Title of Invention

"A VASCULOSTATIC AGENT"

Abstract

The present invention relates to novel vasculostatic of the structure: wherein: each of Z2 and Z4 is C, each of Z1, Z3, Z,, and Z6 is N; each X is NH2; each Y is independently selected from a group consisting of substituted aryl, wherein said substituents are selected from a group consisting of -OH, -P(OXOH)2, or -NR'2, wherein Re is selected from a group consisting of -H, lower alkyl, and aryl; or each Y is independently selected from a group consisting of CH2glycinyl, CH2NHethoxy, and CH2NHCH2t-Bu, and m and n are each independently 1 to 2, wherein when m=n=2, Y is not 4-hydroxyphenyl, or pharmaceutically acceptable salts or tautomers thereof. The agents of the present invention are provided for treating disorders associated with compromised vasculostasis. Invention methods and compositions and compounds are useful for treating a variety of disorders including for example, stroke,myocardial infarction, cancer, ischemia/reperfusion injury, autoimmune diseases such as rheumatoid arthritis, eye diseases such as retinopathies or macular degeneration or other vitreoretinal diseases, inflammatory diseases, vascular leakage syndrome, edema, transplant rejection, adult/acute respiratory distress syndrome (ARDS), and the like.

Full Text

FIELD OF THE INVENTION [0001] The present invention relates generally to treating disorders associated with vascular functioning, and more specifically to compounds and methods of treating such disorders. BACKGROUND OF THE INVENTION [0002] The vascular system is a prime mediator of homeostasis, playing key roles in the maintainence of normal physiologic functioning. For example, the vascular endothelium's barrier function serves to regulate the entry of fluid, electrolytes, and proteins into tissues, blood vessel tone contributes to the regulation of tissue perfusion, and the vascular endothelium's low mitotic index contributes to the regulation of tissue growth. The term "vasculostasis" refers to the maintenance of tin's homeostatic vascular functioning, and "vasculostatic agents" as agents that seek to address conditions in which vasculostasis is compromised by preventing the loss of or restoring or maintaining vasculostasis. [0003] Compromised vasculostasis has serious pathologic consequences. For example, if vascular permeability increases beyond manageable levels, the resulting edema may negatively impact tissue and organ function and ultimately survival. Examples where excessive vascular permeability leads to particularly deleterious effects include pulmonary edema, cerebral edema, and cardiac edema (Ritchie AC: Boyd's Textbook of Pathology. London Lea and Febiger, 1990). In general, however, edema in any tissue or organ leads to some loss of normal function, and therefore to the risk of morbidity or even mortality. Similarly, excessive endothelial proliferation may damage tissues (such as the retina in proliferative retinopathies) or fuel unwanted tissue growth (such as with tumor growth). (0004] Many pathologic and disease situations are marked by multiple disregulations in vasculostasis. AngiogeneKis, for example, encompasses both enhanced vascular proliferation and permeability, as newty-formed blood vessels do not generally exhibit the :;aiTH" level of vascular barrier function as well-established or mature vessels. Examples of such hyper-permeable vasculature can be found in cancers, vasculoproliferative diseases, retinal diseases, and rheumatoid arthritis. The connection between angiogenesis and hyperpermeability may partly result from the dual action of factors such as vascular endothelial growth factor (\TEGF), which induces both endothelial proliferation and vascular permeability. This connection may also reflect the immature nature of angiogenic vessels, in which the. intracellular and/or extracellular structures or mechanisms that establish normal vascular barrier function have not yet fully formed. It may also be the case that angiogenesis and vascular permeability are linked by a co-dependence on common cellular mechanisms, for example in the case of cellular junction disassembly which would serve to enhance both paracellular permeability and cellular migration (both being components of the angiogenic process). A comprehensive treatment for many diseases, then, might involve vasculostatic agents that act upon one or more components of vasculostasis disregulation (based, for example, upon their level of action along intracellular signaling cascades). One such example would be a single therapeutic agent that impacts both angiogenesis and vascular permeability. [0005] One way of impacting vasculostasis is by influencing endothelial cell responses to environmental signals (such as hypoxia) or vasoactive agents. For example, the vascular endothelium regulates fluid balance by adjusting both transcellular permeability (movement of fluid and proteins across endothelial cells via a network of vesicles) and paracellular permeability (movement of fluid and proteins between inter-endothelial cell junctions). Edema is most commonly thought to result from a breakdown in the inter-endothelial cell barrier, leading to increased paracellular permeability at the capillary and postcapillary venule level. Mechanistically, paracellular vascular leakage results from a breakdown in inter-cellular junctional integrity, via the dissolution of tight junctions and coupled to changes in cytoskeletal support elements that maintain normal cell-to-cell apposition. Several vasoactive mediators can trigger dissolution of these cellular elements, including histamine, bradykinin, thrombin, nitric oxide, eicosanoids (e.g., throniboxanes and leukotrienes), platelet activating factor (PAF), tumor necrosis factor (TNF), interleulans (c.ff., IL-] and IL-6), litpatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). Using YEGF as an example, the sequence of events that lead to vascular leakage is generally believed to be as follows: reduced blood flow (e.g., as a result of thrombus formation) leads to tissue hypoxia, which leads to the upregulation of VEGF production, which leads to induction of vascular leakage. This VEGF effect is at the level of the endothelial cell, in other words VEGF binding to specific VEGF receptors expressed on endothelial cells leads to a cascade of intracellular events culminating in the loss of normal intercellular barrier function. Therefore, by affecting these intracellular events, vasulostatic agents could counter the negative effects of environmental signals such as hypoxia or vasoactive mediators such as VEGF, and thereby work to restore vasculostasis. [0006] The cascade of events that leads to the loss of endothelial barrier function is complex and incompletely understood. Data support a role for kinases as at least one aspect of this process. For example, VEGF-mediated edema has been shown to involve intracellular signaling by Src family Icinases, protein kinase C, and Akt kinase. Kinases are believed to mediate the phosphorylation of junctional proteins such as beta-catenin and vascular endothelial (VE)-cadherin, leading to the dissolution of adherens junctions and the dissociation of cadherin-catenin complexes from their cytoskeletal anchors. In addition, proteins which regulate the intercellular contractile machinery such as myosin light chain kinase (MLCK) and myosin light chain (MLC) are also activated, resulting in cellular contraction, and therefore an opening of intercellular junctions. [0007] Maintaining or restoring vasculostasis should be beneficial to overall patient outcome in situations such as inflammation, allergic diseases, cancer, cerebral stroke, myocardial infarction, pulmonary and cardiac insufficiency, renal failure, and retinopathies, lo name a few. In addition, edema formation is a recognized but unwanted consequence of many therapeutic interventions, such as immunotherapy, cancer chemotherapy and radiation therapy, therefore vasculostatic agents that inhibit vascular permeability could be used in a co-therapy approach to reduce the deleterious side-effects of such therapies. Furthermore, in many cases edema formation causes uneven deliver}' of therapeutic agents to diseased tissues, therefore vasculostatic agents that inhibit vascular permeability could be used in a co-therapy approach to enhance delivery and efficacy of such therapies. Finally, as edema :s a general consequence of tissue hypoxia, it can also be concluded that inhibition of vascular leakage represents a potential approach to the treatment of tissue hypoxia. For example, interruption of blood flow by pathologic conditions (such as thrombus formation) or medical intervention (such as cardioplegia, organ transplantation, and angioplasty) or physical trauma, could he treated both acutely and prophylactically using vasculostatic agents that reduce vascular permeability. SUMMARY OF THE INVENTION [0008] The present invention is based on the discovery that certain chemical compounds are effective vasculostatic agents. Compounds of the invention are effective for the treatment of such indications as myocardial infarction (MI), stroke, ischemia or reperfusion related tissue injury and cancer, for example. Thus, compositions and methods are provided for treating disorders associated with compromised vasculostasis, examples of which are edema resulting from excess vascular permeability or vascular leakage and angiogenesis associated with retinal diseases and cancer. Some of the compounds described herein are effective kinase inhibitors, including but not limited to tyrosine, serine or threonine kinase inhibitors, for example, Src-family inhibitors. [0009] Such vasculostatic agents, alone or in combination with other agents, are effective in blocking vascular permeability or leakage or angiogenesis. In one embodiment, the invention provides a composition containing a therapeutically effective amount of a compound of the invention in a pharmaceutically acceptable carrier. [0010] hi one embodiment, the invention provides a method for treating a disorder associated with compromised vasculostasis in a subject, comprising administering to a subject in need thereof an effective amount of a compound that is a vasculostatic agent. In an illustrative example, the method includes use of at least one of the compounds as set forth in Structures I, II, III, IIIa, IV, V, VI or VII or any combination thereof, hi one aspect, the compound is set forth in FIGURE 1. |00ll] In one embodiment, compounds are provided having the structure (I): (Figure Removed) wherein: each Ro is independently -H, -COOH, -OR', -SO3H, wherein R' is - H or lower allcyl, or when x = 2, each ro is taken together to form a 1,3- dioxolyl ring, or each ro is independently allcyl, substituted allcyl, alkenyl, substituted alkenyl, allcynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, allcylaryl, substituted allcylaryl, arylalkyl, substituted aryl allcyl arylalkenyl, substituted arylalkenyl, arylalkynyl substituted arylalkynyl, halogen, amino. amido, nitro, or thioalkyl, ri and R2 are each independently hydrogen, allcyl, substituted allcyl, alkenyl, substituted alkenyl, allcynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl substituted arylalkyl, arylalkenyl, substituted arylalkenyl arylalkynyl, or substituted arylalkynyl, G is NH, O, S, or (CR"2)ps wherein R" is -H, lower all:yl or acetamido, and wherein p is 0-3, Ar is aryl or heteroaryl, and x and y are each independently 1 -4. [0012] In another embodiment, compounds are provided having the structure (II): (Figure Removed) wherein ro, a, x, and y are as defined above. [0013] In yet another embodiment, compounds are provided having the structure (III): (Figure Removed) wherein: ZrZe are each independently C, -C-0, N, or NRa, wherein Ra is -H, alley}, or substituted allcyl, wherein said substituents are halogen, hydroxy, oxo, or amino, each X is independently halogen, -ORb, -NRb2, or ~SRb, wherein R1' is -H lower alkyl, -(CEbhM^CHzCHs), -(CH2)3morpho]yn-l-yl; -'Cii:,,h(.N-methylpiperazinyn-l-yr), aryl,heteroaryl, -(I 7 -(N=N-N.H-RC), wherein Rc is E or lower alkyl, each Y is independently -ORd, -NRd2, -SRd, or-OPO3H2 wherein Rli is H, lower alkyl, aryl, heteroaryl each Y is independently alkyl, substituted allcyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halogen, wherein said substituents are selected from halogen, -ORC, -NRC2> -SRe, -P(0)(OH)2, wherein Re is -H, lower alkyl, aryl, or heteroaryl; or each Y is independently CH2glycinyl, CH2NHethoxy, CH2NHCH2alkyl, CH2NHCH2t-Bu5 CH2NHCH2aryl, CH;,NBCH2substituted aryl, CH2NHCH2heteroaryl, CH2NHCH2substituted heteroaryl; or when n is 2, each Y is taken together to form a fused aromatic or heteroaromatic ring system; and m and n are each independently 1 to 4, wherein when Z|, Zi, Z5, and Zf, are each N, X is NH2, and m = n = 2, Y is not phenyl or 4-hydroxyphenyl, or tautomers thereof. 10014] In still another embodiment, compounds are provided having the structure (IV): (Figure Removed) wherein: 1, is an arylene, substituted arylene, oxyarylene, thioalkylene, substituted thioallcylene, or substituted oxyarylene linking moiety, G is 5- or 6-membered aromatic or heteroaromatic ring, each X is independently H, OR, NR2, or SR, wherein R is H or lower alkyl, Zi-Za are each independently CH or N, and m is 1 to 4. [0015] hi still another embodiment, compounds are provided having the structure (V): (Figure Removed) wherein: ri, x, and y are as defined above, R3 is -H, -SO3H, or -SO2NMe2, M is NH, CO, SO2, (CH2)p, wherein p is 0 to 2, G is aryl or heteroaryl, and x and y are each independently 0-4. f 001 6] hi a further embodiment, there are provided methods for treating disorders associated with compromised vasculostasis, including administering to a subject hi need thereof an effective amount of a compound having the structure (VI): (Figure Removed) wherein: A and B are each independently 5- or 6-membered aromatic rings, wherein at least one of A and B is an aromatic heterocyclic ring having at least one heteroatom in the heterocyclic ring, each X is independently -H, OR, NR2, or SR, wherein R is H or lower allcyl, each Y is independently hydrogen, alkyl, substituted allcyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, ary] alkynyl, substituted arylalkynyl, or oxo, with the proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, and in and n are each independently 1 to 4, thereby treating the disorder. |0017] In yet another embodiment, invention methods include administering to a subject in need thereof an effective amount of a compound having the structure (VII): (Figure Removed) wherein. A, B, C, and D are each independently C, N, 0, or S, each X is independent!}' OR, NRo, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, alkyl, substituted allcyl, allcenyl, substituted alkenyl, allcynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylallcyl, arylallcenyl, substituted arylalkenyl, arylalkynyl, substituted arylallcynyl, with the proviso that at least one Y is not hydrogen, and m and n are each independently 1 to 4, thereby treating the disorder. 10018] In another embodiment, the invention provides a method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof an effective amount of a compound having the structure: (Figure Removed) wherein: each X is independently H, OR, NR.2, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, allcyl, substituted allcyl, allcenyl substituted alkenyl, allcynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylallcyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylallcynyl, aroyl, substituted aroyi, acyl, or substituted acyl, with the proviso that at least one Y is not hydro ten, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, rn is 1 to 4, and n is 1 or 2, thereby treating the disorder. 10019] In another embodiment, the invention provides a method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof an effective amount of a compound having the structure: (Figure Removed) wherein: each X is independently H, OR, NR2, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl., substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alk)daryl, aryl alkyl, substituted arylalkyl, arylalkenyl, substituted aryl alkenyl, aryl alkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, and m and n are each independently 1 or 2. 10020] In another embodiment, the invention provides a method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof an effective, aniounl of a compound having the structure: (Figure Removed) wherein: ZisN, O, orS; each X is independently H, OR, NR2, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, allcyl, substituted alkyl, alkenyl substituted alkenyl, allcynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, and m is 1 to 4, and n is 1 or 2. [0021] In another embodiment, the invention provides a method for treating a disorder associated with compromised vasculostasis comprising administering to a subject in need thereof an effective amou.n1 of a compound having structure (VII): (Figure Removed) wherein: A , B, C, and D are each independently C, N, O, or S, each X is independently H, OR, NR2, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, alkyl, substituted allcyl, alkenyl, substituted allcenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl aryl, substituted alkylaryl, arylallcyl, substituted aryl alkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso that at least one Y is not hydrogen, and m and n are each independently 1 to 4, tliereby treating the disorder. [0022] In one embodiment, the invention provides a method for treating a disorder associated with compromised vasculostasis, comprising administering to a subject in need thereof an effective amount of a compound, wherein the compound is set forth in Structures 1,11, in. Ilia, IV, V, or any combination thereof. The disorder is for example, but not limited to, myocardial infarction, stroke, congestive heart failure, an ischemia or rejierfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, mflammatory disease, edema, transplant rejection, bum, or acute or adult respiratory distress syndrome (ARDS). [0023] In still another embodiment, there are provided articles of manufacture including packaging material and a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition is capable of treating a disorder associated with compromised vasculostasis, wherein the pharmaceutical composition comprises at least one compound having any one of the structures as set forth above. 10024] In one embodiment, the invention provides a pharmaceutical composition comprising a compound as set forth in Structures 1, EL, El, ITIa, IV, V, or VII, or any combination thereof, in a pharmaceutically acceptable carrier. [0025] In one embodiment, the invention provides an article of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said packaging material comprises a label which indicates that said pharmaceutical composition can be used for treatment of disorders associated with compromised vasculostasis and wherein said pharmaceutical composition comprises a compound set forth in Structures I, n, IE, Ela, IV, V, VI or VII, or any combination thereof. [0026] In one embodiment, the invention provides an article of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said packaging material comprises a label which indicates that said pharmaceutical composition can be used for treatment of disorders associated with vascular permeability leakage or compromised vasculostasis selected from is myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, inflammatory disease, edema, transplant rejection, bums, or acute or adult respiratory distress syndrome (ARDS) and wherein said pharmaceutical composition comprises a compound set forth in Structures L II, III, Ela, TV, V, VI or VII, or any combination thereof. [0027] In one embodiment, the invention provides a method of treating a compromised vasculostasis disorder, comprising the administration of a therapeutically effective amount of at least one compound set. forth in Structures I, II, III, Ilia, IV, V, VI or VII, or any combination thereof., or pharmaceutical! y acceptable salts, hydrates, sol vales, crystal furmr. and individual diastereomers thereof, to a subject in need of such treatment. 10028] In one embodiment, the invention provides a method of treating a disorder associated with vasculostasis, comprising the administration of a therapeutically effective amount of at least one compound as set forth in Structures I, II, HI, ffla, IV, V, VI or VII, or any combination thereof, or pharmaceutical!y acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with an anti-inflammatory, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody or a protein lanase inhibitor, to a subject in need of such treatment. [0029] In one embodiment, the invention provides a method of treating a subject having or at risk of having myocardial infarction comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, II, in, ffla, IV, V, 'VI or Vn, or any combination thereof thereby treating the subject. (0030] In one embodiment, the invention provides a method of treating a subject having or at risk of having vascular leakage syndrome (VLS) comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, n, ffl, ffla, IV, V, VI or VII, or any combination thereof thereby treating the subject. [0031] hi one embodiment, the invention provides a method of treating a subject having or at risk of having cancer comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, TI, ffl, Hla, IV, V, or VII, or any combination thereof thereby treating the subject. J0032] hi one embodiment, the invention provides a method of treating a subject having or at risk of having stroke comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures 1, n, ffl, ffla, IV, V, VI or VII, or any combination thereof [hereby treating the subject. (0033] in one embodiment, the invention provides a method of treating a subject having or at risk of having ARDS comprising administering to the subject a t'herapeutically effective amount of a compound as set forth in Structures 1, II, in, IHa, IV, V, VI or VII, or any combination thereof thereby treating the subject. |0034] In one embodiment, the invention provides a method of treating a subject having or at risk of having bums comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures 1, II, HI, Dla, IV, V, VI or VII, or any combination thereof thereby treating the subject. [0035] hi one embodiment, the invention provides a method of treating a subject having or at risk of having arthritis comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, II, III, ITIa, IV, V, VI or VII, or any combination thereof thereby treating the subject. [0036] In one embodiment, the invention provides a method of treating a subject having or at risk of having edema comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, E., IH, Ela, IV, V, VI or VII, or any combination thereof thereby treating the subject. [0037] In one embodiment, the invention provides a method of treating a subject having or at risk of having vascular leakage syndrome (VLS) comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, n, HI, Ula, IV, V, VI or VII, or any combination thereof thereby treating the subject. [0038] In one embodiment, the invention provides a method of treating a subject having or at risk of having, retiriopathy or vitreoretinal disease comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, n, HI, Ilia, IV, V, VI or VII, or any combination thereof thereby treating the subject. 10039] In one embodiment, the invention provides a method of treating a subject having or til risk of having ischemia or reperfusion related tissue injury or damage, comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, II, III, Ilia, IV, V, VI or VII, or an)' combination thereof thereby treating the subject. [0040] In one embodiment, the invention provides a method of treating a subject having or al risk of having autoimmune disease, comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures 1, II, IE, Ilia, IV, V, VI or VII, or any combination thereof thereby treating the subject. |0041 j In one embodiment, the invention provides a method of treating a subject having or at risk of having transplant rejection, comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, n. III, Ilia, IV, V, VI or VII, or any combination thereof thereby treating the subject. 10042] In one embodiment, the invention provides a method of treating a subject having or at risk of having inflammatory disease, comprising administering to the subject a therapeutically effective amount of a compound as set forth in Structures I, II, HI, Ilia, IV, V, VI or VII, or any combination thereof thereby treating the subject. [0043] In one embodiment, the invention provides a process for making a pharmaceutical composition comprising combining a combination of a compound set forth in Structures I, II, HI, IHa, IV, V, VI or VII, or any combination thereof or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof and a pharmaceutically acceptable earner. [0044] hi one embodiment, the invention provides a pharmaceutical composition comprising a compound as set forth in Structure I, II, HI, Ilia, IV, V, VII, or VIII in a pharmaceutically acceptable carrier. 10045] In one embodiment, the invention provides a method for inhibiting or reducing vascular leakage in a subject, comprising administering to a subject in need thereof an effective amount of EL-2 in combination with a compound of Structure set forth in Structures I, II, 111, Ilia, IV, V, VI or VH or any combination thereof, thereby reducing vascular leakage in the subject. In one aspect, the compound may be N-(2-(lH-Indol-2-yl)-phenylj-phlhalamio acid or 6,7-bis-(3-hydroxyphenyl)-pteridme-2,4-diamine.[0046] In one embodiment, the invention provides a pharmaceutical composition comprising IL-2 and at least one compound as set forth in Structures I,II, III, IIIa, IV, V, VI or VII or any combination thereof, in a concentration effective to reduce vascular leakage associated with IL-2 administration. . [0047] In one embodiment, the invention provides a method for treating cancer or a tumor in a subject, comprising administering to a subject in need thereof an effective amount of a therapeutic antibody, chemotherapeutic agent or immunotoxic agents, in combination with a compound set forth in Structures I, II, III, IIIa, IV, V, VI or VII or any combination thereof, thereby treating the cancer or tumor in the subject [0048] In one embodiment, the invention provides a pharmaceutical composition comprising a therapeutic agent and at least one compound as set forth in Structures I, II, III, IIIa, IV, V, VI or VII or any combination thereof, in a concentration effective to treat cancer in a subject. The cancer may be any cancer, including but not limited to an alimentary/gaslromtestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer. [0049] In one embodiment, the invention provides a method for treating a T-cell mediated disorder, comprising the administration of a therapeutically effective amount of at least one compound set forth in Structures I,II, III ,IIIa, IV, V, VI or VII, or any combination thereof or pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, to a subject in need of such treatment. STATEMENT OF INVENTION According to the present invention there is provided a vasculostatic agent of structure (III): (Structure Removed) wherein: each of Z2 and Z4 is C, each of Z1 Z3, Z5, and Z6 is N; each X is NH2; each Y is independently selected from a group consisting of substituted aryl, wherein said substituents are selected from a group consisting of -OH, -P(O)(OH)2, or -NRe2, wherein Re is selected from a group consisting of -H, lower alkyl, and aryl; or each Y is independendy selected from a group consisting of CH2glycinyl, CH2NHethoxy, and CH2NHCH2t-Bu, and m and n are each independently 1 to 2, wherein when m=n=2, Y is not 4-hydroxyphenyl, or pharmaceutically acceptable salts or tautomers thereof. BRIEF DESCRIPTION OF THE FIGURES [0050] FIGURE 1 shows exemplary compounds of the invention. [0051] FIGURE 2 shows the results of 6,7-bis(4rhydroxyphenyl)-pteridin-4-ylamine, sulfate salt and doxorubicin for treatment of rang metastases. Syngeneic Lewis kmg carcinoma cells were injected LV. in order to establish lung metastases in Balb/C mice. Beginning 10 days after cells were injected, doxorubicin (3 mg/kg) and/or 6,7-bis(4-hydroxyphenyI)-pteridiri-4-ylamine, sulfate salt (various doses as shown) was given LP. ever\f 3 days for 3 cycles. Animals were sacrificed at. day 20, lungs were collected, and weighed. Net tumor burden is the weight of tumor-bearing lungs minus the. average weight of normal control lungs. N^S/'group, p |0052] FIGURE 3 illustrates the effect of compounds administered in conjunction with doxorubicin in an in vivo model of metastatic colon cancer (CT-26 adenocarcinoma). Syngeneic CT-26 Colon carcinoma cells were injected IV. in order to establish lung metastases in Balb/C mice. Beginning 10 days after cells were injected, indicated test agents were given IP. every 3 days for 3 cycles. Animals were sacrificed at day 20, lungs were-- collected, and weighed. Net tumor burden is the weight of tumor-bearing lungs minus the average weight of normal control lungs. N=5/group, p [0053] FIGURE 4 illustrates the effects of compounds of the present invention for co-drug therapy with Taxotere as described herein. Syngeneic CT-26 Colon carcinoma cells were used in order to establish lung metastases in Balb/C mice as described for FIGURE 3. 6,7-bis(4-hydroxyphenyl)~pteridm-4-ylarnine, sulfate salt (compound A) and 6,7-diphenyl-pteridine-2,4-diamine (compound B) from FIGURE 1 are shown in FIGURE 4. [0054] FIGURE 5 shows a photo of representative lung samples from the experiment shown in FIGURE 4 with 6,7-diphenyl-pteridine-2,4-diamine (compound B) and doxorubicin. [0055] Fl CURE 6 illustrates the effect of compounds administered in conjunction with docetaxel in. the in vivo model of metastatic colon cancer (CT-26 adenocarcinoma) described for FIGURE 4. 2,3-Bis(3,4-dihydroxyphenyl)-pyrido[2,3-b]pyrazrn-6-ylamine dihydrochloride salt (compound C) from FIGURE 1 is shown in FIGURE 6 as compound C. N=5/group, p 10056] FIGURES 7 and 8 illustrate the effects of compounds of the invention for then-capacity to inhibit H.-2 induced VLS. The graphs present representative examples of (•(impounds cited in this application and their effects on VLS. hi the graphs, compound D is N-(2-(lH-indol-2-y] )-phenyl)-phthalamic acid and compound E is 6,7-bis(3-liydroxyph en yl )-pteri din e-2,4-di amine. )0057] FIGURE 9 illustrates the effects of compounds of the invention for their effect on 1L-2 induced anti-tumor actions. The graph presents representative examples of compounds cited in this application and their effects on IL-2 mediated reductions in metastatic melanoma tumor burden. In the graphs, compound D is N-(2-(lH-indol-2-yl)-phenyl)-phthalamic acid and compound E is 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamine. Invention compound concentrations are listed in parenthesis in mg/lcg while IL-2 concentration is given in parenthesis kilounits. [0058] FIGURES 10 and 11 illustrate the effects of compounds of the invention for their capacity to inhibit IL-2 induced T-cell proliferation. The graphs present representative examples of compounds cited in this application and their effects on T-cell proliferation. In the graphs, compound D is N-(2-(lH-indol-2-yl)-phenyl)-phthalamic acid and compound E is 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diarmne. 10059] FIGURE 12 illustrates the effects of invention compounds for their capacity to inhibit edema associated with Acute Respiratory Distress Syndrome (ARDS). NTH Swiss mice were given an intraperitoneal injection of 1.5 mg/lcg Oleic Acid of (in this example formulated in saline) and/or invention compounds. Four hours subsequent to injection animals were sacrificed followed by collection, blotting and weighing (wet weight) of the lungs. Lungs were then dried at 80°C for 24 hours and weighed (dry weigllt). N-4/group, 6,7-bis(3-hydroxyphenyl)-pteridme-2,4-dianune, sulfate salt (compound E - in the 0.5 rag/kg range, in Ms example formulated in 50% PEG400:50% water) typically reduced ARDS-associated edema by >50% while 4-[4-amino-6-(3,4-dihydroxyphenyl)pteridin-7-yl]benzene-l,2-dio] (compound F - ha the 0.5 mg/lcg range, in this example formulated in 50% PEG400:50% water) typically reduced ARDS-induced edema by >100%. [0060] FIGURE 13 and 14 illustrate the effects of invention compounds for their capacity to inhibit angiogenesis in vivo. The graph presents representative examples of compounds cited in this application which successfully inhibited angiogenesis in vivo. Tumor extracellular matrix infused with the 160 ng of the described growth factors were injected subcutaneously in a Balb/C mouse. The described invention compound was injected daily at the described concentration for 5 days. After 5 days the animals were sacrificed and angiogenesis quantified based on the binding of fluorescently labeled, endothelium specific FITC-lectin. hi the graph, compound A is 6,7-bis(4-hydroxyphenyl)-pteridm-4-ylamine sulfate salt. DETAILED DESCRIPTION OF THE INVENTION |00(il] The invention provides compounds which are vasculostatic agents and methods of use thereof. Invention compounds are useful in treating a variety of disorders, including but 1101 limited to myocardial infarction, stroke, cancer, vascular leakage syndrome (VLS), ocular and retinal disease, bone disease, pleura! effusion, edema, and ischemia. The term "vasculostasis" is hereby defined as referring to the maintenance of ahomeostatic vascular functioning, and "vasculostatic agents" as agents that seek to address conditions in which vasculostasis is compromised by preventing the loss of or restoring or maintaining vasculostasis. [0062] In one embodiment, the present invention provides compounds of structure (I): (Figure Removed) wherein. each R0 is independently -H, -COOH, -OR', -SO3H, wherein R' is -H or lower alkyl, or when x - 2, each ro is taken together to form a 1,3-dioxolyl ring, or each ro is independently allcyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted allcynyl, cycloallcyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylallcenyl, arylalkynyl, substituted arylalkynyl, halogen, amino, amido, nitro, or thioalkyl, ri and Ra are each independently hydrogen, alkyl, substituted allcyl, alkenyl substituted alkenyl, allcynyl, substituted alkynyl, cycloallcyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylallcenyl, arylalkynyl, or substituted arylalkynyl, G is NH, 0, S, or (CR"2)P, wherein R" is -H, lower allcyl, or acetamido, and wherein p is 0-3, Ar is aryl or heteroaryl, and x and y are each independently 0-4. J0063] In one embodiment, ro is -COOH, x = 1, and each R] and R2 is hydrogen. [0064] Exemplary compounds of structure 1 include: (Figure Removed) ) 0065] In another embodiment of the invention, there are provided compounds of structure (II): (Figure Remove) wherein: wherein ro, ri, and R2, x, and y are as defined above. [0066] In one embodiment, ro is -COOH, x = 1, and R] and rt are each hydrogen. [0067] In yet another embodiment of the invention, there are provided compounds of structure (III): (Figure Remove) wherein: Z;-Z(, are each independently C, -C=O, N, or NRa, wherein Ra is -H, alky], or substituted alkyl, wherein said substituents are halogen, hydrox)', oxo. or amino. each X is independently halogen, -ORb, -NRb2, or -SRb, wherein Rb is 4-3 lower alkyl -(CH2)2NH(CH2CH3), -(CH2)3morpholyn-l-yl, -(CH^O^-methylpiperazinj'n-l-yl), aryl, heteroaryl, -(NH-NH-R0), -(N=N-NH-RC), wherein Rc is H or lower alkyl, each Y is independently -ORd, -NRd2, -SRd, or -OPO3H2 wherein Rd is H, lower alkyl, aryl, heteroaryl, -(CH2)2NH(CH2CH3), -(CH2)3iriorpholyn-l-yl, or -(CH2)3(N-methylpiperazinyn-l-yl); or each Y is independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halogen, wherein said substituents are selected from halogen, -ORe, -NRe2, -SRe, -P(O)(OH)2, wherein Re is -H, lower alkyl, aryl, or heteroaryl; or each Y is independently CH2glycinyl, CH2NHethoxy, CH2NHCH2 alkyl, CH2NHCH2t-Bu, CH2NHCH2aryl, CH2NHCH2substituted aryl, CH2NHCH2heteroaryl, CH2NHCH2substituted heteroaryl; or when n is 2, each Y is taken together to form a fused aromatic or heteroaromatic ring system; and m and n are each independently 1 to 4, wherein when Zt, Z3, Z5, and Z6 are each N, X is NH2, and m = n = 2, Y is not phenyl or 4-hydroxyphenyl, or tautomers thereof. [0068] Exemplary compounds of structure HI include pteridines and quinoxalines, such as (Figure Remove) [0069] Particularly effective vasculostatic agents of structure (III) include compounds bearing hydroxy-substituled aryl rings. Exemplar} compounds according to this embodiment are set forth below: (Figure Remove) [0070] An additional exemplary compound of structure (III) is set forth below: (Figure Remove) [0071] Additional exemplary compounds of structure (III) include pteridines having the structure: (Figure Remove) wherein when X] = Xj = -NHR, wherein R is -H, aryl, or substituted aryl, Yj and Y2 include but are not limited to the following structures III-l to 111-24: in-i ffl-2 m-3 in-4 ni-s ffl-6 m-7 II1-8 m-9 m-io iii-ii in-12 in-i3 ra-i4 m-is 111-16 111-17 m-i8 m-i9 IH-20 in-21 m-22 m-23 in-24 Structure Y, C6H5 H C6H5 4- CelitOH H 3,4-C6H3(OH)2 H 4-C6KUF C6H5 4- CetLjBr C6H5 4- 4- 3- 4- C6H4OMe CeEUOMe C6H4OH 3- C6H4OH 3,4-C6H3(OH)2 yi and Y? taken group Y2 H C6H5 H 4- C6H4OH H 3,4-C6H3(OH)2 4- 4- C6H4OPh C6H5 4- C6H4OH C5H4N (pyr) 4-CetLtF C6H4F C6H4OMe C6H4OMe C6H40H 3- C6H4OH 354- C6H3(OH)2 together to form a phenathrolinyl [0072] Further exemplary pteridrnes have the structure X] = X2 = OR, wherein R is -H, aryl, or substituted aryL and Y] and y: include but are not limited to the following the structures 111-25 to III-48: 4- C6H4OH C5H4N(pyr) 4-C6H4F 4- C6H4OMe 4- C6H4OH 3- C6H4OH 3,4-C6H3(OH)2 yi and Y2 taken together to form a phenathrohityl group Structure ffl-25 10-26 111-27 111-28 111-29 ffl-30 111-31 HI-32 111-33 111-34 m-35 111-36 111-37 HI-38 111-39 ni-40 in-41 111-42 111-43 m-44 m-45 m-46 111-47 ni-48 H C6H5 4- CeEUOH H 3,4- C6H3(OH)2 H 4- C6HUF 4- 4- 4- C6H4OH C6H5 C5H4N(pyr) 4- 3- 4- 3- 4- C6HL|OH 3- CeBUOH 3,4- C6H3(OH)2 H H 4- C6H4OH H 3,4- C6H3(OH)2 4- C6H4F 4- C6H4Br C6H5 4- C6H4OPh [0073] Further exemplary pteridines have the structure X) = OR and xt = NHR, wherein R is -H, aryl or substituted aryl. and Y] and Y2 include but are not limited to the following structures 3-C6Fi4F 4- C6FL)OMe 3- 4- 3- 3,4- C6H3(OH)2 yi and Y2 taken together to form a phenathroliny] group Structure 111-49 IH-50 m-si IH-52 m-53 m-54 111-55 m-56 m-57 ffl-58 ni-59 m-60 ni-6i HI-62 ra-63 111-64 in-65 UI-66 IH-67 HI-68 HI-69 m-70 ni-7i 111-72 H 4- C6H4OH H 3,4- C6H3(OH)2 H 4- C6H4F C6H5 4- C6Fi4Br 4- C6H4OPh 4-C6H5 4- 3-C6Fi4F 4- 3- 4- C6EUOH 3- C6H4OH 3,4- C6H3(OH)2 Y; H H 4- H 3,4- C6H3(OH)2 C6H5 4- C6H4F C6H5 4- C6Fi4Br C&H5 4- C6FL|OPh 4- sH4N (pyr) J0074J Further exemplary pteridines have the structure ~X\ = NHR and xt — OR, wherein R ie -H, aryl or substituted aryl., and yi and Y2 include hut are not limited to the following structures Structure 111-73 III-74 111-75 111-76 111-77 111-78 111-79 111-80 111-81 111-82 111-83 111-84 111-85 m-86 111-87 111-88 m-89 m-90 111-91 ni-92 111-93 in-94 111-95 IU-96 \7i H C6H5 C6H5 H 4-H 3,4- C6H3(OH)2 H CfiHs 4- C6a,OH H 3,4- C6H3(OH)2 H 4- C6H5 4- C&H5 4- C6 4- C6H4F C6H5 4- C6H4Br CoHs 4- C6H5 4- CeBUOH 4- 4- 4- 3- 4- C6H4OH 3- C6H4OH 3,4- C6H3(OH)2 4-3-4- C6H4OMe C6H4OMe C6H4OH 3- C6H4OH 3,4- C()H3(OH)2 Yi and group taken together to form a phenathrolinyl [0075] Additional exemplary pteridines have the structure (Figure Remove) wherein X] -- NPIR, wherein R is -H, aryl or substituted aryl, and yi and Y? include but are not limited to the following structures: Structure m-97 111-98 iH-99 iH-ioo in-ioi m-102 in-103 ra-104 ra-ios in-106 111-107 hmos ra-i09 m-no iii-ii] m-112 Y, CcH5 H CcH5 4- C6H4OH H 3,4- C6H3(OH)2 H 4- C6H5 4- 4- 4-C6H5 (pyr) H C6H5 H 4- H 3,4- C6H3(OH)2 4- 4- C6H5 4- C6H4OPh 4- (pyr) yi and Y2 taken together to form a phenatlirolinyl group. 111-114 m-ii5 ra-116 m-ii7 m-118 IH-119 m-120 4- 4- CeHUOMe C6H4OH 3- C6H4OH 3,4- C6H3(OH)2 4- C6IL)OMe 3- 4- 3- C6IL,OH 354-C6H3(OH)2 |0076] Still further exemplary pteridines have the structure: (Figure Remove) wherein Xi = NHR, wherein R is -H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: Structure ffl-12] III-122 m-123 III-124 IIM25 III-126 III-127 HI-128 m-129 II1-I30 ra-132 m-i33 in-i34 III-135 m-i36 ra-i37 in-138 ra-139 in-140 III-143 m-142 m-143 m-144 Y, H Cerli H 4- Ce H 3,4- ( H C6H5 4- CeHUOH H 3,4- C6H3(OH)2 H 4- C(-,H4F C( f^ TT A v^5Jrl5 m— 4- C6H4OPh C6H5 4- C6H4OPh 4- CeftOH CeHs CsBL^I (pyr) 4- 3- 4- CeHjOMe 3- C6EUOMe 3- C6a,OH 3,4- C6H3(OH)2 CsHUN (p>t) 4- 3- 4- C6HLiOMe 3- 4- 3- 3,4-C6H3(OH)2 yi and Y2 taken together to form a phenathrohnyl group. [0077] Additional exemplary pteridines have the structure (Figure Remove) wherein Xi = OR, wherein R is -H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: Structure in-145 IIi-146 H Y; H. C6H5 4- 3- 4- 3- C6FL,OH 3,4- C6H3(OH)2 yi and Y2 taken together to form a phenathrolrny] group. IIM47 III-148 III-149 id-iso iii-isi ID-152 III-153 III-154 III-155 ID-156 m-157 III-158 III-159 111-160 III-161 III-162 in-163 IH-164 III-165 in-166 111-167 in-168 4- C6H4OH H 3,4- C6H3(OH)2 H 4- CCH4F 4- 4- (pyr) 4- C6H5 H 4- H 3,4- C6H3(OH)2 C6H5 4- C6H4F 4- CeEUBr Cfjis 4- CeHUOPh C6H5 4- C6H4OH (pyr) CeHUF C6Fi40Me CeHUOMe C6FL,OH 3- C6F£40H 3,4- C6H3(OH)2 10078] Additional exemplary pteridines have the structure (Figure Remove) wherein X] = OR, wherein R is -H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: Structure Yj Y2 ni-169 m-i7o in-hi III-172 in-i73 m-174 m-i75 III-l 76 III-177 H C6H5 4- H 3,4- CCH3(OH)2 H 4- H H 4- C6FL,OH H 3,4- C6H3(OH)2 4- ffl-178 111-179 Ill-ISO m-181 111-182 m-i83 III-184 m-185 m-i86 m-1 87 III-188 ffl-189 ffl-190 111-191 in-192 4-C6H4Br C6H5 CfiHs 4- C6H4Br 4- C6H4OPh C5H5 C6FI5 4- C6H4OPh 4- C6IL|OH CgHs (pyr) 4- C(,H4F 3- C6H4F 4- 3- 4- C6H4OH 3,4- C6H3(OH)2 4- C6H4OH CsFLtN (pyr) 4-CcH4F" 3-( 4-( 3- C6H4OMe 4-( 3-( 3,4- C6H3(OH)2 yi and Y2 taken together to form a phenathrolinyl group. [0079J In further embodiments, exemplary pteridines have the structure: (Figure Remove) wherein X, - X2 = Cl or NHR, wherein R is H, (CH2)2NHEt, (CH2)3morpholyn-l-yl, (CH2)3(N-methylpiperazinyn-l-yl); yi = CH2glycinyl, CH2NHethoxy, CH2NHCH2aUcyl, CH2NHCH2t-Bu, CH2NHCH2aryl, CH2NHCH2substiruted aryl, CFI2NHCH2heteroaryl, CH2NHCH2substituted heteroaryl with substituents being OH, and OMe, and Y2 includes but is not limited to the following structures: Structure III-193 ffl-194 111-195 III-196 111-197 III-198 111-199 111-200 Y2 H 4- 3- 2- naphthyl isonaphthyl 4-tBuphenyl m-201 IH-202 III-203 III-204 III-205 III-206 III-207 III-208 III-209 111-210 Hl-211 biphenyl 2, 3-di-methylphenyl fluorenyl oxophenyl thioindole C5H4N (pyr) 4-3- 4- C6H4OMe 3- CcHUOMe - [0080] Additional exemplary compounds of structure (El) include compounds having the structure: (Figure Remove) wherein Xj = NHR, wherein R is H, aryl or substituted aryl, and Yj and Y2 include but are not limited to the following structures: Structure in-212 III-213 III-214 III-215 UI-216 III-217 IH-218 m-219 III-220 III-221 III-222 III-223 IH-224 III-225 111-226" 111-221 HI-228 Y, C6H5 H C6H5 4- H 3,4- C6H3(OH)2 H 4- 4- 4-Ce 4- C5IL)N (pyr) 4- Y2 H C6H5 H 4-H 3,4- C6H3(OH)2 4- 4- C6H5 4- (pyr) 4- yi and yt taken together to form a phenathrolinyl group. III-229 III-230 III-231 in-232 IH-233 HI-234 III-235 C6H4F C6H4OMe C6H4OMe C6H4OH 3- C6FL,OH 3,4- C6H3(OH)2 C6H4F C6H4OMe C6H4OMe CfiFuOH 3- CeHUOH 3,4- C6H3(OH)2 10081 ] Still further exemplary compounds of structure (III) include the following: (Figure Remove) wherein X] = OR, wherein R is H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: Structure III-236 III-237 III-238 III-239 ni-240 III-241 ffl-242 UI-243 III-244 111-245 m-246 IH-247 III-248 ID-249 III-250 III-251 III-252 ffl-253 III-254 III-255 H C6H5 4- CeHUOH H 3,4- C6H3(OH)2 H 4- 4- 4- C6H4OPh C6H5 4- (pyr) 4- C6 C6 C6H4OMe 3- Y2 H C6H5 CfiHs H 4- H 3,4- C6H3(OH)2 C&H.5 4- C6H4F C6H5 4- C6H5 4- 4- CsFLtN (pyr) 4- 3- 4- CeBUOMe 3- Cs'FLtOMe III-256 HI-257 III-258 III-259 42 4- C(1H4OH 4- 3- C6H4OH 3- 3,4- C6H3(OH)2 3,4- C6H3(OH)2 yi and Y2 taken together to form a phenathrolinyl group. [0082] Compounds of structure (III) also include the following: [0083] wherein X] - NHR, wherein R is H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: yi and Y2 taken together to form a phenathrolinyl group. Structure IU-260 m-261 m-262 111-263 III-264 m-265 m-266 111-267 III-268 III-269 m-270 m-271 111-272 ID-273 HI-274 III-275 HI-276 111-277 III-278 HI-279 m-280 111-281 111-282 III-283 C6H5 H 4- C5a,OH H 3,4- C6H3(OH)2 H 4- C6H5 4- C6H5 4- C6HUOPh C6H5 4- (pyr) 4- 4- C6rL)OMe 3- 4- 3- 3,4- C6H3(OH)2 Y2 H C6H5 C6H5 H 4- H 3,4- C6H3(OH)2 C6H5 4- 4- Ce C6H5 4- 4- C5EUN (pyr) 4- 3- 4- C6H4OMe 3- 4- 3- 3,4-C6H3(OH)2 10084] Still further exemplar)' compounds of structure (IE) include; (Figure Remove) wherein Xj = OR, wherein R is H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: Y2 H H 4-H 3,4- C6H3(OH)2 4- C6BUF CeEUF CeBUOMe C6H4OMe C6H4OH 3- CeEUOH 3J4-C6H3(OH)2 Structure III-284 Ifl-285 ni-286 III-287 III-288 ffl-289 IU-290 m-291 III-292 III-293 111-294 III-295 III-296 ID-297 III-298 III-299 m-300 III-301 III-302 III-303 III-304 III-305 ID-306 in-307 H Ce 4- H 3,4- C6H3(OH)2 H 4- C6H4F C6H5 4- C6H4Br C6H5 4- CeHUOPh 4- CeFLjF 4- C6H5 4- CcILjOPh C6H5 4- C6BUOH 4- C6H5 C5H4N (pyr) 4- C6BUF 3- 4- 3- 4- C6H4OH 3- C6FL,OH 3,4- C6H3(OH)2 yi and Y2 talcen together to form a phenathrolinyl group. 10085] Additional exemplar)' compounds of structure (III) include quinoxalines having the structure: (Figure Remove) wherein Xi = NHR and Xi = NHR, wherein R is H, aryl or substituted aryl, and Yj and Y? include but are not limited to the following structures: (pf) 4- CeH4F 3- 4- 3- 4- 3- 3,4- C6H3(OH)2 yi and Y2 talcen together to form a phenathrolinyl group. Structure III-308 III-309 III-310 III-311 III-312 m-313 m-314 m-3i5 m-3i6 ni-317 m-3i8 m-3i9 IH-320 m-32i III-322 III-323 III-324 ffl-325 m-326 UI-327 III-328 IH-329 m-330 IH-331 Y, H C6Hs 4- C6H4OH H 3,4- C6H3(OH)2 H 4-C6H4F C6Hs 4- 4- 4- CeHjOH H H 4- H 3,4- C5H3(OH)2 CeHs 4- C5H4F C6H5 4- 4- CeHs 4- CeH4OH 4- 3- 4- C6H4OMe 3- 4- 3- CeKUOH 3,4- C6H3(OH)2 10086] Additional quinoxalines contemplated for use in the practice of the invention include the following: (Figure Remove) wherein Xj = X2 = OR, wherein R is -H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: H 4- H 3,4- CCH3(OH)2 H 4- 4- 4- 4- Structure m-332 m-333 m-334 111-335 in-336 IH-337 m-338 III-339 III-340 in-341 m-342 111-343 111-344 Hl-345 HI-346 111-347 III-348 111-349 m-350 m-353 III-352 III-353 HI-354 ID-355 H C6H5 H 4- C6H4OH H 3,4- C6H3(OH)2 C6H5 C6H5 4- C6H5 4- C6H4OPh C6H5 4- C6HUOH C5a,N (pyr) 4- 3- 4- C6H4OMe C6H40Me C6a,OH 3- C6a,OH 3,4- C6H3(OH)2 C5H4N (pyr) 4- C6H4F 3- 4- C6H4OM6 C6H4OH 3- C6H4OH 3,4- C6H3(OH)2 yi and Y2 taken together to form a phenathrolinyl group. [0(187] Still further exemplary quinoxalines include: (Figure Remove) wherein -when Xi - OR and xt = NHR, wherein R is H, aryl or substituted aryl, and Y] and y:> include but are not limited to the following structures: C6H5 H 4- H 3,4- C6H3(OH)2 H 4- 4-C6H5 4- C5H4N(pyr) 4- Structure ID-356 III-357 IU-358 HI-359 III-360 111-361 ni-362 IH-363 m-364 IH-365 in-366 III-367 III-368 m-369 HI-370 ra-371 111-372 m-373 111-374 III-375 III-376 III-377 III-378 IH-379 Y2 H C6H5 C&H5 H 4- CeHUOH H 3,4- C6H3(OH)2 C6H5 4- C6H5 4- CeHUOPh C6H5 4- C6H4OH C5H4N(pyr) 4- 3- 4-3-4-3-3,4- C6H3(OH)2 4- CeHUOMe 3- 4- 3- 3,4- C.6H3(OH)2 yi and Y2 talcen together to form a phenathrolinyl group. |0088] Additional exemplary quinoxalines have the structure: (Figure Remove) wherein Xi = NHR and X2 - OR, wherein R is H, aryl or substituted aryl, and Y] and Y2 include but are not limited to the following structures: Y] and Y2 taken together to form a phenathrolinyl group. Structure III-380 III-381 III-382 ID-383 m-384 III-385 111-386 HI-387 111-388 ffl-389 m-390 m-391 111-392 ffl-393 HI-394 ni-395 III-396 III-397 111-398 III-399 in-400 111-401 III-402 III-403 Y, H 4- H 3,4- C6H3(OH)2 H 4- 4-C6H5 4- 4- (pyr) 4- C6H4F 3- C6H4F 4- 3- 4- 3- 3,4- C6H3(OH)2 Y2 H H 4-H 3,4- C6H3(OH)2 4- C6H5 4-C6H5 4- C6H5 4- CeEUOH CsH4N (pyr) 4- CeHtF 3- C6H4F 4- 3- 4- 3- C6H4OH 3,4- C6H3(OH)2 [01)89] Still further exemplary quinoxalines have the structure: (Figure Remove) wherein Xi = NHR, wherein R is H, aryl or substituted aryl, and Yj and Y2 include but are not limited to the following structures: Structure yi Y2 4- CeHUF 4- C6H4OMe 3- 4- 3- 3,4- C6H3(OH)2 yi and Y2 talcen together to form a phenathrolinyl group. III-404 III-405 HI-406 ffl-407 ffl-408 ffl-409 111-410 m-411 III-412 ffl-413 m-414 m-415 m-416 m-4i7 III-418 m-419 III-420 m-42i IIT-422 m-423 III-424 HI-425 HI-426 III-427 C6H5 H C6H5 4- H 3,4- C6H3(OH)2 H CeH5 4- C6BUBr 4- 4-C6H5 H CeH5 H 4- H 3,4- C6H3(OH)2 C6H5 4- CeHUF C6H5 4- CeRiBr 4- C6H5 4- C6 C6HUF CeH^OMe C6H4OMe C6HUOH 3- CeHtOH 3,4-CeH3(OH)2 [0090] Additional exemplary quinoxalines have the structure: (Figure Remove) wherein Xi = NHR, wherein R is H, aryl or substituted aryl, and Y] and Y2 include but are not limited to the following structures: 4- 4- C6H4OPh C6H5 4- CcH^OH C6H5 (pyr) Structure III-428 m-429 111-430 III-431 m-432 IU-433 III-434 ffl-435 III-436 m-437 III-438 III-439 ITI-440 III-441 IE-442 ni-443 III-444 III-445 III-446 III-447 IH-448 III-449 III-450 III-451 Y2 H C6H5 Y, H H 4- C6H4OH H 3,4- C6H3(OH)2 C5H5 4- H 3,4- C6H3(OH)2 H 4- C6H5 4- C6 4- C6HUOPh 4- C6H4OH CAN (pyr) 4- 3- 4- C6HL,OMe C6H4OH 3- CelLtOH 3,4- C6H3(OH)2 4- C6H4OMe 3- 4- 3- C6H4OH 3,4- C6H3(OH)2 Yi and Yo talcen together to form a phenathrolinyl group. [00.91] Still farther exemplary quinoxalines have the structure: (Figure Remove) wherein X) = OR, wherein R is H, aryl or substituted aryl, and Yj and Y2 include but are not limited to the following structures: Structure 111-452 III-453 m-454 HI-455 111-456 III-457 Hl-458 IE-459 III-460 m-461 III-462 111-463 III-464 m-465 HI-466 111-467 III-468 111-469 III-470 HI-471 111-472 III-473 III-474 XEM75 Y2 H Y, C6H5 H H 4-H 3,4- C6H3(OH)2 4- CeELtOH H 3,4- C6H3(OH)2 H 4- C6H4F 4- 4- 4- C6H5 4- 4- CeHtOPh 4- C6FL,OH 4- CeBUOH C6H5 (pyr) 4- 3-4- C6IL,OMe CtlLiOH 3- C6H4OH 3,4- C6H3(OH)2 3-4- 3- 4- 3- C6H4OH 3,4- C6H3(OH)2 Yi and y: taken together tn form a phenathrolinyl gi'oup. [0092J Further exemplary quinoxalmes have the structure: (Figure Remove) wherein X\ - OR, wherein R is H, ary] or substituted aryl, and yi and Yi include but are not limited to the folio wine, structures: Y2 H Structure 111-476 111-477 III-478 III-479 ni-480 UI-481 III-482 III-483 HI-484 III-485 III-486 III-487 111-488 m-489 III-490 III-491 m-492 m-493 111-494 111-495 ffl-496 III-497 111-498 III-499 H Cells H 4-H 3,4- C6H3(OH)2 4- cc.huoh H 3,4- C6H3(OH)2 H 4- 4- C6H4F C6H5 4- C6H5 4- 4- C6H4OPh 4- 4- 4- C5H4N (pyr) 4- 3- 4- 3- 4- 3- C6a,OH 3,4- C6H3(OH)2 C5H4N (pyr) 4- 3- 4- 3- C6Fi4OMe 4- 3- 3,4- C6H3(OH)2 yi and yt taken together to form a phenathrolinyl group. 10(193] Still further exemplar}' compounds of structure (III) include: (Formula Remove) wherein Xi - NHR, wherein R is H, aryl or substituted aryl, and 1101 limited to the following structures: and Y2 include hut are Y2 H H 4-H 3,4- C6H3(OH)2 4- C6H4OMe 3- 4-3-3,4- C6H3(OH)2 Structure III-500 III-501 HI-502 III-503 III-504 HI-505 in-506 II1-507 id-sos 111-509 III-510 m-5ii m-5i2 m-513 in-514 IH-515 m-516 ill-si? m-518 III-519 III-520 m-52] ffl-522 ni-523 H 4- H 3,4- C6H3(OH)2 H 4- 4- C6H5 4- C6EUOPh C6H5 4- C6H5 4- 4-C5H4N(Pyr) C6H5 C5H4N (pyr) 4- 3- 4- 3- 4- CeRtOH 3- C6H40H 3,4- C6H3(OH)2 yi and Ya taken together to form a phenathrolinyl group. [0094] Additional compounds of structure (III) include the following: wherein X i = OR, wherein R is H, aryl or substituted aryl, and yi and Y2 include but are not limited to the following structures: 4- Structure III-524 III-525 ffi-526 III-527 111-528 III-529 III-530 III-531 III-532 III-533 III-534 III-535 111-536 III-537 III-538 III-539 ffl-540 in-541 111-542 III-543 III-544 III-545 111-546 III-547 Y2 H Y, C6H5 H H 4- C6IL,OH H 3,4-C6H3(OH)2 4- H 3, 4- C6H3(OH)2 H 4- 4- 4- C6BUBr CeHs 4- C6HUOPh 4-C 4- Ctfis 4- C6H4OH (pyr) 4- CgH^F 4- C6H,OMe C6H4OMe C6H4OH 3- C6H4OH 3,4- C6H3(OH)2 C6HUF C6H4OMe C6H4OMe CdlitOH 3- C6H4OH 3,4- C6H3(OH)2 yi and Y2 taken together to form a phenathrolinyl group. J0095] Still further exemplary compounds of structure (HI) include: (Figure Remove) wherein Y] and Y2 include but are not limited to the following structures: Structure HI-547 III-548 III-549 III-550 III-551 111-552 m-553 III-554 III-555 m-556 HI-557 HI-558 III-559 III-560 III-561 III-562 III-563 Y2 H C6H5 H H 4- CeEjOH 3, 4- C6H3(OH)2 4- 4- 4- C6H4OPh 4-CsBUNCpyr) 4- 3- C6H4OMe 3- C6H4OH 3,4- C6H3(OH)2 4- C6a,OMe 3- 4- 3- 3,4- C6H3(OH)2 Y] and Y2 taken together to form a phenathrolinyl group. [0096] Additional exemplary compounds of structure (HI) include: (Figure Remove) wherein X] = NHR, wherein R is H, aryl, substituted aryl, or aroyl, yi = NHR, or R, wherein R = H, alky] or branched allcyl, and Y2 includes but is not limited to the following structures: Structure Y2 III-564 C6HS III-565 H III-566 4- C6tL,OH III-567 3- C6H40H IH-568 2- CeH^OH HI-569 naphthyl 111-570 isonaphthyl ffl-571 4-tBuphenyl III-572 biphenyl 111-573 2,3-diMephenyl IIJ-574 fluorenyl III-575 oxophenyl III-576 thioindole m-577 C5H4N (pyr) 111-578 4- C6H4F 111-579 3- C6H4F III-580 4- C6H40Me III-581 3- C6H4OMe III-582 2- C6HiOMe 10097] Still further exemplary compounds of structure (in) include asymmetric triazines, such as : (Figure Remove) wherein yi = NHR or R, -wherein R = H, alkyl or branched alkyl, and Y2 includes but is not limited to the following structures: Structure yz III-583 C6H5 III-584 H III-585 4- C6H40H 111-586 3- Cf,H4OH 111-587 2- C5a,OH 111-588 naphthyl III-589 isonaphthyl III-590 4-tBuphenyl m-591 m-592 111-593 111-594 III-595 111-596 III-597 111-598 in-599 111-600 III-601 biphenyl 2, 3-diMephenyl fluorenyl oxophen}'! tliioindole C5H4N (pyr) 4- C6H4F 3- 4- 3- C6tL)OMe 2- C6H4OMe [0098] In yet another embodiment of the invention, compounds are provided having structure (IV): (Figure Remove) wherein: L is an arylene, substituted arylene, oxyarylene, or substituted oxyarylene linlang moiety, C is 5- or 6-menibered 'aromatic or heteroaromatic ring, each X is independently OR, NR2, or SR, wherein R is H or lower alkyl, Z.i-Zj are each independent])' CH or N, and rn is 1 to 4. (0099] In some embodiments, the linldng moiety L is an arylene moiety, and Z is N, as exemplified by the following structures: (Figure Remove) wherein, Z = N or CH, X, = H or OH, and X2 = NH2 or OH. 10100] In another embodiment, the linldng rnoiety L is an oxyarylene moiety, as exemplified by the following structures: (Figure Remove) whereua, Z - N or CH, X, = H or OH, and X2 = NH2 or OH. [OJ01] In still another embodiment, compounds are provided having the structure (V): (Figure Remove) wherein: ri , x, and y are as defined above, R3 is -H, -SO3H, or -SO2NMe2, M is NH, CO, SO2, (CH2)p, wherein p is 0 to 2, G is aryl or heteroaryl, and x and y are each independently 0-4. In an additional embodiment, there are provided bis-pteridine compounds. An exemplary bis-pteridine compound according to the invention has the structure: (Figure Remove) [0102] As used herein, the term "heterocyclic", when used to describe an aromatic ring, means that the aromatic ring contains at least one heteroatom. As used herein, the term "heieroatom" refers to N, 0, S, and the like. f 0103] As used herein, the term "allcyl" refers to a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, including methyl, ethyl, n-propyl, isopropyl. n-butyl, isobufyl, tert-butyl, n-hexyl, and the like. [0104] As used herein, "substituted alky!" refers to alley! groups further bearing one or more substituents selected from hydroxy, alkoxy, mercapto, cycloallcyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryl ox y, substituted aryloxy, halogen, cyano, nitro, aniino, amido, -C(O)H, acyl, oxyacyl, carboxyl. sulfonyl, sulfonarnide, sulfuryl, and the like. [0105] As used herein, "lower alky]" refers to alley! groups having from 1 to about 6 carbon atoms. JO! 06] As used herein, "alkenyl" refers to straight or branched chain hydrocarbyl groups having one or more carbon-carbon double bonds, and having in the range of about 2 up to 12 carbon atoms, and "substituted alkenyl" refers to alkenyl groups further bearing one or more substituents as set forth above. [0107] As used herein, "alkynyl" refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms, and "substituted alkynyl" refers to alkynyl groups further bearing one or more substituents as set forth above. [0108] As used herein, "aryl" refers to aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted aryl" refers to aryl groups further bearing one or more substituents as set forth above. [0109] As used herein, "heteroaryl" refers to aromatic rings containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and "substituted heteroaryl" refers to heteroaryl groups further bearing one or more substituents as set forth above. [0110] As used herein, "alkoxy" refers to the moiety -O-alkyl-, wherein alkyl is as defined above, and "substituted alkoxy" refers to alkoxyl groups further bearing one or more substituents as se1 forth above. 10111] As used herein, "cycloalkyl" refers to ring-containing alkyl groups containing in the range of about 3 up to 8 carbon atoms, and "substituted cycloalkyl" refers to cycloalkyl groups further bearing one or more substituents as set forth above. [0112] As used herein, "heterocyclic". when not used with reference to an aromatic ring, refers to cyclic (i.e., ring-containing) groups containing one or more heteroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and "substituted heterocyclic" refers to heterocyclic groups further bearing one or more substituents as set forth above. [0113] As used herein, "alkylaryl" refers to alkyl-substituted aryl groups and "substituted alkylaryl" refers to alkylaryl groups further bearing one or more substituents as set forth above. [0114] As used herein, "arylalkyl" refers to aryl-substituted alkyl groups and "substituted aryl alkyl" refers to arylalkyl groups further bearing one or more substituents as set forth above. [0115] As used herein, "arylallcenyl" refers to aryl-substituted alkenyl groups and "substituted arylalkenyl" refers to arylalkenyl groups further bearing one or more substituents as set forth above. [0116] As used herein, "arylalkynyl" refers to aryl-substituted alkynyl groups and "substituted arylalkynyl" refers to arylalkynyl groups further bearing one or more substituents as set forth above. [Oil 7] As used herein, divalent aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted aryl en e" refers to arylene groups further bearing one or more substituents as set forth above. [0118] As used herein, "oxyarylene" refers to the moiety "0-arylene", wherein arylene is as defined above arid "•substituted oxyarylene" refers to oxyarylene groups further bearing one or more substituents as set forth above. 101 19] Invention compounds can be prepared by a variety of methods well-known to those skilled in the art. .For example. Scheme A illustrates three exemplary syntheses for invention compounds of structure (I). Scheme A (Figure Remove) [0120] Scheme B illustrates an exemplary synthesis for invention compounds of structure (H). Scheme B (Formula Remove) [0121] Scheme C illustrates two of several exemplary sjtitheses for invention compounds of structure (III). Scheme C (Figure Remove) [0122] Scheme D illustrates an exemplary synthesis for invention compounds of structure (IV). Scheme D (Formula Remove) [0123] Scheme E below iDustrates an exemplary synthesis for compounds of structure (V). Scheme E (Figure Remove) |0124] In a further embodiment of the invention, there provided methods for treating a disorder, comprising administering to a subject in need thereof an effective amount of a compound having the structure (VI): (Figure Remove) wherein: A and B are each independently 5- or 6-membered aromatic rings, wherein at least one of A and B is an aromatic heterocyclic ring having at least one heteroatom in the heterocyclic ring, each X is independently OR, NRa, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl. arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, and m and n are each independently 1 to 4, thereby treating the disorder. [0125] Rings A and B taken together may form a variety of fused aromatic heterocyclic groups suitable for use in the practice of the present invention. For example, rings A and B taken together may form aromatic heterocycles such as quinoxaline, pteridine, benzoxazine, benzoxazole, benziniidazole, 1,2-benzodiazole, iridole, isoindole, quinoline, isoquinoline, plithalazine, naphthyridine, quinazoline, cinnoline, purine, benzothiazole, benzofuran, isobenzofuran, benzothiophene, chroinene, and the like. In one embodiment, rings A and B taken together form a quinoxaline. In a further embodiment, rings A and B taken together form a pteridine. In a still further embodiment, rings A and B taken together form a benziniidazole. [0126] Quinoxalines contemplated for use in the methods of the present invention have the structure: (Figure Remove) wherein: each X is independently H, OR, NRa, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylallcyl, substituted arylallcyl, arylalkenyl, substituted arylallcenyl, arylalkynyl, substituted arylalkynyl, with fee proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, m is 1 to 4, and n is 1 or 2. [0] 27] In one embodiment, quinoxalines contemplated for use in the methods of the present invention have the structure: (Figure Remove) wherein: X is OR, NR2, or SR, wherein R is H or lower alkyl, Y is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and n is 1 or 2. [0128] Pteridiiies contemplated for use in the methods of the present invention have the structure: (Figure Remove) wherein: each X is independently H, OR, NRi, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, alkyl, substituted alkyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylallcenyl, substituted arylalkenyl arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl., with the proviso that at. least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, and m and n are each independently 1 or 2. |0129] In one embodiment, pteridines contemplated for use in the methods of the present invention have the structure: (Figure Remove) wherein: X is OR, NRi, or SR, wherein R is H or lower alkyl, Y is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and n is 1 or 2. {0130] Benzimidazoles, oxazoles, or thiazoles contemplated for use in the methods of the present invention have the structure: (Figure Remove) wherein: Z is i\T, 0, or S, each X is independently H, OR, NR2, or SR, wherein R is H or lower alkyl, each Y is independently hydrogen, allcyl, substituted alkyl, alkenyl substituted allcenyl, alkynyl, substituted allcynyl., cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylallcyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso that at least one Y is not hydrogen, or when n is 2, each Y is taken together to form a fused aromatic ring system comprising at least one aromatic ring, and m is 1 to 4, and n is 1 or 2. [0131] hi one embodiment, benzimidazoles contemplated for use in the methods of the present invention have the structure: (Figure Remove) wherein: alky], each X is independently H, OR, NR2, or SR, wherein R is H or lower Y is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and IT! JS 1-4. [0132] In a further embodiment of the invention, there are provided methods for treating a disorder such as those associated with vascular permeability and/or angiogenesis and/or other aspects of compromised vasculostasis including administering to a subject in need thereof an effective amount of a compound having structure (VII): (Figure Remove) wherein: A , B, C, and D are each independently C, N, O, or S, each X is independently H, OR, NR.2, or SR, wherein R is H or lower allcyl, each Y is independently hydrogen, allcyl, substituted alkyl, allcenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylallcenyl, substituted arylallcenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, or substituted acyl, with the proviso feat at least one Y is not hydrogen, and m and n are each independently 1 to 4, thereby treating the disorder. J0133] In one aspect of this embodiment, the compound has the structure: (Figure Remove) (Figure Remove) wherein: each X is independently H, OR, NR.2, or SR, wherein R is H or lower alkyl, each Y is independently aryl or substituted aryl, m is 1 or 2, and n is 1-4. |0'J 34] In a further aspect of this embodiment, the compound has the structure: (Figure Remove) 10135] In one embodiment, the present invention is based on the discovery that a combination therapy including interleukirt-2 (IL-2) and chemical compounds described herein, some of which are effective kinase inhibitors, administered during IL-2 therapy, mitigates or lessens the adverse effects.of IL-2. While not wanting to be bound by a particular theory, n is likely that the effect occurs while preserving or enhancing the beneficial effect of IL-2 such that the disease or disorder is treated. While IL-2 is described in the present application as an illustrative example, it should be understood that the invention includes cornbination therapy including a compound of the invention, including bul not limited to vasculostatic agents, such as tyrosine, serine or threonine lanase inhibitors, for example. Src-family inhibitors, and immunomodulatory molecules, hi particular, such immunomodulatory molecules include those that result in vascular leakage. Cytokines, and in particular IL-2, are examples of such immunomodulatory molecules. 10136] Such inhibitors, in combination with IL-2, are effective in blocking vascular leakage typically associated with IL-2 adminstration. Thus, compositions and methods are provided for treating disorders associated with VLS. hi one embodiment, the invention provides a composition containing a therapeutically effective amount of IL-2 and a vasculostatic agent or compound as described herein in a pharmaceutically acceptable carrier. J0137] Some of the compounds are kinase inhibitors, such as Src-family tyrosine kinases, and therefore are useful in treating a wide variety of disorders resulting from aberrant kinase activity, in addition to treating disorders associates with LL-2 administration. Kinase-associated disorders are those disorders which result from aberrant kinase activity, and/or which are alleviated by the inhibition of one or more enzymes within a kinase family. For example, Lck inhibitors are of value in the treatment of a number of such disorders (e.g., the treatment of autoimmune diseases), as Lck inhibition blocks T cell activation. Similarly, Src family inhibitors are of value in treating a variety of cancers as Src inhibition impacts tumor cell invasion, metastases and survival. [0138] The compounds and methods of the present invention, either when administered alone or in combination with other agents described herein (e.g., chemotherapeutic agents or protein therapeutic agents) are useful in treating a variety of disorders associated with compromised vasculostasis including but not limited to, for example: stroke, cardiovascular disease, myocardial infarction, congestive heart failure, cardiomyopathy, myocarditis, ischemic heart disease, coronary artery disease, cardiogenic shock, vascular shock, pulmonary hypertension, pulmonary edema (including cardiogenic pulmonary edema), cancer, pleural effusions., rheumatoid arthritis, diabetic retinopathy, retinitis pigmentosa, and retinopathies, including diabetic retinopathy and retinopathy of prematurity, inflammatory diseases, restenosis, edema (including edema associated with pathologic situations such as cancers and edema induced by medical interventions such as chemotherapy), asthma, acute or adult respiratory distress syndrome (AKDS), lupus, vascular leakage, transplant (such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)) rejection; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, transplantation tolerance induction; ischemic or reperfusion injury following angioplasty; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus crythematosis); graft vs. host diseases; T-cell mediated hypersensitiviiy diseases, including contact hypersensitivity, delayed-type hypersensitivity., and gluten-sensitive enteropathy (Celiac disease); Type 1 diabetes; psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; AutoimimmeHyperthyroidism, such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; cancers, including those where kinases such as Src-family kinases are activated or overexpressed, such as colon carcinoma and thymoma, or cancers where Idnase activity facilitates tumor growth or survival; glomerulonephritis, serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hayfever, allergic rhinitis) or skin allergies; mycosis fungoides; acute inflammatory responses (such as acute or adult respiratory distress syndrome and ischemia/reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease: Pustulosis paknoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopic dermatitis; systemic schlerosis; morphea; peripheral limb ischemia and ischemic limb disease; bone disease such as osteoporosis, osteomalacia, hyperparathyroidism, Paget's disease, and renal osteodystrophy;vascular leak syndromes, including vascular leak syndromes induced by chemotherapies or immunomodulators such as 1L-2; spinal cord and brain injury or trauma; glaucoma; retinal diseases, including macular degeneration; vitreoretinal disease; pancreatitis; vasculatides, including vasculitis, Kawasaki disease, thromhoangiitis obliterans, Wegener's grarmlomatosis, and Behcet's disease; scleroderma; preeclampsia; thalassemia; Kaposi's sarcoma; von Hippel Lindau disease; and the like. [0139] "Treating cancer" as used herein refers to providing a therapeutic benefit to the cancer patient e.g. the therapy extends the mean survival time of patients, increases the percentage of patients surviving at a given timepoint, extends the mean time to disease progression, reduces or stabilizes tumor burden or improves quality of life for the patient or an}' of the above, for example. While not wanting to be bound by a particular theory, some of the compounds of tbe inventin may be cytostatic and therefore have activity directly on the tumor cells. [0140] As used herein, "kinase" refers to any enzyme that catalyze the addition of phosphate groups to a protein residue, for example serine and threomne kinases catalyze the addition of phosphate groups to serine and threonine residues. [0141] As used herein, the terms "Src Idnase" or "Src kinase family" or "Src family" refer to the related homologs or analogs belonging to the mammalian family of Src kinases, including, for example, the widely expressed c-Src, Fyn, Yes and Lyn kinases and the hematopoietic-restricted kinases Hck, Fgr, Lck and Blk. As used herein, the terms "Src kinase signaling pathway" or "Src cascade" refer to both the upstream and downstream components of the Sri- signaling cascade. [0142] Src-farnily tyrosme kinases other than Lck, such as Hck and Fgr, are important in the Fc gamma receptor induced respiratory burst of neutrophils as well as the Fc gamma receptor responses of monocyles and macrophages. The compositions and methods of the present invention may be useful in inhibiting the Fc gamma induced respiratory burst response in neutrophiis. and may also be useful in inhibiting the Fc gamma dependent production ofTNF alpha. The ability to inhibit Fc gamma receptor dependent neutrophil, monocyte and macrophage responses would result in additional anti-inflammatory activity for the compounds employed in invention methods. This activity would be especially of value, for example, in the treatment of inflammatory' diseases, such as arthritis or inflammatory bowel disease. The compositions and methods of the present invention may also be useful in the treatment of autoimmune glomerulonephritis and other instances of glomerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses and which can lead to kidney damage. 10143] In addition, certain S re-family fyrosine kinases, such as Lyn and Src, may be important in the Fc epsilon receptor induced degranulation of mast cells and basophils that plays an important role in asthma, allergic rhinitis, and other allergic disease. Fc epsilon receptors are stimulated by IgE-antigen complexes. Compounds employed in the methods of the present invention may inhibit the Fc epsilon induced degranulation responses. The ability to inhibit Fc epsilon receptor dependent mast cell and basopbil responses may result in additional anti-inflammatory activity for the present compounds beyond their effect on T cells. [0144] The present invention also provides articles of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said packaging material comprises a label which indicates that said pharmaceutical composition can be used for treatment of disorders and wherein said pharmaceutical composition comprises a compound according to the present invention. Thus, in one aspect, the invention provides a pharmaceutical composition including both a therapeutic and a compound of the invention (e.g, as shown in FIGURE 1), wherein the compound is present in a concentration effective to reduce vascular leakage associated with indications or therapeutics which have vascular leak as a side-effect. For example, administration of a compound of the invention in conjunction with IL-2, immunotoxins, antibodies or chemotherapeutics. In these cases, IL-2, immunotoxin, antibody or chemotherapeutic concentration can he determined by one of skill in the art according to standard treatment regimen or as determined by an in vivo animal assay, for example. 10145] The present invention also provides pharmaceutical compositions comprising IL-2, immunotoxin, antibody or chemotherapeutic and at least one invention compound in an amount effective for inhibiting vascular permeability, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. 10146] The compounds of the invention may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, citric, p-loluenesulfonic, methanesulfonic acid, oxalic, tartaric, mandelic, and the like. Salts of the invention include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the invention also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, and the like. Additional excipients which are contemplated for use in the practice of the present invention are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVIL, U.S. Pharmacopeia Convention, Inc., Rockville, MD (1.989), the relevant contents of which is incorporated herein by reference. In addition, polymorphs of the invention compounds are included in the present invention. [0147] Invention pharmaceutical compositions may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parsnterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions), nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; m dosage unit formulations containing non-toxic,•pharmaceuticaily acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release maybe achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or., particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally. |(>148] hi addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). [0149] The term "therapeutically effective amount" means the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., restoration or maintainance of vasculostasis or prevention of the compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and/or mortality. [0150] By "pharmaceuticaily acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0151] The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or pharmaceutical composition to the subject, in need of treatment. [0152] The pharmaceutical compositions for the administration of the compounds of this embodiment either alone or in combination with IL-2, immunotoxin, antibody or chemotherapeutic may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. The pharmaceutical compositions containing the active ingredient maybe in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. [0153] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutical!}' elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients maybe for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract arid thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic, therapeutic tablets for control release. [0154] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or a.n oil medium, for example peanut oil, liquid paraffin, or olive oil. (0155] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecitliin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Also useful as a solubilizer is polyethylene glycol, for example. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [0156] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [0157] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. [0158] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. |0159] The pharmaceutical compositions may be in the form of a sterile injectable aqueous 0]- oleagenous suspension. This suspension may be formulated according to the known ait using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable diluent or solvent or coslvent or complexing agent or dispersing agent or excipient or combination thereof, for example 1,3-butane diol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, Tweens, sodium dodecyle sulfate, sodium deoxycholate,dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., saccharose and dextrose). Among the acceptable vehicles and solvents that may be employed are water, dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0160] Depending on the condition being treated, these pharmaceutical compositions may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences" (Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intrarnedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or inrranasal administration. For injection, the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution. Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oiJs such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides. or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0161 ] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [0162] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles). [0163] In one aspect, the invention compounds are administered in combination with an antiinflanimator/, antihistamines, chemotherapeutic agent, rmmunomodulator , therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to a subject in need of such treatment. While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-linking agents, such as cisplatin/carboplatin; allrylating agents, such as canbusil; topoisomerase I inhibitors such as dactinomicin; microtubule inhibitors such as taxol (paclitaxol), and the like. Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, colchicine, dernecoline, etoposide, taxane, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-demetboxy-daunomycin. 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycm-14-octarioate, adriainycin-14-naphthaleneacetate, amsacrme, carmustine, cyciophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. While not wanting to be limiting, therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed against growth factors or growth factor receptors, such as bevacizumab, which targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor; antibodies targeting mtegrin receptors, such as Vitaxin (also known as MED1-522), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26], etc.), and agents that target topoisomerase 1 (e.g., Camptothecin and Isirinotecan [CPT-11], etc.); 2) covalent DNA-binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyciophosphamide, Ifosphamide, and Busulfan [Myleran], etc.), nitrosoureas (e.g., Carmustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethyhnelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA-binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin D], etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cenibidine], Doxorubicin [Adriamycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol], 6-Thioguanine [6-TG], Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine [CdA], and 2'-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar [ara-C] and Fludarabine, etc.); 5) enzymes, including, L-asparaginase, and hydroxyurea, etc.; 6) hormones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutaniide, etc.), and aroraatase inllibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides, etc.; 9) biological response modifiers (e.g., interferons [e.g., JFNI-. alpha., etc.] and inlerleukins [e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents thai induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors of angiogenesis. [0164] The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inllibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inllibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and raparnycin (sirolimus or Rapamune) or derivatives thereof. [0165] Other agents that may be administered in combination with invention compounds include protein therapeutic agents such as cytokines, iinmunomodulatory agents and antibodies. As used herein the term "cytokine" encompasses chemokines, interleukins, lymphokines, monoldnes, colony stimulating factors, and receptor associated proteins, and functional fragments thereof. As used herein, the term "functional fragment" refers to a polypeptide or peptide wliich possesses biological function or activity that is identified through a defined functional assay. [0166] The cytokines include endothelial monocyte activating polypeptide II (EMAP-U), granulocyt:e-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), IL-1, IL-2,1I.-3, 1L-4, H-5, IL-6, EL-12, and IL-13, interferons, and the like and which is associated with a particular biologic, morphologic, or phenotypic alteration in a cell or cell mechanism, [0167] The term antibody as used in this invention is meant to include intact molecules of polyclonal or monoclonal antibodies, as well as fragments thereof, such as Fab and F(ab')2, Fv and SCA fragments which are capable of binding an epitopic determinant. [0168] When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. [0169] In the treatment or prevention of conditions which involve compromised vasculostasis an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day or 1 .Omg/lcg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day for example. The Examples section shows that one of the exemplary compounds was preferred at 0.1 mg/kg/day while another was effective at about 1.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,10.0, 15.0. 20.0, 25.0, 50.0, 75.0,100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to he treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. There may be a period of no administration followed by another regimen of administration. Preferably, administration of the compound is closely associated with the schedule of IL-2 administration. For example, administration can be prior to, simultaneously with or immediately following IL-2 administration |0170] It will be understood, however, that the specific dose level and frequency of dosage lot any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. (0171] Another embodiment described herein is based on the discovery that a compound that is a vasculostatic agent alone or in combination with an effective amount of therapeutic antibody (or therapeutic fragment thereof), chemotherapeutic or immunotoxic agent, is an effective therapeutic regimen for treatment of tumors, for example. While doxorubicin, docetaxel, or taxol are described in the present application as illustrative examples of chemotherapeutic agents, it should be understood that the invention includes combination therapy including a compound of the invention, including but not limited to vasculostatic agents, such as tyrosine, serine or threonine kinase inhibitors, for example, Src-family inhibitors, and any chemotherapeutic agent or therapeutic antibody. [0172] Such vasculostatic agents, in combination with chemotherapeutic agents or therapeutic antibodies are effective in blocking vascular permeability and/or vascular leakage and/or angiogenesis. In one embodiment, the invention provides a composition containing a therapeutically effective amount of a chemotherapeutic agent and a vasculostatic agent in a pharmaceutically acceptable carrier. 10173] In one embodiment, the invention provides a method for reducing the tumor burden in a subject, comprising administering to a subject in need thereof an effective amount of chemotherapeutic agent in combination with a compound that is a vasculostatic agent. In an illustrative example, the method includes use of at least one of the invention compounds e.g.. as set forth in Structures 1, II, HI, Ilia, IV, V, VI or VH or any combination thereof, with the chemotherapeiuic agent. In one aspect, the compound is set forth in FIGURE 1. It should be understood that the tumor burden in a subject can be reduced prior to treatment with a compound of the invention through surgical resection, chemotherapy, radiation treatment or other methods known to those of skill in.the art. [0174] The compounds according to this invention may contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The term "stereoisomer" refers to a chemical compounds which differ from each other only in the way that the different groups in the molecules are oriented in space. Stereoisomers have the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped differently. That is, certain identical chemical moieties are at different orientations in space and, therefore, when pure, have the ability to rotate the plane of polarized light. However, some pure Stereoisomers may have an optical rotation that is so slight that it is undetectable with present instrumentation. All such isomeric forms of these compounds are included in the present invention. [0175] Each stereo genie carbon may be of R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are also envisioned. When chiral centers are found in the derivatives of this invention, it is to be understood that this invention encompasses all possible Stereoisomers. The terms "optically pure compound" or "optically pure isomer" refers to a single stereoisomer of a chiral compound regardless of the configuration of the compound. [0176] Several illustrative compounds employed in the methods of the present invention are inhibitors of kinases and therefore are useful in treating a wide variety of disorders resulting from aberrant Idnase activity. Examples of kinases include Src-family tyrosine kinases and their associated disorders, which result from aberrant tyrosine kinase activity, and/or winch are alleviated by the inhibition of one or more of the enzymes within the Src family. For example, Src inhibitors are of value in the treatment of cancer, as Src inhibition blocks tumor cell migration and survival. Many compounds of the invention are also broad spectrum kinase inhibitors and inhibit other kinases in addition to Src-family tyrosine Icinases or non-Src family kinases. 10177] Cancers that may be treated by compounds of the invention alone or as a combination therapy of the invention include but are not limited to a carcinoma or a sarcoma, including one or more specific types of cancer , e.g., an alimentary/gastrointestinal trad cancer, a liver cancer, a skin cancer, a breast cancer, an ovarian cancer, a prostate cancer, a lymphoma, a leukemia, a kidney cancer, a lung cancer, a muscle cancer, a bone cancer, bladder cancer or a brain cancer. [0178] The present invention also provides articles of manufacture comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said packaging material comprises a label which indicates that said pharmaceutical composition can be used for treatment of disorders and wherein said pharmaceutical composition comprises a compound according to the present invention. Thus, in one aspect, the invention provides a pharmaceutical composition including both a chemotherapeutic agent, immunotoxin or therapeutic antibody and a compound of the invention (e.g, as shown in FIGURE 1), wherein the compound is present in a concentration effective to reduce tumor burden, for example. In one aspect, the invention provides a pharmaceutical composition including a compound of the invention, wherein the compound is present in a concentration effective to reduce vascular permeability, for example. The concentration can be determined by one of skill in the art according to standard treatment regimen or as determined by an in vivo animal assay, for example. [0179] Pharmaceutical compositions employed as a component of invention articles of manufacture can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more of the compounds described above as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Compounds employed for use as a component of invention articles of manufacture may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. [0180] The present invention also provides pharmaceutical compositions including at least one invention compound in an amount effective for treating a tumor, or cancer, alone or hi combination with a chemotherapeutic agent, immunotoxin, immunomodulator or therapeutic antibody and a pharmaceutically acceptable vehicle or diluent. Similarly, the present invention provides pharmaceutical compositions including at least one invention compound capable of treating a disorder associated with vasculostasis in an amount effective therefore. The compositions of the present invention may contain other therapeutic agents as described herein and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation. [0181] The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or pharmaceutical composition to the subject in need of treatment. For example, administration of the vasculostatic agent can be prior to, simultaneously with, or after administration of an invention compound or other agent, hi the Examples provided herein, typically the compounds of the invention are co-administered at the same time as a chemotherapeutic agent. [0182] While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-linking agents, such as cisplatin/carboplatin; alkylating agents, such as canbusil; topoisomerase I inhibitors such as dactinomicin; microtubule inhibitors such as taxol (paclitaxol), and the like. Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, amsacrine, carmusttne, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguaoine, asparaginase, viriblastine, vindesine, tamoxifen, mechlorethamine. colchicine, demecoline, eloposide, taxarie, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-demethoxy-daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adrianiycin-14-benzoate, adriamycin-14-octanoate or adriamycin-] 4-naphthaleneacetate. [0183] Compounds, their prodrugs, or metabolites employed in the methods of the present invention are vasculostatic agents such as inhibitors of vascular permeability and/or vascular leakage and/or angiogenesis. In addition, several illustrative compounds employed in the methods of the present invention are inhibitors of kinases and therefore are useful in treating a wide variety of disorders resulting from aberrant kinase activity. Kinase-associated disorders are those disorders which result from aberrant kinase activity, and/or which are alleviated by the inhibition of one or more of the kinases. [0184] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0185] The Examples set out below include representative examples of aspects of the present invention. The Examples are not meant to limit the scope of the invention but rather serve exemplery purposes. In addtion, various aspects of the invention can be summarized by the following description. However, this description is not meant to limit the scope of the invention but rather to highlight various aspects of the invention. One having ordinary skill in the art can readily appreciate additional aspects and embodiments of the invention. EXAMPLE 1 SYNTHESES OF VASCULOSTATIC AGENTS Experimentals General Analytical Methods 10186] All solvents are used without further purification. Reactions are usually run without an inert gas atmosphere unless specified otherwise. All ]H NMR are run on a 500 MHz Bruker NMR. Chemical shifts are reported in delta (5) units, parts per million (ppm) downfield from tetramethylsilane. Coupling constants are reported in hertz, (Hz). A Water LC/MS system is used in identity and purity analysis. This system includes a 2795 separation module, a 996 photodidode array detector and a ZQ2000 mass spectrometer. A Zorbax SB column (150 x 4.6mm 3.5u,, Agilent Technologies) is used for the LC. Column temperature is 40 °C. Compounds are separated using gradient elution with mobile phases of water (0.05%TFA (A)) and acetonitrile (0.05%TFA (B)). Flow rate is ImL/min. The gradient program used in separation is 0-15min: 5-60 %B; 15-15.5 rnin: 60-100 %B; 15.5-17 rain: 100 %B. [0187] The following gradient programs were used based on the hydrophobicity of the analyzed sample: (1) 0-15min: 30-70% B; 15-15.5min: 70-90% B; 15.5-17min: 90% B for the compounds: 4-Hydroxy-N-(2-(lH-indol-2-yl)-phenyl)-benzamide; 3,4-Dihydroxy-N-(2-(lH-indol-2-yl)-phenyl)-benzamide;N-(2-(lH-Indol-2-yl)-phenyl)-2-phenyl-acetamide; 2-(3,4-Dihydroxy-phenyl )-N-(2-(lH-indol-2-yl)-phenyl)-acetamide; N-(2-(lH-Indol-2-yl)-phenyl)-3-phenyl-propionamide; 3-(4-Hydroxy-phenyl)-N-(2-(lH-indol-2-yl)-phenyl)-propionamide; N-(2-(l Fl-lndol-2-yl)-phenyl)-3-(2-methoxy-phenyl)-propionamide; 3-(3,4-Dihydroxy-phenyl)-N-(2-(lH-indol-2-yl)-phenyl)-propionamide; (2) 0-15min: 30-50% B; 15-15.5min: 50-90% B; 15.5-17min: 90% B for compound N-(2-(2,3-Dihydro-lH-rndol-2-yl)-phenyl)-2-hydroxy-benzamide. (3) 0-15min: 20-40% B; 15-15.5min: 40-90% B; 15.5-17min: 90% B for compound 4-(4-amino-6-(3,4-dihydroxyphenyl)pteridin-7-yl)benzene-1,2-diol. 14) 0-15min: 5-60% B; 15-15.5min: 60-90% B; 15.5-17min: 90% B for compound 2-(4-Hydroxy-phenyl)-N-(2-(lH-indol-2-yl)-phenyl)-acetamide. (5) 0-15min: 40-100% B; 15.-17min: 100% B for compounds N-(2-(lH-Indol-2-yl)-phenyl)-2-(2-methoxy-phenyl)-acetamide and 2-Benzo( 13)dioxol-5-yl-N-(2-(lH-mdol-2-yl)-phenyl)-acetamide. [0188] The mass spectrometer is equipped with an electrospray probe. Source temperature is 120 °C. All of the compounds are identified using the positive mode with mass scan range from 100 to 800. General Procedure for indoles [0189] 2-(2-Aminophenyl) indole and the starting material acid (2 equiv) were dissolved in acetonitrile. To the solution were added 2 equiv of EDC (dimethylaminopropyl ethyl carbodiimide hydro chloride) as powder. The mixture was stirred at either room temperature (23 °C) or at slightly elevated temperature (50 °C) for 3 to 16 hours. [0190] The solvent was removed and the residue dissolved in methanolrethylacetate (5-10 %). The solution was extracted with 1 M HC1 as well as saturated sodium bicarbonate solution. The aqueous phases were re-extracted with EtOAc, respectively. The combined organic phases were dried over magnesium sulfate. The product was purified by column chromatography (silica, typically using EtOAc-hexanes as mobile phase) and/or crystallization from different solvents including methanol and acetonitrile. [0191] 2-(4-Hydroxy-phenyl)-A'r-[2-(lJ::7-indol-2-yl)-phenyl]-acetamide (Figure Remove) [0192] 1 g (4.8 mmol) 2-(2-Aminophenyl) indole was dissolved in 200 ml acetonitrile. 1.46 « (9.6 mmol, 2 eq) of 4-hydroxyphenylacetic acid were dissolved in 50 ml acetonitrile and added to the solution. To the mixture were added 1.84 g (9.6 mmol, 2eq) of EDC ('dimethylaminopropyl ethylcarbodiimide hydrochloride). The reaction mixture was stirred at 23 °C for 1.6 hours. The solvent was removed and the residue was dissolved in 100 ml ethylacetatermethanol (10:1). It was extracted twice with 100 ml of aqueous IM HCI as well as 100 ml of aqueous, saturated sodium bicarbonate solution. The aqueous phases were re-extracted with EtOAc, respectively. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using a etbylacetate/hexane gradient (10%-50%) to obtain 1.23 g of the amide as a pink colored powder in an overall yield of 75 %. 100 % Purity by LC/MS (230 DAD) Mass-spec [M+H4] = 343.9 *H NMR (MeOH-d4): 3.60 s (2H), 6.10 s (IH), 6.70 d, S Hz (2H), 7.03 t, 8 Hz (IH), 7.09-7.13 m (3H), 7.25 t, 7 Hz (IH), 7.34 m (2H), 7.49 d, 8 Hz (IH), 7.53 d, 8 Hz (IH), 7.95 d, SHz(lH). [0193] 4-Hydroxy-N-(2-(lH-indol-2-yl)-phenyl)-benzamide (Figure Remove) [0195] 3,4-Dihydroxy-N-(2-(lH-indol-2-yl)-pheaiyl)-benzamide [0194] Prepared from 2-(2-aminophenyl) indole and 4-hydroxybenzoic acid in 35 % overall yield following procedure 1. The product was chromatographed on silica and crystallized from acetonirrile. 95.6 % Purity by LC/MS (230 DAD) Mass-spec (M+H+) = 329.8 !H NMR (MeOH-d4): 6.65 s (IH), 6.83 m (2H), 7.01 t, 7 Hz (IH), 7.12 td, 7,1 Hz (IH), 7.34 td, 7, 1 Hz (IH), 7.39-7.43 m (2H), 7.51 d, 7 Hz (IH), 7.66 dd, 8,1 Hz (IH), 7.76 m (2H), 7.91 dd, S,lHz(lH). (Figure Remove) [0196] Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxybenzoic acid in 54 % yield following procedure 1. The product was cllromatographed on silica. 100 % Purity by LC/MS (230 DAD), Mass-spec (M+H+) = 345.83, ]H NMR (MeOH-d4): 6.645 s (1H), 6.80 d, 8 Hz (1H), 7.02 t 8 Hz (1H), 7.12 td, 8, 1 Hz (1H), 7.23 dd, 8,1 Hz (1H), 7.33-7.36 m (2H), 7.39-7.42 m (2H). 7.52 d, 7 Hz (1H), 7.65 dd, 8, 1 Hz (13), 7.94 d, 8 Hz (1H). [0197] 2-Hydroxy-N-(2-(lH-indol-2-yl)-phenyl)-benzamide (Figure Remove) [0198] Prepared from 2-(2-aminophenyl) indole and salicylic acid in 46 % yield following procedure 1. The compound was chromatographed on silica using an ethylacetate/hexane gradient. % Purity by LC/MS (230 DAD), Mass-spec (M+H") = 329, !H NMR (MeOH-d4): 6.66 s (1H), 6.86 dd, [0199] N-[2-(lH-Indol-2-yl)-phenyl]-2-phenyl-acetamide (Figure Remove) 10200] Prepared from 2.-i'2-aminophenyl) indole and phenylacetic acid in 62 % yield following procedure 1. The product was crystallized from methanol. 100 % Purity by LCMS (230 DAI)), Mass-spec [M-HH4] = 327, !HNMR (MeOH-d4): 3.69 s (2H), 6.21 s (IH), 7.03 t, 7 Hz (IH), 7.12 t, 8 Hz (IH), 7.21-7.28 ni (6H), 7.33-7.36 m (2H), 7.46 d, 8 Hz (IH), 7.54 dd, 7,1 Hz (IH), 7.89 d, 8 Hz (IH). (Figure Remove) N-f2-(lH-lndol-2-yl)-phenyl]-2-(2-metlioxy-phenyl)-acetamide [0201] Prepared from 2-(2-aminophenyl) indole and 2-methoxyphenylacetic acid in 53 % yield following procedure 1. The product was crystallized from acetonitrile. 100 % Purity by LC/MS (230 DAD), Mass-spec [M+H*] = 357, !H NMR (MeOH-d4): 3.45 s (3H, OMe), 3.67 s (2H), 6.17 s (IH), 6.75 d, 8 Hz (IH), 6.83 t, 8 Hz (IH), 7.061, 8 Hz (IH), 7.141, 8 Hz (IH), 7.17-7.21 m (3H), 7.23-7.36 m (2H), 7.49 t, 8 Hz (2H), 8.13 d, 8 Hz (IH). 2-(2-Hydroxy-phenyl)-N-[2-(lH-indol-2-yl)-phenyl]-acetamide (Figure Remove) [0202] The product was prepared from N-[2-(lH-Indol-2-yl)-phenyl]-2-(2-methoxy-phenyl)-acetamide. Cleavage of the methylether was accomplished using 1.8 eq ofBBra (1M solution in dichloromethane) at -78 "C to room temperature (23 °C) and subsequent hydrolysis (32 % yield). 96 % Purity by HPLC (ELSD), Mass-spec [M+H*] = 343, !H NMR (MeOH-d4): 3.69 s (2H), 6.25 s (IH), 6.71-6.74 m (2H), 7.01-7.07 m (2H), 7.10-7.13 m (2H), 7.22 I, 7 Hz (IH), 7.31-7.36 m (2H), 7.48 d, 8 Hz (IH), 7.52 dd, 8, 1 Hz (IH), 8.08 d, 8 Hz (IH). (Figure Remove) 2-(?,4-Dihydroxy-phein'l)-N-[2-(lH-indol-2-yl)-phenyl]-acetaniide [0203] Prepared from 2-{2-aminophenyl) indole and 3,4-dihydroxyphenylacetic acid in 17 % yield. The product was chromatographed on silica. 100 % Purity by LC/MS (230 DAD), Mass-spec [M+H+] - 359, ]H NMR (MeOH-d4): 3.56 s (2H), 6.10 s (IH), 6.59 dd, 8, 2 Hz (IB), 6.66 d, 8 Hz (IH), 6.78 d, 2 Hz (IH), 7.03 t, 8 Hz (IH), 7.11 t, 8 Hz (IH), 7.25 t, 8 Hz (IH), 7.31-7.35 m (2H), 7.51 d, 7 Hz (IH), 7.55 dd, 8, 1 Hz (IH), 7.99 d, 8 Hz (IH). 2-Benzo[l,3]dioxol-5-yl-N-[2-(lH-mdol-2-yl)-phenyl]-acetamide (Figure Remove) [0204] Prepared from 2-(2-aminophenyl) indole and 3,4-(methylenedioxy)phenylacetic acid in 55 % yield. The product was purified by crystallization from acetonitrile. 100 % Purity by LC/MS (230 DAD), Mass-spec [M+H+] = 371, 'HNMR (MeOH-d4): 3.61 s (2H), 5.82 s (2H), 6.20 s (IH), 6.66 d, 8 Hz (IH), 6.74 dd, 8,1 Hz (IH), 6.76 d, 1 Hz (IH), 7.03 t, S Hz (IH), 7.121, 8 Hz (IH), 7.25 t, 8 Hz (IH), 7.33-7.36 m (211), 7.48 d, 8 Hz (IH), 7.52 d, SHz(lH), 7.99 d, 8 Hz (IH). N-j2-(lH-hidol-2-vl)-pbeny]]-3-phenyl-propionarnide (Figure Remove) |0205] Prepared from 2-(2-aminophenyl) indole and hydrocinnamic acid in 54 % yield following procedure 1. The product was crystallized from methanol. 99 % Purity by LC/MS t'230 DAD), Mass-spec [M+H+] = 341, ]H NMR (DMSO-d6): 2.65 t, 7.5 Hz (2H), 2.91 t, 7.5 Hz (2H), 6.50 s (IH), 7.001, 7 Hz (IH), 7.101, 7 Hz (IH), 7.19-7.34 m (7H), 7.39 d, 8 Hz (IH), 7.51 d, 8 Hz (IH), 7.60-7.62 m (2H), 9.39 s (IH), 11.32 s (IH). 3-(4-Hydroxy-phenyl)-N-[2-(lH-indol-2-yl)-phenyl]-propionamide (Figure Remove) [0206] Prepared from 2-(2-aminophenyl) indole and 3-(4-hydroxyphenyl) propionic acid in 55 % yield following procedure 1. The product was chroniatographed on silica and crystallized from acetonitrile. 100 % Purity by LC/MS (230 DAD), Mass-spec [M+H+] = 357, 'H NMR (MeOH-d4): 2.611, 7.4 Hz (IH), 2.S91, 7.4 Hz (IH), 6.37 s (IH), 6.72 d, 8 Hz (2H), 7.00-7.06 m (3H), 7.111, 7 Hz (IH), 7.27-7.35 m (2H), 7.38 d, 8 Hz (IH), 7.54 d, 7 Hz (IH), 7.58 dd, 7,1 Hz (IH), 7.67 d, 8 Hz (IH). N-'2-(lH-Indol-2-yl)-phenyl]-3-(2-methoxy-phenyl)-propionamide (Figure Remove) J0207] Prepared from 2-(2-ammophenyl) indole and 3-(2-methoxyphenyl) propionic acid in 62 % yield following procedure 1. The product was crystallized from acetonitrile. 96 % Purity by LC/MS (TIC, DAD), Mass-spec [M+H+] = 371, JH NMR (MeOH-d4): 2.62 t 7.5 Hz (2H), 2.97 t, 7.5 Hz (2H)> 3.74 s (3H, OMe), 6.40 s (IH), 6.811, 7 Hz, (IH), 6.88 d, 8 Hz (IH), 7.03 t, 8 Hz (IH), 7.10-7.14 m (2H), 7.17 t, 8 Hz (IH), 7.27 t, 7 Hz (IH), 7.33 td, 7.5, ] Hz (IH), 7.40 d, 8 Hz (IH), 7.54 d, 8 Hz (IH), 7.57 dd, 7,1 Hz (IH), 7.76 d, 8 Hz (IH). 3-(3.4-Dihydroxy-pheny])-N-[2-(lH-indol-2-yl)-phenyl]-propionamide (Figure Remove) [0208] Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxyhydrocinnamic acid in 19 % yield following procedure 1. The product was chromatographed on silica and crystallized from acetonitrile. 100 % Purity by LC/MS (230 DAD), Mass-spec [M+H4] = 373, ]H NMR (MeOH-d4): 2.60 t, 7.4 Hz (2H), 2.85 t, 7.4 Hz (2H), 6.38 s (IH), 6.55 dd, 8,2 Hz (IH), 6.69 m (2H), 7.021, 8 Hz (IH), 7.11 t, S Hz (IH), 7.27-7.35 m (2H), 7.38 d, { Hz (IH), 7.56 d, 8 Hz (IH), 7.58 dd, 7,1 Hz (IH), 7.70 d, 8 Hz (IH). 2_( 4-Hydroxy-ph enox y)-N- [2-( 1 H-indo] -2-yl)-phenyl] - acetamide (Figure Remove) [0209] Prepared from 2-(2-aminophenyl) indole and (4-hydroxyphenoxy) acetic acid in 30 % yield following procedure 1. The product was crystallized from methanol. 89 % Purity by LC/MS (230 DAD), Mass-spec [M+H+] = 359, 'HNMR (MeOH-d4): 4.52 s (2H), 6.55 d, 9 H7. (2H), 6.58 s (IH), 0.61 d, 9 Hz (2H), 7.09 t, 8 Hz (IH), 7.18 t, 8 Hz (IH), 7.261, 8 Hz (IH), 7.37-7.43 m (211), 7.561, 8 Hz (2H), 8.38 d, 8 Hz (IH). 2-Acetylamino-3-(4-hydroxy-plienyl)-N-[2-(lH-indol-2-yl)-phenyl]-propionamide (Figure Remove) [0210] Prepared from 2-(2-aminophenyl) indole and N-acetyl-L-tyrosine in 69 % yield following procedure 1. The product was chromatographed on silica. 99 % Purity by LC/MS (230 DAD), Mass-spec [M+H+] = 414, 'HNMR (MeOH-d4): 1.79 s (3H, COMe), 2.83 dd, 14,9 Hz (IH), 3.14 dd, 14,6 Hz (IH), 4.58 dd, 9,6 Hz (IH), 6.51 s (IH), 6.70 d, 8 Hz (2H), 7.02 t, 7.5 Hz (IH), 7.07 d, 8 Hz (2H), 7.12 td, 8,1 Hz (IH), 7.27 td, 8,1 Hz (IH), 7.33 td, 8,1 Hz (IH), 7.44 d, 8 Hz (IH), 7.56 d, 8 Hz (IH), 7.59 dd, 8,1 Hz (IH), 7.83 d, 8 Hz (IH). Procedure 2: N- f2-( 1 //-Indol-2-y 1 )-phenyl]-phthalamic acid (Figure Remove) [0211] 958 mg (4.6 mmol) 2-(2-Aminophenyl) indole and 675 mg (5.52 mmol, 1.2 eq) DMAP (dimethylamino pyridiiie) were dissolved in 35 ml anhydrous dichloromethane. The mixture was stirred for 10 rnin. 954 mg (6.44 mmol, 1.4 eq) of phthalic anhydride in 3 ml anhydrous dichloromethane were added and the mixture was stirred at 23 °C for three hours. To the mixture were added 20 ml dichloromethane. It was extracted with 50 ml aqueous 1 M HC1. The aqueous phase was re-extracted with 30 ml dichloromethane. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using an ethylacetate/hexane gradient (10 %-90 %) as mobile phase. The solvent was removed and the product was re-crystallized from etbylacetate:hexane (70:30) to obtain 654 mg of ivory colored crystals in 40 % overall yield. [0212] 95 % Purity by LC/MS (230 DAD), Mass-spec [M+H+] = 357, ]H NMR (MeOH-d4): 6.75 e (IH), 6.99 t, 8 Hz (IH), 7.09 t, 7 Hz (IH), 7.35-7.43 m (3H), 7.52-7.57 m (3 H), 7.63 t, 8 Hz (IH), 7.71 d, 8 Hz (IH), 7.84 d, 8 Hz (IH), 8.06 d, 7 Hz (IH). 2 -| 2 -(1 H-Indol -2-yl )-ph en ylcarbamoyl]-nicotinic acid (Figure Remove) (0213] 104 mg (0.5 mmol) 2-(2-Aminophenyl) indole and 74 mg (0.6 mmol, 1.2 eq) DMAP (dimethylamino pyridine) were dissolved in 5 ml anhydrous dichloromethane. The mixture was stirred for 10 min. 104 mg (0.7 mmol, 1.4 eq) of 2,3-pyridinedicarboxylic anhydride were added and the mixture was stirred at 23 °C for three hours. [0214] To the mixture were added 20 ml dichloromethane. It was extracted with 20 ml saturated NaCl solution. The aqueous phase was re-extracted with 20 ml dichloromethane. The combined organic phases were dried over magnesium sulfate. The crude product was chrornatographed on silica and re-crystallized from acetonitrile. 100 % Purity by HPLC (UV, 230 ran), Mass-spec [M+H+] = 358, JH NMR (MeOH-d4): 6.80 s (IH), 7.041, 7 Hz (IH), 7.14 t, 8 Hz (IH). 7.311, 7 Hz (IH), 7.421 (2H), 7.57 d, 8 Hz (IH), 7.61 dd, 8, 5 Hz (IH), 7.67 dd, 8,1 Hz (IH), 8.13 dd, 8,1 Hz (IH), 8.30 d, 8 Hz (IH), 8.61 dd, 5, 1 Hz (IH). 3.4,5-trihydrox)'-N-[2-(lH-indo]-2-y])-phenyl]-benzamide (Figure Remove) [0215] A 25-mL one-necked recovery flask equipped with a stirring bar and a septum was charged with gallic acid (176 mg; 1.03 mmol; 1.00 equiv). A clear, colorless solution was formed on addition of 5 mL of dichloromethane. Solid EDC (197 mg; 1.03 mmol; 1.00 equiv) and 2-(2-aminophenyl)indole (194 mg; 0.932 mmol; 0.904 equiv) were added sequentially as solids. The reaction was worked up after 24 h by extraction with 10 mL of NaHCO3 (satd aq). The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated by rotary evaporation to yield a yellow oily paste. The crude was purified using DCM-MeOH (19:1) to yield a light yellow solid (230 mg; 68%). Representative syntheses of compounds of structure II Compound II-l (Figure Remove) [0216] A 100-mL, one-necked, round bottomed flask with a magnetic stirring bar and a septum was charged with 2-(2-aminophenyl) indole (210 mg; 1.01 mmol). The indole was dissolved in ca. 7 inL of dichloromethane to give a very pale yellow solution. DMAP (143 mg; 1.17 mmol; 1.16 equiv) and phthalic anhydride (179 mg; 1.21 mmol; 1.20 equiv) were added sequentially each dissolving completely with a resulting yellow solution. The solution was stirred at room temperature, and the reaction was followed by TLC, and showed complete conversion in ca. 30 min as indicated by the disappearance of the 2-(2-aminophenyl) indole. The reaction mixture was poured into a 125-mL separator)' funnel and extracted with 15 ml HC1 (aq, ca. 1 M). The aqueous layer was washed with 2x5 mL CH;>Cl2, and the combined organic layer was dried (anhydrous Na2SO4), filtered, and concentrated by rotary evaporation to yield a canary yellow foamy solid (0.377 g) of N-[2-(l#-mdol-2~yi)-phenyl]phtha]amic acid. MS (M+H+: calcd 357; found 357). [0217] A 5-mL reaction vial with a stirring vane and a teflon stopper was charged with 7V-(2-(lF4ndol-2-yl)-phenyl)phthalamic acid, (140 mg; 0.393 mmol) and 0.500 mL of quinoline. To the solution, which was a dark brown-black, was added zinc acetate dihydrate (98.0 mg; 0.464 mmol; 1.16 equiv) and the resulting solution was heated to 120 °C for ca. 2 h. On adding 1 mL of ethyl acetate, a light tan solid resulted. The solid was washed with 4 x 10 mL 1 M HC1, then with 10 mL ethylacetate-hexane (1:1), followed by 10 mL ethyl acetate. The solid was dried in a vacuum dessicator over phosphorus pentoxide to yield 80.1 mg (71 %) of a light tan solid. MS (M+ET: calcd 339; found 339). Pteridine., and substituted pteridine syntheses (Figure Remove) Experimental Procedure 6,7-(4,4'-Dihydroxyphenyl)-pteridin-4-yl-3-morphoIin-4-yI-propyl)-amine hydrochloride salt (Figure Removed) [0218] 1.19 g (3.59 nimol) of 6,7-bis(4-hydroxyphenyl)-pteridm~4-ylamirje was dissolved in 10 niL of M-(3-aminopropyl)morpholine and 0.697 g (7.18 nimol, 2.0 eq.) of sulfamic acid was added. The reaction mixture was heated at 160°C for 18 hrs. Then it was cooled down to r.t., diluted with 20 mL of methanol and added dropwise to 1 L of diethyl ether. The resulting oil was purified by prep-HPLC, fractions were collected and solvent was removed in vacua to give red oily residue, which was dissolved in 20 mL of methanol. 5 g of Amberlite chloride-exchange resin was added to the methanol solution. The reaction mixture was left to stir at r.t. overnight, then it was filtered and resin was washed with methanol. The methanol washes were combined, solvent was removed in vacua. The resulting residue was re-dissolved in 2 mL of methanol and added dropwise to 45 mL of di ethyl ether. The formed bright-yellow precipitate was centrifuged down, washed with 40 mL of diethyl ether twice and dried in vacua to give 281.0 mg (26.2% overall) of the product as a yellow solid. Mass-spec [ES+] - 459.2. 100 % purity by LC/MS (230 DAD). 'H NMR (MeOH-d4) 2.28-2.31 (2H, m), 3.14-3.17 (2H, m), 3.30-3.35 (2H, m), 3.51-3.53 (2H, m), 3.80-3.84 (2H, m), 3.97-4.00( 2H, m), 4.04-4.06 (2H, m), 6.77-6.82 (4H, dd), 7.49-7.54 (4H, dd), 8.84 (1H, s). Acetic acid 4-{7-(4-acetoxy-phenyl)-4-amino-pteridin-6-yI]-phenyl ester (Figure Removed) [0219] 662.6 mg (2.0 mmol) of 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine was dissolved in 20 ml of trifluoroacetic acid. 1.0 mL (14.06 mmol, 7.0 eq) of acetyl chloride was added via syringe to this mixture. Upon heating to 80 °C bubbling of the reaction mixture and evolution of HC1 gas was observed. The reaction mixture was heated at 80 C for 40 rnin, at which point LC/MS indicated a complete conversion of the starting material to the di-acetate. Solvent was removed in vacua to give bright-yellow oil, which upon standing solidified. 40 mL of diethyl ether was added, the solid was crushed with spatula, centrifuged down, washed with 45 mL of diethyl ether twice and dried in vacua to give 1.034 g (97.7%) of the product as a light-yellow solid. 97.5% purity by LC/MS (230 DAD). Mass-spec [ES+] -416.5. 'H NMR (DMSO-d6) 2.280 (3H, s), 2.284 (3H, s), 7.16-7.21 (4H, dd), 7.56-7.62 (4H. dd). 8.80 (1H, s), 9.46 (1H, br.s), 9.52 (1H, br.s). (Figure Removed) Acetic acid 4-|2-(4-acetoxy-phenyl)-6-amino-pyrido[2,3-b]pyrazin-3-yl]-phenyl ester (Figure Removed) 10220] 201.0 mg (0.5 mmol) of 2,3-bis(4-hydroxyphenyl)-p>'rido[2,3-b]pyra2in-6-ylamine was dissolved in 10 ml of trifluoroacetic acid. 0.355 mL (5.0 mmpl., 10.0 eq) of acetyl chloride was added via syringe to this mixture. Upon heating to 80 °C bubbling of the reaction mixture and evolution of HC1 gas was observed. The reaction mixture was heated at 80°C for 1 hr, at which point LC/MS indicated a complete conversion of the starting material to the di-acetale. Solvent was removed in vacua to give brown solid. The solid was dissolved in 3.0 mL of methanol and this solution was added to 40 mL of diethyl ether. Upon standing for about an hour a brown precipitate was formed. It was centrifuged down, washed with 45 mL of diethyl ether twice and dried in vacuo to give 191.9 mg (79.0%) of the product as a light-brown solid. 98% purity by LCMS (230 DAD). Mass-spec [ES+] =415.5. 'H NMR (MeOH-d4) 2.28 (6H, s), 7.10-7.12 (4H, d), 7.24-7.26 (1H, d), 7.48-7.50 (2H, d), 7.54-7.56 (2H, d), 8.24-8.26 (1H, d). Synthesis of 4-substituted 6-phenyl-pteridin-4-yl-amines (Figure Removed) Me2NCH(OMe), General Procedure [0221] 0.55 mmol of arnine was suspended in 4 mL of acetic acid. The mixture was brought to reflux and 0.5 mmol of N'-(3-cyaiio-5-phenyl-pyrazin-2-yl)-N,N'-dimethyl-formamidine was added to the solution. The reaction was refluxed for 2-5 hours. The progress of the reaction was monitored by LC/MS. After the reaction had completed, the reaction mixture was cooled down to ambient temperature and acetic acid was removed in vacua, 5 mL of methanol was added to the resulting residue and it was crushed with a spatula into a fine suspension. The suspension was added to 45 mL of diethyl ether. The solid was centrifuged down, washed with 45 mL of diethyl ether twice and dried in vacuo to give the product as a solid. (3,4-Dimethoxy-phenyI)-(6-phenyl-pteridine-4-yI)-amine (Figure Removed) [0222] 95.7 % yield. 100% purity by LC/MS (230 DAD). Mass-spec [ES+] =360.9. ]H NMR (DMSO-d6) 3.79 (3H, s), 3.81 (3H, s), 7.02-7.03 (1H, d), 7.56-7.63 (5H, m), 8.58-8.60 (2H, m), 8.71 (1H, s), 9.80 (1H, s), 10.27 (1H, s). (3-Chloro-4,6-dimethoxy-phenyI)-(6-phenyI-pteridin-4-yI)-amine (Figure Remove) [0223] 96% purity by LC/MS (230 DAD). Mass-spec [ES+] =394.9. ]H NMR (DMSO-d6) 3.92 (3H, s), 3.97 (3H, s), 6.96 (IH, s), 7.59-7.65 (3H, m), 8.29 (IH, s), 8.42-S.43 (2H, d), S.74 (IH, s), 9.80 (IH, s), 9.89 (IH, s). (3-Hydroiry-4-methoxy-phenyl)-(6-phenyI-pteridin-4-yI)-amine (Figure Remove) [0224] 79.5 % yield. 100% purity by LC/MS (230 DAD). Mass-spec [ES+] =346.9. JH NMR (DMSO-d6) 3.79 (3H, s), 6.97-6.98 (IH, d), 7.29-7.31 (IH, dd), 7.46-7.47 (IH, d), 7.58-7.62 (3H, m), 8.58-8.60 (2H, m), 8.69 (IH, s), 9.15 (IH, s), 9.78 (IH, s), 10.2 (IH, s). (4-Hydroxj'-ph enyl)-(6-pb enyl-pteridin-4-yI)-amine (Figure Removed) |0225] 86.0 % yield. 98% purity by LC/MS (230 DAD). Mass-spec [ES+J -316.8. ]H NMR (DMSO-d6) 6.82-6.84 (2H, d), 7.57-7.62 (3H, m), 7.65-7.67 (2H, d), 8.58 (2H, m), 8.63 (IH, s), 9.45 (IH, s), 9.78 (IH, s), 10.26 (IH, s). (2,5-DimethyI-4-hydroxy-phenyl)-(6-phenyl-pteridm-4-yl)-amine(Figure Remove) [0226] 76.8 % yield. 100% purity by LC/MS (230 DAD). Mass-spec [ES+]-344.9. !H NMR (DMSO~d6) 2.12 (6H, s), 6.73 (IH, s), 7.12 (IH, s), 7.55-7.60 (3H, m), 8.54 (IH, s), 8.57-8.58 (2H, m), 9.29 (IH, s), 9.78 (IH, s), 10.16 (IH, s). 2-IIydroxy-5-(6-pheiiyl-pteridin-4-ylamino)-benzenesulfonic acid (Figure Removed) [0227] 70.1 % yield. 83 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 396.8. ]H NMR (DMSO-d6) 7.17-7.19 (IH, dd), 7.58-7.63 (3H, m), 7.80-7.82 (IH, dd), 7.993-7.999 (IH, d), S.61-8.63 (2H, ra), 8.73 (IH, s), 9.80 (IH, s), 10.51-10.53 (3H, m). 2-Diethylaminomethyl-4-(6-phenyl-pteridin-4-ylamino)-phenol (Figure Removed) [0228] 94.3 % yield. 98.8% purity by ELSD. Mass-spec [ES+] -402.0. 'H NMR (DMSO-d6) 1.28-1.31 (6H, t), 3.11-3.16 (4H, m), 4.25-4.26 (2H, d), 7.07-7.09 (IH, d), 7.58-7.63 (3H, m), 7.75-7.77 (IH, dd), 7.89-7.90 (IH, d), 8.57-8.59 (2H, m), 8.67 (IH, s), 9.81 (IH, s), 10.39 (IH, s), 10.5(1 H, s) 5-('6-Phen}r]-pteridm-4-ylaniino)-quinolin-8-olhydrochloridesalt (Figure Removed) 10229] 79.9 % yield. 85% purity by LC/MS (230 DAD). Mass-spec [ES+] = 367.7. !H NMR (DMSO-d6) 7.39-7.40 (IH, m), 7.61-7.72 (3H, m), 7.73-7.77 (2H, m), 8.60-8.67 (4H, m)r 9.01-9.02 (IH, m), 9.92 (IH, s), 11.58 (IH, br.s.) Benzyl-(6-phenyl~pteridin-4-yI)-amine (Figure Removed) [0230] 50.5 % yield. 95.2 % purity by LC/MS (230 DAD). Mass-spec [ES+] =314.2. JH NMR (MeOH-d4) 4.87 (2H, s), 7.24-7.26 (IH, rn), 7.30-7.33 (2H, m)., 7.43-7.44 (2H, m), 7.51-7.54 (3H, m), 8.30-8.32 (2H, m), 8.58 (IH, s), 9.56 (IH, s). 4-[(6-pheny]-pteridin-4-ylamino)-methyI]-benzene-l,2-diol (Figure Removed) 10231] 39.8 % yield. ] 00% purity by LC/MS (230). Mass-spec [ES+J -346.2. 'tl NMR (DMSO-d6) 5.56 (2H, £;), 6.68-6.70 (IH, d), 6.75-6.77 (IH, dd), 6.875-6.879 (IH, d), 7.62-7.64 (3H, m), 8.53-8.55 (2H, m), 8.97 (IH, s), 9.12 (IH. s), 9.24 (IH, s), 9.89 (IH, s), 10.48 (IH, s), 10.54 (IH, s). ]ndan-2-yl-(6-phenyI-pteridin-4-yl)~amine (Figure Removed) [0232] 53.9 % yield. 96.6 % purity by LC/MS. Mass-spec [ES+] =340.2. !H NMR (DMSO-d6) 3.21-3.26 (2H, dd), 3.35-3.40 (2H, dd), 5.13-5.18 (IH, m), 7.17-7.19 (2H, m), 7.25-7.27 (2H, m), 7.55-7.59 (3H, m), 8.47-8.49 (2H, m), 8.65 (IH, s), 8.94-8.96 (IH, d), 9.72 (IH, s). {2-(3,4-Dimethoxy-phenyl)-ethyI]-(6-phenyI-pteridin-4-yI)-amine (Figure Removed) [0233] 66.5 % yield. 95.5 % purity by LC/MS (230 DAD). Mass-spec [ES+] =388.2. 'H NMR (MeOH-d4) 2.98-3.01 (2H, t), 3.76 (3H, s), 3.78 (3H, s), 3.90-3.93 (2H, t), 6.85-6.88 (2H. m), 6.93-6.93 OH, m), 7.55-7.57 (3H, m), 8.27-8.29 (2H, m), 8.58 (IH, s), 9.56 (IH, s) Synthesis of 4-substituted 7-phenyl-pteridin-4-yl-amines (Figure Removed) [0234] IN aqueous NaOH was added to a suspension of 1.33 g (5.95 mmol) of 4,5,6-triaminopyriniidine sulfate in 20 mL of water until pH reached 8. To this solution was added a solution of 1.0 g (5.95 mmol) of 4-hydroxyphenylglyoxal in 20 mL of methanol. The reaction mixture was left to stir at ambient temperature for 18 hrs. Formation of a yellow precipitate was observed. It was collected, washed with 20 mL of water, 20 mL of meihanol, 45 mL of di ethyl ether 3 times and dried in vacua to give 1.513 g of the product as a light-yellow solid. 100 % yield. 97.5 % purity by LC/MS (230 DAD). Mass-spec [ES+] =. !H NMR (DMSO-d6) 6.95-6.98 (2H, d), 8.31 (1H, br.s.), 8.19 (1H, br.s.), 8.21-8.24 (2H, d), 8.51 (1H, s), 9.34 (1H, s). General Procedure [0235] 239.2 mg (1.0 mmol) of 4-(4-amino-pteridin-7-yl)-phenol was suspended in 3 mL of amine and 194.2 rng (2.0 mmo!) of sulfamic acid was added to this mixure. The reaction mixture was heated ai 160-180 OC for 18 hrs. Then it was cooled down to ambient temperature and dissolved in 5-10 niL of methanol. Methanol solution was added dropwise to 45 niL of diethyl ether, the mixture was vortexed and centrifuged do^m. Solvent was decanted and the residue was purified by prep-HPLC. 4-(4-BenzyIamino-pteridin-7-yI)-phenol (Figure Removed) [0236] 79 % yield. 98.5 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 330.2. JH NMR (DMSO-d6) 4.77-4.78 (2H, d), 6.97-6.98 (2H, d), 7.24-7.26 (1H, m), 7.30-7.33 (2H, m), 7.43-7.44 (2H, m), 8.23-8.24 (2H, d), 8.58 (1H, s), 9.37 (1H, s). Substituted (6-phenyI-5,6,7,8-tetrahydro-pteridm-4-yI)-amines and (7-phenyl-5,6,7,8-tetrahydro-pteridin-4-yI)-amines (Figure Remove) General procedure 10237] To a stirred solution of the pteridine (5.0 mmol) in 15 mL of dry methanol was added sodium horohydride (5 mmol) at room temperature. The reaction mixture was stirred for 30 min and then neutralized with acetic acid. Solvent was removed iii vacuo and the residue was washed with water, cold methanol, diethyl ether and dried in vacuo. The resulting solid was purified by reverse phase prep-HPLC. 6,7-disubstituted pteridines; Method A. (Figure Removed) Method B [0238] The pyridine or pyrimidine is made into the free base with sodium carbonate, sodium bicarbonate or sodium hydroxide using solid or solution by using the correct amount in equivalents to neutralize the acid or by adjusting the pH to neutral to slightly basic (ca. 7 - 9). The benzil or glyoxal is added and the solution is heated for 1 h - 5 h. The free base formed precipitates out of solution and is washed successively with water, methanol and then ether. The solid is vacuum dessicator dried. {0239] This reaction was carried out by method A by using 23.5 mg of the pyrimidine and 22.5 mg of pyndyl. The reaction mixture was heated for 1 h. The product was precipitated into 5 ml. of 1:1 EtOAc-ether, filtered and washed with 50 mL of ether. M+H calcd and found 400. 6,7-bis(3-hydroxyphenyl)-pteridine-2,4,-diamine |0240] A 5-mL reaction vial with a stirring vane and a teflon cap was charged with 3,3'-dihydroxybenzil (Midori Kagaloi Co Ltd; 121 mg; 0.500 minol) and 0.700 mL of m-cresol (Acros) which gives a dull-yellow solution on warming to ca. 50 °C. The clear solution is treated with 2,4,5,6-tetraaminopyrimidine sulfate (Aldrich; 119 mg; 0.500 mmol; 1.00 equiv) which is insoluble in the reaction solution at room temperature and goes into solution on heating to ca. 200 "C to give an almost completely homogeneous dark greenish solution in about 30 min - 45 min. Heating between 200 °C and 220 °C for an additional 1.5 h, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a greenish-yellow precipitate. The solid was centrifuged, the supernatant decanted, the solid precipitate was washed with 5 x 40 mL of diethyl ether and dried in a vacuum dessicator to yield 0.275 g (124 %)' of a yellow-green solid. The only obvious major impurity is the reaction solvent, m-cresol. MS (M+H*: calcd 347; found 347). J0241] In case purified 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamine is required, the crude 3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yi] phenol may be dissolved in methanol, and an aqueous solution of 2.0 equiv. — 2.2 equiv. of sodium bicarbonate (or excess sodium bicarbonate) may be added to neutralize the acid making sure the pH is between 6 and 8 to ensure free-base. The free-base precipitates out of the methanol-water mixture within a few seconds. In case, precipitation does not occur, excess methanol ensures precipitation. The yellowish solid may be isolated and washed with acetonitrile-water or isopropanol-water mixtures and then with methanol-ether, and then ether (x3). The product is dried and stored as the free base, 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamine. [0242] Iii case the purified sulfate is required, the free base is protonated in MeOH by adding a cone, aqueous sulfuric acid (1.0 equiv) to a slurry of the compound in MeOH. The homogeneous protonated product is precipitated out by adding ether to the methanol. 6-pyridin-2-yl-7-pyrjdin-3-ylpteridin-4-amine sulfate salt [0243] A 5-mL reaction vial with a stirring vane and a teflon cap was charged with pyridyl (22.5 mgl) and 0.500 iriL of m-cresol (Acres) which gives a dull-yellow solution on warming to ca. 50 °C. The clear solution is treated with 2,4,5-triaminopyrimidine sulfate (Aldrich; 23.5 mg) which is insoluble in the reaction solution at room temperature and goes into solution on heating to ca. 200 °C to give an almost completely homogeneous dark solution in about 30 min - 45 rain. Heating between 200 °C and 220 °C for an additional 0.5 h, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a dull yellow precipitate. The soh'd was centrifaged, the supernatant decanted, the solid precipitate was washed with 4 x 40 mL of diethyl ether and dried in a vacuum dessicator to yield a yellow solid. MS (M+ET1": calcd 302; found 302). 6,7-bis(3,4-dihydroxyphenyl)pteridine-2,4-diol (Figure Removed) [0244] A 5-mL reaction vial with a stirring vane and a teflon cap was charged with 3,3 ',4,4'-tetrabydroxybenzil (137 mg; 0.500 mmol) and 1.00 mL of m-cresol (Acros) which gives a yellow-brown slurry warming to ca. 50 CC. The suspension is treated with sulfate 5,6-diamino-2,4-dihydroxypyrimidine sulfate (120 mg; 0.500 mmol; 1.00 equiv) which is insoluble in the reaction solution at room temperature and goes into solution on heating to ca. 200 °C to give homogeneous dark solution. Heating between 200 °C and 220 °C for an additional 2 h, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a light yellow precipitate. The solid was cenirifuged, the supernatant decanted, the solid precipitate was washed with 4 x 40 mL of diethyl ether and dried in a vacuum dessicator to yield a yellow solid. MS (M+H+: calcd 381; found 381). 6,7-bis(3-hydrox7phenyI)-pteridine-2,4-diaminediIiydrochloridesalt (Figure Removed) [0245] A 125-mL amber-bottle with a stirring bar and a septum was charged with crude 6,7-bis(3-hydroxyphenyl}-pteridme-2,4-diamine (135 mg; 0.304 mmol) and 5 mL of methanol. To the resulting dark brownish-green solution was added Amberlite (Cl") resin (GFS Chemical; 5.20 g). The heterogeneous mixture was stirred gently for ca. 16 h. with an apparent visual lightening of the solution. The solution was filtered to remove the resin beads, which were rinsed with 5x8 mL of MeOH. The light brown solution was concentrated on a rotary evaporator to yield 133 mg of dark brown oil. The oil was redissolved in ca. 2 mL of MeOH, and added to 40 mL of diethyl ether to yield a flocculent yellow precipitate that was isolated by centrifuging and decanting the supernatant. The solid was washed with 4 x 40 mL of diethyl ether, and dried in a vacuum dessicator to yield a greenish-yellow product (94.0 mg; 0.246 mmol; 81% for two steps). 98 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 347.7. 'H NMR (DMSO-d6) 6.78-6.87 (4H, m), 6.92-6.95 (2H5 m), 7.12-7.16 (2H, m), 7.82 (1H, br.s), 8.68 (1H, br.s), 9.15 (1H, s), 9.25 ('IH, s), 9.58 (1H, s), 9.72 (1H, s). C, N analysis: CigHjeChNeOa (Calcd.: C, 51.56; N, 20.C4; Found: C, 51.64; N, 19.93). Method B (Figure Removed) 6,7-bis(3-hydroxypheny])-pteridine-2,4-dianiiiie (Figure Removed) 10246] 4. 76 g (20.0 mrnol) of 2,4,5,6-tetraaminopyrimidine sulfate was added in small portions to a solution of 3.36 g (40.0 mrnol) sodium bicarbonate in 100 mL of water with vigorous stirring. A brisk evolution of COo gas was observed. The resulting suspension was heated to SO °C and -184 g, (20.0 mrnol) of 3,3'-dihydroxybenzil was added to the raixinre. The reaction mixture was refluxed for 3 hours, at which point a bright-yellow precipitate was formed :m abundance. |0247] The precipitate was filtered, washed with water, then with methanol, followed by dietbyl ether and dried in vacua to give 6.46 g (93.3 % yield) of a bright-yellow solid. 98.10 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 347.7. [H NMR (DMSO-d6) 6.64 (2H, br.s.), 6.69-6.82 (4H, m), 6.S6-6.89 (2H, m), 7.06-7.11 (2H, m), 7.57 (1H, br.s), 7.65 (1H, br.s), 9.38(111 s), 9.49 (1H, s). t),7-bis(3-hydroxypheny!)-pteridme-2,4-diammemethanesulfonatesalt (Figure Removed) [0248] 2.66 g (7.68 mmol) of 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diarnine was added to a solution of 1.55 g (16.13 mmol) of methanesulfonic acid hi 20 mL of MeOH with stirring. Pteridine immediately dissolved to give a dark-greenish solution. The reaction mixture was stirred for 30 min and then added dropwise to 400 mL of diethyl ether with vigorous stining. The formed yellow precipitate was collected, washed repeatedly with ether and dried in vacua to give 3.36 g (99.1 % yield) of the product as a light-yellow powder. 95.5 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 347. ]H NMR (MeOH-d4) 2.71 (3H, s), 6.80-6.S5 (2H, m), 6.90-6.92 (2H, m), 6.95 (1H, m), 7.00 (1H, m), 7.12-7.16 (2H, m). 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamme dihydrobromide salt 10249] The salt is made by malcing a HBr containing solution of methanol using methanol and acetyl bromide (10 equiv - 12 equiv) at -78 °C, and adding the free base to this solution so that the resulting solution concentration is below 0.4 M. The light yellow solution is stirred for ca. 30 miri - 60 min, concentrated by rotary evaporation to a yellow solid and then washed with ether, or with ether-hexanes, and dried in a vacuum dessicator (Figure Removed) [0250] 98.8 % Purity by LC/MS (230 DAD). Mass-spec [ES+] = 347. 1H NMR (MeOH-d4) 6.81-6.86 (2H, m), 6.92-6.95 (2H, m), 6.96-7.01 (2H, m), 7.13-7.18 (2H, m). Elemental analysis; calcd: C, 42.54; H, 3.17; N, 16.54; found: C, 43.11; H, 3.47; N, 16.47 6,7 -bis(3 -hydroxyphenyl )-pteridin-4-ylamine (Figure Removed) [0251] 2.23 g (10.0 mmol) of 4,5,6-triaminopyrimidine sulfate was added in small portions to a solution of 1.68 g (20.0 mmol) sodium bicarbonate in 50 mL of water with vigorous stirring. A brisk evolution of C02 gas was observed. The resulting suspension was heated to 80 °C and 2.42 g (10 mmol) of 3,3'-dihydroxybenzil was added to the mixture. The reaction mixture was refluxed for 1 hour, during which time the starting materials completely dissolved arid the product precipitated out as a light-yellow solid. [0252] The precipitate was collected, washed with water, then with methanol, followed by diethyl ether arid dried in vacua to give 3.14 g (94.8 % yield) of the product as a light-yellow solid. 100 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 332.8. 'H NMR (DMSO~d6) 6.77-6.83 (3H, m), 6.91-6.92 (1H, d), 6.90-6.99 (2H, m), 7.11-7.15 (2H, m), 8.17 (1H, br.s), 8.25 (1H, br.s.), 8.56 (1H, s), 9.55 (2H, br.s). 6,7-bis(34iydrox;ypheny])-pteridin-4-ylamine hydrochloride salt (Figure Removed) [0253] 4.4 g (13.27 mmol) of 6,7-bis(3-hydroxyphenyl)-pteridin-4-ylamine was suspended in 35 ml of MeOH. A solution of 2.61 g of aq. HC1 (26.55 mmol, 12.1 N) hi 5 mL of MeOH was added to the suspension. The reaction mixture became homogeneous withki 5 mm of stirring. It was left to stir for 30 min and then added dropwise to 400 mL of diethyl ether with vigorous stirring. The resulting precipitate was collected, washed repeatedly with ether and dried in vacua to give 4.62 g (94.7 % yield) of the product as a bright-yellow solid. 98.3 % purity by LC/MS (230 DAD). Mass-spec [ES4] = 332.8. *H NMR (MeOH) 6.88-6.90 (2H, m), 6.99-7.02 (2H, m), 7.04-7.08 (2H, m), 7.17-7.20 (2H, m), 8.79 (1H, s). 6,7-bis(3-hydroxyphenyl)-pteridin-4-ylamine methanesulfonate salt (Figure Removed) J0254] 1.308 g (13.63 mmol) of methanesulfonic acid in 10 mL of MeOH was added to the suspension of 2.15 g (6.48 mmol) of 6,7-bis(3-hydroxyphenyl)-pteridin-4-ylamine in 10 mL of MeOH. The mixture became homogeneous and orange-red in color. It was stirred for 30 mm and then added dropwise to 400 mL of diethyl ether with vigorous stining. The formed yellow precipitate was collected, washed with diethyl ether and dried in vacua to give 2.69 g (97.11 % yield) of the product as a light-yellow powder. Mass-spec [ES+] = 332.8. ]H NMR (MeOH-d4) 2.70 (3H, s), 6.86-6.90 (2H, m), 6.99-7.01 (2H, m), 7.04-7.08 (2H, m), 7.16-7.21 (2H, m), 8.80 (1H, s). 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine (Figure Remove) [0255] 1.5 mniol of the sulfate salt (6,7-bis(4-hydroxyphenyl)-pteridin-4-ylainine sulfate salt as 1:1 complex with m-cresol) was dissolved in 10 mL of 1:1 solution of MeOH/HiO. 2.0 eq. of solid NaHCOj were added to this solution. A brisk evolution of CCK was observed and a light-yellow precipitate started to form in ~ 10-15 min of stirring. The mixture Avas left to stir overnight and a yellow precipitate was formed in abundance. 20 mL of water was added, the formed precipitate was filtered, washed twice with water to remove Na2S04, washed with cold MeOH, washed repeatedly with Et2O and dried in vacua to give the product in 81.3 % yield over two steps (reaction in m-cresol and free base synthesis). 95.5 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 332.8. !H NMR (DMSO-d6) 6.72-6.76 (4H, dd), 7.35-7.42 (4H, dd), 8.06 (1H, br.s), 8.14 (1H, br.s), 8.50 (1H, s), 9.77 (1H, br.s), 9.87 (1H, br.s) 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine sulfate salt (Figure Remove) [0256] 1.97 g of 6,7-bis(4-hydroxyphenyl)-pteridm-4-ylaniiiie was added to a solution of 0.585 g of concentrated sulfuric acid in 50 mL of MeOH. The homogeneous mixture was left to stir at ambient temperature for 2 hours, then it was added dropwise to 400 mL of di ethyl ether. The formed orange precipitate was collected, washed repeatedly with ether and dried in vacua to give 2.36 g (92.5 % yield) of the product as a light-orange fluffy powder. 100 % purity by LC/MS (230DAD). Mass-spec [ES+] = 332.8. 'HNMR (MeOH-d4) 6.77-6.80 (4H, m), 7.48-7.53 (4H, m), 8.73 (1H, s). 'HNMR (DMSO-d6) 6.76-6.SI (4H, dd), 7.41 -7.47 (4H, dd), 8.84 (1H, s), 9.85 (1H, s), 10.01 (1H, s), 9.94 (1H, br.s), 10.15(lH,br.s). 6,7-bis(3,4-dihydroxyphenyl)-pteridine-2,4-diamine (Figure Removed) [0257] 105.0 nig (0.253 mmol) of 6,7-bis(3,4-dihydroxyphenyl)-pteridine-2,4-diamine dihydrochloride salt was dissolved in 3 mL of water and 42.53 mg of solid NaHCOS was added to this solution. The reaction mixture was stirred for 30 min. A slurry of yellow precipitate was formed, it was centrifuged down and solvent was decanted. The dark-yellow residue was dissolved in 3 mL of MeOH and added dropwise to 40 mL of di ethyl ether. The formed yellow precipitate was collected, washed with ether and dried in vacua to give 92.5 mg (96.5 % yield) of the product as a yellow, fluffy powder. 97 % purity by LC/MS (230 DAD). Mass-spec [M+H+] = 379.3. 'HNMR (MeOH-d4) 6.68-6.73 (2H, dd), 6.79-6.81 (1H, dd), 6.84-6.86 (1H, dd), 6.93 (1H, d), 7.03 (1H, d). 6,7-bis(3,4-dihydroxyphenyl)-pteridine-2,4-diamine dihydrocliloride salt (Figure Removed) 10258] Mass-spec [ES+] = 379.8. 'tl NMR (MeOH-d4) 6.70 (1H, d), 6.75 (1H, d), 6.88 (1H, dd), 6.93 (1H, dd), 6,95 (1H, d), 7.08 (1H, d). 6J-bis(3,4-dihydroxypherjyl)-pteridin-4-ylaminehydrochloridesalt or 4-i4-amino-6-(3,4-diliydroxypheny])pteridm-7-yl]benzene-l,2-diol hydrochloride salt (Figure Removed) [0259] A 5-mL reaction vial with a stirring vane and a teflon cap was charged with 3,3',4,4'-tetrahydroxybenzil (Midori Kagaku Co Ltd; 548 mg; 2.00 rnmol), 4,5,6-triarninopyrimidine snlfate and 3.00 mL of m-cresol. The heterogeneous mixture was heated, it first goes orange while dissolving at ca. 150 °C and then on heating at 200 °C -220 °C for ca. 2 h goes to a dark blood-red solution. The clear solution is heated for an additional 30 min, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a dark red-orange precipitate. The solid was centrimged, washed with 5x40 mL of diethyl ether and dried in a vacuum dessicator to yield 1.20 g (128 %)J of an orange-red solid. The only obvious major impurity is the reaction solvent, m-cresol. [0260] Mass-spec [ES+] - 364.8. ]H NMR (MeOH-d4) 6.73 (1H, d), 6.78 (1H, d), 7.00-7.02 (2H, dd), 7.07 (1H, d), 7.16 (1H, d). 8.71 (1H, s). 6,7-bis(3,4-dibydroxyphenyl)-pteridm-4-ylamine or4-[4-amino-6-(3,4-dihydroxypheny])pteridin-7-yl]benzene-l,2-diol (Figure Removed) [0261] Mass-spec [ES+J = 364.8. !H NMR (MeOH-d4) 6.70-6.75 (2H, dd), 6.91-6.95 (2H, dd), 7.03 (IH, d), 7.12 (IH, d), 8.49 (IH, s). !H NMR (DMSO-d6) 6.63-6.68 (2H, dd), 6.74-6.76 (IH, dd), 6.85-6.87 (IH, dd), 7.00 (IH, d), 7.06 (IH, d), 7.93 (2H, br.s), 8.47 (IH, s). 6,7-bis(3,4-dihydroxyphenyl)-pteridin-4-ylamine methanesulfonate salt or 4-[4-arnrno-6-(3,4-dihydroxyphenyl)pteridin-7-yl]benzene-l,2-diol methanesulfonate salt (Figure Removed) [0262] 98.07 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 364.8. ]H NMR (MeOH-d4) 2.69 (3H, s), 6.73-6.79 (2H, dd), 7.00-7.04 (2H, dd), 7.08 (IH, d), 7.17 (IH, d), 8.81 (IH, s). (Figure Removed) 4-(2,4-diaminopteridin-6-yl)pkenol [0263] A 50-mL recovery flask, fitted with a stirring bar, a reflux condenser and a heating mantle was charged with 1 mmol of each of hydroxylamine hydrochloride and 4-hydroxyphenj'lglyoxal. The substances were dissolved in methanol (5 mL). To this yellow solution was added the 2,4,5,6-tetraminopyrirnidine sulfate and 20 mL of water. The heterogeneous solution was heated to reflux for 2 h. A yellow precipitate that was formed. The solution was cooled, the reaction mixture was made slightly basic NaOH (4 M, aqueous) to a pH of ca, 3. The precipitated free base was isolated and washed sequentially with water (2 x 40 mL), methanol (1 x 40 mL) and ether (1 x 40 mL) and drying in a vacuum dessicator. (Figure Removed) [0264] A 5-mL reaction vial with a stirring vane and a teflon cap was charged with benzil (420 mg; 2.00 mrnol) and 2.00 mL of m-cresol (Acros) which gives a dull-yellow solution on wanning to ca. 50 °C. The clear solution is treated with 5,6-diamino-2,4-dibydroxypyrimidine sulfate (Aldrich; 482 mg; 2.00 mmol; 1.00 equiv) which is insoluble in the reaction solution at room temperature and goes into solution on heating to ca. 200 °C to give an ahnost completely homogeneous dark solution in about 30 min - 45 min. Heating between 200 °C and 220 °C for an additional 1.5 h, followed by cooling to room temperature, and precipitation by pouring into 40 mL of anhydrous diethyl ether resulted in a dull yellow precipitate. The solid was centrifuged, the supernatant decanted, the solid precipitate was washed with 4 x 40 mL of diethyl ether and dried in a vacuum dessicator to yi eld 960 mg (99%) of a yellow solid. MS (M+H+: calcd 317; found 317). 4-(2.4-Diamino-pteridin-6-y])-phenol [0265] (M+H)+ calcd and found 255; LC (UV-PDA 230 nm) 98% purity.; ]H NMR (500 MHz; DMSO-d6): 5 9.89 (br s, 1 H), 9.24 (s, 1 H), 8.15 (d, J - 8.5 Hz, 2 H), 7.70 (br. s, 1 H), 7.65 (br. s, 1 H) 6.88 (d, J = 8.5 Hz, 2 H), 6.57 (br s, 2 H) 2,3-Diphenyl-pyrido[3,4-b]pyrazin-S-ylamine hydrocliloride salt (Figure Removed) [0266] 60.0 mg (0.37 mmol) of 3,4,5-triaminopyriraidine hydrocliloride and 86.3 mg (0.41 mmol) of benzil were heated at 190 °C in 1.0 mL of m-cresol for 1 hr. Then the mixture was cooled down to r.t., mixed with 35 mL of diethyl ether. The formed brown precipitate was collected, washed repeatedly with ether and dried in vacua to give 51.1 mg (45.8 % yield) of the product as a brown powder. Mass-spec [M+J-f] = 299.2. 1H NMR (MeOH-d4) 7.38-7.41 (3H, m), 7.45-7.49 (3H, m), 7.58-7.60 (2H, m), 7.66-7.68 (2H, m), 8.05 (1H, s), 8.85 (1H, s). 2,3-Bis(4-hydroxyphen)'l)-pyrido[3,4-b]pyrazin-8-ylamine hydrochloride salt (Figure Removed) [0267] 60.0 mg (0.37 mmol) of 3,4,5-triaminopyrimidine hydrocliloride and 99.6 mg (0.41 mmol) of 4,4'-dihydroxybenzil were heated at 190 °C in 1.0 mL of m-cresol for 1 hr. Then the mixture was cooled down to r.t., mixed with 35 mL of diethyl ether. The formed brown precipitate was collected, washed repeatedly with ether and dried in vacua to give 91.3 mg (66.6 % yield) of the product as a dark-green powder. Mass-spec [M+ET] = 331.4. 'H NMR (MeOH-d4) 6.78-6.81 (4H, d), 7.49-7.51 (2H, d), 7.60-7.62 (2H, d), 7.95 (1H, s), 8.71 126 2,3-Bis(3,4-dihydroyyphenyl)-p)'rido[3,4-b]pyrazin-8-ylammehydrochloride salt (Figure Removed) [0268] 60 mg (0.37 mmol) of 3,4,5-triamnopyridine hydrochloride and 112.6 mg (0.41 mmol) of 3,3',4,4'-t.etrahydroxybenzil were dissolved ib 1 mL of in-cresol. The reaction mixture was heated at 190 °C for 1 hr, at wliich point the mixture became homogeneous and dark-brown in color. The reaction was cooled to r.t. and mixed with 35 mL of diethyl ether. The formed brown precipitate was vortexed, collected, washed repeatedly with diethyl ether and dried in vacuo to give 111.0 mg (82 % yield) of the product. Mass-spec [M+H+] = 363.2. ]HNMR(MeOH-d4) 6.76-6.78 (2H, d), 6.98-7.00 (IH, dd), 7.11 (IH, dd), 7.13 (IH, d), 7.21 (IH, dd), 7.94 (IH, s), 8.68 (IH, s). 2,3-Bis(3-h3'droxyphenyl)-pyrido[3,4-b]pyrazin-8-ylamine hydrochloride salt (Figure Removed) [0269] 60.0 mg (0.37 mmol) of 3,4,5-triaminopyrimidine hydrochloride and 99.6 mg (0.41 mmol) of 3,3'-hydroxybenzil were heated at 190 '°C in 1.0 ml of m-cresol for 1 hr. Then the mixture was cooled down to r.t., mixed with 35 ml of diethyl ether. The formed brown precipitate was collected, washed repeatedly with ether and dried in vacuo to give 93.9 mg (68.5 % yield) of the product as a greenish-brown powder. Mass-spec [M+HT] = 331.4. H NMR (MeOB-d4) 6.SS-6.91 (2H, m), 6.99-7.01 (IH, m), 7.07-7.10 (2H, m), 7.13-7.14 (IH, m), 7.18-7.22 (2H, m), 8.03 (IH, s), 8.82 (IH, s). -,3-bis(34iydroxypheny])-pyrido[2,3-b]pyrazin-6-ylaniinedihydrochloride salt (Figure Removed) [0270] 197.0 mg (1.0 mmol) of 2,3,6-triaminopyrimidine dihydrochloride and 242.4 mg (1.0 rnmol) of 3,3'-dihydroxyben2il were dissolved in 3.0 mL of 1:1 mixture of dioxane-water. The reaction mixture was refluxed for 3 hours and then solvent was removed in vacuo. The resulting greenish solid was dissolved in 3 mL of MeOH and this solution was added to 40 mL of diethyl ether with vigorous stirring. The formed precipitate was collected, washed with diethyl ether and dried in vacuo to give 342.9 mg (85.0 % yield) of the product as a light-green powder. 99.0 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 331.8. 'H NMR (MeOH-d4) 6.83-6.85 (2H, m), 6.S8-6.90 (1H, m), 6.95-6.97 (2H, m), 7.02-7.03 (1H, m), 7.14-7.18 (2H, m), 7.36-7.38 (1H, d), 8.43-8.46 (1H, d). 2,3-bis(4-hydroxyphenyl)-pyrido[2,3-b]pyrazui-6-ylamine dihydrochloride salt (Figure Removed) [0271] 1.97 g (10.0 mmol) of 23,6-triarnmopyrimidine dihydrochloride and 2.42 g (10.0 mmol) of 4,4'-dihydroxybenzil were dissolved in 30 mL of 1:1 mixture of dioxane-water. The reaction mixture was refluxed for 6 hours and then solvent was distilled off. The resulting dark-brown solid was suspended in 20 mL of MeOH and this suspension was added to 400 mL of diethyl ether with vigorous stirring. The formed dark-brown precipitate was collected, washed with diethyl ether and dried in vacua to give 3.35 g (83.1 % yield) of the product as a brown fluffy powder. 92.6 % purity by LC/MS (230 DAD). Mass-spec [ES+] - 331.8. 'H NMR (MeOH-d4) 6.72-5.77 (4H, m), 7.29-7.33 (3H, m), 7.40-7.42 (1H, ml, 7.41 (lH,d), 8.35 (1H, d). 10272] Phosphate ester of 4, 4'-dihydroxybenzil (Figure Removed) 10273] A 50-mL one-necked round-bottomed flask with a stirring bar and a septum was charged with 4,4'-dihydroxybenzil (512 mg; 2.11 mmol; 1.00 equiv) and acetonitrile (8 mL). To tills partially dissolved mixture was added triethylamine (1.06 g; 14.9 mmol; 7.06 equiv), dimethylaminopyridine (DMAP) (478 mg; 3.91 mniol; 1.85 equiv) and dichloromethane (DCM) as co-solvent. The reaction mixture was stirred for 3 d at room temperature after which it was concentrated by rotary evaporation to yield a yellow-white slurry. This oily slurry was partitioned between sodium bicarbonate (satd. aq) and dichloromethane (DCM). The aqueous layer was rewashed with 2x5 mL DCM, followed by extraction of the combined organics with 10 mL of 1 M HC1. The DCM layer was dried (anhyd. MgSC>4), filtered and concentrated by rotary evaporation to yield the desired material as a light yellow slightly viscous oil. The compound does not require any purification but is easily purified by column chromatography using DCM-EtOAc (1:1). The chromatographically purified material is a yellow oil (911 mg; 89%). [0274] ]H NMR (500 MHz; DMSO-d6): 6 8.01 (d, J = 8.6 Hz, 4 H), 7.45 (d, J = 8.5 Hz, 4 H). 4.21 - 4.18 (m, 8 H), 1.28 (app t, J = 5.0 Hz, 12 H) [0275] The compound was made by the method B in the pteridine synthesis by using the pyrimidine and the phosphate ester of the 4,4'-dihydroxybenzil. (Figure Removed) [0276] The compound was purified by passing through a plug of silica using ethyl acetate. (M+H)+: calcd. 604; found 604, LC purity 96% (DAD at 230 nm). [0277] 'H NMR (500 MHz; DMSO-d6); S 8.58 (s, 1 H), 8.30 (br s, 2 H), 7.58 (d, J = 6.8 Hz), 7.54 (d, J = 6.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 8.9 Hz, 2 H), 4.17 -4.14 (m, 8 H), 1.26 (app t, J = 6.9 Hz, 12 H) [0278] Phosphate ester deprotected [0279] The above diethylester compound was deprotected in acetonitrile using TMSBr. The reaction was completed by adding water and then concentration by rotary evaporation and drying of the solid. (Figure Removed) [0280] :H NMR (500 MHz; methanol-cLt); 3 8.39 (s, 1 H), 7.31 (d, J = 6.8 Hz, 2 H), 7.26 (d, ] = 6.7 Hz, 2 H), 6.31 (app t J = 6.8 Hz, 4 H) [0281] Phosphate ester of pyridopyrazine (Figure Removed) [0282] 'H NMR (500 MHz; DMSO-d6): 6 8.05 (d, J = 9.0 Hz, 1 H), 7.46 (d, J - 8.7 Hz, 2 H), 7.43 (d, J - 8.6 Hz, 2 H), 7.24 (br s, 2 H), 7.17 (app t, J = 7.7 Hz, 4 H), 7.10 (d, J = 9.0 Hz, 1 H), 4.17 - 4.13 (m, 8 H), 1.26 (app t, J = 5.0 Hz, 12 H) [0283] Phosphate ester deprotected (Figure Removed) [0284] This compound was made in a similar fashion to the one described above. [0285] 'H NMR (500 MHz; methanol-dO; S 8.05 (d, J = 9.0 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 2 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.24 (br s, 2 H), 7.17 (app t, J = 7.7 Hz, 4 H), 7.10 (d, J = 9.0, 2H). [0286] Long chain ester of pteridrne [0287] The benzil was modified using an acid chloride with DMAP as base in DCM. The modified Benzil was then condensed with the pyrimidine to yield the product below. (Figure Removed) 4-(4-amino-pteridin-7-yl )~benzene-l ,2-diol [0288] Tliis compound is made by stirring a 1:1 ratio of the appropriate glyoxal with the free base of the pyrimidine in water at a pH of 7 for ca. 3 h. The product is isolated by filtering the precipitated free base, washing sequentially with water (2 x 40 mL), methanol (1 x 40 mL) and ether (2 x 40 mL) and drying in a vacuum dessicator. (Figure Removed) [0289] ]H NMR (500 MHz; DMSO-d6): 5 9.72 (s, 1 H), 9.40 (br s, 1 H), 9.28 (s, 1 H), 8.51 (s, 1 H), 8.17 (br s, 1 H), 8.12 (br s, 1 H), 7.80 (d, J = 2.3 Hz, 1 H), 7.71 Hz, (dd, J = 8.4 Hz, J - 2.3 Hz, 1 H), 6,92 (d, J - 8.3 Hz, 1 H). 4-(2,4-diamino~pteridin-7-yl)-benzeue-l,2-dio] 102QO] This compound is made by stirring a 1:1 ratio of the appropriate glyoxal with the free base of the pynmidine in water at a pH of 7 for ca. 3 h. The product is isolated by filtering the precipitated free base, washing sequentially with water (2 x 40 mL), methanol (1 x 40 mL) and ether (2 x 40 mL) and drying in a vacuum dessicator. (Figure Removed) 10291] 'H NMR (500 MHz; DMSO-d6): 5 8.71 (s, 1 H), 7.64 (d, J = 2.3 Hz, 1 H), 7.56 -7.53 (br s, 2 H), 7.53 (dd, J - 8.3 Hz, 2.1 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.52 (br s, 2 H) 4-(4-amino-pteridiri-7-yl)-phenol (0292] This compound is made by stirring a 1:1 ratio of the appropriate glyoxal with the free base of the pynmidine in water at a pH of 7 for ca. 3 h. The product is isolated by filtering the precipitated free base, washing sequentially with water (2 x 40 mL), inethanol (1 x 40 mL) and ether (2 x 40 mL) and drying in a vacuum dessicator. (Figure Removed) [0293] 'H NMR (500 MHz; DMSO-d6): 5 10.2 (br s, 1 H), 9.34 (s, 1 H), 8.52 (s, 1 H), 8.23 id .1 - 6.8 Hz, 2 H), 8.19 (br s, 1 H), 8.13 (br s, 1 H), 6.97 (d, J = 8.8 Hz, 2 H) 4-(2,4-diamino-pteridin-7-yl)-phenol J0294] This compound is made by stirring a 1:1 ratio of the appropriate glyoxal with the free base of the pyrimidme in water at a pH of 7 for ca. 3 h, The product is isolated by filtering the precipitated free base, washing sequentially with water (2 x 40 mL), methanol (1 x 40 mL) and ether (!' x 40 mL) and drying in a vacuum dessicator. (Figure Removed) [0295] 'H NMR (500 MHz; DMSO-d6): 5 10.0 (br s, 1 H), 8.81 (s, 1 H), 8.09 (d, J - 8.5 Hz, 2 H), 7.62 (br s, 1 H), 7.55 (br s, 1 H), 6.91 (d, J - 8.5 Hz, 2 H), 6.57 (br s, 2 H) [0296] 4-pheny] -pteridm-4-yl -amine [0297] This compound was prepared by heating ammonium acetate with the appropriate pyrazine in acetic acid for an hour. The product is isolated by concentrating the solution by rotary evaporation and washing with ether. (Figure Removed) [0298] 'H NMR (500 MHz; DMSO-d6): 5 9.73 (s, 1 H), 8.54 (s, 1 H), 8.49 (dd, J = 8.2 Hz, J - 1.9 Hz, 2 H), 8.46 (br s, 1 H), 8.31 (br s, 1 H), 7.60 - 7.55 (m, 3 H) Experimental Procedure 4-[ 2-(6-Phenyl-pteridin-4-ylarnino)-ethyl]benzene-1,2-diol (Figure Removed) 10299] To a suspension of 3-hydroxytyramine hydrochloride (189.6 ing, 1.0 mniol) in 4 mL of glacial acetic acid was added N'-(3-cyano-5-phenyl-pyrazin-2-yl)-N,N'-dimethyl-formamidine (251.3 mg, ] .0 mmol). The reaction was refluxed for 1.5 hours. The progress of the reaction was monitored by LC/MS. After the reaction had completed, the reaction mixture was cooled down to ambient temperature and acetic acid was removed in vacua. 5 mL of methanol was added to the resulting residue and it was crushed with a spatula into a fine suspension. 10 mL of 1:1 mixture of acetonitrile/water was added to the suspension. The solid was centrifuged down, washed with 20 mL of 1:1 mixture of acetonitrile/water twice, 10 mL of methanol, 40 mL of diethyl ether and dried in vacua to give the product as a greenish-yellow solid. 58.5 % yield. 96.9 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 360.5. 'H NMR (DMSO-d6) 2.80-2.83 (m, 2H), 3.72-3.76 (m, 2H), 6.52-6.54 (dd, 1H), 6.65-6.67 (d, 1H), 6.68-6.69 (d, 1H), 7.56-7.61 (m, 3H), 8.45-8.47 (m, 2H), 8.63 (s, 1H), 8.68 (br.s, 1H), 8.80 (br.s, 1H), 8.91-8.94 (t, 1H), 9.72 (s, 1H). UV X max = 239, 209, 279. 4-[(Pheny]-pteridin~4-yiammo)-methyl]-benzene-1,2-diol (Figure Removed) [0300] To a suspension of 3,4-dmydroxyberizylaminehydrobromide (220.1 mg, l.Ommol) in 4 mL of glacial acetic acid was added N'-(3-cyano-5-phenyl-pyrazin-2-yl)-N,N'-dim ethyl -form ami dine (251.3 mg, 1.0 mmol). The reaction was refluxed for 4 hours. The progress of the reaction was monitored by LC/MS. After the reaction had completed, the reaction mixture was cooled down to ambient temperature and acetic acid was removed in vacua. 5 mL of methanol was added to the resulting residue and it was crushed with a spatula into a fine suspension. The suspension was added to 45 mL of diethyl ether. The -;olid was centrifuged dcwn, washed with 45 mL of diethyl ether twice and dried in vacuo to give the product as a yellow solid. The product was purified by prep-HPLC, the major product was collected and solvent was removed in vacuo. 99.6 % purity by LC/MS (230 DAD). Mass-spec [ES+] = 346.5. 'H NMR (DMSO-d6) 5.56 (s, 2H), 6.68-6.70 (d, 1H), 0.75-6,77 (dd, 1H), 0.87-6.87 (d, 1H), 7.62-7.64 (m, 3H), 8.53-8.55 (m, 2H), 8.97 (s, 1H), LU2 (s, 1H), 9.24 (s, 1H), 9.89 (s, 1H), 10.48 (br.s, 1H), 10.54 (br.s, 1.H). UV X max -245, 278,210. ,3-Bis(3,4-dihydroxvphenyl)-pvrido[2,3-b]pyra2in-6-ylamine dihydrochloride salt (Figure Removed) |0301] 107.07 mg (1.0 mmol) of 2,3,6-triamuiopyrimidine dihydrochloride and 274.23 mg {1.0 nimol) of 3,3',4,4'-tetrahydroxybenzil were dissolved in 4 mL of 1:1 mixture of dioxane-water. The reaction was refluxed for S hours. Then solvent was removed in vacuo. The dark-yellow residue was dissolved in 2 mL of methanol and this solution was added dropwise to 40 mL of diethyl ether. The formed dark-yellow precipitate was collected, washed with ether and dried in vacuo to give 370.0 mg (85 % yield) of the product. 100 % purity by LC/MS (230 DAD). Mass-spec [ES+] =363.8. 1H NMR (MeOH-d4) 6.70-6.75 (2H, dd), 6.81-6.92 (2H, dd), 6.96-7.07 (2H, dd), 7.27 (1H, d), 8.34 (1H, d). 2,3-Bis(3-hydroxyphenyl)quinoxaHn-6-ylamine dihydrochloride salt (Figure Removed) 10302] 40.4 mg (0.206 mmol) of 1,2,4-benzenetriamine dihydrochloride and 50 mg (0.20 mmol) of 3,3'-dihydroxybenzil were dissolved in 2 mL of 1:1 mixture of dioxane-water. The reaction was re fluxed for 3 hours. Then solvent was removed in vacua. The residue was dissolved in 2 mL of methanol and this solution was added dropwise to 40 mL of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacua to give 69.8 nig (92.6 % yield) of the product. 97.6 % purity by LC'/MS (230 DAD). Mass-spec [ES+j =330.8. !H NMR (500 MHz, MeOH-d4) 6.81-6.87 (2H, m), 6.96-6.98 (4H, m), 7.10 (1H, m), 7.13-7.16 (1H, t), 7.28-7.31 (1H, t), 7.56-7.58 (1H, m), 8.04-8.06 (1H, d). 2,3-Bis(4-hydroxyphenyl)quinoxalin-6-ylamine dihydrochloride salt (Figure Removed) [0303] 9S.04 mg (0.5 mmol) of 1,2,4-benzenetriamine dihydrochloride and 121.2 mg (0.5 mmol) of 4,4'-dihydroxybenzil were dissolved in 2 ml of 1:1 mixture of dioxane-water. The reaction was refluxed for 3 hours. Then solvent was removed in vacua. The residue was dissolved in 2 ml of methanol and this solution was added dropwise to 40 ml of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacua to give 168.3 mg (83.7 % yield) of the product. 98.7 % purity by LC/MS (230 DAD). Mass-spec [ES+] =330.8. ]H NMR (500 MHz, MeOH-d4) 6.76-6.77 (2H, d), 6.87-6.89 (2H, d), 7.05-7.06 (1H, d), 7.29-7.31 (2H, d), 7.38-7.40 (2H, d), 7.50-7.52 (1H, m), 7.99-8.01 137 23-Bis(3,4-dihydroxyphenyl)qumoxalin-6-ylamine dihydrochloride salt (Figure Removed) 10304] 98.0 mg (0.5 mrnol) of 1,2,4-benzenetriamine dihydrochloride and 137.1 mg (0.5 mmol) of 3,3',4,4'-tetrahydroxybenzil were dissolved in 3 ml of MeOH. The reaction was refluxed for 6 hours. Then the reaction mixture was cooled to r.t. and added dropwise to 40 ml of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacua to give 1 84.0 mg (84.7 % yield) of the product. 97.7 % purity by LC/MS (230 DAD). Mass-spec [ES+] =362.8. !H NMR (MeOH-d4) 6.73-6.75 (1H, d), 6.78-6.80 ( 1H, m), 6.88-6.89 (1H, m), 6.94-6.97 (3H, m), 7.03 (1H, d), 7.49-7.51 (1H, dd), 7.97-7.99 2-Hydroxy-5-(6-phenyl-pteridui-4-ylarnino)-benzenesulfonic acid (Figure Removed) 10305] 70.1 % yield. 83 % purity by LC/MS (230 DAD). Mass-spec [ES+] - 396.S. 'H NMR (DMSO-d6) 7.17-7.19 (1H, dd), 7.58-7.63 (3H, m), 7.80-7.82 (1H, dd), 7.993-7.999 (1H, d), 8.61-8.03 (2H, m), 8.73 (1H, s), 9.80 (1H, s), 10.51-10.53 (3H, m). (6-Phenyl-pteridin-4-ylamino)-quinolin-8-ol hydrochloride salt (Figure Removed) [0306] 79.9 % yield. 85% purity by LC/MS (230 DAD). Mass-spec [ES+] = 367.7. !H NMR (DMSO-d6) 7.39-7.40 (IH, m), 7.61-7.72 (3H, m), 7.73-7.77 (2H, m), 8.60-8.67 (4H, m), 9.01-9.02 (IH, m), 9.92 (IH, s), 11.58 (IH, br.s.) [0307] General procedure Scheme A: (Figure Removed) [0308] 7-Bromo-benz,o[l,2,4]triazm-3-ylamine-l-oxide (Figure Removed) [0309] 4-Bromo-2-nitro-phenylamine (2.48g, 11.4mmol) was mixed with cynamide (1.51 g, 36 rnmol) in a 20 mL vial. The mixture was heated to 100 °C till the mixture was totally melted. The mixture was cooled down to room temperature and 6.5ml concentrated HC1 was added. The mixture was heated at 100°C for 40 minutes and cool down in ice water. 6.5rnl 14M NaOH was carefully added to the above reaction mixture. The resulted mixture was heated at 100°C for 2 hours then cool down to room temperature. After filtration, the precipitate was washed several times with water, methanol and ditheylether to remove the starting material. 0.739g product was obtained. Yield: 27%. ESI-MS: [M+H]+, 241, 243; 5H NMR (DMSO-d6): o 7.48 (d, J= 9.02 Hz, 1 H), 7.89 (dd, Jj - 9.02 Hz, J2 = 2.14 Hz, 1 H), 8.26 (d, .7=2.14 Hz, 1 H). 140 10310] 7-Bromo~5- methyl-benzo[l,2,4]triazin-3-ylamine-1 -oxide (Figure Removed) "-Benzo[l,3Jdioxol-5-yl-benzo[l,2,4]triazin-3-ylamine-l-oxide (0311] 4-Bromo-2-methyl-6-nirro-phenylamine (Ig, 4.33mmol) was mixed with cynamide (0.5g, 12mmol) and 5g pyridine HC1 in a 20ml vial. The mixture was heated to reflux overnight. The mixture was cooled down to room temperature and 10% NaOH was carefully added. The resulted mixture was heated at 100°C for 2 hours then cool down to room temperature. After filtration, the precipitate was washed several times with water, acetone and ditheylether to remove the starting material. 0.4g product was obtained. Yield: 36%. ESI-MS: [M+H]+, 255, 257; 'H NMR (DMSO-d6): 8 2.45 (s, 3 H), 7.81 (d, J= 1.97 Hz, 1 H), 8.26 (d, J - 1.97 Hz, 1 H). (Figure Removed) [0312] To a solution of 7-Bromo-benzo[l,2,4]triazrn-3-ylamine-l-oxide (50mg, 0.21mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 3,4-(Methylenedioxy) phenylboronic acid (6S.6mg, 0.41mmol) dissolved in 1ml ethanol and potassium carbonate (32.4 mg, 0.3mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, (j.034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCCh solution, and CH2C12 was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 20mg 7-Benzo[1,3]dioxol-5-yl-ben2,o[l,2,4]triazin-3-ylarnine-l-oxide was isolated.141 Yield: 34.5%; ESI-MS: [M+H]4, 283; ]H NMR (DMSO-d6): 6 6.09 (s, 2 H), 7.04 (d, J= S.12 Hz, 1H), 7.27 (dcl,/;= 7.88 Hz, .£=1.58 Hz, 1H), 7.37 (s, 1 H), 7.58 (d, J= 8.12 Hz, 1 H), 8.10 (dd, J, = 8.86 Hz, J2= 1.86 Hz, 1 H), 8.25 (d, J= 1.86 Hz, 1 H). 7-Benzo[l,3]dioxol-5-y]-benzo[l,2,4]tiiazin-3-ylamine (Figure Removed) [0313J 10 mg 7-Benzo[l,3]dioxol-5-yl-benzo[l,2,4]triazin-3-ylamine-l-oxide was dissolved in in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 5 mg 7-(2,6-Dimethyl-phenyl)-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 53%; ESI-MS: [M+H]+, 267; 'HNMR (DMSO-de): 5 6.09 (s, 2 H), 7.04 (d, J= 8.00 Hz, 1H), 7.33 (dd, Jf= 7.91 Hz, .7, =1.76 Hz, 1H), 7.46 (d, J- 1.51 Hz, 1 H), 7.58 (d, J= 8.84 Hz, 1 H), S.12 (dd, Jj - 8.84 Hz, J2= 1.96 Hz, 1 PI), 8.39 (d, J- 1.96 Hz, 1 H) . 7-(2,6-Diraethyl-phenyl)-benzo[ 1,2,4]triazin-3-ylamine (Figure Removed) 10314] To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 2,6-dimethylphenylboroiiic acid (240mg, 1.6mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tns 7-(4-Phenoxy-phenyl)-benzo[l,2,4]triazm-3-ylamine (Figure Removed) [0315] To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 4-Phenoxyphenylboromc acid (177mg, 0.83mmoi) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6mrnol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.S3umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaIiCO3 solution, and CH2Cl2 was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml M, N-Dirnethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 1 0% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used. lo isolate the final product. 20mg 3-(3-Amino-benzo[l,2,4]triazin-7-yl)-benzonitrile was obtained. Yield: 15.4%; ESI-MS: [M+H]+, 315; 'HNMR(DMSO-d6): 5 7.09-7.13 (m, 5 H), 7,44 (m, 2 H), 7,62 (d, J = 8.89 Hz, 2 H), 7.87(m, 2 H), 8.15 (dd, J, = 8.89 Hz, J2 = 2.34 Hz, 1 H), 8.43 (d,.7= 2.34 Hz, 1 H). 7-(2,6-Dimethoxy-phenyl)-benzo[l,2,4]triazin-3-ylamine (Figure Removed) [0316] To a solution of 7-Bromo-benzo[l,2,4]triazm-3-ylamine-l-oxide (lOOmg, 0.42mrnol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 2,6-dimethoxy-phenylboronic acid (302mg, 1.66mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and rris(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCOs solution, and CHjCk was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 40mg 7-(2,6-Dimethoxy-phenyl)-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 34.2%, ESI-MS: [M+H]+, 283; !HNMR (DMSO-d6): 5 3.71 (s, 6 H), 6.80 (d, ,/= 8.47 Hz, 2 H), 7.36 (t, J= 8.39 Hz, 1 H), 7.52 (d, J= 8.85 Hz, 1 H), 7.66(dd, J, = 8.85 Hz, .7, = 1.91 Hz, 1 H), 8.00 (d,J= 1.91 Hz, 1 H). -(4-r-ButyJ-phenyl)-benzo[l,2,4]triazin-3-yIamine (Figure Removed) 10317] To a solution of 7-Bromo-ben2o[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved in 6rnl N, N-Dimethylacetamide in a 20ml vial, 4-/-butyl-phenylboronic acid (I48mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0,034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCCh solution, and CH^Cfe was used to extract the product. Solvent hi the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N. N-Dimethylacetanude and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 20mg 7-(4-f-Butyl-phenyl)-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 18%, ES1-MS: [M+H]+, 279; !H NMR (DMSO-d6): 6 1.34 (s, 9 H), 7.53 (d, J - 8.66 Hz, 2 H), 7.61 (d, J= 8.85 Hz, 1 H), 7.77 (d, J= 8.66 Hz, 2 H), 8.16 (dd, J, = 8.84 Hz, J2 = 1.S9 Hz, 1 H), 8.43 (d, J= 1.89 Hz, 1 H). -(2-Trifluoromethy l-phenyl)-benzo[ 1,2,4]triazin-3-ylamine (Figure Removed) |0318] To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamuie-l-oxide (lOOmg, 0.42mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 2-tilfluoromethyl phenylboronic acid {i 57mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHC103 solution, and CH^Ck was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 20mg 7-(2-Trifluoromethyl-phenyl)-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 16.5%, ESI-MS: [M+H]+, 291; 'HNMR (DMSO-d6): 5 7.56 (d, /= 7.56 Hz, 1 H), 7.60 (d, ./ = 8.66 Hz, 1 H), 7.68-7.80 (m, 3 H), 7.89 (d, J= 7.56 Hz, 1 H), 8.11 (d, .7=1.46 Hz, 1 H). 7-Biphenyl-4-yl-benzo[ 1,2,4]tiiazrn-3-ylamine (Figure Removed) 10319] To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, ().42mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 4-biphenylboronic acid (164mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, O.Ommol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034-mmol) and tns(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCCb solution, and CH:C12 was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N- Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 1 0% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. C'elite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 15mg 7-Biphenyl-4-yl-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 12.1 %, ESI-MS: [M+H]H, 299; 'H NMR (DMSO-d6): 5 7.41 (m, 1 H), 7.50 (m, 2 H), 7.55 (m, 2 H), 7.64 (d,./- 8.84 Hz, 1 H), 7.83 (m, 2 H), 7.96 (m, 2 H), 8.24 (dd,.//- 8.84 Hz, J2 -- 1.93 Hz, 1 H), S.53 (d, ./= 1.93 Hz, 1 H). 7 -Benzofuran-2-y l-benzo[ 1,2,4]triazin-3-ylamine (Figure Removed) |0320J To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 2-Benzofuranboronic acid (134mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, O.bmmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCOs solution, and CHjCl^ was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of ] 0% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. C elite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 1 Orng 7-Beiizofuran-2-yl-berizo[l,2,4]triazin-3-ylamine was obtained. Yield: 9.3%, ESI-MS: [M+H]+, 263; 1HNMR (DMSO-d6): 5 6.54 (s, 1 H), 7.29 (t, .7- 7.22 Hz, 1 H), 7.36 ft, ./= ".23 Hz, 1 H), 7.64-7.71 (m, 3 H), 7.34 (dd, J} = 8.86 Hz, J2 = 1.86 H/., 1 Hi. 8.63 (d,,/- 1.86 Hz, 1 H). "'-Dibenzoruran-4-yl-benzo[l,2s4]triazin-3-ylamme (Figure Removed) |0321] To a solution of 7-Bronio-benzo[l,2,4]niazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved in 6ml N, N-Dimethylacetamide in a 20ml vial, 4-Dibenzofuranboronic acid (176mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, ().6mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.S3urnol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCOs solution, and CHbCl? was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 5mg 7-Dibem^ofuran-4-yl-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 3.9%, ESI-MS: [M+H]+, 263; 'H NMR (DMSO-d6): 5 7.46 (t, .7= 7.62 Hz, 1 H), 7.57 (t, J = 7.92 Hz, 2 H), 7.72 (t, J= 8.85 Hz, 1 H), 7.80 (d, J= 8.20 Hz, 1 H), 7.90 Id, J= 8.07 Hz, 1 H), 8.23 (m, 2 H), 8.38 (dd, J, = 8.84 Hz, J2 = 2.06 Hz, 1 H), 8.63 (d, J= 2.06 Hz, 1 H). 7-Naphthalen-1 -yl-benzo[ 1,2,4]triazm-3-ylarnine (Figure Removed) (0322! To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, u.42mmol) dissolved in 6mi N, N-Dimethylacetamide in a 20ml vial, 1-Naphtliylboronic acid (143mg, O.S3mrnol) dissolved in 1ml ethanol and potassium carbonate (64 mg, O.ommol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tns(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCCh solution, and CKhCU was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celite was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. lOmg 7-Naphthalen-l-yl-benzo[l,2,4]triazin-3-ylamine was obtained. Yield: 8.8%, ESI-MS: [M+H]+, 273; !H NMR (DMSO-d6): 5 7.54-7.69 (m, 5 H), 7.84 (d, J = 8.31 Hz, 1 H), 7.94 (dd, J, = 8.60 Hz, J2 = 1.68 Hz, 1 H), 8.05 (m, 2 H), 8.26 (d, J= 1.68 Hz, 1 H). 3-(3-Amino-benzo[ 1,2,4]triazin-7-yl)-phenol (Figure Removed) [0323] To a solution of 7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved in 6ml N, N-Dimethylacetaniide in a 20ml vial, 3-hydroxyphenylboronic acid (114.5mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6rnmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0,034mmol) and tris(ciibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCO3 solution, and CH2C12 was used to extract the product. Solvent in the organic phase was removed under vacuum. The residue was dissolved in a mixture of 2ml N, N-Dimethylacetamide and 1ml ethyl alcohol in a 20ml vial with a septum. Catalytic amount of 10% Palladium on carbon was added to the mixture. A balloon filled with hydrogen was placed on the top of the vial. The mixture was stirred at room temperature for 2 hours. Celitc was used to remove the palladium and carbon. Preparative HPLC was used to isolate the final product. 15mg 3-(3-Amino-benzo[l,2,4]triazin-7-yl)~phenol was obtained. Yield: 15%, ESI-MS: [M+H]+, 239; !H NMR (DMSO-d6): 5 6.82 (dd, J, = 7.94 Hz, J2 = 1.98 Hz, 1 H):, 7.17 (m, 1 H), 7.23 (d, J = 7.80 Hz, 1 H), 7.31 (t, J= 7.73 Hz, 1 H), 7,60 (d, ,/= 8.83 Hz, 1 H), 8.08 (dd, J, = 8.83 Hz, J2 = 1.94 Hz, 1 H), 8.36 (d, ./= 1.94 Hz, 1 H). 7-(2,6-Dimethyl-pbenyl)-benzo[l,2,4]triazin-3-yI]-phenyl-amine (Figure Removed) [0324] 7-(2,6-Dimethyl-phenyl)-benzo[l,2,4]triazin-3-ylaraine(24mg, 0.096mmol) was dissolved in aniline, sulfamic acid (18mg, 0.19mmoi) was added. The mixture was reflux overnight. The final product was isolated by preparative HPLC. Yield: 32%. ESI-MS: [M+Hf, 327; !H NMR (DMSO-d6): 5 2.05(s, 6 H), 7.09(t, J = 7.35 Hz, 1 H), 7.18-7.25 (m, 3 H), 7.40(m, 2 H), 7.71(dd, J,= 8.5 Hz,J2 = 1-9 Hz, 1 H), 7.84(d, J= 8.5 Hz, 1 H), 8.00(4 J= 7.6 Hz, 2 H), S.I 1(4 /= 1.9 Hz, 1 H). [0325] (7-Bromo-5-methyl-benzo[l,2,4]triazin-3-yl)-phenyl-amine (Figure Removed) [0326] 7-Bromo-5-methyl-benzo[l,2,4]triazin-3-ylamine-l-oxide (266mg, 1.04mmol) was dissolved in 5m! acetic acid in a 20ml vial, a few drops of water was added followed by adding of lOOmg Fe powder. The mixture was kept at 100°C for 30 minutes. The solvent was removed under vacuum. The residue was dissolved in 5ml aniline, sulfamic acid (202mg, 2.08mmol - was added to the mixture. The mixture was heat at 140°C for overnight. The final product was isolated by preparative HPLC. Yield: 18.3%, ESI-MS: [M+H]+, 315, 10327] (7-Bromo-5-nicthyl-benzo[l,2,4]triazin-3-yl)-[3-(4-methyl-piperazin-l-yl)-propyl]- anime (Figure Removed) (0328] 7-Bromo-5-metliyl-benzo[l,2,4]triazin-3-ylamine-l-oxide (200mg, 0.78mmol) was dissolved in 5ml acetic acid in a 20ml vial, a few drops of water was added followed by adding of lOOmg Fe powder. The mixture was kept at 100°C for 30 minutes. The solvent was removed under vacuum. The residue was dissolved in 5ml 3-(4-Methyl-piperazin-l-yl)-propylamine, sulfamic acid (152mg, 1.57mmol) was added to the mixture. The mixture was heat at 140°C for overnight. The final product was isolated by preparative HPLC. Yield: 67.3%, ESI-MS: [M+H]+, 379, 381. JH NMR (DMSO-d6): 5 1.05(m, 2H), 1.97 (s, 2 H), 2.77-3.20 (b, 8 H), 3.5 (b, 8 H), 7.84 (d, 7= 1.96 Hz, 1 H), 8.29 (d, J= 1.96 Hz, 1 H). [5-Methyl-7-(2,4,6-tnmethyl-phenyl)-benzo[l,2,4]triazm-3-yl]-phenyl-amine (Figure Removed) ]0329] To a solution of (7-Bromo-5-methyl-benzo[l,2,4]triazin-3-yl)-phenyl-amine (lOmg, 0.032mmol) dissolved in 2ml N, N-Dimethylacetamide in a 20ml vial, 2,4,6-trimethylphenylboronic acid (21mg, 0.12Smmol) dissolved in 1ml ethanol and potassium carbonate (6.4 mg, 0.06mmol) dissolved in 1ml water were added. Triphenylphosphine ! Img, 0.0038mmol) and tris(dibenzylideneacetone) dipalladium (0) (Img, 1.09umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 3mg [5-Methyl-7-(2,4,6-trimetliyl-phenyl)- benzo[l,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 26.8%; ES1-MS: [M+H]+, 355; 'H NMR (CDC13): 5 2.06 (s, 6 H), 2.36 (s, 3 H), 2.72 (s, 3 H), 6.99 (s, 2 H), 7.17 (m, 1 H), 7.45 (m. 2 H), 7.57 (in, 1 H), 7.89 (d, J= 1.36 Hz, 1 H), 7.94(d, J= 8.76 Hz, 2 H) . ?-(2-Fluoro-6-metiioxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-phenyl-amme (Figure Removed) [0330] To a solution of (7-Bromo-5-methyl-benzo[l,2,4]triazin-3-yl)-phenyl-amine (lOmg, 0.032mmol) dissolved in 2rnl N, N-Dimethylacetamide in a 20ml vial, 2-Fluoro-6-methoxy-phenylboronic acid (22mg, 0.128mmol) dissolved in 1ml ethanol and potassium carbonate (6.4 mg, 0.06mmol) dissolved in 1ml water were added. Triphenylphosphine (Img, 0.0038mmol) and tris(dibenzylideneacetone) dipalladium (0) (Img, 1.09umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 2mg [7-(2-Fluoro-6-methoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 17.5%; ESI-MS: [M+H]+, 361; 'H NMR (CDC13): 8 2.73 (s, 3 H), 3.83 (s, 3 H), 6.83-6.86 (m, 2H), 7.14 (m, 1 H), 7.34 (m, 1 H), 7.45 (m, 2 H), 7.75(s, 1 H), 7.92(m, 2 H), 8.24(s, 1 H). [7-(2,6-Dirnethoxy-phenyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-phenyl-ainine (Figure Removed) 10331] To a solution of (7-Bromo-5-methyl-benzo[l,2,4]triazin-3-yl)-phenyl-amine (lOmg, 0.032romol) dissolved in 2ml N, N-Dimethylacetamide in a 20ml vial, 2,6-dimethoxy-phenylboronic acid (23mg, 0.126mmol) dissolved in 1ml ethanol and potassium carbonate (6.4 mg, 0.06mm! >1 > dissolved in 1ml water were added. Triphenylphosphine (Img, 0.0038mmol) and tris(dibenzylideneacetone) dipalladium (0) (Img, 1.09umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 5mg [7-(2,6-Dimethoxy-phenyl)-5-methyl-benzo[l,2,4]tria2in-3-yl]-phenyl-amine was isolated. Yield: 42.4%; ESI-MS: [M+H]+, 373; 'H NMR (CDC13): 6 2,72 (s, 3 H), 3.78 (s, 6 H), 6.70 (d, J = 8.4 Hz, 2 H), 7.13 (m, 1 H), 7.35 (t, J- 8.38 Hz, i H), 7.44 (m, 2 H), 7.89 (m, 1 H), 7.92 (dd, Jj = 8.78 Hz, J2 = 2.02 Hz, 2 H), 8.18 (d. .7= 2.02 Hz, 1 H). [.7-(2,6-Diraethyl-phcnyl)-5-methyl-benzo[l,2,4]triazin-3-yl]-phenyl-amine (Figure Removed) [0332] To a solution of (7-Bromo-5-methyl-benzo[l,2,4]triazin-3-yl)-phenyl-arnine (60mg, 0.19mmol) dissolved in 3ml N, N-Dimethylacetamide in a 20ml vial, 2,6-dimethyl-phenylboronic acid (114mg, 0.76mmol) dissolved in 2ml ethanol and potassium carbonate (31 mg, O.Smmol) dissolved in 1ml water were added. Triphenylphosphine (4.5mg, O.OlVlmmol) and tris(dibenzylideneacetone) dipalladium (0) (4.5mg, 4.9mnol) were added to the mixture, The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 30mg [7-(2,6-Dimethyl-phenyl)-5-memyl-benzo[l,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 46%; ESI-MS: [M+H]+, 341; 'H NMR (DMSO-do): 5 2.05 (s, 6 H), 2.67(s, 3H), 7.07(t, ./= 7.33 Hz, 1 H), 7.17-7.24 (m, 3 H), 7.41 (t, J= 7.56 Hz, 2 H), 7.62 (d, J= 1.49 Hz, 1 H), 7.93 (d, J- 1.49 Hz, 1 H), 8.05 (d, .7-7.72 Hz, 1H). 7-Naphthalen-2-yl-ben7Jo[l,2,4]triazin-3-ylamine-l-oxide (Figure Removed) 10333] To a solution or7-Bromo-benzo[l,2,4]triazin-3-ylamine-l-oxide (lOOmg, 0.42mmol) dissolved m 6ml N, N-Dimethylacetamide in a 20ml vial, 2-Naphthylboronic acid (143mg, 0.83mmol) dissolved in 1ml ethanol and potassium carbonate (64 mg, 0.6mmol) dissolved in 1ml water were added. Triphenylphosphine (9mg, 0.034mmol) and tris(dibenzylideneacetone) dipalladium (0) (9mg, 9.83umol) were added to the mixture. The mixture was reflux overnight. The crude product was poured into 50ml saturated NaHCO3 solution, and CHaCli was used to extract the product. Solvent in the organic phase was removed under vacuum. Preparative HPLC was used to isolate the final product. 20mg 7-Naphthalen-2-yl-benzo[l,2,4]triazin-3-ylamine-l -oxide was obtained. Yield: 16.7%, ESI-MS: [M+H]+, 289; ]H NMR (DMSO-d6): 8 7.56 (m, 2 H), 7.68 (d, J= 8.84 Hz, 1 H), 7.95 (m, 2 H), 8.05 (d, J= 8.64 Hz, 2 H), 8.33 (dd, Jy = 8.84 Hz, J2 = 1.87 Hz, 1 H), 8.38 (s, 1 H), 8.51 (d, .7=1.87 Hz, 1H). J0334] General procedure for the 6-alkyl substituted pteridine synthesis (Figure Removed) [0335] To the solution of dibromotriphenylphosphine (2.4337 g, 5.76 mmol) of 2 ml anhydrous N, N-dimethylacetamide was added (2, 4-Diamino-Pteridin-6-yl)-methanol hydi-obromide (335.8 mg, 1.747 mmol). The mixture is the stirred at RT for overnigllt. The solution was treated with benzene. The filtered solid was then successively treated with benzene and ether and evaporate the remaining solid. The residue was dissolved in minimum 4S%HBr at RT which then was added MeCN to give a tan solid precipitate. Collect the solid in ice water bath and wash it with MeCN and ether. 352 mg product was obtained. Yield 60 %; LH NMR (500 MHz, DMSO-d6): 8 4.86021(s, 2H), 9.01 (s, 1H), 9.15 (s, 2H), 9.22 (s, 2H); ES1-MS: 255, 257(M+ +1) (Figure Removed) 2-[(2, 4-Diamino-pteridin-6-yknethyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester [0336] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (31.2 mg, 0.116 mmol) in anhydrous N, N dimethylacetamide was added 2- amino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester (30.22 mg, 0.127 mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 17.2 mg product was obtained. Yield: 71 %; !H NMR (500 MHz, DMSO-d6): 5 1.33577 (s, 9H), 2.94185-3.02295 (m, 2H), 3.6550(b, 1H), 4.0878 (s, 2H), 6.70174-6.72384 (dd,J}= S.545155 Hz, ,/2 =- 2,59 Hz, 2H), 7.02394-7.04103 (d, J= 8.545 Hz, 2H); 9.38501 (s, 1H); ESI-MS: 412(Jvf +1) '-[{(Pyridin-2-yLmethyl)-araino]-methyl}-2, 4-pteridiaediarnine (Figure Removed) |()337J To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N, N dimethylacetamide was added 2-(aminomethyl) pyridine (22.48 ul, 0.22 mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 32.3 rng product was obtained. Yield: 57 %; lll NMR (500 MHz, DMSO-d6): 5 3.93801 (s, 2H), 4.05772(s, 2H), 7.5758-7.6003 (m, 1H), 7.97993-8.00181 (m, 1H), 8,49332-8.50942 (d, J= 8.05 Hz, 1H), 8.62592-8.64301 (d,J= 8.545 Hz, 1H), 8.9938(s, 1.H); ESI-MS: 283 (M++1) 6- {[(Naphthalen-1 -yl-methyl)-amino]-methyl}-2, 4-pteridrnediamine (Figure Removed) 10338] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N, N dimethylacetamide was added 1-aminomethyl-naphthalene (31.67 ul, 0.22 mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative .HPLC. 9 mg product was obtained. Yield: 15 %; ]H NMR(500 MHz, DMSO-d6): o 4.6479(s, 2H ), 4.7893(s, 2H), 7.575-7.6244(m, 3H), 7.74232-7.7570(d, ./= 6.91 Hz, 1H), 7.9935-8.0276(dd, ./,= S.06Hz, J2 = 8.995 Hz, 2H), 8.1670-8,1831 (d, ,7 = 8.04 Hz, 1H), 8.8430(s, 1H); ESI-MS: m/z 332 (^T -+1) (>-(Benzylamino-methyl)-2, 4-pteridinediamine (Figure Removed) |0339] To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (35.7 mg, 0,106 mmol) in anhydrous N, N dimethylacetamide was added benzylamine (28.6 ul, 0.212 mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 17.7 mg product was obtained. Yield: 62 %; 'H NMR (500 MHz, DMSO-d6): 5 4.30499(s, 2H), 4.51599(s, 2H), 7.42787-7.47298(rn, 3H), 7.50007-7.51927 (m, 2H), 8.87751(3, 1H); ESI-MS: m/z 282 0VT +1) 6-{[(Adamantan-l-yl-methyl)-amino]-methyl}-2, 4-pteridmediamine (Figure Removed) |0340] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (41.6 mg, 0.124 mmol) in anhydrous N, N dimethylacetamide was added 1-aminomethyl adamantane (35.43 ul, 0.2mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 12.7 mg product was obtained. Yield: 40 %; !H NMR (500 MHz, DMSO-d6): 6 ] .56754-1.67101(m, 13H), 1.96741(s, 2H), 2.71139(s, 2H), 4.49166(s, 2H), 8.89918(s, 1H); ESI-MS: m/z 340 (M+ +1) 157 b-{3, 4-Dimethoxy~benzylamino)-2, 4-pteridinediamine (Figure Removed) 10341] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (59 mg, 0.176 mmol) in anhydrous N", N dimethylacetamide was added 3, 4-dimethoxy-benzylamine (51.15 ul, 0.3512 mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 20.3 mg product was obtained. Yield: 34 %; 1H NMR (500 MHz, DMSO-d6): 5 3.67534(s, 3H), 3.70494(s, 3H), 4.05412 (b, 4H), 0.78852-6.80460 (d, .7=8.04 Hz, IH), 6.83624 (s, IH), 6.83624-6.85393 (d, .7=8.195 Hz, IH); 8.96623(s, IH), 9.00584(s, 2H), 9.5577(s, 2H); ESI-MS: 342 (M+ +1) 6-[2, 2-Dimethyl-propylamino)-methyl]-2, 4-pteridinediamine (Figure Removed) [0342] To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (75.2 mg, 0.2237 mmol) in anhydrous N, N dimethylacetamide was added 2, 2-dimethyl-propylamine (136.48 ul, 1.16mmol). The reaction mixture was stirred at room temperature overnight. The resulted precipitate was collected and purified by preparative HPLC. 8.3 mg product was obtained. Yield: 14.2 %; 'H NMR (500 MHz, DMSO-d6): 8 0.98591 (s, 9H ), 2.82895(s, 2H), 4.387650, 2H), 8.77458(s, IH); ESI-MS: m/z 262 (M+ +1) (Figure Removed) 6- {[2-(3, 4-Dimethoxy-phenyl)ethylamino]-methyl}-2, 4-pteridinediamine [0343] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobrornide (55 mg, 0.1638 mmol) in anhydrous N, N dimethylacetamide was added 2-(3, 4-dimethoxyphenyl) ethylamine hydrochloride (55 ul, 0.32 mmol). The reaction mixture was stirred at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 3.8 mg product was obtained. Yield: 19.6 %; !H NMR (500 MHz, DMSO-d6): 5 2.75943-2.79062 (t, J= 7.37 Hz, 2H), 2.92110-2.95356 (t, J- 7.365 Hz, 2H), 3.72197(s, 3H), 3.75135(s, 3H), 4.54559(s, 2H), 6.74441-6.77765 (dd, J}= 8.26 Hz, J2 = 1.955 Hz, IH), 6.84994 (s, IH), 6.88406-6.90401 (dd, Ji = 8.195 Hz, J2 = 1-735 Hz, IH); 8.87126(s, IH); ESI-MS: m/z 356 (M" +1) 6- {[2-(3, 4-Dihydroxy-phenyl)ethylamino]-methyl}-2,4-pteridinediamine (Figure Removed) [0344] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobrornide (67.3 mg, 0.2003mmol) in anhydrous N, N dimethylacetamide was added 2-(3, 4-dihydroxyphenyl) ethylamine (43.6 mg, 0.23 mmol). Under positive pressure of Argon, iPriEtN (32.63 ul) was added. The reaction mixture was stirred at 50 °C for 4 hrs and then at Room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 14.8 mg product was obtained. Yield: 22.6 %; !H NMR (500 MHz, DMSO-d6): 5 2.69242 (b, 4H), 4.03353 (s, 2H), n.37542-6.39065 (d,../ - 7.615 Hz, IH), 6.4851(s, IH), 6.56632-6.58226 (d, J= 7.97 Hz, IH), 8.80972 (s, IH); ESI-MS: m/z 328 (IvT+l) 4- {2-[Di (2, 4-dianiinopi.eridin-6-yl-methyr)-amino]-ethyl}-benzene-1, 2-diol (Figure Removed) J0345] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (67.3 mg, 0.2003mmol) in anhydrous N, N dimethylacetamide was added 2-(3, 4-dihydroxyphenyl) ethylamine hydrochloride (43.6 mg, 0.23 mmol). Under positive pressure of Argon, iP (32.63 ul) was added. The reaction mixture was stirred at 50 °C for 4 hrs and then at Room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 3.2 mg product was obtained. Yield: 6.4 %; 1H NMR (500 MHz, DMSO-d6): 5 2.63154-2.63891 (m, 2H), 2.72839(m, 2H), 4.03844 (s, 4H ), 6.32227-6.33832 (d, J= 8.025 Hz, IH), 6.38857 (s, IH), 6.51654-6.53241 (d,J= S.835 Hz, IH), 8.67743 (s, 2H); ESI-MS: m/z 502 (M+ +1) 6-{[2-(3, 4-Dihydroxy)-benzylamino]-methyl}-2, 4-pteridinediamine (Figure Removed) 10346] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (64 mg, 0.1905 mmol) in anhydrous N, N dimethylacetamide was added 2-(3, 4-dihydroxybenzyl) amine hydrochloride (36.795 mg, 0.23 mmol). Under positive pressure of Argon, iPr2EtN(4().l 5 ul) was added. The reaction mixture was stirred at 50 °C for 4 hrs and then at Room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 7.8 mg product was obtained. Yield: 13.1 %; 1H NMR (500 MHz, DMSO-d6): 5 3.91255 (s, 2H), 4.61898(s, 2H), 6.6094-6.62572(d, J- 8.16 Hz, IH), 6.64921-6.66517(d, J = 7.9S Hz, IH), 6.79669-6.79963 (d,,/- 1.47 Hz, IH), 8.88104 (s, IH); ESI-MS: 314 (M+ +1) 3-(4-ter/vButoxy-pheriyl)-2-[(2, 4-diamino-pteridin-6-ylmethyl)-amino]-propionic acidtert- (Figure Removed) buiyl ester [0347] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (53.7 mg, 0.1 598 mmol) in anhydrous N, N dimethylacetamide was added 2- amino-3-(4- te/^-butoxy -phenyl)-propionic acid tei-f-butyl ester hydrochloride (51.58 mg, 0.1758m mol). Under positive pressure of Argon, iPrjEtN (33.69 ul) was added. The reaction mixture was stirred at 50 °C for 4 hrs and then at room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 2.7.6 mg product was obtained. Yield: 41 %; *H NMR (500 MHz, DMSO-d6): 8 1.22491(s, 9H), 1.26835 (s, 9H), 2.921-2.971 (m, 2H), 4.130 (b, IH), 4.427(s, 2H), 6.91 485-6.93 165(d,. 7= 8.4 Hz, 2H), 7.16037-7.17723(d, J= 8.43 Hz, 2H), 8.89353 (s, IH); 9.13119 (s, 2H), 9.30829 (s, 2H); ESI-MS: m/z 468 (M* +1) 1 - {[di-(2, 4-Diaminopteridin-6-yl-methyl)]-amino-methyl} -naphthalene (Figure Removed) 10348] To a solution of 6-bromomethyl-2, 4-pteridinediamine hydrobromide (51 mg, 0.2 minol) in anhydrous N, N dimethylacetamide was added 1-amuiomethyl-naphthalene (31.67 ul, 0.22 mmol). The reaction mixture was stin-ed at 50 °C overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative ITPLC. 9 mg product was obtained. Yield: 15 %; 1H NMR(500 MHz, DMSO-d6): 5 4,0970 (s, 4H), 4.2526 (s, 2H), 7.3530-7.3692 (dd, ,/!= 7.25 Hz,,/2 = 7.25 Hz, 2H), 7.439-7.5202 (m, 2H), 7.5414-7.5553 (d, J= 6.94 Hz, IH), 7.67408-7.69065 (d, J = 8.285 Hz, IH), 7.78789-7.7713 (d, J= 8.285 Hz, IH), 8.14819-8.1313 (d, J= S.44 Hz, IH), S.7144 (s, 2H), 8.93305 (s, 2H), 9.23424(s, 2H); ESI-MS: m/z 506 (M4 +1) Quinazolines 10349] General procedure for the 3#-quinazolin-4-one synthesis [0350] Method 1: (Figure Removed) 6-bromo-3//-quinazolin-4-one [0352] 2-Animo-5-Bromo-benzoic acid (10.817g, 50 mmol) was suspended in 70 ml formamide. The mixture was heated at 180 °C for 7 hrs. The cooled solution was diluted with 100ml cold water and filtered. The tan solid was washed with di water and used for the next step reaction without further purification. 10.2g product was obtained. Yield: 90%. ]H NMR (500 MHz, DMSO-d6): 8 7.61430-7.63179(d, J= 8.745 Hz, 1H), 7.94922-7.97149 (dd, J,= 8.75Hz. J2 = 2.385 Hz, 1H), 8.142421(s, 1H), S.19136-S.19609(d, J= 2.365 Hz, 1H); ES1-MS: m/z 2.25, 227(1^ +1) >-(2, 6-Dimethylphenyl)-3H-quinazolin-4-one (Figure Removed) 10353] To a solution of 6-bromo-3#-quinazolin-4-one (43.1mg, 0.1915mmoi) dissolved in 2 ml N, N-dimethylacetamide in a 20 ml vial, 2,6-dimethylphenylboronic acid (114.9 nig, 0.76mmol) dissolved m 1ml ethanol and potassium carbonate (26.7mg, 0.193 mmol) dissolved in 1ml water were added. Triphenylphosphine (5mg, 0.019mmol) and tns(dibenzylideneacetone)dipalladium(0) (3.5mg, 3.8umol) were added to the mixture which refluxed overnight. The crude product was poured into 50ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 19.2 ing product was obtained. Yield: 40 %; !H NMR (500 MHz, DMSO-d6): 6 1.96741(s, 6H), 7.114769-7.16307(d, J= 7.69 Hz, 2H), 7.19260-7.22248(dd, ^ - 8.62 Hz, J2 = 6.31 Hz IH), 7.60434-7.62503(dd, J\= 8.335 Hz, J2 = 1.97 Hz, IH), 7.75179-7.76829(d, J= 8.25 Hz, IH), 7.81882-7.S2258(d, J= l.SSHz, IH), 8.17882 (s, IH); ESI-MS: m/z 251 (M+ +1) 6-(2, 6-Dimethoxlphenyl)-3H-quinazolui-4-one (Figure Removed) [0354] To a solution of 6-bromo-3.Hr-quinazolm-4-one (43.1 mg, 0.1915 mmol) dissolved in 2 mlN, N-dimethylacetamide in a 20 ml vial, 2,6-dimethylphenylboronic acid (139.4 mg, 0.76mmol) dissolved in 1ml ethanol and potassium carbonate (26.7mg, 0.193 mmol) dissolved in 1ml water were added. Triphenylphosphine (5 mg, 0.019 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.5 mg, 3.8 umol) were added to the mixture which refuxed overnight. The crude product was poured into 50ml saturated bicarbonate solution and methyl ene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 38.2 mg product was obtained. Yield: 71%; !H NMR (500 MHz, DMSO-d6): 8 3.67800(s, OH), 6.77555-6.79250(d, 7- 8.475 Hz, IH), 7.33529-7.36895(dd, J, - 8.415 Hz, J2= 8.415 Hz Hi), 7.6531 l(s, 2H), 7.93672 (s, IH), 8.13028 (s, IH); ESI-MS: m/z 283 (M+ +1) 0-(2-chloro-6-methoxyphenyl)-377-quinazolin-4-one (Figure Removed) J0355] To a solution of 6-bromo-3#-quinazolin-4-one (38.9 mg, 0.1728 mmol) dissolved in 2 ml N, N-dimethylacetamide in a 20 ml vial, 2-chloro-6-methoxy-phenylboronic acid (128.SS mg, 0.6914 mmol) dissolved in 1 ml ethanol and potassium carbonate (26.28 mg, 0.19 mmol) dissolved in I ml water were added. Triphenylphosphine (4.5 mg, 0.017 mmol) and tris(dibenzylideneacetone)dipalladium(0) (3.2 mg, 3.5 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 3.4 mg product was obtained. Yield: 24.3 %; 'H NMR (500 MHz, DMSO-d6): 8 3.70812(s, 3H), 7.13816-7.15637 (dd, Ji= 7.945 Hz,,/2= 0.32Hz, 1H), 7.18430-7.20184 (dd, J, = 7.85 Hz, J2= 0.92 Hz 1H), 7.40806-7.44074 (dd,/i= 8.205 Hz, J2 = 8.135 Hz, 1H), 7.66531-7.68611 (dd?,/,= 8.305 Hz, J2= 2.04Hz, 1H), 7.71531-7.73209 (d,J= 8.39Hz, 1H), 7.92946-7.93334 (d, ./= 1.94 Hz, 1H), 8.16800 (s, 1H); ESI-MS: m/z 287 (M+ +1) 6-(2, 4, 6-trimethylphenyl)-3//-qumazolin-4-one (Figure Removed) [0356] To a solution of 6-bromo-3#-quinazolin-4-one (43.1mg, 0.1915mmol) dissolved in 2 ml N, N-dimethylacetamide in a 20 nil vial, 2,4,6-trimethylphenylboronic acid (114.9 mg, 0.76mmol) dissolved in 1ml ethanol and potassium carbonate (26.7mg, 0.193 mmol) dissolved in 1ml water were added. Triphenylphosphine (5mg, 0.019mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.5mg, S.Sumol) were added to the mixture which refluxed overnight. The crude product was poured into 50ml saturated bicarbonate solution and methyl ene chloride was used to extract the product. Solvent in the organic phase was removed, under vacuum. The resulted residue was purified by preparative HPLC. 1.9.2 mg product, was obtained. Yield: 40 %; {E NMR (500 MHz, DMSO-d6): 6 1.96741(s, CxH), 7.114769-7.16307(d, J= 7.69 Hz, 2H), 7.19260-7.22248(dd, Ji = 8.62 Hz, J2= 6.31 Hz ] H), 7.60434-7.62503(dd, J\= 8.335 Hz, J2 = 1.97 Hz, 1H), 7.75179-7.76829(d, J= S.25 Hz, 1H), 7.81882-7.82258 6-(Naphthalene-1 -yl )-3/-/-quinazolm-4-one (Figure Removed) [0357] To a solution of 6-bromo-3£/-quinazolin-4-one (45.2 mg, 0.2 mmol) dissolved in 2 ml N,N -dimethylacetamide in a 20 ml vial, naphthalene-1-boronic acid (69.4 mg, 0.4 mmol) dissolved in 1ml ethanol and potassium carbonate (30.5 mg, 0.22 mmol) dissolved in 1ml water were added. Tripenylphosphine (5.27 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.6 mg, 4 umol) was added to the mixture which refluxed overnight. The crude product was poured into 50ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 32.9 mg product was obtained. Yield: 62%; 'H NMR (500 MHz, DMSO-d6): 5 7.52083-7.54615(m, 2H), 7.56877-7.58461(dd, J= 6.88 Hz, 1H), 7.61224-7.64281(dd, jy= 8.255 Hz, J2 = 8.285 Hz, 1H), 7.78775-7.804 (d, J= 8.125 Hz, 1H), 7.82384-7.84054(d, J= 8.35Hz, 1H), 7.93472-7.95545(dd, J^ 8.365 Hz, J2 = 2 Hz, 1H), 8.00847-8.02533(d, J = 8.43Hz, 1H), 8.03829-S.05347(d, .7=7.59 Hz, 1H), 8.15915-8.16300(d, J= 1.925Hz, 1H), 8.19218 (s, 1 H); ESI-M.S: m/z 273 (M+ +1) 6-(Naphthalene-2-yl)-3H-quinaz.olin-4-one (Figure Removed) |()358] To a solution of 6-bromo-3#-quinazolin-4-one (47.1 mg, 0.2093 rnmol) dissolved in 2 nil N, N-dimethylacetamide in a 20 ml vial, naphthalene-1-boronic acid (73 mg, 0.4244 rnmol) dissolved in 1ml ethanol and potassium carbonate (32.7 mg, 0.2366 mm'ol) dissolved in I ml water were added. Triphenylphosphine (5.5 mg, 0.021 mmol) and tns(dibenzylicleneacetone)dipalladium (0) (3.8 mg, 4.1 unaol) were added to the mixture which refluxed overnight. The crude product was poured into 50ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 26.3 mg product was obtained. Yield: 46%; !H NMR (500 MHz, DMSO-d6): 6 7.54020-7.5S965 (m, 2H), 7.80614-7.82312 (d, J = 8.49 Hz, IH), 7.94743-7.96828 (dd,Ji= 8.505 Hz, ./2 = 1.91 Hz, IH), 7.96828-7.98243 (d, J- S.035Hz, IH), 8.05455-8.07187 (d, J = 8.63Hz, IH), 8.16005(s, Hi), 8.30107-8.3226(dd, J}= 8.58 Hz, J2= 2.25 Hz, IH), 8.37163-8.37447(d, J= 1.42Hz, IH), 8.50638-8.51090(d, J= 2.26Hz, IH); ESI-MS: m/z 273 (M4 +1) 6-(4-phenoxy-pheriyl)-3/jr-quinazolin-4-one (Figure Removed) |0359] To a solution of 6-bromo-3#-quinazolin-4-one (44.8 mg, 0.199 mmol) dissolved in 2 nil N, N-dimethylacetamide in a 20 ml vial, naphthalene-1-boronic acid (85.22 mg, 0.3981 mmol) dissolved in Irnl ethanol and potassium carbonate (30.26 mg, 0.2198 mmol) dissolved in 1ml water were added. Triphenylphosphine (5.2 mg, 0.020 mmol) and tns(dibeirzylideneacetone)dipaUadiurn (0) (3.64 mg, 4.0 umol) were added to the mixture which refluxed overnight. The crude product was poured into 50ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 25.3 nig product was obtained. Yield: 41%; *H NMR(500 MHz, DMSO-d6): 5 7.09215-7.] 2687(dd, ./!= 8.58 Hz, J2 = 8.78 Hz, 4H), 7.17733-7.20876 (dd, J^ 6.48 Hz, J2 - 7.375 Hz, IH), 7.42050-7.4?247(Ji= 7.56Hz, J2 = 6.45 Hz, 2H). 7.74247-7.75949(d,.J= 8.51 Hz, 1H). 7.79084-7.S0838(dd,./,= 6.73 Hz, J2 - 2.08 Hz, 2H), 8.1191-8.1408(dd, J,= S.395 Hz, J2 - 2.355 Hz, 1H), 8.14531(s, 1H), 8.31298-8.31761(d, J= 2.315 Hz, 1H); ESI-MS: m/z 315(M++1) 6- -Bromo-3 -(3-hydroxy-propionyl)-3H-quinazolin-4-one (Figure Removed) [0360] To a suspension of NaH (60 % in mineral oil, 199 mg) in 20 ml of N, N-dimethylacetamide was added 6-bromo-3Jcf-qumazolin-4-one(0.9335mg, 4.148 mmol). The mixture was stirred at room temperature for 40 mins resulting clear red solution. Acroyl chloride (471 .Sul, 5.8072mmol) was added. The solution was heated at 70 °C for 8 hrs, cooled to room temperature, and poured into 30ml of ice water. Methylene chloride added and product was in the water phase. The water solvent was evaporated under vacuum. The resulted residue was purified by preparative HPLC. 1.1 g product was obtained. Yield: 74.7 %; !H NMR (500 MHz, DMSO-d6): 6 2.73412-2.76135(t, .7= 6.805 Hz, 2H), 4.14197-4.16922(t, .7= 6.815 Hz, 2H), 7.62305-7.64046(d, J= 8.705 Hz, LH), 7.96596-7.98797(dd, J\= 8.635 Hz, J2 = 2.38 Hz, 1H), 8.2287-8.2335(d, J= 2.4 Hz, 1H), 8.41991(s, 1H); ESI-MS: m/z 297, 299 (M++1) 6-(2, 6-Drmethylphenyl)-3-(3-hydroxy-propionyl)-3jt?-quinazolin-4-one (Figure Removed) [0361] To a solution of 6-Bromo-3-(3-hydroxy-propionyl)-3//-quinazolin-4-one (9.8 mg, 0.033 mmol) dissolved in 1 ml N, N-dimethylacetamide in a 20 ml vial, 2,6-dimethylphenyl boronic acid (9.89 rng, 0.066 mmol) dissolved in 0.5ml ethanol and potassium carbonate (5 mg, 0.036 mmol) dissolved in 0.5ml water were added. Triphenylphosphine (0.87 mg, 3.3 umol) and tris(dibeiizylideneacetone)dipalladium(0) (0.6 mg, 0.6 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 5.2 mg product was obtained. Yield: 49 %; 'H NMR (500 MHz, DMSO-d6): 8 1.96247(8, 6H), 2.76290-2.79002(t, .7= 6.805 Hz, 2H),), 4.15954-4.18664 (t, J- 6.785 Hz,2H), 7.14682-7.7. l()21(d,> 7.64 Hz, 1H), 7.19338-7.21062(dd,Ji= 8.62 Hz, 72 = 6.41 Hz, 1H), 7.60532-7.62604(dd, J}= 8.365 Hz, J2 = 2.03 Hz, 1H), 7.75204-7.76861 (d, J = S.2S5 Hz, 1H), 7.84928-7.S5312(d,7= 1.92 Hz, 1H), 8.41195(s, 1H); ESI-MS: m/z 323 (Ivf +1) 6-(2-chloro-6-methoxyphenyl)-3-(3-hydroxy-propionyl)-3jc/-quinazolin-4-one (Figure Removed) [0362] To a solution of 6-Bromo-3-(3-hydroxy-propionyl)-3fir-qurnazolin-4-one (11.6 mg, 0.039 mmol) dissolved in 1 ml N, N-dimethylacetamide in a 20 ml vial, 2-chloro-6-methoxy-phenylboronic acid (14.55 mg, 0.078 mmol) dissolved hi 0.5 ml ethanol and potassium carbonate (5.92 mg, 0.043 mmol) dissolved in 0.5 ml water were added. Triphenylphosphine (1 mg, 3.8 umol) and tris(dibenzylideneacetone)dipalladium (0) (0.7 nig, 0.78 umol) were added to the mixture which refluxed overnight. The crude product was poured into 5ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 3.4 mg product was obtained. Yield: 24.3 %; !H NMR (500 MHz, DMSO-d6): o 2.75538-2.78226(1, J= 6.835 Hz, 2H), 3.70334(s, 3H), 4.15877-4.18594 (t, J= 6.785 Hz, 2H), 7.13724-7.15535 (dd, Jf* 8.68 Hz, J2 = 0.75 Hz, 1H), 7.18337-7.20169 (dd, J}= 8.375 Hz, J2 = 0.885 Hz, 1H), 7.41001-7.44275 (dd, J^= S,215Hz, J2= 8.185 Hz, 1H), 7.66453-7.68523 (dd,Ji= 8.38 Hz, J2= 2.0 Hz, 1H), 7.72 (d, ./ = 8.4 Hz, 1H), 7.96 (d, 7= 1.9 Hz, 1H), 8.41 (s, 1H); ESI-MS: m/z 359 (M+ +1) (Figure Removed) 4-Amrno-8-bromo-6-nitro-quinazolin-2-ol [0364] 2-Amino-3-bromo-5-nitro-benzonitrile (1.9003 g, 7.85 rnmol) was heated with urea (1.8862g, 31.4mmol) at 180-185 °Cfor3hrs. The cooled mixture was powered and treated with bicarbonate solution, filtered and washed with water. The solid was the collected and washed with ethanol, ether, and used for the next step reaction without further purification. 2.0g product was obtained. Yield 89 %; 'H NMR (500 MHz, DMSO-d6): 5 8.44455-S.4501 l(d, J= 2.78 Hz, 1H), 8.87071-8.87544(d, J= 2.365 Hz, 1H), 9.39866-9.40333(d, J = 2.335 Hz, 1HK 9.50740-9.51282(d, J= 2.71 Hz, 1H); ESI-MS: 285, 287 0^ +1) 170 8-Bromo-4-[3-(4-niethyl-piperazin-lyl)-propylamino]-6-nitro-quinazolin-2-ol (Figure Removed) [0365] A mixture of 4-amino-8-bromo-6-nitro-qumazolin-2-ol (24.1 mg, 0.0845 mmol), sulfamic acid (16.4 mg, 0.169mmol) and l-(3-aminopropyl)-4-methylpiperazine (1ml) was heated at reflux for 7 h. The cooled reaction mixture was poured into 10ml ice water. The resulting precipitate was collected and purified by preparative HPLC. 19.2 mg product was obtained. Yield: 40 %; 'HNMR(500 MHz, DMSO-d6): 6 1.91521-1.95482 (m, 2H), 2.78103(s, 8H), 3.16555(b, 4H), 8.68221-8.68666(d,J= 2.225 Hz, IH), 9.10824-9.11291(d, J= 2.335 Hz, IH); ESI-MS: 425, 427 (M*+l) [0366] Preparation of (6,7-Diphenyl-pteridin-4-yl)-(3-(4-methyl-piperaztn-l-yl)-propyl)-amine (Figure Removed) |()367] 6 J-Diphenyl-pteridin-4-ylamine (200mg, 0.669mmol) and sulfamic acid (SOOrng, 1.91mmol) were dissolved in 4ml l-(3-aminopropyl)-4-methylpiperazine. The mixture was reflux for overnight. Preparative HPLC was used to isolated the product. 50mg (6,7-Diphenyl-pteridin-4-yl)-(3-(4-methyl-piperazin-l-yl)-propyl)-amine was obtained. Yield: ! 7%, ESI-MS: [M+Hf,441 Representative synthesis of compounds of structure IV Compound IV (Figure Removed) |0368] A 3-ml, reaction flask equipped with a stirring vane and a teflon cap was charged with the bis(benzil) species (122 mg; 0.324 mmol) and 5,6-diamino-2,4-dihydroxy pyrimidine sulfate (156 mg; 0.649 mmol; 2.00 equiv). The vial was heated to ca. 210 °C for 2 h and then the contents were poured into 30 mL of ether, the resulting solid was sonicated vortexed and centrifuged. The resulting solid was washed 2 x 20 mL of ethyl acetate-ether (1:1), and dried in a vacuum dessicator resulting in 120 mg (96%) of an orange solid bis(pteridine). MS (M+H+: calcd 647; found 647). Representative synthesis of compounds of structure V Compound V (Figure Removed) |0369j A 5-mL, single-necked, round-bottomed flask with a stirring bar and a septum was charged with 2-aminomethylbenzimidazoIe (119 mg; 0.500 mmol; 1.00 equiv). It does not dissolve in 3 mL of DMF even with heating. To this slurry was added isatin (73.8 mg; 0.502 mmol; 1.00 equiv). The solution is a bright orange-yellow. A few drops of glacial HOAc were added, the reaction was stirred for 15 min, and then sodium cyanoborohydride (62.0 mg; 0,980 mmol; 1.97 equiv). The solution turned a light straw-yellow in 30 rnin. After stirring, for 2 d at room temperature, the reaction was worked up by pouring the mixture into 50:50 saturated aqueous sodium bicarbonate-ice. The white precipitate formed was extracted with ethylacetate (2 x 20 mL). The combined organic layer was extracted again with 10 mL satd sodium bicarbonate, dried (anhydrous Na2SC>4), filtered, and concentrated by rotary evaporation to yield an orange-yellow oil that solidified on standing. The crude was recrystallized from ethylacetate-hexanes to yield 98.9 mg of an orange foam. MS (M+FT: calcd 279; found 279) EXAMPLE 2 ANTI-CANCER THERAPY WITH VASCULOSTATIC AGENTS 10370] The following experiments show the use of vasculostatic agents of the invention alone and in combination with chemotherapeutic agents for treatment of cancer. FIGURE 2 shows the synergistic results of co-drug therapy utilitizing 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine, sulfate salt, (compound A - in this example formulated in 50% PEG400:50% water) illustrated in FIGURE 1, with doxorubicin (in this example formulated in 50% PEG400:50% water). In the experiment shown in FIGURE 2, syngeneic Lewis lung carcinoma cells were injected I.V. hi order to establish lung metastases in Balb/C mice. Beginning 10 days after cells were injected, doxorubicin (3 mg/kg) and/or 6,7-bis(4-hydroxyphenyl)-pteridm-4-ylamine, sulfate salt, (compound A - various doses as shown) was given I.P. every 3 days for 3 cycles. Animals were sacrificed at day 20, lungs were collected, and weighed. Net tumor burden is the weight of tumor-bearing lungs minus the average weight of normal control lungs. N~5/group, p [0371] FIGURE 3 shows the results of using 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine sulfate salt (compound A - in this example formulated in 50% PEG400:50% water), and 6,7-diphenyl-pteridine-2,4-diamine (compound B - in this example formulated in 50% PEG400:50% water) with doxorubicin to treat colon carcinoma. Syngeneic CT-26 Colon carcinoma cells were injected I.V. in order to establish lung metastases in Balb/C mice. Beginning 10 days after cells were injected, indicated test agents were given I.P. every 3 days for 3 cycles. Animals were sacrificed at day 20, lungs were collected, and weighed. Net tumor burden is the weight of tumor-bearing lungs minus the average weight of normal control lungs. N=5/group, p burden by 35% as a stand alone agent or by greater than 60% in combination with doxorubicm. Similarly, in this model, 6,7-diphenyl-pteridme-2,4-diamine (compound B) typically reduced tumor burden by 35% as a stand alone agent or by greater than 65% in combination with doxorubicin. [0372] FIGURE 4 illustrates the effects of the compounds of the present invention for co-drug therapy with doceiaxel (Taxotere*1" in this example formulated in 12.5% Cremaphore:12.5% Ethanol:75% normal saline) as described herein. Syngeneic CT-26 Colon carcinoma cells were injected IV. in order to establish lung metastases in Balb/C mice. Beginning 10 days after cells were injected, indicated test agents were given I.P. every 3 days for 3 cycles. Animals were sacrificed at day 20, lungs were collected, and weighed. Net tumor burden is the weight of tumor-bearing lungs minus the average weight of normal control lungs. N=5/group, p [0373] FIGURE 5 shows a photo of representative lung samples from the experiment shown in FIGURE 3 with 6,7-diphenyl-pteridine-2,4-diamine (compound B - in this example formulated in 50% PEG400:50% water) and doxorubicin (in this example formulated in 50% PEG400:50% water). The tumors in the lungs are apparent in the vehicle (control) lungs, and the vasculostatic agent plus doxorubicin treated lungs show a dramatic reduction in tumor burden. [0374] FIGURE- 6 illustrates the effect of compounds administered in conjunction with docetaxel (Taxotere"" - in this example formulated in 12.5% Cremaphore:12.5% Ethanol:75% normal saline ) in the w vivo model of metastatic colon cancer (CT-26 adenocarcinoma) described for FIGURE 4. 23-Bis(3,4-dmydroxyphenyl)-pyrido[2)3-b]pyrazin-6-ylamine dihydrochloride salt (compound C - in this example formulated in 50% PEG400:50% water) from FIGURE 1 is shown in FIGURE 6 as compound C. N=5/group, p [0375] Similarly, 2,3-bis(4-hydroxyphenyI)-pyrido[2,3-b]pyrazin-6-ylamine dihydrochloride salt inhibited tumor burden alone or with co-drug therapy using docetaxel (Taxotere®"in this example formulated in 12.5% Cremaphore:12.5% Ethanol:75% normal saline) as described herein. Syngeneic CT-26 Colon carcinoma cells were injected I.V. in order to establish lung metastases in Balb/C mice. Beginning 10 days after cells were injected, indicated test agents were given I.P. every 3 days for 3 cycles. Animals were sacrificed at day 20, lungs were collected, and weighed. Net tumor burden is the weight of tumor-bearing lungs minus the average weight of normal control lungs. N=5/group, pphenyl)-pyrido[2,3-b]pyTazm-6-ylamine dihydrochloride salt in 50% PEG400:50% water) typically reduced tumor burden by 63% as a stand alone agent or by greater than 78% in combination with docetaxel. EXAMPLE 3 INHIBITION OF VASCULAR PERMEABILITY [0376] IL-2 is used clinically to treat metastatic melanoma and renal cell carcinoma and the dose-limiting toxicity for IL-2 is Vascular Leak Syndrome (VLS). Two representative examples from distinct chemotype series were selected for initial study in the reduction of IL-2-induced VLS (see FIGURE 1 compounds). The compounds were pre-screened for in vivo reduction of vascular permeability and mere was no observable gross toxicity as single agents at 20-fold higher doses. [0377] The results of the studies shown in FIGURES 7-8 indicate that representative compounds of the invention show inhibition of vascular leak in vivo. There were no effects on T cell proliferation in prescribed dose range (see FIGURES 10-11) and no effects on anti-tumor activity of IL-2 (melanoma model; see FIGURE 9). The following experiments exemplify the results for co-drug therapy. 10378] BalbC mice were given 9 injections of the indicated dose of murine IL-2 (in this example formulated in saline with 5% bovine serum albumin) and/or invention compounds over a.period of 4 days. Animals were then sacrificed followed by collection, blotting and weighing (wet weight) of heart, lungs, and spleen. Organs were then dried at 80°C for 24 hours and weighed (dry weight). N=5/group, p100%. The results are shown in FIGURE 7. [0379] BalbC mice were given 9 injections of the indicated dose of murine IL-2 and/or invention compounds over a period of 4 days. Animals were then sacrificed followed by collection, blotting and weighing (wet weight) of heart, lungs, and spleen. Organs were then dried at 80°C for 24 hours and weighed (dry weight). N=5/group, p100%. The results are shown in FIGURE 8. [0380] Syngeneic B16 melanoma cells were injected I.V. in order to establish lung metastases in C57 mice. Beginning 10 days after cells were injected, 100,OOOU of IL-2 and/or indicated invention compounds were given IP. every 8 hours for 5 days. Animals were sacrificed at day 18, lungs were collected and scored using image analysis software. N=5/group, p in mg/kg while IL-2 concentration is given in parenthesis kilounits. The results are shown in FIGURE 9. [0381 j An IL-2 dependent human T cell line, CTLL2, was used to evaluate IL-2 dependent proliferation over 96 hours hi the presence of 50 pg of human recombinant IL-2 (R&D Systems) and the indicated compounds using the XTT assay. N-(2-(lH-indol-2-yl)-phenyl)-phthalamic acid (compound D - in the 1 mg/kg range, in this example formulated in 50% PEG400:50% water) typically had no significant impact on IL-2 induced T-cell proliferation. The results are shown in FIGURE 10. [0382] An IL-2 dependent human T cell line, CTLL2, was used to evaluate IL-2 dependent proliferation over 96 hours in the presence of 50 pg of human recombinant IL-2 (R&D Systems) and the indicated compounds using the XTT assay. 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamine, sulfate salt (compound E - in the 0.1 mg/kg range, in this example formulated in 50% PEG400:50% water) typically had no significant impact on LL-2 induced T-cell proliferation in the therapeutic range ( [0383] Thus, representative examples from two distinct chemotype series in the present application (shown hi FIGURE 1) indicate that, for example, N-(2-(lH-indol-2-yl)-phenyl)-phthalamic acid (compound D - in the 1 mg/kg range, hi this example formulated in 50% PEG400:50% water) and 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamine, sulfate salt (compound E - in the 0.1 mg/kg range, in Ms example formulated in 50% PEG400:50% water), are effective in reducing VLS by 80-100% in vivo. [0384] Both of the exemplary compounds performed well hi important initial tests, including 1) inhibition of VLS at normal and elevated doses of LL-2; 2) no interference with Tl.,-2 mediated anti-tumor activity; 3) no inhibition of IL-2 induced T cell proliferation in the likely therapeutic dose range; and 4) neither compound elicited gross observable toxicity.These results indicate that invention compounds could be used in conjunction with IL-2 to prevent dose-limiting VLS and thereby increase the clinical application and therapeutic dose range of IL-2. 10385] Acute Respiratory Distress Syndrome (ARDS) is an acute, severe injury to most or all of both lungs causing fluid leak into the lungs. Patients with ARDS experience severe shortness of breath and often require mechanical ventilation (life support) because of respiratory failure. ARDS has also been called some of the following terms: Non-cardiogenic pulmonary edema; Increased-pemieability pulmonary edema; Stiff lung; Shock lung; Adult respiratory distress syndrome; Acute respiratory distress syndrome. Two representative compounds of the invention were selected for initial study in the reduction of ARDS. [0386] NIH Swiss mice were given an intraperitoneal injection of 1.5 mg/kg Oleic Acid of (in this example formulated in saline) and/or invention compounds. Four hours subsequent to injection animals were sacrificed followed by collection, blotting and weighing (wet weight) of the lungs. Lungs were then dried at 80°C for 24 hours and weighed (dry weight). N=4/group, 6,7-bis(3-hydroxyphenyl)-pteridine-2,4-diamine, sulfate salt (compound E - in the 0.5 mg/kg range, in this example formulated in 50% PEG400:50% water) typically reduced ARDS-induced edema by >50% while 4-[4-amino-6-(3,4- dihydroxyphenyl)pteridin-7-yl]benzene-l,2-diol (compound F - in the 0.5 mg/kg range, in this example formulated in 50% PEG400:50% water) typically reduced ARDS-induced edema by >100%. The results are shown in FIGURE 12. [0387] EXAMPLE 4 [0388] INHIBITION OF VEGF-INDUCED EDEMA [0389] Miles Assay Data [0390] A rodent model of vascular edema, the Miles assay, was used to screen compounds for their ability to inhibit VEGF-induced edema. The table below presents several examples drawn from these studies, in which compounds cited in this application successfully inhibited edema formation. Treatment Vehicle Dose (mg/kg BW) Score (scale of 0-1 2) 12 4-{[(2,4-Diamino-pteridin-6-ylmethyl)-ammo]-methyl } -benzene- 1 ,2-diol 5 mg/kg 4-(2,4-Diamino-pteridin-6-yl)-phenol (sulfate salt) 5 mg/kg 2-[2-(lH-Indol-2-yl)-phenyl]-isoindole-1,3-dione(Figure Removed) 1 .5 mg/kg 1.5 mg/kg 6,7-Bis-(3-hydroxy-phenyl)-pteridine-2,4-diol 1.5 mg/kg 3-(4-Hydroxy-phenyl)-N-[2-(lH-indol-2-yl> phenyll-propionamide 2-(4-Hydroxy-phenyl)-N-[2-(lH-indol- 2-yI)-phenyl]-acetamide 1 .5 mg/kg 1.5 mg/kg 2-(3,4-Dihydroxy-phenyl)-N-[2-(lH- indol-2-yI)-phenyl]-acetamide N-[2-(2,3-Dihydro-lH-indol-2-yl)-phenyl | -2 -hy droxy-benzamide 0.5 mg/kg 0.5 mg/kg 3-t2-(lH-Ijidol-2-yl)-phenylcarbamoyl]-pyridine-2-carboxylic acid 2-Hydroxy-5-(6-phenyl-pteridm-4-ylamino)-benzenesulfonic acid 0.5 mg/kg 0.5 mg/kg 5-(6-Phenyl-pteridin-4-ylamino)-quinolin-8-ol hydrochloride salt 0.5 mg/kg 3,4-Dihydroxy-lN'-[2-(lH-indol-2-yl)-phenyl> benzamide 0.1 mg/kg 6-{[fPyridiri-2-ylmethyl)-amino]-methyl}-Dteridine-2,4-diamine 0.1 mg/kg 6-{[(Naphthalen~2-ylmethyl)-amino]-methyl}-pteridine-2,4-diamine 0.1 mg/kg 2,3-(3,4-Diiiydroxyphenyl)-pyrido[3,4- 0.01 mg/kg (Table Removed) Sprague-Dawley rats were first injected IV with vehicle alone or test agent, followed by IV injection of Evans blue dye, followed by intradermal injections of saline and VEGF (200 ng/injection site) along both shaved flanks. After 45 min, intradermal injection sites were photographed and then scored by a blinded observer for extravasation of Evans blue dye into the dermis (dermal bluing) according to a 4 point scoring system (3= maximal bluing, >75% of response in vehicle-treated animals; 2= medium bluing, >25% but 10391] The ability of test agents to influence edema induced by agonists other than VEGF was also tested. Compounds cited in this application inhibited edema formation induced using histamine as an agonist, for example, as shown below. (Table Removed) The ability of test agent to influence vascular edema was tested as above, except that the ability to block edema was tested using either VEGF or histamine as the agonist (200 ng and 10 fig/injection site, respectively). 10392) EXAMPLE 5 [0393] REDUCTION OF MYOCARDIAL INFARCTION [0394] Myocardial Infarct Data [0395] A rodent model of acute myocardial infarct, in which the proximal left anterior descending coronary artery (LAD) is occluded for 60 min followed by reperfusion, was used to detennine whether test agents reduced infarct size at 24 hours. Several examples of the compounds cited in this application significantly reduced infarct size as compared to controls. (Table Removed) Myocardial infarcts were created in Sprague-Dawley rats (200-300 g body weight) by a 60 niin occlusion of the LAD followed by LAD reperfusion. At 90 min post-reperfusion, either vehicle alone or test agents were injected IV. At 24 hr post-treatment, the ischemic zone (area al-risk. AAR) was delineated by re-ligation of the LAD followed by IV injection of alkali blue dye, after which hearts were sectioned along the short axis and stained using triphenyltetrazolium chloride to delineate viable from infarcted myocardium. Photographic images were then analyzed using morphometric software to calculate infarct area as a percent of the at-risk area. Study 1: Group sizes N= 5-6; 6,7-bis(4-hydroxyphenyl)-pteridm-4-ylamme sulfate salt differs from vehicle control (P Study 2: Group sizes N= 5; 6J-bis(3,4-dihydroxyphenyl)-pteridine-2,4-diamme hydrochloride salt differs from vehicle control (P Study 3: Group sizes N= 3-5; 3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl] phenol dilrydrochloride salt at 0.1 mg/kg differs from vehicle control (P Study 4: Group sizes N= 4-5; all 4-[4-amino-6-(3,4-dihydroxyphenyl)pteridin-7- yl]benzene-l,2-diol chloride salt and 6,7-Bis(3-hydroxyphenyl)-pteridme-4-ylamine hydrochloride salt treatment groups differ from vehicle control (P Study 5: 3-[2,4-Diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol dibromide salt was delivered in 8% PEG400 (Vehicle), while 6,7-Bis(3-hydroxyphenyl)-pteridine-2,4- diamine was delivered as one of three product formulations (PF1= 2.8% bydroxypropyl- p-cyclodextrin, 1.84% PEG400, and 0.009% EDTA hi 20 mM pH 3 citrate buffer; PF2= 1.8% hydroxypropyl-p-cyclodexrrin and 0.06% polyvinylpyrrolidone in 20 mM pH 3 citrate buffer; PF3= 0.8% sulfonbutyl ether-(3-cyclodextrin and 0.03% polyvinylpyrrolidone in 20 mM pH 3 citrate buffer). Group sizes N= 5-6; all treatment groups differ from vehicle control (P (0396] The following studies were performed as described above, except that the timing of 3-[2,4-diamino-6~(3-hydroxyphenyl)pteridm-7-yl] phenol dihydrochloride salt administration (at 0.1 mg/kg) was varied, hi one group, 3-[2,4-diamino~6-(3-hydroxyphenyl)pteridin-7-yl] phenol dihydrochloride salt was administered at both 60 and 240 mrn post-occlusion. (Table Removed) Group sizes N= 4-5; all 3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl] phenol dihydrochloride salt treatment groups differ from vehicle control (P [0397] Stroke Data [0398J A rodent model of cerebral stroke, in which the middle cerebral artery is permanently occluded, was used to determine whether test agents reduced infarct size at 24 hours. Several examples of the compounds cited in this application significantly reduced infarct size as compared to controls, and to a greater degree than two commercially available compounds (PP1 and SU6656) described in the literature as Src kinase inhibitors. (Table Removed) |0399] Cerebral strokes were created in mice by permanent ligation of the middle cerebral artery using a cauterizing tool, followed 60 min later by TV injection of either vehicle alone (50% PEG400 m water) or test agents (at 1 mg/kg BW). Twenty four hours later, brains were sectioned and stained using tnphenyltetrazolimn chloride to delineate viable from infarcted tissue. Photographic images were then analyzed using morphometric software to calculate infarct area. Study 1: Group sizes N-- 5-6; the 6.7-diphenyl-pteridine-2,4-diol andN-(2-(lH-indol-2-y])-pheny])-phthalamic acid groups differ from velricle control (P Study 2: Group sizes N= 6-7; the 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine, sulfate salt group differs from vehicle control (P [0400] EXAMPLE 6 [0401] INHIBITION OF Src-FAMTLY KINASES, c-Src AND Yes [0402] The ability of compounds to inhibit the activity of two Src-family kinases (c-Src and Yes) was directly tested. The table below presents data for several compounds, which in most cases inhibited one or both kinases at concentrations of Kinase reactions were conducted in 96-well plates by combining recombinant human c-Src or Yes (280 ng/well, Panvera, Madison WI), ATP (3 pM), a tyrosine kinase substrate (PTK2, 250 |aM. Promega Corp., Madison WI), and test agents (at concentrations ranging from 1 nM to 100 u.M); the buffer used was Src kinase reaction buffer (Upstate USA, Lake Placid NY). After reacting at 90 minutes at room temperature, residual ATP was determined using a luciferase-based assay (KinaseGlo, Promega Corp.) as a measure of lanase activity. Data from four wells were then averaged and used to determine !C5o values for lite Lcsl compounds (Prism software package, GraphPad Software, San Diego CA). ND: not determined. EXAMPLE 7 EFFECTS OF.INVENTION COMPOUNDS ON ANGIQGENESIS [0403] Referring to FIGURES 13 and 14, amurine model of angiogenesis was used to screen compounds for their capacity to inhibit angiogenesis. The graph presents representative examples of.compounds cited in this application which successfully inhibited angiogenesis in vivo. In the graph, compound A is 6,7-bis(4-hydroxyphenyl)-pteridin-4-ylamine sulfate salt. Athymic WeHi (nu/nu) mice were first injected with 400 pis of an ice-cold tumor-denved extracellular matrix substrate, matrigel (Becton-Dickinson) infused with 400 ng/nil of bFGF or VEGF (R&D Systems) which rapidly solidifies into a subdermal plug at body temperature. Mice were subsequently injected intaperitoneally with 10 nig/kg of the indicated compounds bid for four days. On the fourth day mice were injected intravenously with 0.5 rags of a FITC-conjugated endothelial specific lectin (Banderiea Simplifica, Vector Laboratories). Twenty minutes after injection of the lectin, mice were eutlianized, matrigel plugs were then extracted, solublized in PBS with mechanical grinding and the fluorescent content of individual plugs was quantified. Values shown are normalized to control values from groups of 5. [0404] Although the invention has been described with reference to the presently preferred embodiment, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims. We claim: 1 A vasculostatic agent of structure (III): (Structure Removed) wherein: each of Z2 and Z4 is C, each of Z1, Z3, Z5, and Z6 is N; each X is NH2; each Y is independentiy selected from a group consisting of substituted aryl, wherein said substituents are selected from a group consisting of -OH, -P(OXOH)2, or -NR'2, wherein R' is selected from a group consisting of -H, lower alkyl, and aryl; or each Y is independently selected from a group consisting of CH2glycinyl, CH2NHethoxy, and CH2NHCH2t-Bu, and m and n are each independently 1 to 2, wherein when m=n=2, Y is not 4-hydroxyphenyl, or phannaceuticaHy acceptable salts as herein described. 2. A vasculostatic agent as claimed in claim 1, having the structure: (Structure Removed) or phannaceuticaHy acceptable salts thereof. 3 • A vasculostatic agent as claimed in claim 1, having the structure: (Structure Removed) or pharmaceutical^ acceptable salts thereof. A vasculostatic agent as claimed in claim 1, having the structure: (Structure Removed) A vasculostatic agent as claimed in claim 1, having the structure: (Structure Removed) or pharmaceutically acceptable salts thereof. A vasculostatic agent as claimed in claim 1, having the structure: or pharmaceutically acceptable salts thereof. (Structure Removed) A vasculostatic agent as claimed in any of the preceding claims, as and when used to prepare a pharamaceutical preparation. A vasculostatic agent of structure III substantially as hereinbefore described with reference to the foregoing examples.

Documents:

1020-DELNP-2005-Abstract-(12-08-2008).pdf

1020-DELNP-2005-Abstract-(18-12-2008).pdf

1020-delnp-2005-abstract.pdf

1020-DELNP-2005-Claims-(12-08-2008).pdf

1020-DELNP-2005-Claims-(18-12-2008).pdf

1020-DELNP-2005-Claims-(26-12-2008).pdf

1020-delnp-2005-claims.pdf

1020-delnp-2005-complete specification (granted).pdf

1020-DELNP-2005-Correspondence-Others-(12-08-2008).pdf

1020-DELNP-2005-Correspondence-Others-(18-12-2008).pdf

1020-delnp-2005-correspondence-others.pdf

1020-DELNP-2005-Description (Complete)-(18-12-2008).pdf

1020-delnp-2005-description (complete)-12-08-2008.pdf

1020-delnp-2005-description (complete)-26-12-2008.pdf

1020-delnp-2005-description (complete).pdf

1020-DELNP-2005-Drawings-(12-08-2008).pdf

1020-delnp-2005-drawings.pdf

1020-DELNP-2005-Form-1-(12-08-2008).pdf

1020-DELNP-2005-Form-1-(18-12-2008).pdf

1020-delnp-2005-form-1.pdf

1020-delnp-2005-form-18.pdf

1020-DELNP-2005-Form-2-(12-08-2008).pdf

1020-delnp-2005-form-2.pdf

1020-delnp-2005-form-26.pdf

1020-DELNP-2005-Form-3-(12-08-2008).pdf

1020-delnp-2005-form-3.pdf

1020-delnp-2005-form-5.pdf

1020-DELNP-2005-GPA-(01-06-2010).pdf

1020-delnp-2005-pct-101.pdf

1020-delnp-2005-pct-105.pdf

1020-delnp-2005-pct-202.pdf

1020-delnp-2005-pct-210.pdf

1020-delnp-2005-pct-220.pdf

1020-delnp-2005-pct-304.pdf

1020-delnp-2005-pct-401.pdf

1020-delnp-2005-pct-402.pdf

1020-delnp-2005-pct-409.pdf

1020-delnp-2005-pct-416.pdf

1020-DELNP-2005-Petition-137-(18-12-2008).pdf

1020-DELNP-2005Correspondence-Others-(01-06-2010).pdf