EP1678157A2 - Composes heterocycliques, leurs procedes de fabrication et leur utilisation - Google Patents

Composes heterocycliques, leurs procedes de fabrication et leur utilisation

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Publication number
EP1678157A2
EP1678157A2 EP04817481A EP04817481A EP1678157A2 EP 1678157 A2 EP1678157 A2 EP 1678157A2 EP 04817481 A EP04817481 A EP 04817481A EP 04817481 A EP04817481 A EP 04817481A EP 1678157 A2 EP1678157 A2 EP 1678157A2
Authority
EP
European Patent Office
Prior art keywords
group
halogen
heterocyclyl
alkoxy
nitro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04817481A
Other languages
German (de)
English (en)
Other versions
EP1678157A4 (fr
Inventor
Yeleswarapu K. Fl. 202 Krishna Arcade RAO
Manojit Pal
Vedula Manohar Sharma
Akella Venkateswarlu
Ram Pillarisetti
Srinivas Padakanti
Kalleda Srinivasa Rao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Reddy US Therapeutics Inc
Original Assignee
Rao Yeleswarapu Koteswar
Reddy US Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rao Yeleswarapu Koteswar, Reddy US Therapeutics Inc filed Critical Rao Yeleswarapu Koteswar
Publication of EP1678157A2 publication Critical patent/EP1678157A2/fr
Publication of EP1678157A4 publication Critical patent/EP1678157A4/fr
Withdrawn legal-status Critical Current

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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • 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
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Definitions

  • the present invention relates to compounds, pharmaceutical compositions, and methods of making and use thereof.
  • Glycated proteins and advanced glycation end products 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 fo ⁇ nation of protein cross- links. Studies suggest that glycated protein and AGE interactions with cells promote inflammatory processes and oxidative cellular injury. AGE increases lipoprotein oxidisability and atherogenicity. Further, AGE binding to matrix proteins induces synthesis of IL-1, TNFa, VCAM-1, Heme oxygenase, insulin like growth factor, IL-6 and activates NF-?B.
  • glycated protein and AGE accumulation is a suspected etiological factor
  • diseases for which glycated protein and AGE accumulation is a suspected etiological factor include, but are not limited to, vascular complications of diabetes, microangiopathies, renal insufficiency, and Alzheimer's disease.
  • the exact mechanism by which high plasma glucose causes microvascular damage, as seen in diabetes, are not completely understood.
  • One potential mechanism by which hyperglycemia can be linked to microangiopathies is through the process of non-enzymatic glycation of critical proteins. Non-enzymatic glycation of critical proteins is discussed in Nonenzymatic glycosylation and the pathogenesis of diabetic complications, Ann. Intern.
  • Non-enzymatic glycation i.e., the linking of proteins with glucose
  • the first step in this glycation pathway involves the non- enzymatic condensation of glucose with free amino groups in the protein, primarily the epsilon-amino groups of lysine residues, forming the Amadori adducts.
  • These early glycation products can undergo furtl er reactions such as rearrangements, dehydration, and condensations to form irreversible advanced glycation end products (AGE).
  • AGE irreversible advanced glycation end products
  • Inhibitors of AGE formation have been shown to block the formation of AGE and prevent development of diabetes complications, including diabetic retinopathy (Aminoguanidine prevents diabetes- induced arterial wall protein cross-linking, Science, 1986(232)1629-1632; Prevention of cardiovascular and renal pathology of aging by the advanced glycation inhibitor aminoguanidine., Proc. Nati. Acad. Sci. U S A., 1996(93)3902-7; and Potential benefit of inhibitors of advanced glycation end products in the progression of type II diabetes: a study with aminoguanidine in C57/BLKsJ diabetic mice., Metabolism, 1998(47)1477-80.
  • AGE receptor receptor for AGE.
  • RAGE receptor for AGE.
  • Activation of receptor for advanced glycation end products a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis., Circ. Res. 1999(84)489-97; and Roles of the AGE-RAGE system in vascular injury in diabetes., Arm. 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 endothehal cell dysfunction in 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 endothehal receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothehal cells and in mice.
  • VCAM-1 vascular cell adhesion molecule-1
  • RAGE appears to mediate the binding of several other ligands that are involved in normal physiology as well as pathology. See Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases., Nature, 2000(405)354-60; RAGE mediates a novel proinflammatory axis: a central cell surface receptor for SlOO/calgranulin polypeptides., Cell., 1999(97)889-901; and Amyloid-beta peptide-receptor for advanced glycation end product interaction elicits neuronal expression of macrophage-colony stimulating factor: a proinflammatory pathway in Alzheimer disease., Proc. Nati. Acad.
  • 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 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.
  • the sequence of these signaling events leading to inflammation is not clear. Accordingly, what is needed are compounds that can block AGE-induced activities, particularly AGE-induced inflammation, or more particularly, AGE-induced signaling events.
  • SMC hyperplasia is an important factor in the development of atherosclerosis and also is responsible for the significant number of failure rates following vascular procedures such as angioplasty and coronary artery bypass surgery. See, The comparative pathobiology of atherosclerosis and restenosis. Am. J. Cardiol. 86:6H-11H (2000); and Restenosis: a challenge for pharmacology. Trends Pharmacol Sci. 21:274-9.
  • SMC Smooth muscle cell
  • 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.
  • vascular smooth muscles cell (VSMC) proliferation may contribute to the pathogenesis of vascular occlusive lesions, including atherosclerosis, vessel re-narrowing after successful angioplasty (restenosis), and graft atherosclerosis after coronary transplantation.
  • VSMC is discussed in The comparative pathobiology of atherosclerosis and restenosis. Am. J. Cardiol. 86:6H-11H; and Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 100:S87-9. Many humans and animals have limited lifespans and lifestyles because of such conditions.
  • PTCA Percutaneous coronary artery intervention
  • vascular occlusive lesions such as, but not limited to, arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after coronary transplantation. Identification of effective therapeutics with minimal side effects will restore quality of life without requiring additional surgical procedures such, as coronary artery bypass surgery.
  • Smooth muscle cell (SMC) hyperplasia is a major event in the development of atherosclerosis and also may contribute to failure rates following vascular procedures such as angioplasty and coronary artery bypass surgery.
  • SMC Smooth muscle cell
  • U.S. Patent No. 6,028,088 is directed to specific thiazolidinedione compounds, which are described as antiproliferative, anti-inflammatory and antiinfective agents. According to the disclosure, these specific compounds are used in the treatment of certain endocrine diseases, malignant, and non-malignant proliferative diseases, and cardiovascular disorders.
  • 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 invention also is directed to methods and/or compositions comprising compounds that are effective in modulating smooth muscle cell proliferation and the diseases or conditions related thereto.
  • the present invention provides compounds and compositions that inhibit inflammatory responses, particularly those resulting from AGE and glycated protein accumulation. Further, the present invention provides compounds and compositions that inhibit smooth muscle cell proliferation, which may be mediated by pro-inflammatory cytokines like IL-6, IL-1, TNF-a, MCP-1, or by inducing the expression of perlecan, a heparin sulfate proteoglycan (HSPG).
  • cytokines like IL-6, IL-1, TNF-a, MCP-1
  • HSPG heparin sulfate proteoglycan
  • the present invention provides novel compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of such compounds, optionally in combination with other active ingredients.
  • the present invention also provides a process for preparing compounds of the formula (I) as defined above, their salts, and pharmaceutically acceptable compositions thereof.
  • the present invention also provides novel compounds of formula (II), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of such compounds, optionally in combination with other active ingredients.
  • the present invention also provides a process for preparing compounds of the formula (II) as defined above, their salts, and pharmaceutically acceptable compositions thereof.
  • the present invention also provides novel compounds of formula (III), including but not limited to, their pharmaceutically acceptable salts and pharmaceutical compositions containing them, or their mixtures, or in combination with other active ingredients.
  • the present invention also provides a process for preparing compounds of the formula (III) as defined above, their salts, and pharmaceutically acceptable compositions thereof.
  • the present invention also provides novel compounds of formula (IV), their pharmaceutically acceptable salts, and pharmaceutical compositions containing one or more of such compounds, optionally in combination with other active ingredients.
  • the present invention also provides a process for preparing compounds of the 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.
  • 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.
  • a method of using a compound of formula (I) comprises treatment and/or prophylaxis of inflammatory conditions, such as those mediated by AGE or glycated protein accumulation.
  • inflammatory conditions include diabetic vascular complications, including diabetic retinopathy, microangiopathies, renal insufficiency and Alzheimer's disease.
  • a method of inhibiting smooth muscle cell proliferation comprises administering an effective amount of a compound contemplated hereby.
  • the present invention also provides methods for inhibiting an inflammatory response, including inflammatory responses in endothehal 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.
  • the present invention also provides a method for treating or preventing organ transplant vasculopathy in a subject comprising the step of administering a therapeutically effective amount of a compound contemplated hereby.
  • the transplanted organ may include, but is not limited to, liver, kidney, heart, lung, pancreas, pancreatic islets, and skin.
  • Such a method may further comprise the step of administering a therapeutically effective amount of an immunosuppressive agent.
  • the immunosuppressive agent may include, but is not limited to, CellCept, Gengraf, Micrhogam, Neoral, Orthoclone OKT3, Prograf, Rapamune, Sandimmune, Thymoglobulin, and Zenapax.
  • the present invention also provides a method for treating or preventing restenosis in a subject comprising administering a therapeutically effective amount of a compound contemplated hereby.
  • the present invention also provides a method for treating or preventing atherosclerosis in a subject comprising administering a therapeutically effective amount of a compound contemplated hereby.
  • the present invention also provides a method for treating disease mediated by inflammation in a subject comprising the step of administering a therapeutically effective amount of a compound contemplated hereby.
  • the disease mediated by inflammation may be an autoimmune disease.
  • the autoimmune disease may be alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-f ⁇ bromyositis, Graves' disease, Guill
  • the present invention further provides a method for treating or preventing cancer in a subject comprising administering a therapeutically effective amount of a compound contemplated hereby. Moreover, the present invention provides a method for treating or preventing metastases in a subject comprising administering a therapeutically effective amount of a compound contemplated hereby to the subject.
  • Still another aspect of the present invention provides the methods, by using compound of formula (I), which also comprises treatment and/or prophylaxis of proliferative conditions, particularly for inhibition of proliferation of smooth muscle cells, comprising administration of compositions comprising compounds of formula (I).
  • uses of such compositions comprise prevention and treatment of vascular occlusive conditions including atherosclerosis and restenosis.
  • the present invention further provides pharmaceutical compositions containing compounds of the general formula (I), their salts, or any mixture thereof in combination with a suitable carrier, solvent, diluent, or medium typically employed in preparing such compositions.
  • the present invention provides various compounds and compositions that each may be administered by a route that is oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, mtracartilaginous, intracavitary, intracelial, intracelebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.
  • a route that is oral, parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, mtracart
  • 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, 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).
  • the formulations are prepared by unifonnly and intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Still yet another aspect of the present invention provides novel intermediates, a process for their preparation and use of the intermediates in processes for preparation of compound of formula (I), their salts, and pharmaceutically acceptable compositions thereof.
  • the term "compound” includes both the singular and the plural, and includes any single entity or combined entities that have activity that can be measured in the assays of the present invention and combinations, fragments, analogs or derivatives of such entities.
  • glycated protein 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, as used herein, includes not only proteins containing these initial glycation products, but also glycation products resulting from further reactions such as rearrangements, dehydration, and condensations that form irreversible advanced glycation. end products (AGE). It should be understood that any agent that causes the cells or components of the assay to respond in a measurable manner is contemplated by the present invention.
  • 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.
  • diabetes-related complications can be reduced by (1) preventing glycation of proteins, (2) by breaking the cross-links in glycated proteins (The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end- product accumulation., Diabetologia., 2000(43)660-4) (or (3) by blocking glycated protein interaction with receptors.
  • phenylamine refers to a primary or secondary benzeneamine, more commonly known as aniline.
  • the amino group on the aniline may be optionally substituted with hydrogen, alkyl (Cj-C ⁇ 2 , straight chain or branched), cycloalkyl (C 3 - 0 ), 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 amino, acyl, carboxyl, 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.
  • naphthylamine refers to a primary or secondary a- or ⁇ -naphthylamine.
  • 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, thlomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazoyl, phosphate, phosphonic acid, or phosphonate.
  • naphthylalkyl amine refers to a primary or secondary a- and ⁇ - naphthylalkyl amine (for example, 2-a-naphthylethyl amine).
  • benzalkyl amine refers to a primary or secondary benzylalkyl amine (for example, phenylethyl amine). These aryl alkyl substructures or compounds can be optically active or optically inactive.
  • the aryl (ring) substructures of the naphthylalkyl and benzalkyl amines can be optionally subsituted with one or a combination of functional groups, such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, 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 protected or unprotected forms used in standard organic synthesis.
  • 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, 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
  • 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, alkyltl io, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, thiomorpholino, piperazinyl, phosphate, phosphonic acid, or phosphonate.
  • functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, hal
  • polynucleotide refers generally to polymeric forms of nucleotides of any length, either ribonucleotides or deoxynucleotides. Thus, this term includes, but is not limited to, single-stranded, double-stranded, or 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.
  • a polynucleotide may comprise, in part, modified nucleotides such as methylated nucleotides or nucleotide analogs.
  • Polynucleotides also may comprise sugars, caps, nucleotide branches, and linking groups such as fluororibose and thioate.
  • the sequence of nucleotides may be interrupted by non-nucleotide components.
  • 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 sugar and/or phosphate groups.
  • 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 ah, NUCL. ACIDS RES. (1996) 24:2318-2323.
  • a partially complementary sequence is one that at least partially inhibits an identical sequence from hybridizing to a target polynucleotide; it is referred to using the functional term "substantially homologous".
  • the inhibition of hybridization of the completely complementary sequence to the target sequence may be examined using a hybridization assay (Southern or Northern blot, solution hybridization) under conditions of low stringency.
  • a substantially homologous sequence or probe will compete for and inhibit the binding (i.e., the hybridization) of a completely homologous sequence or probe to the target sequence under conditions of low stringency.
  • low stringency conditions require that the binding of two sequences to one another be a specific (i.e., selective) interaction.
  • the absence of non-specific binding may be tested by the use of a second target sequence which lacks even a partial degree of complementarity (for example, less than about 30% identity); in the absence of non-specific binding, the probe will not hybridize to the second non-complementary target sequence.
  • the term "gene” refers to a polynucleotide sequence that comprises coding sequences necessary for the production of a polypeptide or precursor, and also may include expression control sequences.
  • the polypeptide can be encoded by a full length coding sequence or by any portion of the coding sequence.
  • the gene may be derived in whole or in part from any source known to those of ordinary skill in the art including a plant, a fungus, an animal, a 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.
  • a gene may contain one or more modifications in either the coding or the untranslated regions that could affect certain properties of the polynucleotide or polypeptide, such as the biological activity or the chemical structure of the expression product, the rate of expression, or the manner of expression control.
  • Such modifications include, but are not limited to, mutations, insertions, deletions, and substitutions of one or more nucleotides.
  • modified genes may be referred to as "variants” of the "native” gene (dis ussed 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.
  • gene expression profile refers to a group of genes representing a particular cell or tissue type (for example, neuron, coronary artery endothelium, or disease tissue) in any activation state. In one aspect, a gene expression profile is generated from cells exposed to a compound of the present invention.
  • This profile may be compared to a gene expression profile generated from the same type of cell prior to treatment with a compound of the present invention. 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.
  • differential expression refers to both quantitative as well as qualitative differences in the temporal and tissue expression patterns of a gene.
  • a differentially expressed gene may have its expression activated or completely inactivated in normal versus disease conditions.
  • Such a qualitatively regulated gene may exhibit an expression pattern within a given tissue or cell type that is detectable in either control or disease conditions, but is not detectable in both.
  • “Differentially expressed polynucleotide”, as used herein, refers to a polynucleotide sequence that uniquely identifies a differentially expressed gene so that detection of the differentially expressed polynucleotide in a sample is conelated with the presence of a differentially expressed gene in a sample.
  • differentially expressed protein may have its expression activated or completely inactivated in normal versus disease conditions. Such a qualitatively regulated protein may exhibit an expression pattern within a given tissue or cell type that is detectable in either control or disease conditions, but is not detectable in both.
  • a "differentially expressed protein”, as used herein, refers to an amino acid sequence that uniquely identifies a differentially expressed protein so that detection of the differentially expressed protein in a sample is correlated with the presence of a differentially expressed protein in a sample.
  • Cell type refers to a cell from a given source (for example, tissue or organ), a cell in a given state of differentiation, or a cell associated with a given pathology or genetic makeup.
  • 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.
  • polypeptide refers to proteins, polypeptides, and peptides of any size, structure, or function.
  • 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.
  • a polypeptide also may comprise a fragment of a naturally occurring protein or peptide.
  • a polypeptide may be a single molecule or may be a multi-molecular complex. In addition, such polypeptides may have modified peptide backbones as well.
  • polypeptide further comprises immunologically tagged proteins and fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence, fusion proteins with heterologous and homologous leader sequences, and fusion proteins with or without N-terminal methionine residues.
  • 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.
  • protein expression profile refers to a group of proteins representing a particular cell or tissue type (for example, neuron, coronary artery endothelium, or disease tissue).
  • 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.
  • a series of protein expression profiles may be generated from cells treated with a compound of the present invention, specifically, at different doses or a time-course to assess the effects of the compound.
  • a protein expression profile also is known as a "protein expression signature".
  • a "biomolecule” includes polynucleotides and polypeptides.
  • a "biomolecular sequence” is a term that refers to all or a portion of a polynucleotide sequence.
  • a biomolecular sequence also may refer to all or a portion of a polypeptide sequence.
  • a "host cell” as used herein refers to a microorganism, a prokaryotic cell, a eukaryotic cell or cell line cultured as a unicellular entity that may be, or has been, used as a recipient for a recombinant vector or other transfer of polynucleotides, and includes the progeny of the original cell that has been transfected. It is understood that the progeny of a single cell may not necessarily be completely identical in morphology or in genomic or total DNA complement as the original parent due to natural, accidental, or deliberate mutation.
  • the term “functional equivalent” refers to a protein or polynucleotide molecule that possesses functional or structural characteristics that are substantially similar to all or part of the native Perlecan protein or native Perlecan-encoding polynucleotides.
  • a functional equivalent of a native Perlecan protein may contain modifications depending on the necessity of such modifications for a specific structure or the performance of a specific function.
  • the term “functional equivalent” is intended to include the "fragments”, “mutants”, “derivatives”, “alleles”, “hybrids”, “variants”, “analogs”, or “chemical derivatives", of native Perlecan.
  • the term “functional equivalent” refers to immunoglobulin molecules that exhibit immunological binding properties that are substantially similar to the parent immunoglobulin.
  • 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.
  • a functional equivalent of a monoclonal antibody immunoglobulin may inhibit 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.
  • isolated refers to a polynucleotide, a polypeptide, an antibody, or a host cell that is in an environment different from that in which the polynucleotide, the polypeptide, the antibody, or the host cell naturally occurs.
  • An isolated polynucleotide, polypeptide, antibody, or host cell is generally substantially purified.
  • 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, 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.
  • composition containing A is "substantially free of B when at least about 85% by weight of the total A+B in the composition is A.
  • A comprises at least about 90% by weight of the total of A+B in the composition, further still, at least about 95% or even 99% by weight.
  • Diagnosis as used herein, generally includes a determination of a subject's susceptibility to a disease or disorder, a determination as to whether a subject is presently affected by a disease or disorder, a prognosis of a subject affected by a disease or disorder (for example, identification of pre-metastatic or metastatic cancerous states, stages of cancer, or responsiveness of cancer to therapy), and therametrics (for example, monitoring a subject's condition to provide information as to the effect or efficacy of therapy).
  • biological sample encompasses a variety of sample types obtained from an organism which may be used in a diagnostic, monitoring, or other assay.
  • the term encompasses blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen, or tissue cultures or cells derived therefrom and the progeny thereof.
  • the term specifically encompasses a clinical sample, and further includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, urine, amniotic fluid, biological fluids, and tissue samples.
  • samples that have been manipulated in any way after procurement such as treatment with reagents, solubilization, or enrichment for certain components.
  • the terms “individual”, “subject”, “host”, and “patient” refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired.
  • the individual, subject, host, or patient is optionally a human.
  • Other subjects may include, but are not limited to, cattle, horses, dogs, cats, guinea pigs, rabbits, rats, primates, and mice.
  • treatment used herein to refer generally to obtaining a desired pharmacological and/or physiologic effect.
  • the effect may be 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 covers airy treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom, but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.
  • terapéuticaally effective amount refers to an amount of, for example, a compound contemplated hereby, that is effective for preventing, ameliorating, treating, or delaying the onset of a disease or condition.
  • prophylactically effective amount refers to an amount of, for example, a compound contemplated hereby that is effective for preventing a disease or condition.
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant, which is useful for delivery of a drug to a mammal.
  • the compounds of the present invention may be delivered by a liposome.
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • Hybridization refers to any process by which a polynucleotide 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 under certain conditions, such as normal physiological conditions.
  • 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.
  • 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.
  • the biological activity of a protein may be affected by changes at the molecular level.
  • an antisense ohgonucleotide may prevent translation of a particular mRNA, thereby inhibiting the biological activity of the protein encoded by the mRNA.
  • an antibody may bind to a particular protein and inhibit that protein's biological activity.
  • the term "ohgonucleotide” 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 ohgonucleotide may be a naturally occurring ohgonucleotide or a synthetic ohgonucleotide.
  • Oligonucleotides may be prepared by the phosphoramidite method (Beaucage and Carruthers, TETRAHEDRON LETT. (1981) 22:1859- 1862), or by the triester method (Matteucci et al., J. AM. CHEM. SOC. (1981) 103:3185), or by other chemical methods known in the art.
  • microarray refers generally to die type of genes or proteins represented on a microarray by oligonucleotides (polynucleotide sequences) or protein-binding agents, and where the type of genes or proteins represented on die 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 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).
  • one microarray type may be a "cancer microarray” in which each of the microarray oligonucleotides or protein-binding agents conespond to a gene or protein associated with a cancer.
  • An "epithelial microarray” may be a microarray of oligonucleotides or protein-binding agents corresponding to unique epithelial genes or proteins.
  • a "cell cycle microarray” may be an microarray type in which the oligonucleotides or protein-binding agents correspond to unique genes or proteins associated with the cell cycle.
  • the term “detectable” refers to a 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 those of skill in the art.
  • 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 ohgonucleotide probe is designed specifically to hybridize. It is either the presence or absence of the target polynucleotide that is to be detected, or the amount of the target polynucleotide 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 mRNA) whose expression levels it is desired to detect.
  • 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 conesponding 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.
  • complementary refers to the topological compatibility or matching 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 ohgonucleotide probe and a target are complementary.
  • 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.
  • background refers to hybridization signals resulting from non-specific binding, or other interactions, between the labeled target polynucleotides and components of the ohgonucleotide microanay (for example, the ohgonucleotide probes, control probes, the microarray support) or between target proteins and the protein-binding agents of a protein microanay. Background signals also may be produced by intrinsic fluorescence of the microarray components themselves. A single background signal may be calculated for the entire microanay, or a different background signal may be calculated for each target polynucleotide or target protein.
  • the background may be calculated as the average hybridization signal intensity, or where a different background signal is calculated for each target gene or target protein.
  • 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 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 microanay which lack any probes or protein-binding agents at all.
  • a "small molecule” refers to a compound or molecular complex, either synthetic, naturally derived, or partially synthetic, composed of carbon, hydrogen, oxygen, and nitrogen, that also may contain other elements, and that may have a molecular weight of less than about 15,000, less than about 14,000, less than about 13,000, less than about 12,000, less than about 11,000, less than about 10,000, less than about 9,000, less than about 8,000, less than about 7,000, less than about 6,000, less than about 5,000, less than about 4,000, less than about 3,000, less than about 2,000, less than about 1,000, less than about 900, less than about 800, less than about 700, less than about 600, less than about 500, less than about 400, less than about 300, less than about 200, or less than about 100.
  • fusion protein refers to a protein composed of two or more polypeptides that, although typically not joined in their native state, are joined by their respective amino and carboxyl termini through a peptide linkage to form a single continuous polypeptide. It is understood that the two or more polypeptide components can either be directly joined or indirectly joined through a peptide linker/spacer.
  • normal physiological conditions means conditions that are typical inside a living organism or a cell. Although some organs or organisms provide extreme conditions, 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 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.
  • cluster refers to a group of clones or biomolecular sequences related to one another by sequence homology. In one example, clusters are formed based upon a specified degree of homology and/or overlap (for example, stringency). “Clustering” may be performed with the sequence data. For instance, a biomolecular sequence thought to be associated with a particular molecular or biological activity in one tissue might be compared against another library or database of sequences. This type of search is useful to look for homologous, and presumably functionally related, sequences in other tissues or samples, and 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 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 private database behind a firewall within an ente ⁇ rise 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 ente ⁇ rise that maintains the database, and also may include sequence data obtained from external sources.
  • external database refers to a database located outside all internal databases.
  • an ente ⁇ rise network differing from the ente ⁇ rise 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.
  • the external database may be GenBank and associated databases maintained by the National Center for Biotechnology Information (NCBI), which is part of the National Library of Medicine. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention is directed to compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymo ⁇ hs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. Further, the present invention is directed to pharmaceutical compositions comprising compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymo ⁇ hs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, either individually or in any combination thereof.
  • the present invention is directed to methods of use of compounds of general formula (I), its analogs, tautomeric forms, regioisomers, stereoisomers, polymo ⁇ hs, 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, polymo ⁇ hs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.
  • 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 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.
  • R , R", and R independently are hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkoxy group, a heterocyclyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, a heteroaryloxy group, a heteroaralkoxy group, an alkoxycarbonyl group, an aryloxycarbonyl
  • the cyclic ring formed by any two of R 1 , R 2 , or R 3 may be oxlanyl, 1,3-dioalanyl, or 1,4- dioxalanyl.
  • 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 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
  • 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.
  • 'Halogen' is fluorine, chlorine, bromine, or iodine
  • 'Alkyl' group is a linear or branched (C ⁇ -C ⁇ o)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.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • 'Alkoxy' is ( -C ⁇ o)alkyl-O-, wherein the (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • exemplary alkyl groups include methoxy, ethoxy, propoxy, butoxy, iso-propoxy.
  • 'Cycloalkoxy' is a (C 3 -C 6 )cycloalkoxy group.
  • exemplary cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy.
  • 'Alkenyl' is a (C 2 -C 6 )alkenyl group.
  • Exemplary alkenyl groups include efhenyl, propenyl, butenyl, pentenyl, hexenyl.
  • 'Cycloalkenyl' is (C 3 -C 7 )cycloalkenyl group.
  • exemplary cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl.
  • 'Alkoxyalkyl' is a (C ⁇ -C6)alkoxy(C ⁇ -C ⁇ o)alkyl group, where alkoxy and alkyl groups are as defined above.
  • alkoxyalkyl groups include methoxymethyl, methoxyethyl, med oxypropyl, ethoxymethyl, ethoxyethyl.
  • 'Alkenyloxy' is (C 2 -C 6 )alkenyl-O-, where the (C 2 -Ce)alkenyl group is as defined above.
  • Exemplary alkenyl groups include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy.
  • 'Cycloalkenyloxy' is a (C 3 -C )cycloalkenyl-O-, where the (C 3 -C 7 )cycloalkenyl group is as defined above.
  • Exemplary cycloalkenyloxy groups include cycloethenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy.
  • 'Acyl' is H-CO- or (C ⁇ -C ⁇ o)alkyl-CO-, where (C ⁇ -Cjo)alkyl group is as defined above.
  • Exemplary acyl groups include
  • 'Acyloxy' is (C]-C 6 )acyl-O-, where acyl group is as defined above.
  • exemplary acyloxy groups include acetyloxy, propionyloxy.
  • 'Aryl' is monocylic or polycyclic ring system of about 5 to 14 carbon atoms.
  • Exemplary groups include phenyl, naphthyl.
  • 'Aryloxy' is an aryl-O- group, where the aryl group is as defined above.
  • exemplary aryloxy groups include phenoxy, naphthyloxy.
  • 'Aroyl' is the aryl-CO- group, wherein the aryl group is as defined above.
  • exemplary 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-(C ⁇ -C ⁇ o)alkyl group, wherein aryl and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • exemplary aralkyl groups include benzyl, 2-phenylethyl.
  • 'Aralkenyl' is aryl-(C 2 -C 6 )alkenyl group, wherein aryl and (C -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.
  • exemplary aralkoxy groups include benzyloxy, 2-phenethyloxy.
  • Heterocyclyl' is a non-aromatic saturated monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one hetero atom selected from O, S or N.
  • exemplary heterocyclyl groups include aziridinyl, pynolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl.
  • '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 O, S or N and one double bond.
  • exemplary heterocyclenyl groups include 1,2,3,4- tefrahydropyrimidine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tefrahydropyrimidine, 2-pyrrolinyl, 3-pynolinyl, 2-imidazolinyl, 2-pyrazolinyl.
  • 'Heteroaryl' is an aromatic monocyclic or polycyclic ring system of about 5 to about
  • heteroaryl groups include as pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furyl, indolyl, isoindolyl, 1,3-benzodioxole, 1,3-benzoxathiole, quinazolinyl, pyridyl, thiophenyl.
  • Heteroaralkyl' is a heteroaryl-(Cj-C]o)alkyl group, wherein the heteroaryl and ( - C ⁇ o)alkyl groups are as defined above.
  • exemplary heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmetiiyl.
  • Heteroaryloxy' is heteroaryl-O-, wherein the heteroaryl group is as defined above.
  • exemplary heteroaryloxy groups include pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, phthalazinyloxy, indolyloxy, quinazolinyloxy, pyridyloxy, thienyloxy.
  • Heteroaralkoxy' is heteroaralkyl-O-, wherein the heteroaralkyl group is as defined above.
  • exemplary heteroaralkoxy groups include thienylmethyloxy, pyridylmethyloxy.
  • 'Alkylcarbonyl' or 'acyl' is (C ⁇ - o)alkyl-CO-, wherein the (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • exemplary alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl.
  • 'Alkoxycarbonyl' is (C C ⁇ o)alkyl-O-CO-, wherein the (C ⁇ -C ⁇ o)alkyl group is as defined above.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl.
  • 'Arylcarbonyl' or 'aroyl' is aryl-CO-, wherein the aryl group is as defined above.
  • exemplary arylcarbonyl groups include phenylcarbonyl, naphfhylcarbonyl.
  • 'Aryloxycarbonyl' is aryl-O-CO-, wherein the aryl group is as defined above.
  • 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.
  • exemplary heteroarylcarbonyl groups include pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pynolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl.
  • 'Alkylsulfonyl' is (C]-C ⁇ o)alkyl-SO 2 -, wherein the (CrC ⁇ o)alkyl group is as defined above.
  • exemplary alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl.
  • 'Arylsulfonyl' is aryl-SO 2 -, wherein the aryl group is as defined above.
  • Exemplary arylsulfonyl groups include benzenesulfonyl.
  • 'Heteroarylsulfonyl' is heteroaryl-SO -, wherein heteroaryl is as defined above.
  • heteroarylsulfonyl groups include pyrazinylsulfonyl, isothiazolylsulfonyl, oxazolylsulfonyl, pyrazolylsulfonyl, pynolylsulfonyl, pyridazinylsulfonyl, phthalazinylsulfonyl, quinazolinylsulfonyl, pyridylsulfonyl, thienylsulfonyl.
  • 'Alkylsulfinyl' is (C ⁇ -C ⁇ o)alkyl-SO-, where (C ⁇ -C ⁇ o)alkyl is as defined above.
  • alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl.
  • 'Arylsulfinyl' is aryl-SO-, wherein the aryl group is as defined above.
  • exemplary arylsulfonyl groups include phenylsulfinyl.
  • Heteroarylsulfinyl' is heteroaryl-SO-, wherein heteroaryl is as defined above.
  • exemplary heteroarylsulfinyl groups include pyrazinylsulfinyl, isothiazolylsulfinyl, oxazolylsulfinyl, pyrazolylsulfinyl, pyrrolylsulfinyl, pyridazinylsulfinyl, phthalazinylsulfinyl, quinazolinylsulfinyl, pyridylsulfinyl, and thienylsulfinyl.
  • 'Aralkylsulfinyl' is aryl-(C]-C ⁇ o)alkyl-SO- group, where in aryl and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • exemplary aralkylsulfmyl groups include benzylsulfinyl, 2- phenethylsulfinyl.
  • 'Alkylthio' is (C ⁇ -C ⁇ o)alkyl-S-, wherein (C ⁇ -C ⁇ o)alkyl is as defined above.
  • exemplary alkylthio groups include methylthio, ethylthio, and propylthio.
  • 'Arylthio' is aryl-S-, wherein aryl group is as defined above.
  • Exemplary arylthio groups include phenylthio groups.
  • 'Heteroarylthio' is heteroaryl-S-, wherein heteroaryl is as defined above.
  • Exemplary heteroarylthio groups include pyrazinylthio, isothiazolylthio, oxazolylthio, pyrazolylthio, pynolylthio, pyridazinylthio, phthalazinylthio, quinazolinylthio, pyridylthio, and thienylthio.
  • 'Aralkylthio' is aryl-(C 1 -C ⁇ 0 )alkyl-S- group, wherein aryl and (C ⁇ -C ⁇ o)alkyl groups are as defined above.
  • Exemplary aralkylthio groups include benzylthio, and 2-phenethylthio.
  • 'Aryloxyalkyl' is aryl-O-(C ⁇ -C ⁇ o)alkyl, where aryl and (C ⁇ -Cjo)alkyl groups are as defined above.
  • Exemplary aryloxyalkyl groups include phenoxymethyl, phenoxyethyl, and phenoxypropyl.
  • 'AralkoxyalkyP is aryl-(C 1 -C 10 )alkyl-O-(C 1 -C ⁇ o)alkyl, where (C ⁇ -C ⁇ o)alkyl and aryl groups are as defined above.
  • Exemplary aralkoxyalkyl groups include benzyloxymethyl, benzyloxyethyl, and benzyloxypropyl.
  • 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 heteroarylcycloalkyl groups include 5,6,7, 8-tetrahydroquinolinyl, and 5,6,7,8- tetrahydroisoquinolyl.
  • 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 heteroarylcycloalkenyl groups include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6- dihydroquinoxalinyl .
  • 'Fused heteroarylheterocyclenyP is fused heteroaryl and heterocyclenyl, wherein heteroaryl and heterocyclenyl groups are as defined herein.
  • exemplary fused heteroarylheterocyclenyl groups include 7,8-dihydro[l,7]naphthyridinyl, 1,2- dihydro[2,7]naphthyridinyl.
  • Carboxylic acid or its derivatives' may be amides or esters.
  • Exemplary carboxylic acid groups include CONH 2 , CONHMe, CONMe 2 , CONHEt, CONEt,, 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 groups include SO 2 NH 2 , SO 2 NHMe, SO 2 NMe 2 , SO 2 NHCF 3 , COOCH 3 , COOC 2 H 5 , or COOC 3 H 7 .
  • R a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group
  • R b is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group
  • R c is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group;
  • R la 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 cycloalkenyloxy group;
  • R lb 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;
  • R lc is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an arallcylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfmyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkyhhio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof;
  • R 2a 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 cycloalkenyloxy group;
  • R 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;
  • R c is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an aralkylsulfmyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfmyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an arallcylthio group, an aryloxyalkyl group, carboxylic acid or a derivative thereof, or sulfonic acid or a derivative thereof;
  • R 3a 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 cycloalkenyloxy group;
  • R 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;
  • R 3c is an alkylsulfonyl group, an arylsulfonyl group, a heteroarylsulfonyl group, an arallcylsulfinyl group, an alkylsulfinyl group, an arylsulfinyl group, a heteroarylsulfinyl group, an aralkylsulfmyl group, an alkylthio group, an arylthio group,
  • R 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;
  • R c 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 aralkylsulfmyl 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 5a is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino group
  • R 5b is an alkyl group, an alkoxy group, an alkenyl group, or an alkoxyalkyl group
  • R 5c is a cycloalkenyloxy group, an acyl group, an aryl group, an aralkyl group, a heterocyclyl group, or a heteroaryl group;
  • R' 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;
  • R' c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl 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 heterocyclyl group, or an aralkyl group;
  • R" c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an
  • R 9b 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;
  • 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, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an
  • R 10b 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;
  • R 10c 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
  • R l lb 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;
  • R I lc 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 witi 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 mo ⁇ holinyl group, a thiomo ⁇ holinyl 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 12b 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;
  • R 12c 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 mo ⁇ holinyl group, a thiomo ⁇ holinyl 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 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;
  • R 13c 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 mo ⁇ holinyl group, a thiomo ⁇ holinyl 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 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;
  • R 1 c is an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, or a heterocyclyl sulfonyl group, which is optionally substituted with a halogen, a hydroxyl group, a nitro group, an amino group, an alkyloxy group, or any combination thereof, and wherein the heterocycle group is optionally a substituted mo ⁇ holinyl group, a thiomo ⁇ holinyl 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 20b 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;
  • R 20c 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
  • R 1b 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;
  • R 21c 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
  • G a is -(CH 2 ) S -, where s is an integer from 0-5;
  • Z a is O;
  • Z b is NR;
  • E a is O;
  • E is S;
  • E c is NR;
  • p a is 0-1 ;
  • p b is 2-3;
  • p c is 4-5;
  • v a is 0-l;
  • v b is 2-3;
  • v c is 4-5;
  • R 1 , R 2 , R 3 , and R 5 are as defined above;
  • R 4 is an optionally substituted aryl group, and in some instances, is a phenyl group optionally substituted with a halogen, an alkoxy group, or both;
  • E is O or -NR, where R is as defined above;
  • s is an integer from 1-3;
  • R' and R" 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.
  • R, R 5 , R, R , and E of formula (30) are selected to produce various compounds of formula (30-1) through formula (30-243) as follows:
  • R is hydrogen, a hydroxy group, a halogen, a nitro group, or an optionally substituted amino 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' 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
  • E is O, S, or NH.
  • R is hydrogen, an alkyl group, potassium, or sodium
  • R 5 is hydrogen or an alkyl group
  • E is O, S, or NH;
  • R' and R? independently are -H, -CI, -Br, or -CH 3 ;
  • R 5 is -H, -CH 3 , or -CH 2 CH 2 CH 3 ; and
  • R is -H, K, or Na.
  • Examples of compounds of formula (30) include, but are not limited to:
  • R 1 , R 2 , R 4 , E, R', and R" of formula (31) are selected to produce various compounds of formula (31-1) to (31-729) as follows:
  • R and R independently are 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 cycloalkenyloxy group;
  • 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, a cycloalkenyloxy group; an acy
  • 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
  • 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 group, 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 all other symbols are as defined above in connection with formula (I).
  • R 1 is hydrogen or an alkoxy group
  • R is hydrogen or an alkoxy group
  • R 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
  • E is O, S, or NH.
  • R 1 is -H or -OCH 3 ;
  • R 2 is -H or -OCH 3 ;
  • R 4 is a substituted aryl group, R' is -H, -CI, -Br, or -CH 3 ; and R" is -H, -CI, - Br, or -CH 3 ; and E is O, S, or NH.
  • the present invention further contemplates various compounds of general formula (III) having die general formula:
  • R 4 , R', and R" of formula (32) are selected to produce various compounds of formula (32-1) through formula (32-27) as follows:
  • R is hydrogen, a hydroxy group, a halogen, a nitro group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, or a cycloalkoxy group;
  • R" is hydrogen, a halogen, a nitro group, an amino group, a mono- or di- substituted amino group, a hydroxy group, an alkoxy group, or a
  • R 4 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group, an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an araikyl group, an aralkenyl group, an aralkynyl group, or an aralkoxy group;
  • E is O or -NR; R is optionally
  • 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.
  • 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.
  • R 4 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 aralkylsulfmyl 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 is V ⁇ // Examples of such
  • R, R 5 , 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:
  • 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 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 is hydrogen or an alkyl group;
  • R is hydrogen or an alkyl group;
  • R' and R? independently are hydrogen or a halogen;
  • R 20 is hydrogen or a halogen;
  • R 21 is hydrogen or a halogen.
  • R is -H, CH , or CH 2 CH 3 ;
  • R 5 is -H or CH 3 ;
  • R' and R? independently are -H, -F, or -CI;
  • R 20 is -H, -F, -CI, or -Br; and
  • R 21 is -H, CH 3 , or -F.
  • Exemplary compounds include, but are not limited to:
  • R 1 is a halogen
  • R 20 is hydrogen or a halogen
  • R 21 is hydrogen or a halogen
  • R 1 is CI or F
  • R 20 is - H or -F
  • R 21 is -F.
  • Exemplary compounds of formula (35) include, but are not limited to:
  • R, R , R' and R" of formula (36) are selected to produce compounds of formula (36-1) through formula (36-81) as follows:
  • 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 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group; and R' and R" independently are
  • 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 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.
  • R is -H or CH 3; R is a halogen substituted aryl group; and R' and R" independently are -H or -CI; and all other symbols are as defined above in connection with formula (I).
  • Examples of compounds of formula (36) include, but are not limited to:
  • E, R 1 , and R 4 of formula (37) are selected to produce compounds of formula (37-1) through formula (37-27):
  • R 1 is hydrogen, a hydroxy group, a halogen, a nitro group, a carboxy group, a carbamoyl group, an optionally substituted amino group, an alkyl group, a cycloalkyl group, an alkoxy group, a cycloalkoxy group, an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, or a cycloalkenyloxy group;
  • 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
  • R 1 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, 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).
  • R 1 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 heteroaryloxy group, or a heteroaralkoxy group; and all other symbols are as defined above in connection with formula (I).
  • R 1 is hydrogen, a
  • R 1 is hydrogen or a halogen
  • E is O or NMe
  • R 4 is a substituted aryl group or a heterocycyl group
  • R 22 is hydrogen or an alkoxy group
  • R is hydrogen or an alkoxy group
  • all other symbols are as defined above in connection with formula (I).
  • R 1 is -H, -F, or MeO;
  • E is O or NMe; R 4 is or vJl . where R 22 is -H or OMe; and R 23 is -F or OMe.
  • An exemplary compound includes, but is not limited to:
  • the present invention encompasses various compounds of general compound (IV) having the formula:
  • R, R 1 , R 4 , G, and Z of formulae (88), (89), (90), (91), (92) are selected to produce compounds of formulae (88-1), (89-1), (90-1), (91-1), and (92-1) through formulae (88-729), (89-729), (90-729), (91-729), and (92-729) as follows:
  • R is -H or CH , and all other symbols are as defined above in connection with formula (I).
  • R is H or CH 3
  • R 5 is -H
  • all other symbols are as defined above in connection with formula (I).
  • R is -H or CH ; R is CH ; and all other symbols are as defined above in connection with formula (I).
  • 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).
  • R is -H or -CH 3 ; R 5 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).
  • R is -H or CH 3 ;
  • R 5 is CH ;
  • 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).
  • R is -H or CH 3 , Z is -NR; and all other symbols are as defined above in connection with formula (I).
  • R is -H or CH 3
  • R 5 is -H or CH 3
  • Z is -NR; and all other symbols are as defined above in connection with formula (I).
  • R is -H or CH 3
  • G is -(CH 2 ) S -, where s is an integer from 0-5
  • Z is -NR
  • all other symbols are as defined above in connection with formula (I).
  • R is -H or CH 3 ;
  • R 5 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).
  • R is -H or CH 3 , Z is O; and all other symbols are as defined above in connection with formula (I).
  • R is -H or CH ;
  • R 5 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).
  • R is -H or CH 3
  • R 5 is -H or CH 3
  • Z is O
  • R is -H or CH 3 ; G is -(CH 2 ) S ⁇ , where s is an integer from 0-5; Z is O; and all other symbols are as defined above in connection with formula (I).
  • R is -H or CH 3 , G is -(CH 2 ) S -, where s is an integer from 0-5; Z is O; and all other symbols are as defined above in connection with formula (I).
  • R is -H or CH ; R 5 is -H; G is -(CH 2 ) S -, where s is an integer from 0-5; Z is O; and all other symbols are as defined above in connection with formula (I).
  • 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 O; and all other symbols are as defined above in connection with fonnula (I).
  • 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:
  • 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:
  • R is -H or CH 3 , and all other symbols are as defined above in connection with formula (I).
  • R 4 is a substituted or unsubstituted aryl group; and all other symbols are as defined above in connection with formula (I).
  • R 5 is -H or CH 3 , and all other symbols are as defined above in connection with formula (I).
  • 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).
  • 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 is an alkenyl group, a cycloalkenyl group, an alkoxyalkyl group, an alkenyloxy group, a cycloalkenyloxy group, an acyl group or an acyloxy group, an aryl group, an aryloxy group, an aroyl group, an aroyloxy group, an aralkyl group, an aralkenyl group, an aralkynyl group, an aralkoxy group, a heterocyclyl group, a heterocyclenyl group, a heteroaryl group, a heteroaralkyl group, a heteroaryloxy group, or a heteroaralkoxy group;
  • R 5 is hydrogen, a
  • 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, a 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, an alkyl group, or an alkoxy group; and all other symbols are as defined
  • R is hydrogen or an alkyl group
  • R 4 is a substituted or unsubstituted aryl group
  • G is (CH 2 ) , (CH 2 ) 3 , or (CH 2 ) 4
  • Z is O, S, or NH
  • R 5 is hydrogen or an alkyl group.
  • R is -H or CH 3 ;
  • R 4 is a substituted or unsubstituted aryl group;
  • G is (CH 2 ) , (CH 2 ) 3 , or (CH 2 ) ;
  • Z is O, S, or NH;
  • R 5 is -H or CH 3 .
  • the present invention also encompasses various compounds of general formula (IV) as follows:
  • R, R 5 , G, Z, R 9 , and R 10 of any of formulae (94), (95), (96), and (97) are selected to produce compounds of formulae (94-1), (95-1), (96-1), and (97-1) through formulae (94-729), (95-729), (96-729), and (97-729) as follows:

Abstract

L'invention concerne des composés de formule (I) et des procédés et/ou des compositions comprenant des composés qui sont efficaces dans la modulation des réponses inflammatoires, telles que celles résultant d'une accumulation d'AGE et de protéine glycatée. L'invention concerne en outre des procédés et/ou des compositions comprenant des composés qui sont efficaces dans la modulation de la prolifération cellulaire du muscle lisse et des maladies ou états en rapport avec cette prolifération.
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PT2118074E (pt) 2007-02-01 2014-03-20 Resverlogix Corp Compostos para a prevenção e tratamento de doenças cardiovasculares
US8952021B2 (en) 2009-01-08 2015-02-10 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular disease
AU2010224523B2 (en) 2009-03-18 2014-05-08 Resverlogix Corp. Novel anti-inflammatory agents
MX352614B (es) 2009-04-22 2017-12-01 Resverlogix Corp Nuevos agentes anti-inflamatorios.
CZ2009358A3 (cs) * 2009-06-03 2010-12-15 C3 Bio Gmbh 5,7-Disubstituované 3-isopropylpyrazolo[4,3-d]pyrimidiny pro použití jako lécivo a farmaceutické prípravky tyto látky obsahující
TWI495465B (zh) * 2009-09-30 2015-08-11 Shiseido Co Ltd A heparinase activity inhibitor and a wrinkle improving agent and a pharmaceutical composition containing the same
PT2773354T (pt) 2011-11-01 2019-07-17 Resverlogix Corp Formulações orais de libertação imediata para quinazolinonas substituídas
WO2014080291A2 (fr) 2012-11-21 2014-05-30 Rvx Therapeutics Inc. Dérivés biaryle servant d'inhibiteurs de bromodomaines
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
JO3789B1 (ar) 2015-03-13 2021-01-31 Resverlogix Corp التراكيب والوسائل العلاجية المعتمدة لمعالجة الامراض المتعلقة بالمتممة
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RU2635112C1 (ru) * 2016-12-12 2017-11-09 федеральное государственное автономное образовательное учреждение высшего образования "Южный федеральный университет" Галогениды 1-(4-трет-бутилфенил)-2-{ 3-[2-(4-фторфенокси)этил]-2-метил-3Н-бензимидазол-1-ил} этанона, обладающие свойством разрывателей поперечных сшивок гликированных белков
CA3123843A1 (fr) * 2018-12-21 2020-06-25 Acurx Pharmaceuticals, Llc Inhibiteurs d'adn polymerase iiic et leur utilisation
CN112300141B (zh) * 2020-10-12 2023-04-18 贵州大学 含喹唑啉的杨梅素衍生物、其制备方法及用途
WO2022255765A1 (fr) * 2021-06-01 2022-12-08 주식회사 에즈큐리스 Nouveau dérivé de flavonoïde substitué par du fluor, et composition pharmaceutique pour prévenir ou traiter des maladies allergiques le comprenant
TW202334089A (zh) 2021-11-02 2023-09-01 美商夫雷爾醫療公司 Ｐｐａｒｇ反向激動劑及其用途

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