I) Ri R2 A L-Q 5 its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, Ri 2B\A R2 3y'J K' wherein R 3 L-Q is R 3 ,\A E R RK (1a) DK _ D~i ) i L- Q 1) R X ;or R3 ,\A E R' K (Ib) 10 2) R X -Y-G-C II wherein L is -Y-G=Z-Ar- , or -(CH 2 )t Y 1 F X'NR X 4 -S(O),-Ar -(CH 2 )v-X-(H 2 )pK- 2 C-0-R wherein Q is R 5 or X3 wherein R 1 , R 2 , and R 3 independently are hydrogen, a hydroxy group, a halogen, a 15 nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an allyl 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 316 WO 2005/042712 PCT/US2004/035939 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 5 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 R', R 2 , 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 0, S, or N; 10 wherein R 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, 15 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 20 aralkylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfmyl 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; 25 wherein A, B, D, and J independently are 0, S, N, >CH, or (CH 2 )n; wherein '----' is an optional chemical bond; wherein E is 0, S, or -NR; wherein K is N, C, or CH; wherein Y and Z independently are 0, -NR, (CH 2 )., or S(=O)u; 30 wherein G is -(CH 2 )s-, -(CH 2 )s-CH=CH-(CH 2 )s-, or -(CH2)s-C=C-(CH2)s-; wherein X, Xi, X 2 , X 3 , and X 4 independently are 0, S, or -NR; wherein F is 0, S, or -NR; 317 WO 2005/042712 PCT/US2004/035939 wherein Y and Y2 independently are 0 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 R 5 independently are hydrogen, potassium, sodium, a hydroxy group, 5 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. 10
2. The compound of claim 1, wherein any of R', R 2 , R 3 , and R 4 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 15 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, 20 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. 25
3. A compound of general formula (II) Y \A E R F NR SY-G=Z-Ar y2 R 3 ,R 5 x 318 WO 2005/042712 PCT/US2004/035939 its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R', R 2 and R 3 independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an 5 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 10 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 15 two of R 1 , R 2 , 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 0, 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 20 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 25 aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl 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 heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl 30 group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof; wherein A, B, D, and J independently are 0, S, N, >CH, or (CH 2 ),; 319 WO 2005/042712 PCT/US2004/035939 wherein '----' is an optional chemical bond; wherein E is 0, S, or -NR; wherein Y and Z independently are 0, -NR, (CH 2 )u, or S(=O)u; wherein G is -(CH 2 )s-, -(CH 2 ),-CH=CH-(CH 2 )s-, or -(CH2),-C=C-(CH2)s-; 5 wherein X is 0, S, or -NR; wherein F is 0, S, or -NR; wherein Y and Y2 independently are 0 or S; wherein n and u independently are an integer from 0-2; wherein s is an integer from 0-5; 10 wherein R and R 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 15 naphthyl group.
4. The compound of claim 3, wherein any of R1, R 2 , R, and R 4 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, 20 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 arylsulfiyl group, an alkylthio group, an 25 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, 30 an alkyl group, an alkoxy group, or an aryl group.
5. A compound of general formula (III) 320 WO 2005/042712 PCT/US2004/035939 0 RO-G-Z NR R (R" its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R', R 2 , and R 3 independently are hydrogen, a hydroxy group, a halogen, a 5 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 10 heteroaralkyl group, a heteroaryloxy group, a ieteroaralkoxy 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, 15 carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof, wherein any two of R1, R, and R 3 in combination optionally form a 5-member or 6-member saturated cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are 0, S, or N; wherein R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, 20 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 25 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, 321 WO 2005/042712 PCT/US2004/035939 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; 5 wherein '----' is an optional chemical bond; wherein E is 0, S, or -NR; wherein Z is 0, -NR, (CH 2 )u, or S(=O),; wherein G is -(CH 2 ),-, -(CH 2 ),-CH=CH-(CH 2 )s-, or -(CH2),-C=C-(CH2)s-; wherein u is an integer from 0-2; 10 wherein s is an integer from 0-5; wherein R and RW 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 15 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 cycloallyl group, an aryl group, a benzyloxy group, an acyl group, an acyloxy group, an aroyl group, an alkoxycarbonyl group, an 20 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. 25 6. The compound of claim 5, wherein any of R', R 2 , R3, and R 4 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 30 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 322 WO 2005/042712 PCT/US2004/035939 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, 5 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 10 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. 15
9. The compound of formula (III) as claimed in claim 5, wherein the compound is: 0 OMe 0 3 S 0 OMe 0N\- N Me :6 O o \ 00 O ~ O 0 H 3 C /\ OMe O NH 0 - CH 3 OMe 0 NH 0 MeO O OMe s I NH O o F N 0 ~~* 0 N OMe O C F o M e O N H 00 M O eO OHe N O~ee 0; CH, F 32 H 3 OMeO NF 323 WO 2005/042712 PCT/US2004/035939 MeO OMe MeG 0 ~ OMe O~e N 0ONH Oe 0 &N~eO~ 0e 0 -NH I ~s 0 -s I I 0 Ome 0 0 NH F ome MeO N 0 0 0 s- I I00 OMeO 0 - NH N N CH, 0 CH, , OMe OMe 0 5 e 0 F O e N 0 NH I~ 5 0 0 O~eG N I I cI N 0 F Me 0OMe 0 -s 0 I -_1 S4 0 OMeG 0 NH N- N1 0H F 324 WO 2005/042712 PCT/US2004/035939 OMe MeO N 0 N m 0 0 0 S NHN OMeO 0 NH 0 N OMe . N MeO N 0 N OMe 0, 0 N~ NN NNa N N OMeO 0 ~ a I 0o OH 3 F Oee 0 Me 0 N OMe 0H 0; OH O~e 0 CHNH I 0 F F 0 1 . NH N o OCH 3 Br 5 OCH 3 0)- 0~ - N N 0 NS 0 N N F 0' oN,0 H 3 0 0 i O C H 3 0 O - 0 N F -~ 0 N NN o 0 S I . NH HCH 00 H 3 C 0;C F 325 WO 2005/042712 PCT/US2004/035939 0 0 ~ NH0 0s 0 NHf 00 S\ '>-NH Nz -~ 0 s I 0 0 ' -Cl- 3 0 N N cI H 0 0*0 NH ~ F F Cl-I 3 F N 0 0NFjI 0 0 rs-NH 0 NH 0 CH 0 N N 0 N0 S N 0 0 N10 tr N F 0 ' 0 o0NH F N N 50F 0 Cl> 0\ N0 N1'-1 NH 00 0 INH N N 326 WO 2005/042712 PCT/US2004/035939 0 O S NH C1' F O CH 3 F O ' NH C' : C N 0 NH F MN Me N N O S NH3 O C" ' NH 5 Me Me~ 0 0 00 0 ~ sNO ' F O0 -- N NH 0 N H N O NH ;O OH 3 O 327 0 Me 0 " NH N FN N N ' I OH 0- F S OH 3 0 NH OH 3 MeW I~~ ~ NH N aN N sNH OH27 WO 2005/042712 PCT/US2004/035939 1 RE R 4 F N R G=-Z-Ar 2R x its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R' and R2 independently are hydrogen, a hydroxy group, a halogen, a nitro 5 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 10 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 arailcylsulfinyl group, an alkylsulfinyl group, an arylsulfmyl group, a heteroarylsulfinyl group, an aralkylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, 15 carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof, wherein any two of R 1 , R 2 , 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 0, 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, 20 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 25 heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, a heteroarylcarbonyl group, an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an alkylsulfmyl group, an arylsulfinyl group, an aralkylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfmyl group, an alkylthio group, 328 WO 2005/042712 PCT/US2004/035939 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, 5 wherein D and J independently are 0, S, N, >CH, or CH 2 ; wherein '---' is an optional chemical bond; wherein E is 0, S, or -NR; wherein K is N, C, or CH; wherein Z is 0, -NR, (CH 2 )u, or S(=O)u; 10 wherein G is -(CH 2 ))-, -(CH 2 ),-CH=CH-(CH 2 ),-, or -(CH 2 )s-C=C-(CH 2 )s-; wherein X is 0, S, or -NR; wherein F is 0, S, or -NR; wherein Y' and Y 2 independently are 0 or S; wherein u is an integer from 0-2; 15 wherein s is an integer from 0-5; wherein R and R 5 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 20 wherein 'Ar' is a substituted or unsubstituted phenyl or a substituted or unsubstituted naphthyl group.
11. The compound of claim 10, wherein any of R', R 2 , R 3 , and R 4 independently are substituted with hydrogen, a halogen, a nitro group, an amino group, a mono- or di 25 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 30 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 nitro group, an amino 329 WO 2005/042712 PCT/US2004/035939 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. 5
12. The compound of formula (IV) as claimed in claim 10, wherein the compound is: N N\ N O0N HN 00 MeOMeO S NH NS O 0 OCH 3 CaOCH N- N- (CHa ' N 'N N\ OCH3 N, OCH3 NN (C H 'N N-N NO, OCH, NN 10 0 o N 'N O 0CH3 N-N 10 FI'C0 330 WO 2005/042712 PCT/US2004/035939 NCH3 N XX ,N 00 OEt o\ N H N 0N ON N OHN 0;Nr -C~ or
13. A compound of general formula (V) R1 A E R4 XS(O Ar D- K-L CH 2 ) v X-CH 2 ) O-R X X3 5 its tautomeric forms, its stereoisomers, its polymorphs, its pharmaceutically acceptable salts, or its pharmaceutically acceptable solvates, wherein R', R 2 , and R 3 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 10 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 15 arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfinyl group, an alkylsulfinyl group, an arylsulfmyl 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 R', R2, and R 3 in combination optionally form a 5-member or 6-member saturated 20 cyclic ring having from 1 to 3 heteroatoms, wherein the heteroatoms are 0, S, or N; wherein R 4 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, 331 WO 2005/042712 PCT/US2004/035939 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 5 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 heteroarylsulfmyl group, an aralkylsulfinyl group, an alkylthio group, 10 an arylthio group, a heteroarylthio group, an aralkylthio group, an aryloxyalkyl group, an aralkoxyalkyl group, a fused heteroarylcycloalkyl group, a fused heteroarylcycloalkenyl group, a fused heteroarylheterocyclenyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof, wherein A, B, D, and J independently are 0, S, N, >CH, or (CH 2 )n; 15 wherein E is 0, S, or -NR; wherein K is N, C, or CH; -Y-G-C II wherein L is -Y-G--Z-Ar- X1 , or -(CH2)c-; wherein Y and Z independently are 0, -NR, (CH 2 )u, or S(=O)u; wherein G is -(CH 2 )s-, -(CH 2 )s-CH=CH-(CH 2 )s-, or -(CH 2 )s-C=C-(CH 2 )s-; 20 wherein X 1 , X 2 , X 3 , and X 4 independently are 0, S, or -NR; wherein X is 0, 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, 25 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. 30 332 WO 2005/042712 PCT/US2004/035939
14. The compound of claim 13, wherein any of R1, R 2 , R 3 , 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 5 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 arylsulfmyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, 10 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
15. The compound of formula (V) as claimed in claim 13, wherein the compound is: O-CH, H,C-O 'N 0 ' N NH CHC0 2 0H O NeO NN OC00 O O HO 0 N rO F):& e NeC0C o N'HH Me NOHeO NN C OO NO COO C2H 0o~ M. 0 N H 0 OMCH N OMO 0M eO'NOOCO2C0 0 0CH N NH - 0 '-r--MeO N C02C2Hs H MeO N O HN O M O OS F F, F 20 333 WO 2005/042712 PCT/US2004/035939 OCH, 0CH 3 0 0H N H 0 IN~ N -- ,N,_,COOCH-i NN 0 0 a H 3 00 0 0 0~~ NH HOO H, 0 0 NH HN~ COO 2 Hs 0CH 0 CO 2 q vo. O-CH, N 0 NN H0-0 0 -0 0 I O-CH l OCHN0 014 0 'N-0 N -- NO HNQ -CO N O 0 0 0 0 OMe 0 00H, ON ,_fi N H 0 -OCH, H 3 00 0 N F 'F OH S< N HN 4 MoOD OMe N OcI N 0 S0,H 0 o N 5 - 00H, 0 0N 0 0~ 0 O25cl N OH N-I 01-1 - N ;or OCH 3 . CH, H3CO 0 1 N ' 334 WO 2005/042712 PCT/US2004/035939
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. 5
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. 10 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. 15
20. The method of claim 19, wherein the pro-inflammatory cytokine comprises IL-6, IL 1, TNF-a, or MCP-1.
21. The method of claim 16, wherein the smooth muscle cell proliferation is inhibited by 20 inducing the expression of perlecan.
22. The method of claim 16, wherein the smooth muscle cell proliferation is mediated by a pro-inflammatory cytokine. 25 23. The method of claim 22, wherein the pro-inflammatory cytokine comprises IL-6, IL I, TNF-a, 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 30 composition comprising a therapeutically or prophylactically effective amount of a compound according to claim 1. 335 WO 2005/042712 PCT/US2004/035939
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. 5
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. 10
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, 15 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 20 mellitus, diabetic nepropathy, or diabetic retinopathy.
30. The method of claim 26, wherein the cell adhesion molecule is VCAM-l.
31. The method of claim 26, further comprising administering a therapeutically or 25 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 B blocker, a non-steroid antiinflamatory agent, a COX II inhibitor, a corticosteroid, a TNF-a modulating agent, a HMGCoA reductose inhibitor, a PPAR-? agonist, an HDL elevator, or a retinoid. 30 336 WO 2005/042712 PCT/US2004/035939
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. 5 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 10 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 15 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. 20
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. 25 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 inununosuppressive agent. 30 337 WO 2005/042712 PCT/US2004/035939
40. The method of claim 39, wherein the immunosuppressive agent is CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, Zenapax. 5 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, 10 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. 15
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 20 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. 25
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. 30 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. 338 WO 2005/042712 PCT/US2004/035939
48. The method of claim 47, wherein the disease mediated by inflammation is an autoimmune disease. 5 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, 10 cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barr6, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, lichen plans, m6niere's disease, mixed connective tissue disease, multiple sclerosis, 15 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, rhemnatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sj6grcn's syndrome, stiff-man syndrome, systematic lupus 20 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 25 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. 30 339 WO 2005/042712 PCT/US2004/035939
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. 5 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. 10 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. 15
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 anastomosis device, a vertebral disk, a bone pin, a suture anchor, a hemostatic barrier, a clamp, a screw, a plate, a clip, a 20 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 25 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. 30 340
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ES2199366T3 (en) * 1996-12-31 2004-02-16 Dr. Reddy's Laboratories Ltd. HETEROCICLICAL COMPOUNDS, PROCEDURE FOR THE PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND THEIR USE IN THE TREATMENT OF DIABETES AND RELATED ILLNESSES.
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US6028088A (en) * 1998-10-30 2000-02-22 The University Of Mississippi Flavonoid derivatives
US6608038B2 (en) * 2000-03-15 2003-08-19 Novartis Ag Methods and compositions for treatment of diabetes and related conditions via gene therapy
WO2005042712A2 (en) * 2003-10-28 2005-05-12 Reddy Us Therapeutics, Inc. Heterocyclic compounds and methods of making and using thereof

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EP1678157A2 (en) 2006-07-12
RU2006112343A (en) 2007-12-10
IL174249A0 (en) 2006-08-01
JP2008074858A (en) 2008-04-03
WO2005042712A2 (en) 2005-05-12
NO20061292L (en) 2006-07-28
KR20070026306A (en) 2007-03-08

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