RS34004A - Methods and compositions of novel triazine compounds - Google Patents

Abstract

The present invention relates to methods and compositions comprising compounds that treat pathophysiological conditions arising from inflammatory responses. In particular, the present invention is directed to compounds that inhibit or block glycated protein produced induction of the signaling-associated inflammatory response in endothelial cells. The present invention relates to compounds that inhibit smooth muscle proliferation. In particular, the present invention is directed to compounds that inhibit smooth muscle cell proliferation by modulating HSPGs such as Perlecan. The present invention further relates to the use of compounds to treat vascular occlusive conditions characterized by smooth muscle proliferation such as restenosis and atherosclerosis.

Description

PROCEDURE OF NEW TRIAZINE COMPOUNDS

FIELD OF INVENTION

The present invention relates to triazine compounds. More specifically, the invention relates to processes and compositions for the preparation and use of triazine compounds.

STATE OF THE ART

The synthesis of new compounds leads to new possibilities for the discovery of new therapeutic interventions. Using structure-activity relationship research, compounds can be tailored so that the compound has at least one activity that can be predicted from its structure.

The use of high-throughput imaging allows rapid determination of the activity of recently synthesized compounds.

New compounds for new therapeutic interventions are needed in many areas of medicine and disease treatment. For example, chronic and acute inflammatory conditions form the basis for diseases affecting organ systems including, but not limited to, asthma, acute inflammatory diseases, vascular inflammatory disease, chronic inflammation, atherosclerosis, angiopathy, myocarditis, nephritis, Crohn's disease, arthritis, type I and type II diabetes and related vascular pathologies. The incidence of these inflammatory conditions is increasing in the entire population, with diabetes alone affecting 16 million people.

While inflammation is coded with or without the body's normal immune response, chronic inflammation leads to complications and permanent systemic damage due to interactions of unknown cellular factors. In particular, chronic inflammation can cause endothelial damage that results in vascular complications. Heart artery disease, cerebrovascular and peripheral vascular disease resulting from atherosclerotic and thromboembolic macroangiopathy are the primary causes of mortality in chronic inflammatory disease.

Many people and animals have limited lifespans and lifestyles due to conditions related to lifestyle choices, such as diet or exercise, or due to genetic predispositions to develop disease. For example, vascular smooth muscle cell proliferation is a common consequence of endothelial injury and is believed to be an early pathogenetic event in the formation of atherosclerotic rings or complications related to vascular injury or as a result of surgical interventions. Abnormal vascular smooth muscle cell (SMC) proliferation is thought to contribute to the pathogenesis of occlusive organ vasculature, including arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after organ transplantation.

Percutaneous coronary intervention (PTCA) procedures are the most common inpatient procedure in the United States. According to the American Heart Association, about one-third of patients who undergo balloon angioplasty have a dilated segment of the vessel develop within about 6 months. It may be necessary to perform another angioplasty or coronary artery bypass surgery on arteries that have restenosis. A key feature of restenosis is the response to injury that results in the activation of the inflammatory cascade and cell remodeling both inside and outside the carotid artery wall. These include increased growth of connective tissue and smooth muscle in the lumen of the artery known as neointimal hyperplasia. There are currently no effective pharmacological treatments available to control the pathogenesis of occlusive organ vasculature, such as, but not limited to, arteriosclerosis, atherosclerosis, restenosis, and graft atherosclerosis after organ transplantation. Identification of effective therapeutic agents with minimal side effects will restore quality of life without requiring additional surgical procedures such as coronary artery bypass surgery.

Control or modulation of factors produced by the body in response to injury, surgery, metabolic factors, or loss of control in feedback mechanisms, leading to too much or too little of the factor has long been the goal of administering pharmacological agents. Another disease that is rapidly increasing in industrialized countries is the appearance of diabetes and all its sequelae. One factor that is important in the damage associated with diabetes is the presence of glycated proteins.

Glycated proteins and advanced glycation end products (AGE) contribute to cellular damage, in particular, diabetic tissue damage, through at least two main mechanisms: modulation of cellular functions through interactions with specific cell surface receptors, and alteration of the extracellular matrix leading to the formation of protein cross-links. Studies suggest that protein glycans and AGE interactions with cells can promote inflammatory processes and oxidative cellular injury. AGE increases the oxidation capacity and atherogenicity of lipoproteins. Its binding to the protein matrix causes the synthesis of cytokines and activates cellular messengers. Diseases where glycated protein and AGE accumulation is a suspected etiologic factor include vascular complications of diabetes, mycoangiopathies, renal failure, and Alzheimer's disease.

The exact mechanisms by which high plasma glucose, seen as diabetes, causes microvascular damage are still not fully understood. One possible mechanism by which hyperglycemia may be associated with microangiopathies is through the process of non-enzymatic glycation of critical proteins. Non-enzymatic glycation, ie linking of proteins with glucose, leads to the formation of glycated proteins. The first step in this glycation pathway involves the non-enzymatic condensation of glucose with free amino groups in the protein, primarily the epsilon-amino groups of lysine residues, forming Amadori coupling products. Early glycation products can undergo further reactions such as rearrangements, dehydration and condensations to form irreversible advanced glycation end products (AGEs). This is an extremely reactive group of molecules whose interaction with specific receptors on the cell surface is thought to lead to pathogenic phenomena.

Another major area of diseases where treatments are needed and for which adequate and effective therapies do not exist are cell proliferative disorders, or disorders caused by desired or unintended cell growth. As previously mentioned, smooth muscle cell (SMC) hyperplasia is a major event in the development of atherosclerosis and is also responsible for a significant number of error rates accompanying vascular procedures such as angioplasty, stent implantation, and coronary artery bypass graft surgery. In a normal blood vessel, SMCs are quiescent, but they proliferate when endothelial damage occurs. Naturally occurring growth modulators, many of which are derived from the endothelium, strictly control SMC proliferation in vivo. When control becomes dysregulated, a pathological state is induced in the subject.

The next major area of unwanted cellular growth, which is unchecked by the body's regulatory system, is cancer or oncological conditions. Many therapies are used to try to restore health or at least stop unwanted cell growth. Many times, therapeutic agents may work individually, but often, therapeutic regimens require combinations of different pharmacological agents with treatments such as surgery or radiation.

There is currently a need for treatments for chronic or acute diseases, such as atherosclerosis, unwanted cell growth or cell proliferation, diabetes, inflammatory conditions and vascular occlusive pathological conditions, since their occurrence is frequent, currently available treatments are expensive and the conditions are difficult to treat for many pharmacological therapies. The mechanisms involved in the control or prevention of such diseases are not clear and there is a need for preventive and therapeutic treatments for these and other diseases. Thus, what is needed at this time are new compounds that find utility in methods and compositions for the treatment and prevention of chronic and acute diseases.

THE ESSENCE OF THE INVENTION

The present invention is directed to methods and compositions comprising novel compounds, primarily based on a substituted triazine nucleus. Disclosed herein are methods for making novel compounds, compounds, compositions containing those compounds, and methods and compositions for using those compounds. The compounds and compositions containing these compounds are useful in the treatment of various diseases.

The composition according to the present invention contains triazine compounds, analogs, derivatives, and mixtures thereof. Such triazine compounds consist of the following structure, where N<A>, N<B>, and N<c> are typically used to represent substituted amino groups attached to the 1,3,5-triazine at positions 2, 4, and 6:

Examples of such triazine compounds include compounds having the following structure.

In this example, each counterpart amino (NRR') group can represent a simple NH 2 group or a secondary or tertiary amino group, including a cyclic secondary amide, and a range of other substituents described herein. Compositions according to the present invention also include analogs of tris(amino) compounds, which include intermediate compounds in the synthesis of tris(amino) triazine compounds indicated above, for example diamino chlorotriazine compounds, or amino dichlorotriazine compounds shown below, where N<A> and N<B> are equivalently substituted amino groups as described above.

Compositions in accordance with the present invention also include analogs of the tris(amino)triazine compounds indicated above, including compounds isolated as byproducts in the synthesis of tris(amino)triazine compounds, such as the bis(amino)alkoxy triazine compounds as shown below, where E = O or S and the like.

The present invention also includes compositions for use in making the novel compounds and methods of making the novel compounds disclosed herein.

The present invention is directed to methods and compositions comprising compounds useful in the treatment of pathological conditions. One aspect of the present invention includes compounds and compositions comprising such compounds in methods of treating diseases related to unwanted cell proliferation. Many vascular diseases, such as cardiovascular disease, organ transplants, vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, graft vasculopathy, cardiac allograft vasculopathy, atherosclerosis, and arteriosclerosis, are caused by or have collateral damage due to unwanted cellular proliferation, such as smooth muscle cell (SMC) hyperplasia. At least one activity of one or more of these compounds is that the compound has the activity of affecting proteoglycan synthesis including the induction and synthesis of proteoglycans and active proteoglycan fragments. The methods include administering compositions comprising compounds that have at least the activity of affecting cell proliferation and affecting the synthesis and activity of proteoglycans.

The present invention also encompasses methods and compositions comprising compounds described herein that have activity associated with modulating glycosidase enzymes and thus affecting substrates for such enzymes. Glycosidase enzymes and their activity with their substrates, such as proteoglycans or glycated proteins, are aspects of various diseases such as vascular conditions, proteoglycan-related diseases, kidney diseases, autoimmune diseases and inflammatory diseases. The compounds described herein that have activity that affects glycosidase enzyme substrate concentrations are used in the treatment of such vascular, inflammatory, metastatic and systemic diseases.

Embodiments of the present invention include methods and compositions containing the compounds of the present invention for the treatment and prevention of conditions or diseases that have inflammation as an aspect of the disease or condition. An aspect of the present invention is directed to methods and compositions comprising compounds that affect the inhibition of inflammation, particularly inflammation associated with the accumulation or presence of glycated proteins or AGEs. Treatment methods include administering compositions containing compounds that have at least activity to modulate inflammatory responses that are components of biological conditions including, but not limited to, vascular complications caused by vasculopathy caused by type I and type II diabetes, other vasculopathies, microangiopathy, renal insufficiency, Alzheimer's syndrome, and diseases caused by inflammation such as atherosclerosis. An aspect of the present invention includes methods and compositions for the treatment of diseases, preexisting conditions, or pathologies associated with inflammatory cytokines and other molecules related to inflammation.

A further embodiment of the present invention includes methods and compositions comprising compounds having at least the activity of inducing cell death or termination of cell activity, referred to herein as cytotoxic activity. This activity can be used in in vitro or in vivo cytotoxicity procedures. For example, compounds having this activity can be selectively delivered to an area within a living organism to selectively kill cells in that area. Such procedures are used in the treatment of hyperproliferative cells, such as cancers, or other unwanted cell growth or cell activity. One aspect of the invention provides compositions containing compounds that indiscriminately kill cells. A further aspect of the invention provides compounds that selectively kill cells, for example, cells that have a particular cell marker or other identifying characteristic such as the metabolic rate or resorption of a particular compound.

The present invention also encompasses pharmaceutical compositions comprising the compounds disclosed herein. Routes of administration and dosages of effective amounts of compounds and pharmaceutical compositions are also disclosed. For example, compounds of the present invention may be administered in combination with other pharmaceutical agents in various protocols to effectively treat a disease.

In another aspect, the present invention relates to the delivery of a drug or eluting medical devices containing or coated with at least one compound disclosed herein. Medical devices suitable for use with the compounds of the present invention include stents and other medical devices that provide a substrate for the delivery of at least one compound.

Other aspects of the present invention include compositions and methods for the device of microarrays. Such microarray devices and methods include a variety of microarrays that can be used, for example, to study and monitor gene expression in response to treatment with compounds of the present invention. Microarrays may contain nucleic acid sequences, carbohydrates, or proteins that target specific cells, tissues, species, disease states, prognoses, disease progression, or any other combination of molecules that can be used to determine the effect of one or more compounds of the present invention. Other embodiments of the present invention include methods of using databases and computer applications.

BRIEF DESCRIPTION OF THE PICTURES

Figure 1.<1>H NMR N-(3-Chloro-4-methoxy-phenyl)-N'-cyclohexylmethyl-N"-methyl-N"-(1-methyl-piperidin-4-yl)-| 1,3,5jtriazine-2,4,6-triamine.

Figure 2. 'H NMR of N-Cycloheptyl-N'-(1-ethyl-pyrrolidin-2-ylmethyl)-N"-(3-fluoro-4-methoxy-phenyl)-|1,3,5]triazm-2,4,6-triamine.

Figure 3.<1>H NMR of N-(3-Chloro-4-methoxy-phenyl)-N'-methyl-N'-(1-methylpiperidin-4-yl)-N"-(1-propyl-butyl)-[ 1,3,5"|triazine-2,4,6-triamine. Figure 4.<1>H NMR N-(1-Aza-bicyclo|2.2.2|oct-3-yl)-N'-(3-chloro-4-methoxy-phenyl)-N"-)1 ethyl-pyrrolidin-2-ylmethyl)-(_1,3,5]triazin-2,4,6-triamine).

Figure 5.<1>H NMR of N2-(3-Chloro-4-methoxy-phenyl)-N4-cycloheptyl-N6-methyl-N6-piperidin-4-yl-[1,3,5-triazin-2,4,6-triamine.

Figure 6. 'H NMR of N-Cycloheptyl-N'-ethyl-N"-(3-fluoro-4-methoxy-phenyl)-(1,3,5|triazine-2,4-diamine).

Figure 7.<1>H NMR N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-pyrrolidin-1-yl-| 1,3,5]triazine-2,4-diamine.

Figure 8. 'H NMR N-Cyclohexylmethyl-N,-(1-ethyl-pyrrolidin-2-ylmelyl)-N<M->

(3-fluoro-4-methoxy-phenyl)-| 1,3,5|triazine-2,4,6-tnamine. Figure 9.<1>H NMR of 6-Chloro-N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine.

Figure 10.<1>H NMR of N-(3-Chloro-4-methoxy-phenyl)-(4,6-dichloro-[1,3,5N-triazin-2-yl)amine.

Figure 11.<1>H NMR of N-(3-Chloro-4-methoxy-phenyl)-N'-isopropyl-N"-methyl-N',-(1-methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triarnine. Figure 12.<1>H NMR N2-(3-chloro-4-methoxy-phenyl)-N4-isopropyl-N6-methyl-N6-piperidin-4-yl-1,3,5-triazin-2,4,6-triamine.

Figure 13.<1>H NMR of 5-14-(3-Chloro-4-methoxy-phenylamino)-6-|methyl-(1-methyl-piperidin-4-yl)-aminoJ-| 1,3,5]triazin-2-ylamino-pentan-1-ol.

Figure 14<1>H NMR of 5-|4-(3-chloro-4-methoxy-phenylamino)-6-(methyl-pipedin-4-yl-amino)-1,3,5-triazin-2-ylamino|-pentan-1-ol. Figure 15.<1>H NMR of 6-Chloro-N!N"-bis-(3-chloro-4-methoxy-phenyl)-11,3,5 N-triazine-2,4-diamine.

Figure 16.<1>H NMR N,N'-Bis-(3-chloro-4-methoxy-phenyl)-N"-methyl-N"-(4-methyl-cyclohexyl)-| 1,3,5"|triazine-2,4,6-triamine.

Figure 17.<1>H NMR of N,N,-Bis-(3-chloro-4-methoxy-phenyl)-N"-cycloheptyl-11,3,5[triazine-2,4,6-triamine.

Figure 18.<1>H NMR of N-Butyl-N,-(3-chloro-4-methoxy-phenyl)-N"-(1-methylpiperidin-4-yl)-N-propyl-[1,3,5]triazine-2,4,6-triamine.

Figure 19.<1>H NMR of N2-Butyl-N4-(3-chloro-4-methoxy-phenyl)-N6-methyl-N6-piperidin-4-yl-N2-propyl-1,3,5-triazine-2,4,6-triamine.

Figure 20.<1>H NMR of 6-Cyclohexylmethoxy-N,N'-bis-(3-chloro-4-methoxy-phenyl)-1,3,5-triazine-2,4-diamine.

Figure 21.<1>H NMR of (4-Chloro-6-cyclohexylmethoxy-[1,3,5|tnazin-2-yl)-(3-fluoro-4-methoxy-phenyl)-amine.

Figure 22.<1>H NMR of N,N'-bis-((3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-1,3,5-triazine-2,4-diamine).

Figure 23.<1>H NMR of (4-Chloro-6-cyclohexylmethoxy-[1,3,5|triazin-2-yl)-(3-chloro-4-methoxy-phenyl)-amine.

Figure 24.<1>H NMR of 6-Cyclohexylmethoxy-N-(1-ethyl-pyrrolidin-2-ylmethyl)-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine.

Figure 25.<1>H NMR of N-(3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-N'-methyl-N'-(1-methyl-piperidin-4-yl)-[1,3,5|triazine-2,4-diamine. Figure 26.<1>H NMR of N-Azepan-1-yl-N'-(3-chloro-4-methoxy-phenyl)-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine.

Figure 27.<1>H NMR of N4-(3-chloro-4-methoxy-phenyl)-N6-methyl-N2-perhydro-azepin-1-yl-N6-piperidin-4-yl-1!3,5-triazin-2,4,6-triamthne. Figure 28.<1>H NMR of N-Azepan-1-yl-6-chloro-N'-(3-chloro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine.

Figure 29.<1>H NMR of N"-(3-chloro-4-methoxy-phenyl)-N,N'-bis-perhydro-azepin-1,3,5-triazine-2,4,6-triamine.

Figure 30.<1>H NMR of N-(3-Bromo-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-N"-(1-methyl-piperidin-4-yl)-11,3,5|triazine-2,4,6-triamine. Figure 31.<1>H NMR of N-(benzyl-piperidin-4-yl)-N'-(3-chloro-4-methoxy-phenyl)-N"-cycloheptyl-|1,3,5|-2,4,6-triamine.

Figure 32.<1>H NMR of 2-chloro-4-|4-cycloheptylamino-6-[methyl-(1-methylpiperidin-4-yl-amino]-1,3,5-triazin-2-ylamino|-phenol).

Figure 33.<1>H NMR of N2-cycloheptyl-N4-((S)-1-ethyl-pyrrolidin-2-ylmethyl)-N6-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine.

Figure 34.<1>H NMR of N2-cycloheptyl-N4-((R)-1-ethyl-pyrrolidin-2-ylmethyl)-N6-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine.

Figure 35.<1>H NMR of N2-cyclohexylmethyl-N4-((S)-1-ethyl-pyrrolidin-2-ylmethyl)-N6-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine.

Figure 36.<1>H NMR of N2-cyclohexylmethyl-N4-((R)-1-ethyl-pyrrolidin-2-ylmethyl)-N6-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine.

Figure 37. 1H NMR of (;4-cycloheptylamino-6-[((S)-1-ethyl-pyrrolidin-2-ylmethyl)-amino|-1,3,5-triazin-2-yl j -phenyl-amino)-acetonitrile. Figure 38. <1>H NMR of (!4-cycloheptylamino-6-|((R)-1-ethyl-pyrrolidin-2-ylmethyl)-amino|-1,3,5-triazin-2-yl j -phenyl-amino)-acetonitrile.

Figure 39.<1>H NMR of N2-[(1-ethyl-2-pyrrolidinyl|-N4-((3-fluoro-4-methoxy-phenyl)-6-|(S)-2-(methoxymethyl)-1-pyrrolidinyl]-1,3,5-triazine-2,4-diamine).

Figure 40.<1>H NMR of 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-11,3,5'|triazine-2,4-diamine.

Figure 41.<1>H NMR of N-(3-Chloro-4-methoxy-phenyl)-N,-cycloheptyl-N"-methyl-N"-(1-methyl-piperidin-4-yl)-11,3,5N-triazin-2,4,6-triamine. Figure 42. 1H NMR of 4-(3-Chloro-4-methoxy-phenylamino)-6-cycloheptylamino-1,3,5-triazin-2-ol.

Figure 43. <1>H NMR of N2-(3-chloro-4-diethylamino-phenyl)-N4-cycloheptyl-N6-(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5-triazin-2,4,6-triamine.

Figure 44. 1H NMR of N2-cycloheptyl-N4-(2-dimethylamino-ethyl)-N6-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine.

Figure 45.<1>H NMR of (;4-cycloheptitamino-6-|1-ethyl-pyrrolidin-2-ylmethyl)-amino|-1,3,5-triazin-2-yl 1-phenyl-amino)-acetonitrile.

Figure 46.<1>H NMR of N,N,-di-N-propyl-N"-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine.

Figure 47.<1>H NMR of N,N'-dicyclopropyl-N"-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-thnamine.

Figure 48.<1>H NMR of N2-Cycloheptyl-N4-(3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine. Figure 49.<1>H NMR of N2-Cycloheptyl-N4-(3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-piperidin-4-yl-1,3,5-triazin-2,4,6-triamine.

Figure 50.<1>H NMR N2-Cycloheptyl-N4-(3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, hydrochloride salt.

Figure 51.<1>H NMR N2-(3-chloro-4-diethylamino-phenyl)-N4-cycloheptyl-N6-(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5-triazin-2,4,6-triarnineS42-63

hydrogen chloride salts.

Figure 52.<1>H NMR N2-Cycloheptyl-N4-(1-ethyl-pyrrolidin-2-ylmethyl)-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, salt

hydrogen chloride.

Figure 53. Map showing the effects of the compounds in the experiment where gikovani

human serum albumin (G-HSA) induced IL-6 production. Figure 54. Map showing the effects of compounds in antiproliferative

experiment.

DETAILED DESCRIPTION OF THE INVENTION

It should be understood that this invention is not limited to the particular methodology, protocols, cell lines, constructs and reagents described herein and as such may vary. It should also be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to limit the present invention to be limited only by the appended claims.

All publications and patents mentioned herein are incorporated herein by reference for the purpose of describing and disclosing, for example, the constructs and methodologies described in the publications, which may be used in connection with the invention described herein. The publications discussed above and throughout are provided for disclosure only prior to the filing date of the present application. Nothing herein shall be construed as an admission that the inventors are not entitled to such discovery by reason of prior invention.

I. DESCRIPTION OF THE COMPOUND

In one aspect, the present invention includes novel organic compounds generally described as N2,N<4>,N<6->tris(amino)-1,3,5-triazines which are represented by names in Table 1 and structural formulas in the remaining Tables 2 et seq. Representative compounds of the present invention can be described by the general structural formula below, where N<A>, N<B> and N<c> are equivalently substituted amino groups attached to 1,3,5-triazines at the 2, 4 and 6 positions.

Thus, typical compounds encompassed by the present invention include triazine compounds comprising the following structure:

In this typical embodiment, each counterpart NRiR2NR3R4i NR5R6 amino group can represent a primary, secondary, or tertiary amine when attached to the triazine nucleus, including a secondary amide substituent (eg, a pyrrolidin-N-yl group), and a range of other substituents as described herein. Compositions according to the present invention also contain analogs of tris(amino) compounds, for example, compounds that are prepared as intermediate compounds in the synthesis of tris(amino) triazine compounds indicated above, or compounds representing a partially substituted triazine nucleus. Many of the syntheses of the triazine compounds of this invention typically use cyanuric acid chloride C3N3CI3 as a starting compound, and thus intermediate species such as bis(amino)chlorotriazine compounds, or amino dichlorotriazine groups as described above, are also encompassed by this invention.

Compositions according to the present invention also contain analogs of the tris(amino)triazine compounds indicated above, including compounds isolated as by-products in the synthesis of tris(amino)triazine compounds of the general formula shown below, where E = O or S. An example of such a compound is a bis(amino)alkoxy triazine compound. In general terms, compounds and compositions according to the present invention include analogues of tris(amino)triazine compounds of the following general structure:

Or their ene, diene, triene, or yne derivative; their saturated derivative; a stereoisomer thereof, or a salt thereof;

whereby:

R<1> is at each occurrence independently selected from -H; alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkadienyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 12 carbon atoms and including linear or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, or heterocyclic derivatives thereof; arilla; heteroaryl; aryloxy; arylthio; halogen; or amino;

G is selected from NR<1> or O;

E is selected from CH or N;

z is an integer from 0 to 3;

X<1>is selected from R<1>, NR<1>3<+>, CN, N02, CO2R<1>, C(0)NR<1>2, CH=CR12,OCR\ C(0)R<1>, SO2R<1>, SO2OR<1>, or NC(0)R<1>, or X<1>and X<2> are fused together with aryl, pyridine, dioxane, pyrrole, pyrrolidine, furan, thiophene ring; provided that the R<1>residue of the C(0)R<1>substituent in the X<1>position excludes amino or dialkylamino when X<1>C(0)R<1>;

X<2> is selected from R<1>; CXXH3.X, wherein X is halogen and x is an integer from 1 to 3; OR<1>; SR<1>; NR<1>2; CN; C(0)OR<1>; 4-morpholinyl; 4-methyl-1-piperizinyl;OR<2>, wherein R<2>is selected from CH2OCH3, CH2OCH2OCH3, CH2OCH2CH2OCH3, or C(0)R<1>;SR<3>, wherein R<3>is selected from CH2OCH3, CH2OCH2CH2OCH3, CH2OCH2CH(CH3)2, CH2NHC(0)CH3, or SR<1>; OM or SM, wherein M is selected from Li, Na, K, Mg, or Ca;

AY<1>is halogen, or A is selected from NR<1>or O, and

Y<1>is selected from R<1>;CR43;NR<4>2; OR<4>; or SR<4>;

, where n is an integer from 0 to 8, m is an integer

a number from 1 to 8, Z<1>is independently selected from CR<1>or N, Z2 is independent

selected from CR<1>2, NR<1>, O, or S, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z2 residues are NR<1>;

R<4> is at each occurrence independently selected from in the normal sequence or branched alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, acylthio, alkylamino, or dialkylamino, each containing up to 10 carbon atoms, -H, aryl, heteroaryl, aryloxy, arylthio, halogen, amino, their NR<1>2-substituted derivatives, their OR<1->substituted derivatives; their SR<1->substituted derivatives; or their halogen-substituted derivatives; and

DY<2>is halogen, or D is selected from NR<1>or O where R<1>is defined as above, and

Y<2> is selected from R<1>,

or

wherein Z<1>is independently selected from N or CR<4>and Z<2>is

independently selected as defined above, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z<2>residues are NR<1>. The compounds of the present invention according to

this general description does not include those comprising a unique combination of substituents which provide the following compounds: N-Cycloheptyl-N'-methyl-N,-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-11,3,5]triazin-2,4,6-triamine;

N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methylpiperidin-4-yl)-| 1,3,5]triazine-2,4,6-triamine;

|4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-(4-methoxy-phenyl)-amine;

N-Cycloheptyl-6-morpholin-4-yl-N'-naphthalen-2-yl-n,3,5|tnazine-2,4-diamine;

N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-11,3,5]triazin-2,4-diamine;

N-Cycloheptyl-6-morpholin-4-yl-N'-phenyl-[1,3,5]triazine-2,4-diamine;

N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5'N-triazin-2,4-diamine;

N-Benzyl-N'-cycloheptyl-N"-(4-methoxy-phenyl)-N-methyl-[1,3,5|triazine-2,4,6-triamine;

N-(2-|1,3]Dioxolan-2-yl-ethyl)-N'-methyl-N,-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-|1,3,5-triazine-2,4,6-triamine;

N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-1,3,5"|triazine-2,4,6-triamine.

Because the invention includes compounds that are saturated derivatives of the above general structure, and compounds that include various states of unsaturation (for example, -ene, -diene, -triene, and -yne derivatives of the above compounds), then the aryl or pyridyl ring shown in the above general formula may be partially or fully hydrogenated in this invention. As a result, the C5E ring in the above structure may represent a cyclohexyl or piperidinyl ring that is X<1> or X<2> substituted. In general terms, X<1>is usually, but not always, an electron withdrawing group such as a halide or nitro, while X<2>is usually, but not always, an electron donating group such as an alkoxide or amino.

As indicated in the general structure above, AY<1> and DY<2> typically represent an NR<1> residue (with R<1> as defined above), in which case these substituents constitute part of an amino or substituted amino group and thus the compound itself constitutes a triazine. In this case, Y<1> and Y<2> can be selected from a wide range of substituents, including, but not limited to,

cycloalkyl of up to 10 carbon atoms;

where n is 1 or 2; ; straight-chain or branched alkyl of up to 10 carbon atoms; CH2R<1>; (CHR<1>)XNR<1>2 where x is 1-6; CH2R<1>; CH2R<1>; (CHR<1>)xOR<1>2where x is from 1 to 6; where x is from 3 to 5; CH2CF3; (CHR<1>)XZ<1>wherein x is from 1 to 6 and Z<1>is selected from NR<1>2, wherein y is from 3 to 5, or In these examples, R1 is independently selected as defined above. These are only representative examples of the definitions of Y and Y substituents, and are not intended to be exclusive. It is also noted that AY<1>together and DY<2>together can also represent a wide range of chemical residues attached to the triazine nucleus such as halide or secondary amino groups such as In the latter cases, the amino substituted groups are notional secondary amino groups, yet upon attachment to the triazine nucleus, the amino nitrogens become tertiary amine residues. Examples of AY<1>together and DY<2>together include, but are not limited to: halide; where x is from 3 to 5; where X is from 0 to 6; where Z<2> is selected from R<1>, C(0)R1, C(0)OR1, pyridinyl, aryl,

where x is from 0 to 6, and where R1 is independently selected as

is defined above. These are also only representative examples of the definitions of these substituents, and are not intended to be exclusive.

Representative compounds in accordance with the present invention are shown in Table 1. This table is not intended to be exclusive of the compounds of the present invention, but to exemplify the triazine compounds encompassed by the present invention.

In general terms, compositions according to the present invention also include tris(amino)triazine compounds of the following structure:

wherein Rido R 6 is H, alkyl, aryl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroaryl, halide, alkoxy, aryloxy, alkylthio, arylthio, silyl, siloxy, amino, alkylamino, dialkylamino and the like, including straight-chain or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatoms thereof derivatives, their heterocyclic derivatives, their functionalized derivatives, their salts, their isomers, or their combinations.

For example, a typical substituent of R: to R6 is substituted alkyl, wherein the substituent is a heterocyclic derivative. Examples of nitrogen-retaining heterocyclic moieties include, but are not limited to, groups such as pyridinyl (derived from pyridine, attached via a carbon ring), piperidinyl (derived from either piperidine and attached via a nitrogen atom or ring carbon), and pyrrolidine (derived from pyrrolidine and attached via a nitrogen atom or ring carbon).

Examples of substituted or functionalized derivatives of Rido R6 include, but are not limited to, residues containing substituents such as acyl, formyl, hydroxy, acyl halide, amide, amino, azido, acid, alkoxy, aryloxy, halide, carbonyl, ether, ester, thioether, thioester, nitrile, alkylthio, arylthio, sulfo acid and its salts, thiol, alkenyl, alkynyl, nitro, imine, imide, alkyl, aryl, combinations thereof, and the like. Moreover, in the case of alkylated derivatives of said residues, the alkyl substituent can be a counterpart according to said chemical residue, or used to attach to the amine nitrogen via an alkyl substituent.

Examples of Rido R6 chemical residues of the present invention further include, but are not limited to: H; methyl; ethyl; propyl; butyl; pentyl; hexyl; heptyl; octyl; ethenyl; propenyl; butenyl; ethynyl; propynyl; butynyl; cyclobutyl; cyclopentyl; cyclohexyl; cyclobutenyl; cyclopentenyl; cyclohexenyl; phenyl; tolyl; xylyl; benzyl; naphthyl; pyridinyl; furanyl; tetrahydro-1-naphthyl; piperidinyl; indolyl; indolinyl; pyrrolidinyl; 2-(Methoxymethyl) pyrrolidinyl; piperazinyl; quinolinyl; quinolyl; alkylated-1,3-dioxolane; triazinyl; morpholinyl; phenyl pyrazolyl; indanyl; indonyl pyrazolyl; thiadiazolyl; rhodaninyl; thiolactonyl; dibenzofuranil; benzothiazolyl; homopiperidinyl; thiazolyl; ninonuclidinyl; isoscazolidinonyl; any isomers, derivatives, or substituted analogs thereof; or any substituted or unsubstituted chemical groups such as alcohol, ether, thiol, thioether, tertiary amine, secondary amine, primary amine, ester, thioester, carboxylic acid, diol, diester, acrylic acid, acrylic ester, methionine ethyl ester, benzyl-1-cysteine ethyl ester, imine, aldehyde, ketone, amide, or diene.

Further examples of chemical residues R-i to R6 of the invention include, but are not limited to, the following types or substituted or alkylated derivatives of the following types, covalently attached to the amine nitrogen: furan; tetrahydrofuran; indole; piperazine; pyrrolidine; pyrrolidinone; pyridine; quinoline; anthracene; tetrahydroquinoline; naphthalene; pyrazole; imidazole; thiophene; pyrrolidine; morpholine; and the like. One characteristic of the mentioned species or substituted or alkylated derivatives of these species, is that they can be covalently attached to the amine nitrogen in any way; including via a counterpart substituent or alkyl group, via a heteroatom as appropriate, or via a ring atom as appropriate, as understood by one of ordinary skill in the art.

Chemical moieties R 1 to R 6 of the present invention also include, but are not limited to, cyclic alkanes and alkenes and include bridged and unbridged rings. Examples of displaced rings include, but are not limited to, groups such as norbornyl; norbonadienyl, adamantyl; 6-azabicyclo [3,2,1 Joctanyl; 3-azabicyclo[2,2,2]octanyl, and the like.

In one embodiment of the present invention, NR-|R 2 , NR 3 R 4 , or NR 5 R 6 are derived from a cyclic secondary amine. Examples of the cyclic amino chemical residue of the present invention include, but are not limited to, piperidine; 4-benzyl-piperidine; 3-piperidinemethanol; morpholine; 4-piperidinopiperidine; 1-(2-amino-methyl)-piperazine; decahydroquinoline; 1,2,3,4-tetrahydro-pyridoindole (or amino residue); 3-amino-5-phenyl pyrazole;

3-aminopyrazole; histidinol; hexamethyleneimine; 4-hydroxypiperidine; 2-piperidinemethanol; 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane; 3-pyrrolidinol; 1-methylpiperazine; 2-ethyl-piperidine; 1,2,3,4-tetrahydroisoquinoline; 1,2,3,4-tetrahydroquinoline; 1-(2-methoxyphenyl)piperazine; 2,6-dimethylpiperazine (or amino residue); iminodibenzyl; 5-methoxytryptamine; 4,4'-bipiperidine; 1-(2-hydroxyethyl)piperazine; 4-methylpiperidine; and the like.

Importantly, the general structure of the present invention includes all saturation states of the depicted substituents, such as all ene, diene, triene, and yne derivatives of any substituent. The general structure also includes all conformational isomers, regioisomers, and stereoisomers that may result from a particular set of substituents. The general structure also includes all enantiomers, diastereomers, and other optical isomers in either enantiomeric or racemic forms, or mixtures of stereoisomers.

Preparation of a focused compound library

Many of the compounds of this invention have been prepared in parallel synthetic procedures according to the procedures described below. Examples of compounds prepared via parallel synthesis techniques are given in Table 2. These preparations involve the reaction of individual amine compounds (monomers) with ciyuric acid chloride, which are also presented in Table 2, along with the chemical structures of compounds prepared via parallel synthesis procedures.

A library of compounds was synthesized in accordance with the present invention to provide N<2>,N4,N<6->tris(amino)-1,3,5-triazines, as follows. The design of the compound library is primarily based on the structure 95 shown below. Specifically, the N2,N<4>,N<6->tris(amino)-1,3,5-triazine design is focused so that only one of the counterpart amino groups (N<A>, N<B>, or N<c> in the above structure) changes during each synthesis, while the other two groups remain constant. The combination of specific amines employed produces a library of compounds of new composition. Initially, the library was developed using methyl-(1-methyl-piperidin-4-yl)amine, where the cycloheptyl and m-fluoroanisidyl groups are held constant (in the lower structure 95). Synthesis of triazines around methyl-(1-methyl-piperidin-4-yl)amine is not optimal, and the amine is then replaced by (1-ethyl-pyrrolidin-2-yl)methylamine, which provides a more flexible synthesis.

The N<2>,N<4>,N<6->tris(amino)-1,3,5-triazine library is prepared based on the strategy of changing only one counterpart amino group per synthesis, and based on the parent structure 95 shown above. The library is divided into three subgroups: Libraries I, II, and III (shown in Table 2). Library I includes compounds containing unchanged N<B>and N<c>groups but different N<A>groups (6). The counterpart amino group N<A> is changed according to the specific examples listed below. Library II includes compounds containing unchanged N<a>and N<c>groups but different N<B>groups (7). The counterpart amino group of N<B> is changed according to the specific examples listed below. Library III includes compounds containing unchanged N<A> and N<B> groups but different N<c> groups (8). The corresponding amino group of N<c> is changed according to the specific examples listed below.

The N<2>,N<4>,N<6>-tris(amino)-1,3,5-triazine structures shown in Tables 2 are still generated using ISIS-DrawTM version 2.4.0.20, and are generated with the option to show non-specific hydrogen atoms if not shown, however, not all hydrogen atoms are shown in the given structures. In all structures shown in any text, table, scheme or figure contained herein, any hydrogen atoms required for any atom to achieve its normal valence, whether a carbon atom or a heteroatom, should be included unless specifically indicated in the structure.

One procedure for preparing the compound is shown in the scheme below. The compounds are prepared by reacting ciyuric acid chloride sequentially with monomers of primary or secondary amines to obtain the desired 1,3,5-triazine derivatives [1,2,3,4]. Thus, the starting amine compounds used to react with ciuric acid chloride are called "monomers". N<2>,N<4>,N<6>-tris(amino-substituted)-1,3,5-triazines are prepared without the need for purification between each step of the synthesis, and the final product is isolated by more standard procedures. Purification is achieved using flash chromatography columns as required. It is up to one skilled in the art of organic synthesis to prepare, isolate, and purify the organic compounds described herein, and to modify the synthesis shown. For example, it is possible to synthesize the compounds of the present invention using an excess of any primary or secondary amine monomer if any of the three steps shown in Scheme 1, such as the excess monomer, serve as both a substituent of the triazine core as well as the base, in which case the i-Pr2NEt base can be excluded.

The counterpart amino groups can be substituted with functional groups designated as R-ido R6 groups in Scheme 1. The degree of functionality of the counterpart amino group is determined by the structure and complexity of the amine monomer, and will affect the overall molecular diversity of N<2>,N<4>,N<6->tris(amino-substituted)-1,3,5-triazines. A wide range of amine monomers can be used in this invention. Once attached to the triazine nucleus, the counterpart amino groups can be described as secondarily or tertiary substituted, depending on the degree of nitrogen atom substitution.

Table 2 shows charts of N<2>,N<4>,N<6>-tris(amino)-1,3,5-triazine compounds of Libraries 1-lll of the present invention, each separately, together with amine

precursor monomers used in the preparation of compounds. General procedures and synthetic procedures are detailed in Examples 1-5. The sequence in which each monomer is added in Scheme 1 is also shown in

Table 2, where Monomer 1 is added first, Monomer 2 is added second, and Monomer 3 is added third, is not intended to be easily bound by the following statement, it is believed that this order of addition is significant, because each synthetic stop necessarily involves the reaction of a monomer with a different triazine precursor. Specifically, monomer 1 reacts with ciaric acid chloride, monomer 2 reacts with amino dichloro(triazine), and monomer 3 reacts with diamino chloro(triazine), as shown in Scheme 1. Thus, the order in which the monomers are employed is based on the general synthetic principle that the relative nucleophilicity and/or basicity of monomers 1-3 used in the synthetic scheme should generally increase from monomer 1 to monomer 3. strategy allows the most nucleophilic and/or basic amine monomer to react with the more sterically saturated and presumably less reactive diamino chloro(triazine), where greater reactivity may help drive the reaction to completion. In some cases, more than one order of monomer addition will provide the desired product, but the reaction sequences given in Table 2 represent the optimal synthetic procedures currently known.

It should be noted that only in a general sense the substituents indicated as N<A>, N<B>, and N<c> in the general structures above correspond to the actual N<2>,N<4>,N<6->nomenclature N<2>,N<4>,N<6>-tris(amino)-1,3,5-triazine. Because the order in which the N<2>, N<4>, and N<6> substituents are placed at the 2-, 4-, or 6-position of the triazine nucleus depends on the name of each amino group in the molecule, it is not always true that a particular amino group appears as an N<2>, N<4>, or N<6> substituent, even when only one substituent is permuted at one position. For example, many of the compounds in Table 2 contain both cycloheptyl amino and 3-fluoro-4-methoxyphenyl amino groups, yet these groups occupy different 2-, 4-, or 6-positions as a function of the name of the third substituent on the triazine ring. As a result, in the above structure, the synthesis is considered in terms of permuting the amino groups at one counterpart N<A>, N<B>, or N<c>-position (rather than the N<2>, N<4>, or N<6>-position), while keeping the other amino groups constant. Further, it should be noted that compound names used in the Table, Claims, and Description are typically determined using Beilstein's Atonom™ 4.01.188, as well as the earlier CD stand-alone version of Beilstein's Autonom™, Autonom 2000. Typically, names generated in this manner are used, regardless of whether the compound name is IUPAC, CAS, Beilstein, or other nomenclature. Yet in each case, the names unambiguously identify the specified compound.

A. Amino groups derived from Monomer 1

The reaction sequence of monomers with the triazine core, shown in Scheme 1, is Monomer 1, Monomer 2, and Monomer 3, added in that order. Thus, amino dichloro(triazine) is formed from Monomer 1 and ciuric acid chloride. For the first counterpart amino group derived from Monomer 1 and ciyuric acid chloride, Monomer 1 amine used and suggested includes primarily, but not always, aryl amines, specifically phenyl, naphthyl, naphthylalkyl, quinolinyl, heteroaryl derivatives, and the like.

Specific examples of Monomer 1 used to produce the first counterpart amino group of uN<2>,N4,N<6->tris(amino)-1,3,5-triazines, and their [Chemical Abstract Registry numbers] include, but are not limited to, 4-chloroaniline [106-47-9], 3,4-ethylenedioxaniline [22013-33-8], 4-47 bromoaniline [106-40-1], ethyl 4-aminobenzoate [94-09-7], 4-fluoro-aniline [371-40-4], 4-aminobiphenyl [92-67-1], 3-fluoroaniline [372-19-0], 2-aminonaphthalene [91-59-8], 3-chloroaniline [108-42-9], 4-morpholinoaniline [2524-67-6], 3-bromoaniline [591-19-5], 4'-aminoacetanilide [122-80-5], ethyl 3-aminobenzoate [582-33-2], m-aminoacetanilide [102-28-3], 2-fluoroaniline [348-54-9], m-anisidine [536-90-3], 2-chloroaniline [95-51-2], p-phenetidine [156-43-4], 2-bromoaniline [615-36-1], 4-(methylthio)aniline [104-96-1], 3,4-(methylenedioxy)aniline [14268-66-7], 2-aminopyridine [504-29-0], o-toluidine [95-53-4], 2,4-difluoro-N-methylaniline [138564-16-6], 4-phenoxyaniline [139-59-3], /V-phenylglycinonitrile [3009-97-0], m-toluidine [108-44-1], 3-chloro-N-methylaniline [7006-52-2], p-toluidine [106-49-0], 2-(methylamino)benzotrifluoride. 4-chloro-N-methylaniline [932-96-7], 4-aminobenzonitrile [873-74-5], 3-anilinopropionitrile, [1075-76-9], tetracaine [94-24-6], /V-methyl-p-anisidine [5961-59-1], 3-chloro-p-anisidine [5345-54-0], sulfabenzamide [127-71-9], 3-aminoquinoline [580117-6], 1-amino-4-bromonaphthalene [2298-07-9], 6-aminoquinoline [580-15-4] 1-amino-4-chloronaphthalene, [4684-12-2] 8-aminoquinoline [578-66-5], S-(-)-1-(2-naphthyl)-ethylamine [3082-62-0], 3,4-dichloroaniline [95-76-1], 3,4-difluoroaniline [3863-11-4], N-methyl-4-(trifluoromethoxy)aniline [41419-59-4], 4-(trifluoromethoxy)aniline [461-82-5], 2-amino-4-methylthiophene-3-carboxamide. [4651-97-2], A/,/V-diethyl-A/'-phenethylenediamine [1665-59-4], 1-(4-amino-phenyl)-4-methylpiperazine hydrochloride [94520-33-9], 2-chloro-A/',A/'-diethyl-1,3-phenylenediamine monohydrochloride [196938-07-5] 2-(dimethylamino)ethyl 4-aminobenzoate [11012-47-2], A/,A/-dimethyl-1,4-phenylenediamine [1665-95-4].

B. Amino groups derived from Monomer 2

The reaction of Monomer 2 with previously formed amino dichloro(triazine) provides intermediate diamino chloro(triazine) in the synthesis of N<2>,N4,N<6->tris(amino)-1,3,5-triazine. Thus, for attachment of the second counterpart amino group to the triazine nucleus, Monomer 2 amine that is used and suggested includes amines, specifically alkyl (CrC12, with a chain in normal sequence or branched), cycloalkyl (C3-C10 ring size), azacyclo (C2-C10), and benzyl amine derivatives. The cycloalkyl and azacycloamine ring, and the phenyl ring of the benzyl derivative may be optionally substituted with one or more residues, or a combination of residues, such as, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfoacid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, phosphonate, and the like. These groups can be presented in the protected or unprotected form used in standard organic synthesis.

Additionally, any described monomer having a stereocenter includes its enantiomers, diastereomers, and optical isomers in either enantiomeric or racemic forms, or mixtures of stereoisomers. This includes all 1,3,5-triazine derivatives and their stereoisomers presented herein which are formed as a result of the use of optically active, scalemic or racemic monomers.

Specific examples of Monomer 2 used to attach the other counterpart amino group in the synthesis of N<2>,N<4>,N<6->tris(amino-substituted)-1,3,5-triazines, and their corresponding [Chemical Abstract Registry numbers]

include, but are not limited to, ethylamine [75-04-07], cyclohexanemethylamine [3128-02-8] tert-butylamine [75-64-9], furfurylamine [617-89-0], benzylamine [100-46-9], 2,2,2-trifluoroethylamine [753-90-2], cyclooctylamine [5452-37-9], A/,A/-dimethylethylenediamine cyclohexylamine [108-91-8], cyclopentylamine

[1003-03-8], 1-(2-aminoethyl)-piperidine [26116-12-1], 1-acetylpiperazine [13096-96-3], pyrrolidine [123-75-1], 1-piperonylpiperazine [32231-06-4], hexamethyleneimine [111-49-9], 1-(2-pyridyl)piperazine. [34803-66-2], decahydroquinoline (cis/trans) [2051-28-7], 1-methylpiperazine [109-01-3], 1-(3-aminopropyl)-imidazole [5036-48-6], ethyl 1-piperazine carboxylate [120-43-4], 4-methylcyclohexylamine (cis/trans) [6321-23-9], 1-(3-aminopropyl)-2-pyrrolidine [7663-77-6], 2-(aminomethyl)-ethyl-pyrrolidine [26116-12-1], (+?-S-2-(methoxymethyl)pyrrolidine [63126-47-6], 1 -(pyrrolidineocarbonylmethyl)piperazine [33890-45-4].

C Amino groups derived from Monomer 3

The reaction of Monomer 3 with previously formed diamino gholo(triazine) provides the final step in the synthesis of N<2>,N4,N<6->tris(amino-substituted)-1,3,5-triazine. Thus, for the attachment of the third counterpart amino group to the triazine core, Monomer 3 that is used and proposed contains amines, specifically alkyl (CrC12, with a chain in a normal sequence or branched), cycloalkyl (C3-C10 ring size), azacyclo (C2-C10), and benzyl amine derivatives. The ring of these cycloalkyl- and azacycloamine, and the phenyl ring of the benzyl derivatives may be optionally substituted with one or more residues, or a combination of residues, such as, alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkylamino, arylamino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfoacid, morpholino, thiomorpholino, piperazinyl, pyridyl, thienyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, phosphonate, and the like.

Additionally, any described monomer having a stereocenter includes its enantiomers, diastereomers, and optical isomers in either enantiomeric or racemic forms, or mixtures of stereoisomers. This includes all 1,3,5-triazine derivatives and their stereoisomers presented herein that are formed as a result of the use of optically active, scalel or racemic monomers.

Specific examples of Monomer 3 used to attach the second counterpart amino group in the synthesis of N2,N<4>,N<6->tris(amino-substituted)-1,3,5-triazines, and their corresponding [Chemical Abstract Registry numbers] used in the synthesis of N2,N<4>,N<6->tris(amino-substituted)-1,3,5-triazine derivatives include, but are not limited to, ethylamine [75-04-07], cyclohexanemethylamine [3128-02-08], tert-butylamine [75-64-9], furfurylamine [617-89-0], benzylamine [100-46-9], 2,2,2-trifluoroethylamine [753-90-2], cyclooctylamine [5452-37-9], A/,A/-dimethylethylenediamine cyclohexylamine [108-91-8], cyclopentylamine [1003-03-8], 1-(2-aminoethyl)-piperidine [26116-12-1], 1-acetylpiperazine [13096-96-3], pyrrolidine [123-75-1], 1-piperonylpiperazine [32231-06-4], hexamethyleneimine [111-49-9], 1-(2-pyridyl)piperazine [34803-66-2], decahydroquinoline (cis/trans) [2051-28-7], 1-methylpiperazine [109-01-3], 1-(3-aminopropyl)-imidazole [5036-48-6], ethyl 1-piperazine carboxylate [120-43-4], 4-methylcyclohexylamine (cis/trans)

[6321-23-9], 1-(3-aminopropyl)-2-pyrrolidine [7663-77-6], 2-(aminomethyl)-

ethyl-pyrrolidine [26116-12-1], (+?-S-2-(methoxymethyl)pyrrolidine [63126-47-6], 1-(pyrrolidineocarbonylmethyl)piperazine [33890-45-4].

In addition to the parallel synthetic procedures used to prepare the compounds of Table 2, Table 1 also provides other exemplary triazine compounds of the present invention, which are synthesized individually rather than using parallel synthesis. The complete preparation and properties of the compounds are presented in the Examples, where details of the synthetic procedures are given. Synthetic procedures for these compounds include the substitution of chloride groups on ciyuric acid chloride, as well as various chemical modifications of these groups when attached to the triazine nucleus. In particular, this invention also includes the salts of neutral triazine compounds, as given in the examples and tables.

In another aspect of the present invention, the compounds of the present invention include, but are not limited to, those having the following formula:

or an ene, diene, triene, or yne derivative thereof, a saturated derivative thereof, a stereoisomer thereof; or its salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from m-F, m-Cl, m-Br, m-CN, m-NO2, m-SO2R<1>, or im-SO2OR\or X<1> and X<2> are fused together a benzene, pyridine, or dioxane ring; X<2>is selected from p-OR1, p-SR<1>, p-NR<1>2,<p->OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; in the normal chain or branched alkyl of up to 10 carbon atoms; CH2R<2>, wherein R<2> is cycloalkyl with up to 10 carbon atoms; or where n is 1 or 2; AY<2>is selected from halogen or OR<1>, or A is NR1 and Y2 is selected from R1,

Compositions containing compounds of this formula are also encompassed by the present invention, as are mixtures and combinations of compounds of this formula.

In a further aspect of the present invention, the compounds of the present invention include, but are not limited to, those having the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms;

E is CH or N;

n is an integer from 0 to 3;

X<1> is selected from -H,m- F,m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, or X<1>and X<2> are fused together a benzene or pyridine ring;

X2 is selected from -H, o-CI, o-Br, p-OR<1>, p-SR<1>, p-NR<1>2, p-Cl p-Br, p-CF3, p-C(0)OR<1>, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca;

A is selected from NR<1> or O, wherein Y<1> is selected from cycloalkyl of up to 10 carbon atoms, with a normal chain or branched alkyl of up to 10 carbon atoms, or

when A is NR<1>, and wherein Y<1>is selected from R<1>or CH2R<1>when A is O; or AY<1>is selected from halogen, DY<2>is halogen, or D is NR<1>and Y<2>is selected from

or (CHR<1>)XNR<1>2, where x is an integer from 1 to 6.

Compositions containing compounds of this formula are also encompassed by the present invention, as are mixtures and combinations of compounds of this formula.

In yet another aspect of the present invention, the compounds of the present invention include, but are not limited to, those having the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; arilla; or (CH2)XCN, where x is an integer from 0 to 6; Eje CH or N; n is an integer from 0 to 3; X<1>is selected from -H,m- F,m- C\, m-Br,m- J,m- CN, m-NO2, m-SO2R<1>, or m-SO2OR1, m-NC(0)R<1>, or o-F, or X<1>and X<2> are fused together with a benzene, pyridine, or dioxane ring; X2 is selected from -H, o-CI, o-Br, o-CF3, o-R<1>, p-OR<1>, p-SR<1>, p-NR<1>2,<p->F, p-CI p-Br, p-CF3, p-CN, p-C(0)OR<1>, p-NC(0)R<1>, p-(4-morpholinyl), or p-(4-methyl-1-piperidinyl); AY<1>is halogen, or A is NR<1>or O and Y<1>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, (CHR<1>)yOR<1>, where y is an integer from 1 to 6, or AY<1>together

where x is an integer

from 3 to 5; and

DY<2>is halogen, or D is NR<1>and Y<2>is selected from

cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, wherein x is an integer from 3 to 5, CH2CF3, (CHR<1>)ZZ<1>, wherein z is an integer from 1 to 6, and Z1 is selected from NR<1>2, where wherein x is an integer from 3 to 5, or NY2R1 is collectively selected from wherein Z2 is selected from R<1>, C(0)R<1>, C(0)OR<1>, pyridinyl, aryl, or

where q is an integer from 0 to 6.

Compositions containing compounds of this formula are also encompassed by the present invention, as are mixtures and combinations of compounds of this formula.

Included as a further aspect of the present invention are the compounds of the present invention which include, but are not limited to, those having the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from H, m-F, m-C1, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>; X<2>is selected from o-R<1>, p-OR<1>, p-SR<1>, p-NR<1>2,<p>-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms or Y2 is selected from straight-chain or branched alkyl of up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms, or and R 2 is -H; or NY2R2 are jointly selected from where x is an integer number from 3 to 5, where q is an integer from 0 to 6, or wherein Z2 is selected from R<1>or

Compositions containing compounds of this formula are also encompassed by the present invention, as are mixtures and combinations of compounds of this formula.

In yet another aspect of the present invention, the compounds of the present invention include, but are not limited to, those having the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms;

X<1> is at each occurrence independently selected from -H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>;

X<2> is at each occurrence independently selected from o-CH3, p-OR<1>, p-SR<1>, p-NR<1>2, or p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca;

Y<1> is selected from cycloalkyl with up to 10 alkyl atoms:

where n is 1 or 2; or Y2 is selected from

Compositions containing compounds of this formula are also encompassed by the present invention, as are mixtures and combinations of compounds of this formula.

These compounds and compositions presented above are not intended to be limiting, but merely representative of the chemical structures and formulas encompassed by the present invention.

Pharmaceutically acceptable salts

For the proposed N<2>,N<4>,N<6->tris(amino-substituted)-1,3,5-triazines, the terms "non-toxic, pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt or complex of a 1,3,5-triazine compound that retains or enhances the biological activity of the compounds described herein. Examples of salts are those derived from the interaction of 1,3,5-triazine compounds or derivatives and inorganic (mineral) acids or organic acids, as well as compounds derived from the deprotonation of the amine nitrogen of triamine derivatives.

Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, nitric acid, perchloric acid, chloric acid, hypochlorous acid, perchloric acid, phosphoric acid, sulfuric acid, sulfuric acid, and carbonic acid. Examples of organic acids include, but are not limited to, acetic acid, benzene sulfonic acid, benzoic acid, butyric acid, camphorsulfonic acid, citric acid, ethane sulfonic acid, fumaric acid, glutaric acid, 2-hydroxyacetic acid (derivatives where the alkyl group is c=3-7 and the hydroxy group is located accordingly), 2-hydroxy sulfoacids (derivatives where the alkyl group is c=3-7 and the hydroxy group is located accordingly), lactic acid, maleic acid, malic acid, methane sulfoacid, naphthalene sulfoacid, oxalic acid, palmitic acid, propionic acid, phthalic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid acid, p-toluene sulfonic acid, and amino acids (eg, alanine, N-acetylglycine, arganine, aspartic acid, glutamic acid, glycine, lysine, and phenylalanine).

Examples of salts described herein include compounds derived from the deprotonation reaction of the amine nitrogen of a triamine derivative with a strong base to form an amido salt, compound, or complex. For example, these compounds include those derived from the interaction or chemical reaction of a 1,3,5-triazine compound or derivative that behaves as a Bronsted or Lewis acid in an inorganic or organic base to form ionic and/or complex species. Examples of inorganic bases include, but are not limited to, metal bases or organometallic bases such as alkyllithiums or metal hydrides, wherein the metal counter ion includes, but is not limited to, aluminum, barium, calcium, lithium, magnesium, potassium, sodium, and zinc.

Examples of organic bases include, but are not limited to, alkyl and aryl amines as well as ammonia. Included in this description are salts formed from the combination or interaction of inorganic acids (eg, Lewis acids) and metal counterions and 1,3,4-triazine compounds or derivatives that act as Bronsted or Lewis bases resulting in the formation of ionic and/or complex species. All salts and complexes as described above are intended to include hydrated or solvated forms of the compound.

Additionally, this invention also includes salts of those triazine derivatives which are non-toxic and pharmaceutically acceptable, such as quaternary ammonium salts, for example, [N<+>R2R']X~, wherein the R and R' groups represent hydrogen or an organic group (such as alkyl, alkenyl, alkynyl, aryl, and the like) and the X group is a counter ion (halogen, hydroxide, alkoxide, thioalkoxide, or conjugate base of an organic or inorganic salt). All salts and complexes as described above are intended to include hydrated or solvated forms of the compound.

II. ANTI-PROLIFERATIVE ACTIVITIES

One embodiment of the present invention includes methods and compositions comprising the compounds of the present invention for the treatment and prevention of conditions or diseases that have as an aspect of the disease or condition, unwanted cell proliferation or result from cell proliferation. For example, many vascular diseases, such as cardiovascular diseases, organ transplants, vascular occlusive conditions including, but not limited to, neointimal hyperplasia, restenosis, transplant vasculopathy, cardiac allograft vasculopathy, atherosclerosis, arteriosclerosis, are caused or have collateral damage due to unwanted cell proliferation. Smooth muscle cell (SMC) hyperplasia is a major event in the development of atherosclerosis and is also responsible for a significant number of failures following vascular procedures such as angioplasty and coronary artery bypass graft surgery, particularly due to restenosis. Proliferation of arterial wall SMCs in response to local injury is a major feature of many vasculoma proliferative disorders. Neointimal hyperplasia is commonly seen after various forms of vascular injury and is a major component of the venous graft response to yield and surgical implantation in the high-pressure arterial circulation. SMC proliferation in response to local injury is a major feature of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty.

One aspect of the present invention relates to methods and compositions for the treatment and prevention of smooth muscle cell (SMC) proliferation, purportedly comprising compositions and compounds having cellular antiproliferative activity. These compounds and compositions containing such compounds are considered antiproliferative compounds and compositions. At least one activity of one or more of these compounds is that the compound has the activity of effecting proteoglycan synthesis including the induction and synthesis of proteoglycans and active proteoglycan fragments. Thus, one aspect of the activity of one or more compounds and compositions of the present invention comprises molecules that induce HSPG production and that regulate SMC (smooth muscle cell) proliferation.

Compounds of the present invention having at least cell proliferation activity are shown in TABLE 3. The compounds shown in this Table have cell proliferation activity as measured by the assays included herein. Inclusion of compounds in the Table categories disclosed herein should not be construed as limiting, in that compounds included in the Tables have at least the activity shown for inclusion in the Table and may have more or other activities. The tables should not be seen as limiting in that only the compounds published in them have that activity, but representative compounds are shown in the Tables that have at least that certain activity that is why they are included in the Table. One or more compounds disclosed herein have at least activity useful in the treatment of a disease state.

Examples of compounds that exhibit at least this activity and utility are shown in the following structure:

or an ene, diene, triene, or yne derivative thereof, a saturated derivative thereof, a stereoisomer thereof; or its salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from m-F, m-Cl, m-Br, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR1, or X<1> and X<2> are fused together a benzene, pyridine, or dioxane ring; X<2>is selected from p-OR<1>, p-SR<1>, p-NR<1>2,<p->OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; in the normal chain or branched alkyl of up to 10 carbon atoms; CH2R<2>, wherein R<2> is cycloalkyl with up to 10 carbon atoms; or .where n is 1 or 2; AY2 is selected from halogen or OR1, or A is NR<1> and Y2 is selected from R<1>,

Further examples of compounds exhibiting at least this activity and utility are shown in Table 3, where the activity of the compounds is also shown. The activity hall used in Table 3 is as follows (numbers included): "+++" represents an IC50 of less than about 3 µM; "++" represents an IC50 between about 3 and about 7 µM; and "<+>" represents an IC50 of greater than about 7 µM. Further, any hydrogen atoms required for any atom to achieve its usual valence in the structure shown in Table 3, whether a carbon atom or a heteroatom, should be included unless specifically indicated.

In addition to the above compounds, the following compounds and compositions containing these compounds are active in the anti-proliferation assay (Perlecan). These compounds and compositions containing these compounds are, among other things, generally useful for the treatment of cardiovascular disorders associated with proliferative activity. Specifically, these compounds include N<2->cycloheptyl-N<4->(3-fluoro-4-methoxypheny)-N<6->methyl-N<6->(1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, and N<2->cycloheptyl-N<4->methyl-N<4->(1-methyl-piperidin-4-yl)-N<6->naphthalen-2-yl-1,3,5-triazin-2,4,6-triamine. Using the same activity scale used in Table 3, and discussed above, the first compound, N2-cycloheptyl-N4-(3-fluoro-4-methoxypheny)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, is characterized as showing moderate to mild activity, while the second compound, N<2->cycloheptyl-N<4->methyl-N<4->(1-methyl-piperidin-4-yl)-N<6->naphthalen-2-yl-1,3,5-triazin-2,4,6-triamine, is characterized as a compound showing high activity.

As used herein, when reference is made to a proteoglycan, the entire molecule or fragments are included. Different perlecan fragments can have the same or different effects on cells and the effects can be the same as or different from the effects that the whole perlecan molecule has on cells. N<2->cycloheptyl-N<4->methyl-N^Cl-methyl-piperidin^-iO-N^naphthalene^-yl-I.S.S-triazine^^^-triamine. These fragments and activities are contemplated in the present invention and the compounds included in the present invention may have at least one activity that modulates or affects the activities of the fragments or the activities of the entire molecule, while the discussion herein relates specifically to perlecans it is important to note that the compositions, methods, and assays described herein are equally applicable in the context of other proteoglycans, including HSPGs, and including but not limited to, chondroitin sulfates (e.g., A, B, and C), dermatan sulfates, syndecans and glypicans.

Methods for identifying activity and screening for one or more of these compounds or molecules that induce the synthesis of proteoglycans such as HSPG (heparan sulfate proteoglycan) have been studied in U.S. Pat. Patent application no. 10/091,357, which are incorporated herein in their entirety. Examples of the in vivo effects of the compounds are also discussed in the incorporated references and known to those skilled in the art. In general, the methods include adding such compounds to assays and measurements of HSPG synthesis including, but not limited to, production of syndecans, glypicans, and perlecans, for example, syndecans 1, 2, and 4; and glypican-1. Other assays used to determine the activity of compounds of the present invention include other methods for measuring the induction of perlecan synthesis. For example, in one experiment, perlecan was induced in cells by certain inducers, and the response was measured. Compounds of the present invention are then added to a replicate trial and the effect on perlecan induction is determined. Using such procedures, compounds are determined to either inhibit perlecan, enhance perlecan induction, or have no effect. These compounds are effective as therapeutic agents that can be used in animals, humans, and patients with aspects of cell proliferative diseases, such as vascular-related diseases or SMC proliferative pathologies.

A further assay for identifying compounds that have SMC effects consists of adding a compound suspected of having an effect on SMC proliferation in smooth muscle cells to growth medium or serum-free medium. The change in proliferation can be measured by methods known to those skilled in the art, such as incorporation of labeled nucleotides into dividing cellular DNA, and compared to the proliferation of cells not treated with the compound. Other measurements include directly determining the level of HSPG synthesis by measuring the amount or change in the amount of HSPG such as with an ELISA for HSPGs, and comparing the amount of HSPG synthesis in untreated cells. Other indirect or direct measurements are contemplated by the present invention and are known to those skilled in the art. For example, such procedures include, but are not limited to, measurements of RNA levels, RT-PCR, Northern blotting, promoter-based Western blotting assays to identify compounds that may affect one or more proteoglycans, and assays for the biological activity of proteoglycans using recombinant proteins, partially purified proteins, or lysates from cells expressing proteoglycans in the presence or absence of the compound of interest.

An experiment to identify and determine the activity of one or more compounds of the present invention consists of identifying compounds that interact with gene promoter regions, or interact and act on proteins that interact with the promoter region, and which are important in the transcriptional regulation of protein expression. For example, if perlecan is a protein, generally the method consists of a vector containing regulatory sequences of the perlecan gene and an indicator region controlled by regulatory sequences, such as enzymes, in a promoter-reporter construct. The indicator region protein product here refers to a reporter enzyme or reporter protein. The regulatory region of the perlecan sequence comprises a range of nucleotides from approximately -4000 to +2000 where the transcription initiation position is +1, preferably from -25000 to +1200, most preferably from -1500 to +800 depending on the transcription initiation position.

Cells are transformed by infection with a vector containing a promoter-reporter construct and then treated with one or more compositions containing at least one compound of the present invention. For example, cells altered by infection are treated with a composition containing a compound believed to affect perlecan transcription and the level of activity of perlecan regulatory sequences is compared to the level of activity in cells not treated with the compound. The level of activity of the perlecan regulatory sequences is determined by measuring the amount of reporter protein or by determining the activity of the reporter enzyme that is controlled by the regulatory sequences. An increase in the amount of reporter protein or reporter enzyme activity shows a stimulating effect on perlecan, through a positive effect on the promoter, while a decrease in the amount of reporter protein or reporter enzyme activity indicates a negative effect on the promoter and thus, on perlecan.

Additionally, the present invention comprises methods and compositions that can be used in gene therapy methods and compositions, such as those gene therapy methods that consist of administering a composition that

'R1CK- How does this apply to this invention-compounds that treat disease? There is no discussion or support that altered gene infection affects HSPG synthesis. Should we remove this paragraph and leave it to the report we refer to (1863 1-0141).

contains nucleic acids that affect the synthesis or expression of HSPGs, especially perlecan. Such processes and compositions have been studied in U.S. Pat.

Patent application no. 10/091,357, are incorporated herein by reference.<1>

The present invention includes methods and compositions for mediating the synthesis and expression of proteoglycans, and for maintaining SMCs in a quiescent state. The methods and compositions of the present invention include the treatment and prevention of vascular diseases and pathologies related to cell proliferation, such as SMC proliferation. Such methods and compositions include methods for inhibiting smooth muscle cell (SMC) growth and proliferation, and for inducing quiescence in smooth muscle cells. Embodiments of the present invention comprise methods and compositions for inducing proethoglycan synthesis, particularly HSPG synthesis and expression including, but not limited to, induction of HSPGs such as syndecans, glypicans and perlecans, and presumably perlecan synthesis and gene expression. Perlecan is the major extracellular HSPG in the blood vessel matrix. It interacts with extracellular matrix proteins, growth factors and receptors. Perlecan is also present in non-vascular basement membranes and other extracellular matrix structures.

The activities of the compounds included in the present invention act on cells and tissues to increase the synthesis of proteoglycans of those cells and tissues or can modulate the biological activity of one or more proteoglycans or increase the biological stability of the proteoglycan itself, for example, the perlecan protein. Activities also included herein are those that increase the biosynthesis of one or more proteoglycans by increasing the transcription of a proteoglycan gene, increasing the biological stability of a proteoglycan mRNA, or increasing the translation of a proteoglycan mRNA into protein. Further activities include the activities of compounds that can block or reduce the effects of agents or proteins that inhibit proteoglycan activity.

The present invention includes methods and compositions for the treatment and prevention of smooth muscle cell proliferation, including vascular occlusive pathologies. Such methods comprise administering a composition comprising compounds capable of inhibiting SMC proliferation, such as compositions comprising the compounds disclosed herein that inhibit SMC proliferation. Administration of such compounds effective in inhibiting SMC proliferation is administration to humans and animals suspected of having or having, for example, vasculopathy or having undergone angioplasty or other procedures that damage the endothelium. Effective amounts are administered to such humans or animals at doses that are safe and effective, including, but not limited to, the ranges studied herein. Routes of administration include, but are not limited to, those disclosed herein. As disclosed herein, compositions comprising such compounds may be used in conjunction with other therapeutic agents or in procedures comprising steps such as altered patient activity, including, but not limited to, changes in exercise or diet.

The compounds of the present invention are useful in the treatment or prophylaxis of at least one cardiovascular disease in a cell, tissue, organ, animal or patient including, but not limited to, vascular occlusive disease including atherosclerosis, transplant vasculopathy, cardiac allograft vasculopathy, restenosis, post-heart transplant graft atherosclerosis, cardiac arrest syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic arteriosclerotic disease, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system, cardiac arrest, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic heartbeats, atrial outflow, atrial fibrillation (delayed or paroxysmal), post perfusion syndrome, cardiopulmonary bypass as response to inflammation, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrhythmias, ventricular fibrillation, His driven arrhythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, heart artery disease, angina pectoris, myocardial infarction, cardiomyopathy, valvular heart disease, endocarditis, pericardial disease, cardiac tumors, aortic and peripheral aneurysms, aortic dissection, inflammation of the aorta, occlusion of the abdominal aorta and its branches, peripheral vascular disorders, occlusive arterial disorders, peripheral atherosclerotic disorders, thromboangitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphoderma, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury, and the like. Such methods may optionally comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one compound to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.

Proteoglycan-related diseases that can be treated with the compounds of the present invention include, but are not limited to, hereditary multiple escostosis, mucopolysaccharidosis types l-lll and VII, commonly known as Hurler's syndrome, Hunter's syndrome, Sanfillipo's syndrome and Sly's syndrome each separately, Alzheimer's disease, Simpson-Golabi-Gehmel syndrome, fibroblast growth factor-related disorders, herpes simplex virus, dengue fever, Parkinson's disease, renal disease, muscular dystrophy, Scharts-Jampel syndrome, proteinuric glomerulopathies, myotonia and skeletal dysplasia, kyposcoliosis, dissegmental dysplasia, Silverman-Handmaker type, chondrodysplasia, periodontitis, rheumatoid and osteoarthritis, Gerstmann-Straussler syndrome, Creutzfeldt-Jakob disease, scrapie, cancers, Happle syndrome, macular dystrophy, bone diseases, corneal diseases, mediated disease leukocyte, a disorder of collagen fibril collection and coronary heart disease and other vascular disorders.

IV. Glycosidase modulation activity

The present invention also comprises methods and compositions comprising the compounds described herein that have activity associated with modulation of glycoidase enzymes and, in particular, actions on substrates for such enzymes. Glycosidase enzymes and their activity with their substrates, such as proteoglycans or glycated proteins, are aspects of various diseases such as vascular conditions, including conditions discussed supra, proteoglycan-related diseases, supra, diseases associated with vascular components, including but not limited to, kidney disease, ischemic heart disease, cardiovascular disease, general vascular disease, proliferative retinopathy, and macroangiopathy, inflammatory and metastatic diseases such as cancer, cell proliferative conditions, both solid and blood-born tumors or other oncological conditions. The compounds described herein which have activity that affects glycosidase enzyme substrate concentrations are used in methods of treating such vasculoma, inflammatory, metastatic and systemic diseases.

An aspect of the present invention comprises methods and compositions for modulating enzymes, such as glycosaminoglycan-degrading enzymes, that act on or are affected by proteoglycan levels, amount, and activity. For example, the present invention comprises methods and compositions comprising compounds that modulate enzymes including, but not limited to, heparanase, chondroitanase, heparan sulfate endoglycosidase, heparan sulfate exoglycosidase, polysaccharide lyase, keratinase, hyauronidase, glucanase, amylase, glycosidase, or other proteoglycan-degrading enzymes and are useful for treating conditions such as diabetic vasculopathy, cancer, inflammatory diseases, autoimmune diseases and cardiovascular diseases. For example, the present invention comprises methods and compositions of compounds that inhibit, impair, or down-regulate the activity of proteoglycan-degrading enzymes.

Proteoglycans such as HSPGs are important components of the subendothelial extracellular matrix, which is composed of collagenous and non-collagenous proteins and proteoglycans that separate parenchymal cells from the underlying interstitial connective tissue. They have the characteristic of permeability and play a role in maintaining tissue architecture.

In addition to HSPGs, the basal lamina consists predominantly of a complex matrix of adhesion proteins, fibronectin, laminin, collagen and vitronectin. Wight et al., 6 Curr. Opin. Lipidol. 326-334

(1995). Heparan sulfate (HS) is an important structural component of the basal lamina. Each of the adhesion proteins interacts with the HS side chains of HSPGs within the matrix. Thus, HSPGs function as a barrier against the shedding of metastatic and inflammatory cells. Cleavage of HS by the endoglycosidase heparanase produced by metastatic tumor cells and inflammatory cells destroys the filtering properties of the lamina. Additionally, degradation of HS may help break down the extracellular matrix and thus help by allowing blood-born cells to escape into the bloodstream. Vlodavskv et al., 12 Invasion Metastasis 112-127 (1992).

Heparanase activity has been described in numerous tissue and cell types

including liver, placenta, platelets, fibroblasts, neutrophils, activated T and B-lymphocytes, monocytes, and endothelial cells (6-16). Nakajima et al., (31) Cancer Lett. 277-283 (1986); Nakajima et al., 36 J. Cell. Biochem. 157-167 (1988); Ricoveri et al., 46 Cancer Res. 3855-3861 (1986); Gallagher et al., 250 Biochem. J. 719-726 (1988); Dempsey et al., 10 Glycobiology 467 (2000); Goshen et al., 2 Mol. Hum. Reprod. 679

(1996); Parish et al., 76 Immunol Cell Biol. 104-113 (1998); Gilat et al., 181 J. Exp. Med. 1929-1934 (1995); Graham, et al., 39 Biochem. Mol. Biol. Int. 56371 (1996); Pillahsetti et al., 270 J. Biol. Chem. 29760-29765 (1995). An important process in tissue invasion by blood-born tumor cells and white cells involves their passage through the layers of vascular endothelial cells and subsequent degradation of the underlying basal lamina or lower membranes and extracellular matrix with a battery of secreted proteases and glycosidases. Nakajinia et al., 220 Science 611-613 (1983); Vlodavsky et al., 12 Invasion Metastasis 112-127 (1992).

Hyperanase activity has been shown to correlate with the metastatic potential of animal or human tumor cell lines. Nakajima et al., (31) Cancer Lett. 277-283 (1986); Nakajima et al., 212 Prog Clin Biol Res. 113-122 (1986); Freeman et al., 325 Biochem. J. 229-237 (1997); Vlodavsky et al., 5 Nat. Med. 793-802 (1999); Hulett et al., 5 Nat Med. 803-809 (1999). It is also known to regulate growth factor activity. Many growth factors remain bound to heparan sulfate in a stored form and are cleaved by heparanase during angiogenesis, improving the survival rate of cancer cells.

Serum levels of heparanase in rats are much higher than when boosted after injection into rats of highly metastatic mammary adenocarcinoma cells. Additionally, heparanase activity in rats bearing MTLn3 tumors correlated well with the size of the metastasis. Moreover, serum/urine heparanase activity in cancer patients shows a 2-4 fold increase especially where tissue metastases are present. Because HS cleavage appears to provide the basis for the passage of metastatic tumor cells and leukocytes across basement membranes, studies of heparanase inhibitors provide the potential for the development of a new and highly selective class of anti-metastatic and anti-inflammatory drugs.

The present invention consists of methods and compositions containing compounds that modulate the activity of heparanase or the activity of other glycosidases, including but not limited to enzymes with glycosaminoglycan activity such as chondroitinase, heparan sulfate endoglycosidase, heparan sulfate exoglycosidase, polysaccharide lyase, keratianase, hyaluranidase, glucanase, and amylase. Compounds of the present invention that have at least glycosidase enzyme activity modulating activity are listed in TABLE 6. The compounds shown in this Table have glycosidase enzyme activity modulating activity as measured by the assays studied herein. Inclusion of compounds in the Table categories disclosed herein should not be construed as limiting, in that compounds included in such Tables have at least the activity shown for inclusion in the Table and may have multiple or other activities. The Tables should not be viewed as limiting in that only compounds having activity are provided herein, and which representative compounds shown in the Tables have at least some activity for inclusion in the Table. One or more compounds disclosed herein have at least an activity useful in the treatment of a disease state.

Examples of compounds that show at least this activity and utility are shown by the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms;

X<1>is selected from H, m-F, m-C1, m-Br, m-J, m-CN, m-NO2, m-SO2R1, or m-SO2OR1;

X<2> is selected from o-R1, p-OR<1>, p-SR<1>, p-NR<1>2, p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca;

Y<1> is selected from cycloalkyl of up to 10 carbon atoms or

Y<2> is selected from straight-chain or branched alkyl having up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms, or

and R<2> is -H; or NY<2>R<2>are jointly selected from

where x is an integer from 3 to 5, or q is an integer from 0 to 6, or where Z2 is selected from R<1>or

Further examples of compounds exhibiting at least one activity and utility are shown in Table 6, where the activity of the compounds is also shown. The activity scale used in Table 6 is as follows (numbers may be included): "+++" represents between about 70 and about 100% inhibition; "++" represents between about 30 and about 40% inhibition; and "+" indicates between 0 and about 30% inhibition, all at 5 µM compound concentration. It should also be noted that any hydrogen atoms required for any atom to achieve its usual valence in the structure shown in Table 6, whether a carbon atom or a heteroatom, should be included unless specifically indicated.

Compounds or compositions containing such compounds that are effective in modulating the activity of glycosidase enzymes are useful in treating and/or

cancer prevention and include, but are not limited to, malignant and non-malignant cell growth, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML),

chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Karposi's sarcoma, colorectal cancer, pancreatic cancer, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia malignancies, solid tumors, adenocarcinomas, sarcomas, malignant melanoma, hemangioma, metastatic disease, connective tissue cancer with bone resorption, cancer associated with bone pain, and the like.

In another aspect of the present invention, the compounds disclosed herein are useful in modulating the activity of heparanase or the activity of other glycosidases as agents for the treatment and prevention of autoimmune diseases. General autoimmune disease results when (1) the immune system mistakenly identifies a molecule on the cell surface of normal tissue as a foreign molecule (2) the synthesis and secretion of chemokines, cytokines, and lymphokines is not shut down before the disease is eradicated or (3) the immune system overreacts to an apparent infection and destroys large amounts of surrounding normal tissue.

In order to act effectively in an immune response, immune effector cells must bind to the luminal/apical surface of blood vessel walls. This is accomplished through the interaction of adhesion molecules on immune effector cells with their locally upregulated cognate receptors on endothelial cells that line the vasculature near the site of infection. After binding to the apical surface and before entering the inflamed tissue, immune effector cells must pass the basement membrane (BM) and extracellular matrix (ECM) surrounding the basal part of blood vessels and give the vessels their shape and strength. BM and ECM consist of structural proteins embedded in a fibrous meshwork consisting mainly of complex carbohydrates containing structures (glycosaminoglycans), the main constituent of which is heparin sulfate proteoglycan (HSPG). In order to pass this barrier, immune effector cells must weaken or destroy it, which is achieved through the local secretion of proteases and haranase(s).

Thus, this inhibition of heparanase or activity of other glycosidases using the compounds of the present invention finds utility in the treatment of arthritis and other autoimmune diseases. More specifically, the compounds of the present invention are useful in the treatment or prophylaxis of at least one autoimmune-related disease in a cell, tissue, organ, animal, or patient including, but not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, transplant rejection, graft-versus-host disease, systemic inflammatory response, sepsis syndrome, gram positive sepsis, gram-negative sepsis, culture-negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningoedema, trauma/hemorrhage, burns, exposure to ionizing radiation, acute pancreatitis, respiratory distress syndrome in adults, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, Crohn's disease, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitivity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, pernicious anemia, hemolytic disease, thrombocytopenia, transplant rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage rejection transplant, bone graft rejection, rejection small intestine transplant, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves' disease, Raynoud's disease, type B ana insulin resistant diabetes, asthma, mvasthenia gravis, mediated cytotoxicity, type III hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin change syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin change syndrome, anti-phospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, idiopathic pulmonary fibrosis, scleroderma, diabetes mellitus, chronic active hepatitis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granuloma due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hamachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis, hyptthalamic-pituitary-adrenal axis assessment, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatological conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, ankylosing spondylitis, Behcet's disease, bullous blister, cardiomyopathy, typhoid fever-dermatitis, chronic immune dysfunctional malaise syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, scar blister, CREST syndrome, cold agglutinin disease, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillian-Barre, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes, juvenile arthritis, lichen planus, Meniere's disease, multiple sclerosis, pemphigus vulgaris, polyarteritis nodosa, Cogan's syndrome, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, Ravnaud's phenomenon, Reiter's syndrome, rheumatic fever, Sjogren's syndrome, stiffness syndrome, Takayasu arteritis, temporal arteritis/giant cell arteritis, Wegener's granulomatosis, oct3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (eg, including but not limited to asthenia, anemia, cachexia, and the like), chronic salicylate intoxication, and the like.

Compounds having heparanase inhibitory activity, which is effective, for example, in the treatment of cancer and autoimmune disease, can be determined using assays such as those published in U.S. Pat. Patent application no. 09/952,648, which is incorporated herein in its entirety. Such assays, which are used to measure cellular and enzymatic activities, both qualitatively and quantitatively, and in procedures for diagnosing metastasis, metastatic potential, and inflammatory conditions, are performed with and without the addition of at least one of the compounds of the present invention to determine the activity of the compound. Existing trials of hyperanase are reviewed in Goshen et al., 2 Mol. Hum. Reprod. 679-84 (1996); Nakajima et al., 31 Cancer Lett. 277-83 (1986); and Wlodaskv et al., 12 Invasion Metastatis 112-27 (1992); Freeman and Parish, 325 Biochem. J. 229-37 (1997); Kahn and Newman, 196 Anal. Biochem. 373-76 (1991). Solid-phase hyperanase assays have also been developed where chemically and biosynthetically radiolabeled heparin and HS chains are attached to a solid support, with the release of radiolabel from the solid support being a measure of enzymatic activity. Experiments using such procedures have been studied in the U.S. Patent no. 4,859,581, which is expressly incorporated herein by reference in its entirety.

In general, a putative assay involves attaching one of the binding partners to a substrate for the enzyme to be measured, forming a substrate-binding partner. Incubation with a sample containing the enzyme to be measured allows the enzyme activity of the enzyme activity to be measured in the reaction mixture. Part or all of the reaction mixture, depending on the amount required, is then mixed with the complementary binding partner so that the binding partners are bound together. This is the first binding reaction. After incubation to allow binding, washes are performed. A complementary binding partner is added, complementary to the first binding partner attached to the substrate. The complementary binding partner may or may not be the same as the first complementary binding partner. This is the second bonding reaction. The complementary binding partner in the second binding reaction is detectably labeled. For example, the complementary binding partner is labeled with an enzyme that causes a detectable color change when the appropriate reaction conditions are present. The difference between the activity of the enzyme in the presence of the compound and the absence of the compound is used to determine the activity of the compound.

An example of a heparanase assay consists of the following steps. The composition containing biotin-HS (heparan sulfate) is mixed with a biological sample such as a tumor sample, body fluid, or other fluid suspected of having heparanase activity, to form a reaction mixture. This sample can be pretreated to remove contaminating or reactive substances such as endogenous biotin. A control portion for this reaction mixture contains no compound of the present invention, while a test portion contains one or more compounds disclosed herein. After incubation, an aliquot or portion of the reaction mixture is removed and placed on a biotin-binding plate. A biotin-binding plate contains any means for binding biotin, presumably to a solid surface. See WO 02/23197, which is expressly incorporated herein by reference in its entirety. After washing with buffers, streptavidin-enzyme conjugate is added to the biotin-binding plate. They are added to the enzyme reagent to form a detectable colored product. For example, a decrease in color formation, from a known standard, indicates that heparanase activity is present in the sample. The difference between the activity of the enzyme in the presence of the compound and the absence of the compound is used to determine the activity of the compound.

Using the above samples or those studied in the Examples, the amount of enzyme activity in the sample and the activity of the compounds of the present invention can be determined. For example, a composition containing a compound of the present invention is added to a known amount of heparanase either before or during the incubation of the heparanase and its substrate-binding partner. If the compound replaces heparanase activity, the assay methods of the present invention will show a change in the amount of detectable label. See WO 02/23197. which is expressly incorporated herein by reference in its entirety.

The activities of the compounds included in the present invention modulate the activity of glycosidases either directly or indirectly. The compounds may modulate the synthesis of glycosidases by cell or tissue or act directly on one or more glycosidases to modulate the biological activity or biological stability of the enzyme itself, for example, heparanase. Activities also included herein are those that increase the biosynthesis of one or more glycosidases by increasing the transcription of the glycosidase gene, increasing the biological stability of the glycosidase mRNA, or increasing the translation of the glycosidase mRNA into protein. Further activities include the activities of compounds that can block or reduce the effects of agents or proteins that inhibit glycosidase activity. Additionally, activities that affect the substrates of glycosidases, such as those discussed above in connection with proteoglycans, or that affect the binding parameters of the enzyme to its substrate, cofactors, or stimulatory or inhibitory factors, are included.

The present invention comprises methods and compositions for the treatment and prevention of diseases or conditions exhibiting or resulting from glycosidase activity. Such methods consist of administering compositions comprising the compounds disclosed herein that inhibit heparanase activity. Administration of such compounds effective in modulating heparanase activity is administered to humans or animals suspected of having or having, for example, inflammatory conditions, autoimmune diseases, or diabetic vasculopathy. Effective amounts are administered to such humans and animals at doses that are safe and effective, including, but not limited to, the ranges studied herein. Routes of administration include, but are not limited to, those disclosed herein. As disclosed herein, compositions comprising such compounds may be used in conjunction with other therapeutic agents or in procedures comprising steps such as altered patient activity.

V. Modulation of inflammation

The implementation of the present invention consists of methods and compositions containing compounds of the present invention for the treatment and prevention of conditions or diseases that have inflammation as an aspect of the disease or condition. An aspect of the present invention is directed to methods and compositions comprising compounds effective in inhibiting inflammation, particularly inflammation associated with the accumulation or presence of glycated proteins or AGEs. Inflammation modulating activity includes, but is not limited to, inhibiting inflammation and/or its associated cellular activation via glycated proteins or AGEs, by blocking protein glycation, blocking AGE interactions with receptors, blocking AGE-induced signaling or signaling-related inflammatory responses, cytokine induction, synthesis or release, AGE formation or AGE cross-linking.

The present invention also provides compositions for and methods of treating biological conditions including, but not limited to, vascular complications of type I and type II diabetes-induced vasculopathies, other vasculopathies, microangiopathies, renal failure, Alzheimer's syndrome, and inflammatory diseases such as atherosclerosis. Other inflammation-related diseases include, but are not limited to, joint inflammatory diseases such as rheumatoid arthritis, osteoarthritis, autoimmune diseases such as those discussed above, streptococcal cell wall-induced arthritis, adjuvant-induced arthritis, bursitis; inflammatory thyroid diseases such as acute, subacute and chronic thyroiditis, pelvic inflammatory disease, hepatitis; inflammatory bowel disease such as Crohn's disease and colitis; neuroinflammatory diseases such as multiple sclerosis, abscess, meningitis, encephalitis, and vasculitis; Inflammatory heart diseases such as myocarditis, chronic obstructive pulmonary disease, atherosclerosis, pericarditis; inflammatory skin diseases such as acute inflammatory dermatosis (urticaria (hives), spongiotic dermatitis, erythema multiforme (em minor), Sevens-Johnson syndrome

(sjs, em major), toxic epidermal necrolysis (ten) and chronic inflammatory dermatoses (psoriasis, lichen planus, discoid lupus erythematosus, acne vulgaris); inflammatory eye diseases such as uveitis, allergic conjunctivitis, corneal inflammation, intraocular inflammation, iritis; laryngitis, and asthma.

The compounds of the present invention have the ability to inhibit inflammation and/or associated cellular activation via glycated proteins or AGEs. Pharmacological inhibition of AGE-induced cellular activation provides a basis for therapeutic intervention in many diseases, notably diabetic complications and Alzheimer's disease. Therapeutic approaches to inhibit AGE-induced inflammation include, but are not limited to, blocking protein glycation, blocking AGE interactions with receptors, and blocking AGE-induced signaling or signaling-related inflammatory responses.

At least one activity of some of the compounds of the present invention is to block AGE actions through inhibition of AGE-induced signaling. The sequence of these signaling events leading to inflammation is not clear, but inhibition of these signaling events leads to reduced or no inflammation results. Compounds that block AGE-induced up-regulation of inflammatory molecules are identified in a screening assay. Other aspects of the present invention comprise methods and compositions comprising compounds that block glycated protein-induced inflammation. Some compounds may have an effect on AGE formation or AGE cross-linking.

At least one activity of some of the compounds of the present invention is to block AGE actions via inhibitory reactions with AGE receptors and such activities are also contemplated by the methods of the present invention for the treatment of related pathologies. For example, RAGE, a known receptor for AGEs, is a therapeutic target. Blocking RAGE inhibits AGE-induced inflammation. Prior to the use of the compounds of the present invention, the multiple functions of RAGE and the possible long-term side effects of accumulated plasma AGE prevented this treatment procedure from being implemented. However, using the methods and compositions of the present invention, more specific inhibitory compounds can be used for treatments and overcome the current problems with treatments targeting those receptors.

Compounds of the present invention that have at least inflammation modulating activity are shown in TABLE 5. The compounds shown in this Table have inflammation modulating activity as measured by the assays studied herein. The inclusion of compounds in the Table categories published herein should not be viewed as limiting, in that compounds included in such Tables have at least the activity shown for inclusion in the Table and may have more or other activities. Also, the Tables should not be viewed as limiting in that they are the only compounds that have that activity, only representative compounds are shown in the Tables that have at least a certain activity for inclusion in the Table. One or more compounds disclosed herein have at least an activity capable of treating a disease state.

Examples of compounds exhibiting at least this activity and ability are shown in the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; arilla; or (CH2)XCN, where x is an integer from 0 to 6;

E is CH or N;

n is an integer from 0 to 3;

X<1> is selected from -H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, m-NC(0)R<1>, or o-F, or X<1> and X<2> are fused together with a benzene, pyridine, or dioxane ring;

X2 is selected from -H, o-CI, o-Br, o-CF3, o-R<1>, p-OR<1>, p-SR1, p-NR<1>2, p-F, p-CI p-Br, p-CF3, p-CN, p-C(0)OR<1>, p-NC(0)R<1>, p-(4-morpholinyl), or p-(4-methyl-1-piperidinyl);

AY<1>is halogen, or A is NR<1>or O and Y<1>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, (CHR<1>)yOR<1>, where y is an integer from 1 to 6,

or are AY<1> together where x is an integer from 3 to 5; and DY<2>is halogen, or isDNR<1>and Y<2>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence, or branched alkyl of up to 10 carbon atoms, CH2R<1>, wherein x is an integer from 3 to 5, , CH2CF3, (CHR<1>)ZZ<1>, where z is an integer from 1 to 6, and Z1 is selected from NR<1>2,

, at

where x is an integer from 3 to 5,

or NY2R1 is jointly selected from wherein Z2 is selected from R<1>, C(0)R<1>, C(0)OR<1>, pyridinyl, aryl, or

where is it? an integer from 0 to 6.

Further examples of compounds exhibiting at least this activity and capability are shown in Table 5, where the activity of the compounds is also shown. The activity scale in Table 5 is as follows (numbers included): "++++" represents between 0 and about 25% of IL6 production compared to cells not receiving Compound I or percentage of control IL6 production); "+++" represents between about 25 and about 50% of control IL6 production; "++" represents between about 50 and about 75% of control IL6 production; and "+" represents between about 75 and 100% of control IL6 production. Remark "n.d." indicates that the activity of the compound was not determined in the given experiment. It should further be noted that any hydrogen atoms required for any atom to achieve its usual valence in the structure shown in Table 5, whether a carbon atom or a heteroatom, should be included unless specifically indicated.

In addition to the above compounds, the compounds shown in Table 7, and compositions containing those compounds, also exhibit anti-inflammatory activity as measured by the assays studied herein. The activity scale used in Table 7 is as follows (numbers included): "+++" represents between about 85 and 100% inhibition of IL6 production in the presence of AGE or TNF, compared to cells that did not receive any compound; "++" represents between 65 and about 85% inhibition of IL6 production in the presence of AGE or TNF; and"+" represents between about 50 and about 65% inhibition of IL6 production in the presence of AGEs or TNF. As before, the inclusion of compounds in the categories of the Tables shown here should not be seen as limiting, but rather the compounds included in the Tables have at least the activity shown for inclusion in the Tables and may have more or other activities. Also, the Tables should not be viewed as limiting in that they are the only compounds that have that activity, only representative compounds are shown in the Tables that have at least a certain activity for inclusion in the Table. One or more compounds disclosed herein have at least an activity capable of treating a disease state.

Increased formation and accumulation of glycated proteins and AGEs is thought to play a major role in the pathogenesis of diabetic complications, and atherosclerosis, leading to the development of diabetic complications including nephropathy, retinopathy and neuropathy. There is extensive in vivo evidence suggesting that diabetes-related complications can be reduced by 1) preventing protein glycation, 2) interrupting the cross-linking of glycated proteins, and 3) blocking the interaction of glycated proteins with receptors. Despite the importance of AGEs in the pathogenesis of diabetic microangiopathy, there are currently no known medications available to block AGE formation.

The endothelium is a target organ for damage in diabetes. See Laight et al., 15 Diabetes Metab. Res. Rev. 274-82 (1999); Stehouver et al., 34 Cardiovasc. 55-68 (1997). Upregulation of molecules involved in endothelial inflammation, such as IL-6 and monocyte chemoattractant protein-1 (MCP-1), leads to endothelial dysfunction and vasculopathy. See Stehouver et al., 34 Cardiovasc. 55-68 (1997); Libby, 247 J. Int. Med. 349-58 (2000); Van Lente, 293 Clinica. Chemistry. Acta. 31-52 (2000). IL-6 is a pro-inflammatory cytokine known to play a major role in the pathogenesis of diabetes and atherosclerosis. See Horii et al., 39 Kidney Int. Suppl. 71-5 (1993); Huber et al., 19 Arterioscler Thromb. Vasc. Biol. 2364-67 (1999); Shikano et al., 85 Nephron 81-5 (2000); Pickup et al., 8(67) Life Sci. 291-300 (2000). IL-6 also promotes the growth of renal messenger cells and thus contributes to nephropathy. See Kado et al., 36 Acta. Diabetol. 67-72 (1999). Serum IL-6 levels in diabetic subjects were significantly higher than in normal healthy controls (3.48 +/- 3.29 pg/mL vs. 0.784 +/- 0.90 pg/mL, mean +/- SD). Additionally, the urinary level of IL-6 is a good indicator of diabetic nephropathy. Serum IL-6 is useful in the assessment of atherosclerosis and nephropathy.

MCP-1, the next pro-inflammatory cytokine, was found to be highly expressed in human atherosclerotic organs and is required to have a central role in monocyte recruitment to the arterial wall and organ development. See Libby, 247 J. Int. Med. 349-58 (2000). Recent results indicate that MCP-1 is also a key pathogenic molecule in diabetic nephropathy. See Eitner et al., 51 Kidney Int. 69-78 (1997); Banba et al. 58 Kidney Int. 684-90 (2000). Glycated albumin stimulates endothelial production of IL-6 and MCP-1. The effects of glycated albumin on IL-6 production are comparable to those of TNFα, a known inducer of IL-6. These cytokines are also known to be factors in vascular diseases.

The activity of the compounds of the present invention in inhibiting glycated protein- and AGE-induced inflammation can be determined using assays disclosed herein and in U.S. Pat. patent application no.

10/026,335, which is incorporated herein in its entirety. Such assays consist of measuring the specific activity of biological components involved in a known cellular response. The assays provide a measurable response that determines the activity of the compound. One assay consists of measuring the effects of a compound on the inflammatory response of cells to the presence of a stimulating agent. The next experiment consists of endothelial cells being stimulated by the addition of a glycated protein, a stimulating agent. Endothelial cells respond by producing specific cytokines. The amount of cytokines produced is determined by measurement protocols known to experts in this field of science. Compounds of the present invention are then added to the assay and cytokine production is measured. By comparing the trial without the compound to the trial with the compound, the biological effect of the compound can be determined. The compound may have an inhibitory effect, a stimulating effect, or may have no effect at all.

The amount and type of cytokine produced can be determined using immunological procedures, such as an ELISA assay. The methods of the present invention are not limited to the type of assay used to measure the amount of cytokine produced, and any methods known to those skilled in the art as well as those later developed may be used to measure the amount of cytokine produced in response to a stimulating agent and to a compound having an unknown activity.

An aspect of the present invention comprises methods and compositions for treating diseases, pre-existing conditions or pathologies associated with inflammatory cytokines and other inflammation-related molecules including, but not limited to IL-6, VCAM-1, AGE-induced MCP-1, (monocyte chemoattractant protein 1), heme oxygenase, insulin-like growth factor, selectins, IP-10, MIG and l-TAC, NF-kB, IL-1p (interleukin ip), IL-11 (interleukin 11), m-CSF (macrophage colony stimulating factor), fibrinogen, TNF-a (tumor necrosis factor a), adhesion molecules, selectins, VCAM-1 (Vascular cell adhesion molecule-1), CRP (C-reactive protein), and PAI-1 (plasminogen activator inhibitor-1). Examples of such diseases include the pathogenesis of atherosclerosis and the development of diabetic vasculopathy in type II diabetes. For example, influencing the activity or level of TNFα is a key mediator of tissue damage that accompanies acute or chronic inflammatory responses. The present invention contemplates the provision of compositions and methods that modulate the effects of cytokines and inflammatory molecules such as TNFα, IL-6, VCAM-1, IP-10, MIG, I-TAC and AGE-induced MCP-1, and the treatment of associated diseases, acute or chronic conditions, pre-existing conditions and pathologies.

Experiments to determine the activity of compounds capable of modulating inflammation include those discussed in the US patent application no. 10/026,335 and 09/969,013, both of which are expressly incorporated by reference. In general, once a baseline response to a stimulatory agent for endothelial cell cytokine production has been established, containing control levels for the screening assay, the methods comprise adding a compound of the present invention. The effect of the compound on the baseline response was determined by comparing the amount of cytokine produced in the presence of the stimulating agent and the amount of cytokine produced in the presence of the stimulating agent and the compound of the present invention. In the proposed method, compounds that have inhibitory effects on cell inflammation in the presence of glycated albumin are then used as therapeutic agents. One or more compounds can be added to the search experiment. Combinations or mixtures of compounds may be added. Different amounts and formulations of compounds are added to determine the effects on the search experiment. A screening assay can also be used to identify stimulatory compounds or compounds that have no effect on the assay.

The present invention comprises methods and compositions for the treatment and prevention of diseases, conditions and pathologies associated with inflammation. Such methods comprise administering compositions containing compounds capable of modulating the activity of inflammation-related molecules such as AGEs or cytokines or other cellular factors, including release rates or activity, and include compositions containing compounds disclosed herein with inflammation-modulating activity. Administration of such compounds effective in modulating inflammation is administered to rats or animals suspected of having or having inflammatory diseases, for example, diabetic-induced vasculopathies, autoimmune diseases, renal failure, Alzheimer's syndrome, and inflammation-induced diseases such as atherosclerosis. Effective amounts are administered to such humans and animals at doses that are safe and effective, including, but not limited to, the ranges studied herein. Routes of administration include, but are not limited to, those disclosed herein. As disclosed herein, compositions comprising such compounds may be used in conjunction with other therapeutic agents or in procedures comprising steps such as alternative patient activities, including, but not limited to, changes in exercise and diet.

VI. Cytotoxic activity

Embodiments of the present invention comprise methods and compositions comprising compounds having at least the activity of inducing cell death or termination of cell activity, referred to herein as cytotoxic activity. This activity can be used in in vitro or in vivo cytotoxicity procedures. For example, compounds having that activity can be selectively delivered to an area within a living organism to selectively kill cells in that area. Such procedures are used to treat hyperproliferative cells, such as cancers, or other unwanted cell growth or cell activity. One aspect of the invention provides compositions containing compounds that indiscriminately kill cells. A further aspect of the invention provides compounds that selectively kill cells, for example, cells that have a particular cell marker or other identifying characteristic such as metabolic rate or uptake of a particular compound, such as sodium, calcium or thymidine.

The present invention also provides compositions for and methods of treating biological conditions including, but not limited to, conditions for which cytotoxicity is the treatment. For example, compositions and methods for providing compounds having at least cytotoxic activity are useful in the treatment of prophylaxis of at least one hyperproliferative disease in a cell, tissue, organ, animal, or patient including, but not limited to, malignant and non-malignant cell growth, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodiplastic syndrome (MDS), lymphoma, Hodgkin's disease, malignant lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal cancer, pancreatic cancer, nasopharyngeal cancer, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia malignancies, solid tumors, adenocarcinomas, malignant melanoma, hemangioma, metastatic disease, cancer associated with bone resorption, cancer associated with bone pain, and the like.

Compounds of the present invention that have at least cytotoxic activity are shown in TABLE 4A and B. Compounds shown in this Table have cytotoxic activity as measured by the assays studied herein. The inclusion of compounds in the categories of the Tables disclosed herein should not be viewed as limiting, but rather the compounds included in the Tables have at least the activity shown for inclusion in the Tables and may have more or other activities. Also, the Tables should not be viewed as limiting in that they are the only compounds that have that activity, only representative compounds are shown in the Tables that have at least a certain activity for inclusion in the Table. One or more compounds disclosed herein have at least an activity capable of treating a disease state.

Examples of compounds exhibiting at least this activity and ability are shown in the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; or aryl; Eje CH or N; n is an integer from 0 to 3; X<1>is selected from -H,m- F, m-C\,m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, or X<1>and X<2> are fused together a benzene or pyridine ring; X2 is selected from -H, o-CI, o-Br, p-OR<1>, p-SR<1>, p-NR<1>2, p-Cl p-Br, p-CF3, p-C(0)OR<1>, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; A is selected from NR<1> or O, wherein Y<1> is selected from cycloalkyl of up to 10 carbon atoms, normal chain or branched alkyl with up to 10 carbon atoms, or where A is NR1, and wherein Y1 is selected from R<1> or CH2R<1> when A is O; or AY<1>is selected from halogen, DY<2>is halogen, or D is NR<1>and Y<2>is selected from

or (CHR<1>)XNR<1>2, where x is an integer from 1 to 6.

An additional example of a compound that exhibits at least this activity and capability is shown in the following formula:

or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt;

whereby:

R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is at each occurrence independently selected from -H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>; X2 is at each occurrence independently selected from o-CH3, p-OR<1>, p-SR<1>, p-NR<1>2, or p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; where n is 1 or 2; or

Y2 is selected from

Further examples of compounds exhibiting at least this activity and capability are shown in Tables 4A and 4B. The compound nomenclature in Tables 4A and 4B, as well as in the other tables shown here, is generated using Autonom, where the given name can be the Beilstein or CAS version of the chemical name. It should be noted that any hydrogen atoms required for any atom to achieve its normal valence in the structure shown in Tables 4A and 4B, whether a carbon atom or a heteroatom, should be included unless specifically indicated.

Assays for determining the activity of compounds capable of cytotoxic activity include those studied herein and others well known in the art. In general, to determine whether there is cytotoxic activity associated with a compound, cells of a particular type, either in the growing or resting phase, are treated with the compound of interest. Various parameters of cell death or termination are used to measure the effects of compounds. For example, the amount of nucleic acid or protein synthesis can be measured, or a visual observation of cell state, such as substrate release, can be used to measure cell state.

The present invention comprises methods and compositions for the treatment and prevention of diseases or conditions that exhibit or result from cell proliferation or unwanted cell growth or cell activity. Such methods consist of administering compositions containing compounds capable of modulating cell activity or inducing cell death or growth arrest such as compositions containing compounds having cytotoxic activity. Administration of such compounds effective in cytotoxic activity is administered to humans and animals suspected of having or having, for example, cancer, overactive tissues such as the thyroid or hypothalamus, or cellular conditions where factors are released in undesired amounts. Effective amounts are administered to such humans or animals in doses that are safe and effective, including, but not limited to, the ranges studied herein. Routes of administration include, but are not limited to, those disclosed herein. As disclosed herein, compositions comprising such compounds may be used in conjunction with other therapeutic agents or in procedures involving conditions such as altered patient activity.

Compound/ Composition- Coated medical devices

The compounds of the present invention may be used alone or in combination with other means in conjunction with means of delivery to effectively prevent and treat the diseases described herein, although particular application is found in vascular disease, and in particular, vascular disease that is caused by injury and/or transplantation, easily such an example focuses on vascular disease, the provision of compounds of the present invention with medical means to treat diseases and conditions capable of being treated with the compounds are contemplated by the present invention.

Various medical treatment agents used in the treatment of vascular disease can ultimately cause further complications. For example, balloon angioplasty is a procedure used to increase blood flow through an artery and is the predominant treatment for coronary artery stenosis. However, the procedure typically causes some degree of damage to the vessel wall, thereby creating new problems or exacerbating the original problem at some later point in time, easily other disease processes can cause similar damage, exemplary embodiments of the present invention will be described with respect to the treatment of restenosis and related complications accompanying percutaneous transluminal coronary angioplasty and other atrial/venous procedures, including joining arteries, veins and other channels that carry fluid to other organs and body locations, such as liver, lungs, bladder, kidney, brain, prostate, neck and legs.

Local delivery of the compounds of the present invention and, in some embodiments, together with other therapeutic agents, from the stent prevents rejection and remodeling of the vessel by enhancing the effect of the stent. The activity of a provided compound, with or without other therapeutic agents, helps determine for which application, to treat which disease, the coated medical device is administered. For example, compound-coated stents can prevent multiple components of neointimal hyperplasia or restenosis as well as reduced inflammation and thrombosis. Local administration of compounds of the present invention and other therapeutic agents to stented coronary arteries may also have additional therapeutic benefit. For example, higher tissue concentrations of compounds of the present invention and other therapeutic agents can be achieved by utilizing local delivery rather than systemic administration. Additionally, reduced systemic toxicity may be achieved by utilizing local delivery rather than systemic administration while maintaining higher tissue concentrations. By utilizing local stent delivery rather than systemic delivery, one procedure may result in better patient compliance to therapy. An additional benefit of a combination therapeutic agent and/or combination therapy may be a reduced dose of each therapeutic agent, thereby limiting toxicity while still achieving a reduction in restenosis, inflammation, or thrombosis. Local stent-based therapy is therefore a means to improve the therapeutic ratio (efficacy/toxicity) of anti-restenosis, anti-inflammatory, and anti-thrombotic therapeutic agents.

readily exemplary embodiments of the invention will be described with respect to the treatment of restenosis and other related complications, it is important to note that local delivery of a compound of the present invention, alone or as part of a combination therapeutic agent, can be used to treat a wide range of different conditions using any number of medical agents, or to enhance the function and/or lifespan of the agent. For example, intraocular lenses, placed to restore vision after cataract surgery, are often compromised by the formation of secondary cataracts. The latter is often the result of cellular overgrowth on the surface of the lens, and can potentially be minimized by combining one or more compounds of the present invention having activity that affects the prevention of unwanted cellular growth with the agent. Other medical devices that frequently fail due to tissue ingrowth or accumulation of proteinaceous material in, on, and around the device, such as hydrocephalus drains, dialysis grafts, colostomy bag slings, ear drainage tubes, pacemaker leads, and implantable defibrillators may also benefit from combinations of compounds.

of the present invention, possibly other pharmaceutical agents and devices. Other surgical devices, sutures, drivers, staplers, vertebral discs, bone pins, suture lengtheners, hemostatic barriers, clips, screwdrivers, plates, clips, vascular implants, tissue adhesives and fasteners, tissue lifters, various types of dressings, bone substitutes, intraluminal devices, and vascular carriers may also provide increased patient benefit using a compound-device combination approach. Basically, any type of medical device can be coated in some way with at least one compound of the present invention, alone or as part of a therapeutic agent combination, for enhanced treatment use of the agent or therapeutic agent without combination with the compound.

As disclosed above, the compounds of the present invention may be administered in combination therapies with other therapeutic agents, and are not limited to the other therapeutic agents disclosed herein. Thus, the present invention also contemplates that, in addition to various medical devices, coatings on these devices may be used to deliver the compounds of the present invention in combination with other therapeutic agents. This illustrative list of therapeutic agents may be administered via pharmaceutical means along with medical means, and such therapeutic agents include, but are not limited to, antiproliferative/antimitotic agents including natural products such as vinca alkaloids (eg, vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (eg, etoposide, teniposide), antibiotics (dactionomycin (actinomycin D) daunorubicin, doxorubicin). and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase which systemically metabolizes L-asparagine and deprives cells that do not have the capacity to synthesize their own asparagine); antiplatelet agents such as G(GP) llb/llla inhibitors and bitronectin receptor antagonists; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and analogs, melphalan, chlorambucil, ethyleneimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-bisulfan, nirtosaurs (carmustine (BCNU) and analogs, streptozocin), trazeni-dacarbazine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogues (fluorouracil, and cytarabine), purine analogues and related inhibitors (mercaptopurine, thioguanine and 2-chlorodeoxyadenosine (cladribine)); platinum coordination complexes (cisplatin, carboplatin); hormones (e.g., heparin and other thrombin inhibitors); fibrinolytic agents (such as plasminogen activator tissues, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; anti-migration; antisecretory (vreveldine); anti-inflammatory agents such as adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamquinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, ie, aspirin; para-aminophenol derivatives, ie, acetominophen; indole and indene acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefanamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxypentatrazone), nabumetone, gold compounds (aruanofin, aurothioglucose, gold sodium thiomalate); (Cyclosporin, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents; vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF); angiotensin receptor blockers; nitric oxide donors; anti-sense oligonucleotides and their combinations; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors.

easily any number of stents may be used according to the present invention, for the sake of simplicity, a limited number of stents will be described in exemplary embodiments of the present invention. One skilled in the art will recognize that any number of stents may be utilized in connection with the present invention. Additionally, as noted above, other medical agents may be used. For example, although stents are described, extravascular stents are also contemplated, as are other medical devices that can provide a substrate for delivery of at least one of the compounds of the present invention.

A stent is commonly used as a tubular structure that is left within the lumen of the duct to alleviate the obstruction. Typically, stents are inserted into the lumen in an unexpanded form and then expanded autonomously, or with the help of another means in situ. A common expansion procedure appears to be through the use of a catheter-placed, angioplasty balloon that is inflated into the lumen of a stenosed vessel or passageway into the body to divide or terminate obstructions associated with vessel wall components and to obtain an enlarged lumen.

A stent may resemble an expandable cylinder and may consist of a hollow structure for placement in a blood vessel, channel or lumen to hold the vessel, channel or lumen open, more specifically to protect an artery segment from restenosis after angioplasty. The stent can expand circumferentially and is maintained in an expanded configuration that is circumferentially or radially rigid. The stent may be axially flexible and when coiled, for example, the stent avoids any externally protruding portions of the component.

A stent can be made using a number of procedures. For example, a stent can be made from a hollow or formed stainless steel tube that can be machined using a laser. The stent is inserted into the body and placed in the desired position in an unexpanded form. In one embodiment, the expansion can be performed in a blood vessel via a balloon catheter, with the final diameter of the stent being a function of the diameter of the balloon catheter being used. It should be recognized that the stent according to the present invention can be realized in a shape-memory material including, for example, a suitable nickel or titanium alloy or stainless steel.

Formed stainless steel structures can be self-expandable by placing the stainless steel configuration in a predetermined manner, for example, by twisting into a twisted configuration. In this embodiment, once the stent is formed it can be compressed to occupy a space small enough to allow insertion into a blood vessel or other tissue by insertion means, wherein the insertion means includes a suitable catheter, or flexible rod. Upon emerging from the catheter, the stent may be configured to expand into a desired configuration wherein the expansion is automatic or initiated by a change in pressure, temperature, or electrical stimulation.

Furthermore, the stent may be modified to consist of one or more reservoirs. Each of the tanks can be opened or closed as desired. These reservoirs may be specifically designed to hold the compound or compound/therapeutic agent combination to be delivered. Regardless of the stent design, it is assumed that the dose of the compound or compound/therapeutic agent combination is administered with sufficient specificity and sufficient concentration to provide an effective dose to the affected space. In this regard, the size of the reservoir in the dressings is assumed to be of a size that adequately corresponds to the dose of the compound or compound/therapeutic agent combination at the desired location and in the desired amount.

In an alternative embodiment, the entire inner and outer surface of the stent may be coated with the compound or compound/therapeutic agent combination in therapeutic dosage amounts. Plating techniques may vary depending on the material comprising the stent or other intraluminal medical device.

One or more compounds of the present invention and, in some instances, other therapeutic agents in combination, may be incorporated into or attached to the stent in a number of ways. In one embodiment, the compound is directly incorporated into the polymer matrix and sprayed onto the outer surface of the stent. The compound elutes from the polymer matrix over time and enters the surrounding tissue. The compound is assumed to remain on the stent for at least three days and up to approximately six months, preferably between seven and thirty days.

Any number of non-erodible polymers may be used with the compound, and such polymeric compositions are well known in the art. In one embodiment, the polymer matrix consists of two layers. The base layer consists of a solution of poly(ethylene-vinyl acetate) and polybutyl methacrylate. The compound is incorporated on this base layer. The outer layer consists only of polybutyl methacrylate and acts as a diffusion barrier to prevent the compound from eluting too quickly. The thinness of the outer layer or surface coating determines the rate at which the compound is eluted from the matrix. Basically, the compound elutes from the matrix by diffusion through the polymer matrix.

Polymers are permeable, so they allow solids, liquids and gases to escape. The overall thickness of the polymer matrix ranges from about one micron to about twenty microns or more. It is important to note that primary layer and metal surface treatments can be used before the polymer matrix is attached to the medical device. For example, acid cleaning, alkaline (base) cleaning, salinization, and parylene deposition may be used as part of the overall process described above.

Poly(ethylene-co-vinyl acetate), polybutyl methacrylate, and solution compounds can be incorporated into or onto the stent in a number of ways. For example, the solution can be sprayed onto the stent or the stent can be immersed in the solution. Other processes include spin coating and plasma polymerization. In another embodiment, the solution can be electrically charged to one polarity and the stent electrically charged to the opposite polarity. In this way, the solution and the stent will attract each other. In using this type of spraying process, loss can be reduced and more precise control of coating thickness can be achieved.

Drug-eluting stents are manufactured by a number of companies including Johnson & Johnson, Inc. (New Brunswick, NJ), Guidant Corp. (Santa Clara, CA), Medtronic, Inc. (Minneapolis, MN), Cook Group Incorporated (Bloomington, IN), Abbott Labs., Inc. (Abbot Park, IL), and Boston Scientific Corp. (Natick, MA). See, e.g., U.S. Patent no. 6,273,913; U.S. Patent application no. 20020051730; WO 02/26271; and WO 02/26139, each expressly incorporated herein by reference in its entirety.

Expression profiles and microarray procedures used

Other aspects of the present invention consist of compositions and methods for microarray devices. Such microarray devices and methods consist of various microarrays that can be used, for example, to study and monitor gene expression in response to treatment with compounds of the present invention. Microarrays may contain nucleic acid, carbohydrate, or protein sequences that are specific for specific cells, tissues, species, disease states, prognoses, disease progression, or any other combination of molecules that may be used to determine the effect of one or more compounds of the present invention.

For example, microarrays of the present invention may be derived from, or representative of, for example, a specific organism or cell type, including human microarrays, vascular microarrays, inflammation microarrays, cancer microarrays, apoptosis microarrays, oncogenic and tumor suppressive microarrays, cell-cell interaction microarrays, cytokine and cytokine receptor microarrays, blood microarrays, or a combination thereof. In further embodiments, microarrays can represent diseases including cardiovascular diseases, valculopathic conditions, inflammatory diseases, autoimmune diseases, neurological diseases, immunological diseases, various cancers, infectious diseases, endocrine disorders, and genetic diseases.

Alternatively, microarrays useful in evaluating the efficacy of compounds of the present invention may represent a particular tissue type including, but not limited to, heart, liver, prostate, lung, nerve, muscle, or connective tissue; presumed coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, myometrial microvascular endothelium, kerationocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, smooth pulmonary artery muscle, dermal fibroblast, neural progenitor cells, skeletal muscle, bronchial smooth muscle, uterine smooth muscle, lung fibroblast, osteoblasts, prostate stromal cells, or combinations thereof. The present invention further contemplates microarrays comprising a gene expression profile comprising one or more polynucleotide sequences including complementary and homologous sequences, wherein said gene expression profile is generated from a cell type treated with a compound of the present invention and selected from the group consisting of coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, myometrial microvascular endothelium, epithelium kerationocyte, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cells, skeletal muscle, bronchial smooth muscle, uterine smooth muscle, lung fibroblast, osteoblasts, prostate stromal cells.

The present invention contemplates microarrays comprising one or more protein binding agents, wherein the protein expression profile is generated from a cell type treated with a compound of the present invention and selected from the group consisting of coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, myometrial microvascular endothelium, kerationocyte epithelium, bronchial epithelium, mammary epithelium, prostate, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cells, skeletal muscle, bronchial smooth muscle, uterine smooth muscle, lung fibroblast, osteoblasts, prostate stromal cells.

More specifically, the present invention contemplates methods for reproducibly measuring and evaluating the expression of specific mRNAs or proteins in, for example, a specific set of cells. One procedure combines and utilizes laser microdissection capture techniques, T7-based RNA amplification, production of cDNA from the amplified RNA, and DNA microarrays containing immobilized DNA molecules for various specific genes, including HSPGs such as perlecan, to produce a gene expression analysis profile for very small numbers of specific cells. The desired cells are individually identified and attached to the substrate via a laser trapping technique, and the trapped cells are then separated from the remaining cells. RNA is then extracted from the captured cells and amplified about a million times using a T7-based amplification technique, and cDNA can be prepared from the amplified RNA. Various specific DNA molecules are prepared that hybridize to specific microarray polynucleotides, and the DNA molecules are immobilized on the appropriate substrate. cDNA produced from captured cells is applied to the microarray under conditions that allow cDNA hybridization to the immobilized microarray DNA. The expression profile of captured cells is obtained from analysis of hybridization results using amplified RNA or cDNA made from amplified RNA of captured cells, and specific immobilized DNA molecules on a microarray. Hybridization results demonstrate, for example, which genes from those represented on the microarray as probes hybridized to the cDNA of captured cells, and/or the amount of specific gene expression. Hybridization results represent the gene expression profile of captured cells. The gene expression profile of captured cells can be used to compare the gene expression profile of a different set of captured cells. For example, gene expression profiles can be generated from cells treated (and untreated) with a compound of the present invention. Similarities and differences provide useful information for distinguishing between the same cell type under different conditions, more specifically, changes in gene expression in response to treatment with a compound of the present invention.

Techniques used for gene expression analysis are equally applicable in the context of protein expression profiling. Total protein can be isolated from a cell sample and hybridized to a microarray consisting of a variety of protein binding agents, which can include antibodies, receptor proteins, small molecules, and the like. Using several assays known in the art, hybridization can be detected and analyzed as described above. In the case of fluorescent detection, algorithms can be used to extract a protein expression profile that is representative of a particular cell type. In this regard, the change in protein expression in response to treatment of cells with a compound of the present invention can be assessed.

Thus, in one aspect, the present invention comprises at least one microarray that corresponds to a population of genes isolated from a particular tissue or cell type in methods used to detect changes in gene transcription levels resulting from exposure of the selected tissue or cells to at least one compound of the present invention. In this embodiment, a biological sample derived from an organism, or an established cell line, can be exposed to at least one compound of the present invention in vivo or ex vivo. Then, transcripts of the gene, primarily mRNA, tissue or cell are isolated by methods well known in the art. Sambrook et al., Molecular Cloning: A Lab. Manual (2001). The isolated transcripts are then contacted with the microarray under conditions where the transcripts hybridize with the appropriate probe to form a hybridization pair. Thus, the microarray provides a model of the transcriptional capacity response following exposure to at least one compound of the present invention. Such information can be used to identify candidates for therapy. The hybridization signal can then be detected on each hybridization pair to obtain a gene expression profile.

Gene and/or protein expression profiles and microarrays can also be used to identify activating or non-activating compounds of a particular gene such as perlecan or other HSPGs. Compounds that increase transcription rates or stimulate, maintain, or stabilize protein activity are considered activating while compounds that decrease rates or inhibit protein activity are non-activating. Moreover, the biological effects of the compound can be reflected on the biological state of the cell. This condition is characterized by cellular constituents. One aspect of a cell's biological state is its transcriptional state. The transcriptional state of a cell includes the identities and amounts of constituent RNA species, particularly mRNA, in a cell under a given set of conditions. Thus, the gene expression profiles, microarrays, and algorithms discussed herein can be used to analyze and characterize the transcriptional state of a given cell or tissue following exposure to an activating or non-activating compound, specifically, a compound of the present invention.

Microarray techniques and procedures for analyzing the results are well known in the art. See U.S. Patent numbers 6,263,287; 6,239,209; 6,218,122; 6,197,599; 6,156,501; 5,874,219; 5,837,832; 5,700,637; 5,445,934; U.S. Patent application numbers 2001/0014461 A1; 2001/0039016 A1; 2001/0034023 A1; WO 01/94946; and WO 01/77668. See also, Haab et al., 2 Genome Biology 1-12 (2001); Brown et al., 97 Proc. Natl. Acad. Sci. US 262-7 (2000); Getz et al., 97 Proc. Natl. Acad. Sci. USA - 12079-84 (2000); Harrington et al., 3 Current Opinion Microbiol 285-91

(2000); Holter et al., 97 Proc. Natl. Acad. Sci. USA 8409-14 (2000); MacBeath et al., 289 Science 1760-63 (2000); Duggan et al., 21 Nature Genet 10-14 (1999); Lipshutz et al., 21 Nature Genet 5-9 (1999); Eisen et al., 95 Proc. Natl. Acad. Sci. US 14863-68 (1998); Ermolaeva et al., 20 Nature Genet. 19-23 (1998); Hacia et al., 26 Nucleic Acids Res. 3865-66 (1998); Lockhart et al., Nucleic Acids Symp. Sir. 11-12 (1998); Schena et al., 16 Trends Biotechnol. 301-6 (1998); Shalon, 46 Pathol. Biol. 107-9 (1998); Welford et al., 26 Nucleic Acid Res. 3059-65 (1998); Blanchard et al., 11 Biosensors Bioelectronics 687-90 (1996); Lockhart et al., 14 Nature Biotechnol. 1675-80 (1996); Schena et al., 93 Proc. Natl. Acad. Sci. USA 10614-19 (1996); Tomavo et al., 96 Proc. Natl. Acad. Sci. USA 2907-12 (1996); Schena et al., 270 Science 467-70

(1995).

Database creation, database access, and related procedures

uses

Another embodiment of the present invention consists of various methods of managing and using data associated with the compounds, methods of making the compounds, methods of using and administering the compounds, and diagnosing, prognosticating, and post-traumatic diseases in which the compounds are effective in treatment. For example, methods for providing diagnostics and predictors associated with biomolecules including HSPGs, in particular, perlecan, are contemplated by the present invention. Also within the scope of this invention are methods for providing diagnostics and predictors associated with the efficacy of compounds of the present invention. The present invention further contemplates methods of providing databases of expression profiles, and methods of producing such databases, for normal and diseased tissues.

The expression profile database may be an internal database that includes annotation information on expression profiles generated to evaluate the effects of compounds of the present invention through other sources and methods. Such information may include, for example, databases in which a given biomolecule has been found, patient information associated with an expression profile, including age, cancer or tumor type or progression, information associated with a compound of the present invention such as dose and administration information, descriptive information about related cDNAs associated with the sequence, tissue, or cellular source, sequence data obtained from external sources, expression profiles for given genes, and related disease states or disease course, such as whether the profile expressions refer to or make more significant a certain disease state, preparation procedures. Expression profiles can be based on protein and/or polynucleotide microarray data obtained from publicly available or proprietary sources. Databases can be divided into two sections: one for storing sequences and associated expression profiles and another for storing related information. This database can be maintained as a private, firewalled database within a central computer space. However, this invention is not intended to be limited and the expression profile database may be made available to the public.

A database can be a networked system that connects a network server to clients. The network may be any of a number of conventional network systems, including a local area network (LAN) or a wide area network (WAN), as known in the art (eg, Ethernet). The server may include software to access database information for processing user requests, and provide an interface for providing information to the client's machine. The server can support the World Wide Web and host a website and web browser for use by clients. Client/server environments, database servers, and networking are very well documented in the technical, trade, and patent literature.

Through a Web browser, clients can construct search queries to retrieve data from, for example, microarray databases and expression profile databases. For example, the user can "point and click" on user interface elements such as buttons, pull-down menus, and scroll bars. Client requests can be transmitted to a Web application that formats them to produce a query that can be used to retrieve information from a database system, based, for example, on microarray and/or expression data provided by the client, and/or other phenotypic or genotypic information. Specifically, a client can submit expression data based on a microarray expression profile obtained from a patient treated with a compound of the present invention and use the system to obtain a diagnosis based on that information based on the system's comparison of the client expression data with expression data existing in the database. By way of example, the system compares the expression profiles submitted by the client to the expression profiles existing in the database and then provides the client with diagnostic information based on the best match of the client's expression profile to the database profiles. Thus, in one aspect, comparison of expression profiles assists clinicians in determining the efficacy of treatment with a compound of the present invention. Based on such a comparison, the clinician can change or adjust the treatment regimen.

Additionally, the Website may provide hypertext links to public databases such as GenBank and related databases maintained by the National Center for Biotechnology Information (NCBI), part of the National Library of Medicine as well as any links that provide relevant information for gene expression analysis, genetic disorders, scientific literature, and the like. Information including, but not limited to, identifiers, identifier types, biomolecular sequences, common cluster identifiers (GenBank, Unigene, lncyte template identifiers, and so on), and the types of names associated with each gene are considered.

The present invention also provides a system for accessing and comparing bioinformation, specifically expression profiles and other information useful in the context of the compositions and methods of the present invention. In one embodiment, the computer system may comprise a computer processor, a suitable memory operatively connected to the computer processor, and a computer process stored in the memory executed by the computer processor and comprising means for comparing a match of the expression profile of a biomolecular sequence from a patient to the expression profile and sequence identification information from the biomolecular sequences in the database. More specifically, a computer system is used to compare the match of the expression profile generated from a biological sample treated with a compound of the present invention to the expression profile and other information in the database.

Further, the system for accessing and comparing the information contained in the biomolecular database comprises a computer program containing computer code that provides an algorithm for comparing the match of an expression profile generated from a patient, for example, treated with a compound of the present invention, to the expression profile and information from the sequence identification of biomolecular sequences in the biomolecular database.

The present invention contemplates, in one embodiment, the use of a Graphical User Interface ("GUI") to access expression profile information stored in a biomolecular database. In a specific embodiment, the GUI may be composed of two frames. The first frame may contain a selectable list of biomolecular databases that the user may access. When a biomolecular database is selected in the first frame, the second frame may display information resulting from a pairwise comparison of the expression profile database with the client-supplied expression profile as described above, along with any other phenotypic or genotypic information.

Another GUI frame may contain a listing of biomolecular sequence expression information and profiles that exist in a selected database. Further, another frame may allow the user to select a subset, including all biomolecular sequences, and perform an operation on the list of biomolecular sequences. In one embodiment, the user can select a subset of biomolecular sequences by selecting a selection window associated with each biomolecular sequence. In the following embodiment, operations that can be performed include, but are not limited to, downloading all biomolecular sequences in the list to a separate sheet of the database with classification information, while saving a selected subset of biomolecular sequences to the user's file, downloading all biomolecular sequences from the list to a separate sheet without classifying the information, and displaying the classification information on the selected subset of biomolecular sequences.

If the user chooses to display classification information on a selected subset of biomolecular sequences, another GUI may be displayed to the user. In one embodiment, the second GUI may include a list of one or more external databases used to create expression profile databases as described above. Further, for each external database, the GUI can display a list of one or more fields associated with each external database. In yet another embodiment, the GUI may allow the user to select or deselect each of the one or more fields that are displayed in the second GUI. In yet another embodiment, the GUI may allow the user to select or deselect each of the one or more external databases.

The methods of the present invention further relate to commercial and other uses of the compositions and methods of the present invention. In one aspect, the methods include marketing, selling, licensing the compositions or methods of the present invention in the context of providing consumers, i.e., patients, medical professionals, medical service providers, researchers, and pharmaceutical distributors and manufacturers, with expression profile databases including, in particular, databases produced in accordance with the use of compounds of the present invention.

In another embodiment, the methods of the present invention include setting up a distribution system for distributing the pharmaceutical compositions of the present invention for sale, and may optionally include setting up sales groups for marketing the pharmaceutical composition. Another aspect of the present invention provides a method for conducting target discovery comprising identifying, by one or more of the above drug discovery methods, a test compound, as described above, that modulates the level of gene expression or the activity of a gene product such as perlecan; conducting therapeutic profiling of identified agents, or their further analogs, for efficacy and toxicity in animals; and optionally formulating a pharmaceutical composition including one or more agents identified as having an acceptable therapeutic profile; and optional licensing or sale, rights for further drug development from said identified assets.

Pharmaceutical compositions

In addition to the compounds disclosed herein, the pharmaceutical composition of the present invention may further contain at least one of any suitable excipients such as, but not limited to, a diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservatives, adjuvants, and the like. Pharmaceutically acceptable adjuvants are assumed. Examples and methods of preparation such as sterile solutions are well known in the art and can be found in widely known texts such as, but not limited to, Remingtons Pharmaceutical Sciences (Gennaro, Ed., 18th Edition, Mack Publishing Co. (1990). Pharmaceutically acceptable carriers can be routinely selected to suit the route of administration, solubility and/or stability of the compound.

Pharmaceutical inert fillers and additives useful in the present invention include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers), which may be present alone or in combination, contained alone or combined in ranges of 1-99.99% by mass or volume. Exemplary protein inert fillers include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid components that may also function as buffers include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.

Inert bulking carbohydrates suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lacthiotol, xylitol, sorbitol (glucitol), myoinositol, and the like.

Pharmaceutical compositions comprising compounds of the present invention may also include a buffer or pH adjusting agent. Typically, a buffer is a salt prepared from an organic acid or base. Representative buffers include salts of organic acids such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tometamine hydrochloride, or phosphate buffers.

Additionally, the pharmaceutical compositions of the invention may also include polymeric inert fillers/additives such as polyvinylpyrrolidones, ficols (polymeric sugar), dextrates (e.g., cyclodextrins such as 2-hydroxypropyl-p-cyclodextrin), polyethylene glycols, flavoring agents, anti-microbial agents, sweeteners, antioxidants, anti-static agents, surfactants (e.g., polysorbates such as "TVVEEN" 20" and "TVVEEN 80"), lipids (eg, phospholipids, fatty acids), steroids (eg, cholesterol), and reagents that cause the formation of chelating compounds (eg, EDTA). These and additional known pharmaceutical inert fillers and/or additives suitable for use in the present invention are known in the art, e.g., as listed in Remington: The Science & Practice of Pharmacv (19th ed., Williams & Williams (1995)) and Physician's Desk Reference (52nd ed., Medical Economics (1998)), which are expressly incorporated herein by reference in their entirety.

Pharmaceutical compositions for oral administration

For oral administration in tablet or capsule form, the compound may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrants, and coloring agents may also be incorporated into the composition. Release binders include, but are not limited to, starch; gelatin; natural sugars such as glucose or beta-lactose; corn sweeteners; natural and synthetic gums such as acacia, gum tragacanth, or sodium alginate, carboxymethylcellulose; polyethylene glycol; paraffins and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methyl cellulose, bentonite, xanthan gum, and the like.

Formulations of the present invention suitable for oral administration may be presented as separate units such as capsules, tablets or tablets each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or in a water-in-oil emulsion and as large tablets, etc.

The tablet may be formed by compression or melting, optionally with one or more excipients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molten tablets may be made by melting, in a suitable machine, a mixture of a powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and may be formulated to provide slow and controlled release of the active ingredient therein.

Additionally, the combinations may be incorporated into biodegradable polymers that allow for delayed release of the compound, polymers that are implanted near or where drug delivery is desired, for example, to the site of restenosis. Biodegradable polymers and their uses are described, for example, in detail in Brem et al., 74 J. Neurosurg. 441-46 (1991). Suitable examples of sustained release compositions include semi-permeable matrices of solid hydrophobic polymers containing a compound of the present invention, the matrices of which are in the form of molded products, eg, films, or microcapsules. Delayed-release matrix primers include polyesters, hydrogels (eg, poly(2-hydroxyethyl methacrylate), or poly(vinyl alcohol)), polyactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degrading ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT® (Tap Pharmaceuticals, Inc., Chicago, IL) (injectable microspheres of lactic acid glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

Pharmaceutical compositions for parenteral administration

Suitable formulations for parenteral administration include liquid and non-liquid sterile injectable solutions which may contain antioxidants, buffers, bacteriostatics and solubilizing agents which render the formulation isotonic with the blood of the recipient to be administered; liquid and non-liquid sterile suspensions which may include suspending agents and thickening agents. Formulations may be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid vehicle, e.g., water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the types previously described.

For parenteral administration, sterile suspensions and solutions are preferred. Isotonic preparations generally containing suitable preservatives are employed when intravenous administration is desired. The pharmaceutical compositions may be administered parenterally by injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. The term "parenteral" as used herein includes, but is not limited to, subcutaneous injections, intravenous, intramuscular, intraperitoneal injections, or infusion techniques. Acceptable liquid carriers include, for example, vegetable oils such as peanut oil, cottonseed oil, sesame oil, and the like, as well as organic solvents such as solketal, glycerol formal, and the like. Formulations can be prepared by dissolving or suspending the active ingredient in a liquid carrier so that the final formulation contains about 0.005 wt% to 30 wt% of the active ingredient, i.e. the compound of the present invention.

Pharmaceutical compositions for other routes of administration

Formulations suitable for oral administration include lozenges consisting of palatable base ingredients, typically sucrose and acacia or tragacanth gum; lozenges consisting of the active ingredient on an inert base such as gelatin or glycerin, or sucrose and acacia; and mouthwashes consisting of the compound provided in a suitable liquid vehicle. Liquid forms may include suitable flavor-added suspending or dispersing agents such as synthetic and natural gums, for example, gum tragacanth, acacia, methyl cellulose, and the like.

Formulations for rectal administration may be presented as a suppository with an emollient base consisting of, for example, coconut oil or salicylate.

Formulations suitable for vaginal administration may be presented as uterine plugs, tampons, creams, gels, pastes, foams or spray formulations which, in addition to the active ingredient, contain such carriers as are well known in science to be suitable.

The compounds can also be placed in microcapsules prepared, for example, by coacervation techniques or via interfacial polymerization, for example, hydroxymethylcellulose or gelatin microcapsules and poly(methylmethacylate) microcapsules, each separately, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Remington's Pharmaceutical Sciences (A. Osol ed., 16th ed. (1980)).

In a specific embodiment, the compounds disclosed herein are formulated as liposomes. Liposomes containing a compound of the present invention are prepared by procedures known in the art. See, e.g., U.S. Patent 5,013,556; 4,485,045; 4,544,545; WO 97/38731; Epsetin etal., 82 Proc. Natl. Acad. Sci. US 3688 (1985); and Hvang et al., 77 Proc. Natl. Acad. Sci. US 4030 (1980). The compounds of the present invention may also be provided in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine or phophatidylcholines.

The compounds of the present invention may also be delivered through the use of monoclonal antibodies as individual carriers to which the compound molecules are paired. The compounds of the present invention may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with a palmitoyl moiety.

Pharmaceutically acceptable preservatives

The present invention provides stable formulations as well as preserved solutions and formulations containing a preservative as well as multi-use preserved formulations suitable for pharmaceutical or veterinary use, comprising at least one compound disclosed herein and a pharmaceutically acceptable formulation. Formulations according to the present invention may optionally contain at least one known preservative. Preservatives include, but are not limited to, phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercury nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (eg, hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl, and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof in liquid form. thinner. Any suitable concentration or mixture may be used as known in the art, such as 0.001-5% or any range or value within that. Non-limiting examples include, without preservative, 0.1-2% m-cresol, 0.1-35% benzyl alcohol, 0.001-0.5% thimerosal, 0.001-2.0% phenol, 0.0005-1.0% alkylparaben(s), and the like.

Other inert fillers, eg, isotonic agents, buffers, antioxidants, preservative enhancers, may optionally be added to the diluent. Isotonic agents such as glycerin are commonly used at known concentrations. A physiologically tolerated buffer is presumably added to provide improved pH control. The formulations can cover a wide range of pHs, such as from about pH 4 to about pH 10, specifically, the range from about pH 5 to about pH 9, and more specifically, the range from about 6.0 to about 8.0. In one embodiment, the formulations of the present invention have a pH between about 6.8 and about 7.8. Suitable buffers include phosphate buffers, for example, sodium phosphate and phosphate buffered saline (PBS).

Other additives, such as pharmaceutically acceptable solvents such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polys, other block copolymers, and chelators such as EDTA and EGTA may optionally be added to pharmaceutical compositions to reduce aggregation. These additives are particularly useful if a plastic or pump container is used to administer the pharmaceutical composition. The presence of a pharmaceutically acceptable surfactant moderates the tendency of the composition to clump.

During any of the procedures for preparing the compounds of the present invention, it may be necessary and/or desirable to protect the sensitive and reactive groups of any molecule of interest. This can be accomplished by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (1973); and Greene and Wuts, Protective Groups in Organic Chemistry 81991). Protecting groups can be removed at a suitable subsequent stage using methods known in the art.

Ways of giving

The invention further relates to the administration of at least one compound disclosed herein by the following routes, including, but not limited to, oral, parenteral, subcutaneous, intramuscular, intravenous, intraarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracellular, intracerebral, intracerebroventicular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, large vessel, vaginal, rectal, buccal, sublingual, intranasal, iontophoretic, or transdermal.

Pulmonary/nasal administration

There are several desirable features of an inhalation device for delivering the compounds of the present invention. For example, delivery via an inhalation device is reliable, repeatable, and accurate. For pulmonary administration, at least one pharmaceutical composition is delivered in an effective particle size to reach the lower airways of the lungs and sinuses. The inhalation device can optionally deliver small dry particles, e.g. less than about 10 µm, assumed to be around 1-5 µm, to achieve good breathability.

According to the invention, at least one pharmaceutical composition can be delivered by any of the various inhalation or nasal devices known in the art for administering a therapeutic agent by inhalation. Devices capable of depositing aerosolized formulations into the patient's sinus cavity or alveoli include metered-dose inhalers, nebulizers, dry powder generators, sprays, and the like. Other devices suitable for directing pulmonary or nasal administration are also known in the art.

All such devices can be used to deliver a pharmaceutical composition in an aerosol. Such aerosols can consist of either solutions (both liquid and non-liquid) or solid particles. Metered dose inhalers such as the Ventolin<®>metered dose inhaler typically use a reactive gas and attempt to trigger during inspiration. See, e.g., WO 98/35888; WO 94/16970. Dry powder inhalers such as Turbular<®>

(Astra), Rothaler<®>(Glaxo), Diskus<®>(Glaxo), Spiros<®>inhaler (Dura),

devices recalmed by Inhale Therapeutics, and the Spinhaler<®>powder inhaler (Fisons), use inhalation initiation of a mixed powder. See U.S. Patent numbers 5,458,135; 4,668,218; WO 97/25086; WO 94/08552; WO 94706498; and EP 0 237 507, each of which is expressly incorporated herein by reference in its entirety. Nebulizers such as AERx<®>, Aradigm, Ultravent® Nebulizer (Mallinckrodt), and Acorn II® Nebulizer

(Marquest Medical Products), the above references fully incorporated herein by reference, produce aerosols from solutions, while metered dose inhalers, dry powder inhalers, etc. generate aerosols of small particles. These specific examples of commercially available inhalation devices are intended to be representative of specific devices suitable for use with the invention, and are not intended to limit the scope of the invention.

Suitable formulations for nasal administration, where the carrier is solid, include ordinary powders having a particle size, for example, in the range of 20 to 500 microns which are administered by a snorting method, i.e., by rapid inhalation through the nasal passage from a powder container held close to the nose. Suitable formulations, where the carrier is liquid, for administration, for example, nasal spray or nasal drops, include liquid and oily solutions of the active ingredient.

A spray containing a pharmaceutical composition of the present invention may be produced by forcing a suspension or solution of a compound disclosed herein through a syringe under pressure. The size and configuration of the nozzle, applied pressure, and liquid filling rate can be selected to achieve the desired outcome and particle size. An electrospray can be produced, for example, by an electric field associated with capillaries or filling a syringe. It is advantageous when the particles of at least one compound delivered by spray have a particle size ranging from about less than 1 µm to less than about 20 µm.

Pharmaceutical compositions of at least one of the compounds of the present invention

suitable for use with a spray typically include a compound disclosed herein in liquid solution at a concentration of from about 0.1 mg to about 100 mg of compound disclosed herein per ml_ of solution or mg/gm or any range or value within that, including but not limited to, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/mL or mg/gm. The pharmaceutical composition may include agents such as inert fillers, buffers, isotonic agents, preservatives, surfactants, or other known pharmaceutical composition agents.

The pharmaceutical composition of the present invention can be administered via a nebulizer such as a jet nebulizer or an ultrasonic nebulizer. Typically, in a jet atomizer, a source of compressed air is used to create a high velocity air jet through an orifice. As the gas expands behind the injector, an area of low pressure is created, which pulls the protein solution through a capillary tube connected to the liquid reservoir. The liquid stream from the capillary tube expands into unstable fibers and droplets as it leaves the tube, creating an aerosol. A range of configurations, flow rates, and baffle types can be employed to achieve the desired performance characteristics of a given jet atomizer. In an ultrasonic atomizer, high frequency electrical energy is used to create vibrating, mechanical energy, typically employing a piezoelectric transducer. This energy is transferred to the protein composition formulation either directly or through a vaporizing fluid, creating an aerosol including the protein composition. It is advantageous when the particles of the pharmaceutical composition delivered by the nebulizer have a particle size of about less than 1 µm to less than about 20 µm.

Pharmaceutical compositions containing a compound of the present invention suitable for use with a nebulizer, whether jet or ultrasonic, typically include a concentration of from about 0.1 mg to about 100 mg of a compound disclosed herein per ml_ of solution or mg/gm, or any range or value within that including, but not limited to, the individual amounts disclosed for spray compositions. The pharmaceutical composition may include other pharmaceutical agents such as an inert filler, buffer, isotonic agent, preservative, surfactant, and those known in the art for use in nebulizer administration.

In a metered dose inhaler (MDI), the reactive agent, a compound of the present invention, and any inert fillers or other additives are contained in a canister as a mixture including a liquid, compressed gas. Actuation of the metering valve releases the mixture as an aerosol, assumed to contain a particle size ranging from about less than 1 µm to less than about 20 µm.

The desired aerosol particle size can be obtained by employing a formulation of the compounds of the present invention produced by various methods known to those skilled in the art, including, but not limited to, jet crushing, spray drying, critical condensation point, and the like. Metered dose inhalers include those manufactured by 3M or Glaxo and use hydrofluorocarbon as the reactive fuel.

Pharmaceutical compositions for use with metered dose inhaler devices will generally include a finely divided powder containing a compound disclosed herein as a suspension in a non-liquid medium, for example, suspended in a reactant with the aid of a surfactant. The reactant can be any conventional material used for this purpose such as chlorofluorocarbon, hydrochlorofluorocarbon, hydrofluorocarbon, hydrocarbon including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluoroalkane-134a), HFA-227 (hydrofluoroalkane-227), and the like. In one embodiment, the reactant is a hydrofluorocarbon. The surfactant may be selected to stabilize the compound of the present invention as a suspension in the reactant, to protect the active agent against chemical degradation, and the like. Suitable surfactants include sorbitan trioleate, soy lecithin, oleic acid, and the like. In some cases, the aerosol solution preferably uses solvents such as ethanol. One of ordinary skill in the art will recognize that the methods of the present invention may be accomplished by pulmonary administration of the compounds disclosed herein by means of devices not described herein.

For absorption through a mucosal surface, the compositions and methods of the present invention for administering the compounds disclosed herein include an emulsion containing a plurality of submicron particles, mucoadhesive macromolecules, bioactive peptides, and a liquid continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion of the emulsion particles. See, e.g., U.S. Patent no. 5,514,670. Mucosal surfaces suitable for application of the emulsion of the present invention include corneal, ocular, oral, sublingual, nasal, vaginal, pulmonary, abdominal, intestinal, and rectal routes of administration. Pharmaceutical compositions for vaginal and rectal administration such as suppositories may contain as an inert filler, for example, polyalkylene glycols, petrolatum, coconut oil, and the like. The pharmaceutical composition for intranasal administration may be solid and contain inert fillers, for example, lactose, or may be a liquid or oily solution of nasal drops. For oral administration, inert fillers include sugars, calcium stearate, magnesium stearate, pregelatinized starch, and the like. See, e.g., U.S. Paten no. 5,849,695.

In another embodiment, the pharmaceutical compositions of the present invention may be administered by transdermal routes using the form of transdermal skin patches well known to those skilled in the art. For transdermal administration, a compound of the present invention is encapsulated in a delivery device such as a liposome or polymeric nanoparticles, microparticles, microcapsules, microspheres (collectively microparticles unless otherwise stated). A number of suitable devices are known, including microparticles made of synthetic polymers such as polyhydroxy acids such as polylactic acid, polyglycolic acid and their copolymers, polyorthoesters, polyanhydrides, polyphosphazenes, and natural polymers such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides, and combinations thereof. See, e.g., U.S. Patent no. 5,814,599. To be administered in the form of a transdermal delivery system, the administration dose may be, for example, continuous rather than intermittent throughout the dose regimen.

Suitable topical formulations may be presented as ointments, creams, gels and pastes containing the ingredient to be administered in a pharmaceutically acceptable carrier. A proposed topical delivery system is a transdermal patch containing a compound of the present invention.

A meat composition containing a compound of the present invention can be mixed with various carrier materials well known in the art including alcohols, aloe vera gel, allantoin, glycerin, oils with vitamins A and E, mineral oils, PPG2 myristyl propionate and the like to form, for example, alcohol solutions, meat cleaners, cleansing creams, skin gels, skin lotions, and shampoos in a cream or gel formulation. Examples of such carriers and formulation procedures can be found in Remington's Pharmaceutical Sciences (1990). Pharmaceutical formulations may contain from about 0.005 wt % to about 10 wt % of the active ingredient. In one embodiment, the pharmaceutical formulations contain from about 0.01 wt % to 5 wt % of a compound of the present invention.

Sometimes it may be desirable to deliver the compounds of the present invention to a subject over extended periods of time, for example, for periods of one week to one year from a single administration. Certain medical devices may be employed to provide continuous, intermittent, or on-demand patient dosing. The devices may be a pump or diffusion apparatus, or other devices that contain a drug reservoir and optionally diagnostic and monitoring components to regulate drug delivery. Various slow-release, part or implant dosage forms can be used. For example, a dosage form may contain a pharmaceutically acceptable non-toxic salt of a compound disclosed herein that has a low degree of solubility in body fluids, for example, (a) an acid addition salt with a polybasic acid such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, stearic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- or di-sulfonic acid, polygalacturic acid, and the like; (b) a salt with a polyvalent metal cation such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from, e.g., N,N'-dibenzylethylenediamine or ethylenediamine; or (c) combinations of (a) and (b) e.g., zinc tannate salt. Additionally, the compounds of the present invention or, presumably, a relatively insoluble salt such as those just described, may be formulated into a gel, for example, aluminum monostearate gel with, for example, sesame oil, suitable for injection. Examples of salts include, but are not limited to, zinc salts, zinc tannate salts, pamoate salts, and the like. Another type of injectable slow-release depot formulation contains the compound or salt dispersed or encapsulated in a poorly degrading, non-toxic, non-antigenic polymer such as a polylactic acid/polyglycolic acid polymer, for example, as described in U.S. Pat. 3,773,919. Compounds or relatively insoluble salts thereof such as those described above may also be formulated in a cholesterol network of silastic granules, eg, liposomes in a gaseous or liquid state are well known in the literature. See, e.g., U.S. Patent No. 5,770,222; Sustained and Controlled Release Drug Delivery Systems (1978).

Other examples include the requirement that the compounds of the present invention be administered via a sustained release delivery system comprising

biodegradable composition. The biodegradable composition may be composed of a biodegradable, non-toxic organic solvent that is miscible to dispersible in a liquid medium. The delivery system can be implanted at the implant site thereby causing the solvent to dissipate, disperse or leach from the composition into the surrounding tissue fluid through the resulting microporous matrix.

As used herein, the term "implant site" is intended to include the site in or to which the non-polymeric composition is applied. Implantation or implant placement may also involve the incorporation of a pharmaceutical composition comprising at least one compound of the present invention with a solid device. For example, the pharmaceutical composition is incorporated into a coating on a stent that is implanted in a subject. Additionally, other solid or biodegradable materials may be used as the substrate to which the pharmaceutical composition is applied. The coated material, containing the pharmaceutical composition, is then implanted, inserted, or adjacent to the subject or patient. The term "biodegradable" means that the non-polymeric material and/or implant matrix will degrade over time by the action of enzymes, by simple or enzyme-catalyzed hydrolytic action, and/or by other similar mechanisms in the human body. By "bioerodible" is meant that the implant matrix will erode and degrade over time due, at least in part, to contact with substances found in surrounding tissue fluids, cellular action, and the like. By "bioabsorbable" is meant that the non-polymeric matrix will be broken down and absorbed in the human body, for example, by cells, tissues, and the like.

Non-polymeric materials that can be used in the composition are generally those that are biocompatible, substantially insoluble in water and body fluids, and biodegradable and/or bioerodible. The non-polymeric material is capable of being at least partially dissolved in a water-soluble organic solvent. Non-polymeric materials are also capable of coagulating or solidifying to form a solid implant matrix. The non-polymeric material is combined with a compatible and suitable organic solvent to form a composition having a desired consistency ranging from aqueous to viscous to spreadable putty or paste.

Suitable organic solvents are those that are biocompatible, pharmaceutically acceptable, and will at least partially dissolve the non-polymeric material. The organic solvent has a solubility in water ranging from miscible to dispersible. Optionally, a pore-forming agent may be included in the composition to generate additional pores in the implant matrix. The pore forming agent can be any organic or inorganic, pharmaceutically acceptable substance that is substantially soluble in water or body fluid, and that will diffuse from the non-polymeric coagulating material and/or solid matrix of the implant into the surrounding body fluid at the implant site.

The compounds of the present invention are capable of providing a local or systemic biological, physiological or therapeutic action in the body of an animal. In formulating some of the pharmaceutical compositions described herein, the compound is assumed to be soluble and dispersible in the non-polymeric composition to form a homogeneous mixture, and upon implantation, becomes incorporated into the implant matrix. As the solid matrix degrades over time, the compound is capable of being released from the matrix into the adjacent tissue fluid, and suitable tissues and organs of the body, either adjacent to or remote from the implant site, presumably at a controlled rate. The release of the compound from the matrix can vary, for example, the solubility of the compound in the liquid medium, the distribution of the compound within the matrix, the size, shape, porosity, and solubility and biodegradability of the solid matrix. See, e.g., U.S. Patent No. 5,888,533. The amounts and concentrations of the ingredients in the composition administered to the patient will generally be effective to accomplish the intended task.

The compounds of the present invention may be administered via a bioactive agent delivery system comprising microparticles suspended in a polymer matrix. Microparticles can be microcapsules, microspheres and nanospheres that are currently known in science. Microparticles should be able to be loaded intact within a polymer that is or becomes a gel once inside the biological environment. Microparticles can be biodegradable or non-biodegradable. Many microencapsulation techniques used to incorporate a bioactive agent into a microparticle carrier have been studied in science. See, e.g., U.S. Patent numbers 4,652,441; 5,100,669; 4,438,253; and 5,665,428.

The putative polymer matrix will be biodegradable and exhibit low temperature water solubility and will undergo reversible thermal gelatinization at physiological mammalian body temperatures. The polymer matrix is capable of releasing the substance loaded within the matrix over time and in a controlled manner. Polymers gradually degrade via enzymatic or non-enzymatic hydrolysis in liquid or physiological environments. See, e.g., U.S.: Patent No. 6,287,588.

The compounds of the present invention may be administered via a drug delivery composition consisting of microparticles containing at least one chemotherapeutic agent and at least one chemosensitizer suspended in a polymer matrix. Microparticles can be microcapsules, microspheres or nanospheres that are currently known in science. Microparticles should be biodegradable and stable in physiological environments. The microparticles also allow diffusion of the chemotherapeutic agent and chemosensitizer oz core through the matrix at a predetermined release rate. Ionic chemotherapeutic agents are suitable for use in the delivery of the compositions of the invention. Ionic chemosensitizers are suitable for use in delivering the compositions of the invention. Drug delivery compositions can be delivered to the target site through a variety of known routes of administration. The doses of the chemotherapeutic agent and chemosensitizer incorporated into the drug delivery composition will depend on individual needs, the desired effect and the chosen route of administration. See, e.g., WO 98/50018.

Dose determinations

In general, the compounds disclosed herein may be used alone or in combination with other therapeutic agents at appropriate doses as defined by routine testing to obtain optimal efficacy while minimizing any potential toxicity. The dosage regimen utilizing the compound of the present invention may be selected according to various factors including the type, species, age, weight, sex, medical condition of the patient; the seriousness of the condition to be treated; way of giving; renal and hepatic function of the patient; and which compound is employed. An ordinary doctor or veterinarian can easily determine and prescribe the effective amount of medicine required to prevent, attack or stop the progress of the condition.

Optimal precision in achieving drug concentrations within a range that yields maximal efficacy with minimal toxicity may require a regimen based on the kinetics of compound availability to one or more target sites. Distribution, equilibrium, and elimination of a drug can be considered when determining the optimal concentration for a treatment regimen. Doses of the compounds disclosed herein may be adjusted when combined to achieve desired effects. On the other hand, the doses of these different therapeutic agents can be independently optimized and combined to achieve a synergistic result whereby the pathology is reduced more than it would be with any of the agents used alone.

In particular, the toxicity and therapeutic efficacy of the compounds disclosed herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., to determine the LD50 (lethal dose to 50% of the population) and ED50 (therapeutically effective dose to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD5o/ED5o ratio. Compounds exhibiting high therapeutic indices are contemplated except when cytotoxicity of the compound is the activity or therapeutic outcome desired, easily compounds exhibiting toxic side effects may be employed, the delivery system may target such compounds to the affected tissue location to minimize potential damage to uninfected cells and, therefore, reduce side effects. Generally speaking, the compounds of the present invention can be administered in a manner that maximizes efficacy and minimizes toxicity.

Data obtained from cell culture experiments and animal studies can be used in formulating a range of doses for use in humans. Doses of such compounds are assumed to be within the range of circulating concentrations that include ED50s with little or no toxicity. The dose may vary within this range depending on the dosage form employed and the route of administration used. For any compound used in the methods of the invention, a therapeutically effective dose can be initially estimated from cell culture experiments. The dose can be formulated in animal models to achieve circulating plasma concentrations in a range that includes the IC50 (concentration of the test compound that achieves half-maximal inhibition of symptoms) as determined in cell culture. Such information may be useful to precisely determine useful doses in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

Furthermore, dosing of the pharmaceutical compositions of the present invention can be optimized using a pharmacokinetic/pharmacodynamic modeling system. For example, one or more dosage regimens can be selected and a pharmacokinetic/pharmacodynamic model can be used to determine the pharmacokinetic/pharmacodynamic profile of one or more dosage regimens. Next, one of the dosage regimens for administration can be selected to achieve the desired pharmacokinetic/pharmacodynamic response based on the particular pharmacokinetic/pharmacodynamic profile. See WO 00/67776, which is expressly incorporated herein by reference in its entirety.

Procedures are known in the art for determining effective doses for therapeutic and prophylactic purposes for disclosed pharmaceutical compositions or disclosed drug combinations, whether or not they are formulated in the same composition. For therapeutic purposes, the term "combined effective amount", as used herein, means that amount of any active compound or pharmaceutical agent, alone or in combination, that produces a biological or medical response in a tissue system, animal or human so viewed by an investigator, veterinarian or doctor or other clinician, that includes the reduction of symptoms of the disease or disorder being treated. For prophylactic purposes (eg, inhibiting the onset or progression of a disease), the term "common effective amount" refers to the amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as seen by an investigator, veterinarian, physician, or other clinician. Thus, the present invention provides combinations of two or more therapeutic agents wherein, for example, (a) each therapeutic agent is administered in an independent and therapeutically and prophylactically effective amount; (b) at least one therapeutic agent in combination provides an amount that is sub-therapeutic or sub-prophylactic when administered alone, but is therapeutic and prophylactic when administered in combination with another additional therapeutic agent according to the invention; (c) both therapeutic agents are administered in an amount that is sub-therapeutic and sub-prophylactic when administered alone, but is therapeutic and prophylactic when administered together. Combinations of three or more therapeutic agents are analogously possible. Combination therapy procedures involve co-administration of a single formulation containing all active agents; essentially simultaneous administration of more than one formulation; and administering two or more separately formulated active agents.

Doses

More specifically, the pharmaceutical compositions may be administered in a single daily dose, or the total daily dose may be administered in separate doses two, three, or four times a day. In the case of oral administration, the daily dosage of the composition may vary widely from about 0.0001 to about 1,000 mg per patient, per day. The range may more specifically be from about 0.001 mg/kg to 10 mg/kg body weight per day, about 0.1-100 mg, about 1.0-50 mg or about 1.0-20 mg per day for adults (with about 60 kg).

The daily dose of the pharmaceutical compositions can vary widely from about 0.001 to about 1000 mg per adult per day. For oral administration, the pharmaceutical compositions are preferably provided in the form of tablets containing from about 0.1 mg to about 1000 mg of the compound or 0.1, 0.2, 0.5, 1.0, 2.0, 5.0, 10.0, 15.0, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, or 1000 milligrams of the active compound to symptomatically adjust the dose to the patient being treated. An effective amount of the drug is usually supplied at a dosage level of about 0.1 mg/kg to about 20 mg/kg of body weight per day. In one embodiment, the range is from about 0.2 mg/kg to about 10 mg/kg of body weight per day. In another embodiment, the range is from about 0.5 mg/kg to about 10 mg/kg of body weight per day. The compounds may be administered in a regimen of about 1 to about 10 times per day.

In the case of injection, it is usually convenient to administer intravenously in an amount of about 0.01-30 mg, about 0.1-20 mg or about 0.1-10 mg per day to an adult (at about 60 kg). In the case of other animals, a dose calculated at 60 kg may also be administered.

Doses of the compounds of the present invention may optionally include 0.0001 to 1,000 mg/kg/administration, or 0.001 to 100.0 mg/kg/administration, from 0.01 to 10 mg/kg/administration, from 0.1 to 10 mg/kg/administration, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and/or 100-500 mg/kg/administration or any range, value, or fraction thereof, or to achieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9, 2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10,010.5, 10.9, 11, 11.5, 11.9, 12.012.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and/or 5000 ug/mL serum concentrations per single or multiple giving or of it to any range, value or fraction.

As a non-limiting example, treatment of humans or animals may be provided as a single or periodic dose of a compound of the present invention of 0.1 to 100 mg/kg such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg per day, at least for one day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or alternatively or additionally, at least once a week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 17, 18, 19, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, or alternatively or additionally, at least one 1, 2, 3, 4, 5, 6" 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years, or any combination thereof, using single, infusion, or repeated doses.

Specifically, the pharmaceutical compositions of the present invention can be administered at least once a week for several weeks. In one embodiment, the pharmaceutical compositions are administered at least once a week for several weeks to several months. In another embodiment, the pharmaceutical compositions are administered once a week for four to eight weeks. In another embodiment, the pharmaceutical compositions are administered once a week for four weeks.

More specifically, the pharmaceutical compositions can be administered at least once a day for about 2 days, at least once for about 3 days, at least once a day for about 4 days, at least once a day for about 5 days, at least once a day for about 6 days, at least once a day for about 7 days, at least once a day for about 8 days, at least once a day for about 9 days, at least once a day for about 10 days, at least once a day for about 11 days, at least once a day for about 12 days, at least once a day for about 13 days, at least once a day for about 14 days, at least once a day for about 15 days, at least once a day for about 16 days, at least once a day for about 17 days, at least once a day for about 18 days, at least once a day for about 19 days, at least once a day for about 20 days, at least once a day for about 21 days, at least once a day for about 22 days, at least once a day for about 23 days, at least once a day for about 24 days, at least a day for about 25 days, at least once a day for about 26 days, at least once a day for about 27 days, at least once a day for about 28 days, at least once a day for about 29 days, at least once a day for about 30 days, or at least once a day for about 31 days.

Alternatively, the pharmaceutical compositions may be administered about once every day, about once every 2 days, about once every 3 days, about once every 4 days, about once every 5 days, about once every 6 days, about once every 7 days, about once every 8 days, about once every 9 days, about once every 10 days, about once every 11 days, about once every 12 days, about once every 13 days, about once every 14 days, about once every 15 days, about once every 16 days, about once every 17 days, about once every 18 days, about once every 19 days, about once every 20 days, about once every 21 days, about once every 22 days, about once every 23 days, about once every 24 days, about once every 25 days, about once every 26 days, about once every 27 days, about once every 28 days, about once every 29 days, about once every 30 days, or about once every 31 days.

The pharmaceutical compositions of the present invention may alternatively be administered about once every week, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, about once every 12 weeks, about once every 13 weeks, about once every 14 weeks, about once every 15 weeks, about once every 16 weeks, about once every 17 weeks, about once every 18 weeks, about once every 19 weeks, about once every 20 weeks.

Alternatively, the pharmaceutical compositions of the present invention may be administered about once every month, about once every 2 months, about once every 3 months, about once every 4 months, about once every 5 months, about once every 6 months, about once every 7 months, about once every 8 months, about once every 9 months, about once every 10 months, about once every 11 months, about once every 12 months.

Alternatively, the pharmaceutical compositions may be administered at least once a week for about 2 weeks, at least once a week for about 3 weeks, at least once for about 4 weeks, at least once for about 5 weeks, at least once for about 6 weeks, at least once for about 7 weeks, at least once for about 8 weeks, at least once for about 9 weeks, at least once for about 10 weeks, at least once for about 11 weeks, at least once for around 12 weeks, at least once around 13 weeks, at least once around 14 weeks, at least once around 15 weeks, at least once around 16 weeks, at least once around 17 weeks, at least once around 18 weeks, at least once around 19 weeks, or at least once around 20 weeks.

Alternatively, the pharmaceutical compositions can be administered at least once a week for about 1 month, at least once a week for about 2 months, at least once a week for about 3 months, at least once a week for about 4 months, at least once a week for about 5 months, at least once a week for about 6 months, at least once a week for about 7 months, at least once a week for about 8 months, at least once a week for about 9 months, at least once a week for about 10 months, at least once a week for about 11 months, or at least once a week for about 12 months.

Combination therapy

Additionally, simultaneous or sequential administration of compounds of the present invention and other therapeutic agents may be desirable, such as chemotherapeutic agents, immunosuppressive agents, cytokines, cytotoxic agents, nucleolytic agents, radioactive isotopes, receptors, and prodrug-activating enzymes, which may be naturally occurring or produced by recombinant methods. Combined administration includes simultaneous administration, using one formulation or one pharmaceutical formulation, and one after the other administration in one or another order, where there is assumed to be a period in which both (or all) active therapeutic agents simultaneously exert their biological activities.

The compounds of the present invention may be administered in combination with at least one selected from the group consisting of an antirheumatic (eg, methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxant, narcotic, non-steroidal anti-inflammatory drug, analgesic, anesthetic, sedative, local anesthetic, neuromuscular blocking agent, anti-cancer, antimicrobial agent. (eg, aminoglycoside, antifungal, antiparasitic, antiviral, carbapenem, cephalosporin, fluoroquinolone, macrolide, penicillin, sulfonamide, tetracycline, other antimicrobial), anti-psoriatic, corticosteroid, anabolic steroid, diabetes-related agent, mineral, nutritional agent, thyroid agent, vitamin, calcium-related hormone, antidiarrheal, antitussive, anti-emetic, anti-ulcer, laxative, anticoagulant, erythropoietin (e.g., epoetin alfa), filgrastim (eg, G-CSF, Neupogen), sargastim (GM-CSF, Leukine), immunization, immunoglobulin, immunosuppressive agent (eg, basiliximab, cyclosporine, daclizumab), growth hormone, drug-displacing hormone, estrogen receptor modulator, mydriatic agent, cycloplegic agent, alkylating agent, anti-metabolite, mitotic inhibitor, radiopharmaceutical agent, anti-depressant, anti-manic agent, anti-psychotic, anxiolytic, hypnotic, sympathomimetic, stimulant, donepezil, tacrine, asthma medication, beta agonist, inhaled steroid, leukotriene inhibitor, methylxanthine, cromolyn, epinephrine or its analog, dornase alfa (Pulmozym), or cytokine.

Such anti-cancer and antimicrobial compounds may also include molecules that are linked, bound, co-formulated, co-administered or administered one after the other, in one order or another, with at least one of the compounds of the present invention. The toxime may optionally act to selectively kill the pathological cell or tissue. A pathological cell can be a cancer or another cell. Such toxins may be, but are not limited to, a purified or recombinant toxin or toxin fragment consisting of at least one functional cytotoxic domain of the toxin, e.g., at least one selected from ricin, diphtheria toxin, venom toxin, bacterial toxin. The term toxin also includes endotoxins and exotoxins produced by any naturally occurring, mutant or recombinant bacteria or virus capable of causing any pathological condition in humans and other mammals, including toxic shock, which may result in death. Such toxins may include, but are not limited to, heterotoxigenic E. Coli temperature labile enterotoxin (LT), temperature stable enterotoxin (ST), Shigella cytotoxin, Aeromonas enterotoxins, toxic shock syndrome toxin-1 (TSST-1), Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcal enterotoxins, and the like. Such bacteria include, but are not limited to, strains of enterotoxic E. Coli (ETEC), enterohemorrhagic E. Coli (e.g., strains of serotype 0157:H7), Staphylococcal species (e.g., Staphvlococcus aureus, Staphvlococcus pvogenes), Shigella species (e.g., Shigella dvsenteriae, Shigella flexneri, Shigella bovdii, and Shigella sonnei), Salmonella species (e.g., Salmonella typhi, Salmonella cholera-suis, Salmonella enteriditis), Clostridium species (e.g., Clostridium perfringens, Clostridium dificile, Clostridium botulinum), Camphlobacter species (e.g., Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species (e.g., Heliobacter pvlori), Aeromonas species (e.g., Aeromonas sobria, Aeromonas hvdrophila, Aeromonas caviae), Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (eg, Vibrios cholerae, Vibrios parahemolvticus), Klebsiella species, Pseudomonas aeruginosa, and Streptococci. See, e.g., Stein, ed., INTERNAL MEDICINE, 3rd ed., pp. 1-13, Little, Brown and Co., Boston, (1990); Evans et al., eds., Bacterial Infections of Humans: Epidemiology and Control, 2d. Ed., pp. 239-254, Plenum Medical Book Co., New York (1991); Mandell et al, Principles and Practice of Infectious Diseases, 3d. Ed., Churchill Livingstone, New York (1990); Berkow et al, eds., The Merck Manual, 16th edition, Merck and Co., Rahway, N.J., 1992; Wood et al, FEMS Microbiology Immunology, 76:121-134 (1991); Marracketal, Science, 248:705-711 (1990), the contents of which are incorporated by reference in their entirety.

More specifically, a compound of the present invention may be administered in combination with at least one immunosuppressive agent for use in, for example, the treatment or prevention of vascular occlusive conditions such as transplant vasculopathy. Suitable immunosuppressive agents include, but are not limited to, CellCept (Roche Labs.), Gengraf (Abbot Labs., Inc.), Micrhogam (Ortho-Clinical), Neoral (Novartis), Orthoclone OKT3 (Ortho-Biotech), Prograf (Fujisavva), Rapamune (Wyeth-Ayerst), Sandimmune (Novartis), Thymoglobulin (SangStat), Zenapax (Roche).

In one embodiment, a therapeutic agent that is administered simultaneously or sequentially, in one or another order and at different times with a compound of the present invention, comprises a chemotherapeutic agent. A "chemotherapeutic agent" is a compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbochion, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoaoramide, and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazin, holophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiequin, fenesterin, prednimustine, trophosphamide, uracil mustard; nitroureas such as canustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycins, actinomycins, authramycins, azaserin, bleomycins, cactinomycins, calichemycins, carabicins, carminomycins, carcinophyllin, chromoicins, dactinomycins, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idambicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, cynostatin, zorubicin; anti-metabolites such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epithiostanol, meptithiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; a folic acid filler such as frolic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisenteric; edatraxate; Defofamine; demecolcin; diaziquone; elformitin; elliptinium acetate; ethoglucide; gallium nitrate; hydroxyurea; lentinan; londidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophilic acid; 2-ethylhydrazide; procarbazine; PSK®; razoksan schizophrenic; spirogermanium; tenuazonic acid; triaziquinone; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gakitosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); hlorambucil; gemcitabin; 6-tioguanin; merkaptopurin; metotreksat; analozi platine kao što su cisplatin i karboplatin; vinblastin; platina; etopozid (VP-16); ifosfamid; mitomicin C; mitoksantron; vinkristin; vinorelbine; navelbin; novantrop; tenipozid; daunomicin; aminopterin; kseloda; ibandronat; CPT-11; inhibitor topoizomeraze RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamycins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Thus included in this definition are anti-hormonal agents that act to regulate or inhibit the action of hormones on tumors such as anti-estrogens including for example tamoxifen, raloxifene, keoxifene, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

In another embodiment, the therapeutic agent comprises a cytokine. The term "cytokine" is a general term for proteins released by one cell population that act on another cell as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as pituitary gonadotropin hormone (FSH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LG); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-a and -B; mulerian-inhibiting substance; murine gonadotropin-related peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-B; platelet growth factor; transforming growth factors (TGFs) such as TGF-α and TGF-B; insulin-like factor-1 and -II; erythropoietin (EPO); osteoindicative factors; interferons such as interferon-α, -β, and -γ; colony stimulating factors (CSFs) such as macrophage-CSF (GCSF); interleukins (ILs) such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15; tumor necrosis factor such as TNF-α or TNF-β; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the cytokine parent sequence.

In another embodiment, the compounds of the present invention may be administered in combination with an anti-inflammatory agent including, but not limited to, adrenocortical steroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, thiramquinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, i.e., aspirin; para-aminophenol derivatives, i.e., acetominophen, indole, and indene) acetic acids (indomethacin, sulindac, etodalac), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyfentatrezone), nabumeton, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate). Commercially available non-steroidal anti-inflammatory drugs include, but are not limited to, Anaprox (Roche Labs.), Arthrotec (Searle), Cataflam (Novartis), Celebrex (Pfizer), Clinoril (Merck), Dolobid (Merck), Feldene (Pfizer), Indocin (Merck), Lodine (Wyeth-Averst), Mobic (Boehringer Ingelheim), Motrin (McNeil Consumer), Naprosyn (Roche Labs.), Orudis (Wyeth-Ayerst), Oruvail. (Wyeth-Ayerst), Ponstel (First Horizon), Relafen (GlaxoSmithKline), Tolectin (Ortho-McNeil), Toradol (Roche Labs., Inc.), Vioxx (Merck), Voltaren (Novartis), Advair (GlaxoSmithKline), Flovent (GlaxoSmithKline), Pulmicort (AstranZaneca), and Vanceril (Schering), Asacol (Procter & Gamble), Colazal (Salix), Dipentum (Pharmacia). & Upjohn), and Rowasa (Solvav).

In yet another embodiment, the compounds of the present invention may be administered in combination with an antirheumatic agent. Commercially available antirheumatic agents include, but are not limited to, Anaprox (Roche Labs.), Arava (Aventic), Arthotec (Searle), Azulfidine (Pharmacia & Upjohn), Cataflam (Novartis), Celebrex (Pfizer), Celestone (Schering), Cuprimine (Merck), Enbrel (lmmunex), Feldene (Pfizer), Gengraf (Abbott), Indocin (Merck), Lodine (Wyeth-Ayerst), Naprosyn (Roche Labs.), Neoral (Novartis), Pediapred (Celltech), Prednisone (Roxanne), Remicade (Centocor), Solu-Medrol (Pharmacia & Upjohn), Triliate (Purdue Frederick), and Voltaren (Novartis).

Moreover, the compounds of the present invention may be used in combination with any cardiovascular agent including, but not limited to, adrenergic blocking agents such as Cardura (Pfizer), Dibenzvline (WellSpring), Hvtrin (Abbott), Minipress (Pfizer), and Minizide (Pfizer); adrenergic stimulants such as Aldoclor (Merck), Aldomet (Merck), Aldoril (Merck), Catapres (Boehringer Ingelheim), Clorpres (Bertek), and Tenex (Robins); alpha/beta adrenergic blockers such as Coreg (GlaxoSmithKline), and Normodvne (Schering); angiotensin-converting enzyme inhibitors such as Accupril (Parke-Davis), Aceon (Solvav), Altace (Monarch), Captopril (Mylan), Enalaprilat (Baxter Anesthesia), Lotensin (Novartis), Mavik (Abbott), Monopril (Bristol-Myers Squibb), Prinivil (Merck), Univasc (Schwarz), Vaotec (Merck), and Zestril (AstraZeneca); angiotensin converting enzyme inhibitors such as Lexxel (AstraZeneca), Lotrel (Novartis), Tarka (Abbott), Accuretic (Parke-Davis), Lotensin (Novartis), Prinzide (Merck), Uniretic (Schwarz), Vaeretic (Merck), and Zestoretic (AstraZeneca); angiotensin II receptor antagonists such as Atacand (AstraZeneca), Avapro (Briston-Myers Squibb), Cozaar (Merck), Diovan (Novartis), Micardis (Boehringer Igelheim), and Teveten (Unimed); antiarrhythmics (Groups 1-IV), antilipemic agents such as bile acid sequestrants, fibric acid derivatives, HMG-CoA reductase inhibitors, and nicotinic acid; inotropic agents; vasodilators including coronary vasodilators, natriuretic peptides, and peripheral vasodilators; and vasopressors.

In another aspect of the present invention, the therapeutic agent comprises small molecule toxins, including maytansine, calichemycin, trichothene, and CC 1065. In a specific embodiment, the therapeutic agent may comprise one or more calichemycin molecules. The calichemicin family of antibiotics is capable of producing double-stranded DNA breaks at sub-picomolar concentrations. Structural analogs of calichemicin are also known. See Hinman et al., 53 Cancer Research 3336-42 (1993); Lode et al., 58 Cancer Research 2925-28 (1998).

In yet another aspect of the present invention, the therapeutic agent may comprise one or more enzymatically active toxins and fragments thereof. Examples of such toxins include non-binding active fragments of diphtheria toxin, diphtheria A chain, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modecin A chain, alpha-sarcin, diantin proteins, Phvtolaca americana proteins (PAPI, PAPAIII, and PAP-S), momordica charantia inhibitor, circin, crotin sapaonaria officinalis inhibitor, gelonin, mitogelin, restrictoein, phenomvicin, enomycin. and trichothecenes. See, e.g., WO 93/21232.

The present invention further contemplates therapeutic agents having nucleolytic activity such as ribonucleases and deoxyribonucleases. Additionally, a variety of radioactive isotopes are available to produce radioactively conjugated binding partners. Examples include Y<90>, At2<22>, Ref<36>, Re<186>, Sm<153>, Bi<212>, P<32> and the radioactive isotopes Lu.

In yet another aspect of the present invention, at least one compound can be conjugated to a receptor, such as streptavidin, for use in pre-targeting a tumor. Briefly, the compound-receptor conjugate is administered to the patient and the unbound conjugate is removed from the circulation with a scavenger. A ligand, such as biotin, which is conjugated to the cytotoxic agent is then administered.

Time of giving

In several embodiments of the present invention, a compound described herein is administered before or after administration of another therapeutic agent. Administration of the compound can occur anywhere from a few minutes to a few hours before the administration of the other therapeutic agent. Alternatively, the compound may be administered anytime from a few hours to a few days, possibly a few weeks, up to a few months before the other therapeutic agent.

More specifically, a compound of the present invention may be administered for at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, at least about 21 minutes, at least about 22 minutes, at least about 23 minutes, at least about 24 minutes, at least about 25 minutes, at least about 26 minutes, at least about 27 minutes, at least about 28 minutes, at least about 29 minutes, at least about 30 minutes, at least about 31 minutes, at least about 32 minutes, at least about 33 minutes, at least about 34 minutes, at least about 35 minutes, at least about 36 minutes, at least about 37 minutes, at least about 38 minutes, at least about 39 minutes, at least about 40 minutes, at least about 41 minutes, at least about 42 minutes, at least about 43 minutes, at least about 44 minutes, at least about 45 minutes, at least about 46 minutes, at least about 47 minutes, at least about 48 minutes, at least about 49 minutes, at least about 50 minutes, at least about 51 minutes, at least about 52 minutes, at least about 53 minutes, at least about 54 minutes, at least about 55 minutes, at least about 56 minutes, at least about 57 minutes, at least about 58 minutes, at least about 59 minutes, or at least about 60 minutes before or after the other therapeutic agent. Further, the compound of the present invention may be administered for at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours, at least about 16 hours, at least about 17 hours, at least about 18 hours, at least about 19 hours, at least about 20 hours, at least about 21 hours, at least about 22 hours, at least about 23 hours, or at least about 24 hours before or after the other therapeutic agent.

Moreover, the compound of the present invention can be given for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days or at least about 31 days before or after the administration of another therapeutic agent.

In another aspect of the present invention, a compound of the present invention can be administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, or at least about 20 weeks before or after the other therapeutic agent.

In a further aspect of the present invention, a compound of the present invention may be administered at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months before or after the other therapeutic agent.

For practical reasons, the meaning of certain terms and phrases used in the description, examples, and claims is given below.

DEFINITIONS

As used herein, the term "compound" includes both the singular and the plural, and includes any single entity or combined entities having at least the activity disclosed herein and combinations, fragments, analogs, or derivatives of such entities. Such entities include, but are not limited to, chemical elements, molecules, compounds, mixtures, emulsions, chemotherapeutic agents, pharmacological agents, hormones, antibodies, growth factors, cellular factors, nucleic acids, proteins, peptides, peptidomimetics, nucleotides, carbohydrates, and combinations, fragments, analogs, or derivatives of such entities.

The term "phenylamine" refers to primary or secondary benzenamine, commonly known as aniline. The amino group on the aniline can be substituted with hydrogen, alkyl (CrC12 straight-chain or branched), cycloalkyl (C3-C10), or an aryl-substituted aryl group. The phenyl ring of this aniline derivative may be optionally substituted with one or more functional groups, or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfoxyacid, morpholino, piperazinyl, pyridyl, phenyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, or phosphonate. If applicable, these groups may be represented in the protected or unprotected forms used in standard organic synthesis.

The term "naphthylamine" refers to primary or secondary α- or β-naphthylamine. The ring substructure in naphthylamine may be optionally substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfoxyline, morpholino, piperazinyl, pyridyl, phenyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, phosphonate and the like. These groups can be represented in protected or unprotected forms used in standard organic synthesis.

The term "naphthylalkyl amine" refers to a primary or secondary α- or β-naphthylalkyl amine (eg, 2-oc-naphthylethyl amine). The term "benzalkyl amine"

refers to a primary or secondary benzalkyl amine (eg, phenylethyl amine). These aryl alkyl substructures or compounds can be optically active or optically inactive. The aryl (ring) naphthylalkyl and benzalkyl amine substructures may be optionally substituted with one or a combination of functional groups, such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfonic acid, morpholino, piperazinyl, pyridyl, phenyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, phosphonate and the like. If applicable, these groups may be represented in the protected or unprotected forms used in standard organic synthesis.

The term "quinolinyl amine" refers to primary or secondary quinolyl amines. These amines can be in optically active or inactive forms. The aryl (ring) quinolyl amine substructure may be optionally substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfoacid, morpholino, piperazinyl, pyridyl, phenyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, phosphonate and the like. These groups can be represented in protected or unprotected forms used in standard organic synthesis.

The term "heteroaryl amines" refers to pyrroles, pyrazoles, imidazoles and indoles. The aryl (ring) heteroaryl amine substructure may be optionally substituted with one or a combination of functional groups such as alkyl, alkenyl, alkynyl, phenyl, benzyl, halo, cyano, nitro, hydroxy, thioxy, alkoxy, aryloxy, haloalkyloxy, alkylthio, arylthio, amino, alkyl amino, aryl amino, acyl, carboxyl, amido, sulfonamido, sulfonyl, sulfate, sulfoxyacid, morpholino, piperazinyl, pyridyl, phenyl, furanyl, pyrroyl, pyrazolyl, phosphate, phosphonic acid, or phosphonate. These groups can be represented in protected or unprotected forms used in standard organic synthesis.

The term "glycated proteins" as used herein includes proteins linked to glucose, either enzymatically or non-enzymatically, primarily by condensation of free epsilon-amino groups in the protein with glucose, forming Amadori fusion products. Further, glycated protein, as used herein, includes not only proteins that contain these initial glycation products, but also glycation products that result from further reactions such as rearrangement, dehydration, and condensation from irreversible advanced glycation end products (AGEs).

The term "polynucleotide" refers generally to polymeric forms of nucleotides of any length, whether ribonucleotides or deoxynucleotides. Thus, this term includes, but is not limited to, single-stranded, double-stranded, or multi-stranded DNA or RNA. Polynucleotides can further consist of genomic DNA, cDNA, or DNA-RNA hybrids. Moreover, the polynucleotides of the present invention may be synthetically produced.

Polynucleotides may contain chemically modified, biochemically modified, or derivatized nucleotides. For example, a polynucleotide may consist, in part, of modified nucleotides such as methylated nucleotides or nucleotide analogs. In another embodiment, polynucleotides may consist of sugars, caps, nucleotide forks, and linking groups such as fluororibose and thioate. Additionally, the nucleotide sequence may be interrupted by non-nucleotide components. Still further, a polynucleotide can be modified after polymerization to aid its attachment to other polynucleotides, proteins, metal ions, labeling components, or a solid support.

The polynucleotide backbone may consist of modified or substituted sugar and/or phosphate groups. Alternatively, the backbone of the polynucleotide may consist of synthetic subunit polymers such as phosphoramidites and thus may be an oligodeoxynucleoside phosphoramidate or a mixed phosphoramidate-phosphodiester oligomer. See Pevrottes et al., Nucl. Acids Res. (1996) 24:1841-1848, and Chaturvedi et al., Nucl. Acids Res.

(1996)24:2318-2323.

The term "homology," as used herein, refers to the degree of complementarity. It can be partial homology or complete homology (that is, identity). A partially complementary sequence is one that at least partially inhibits an identical sequence from hybridizing to a target polynucleotide; refers to the use of the functional term "essential homologues". Inhibition of hybridization of a fully complementary sequence to a target sequence can be assayed using hybridization assays (Southern and Northern blots, hybridization solution, and the like) under low stringency conditions. A substantially homologous sequence or probe will compete to inhibit the binding (ie, hybridization) of a fully homologous sequence or probe to the target sequence under low stringency conditions. This is not to say that low stringency conditions are such that non-specific binding is permitted; low stringency conditions require that the binding of two sequences to each other be a specific (ie, selective) interaction. The absence of non-specific binding can be tested using another target sequence that lacks even a partial degree of complementarity (eg, less than about 30% identity); in the absence of non-specific binding, the probe will not hybridize to another non-complementary target sequence.

The term "gene" refers to a polynucleotide sequence consisting of a coding sequence necessary for the production of a polypeptide or precursor, and which may also include expression control sequences or other control or regulatory sequences. The polypeptide may be encoded by the full-length coding sequence or a portion of the coding sequence. A gene may be derived in whole or in part from any source known to one of ordinary skill in the art including, plant, fungi, animal, bacterial genome or episome, eukaryotic, nuclear or plasmid DNA, cDNA, viral DNA, or chemically synthesized DNA. A gene may constitute an uninterrupted coding sequence or may include one or more introns, linked by an appropriate junction junction. Moreover, a gene may contain one or more modifications in either coding or untranslated regions that may affect certain properties of the polynucleotide or polypeptide, such as biological activity or chemical structure of the expression product, rate of expression, mode of expression control. Such modifications include, but are not limited to, mutations, insertions, deletions, and substitutions of a single or multiple nucleotides. In this respect, such modified genes can be considered as variants of the parent gene.

"Gene expression" refers to the process by which a polynucleotide sequence is subjected to successful transcription and translation such that detectable levels of the nucleotide sequence are expressed as proteins of the polynucleotide sequence undergoing transcription, if RNA is copied from DNA, or replication, if DNA is copied from DNA, so that the resulting nucleotide copies are detectable.

The term "gene expression profile" refers to a group of genes that represent a particular cell or cell type (eg, neuron, coronary artery endothelium, or diseased tissue) in any state of activation. In one embodiment, a gene expression profile is generated from cells exposed to a compound of the present invention. This profile can be compared to the gene expression profile from the same cell type or tissue prior to treatment with a compound of the present invention. Moreover, a series of gene expression profiles can be generated from cells or tissues treated with a compound of the present invention, specifically, at different doses or time course to assess the effects of the compound. A gene expression profile is also known as a gene expression signature.

The term "differential expression" refers to both quantitative and qualitative differences in the temporal and tissue expression patterns of genes. For example, a differentially expressed gene may have its expression activated or completely inactivated in normal versus disease states. Thus, a qualitatively regulated gene may display an expression pattern within a given tissue or cell type that is detectable in either control or disease states, but not detectable in both. "Differentially expressed polynucleotide" as used herein refers to a polynucleotide sequence that uniquely identifies differentially expressed genes such that the detection of a differentially expressed polynucleotide in a sample is correlated with the presence of a differentially expressed gene in the sample.

Similarly, a differentially expressed protein may have its expression activated or completely inactivated in normal versus disease states. Thus a qualitatively regulated protein may display an expression pattern within a given tissue or cell type that is detectable in either control or disease states, but not detectable in both. "Differentially expressed protein", as used herein, refers to an amino acid sequence that uniquely identifies a differentially expressed protein such that the detection of a differentially expressed protein in a sample is correlated with the presence of a differentially expressed protein in the sample.

"Cell type", as used herein, refers to a cell from a given source (eg, tissue or organ), a cell in a given state of differentiation, a cell associated with a given pathology or genetic form.

The term "polypeptide" refers to the polymeric form of amino acids of any length, which may include translated, untranslated, chemically modified, biochemically modified, and derivatized amino acids. A polypeptide can be naturally occurring, recombinant, synthetic, or any combination of these. Moreover, the term "polypeptide" as used herein refers to proteins, polypeptides, and peptides of any size, structure, or function. For example, a polypeptide may consist of a series of amino acids held together by peptide bonds. A polypeptide may alternatively consist of a long chain of amino acids held together by peptide bonds. Moreover, the polypeptide may also consist of a fragment of a naturally occurring protein or peptide. A polypeptide can be a single molecule or it can be a multi-molecule complex. Additionally, such polypeptides may also have modified peptide backbones.

The term "polypeptide" further includes immunolabeled proteins and fusion proteins, including, but not limited to, fusion proteins with heterologous amino acid sequences, fusion proteins with heterologous and homologous leader sequences, and fusion proteins with or without N-terminal methionine residues.

The term "protein expression" refers to the process by which a polynucleotide sequence undergoes successful transcription and translation such that detectable levels of the amino acid sequence or protein are expressed.

The term "protein expression profile" refers to a group of proteins that represent a particular cell or tissue type (eg, neuron, coronary artery endothelium, or diseased tissue). In one embodiment, a protein expression profile is generated from cells or tissues exposed to a compound of the present invention. This profile can be compared to the protein expression profile generated from the same cell type or tissue prior to treatment with a compound of the present invention. Moreover, a series of protein expression profiles can be generated from cells or tissues treated with a compound of the present invention, specifically, at different doses or time course to assess the effects of the compound. A protein expression profile is also known as a protein expression signature.

As used herein, "biomolecule" includes polynucleotides and polypeptides. Moreover, "biomolecular sequence", as used herein, is a term that refers to all or part of a polynucleotide sequence. A biomolecular sequence may also refer to all or part of a polypeptide sequence. In the context of biomolecules, eg, perlecan, the term "functional equivalent" refers to a protein or polynucleotide molecule that possesses functional and structural characteristics that are substantially similar to all or part of the parent perlecan protein or parent perlecan-encoding polynucleotides. The functional equivalent of the parent perlecan protein may contain modifications depending on the necessity of such modifications for specific structures or performance of specific functions. The term "functional equivalent" is intended to include "fragments", "mutants", "derivatives", "alleles", "hybrids", "variants", "analogs", or "chemical derivatives" of the parent perlecan.

"Host cell" as used herein refers to a microorganism, prokaryotic cell, eukaryotic cell, or cell line cultured as a unicellular entity that can be used as recipients for

a recombinant vector or other polynucleotide transfer, and includes the progeny of the original cell that has been altered by the infection. It is understood that the progeny of a single cell need not be completely identical in morphology or genomics or total DNA complement to the original parent due to natural, accidental or intentional mutation.

In the context of immunoglobulins, the term "functional equivalent" refers to immunoglobulin molecules that exhibit immunological binding properties that are substantially similar to the parent immunoglobulin. As used herein, the term "immunological binding properties" refers to non-covalent interactions of the type that occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific. Certainly, the functional equivalent of an immunoglobulin monoclonal antibody, for example, can display the binding of the parent monoclonal antibody to its antigen. A functional equivalent may consist of F(ab')2 fragments, F(ab) molecules, Fv fragments, single chain fragment differentially displayed on phage (scFv), single antibody domains, chimeric antibodies, or the like as long as the immunoglobulin displays the characteristics of the parent immunoglobulin.

As used herein, the term "isolated" refers to a polynucleotide, polypeptide, antibody, or host cell that is in a different environment from that in which the polynucleotide, polypeptide, antibody, or host cell occurs naturally. An isolated polynucleotide, polypeptide, antibody, or host cell is generally substantially purified.

As used herein, the term "substantially purified" refers to a compound that has been removed from its natural environment and is at least about 60% to 99.9% free of other components, or at least about 60% free, at least about 65% free, even about 70% free, at least about 80% free, at least about 83% free, at least about 85% free, at least about 88% free, at least about 90% free, at least about 91% free, at least about 92% free, at least about 93% free, at least about 94% free, at least about 95% free, at least about 96% free, at least about 97% free, at least about 98% free, at least about 99% free, at least about 99.9% free, or at least about 99.99% free of other components with which it is naturally associated. For example, a composition comprising A is "substantially free of" B when at least about 85% by weight of the total A+B is in the composition A. Alternatively, A comprises at least about 90% by weight of the total A+B in the composition, further even, at least about 95% or even 99% by weight.

"Diagnosis," as used herein, generally includes determining a subject's susceptibility to a disease or disorder, determining whether the subject is currently affected by the disease or disorder, predicting the effect of the disorder or disease on the subject (e.g., identifying pre-metastatic or metastatic cancerous conditions, the stage of the cancer, or the response of the cancer to therapy), and therametrics (e.g., monitoring the subject's condition to provide information regarding the effects or efficacy of therapy).

The term "biological sample" includes various types of sample obtained from or originating from an organism that may be used in diagnostic, monitoring, or other tests. The term includes blood, serum, plasma, cells, proteins, carbohydrates, nucleic acids, urine, nasal secretions, mucosal secretions, cell fluid, cell secretions and other fluid samples of biological origin, solid tissue samples such as biopsy clippings, or tissue or cell cultures derived therefrom and their progeny. The term specifically includes a clinical sample, and further includes cells and cell culture, cell surface layer, cell lysates, amniotic fluid, biological fluids, and tissue samples. This term also includes samples handled in any way after receiving such treatment with reagents, solubilization, enrichment of components. A biological sample can be derived from the organism directly or it can be collected from the environment.

The terms "individual," "subject," "host," and "patient" refer to any subject for whom diagnosis, treatment, or therapy is desired. In one embodiment, the individual, subject, host, or patient is a human. Other subjects may include, but are not limited to, animals including, but not limited to, cattle, sheep, horses, dogs, cats, guinea pigs, rabbits, rats, primates, possums, and mice. Other subjects include species of bacteria, phages, cell cultures, viruses, plants and other eukaryotes, prokaryotes and unclassified organisms.

The terms "treatment," "treating," "treating," and the like are used herein to refer generally to obtaining a desired pharmacological and/or physiological effect. The action may be prophylactic in terms of complete or partial prevention of the disease or its symptom and/or may be therapeutic in terms of partial or complete stabilization or treatment of the disease and/or adverse effects attributable to the disease. "Treatment" as used herein covers any treatment of a disease in a subject, particularly a human, and includes: (a) preventing a disease or symptom from occurring in a subject who may be predisposed to the disease or symptom but not yet diagnosed as having it; (b) inhibiting the symptoms of the disease, that is, stopping its development; or (c) relieving the symptoms of a disease, ie, causing regression of the disease or symptoms.

The term "therapeutically effective amount" refers to an amount, for example, of a compound disclosed herein, that is effective for preventing, ameliorating, treating, or delaying the onset of a disease or condition.

A "prophylactically effective amount" refers to an amount, for example, of a compound disclosed herein that is effective in preventing a disease or condition.

A "liposome" is a small bubble composed of various types of lipids, phospholipids, and/or a surfactant, which is useful for delivering a drug to a subject, such as a mammal or other animal. The compounds of the present invention can be delivered via liposomes. Liposome components are usually arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Liposome formulations, liposome loading, and liposome administration and delivery are known in the art.

"Hybridization", broadly defined, refers to any process by which a polynucleotide sequence is linked to a complementary sequence via base pairing. Hybridization conditions can be defined by, for example, the concentration of salt or formamide in the pre-hybridization and hybridization solutions, or by the hybridization temperature, and are known in the art. Hybridization can occur under conditions of varying stringency. Hybridization can also refer to binding agents

for protein capture to a target protein under certain conditions, such as normal physiological conditions.

As understood herein, the term "activation" refers to the alternation of a signaling pathway or biological response including, for example, an increase above baseline levels, a return to baseline levels from an inhibited state, and stimulation of a pathway beyond baseline levels.

The term "biological activity" refers to the biological behavior and effects of proteins or peptides. The biological activity of proteins can be influenced at the cellular and molecular level. For example, an antisense oligonucleotide can prevent the translation of a particular mRNA, thereby inhibiting the biological activity of the protein encoded by the mRNA. Additionally, an antibody can bind to a specific protein and inhibit the biological activity of that protein.

The term "oligonucleotide" as used herein refers to polynucleotide sequences consisting of, for example, from about 4 nucleotides (nt) to about 1000 nt. Oligonucleotides for use in the present invention are preferably from about 15 nt to about 150 nt, more preferably from about 150 nt to about 1000 nt in length. The oligonucleotide can be a naturally occurring oligonucleotide or a synthetic oligonucleotide. Oligonucleotides can be prepared by the phosphoramidite method (Beaucage and Carruteher, Tetrahedron Lett. (1981) 22:1859-1862), or by the triester method (Matteucci et al., J. Am. Chem. Soc. (1981) 103:3185), or by other chemical methods known in the art.

The term "microarray" refers generally to the type of gene or protein represented on the microarray by means of oligonucleotides (polynucleotide sequences) or protein binding agents, and where the type of gene or protein represented on the microarray is dependent on the intended purpose of the microarray (eg, to monitor the expression of human genes or proteins). Oligonucleotides or protein binding agents on a given microarray may correspond to the same type, category, or group of genes or proteins. Genes or proteins can be considered to be of the same type if they share the same characteristics as species of origin (eg, human, mouse, rat); disease state (eg, cancer); function (eg, protein kinases, tumor suppressors); the same biological process (eg, apoptosis, signal transduction, cell cycle regulation, proliferation, differentiation). For example, one type of microarray may be a "cancer microarray" in which each of the microarray oligonucleotides or protein binding agents corresponds to a gene or protein associated with cancer. An "epithelial microarray" can be a microarray of oligonucleotides or protein binding agents that correspond to unique epithelial genes or proteins. Similarly, a "cell cycle microarray" can be a type of microarray in which oligonucleotides or protein binding agents correspond to unique genes or proteins associated with the cell cycle.

The term "detectable", in one sense, refers to the expression pattern of a polynucleotide detectable by standard techniques of polymerase chain reaction (PCR), reverse transcriptase (RT) - PCR (RT-PCR), differential display, and Northern analysis, which are well known to those skilled in the art. Similarly, polypeptide expression patterns can be "detected" by standard techniques including immunoassays such as Western blots. In general, the term "detectable" is used when the result of an action, such as the addition of a compound in an assay step, is detectable, particularly by physical means, such as a change in color.

"Target gene" refers to polynucleotides, often derived from a biological sample, to which an oligonucleotide probe is designed to specifically hybridize. It was the presence or absence of the target polynucleotide to be detected, or the amount of the target polynucleotide to be quantified. The targeting polynucleotide has a sequence that is complementary to the polynucleotide sequence of the corresponding targeting probe. A target polynucleotide may also refer to specific subsequences of the larger polynucleotide to which the probe is directed or to the overall sequence (eg, gene or mRNA) whose expression level is desired to be detected.

"Target protein" refers to a polypeptide, often derived from a biological sample, to which a protein capture agent specifically hybridizes or binds. This is either the presence or absence of the target protein to be detected, or the amount of the target protein to be quantified. The target protein has a structure that is recognized by the appropriate targeting protein capture agent. A target protein or amino acid may also refer to specific substructures of a larger protein to which the protein capture agent is directed or the overall structure (eg, a gene or mRNA) whose expression level is desired to be detected.

The term "complementary" refers to the topological compatibility or mutual matching of the interacting surfaces of the probe molecule and its target. The target and its sample can be described as complementary, and even further, the features of the contact surface are complementary to each other. Hybridization or base pairing between nucleotides or nucleic acids, such as, for example, between two strands of a double-stranded DNA molecule or between an oligonucleotide probe and a target are complementary.

The term "background" refers to non-specific binding or other interactions between, for example, polynucleotides, polypeptides, small molecules and polypeptides, or small molecules and polynucleotides. "Background" can also refer to non-specific binding or other interactions in the context of an assay including an immunoassay.

In the context of microarrays, the term "background" refers to hybridization signals resulting from non-specific binding, or other interaction, between labeled target polynucleotides and oligonucleotide microarray components (eg, oligonucleotide probes, control probes, microarray carrier) or between target proteins and protein binding agents of the protein microarray. Background signals can also be produced by the intrinsic fluorescence of the microarray components themselves. A single background signal can be calculated for the entire microarray, or a different background signal can be calculated for each target polynucleotide or target protein. The background can be calculated as the average intensity of the hybridization signal, or where different the background signal is calculated for each target gene or target protein. Alternatively, background can be calculated as the total hybridization signal intensity produced by hybridization to probes that are not complementary to any sequence found in the sample (eg, probes directed to polynucleotides of opposite orientation or to genes not found in the sample such as bacterial genes where the sample is mammalian polynucleotides). Background can also be calculated as the average signal intensity produced by areas of the microarray that completely lack any probe or protein binding agent.

"Small molecule" includes a compound or molecular complex, whether synthetic, naturally derived, or partially synthetic, composed of carbon, hydrogen, oxygen, and nitrogen, which may also contain other elements, and which may have a molecular weight of less than about 100 to about 15,000 Daltons, or less than about 15,000, less than about 14,000, less than about 13,000, less than about 12,000, less than about 11,000, less than about 10,000, less than about 9,000, less than about 8,000, less than about 7,000, less than about 6,000, less than about 5,000, less than about 4,000, less than about 3,000, less than about 2,000, less than about 1,000, less than about 900, less than about 800, less than about 700, less than about 600, less than about 500, less than about 400, less than about 300, less than about 200, or less than about 100.

The term "fusion protein" refers to a protein composed of two or more polypeptides which, although typically not joined in their native state, are joined at their individual amino and carboxyl termini via peptide bonds to form a single continuous polypeptide. It is understood that two or more polypeptide components may be either directly linked or indirectly linked via a peptide linker/spacer group.

The term "normal physiological conditions" means conditions that are typical inside a living organism or cell, easily some organs or organisms give extreme conditions, the intra-organism and intra-cellular environment normally varies around pH 7 (that is, from pH 6.5 to pH 7.5), contains water as the predominant solvent, and exists at temperatures above 0°C and below 50°C. The concentration of different salts depends on the organ, organism, cell, or cell compartment used as a reference.

The term "cluster" refers to a group of clones or biomolecular sequences that are related to one another by sequence homology. In one example, clusters are formed based on a specific degree of homology and/or overlap (eg, stringency) "Clustering" can be performed with sequence data. For example, biomolecular sequences thought to be associated with a particular molecular or biological activity in one tissue can be compared against another sequence library or database. This type of search is useful to find homologous, and putatively functionally related, sequences in other tissues or samples, and can be used within one or more databases for a cluster of biomolecular sequences prior to performing the invention process. Sequences showing sufficient homology to a representative sequence are considered part of a "cluster". Such "sufficient" homology may vary within the needs of one skilled in the art.

As used herein, the term "internal database" refers to a database maintained within a local computer network. It contains, for example, biomolecular sequences related to the project. It may also contain information associated with the sequences including, but not limited to, the library in which the given sequence was found and descriptive information about the likely gene associated with the sequence. An internal database can typically be maintained as a private database behind a firewall within the enterprise network. An internal database may include sequence data generated by the same company that maintains the database, and may also include sequence data obtained from external sources.

The term "external database" is understood here to refer to a database located among all internal databases. Typically, an enterprise network that is different from the enterprise network that maintains the internal database will maintain the external database. An external database can be used, for example, to provide some descriptive information about biomolecular sequences stored in an internal database. In one embodiment, the external database is GenBank and linked to databases maintained by the National Center for Biotechnology Information (NCBI), part of the National Library of Medicine.

As used here and in claims, the English forms for the singular "a." "an," and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, a reference to "a compound" is a reference to one or more such compounds and includes equivalents thereof known to those skilled in the art, and so on.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains, readily any methods, devices, and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, the assumed methods, devices, and materials are now described.

All publications and patents mentioned herein are incorporated by reference for the purpose of describing and disclosing, for example, the constructs and methodologies described in those publications that may be used in connection with the invention described herein. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein shall be construed as an admission that the inventors are not entitled to cite such prior discovery by reason of being an earlier invention.

It should be understood that the present invention is not limited to the particular methodology, protocols, cell lines, constructs, and agents described herein and as such may vary. It should also be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to limit the scope of the present invention, which will be limited only by the claims.

EXAMPLES

The present invention is further illustrated by the following examples, which are in no way intended to limit the scope of this text, but are merely illustrative. Conversely, it should be clearly understood that various embodiments, modifications, and equivalents thereof, after reading the description provided herein, may be suggested to those skilled in the art without departing from the spirit of the present invention or the scope of the claims as an aid to the work.

The following acronyms, abbreviations, terms and definitions are used throughout the experimental section. Acronyms and abbreviations: DIEA (N,N-diisopropylethylamine), THF (tetrahydrofuran), HPLC (high performance liquid chromatography), TLC (thin layer chromatography), mp (melting point), rt (room temperature), aq (aqueous), min (minute), h (hr, hour), atm (atmosphere), conc. (concentrated), MS (mass spectroscopy/spectrometry), NMR (nuclear magnetic resonance), Rf (TLC retention factor), and Rt (HPLC retention time). NMR abbreviations: br (broad), apt (apparent), s (singlet), d (doublet), t (triplet), q (quartet), dq (doublet quartet), dd (doublet doublet), dt (doublet triplet), m (multiplet).

EXAMPLE 1

General synthetic, spectroscopic and purification procedures and

characterizations

General synthetic procedure. Room temperature is defined as the ambient temperature range, typically 20-25°C. The temperature of the ice bath (crushed ice/water) is defined as a range, typically -5°C to 0°C. The reflux temperature is defined as ±15°C from the boiling point of the primary reaction solvent. Overnight is defined as time in the range of 8-16 hours. Vacuum filtration (water aspirator) is defined as a range of 5-15 mm Hg. Vacuum dried is defined as the use of a high vacuum pump as a range of 0.1-5 mm Hg. Neutralization is defined as a typical acid-base neutralization procedure and is measured in the pH range 6-8 using pH-indicating paper. Saline is defined as saturated aqueous sodium chloride. A nitrogen atmosphere is defined as the positive static pressure of nitrogen gas passed through a Drierite column with an oil boiling system. Concentrated ammonium hydroxide is defined as an approximately 15 M solution.

Column or thin layer chromatography eluents are prepared and referred to as volume:volume (v:v) solutions, and HPLC eluent ratios are v:v ratios. Aqueous sodium hydroxide or sodium bicarbonate solutions are prepared as mass:volume (w:v) ratios. Aqueous solutions of hydrochloric acid are prepared as v:v ratios.

The amounts of solvents and/or reagents used to carry out the reaction or isolate the products are those typically used by one skilled in the art of organic chemical synthesis, and the amount of these solvents and/or reagents used is determined based on experience and whether it is appropriate for the specific reaction. In column chromatography, it depends on the amount of material, the complexity of the mixture, and the size of the column used in the chromatography and ranges from about 5 - 1000 g, 3) the volume of the extraction solvent is in the range of about 10 - 1000 ml_ depending on the size of the reaction, 4) the washings used in the isolation of the compounds are in the range of 10 - 100 mL of the solvent in the aqueous reagent depending on the scale of the reaction 5) drying reagents (potassium carbonate, sodium carbonate or magnesium sulfate) are in the range of about 5 - 100 g depending on the amount of solvent to be dried and its water content.

Melting points are measured with a mercury thermometer and are uncorrected.

For column chromatography employing concentrated ammonium hydroxide as part of the mobile phase, fractions collected from the column are dried over sodium sulfate, potassium carbonate, or a mixture of both. The organic layer is filtered by gravity or vacuum to remove the drying agent before concentration/evaporation.

Flash Chromatography: In the Tables, "ISCO" indicates purification by flash chromatography as follows: Instrument: ISCO CombiFlasha Si 10x. Column: ISCO RediSepa - Disposable columns for Flash Chromatography (10 g silica gel - normal phase

- 35-60 micron particle size (230-400 mesh). Mobile phase A: CH2CI2; Mobile phase B: 10% NH4OH in MeOH; Gradient; 0-10% B in 22 min, hold 10% B for 18 min; Fractions: 30 fractions are collected per column, 1.5 min each. Flow rate: 8.93 mL/min. The main factions

analyzed by MS and TLC (90:9:1 CH2Cl2:MeOH:NH4OH - Rf range 0.15 - 0.45) and combined in vials lined with code labels. Samples for LC/MS analysis are made from the resulting solutions, concentrated in vacuo and their masses and yields are determined as indicated in the Tables.

If no additional purification is performed after the Parallel Synthesis is completed, this is indicated as "None" in Table 2.

Analytical HPLC procedures. Analytical HPLC procedures are performed according to one of two specific procedures, depending on the availability of instruments and sample requirements, as follows: HPLC Procedure A. Column: Thomson Inst. Co. 4.6 x 50 mm C18 5 um 60 A; Mobile phase A: H 2 O with 0.1% TFA; Mobile phase B: CH3CN with 0.1% TFA; Detection: UV254 nm. Gradient 1: ELSD12MG; 10-90% B in 10 min, hold 90% B 5 min; Flow: 1.0 mL/min. Gradient 2. ELSD5MG; 15-100% B in 5 min, hold 100% B 3 min; Flow - 2.0 mL/min.

HPLC Procedure B. Column: Thomson Inst. Co. 21 x 50 mm C18 5 um 60 A; Mobile phase A: H 2 O with 0.1% TFA; Mobile phase B: CH3CN with 0.1% TFA; Detection: UV 254 nm. Gradient 1: MIC8MG; 0-100% B in 8 min, hold 100% B 2 min; Flow: 0.5 mL/min. Gradient 2: MIC15MG; 10-90% B in 15 min, hold 90% B 3 min; Flow - 0.5 mL/min.

Preparative HPLC procedures: Preparative HPLC is performed as follows: Instrument: Gilson; Column: Thomson Inst. Co. 21.5 x 150 mm C18 5 in 60 A; Mobile phase A: H 2 O; Mobile phase B: CH3CN; Detection: UV 254 nm. Gradient: 15-100% B in 10 min, retention 100% B 5 min; Flow: 22 mL/min; Detection: UV254 nm. Fractions containing the desired compounds are collected and coded into vials, with samples for LC/MS analysis, concentrated in vacuo and their masses and yields determined as shown in the Tables.

Spectroscopic and instrumental procedures.

NMR. The 1H and 13C NMR spectra described here were obtained using a Varian INOVA600 (600 MHz), Varian UNITY600 (600MHz), or Varian 400

(400MHz) spectrometers. The spectrometer field strength and NMR solvent used for a particular sample are indicated in the Examples, or on any NMR spectra actually shown as Figures. Typically,<1>H NMR chemical shifts are reported as 5 values in parts per million (ppm) downfield from tetramethylsilane (TMS) (5 = 0 ppm) as an internal standard, and 13C NMR chemical shifts are reported in ppm downfield from TM S and reported relative to the CDCl3 central signal line (5 = 77.0 ppm). Solid or liquid samples are dissolved in the appropriate NMR solvent (CDCl3 or DMSO-d6), placed on the NMR sample tube, data collected according to the spectrometer instruction manual. Most samples are analyzed in Variable Temperature mode, typically at around 55°C, although some data for some samples were collected with the sample at ambient temperature. NMR data is processed

using NUTS: NMR Utility Transformation Software (Lite Version-20011128) via Acorn NMR. LC-MS. The Liquid Chromatography-Mass Spectrometry (LC-MS) instrumentation used to examine the compounds of the present invention is typically a quadrupole/time-of-flight mass spectrometer, with electrospray ionization (ESI). For example, a typical LC-MS instrumentation used is a Micromass Q-Tof using electrospray ionization (ESI). This instrument is a quadrupole/time-of-flight mass spectrometer capable of mass resolution up to m/z of about 7500. Samples are introduced by direct injection by first dissolving and diluting the sample in methanol or acetonitrile and injecting the sample solution into the ESI source via a 10uL circular Rheodvne injection valve. The carrier solvent is typically a mixture of 70% CH3CN or MeOH and 30% H2O (v:v), containing about 0.1% formic acid. Precision mass analyzes are performed in a similar manner except using a multi-point mass calibration with the same instrument under the ultimate conditions of mass resolution. Samples are spiked with an appropriate internal mass reference compound, as is known to one skilled in the art, and analyzed as described above.

EXAMPLE 2

General procedures of parallel synthesis

Examples 3-5 describe synthetic procedures for the preparation of a "library" of N2,N4,N6-tris(amino)-1,3,5-triazines prepared based on a strategy of changing only one counterpart amino group per synthesis, and based on the parent structure 95 shown below, where each compound in the library contains two of the counterpart groups in 95.

The library is divided into three subgroups, and all three subgroups are shown in Table 2. Library I (compounds 1-50) includes compounds having unchanged cycloheptylamino and [(1-ethyl-2-pyrrolidinyl)methyl]amino substituents, with various groups permuted at the remaining triazine amino position, prepared by Method A as shown in Example 3. Library II (compounds 51-75) includes compounds having unchanged [(1-ethyl-2-pyrrolidinyl)methyl]amino and (3-fluoro-4-methoxyphenyl)amino substituents, with various groups permuted at the remaining triazine amino position, prepared by Method B as shown in Example 4. Library III (compounds 76-100) includes compounds having unchanged (3-fluoro-4-methoxyphenyl)amino and cycloheptylamino substituents, with various groups permuted at to the remaining triazine amino position, prepared by Method C as is described in Example 5. Thus, the combination of specific amines employed produces a library of compounds of novel composition. The sequence in which each monomer was added to form the library compounds is also shown in Table 2, as Monomer 1 amine is added first, Monomer 2 amine is added second, and Monomer 3 amine is added third.

EXAMPLE 3

Parallel synthetic procedure A, for Library I compounds

The following reaction scheme shows the general reagents and conditions for the parallel synthetic procedure A used for the compound of Table 2 designated procedure A.

Reagents and conditions: (a) ArNHR, DIEA, CH,CN/l,4-dioxane, -11C, lh

(b) cycloheptylamine, DIEA, CH3CN/1,4-dioxane, rt, overnight (c) 2-(aminomethyl)-1-ethylpyrrolidine, DIEA, CH3CN/1,4-dioxane, 80 C, 15

A stock solution of cyanuric acid chloride (0.542 M) in 1,4-dioxane is prepared and 1 mL of this solution (containing 100 mg or 0.542 mmol) is dispensed into each of 50 labeled 40 mL vials. These solutions are cooled to about -11 °C (freezing) using a J-KEM block connected to a circulating cooler. Meanwhile, individual solutions of each aryl amine ArNHR (specified as Monomer 1 in Table 2, 0.542 mmol) and diisopropylethylamine (DIEA) (77 mg/104uL, 0.596 mmol) in 1 mL of CH3CN were prepared. (204uL of DIEA (approximately 2.1 equiv.) is used for the HCl salts). Over a period of about 1 hour, the amine/DlEA solutions are added to the corresponding ciuric acid chloride solutions, one at a time, with swirling. The resulting solutions are then stirred at about -11 °C for about 1 hour and the reaction block is allowed to warm to room temperature over the next hour. The resulting 2-amino-4,6-dichlorotriazine solutions are carried to the next step without purification.

A stock solution of cycloheptylamine (1.08 M) and DIEA (1.19 M) in CH3CN is prepared and 0.5 mL (containing 61 mg/69 µL, 0.542 mmol amine and 77 mg/104 µL, 0.596 mmol DIEA) is dispensed into each of the 40 mL vessels from the first step. The dishes are shaken on a J-KEM block overnight at room temperature and placed in a freezer (around -14°C) without purification until the next reaction.

A stock solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.08 M) and DIEA (1.19 M) in CH3CN is prepared and 0.5 mL (containing 68 mg/79 µL, 0.542 mmol

amine and 77 mg/104 uL, 0.596 mmol DIEA) was divided into each of the 40 mL from the second step. The containers are then shaken on a J-KEM block at about 80°C for about 15 hours. The solution was cooled to room temperature and evaporated to dryness in vacuo. The residue was extracted with ethyl acetate and the extract was washed with brine. The aqueous layers were extracted a second time with ethyl acetate and the combined organic layers were dried over Na 2 SO 4 and passed through a plug of Celite™ into a code-labeled container. After in vacuo concentration, masses are determined and yields are calculated, and compounds are sampled for LC/MS analysis.

EXAMPLE 4

Parallel Synthetic Procedure B, for Compound Library II

The following reaction scheme presents the general reagents and conditions for parallel synthetic procedure B, which is used for the compounds of Table 2 designated procedure B.

Reagents and conditions: (a) 3-Fluoro-p-anisidine, DIEA, CH3CN/1,4-dioxane, -20C, lh (b) R2NHR, DIEA, CH3CN/1,4-dioxane, rt, overnight

(c) 2-(aminomethyl)-1-ethylpyrrolidine, DIEA, CH3CN/1,4-dioxane, 80 C, 15

In an oven-dried round-bottom flask, a solution of ciuric acid chloride (5.0 g, 27.1 mmol) in 1,4-dioxane (40 mL) was cooled to freezing in a CH 3 CN/dry ice bath. This frozen solution was added to 40 mL of CH 3 CN followed by DIEA (3.85 g/5.19 mL, 29.8 mmol). A solution of 3-fluoro-p-anisidine (3.83 g, 27.1 mmol) in 10 mL CH 3 CN was then slowly added via syringe. The reaction mixture was stirred at about -20 °C for about 1 hour and allowed to warm to room temperature over about 1 hour. The resulting 2-amino-4,6-dichlorotriazine solution was carried to the next step without purification.

Fifty mL (13.5 mmol) of the prepared (4,6-dichloro-[1,3,5]triazin-2-yl)-(3-fluoro-4-methoxy-phenyl)amino solution was divided into equal portions (2 mL or 0.54 mmol each) among 25 labeled 40 mL scintillation vials. Individual solutions of each R 2 NHR (where R 2 amine denotes Monomer 2 in Table 2, 0.542 mmol) and DIEA (77 mg/104 uL, 0.596 mmol) in 0.5 mL CH 3 CN are prepared and added to appropriately labeled 40 mL vials. The resulting solutions are shaken on a J-KEM block overnight at room temperature and then placed in a freezer (around -14°C) without purification until the next reaction.

A stock solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.08 M) and DIEA (1.19 M) in CH3CN is prepared and 0.5 mL (containing 69 mg/79 µL, 0.542 mmol amine and 77 mg/104 µL, 0.596 DIEA) is dispensed into each of the 40 mL vessels from the second step. The vessels are shaken on a J-KEM block at around 80°C for about 15 hours. The solutions were cooled to room temperature and concentrated in vacuo. The residues were then extracted with ethyl acetate and the extract was washed with brine. The aqueous layers were extracted a second time with ethyl acetate and the combined organic layers were dried over Na 2 SO 4 and passed through a plug of Celite™ into a code-labeled container. After in vacuo concentration, masses are determined and yields are calculated, and compounds are sampled for LC/MS analysis.

EXAMPLE 5

Parallel Synthetic Procedure C, for Compound Library III

The following reaction scheme shows the general reagents and conditions for parallel synthetic procedure C, which is used for the compounds of Table 2 designated as procedure C.

Reagents and conditions: (a) 3-fluoro-p-anisidine, DIEA, CH3CN/l,4-dioxane, -20C, lh (b) cycloheptylamine, DIEA, CH3CN/l,4-dioxane, rt, overnight (c) R3NHR, DIEA, CH3CN/I,4-dioxane, 80C, 15

In an oven-dried round-bottom flask, a solution of ciuric acid chloride (5.0 g, 27.1 mmol) in 1,4-dioxane (40 mL) was cooled to freezing in a CH 3 CN/dry ice bath. This frozen solution was added to 40 mL of CH 3 CN followed by DIEA (3.85 g/5.19 mL, 29.8 mmol). A solution of 3-fluoro-p-anisidine (3.83 g, 27.1 mmol) in 10 mL CH 3 CN was then slowly added via syringe. The reaction mixture was stirred at about -20 °C for about 1 hour and allowed to warm to room temperature over about 1 hour. The resulting 2-amino-4,6-dichlorotriazine solution was carried to the next step without purification.

Fifty mL (13.5 mmol) of the prepared (4,6-dichloro-[1,3,5]triazin-2-yl)-(3-fluoro-4-methoxy-phenyl)amino solution was treated with a solution of cycloheptylamine (1.53 g/1.73 mL, 13.5 mmol) and DIEA (1.93 g/2.60 mL, 14.9 mmol) in CH3CN (8 mL). The resulting solution is stirred overnight at room temperature and introduced to the next step without purification. The resulting 6-chloro-N-cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine solution (13.5 mmol) was diluted to 62.5 mL with CH3CN and aliquoted (2.5 mL or 0.54 mmol each) among 25 40 mL labeled scintillation vials. Individual solutions of each R3NHR (where R3amine denotes Monomer 3 in Table 2, 0.542 mmol) and DIEA (77 mg/104 µL, 0.596 mmol) in 0.5 mL CH3CN were prepared and added to appropriately labeled 40 mL vials. The resulting solutions are shaken on a J-KEM block at about 80°C for about 15

hours. The solutions were cooled to room temperature and concentrated in vacuo. The residues were extracted with ethyl acetate and the extract was washed with saline. Each organic layer was dried over Na 2 SO 4 and passed through a plug of Celite™ into a code-labeled container.

After in vacuo concentration, masses are determined and yields are calculated, and compounds are sampled for LC/MS analysis.

EXAMPLE 6

Synthesis of 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-cyclohexylmethyl-[1,3,5]triazine-2,4-diamine (102)

To sample 101 (0.3004 g, 1.0 mmol, prepared as indicated herein) dissolved in acetone (4 mL) was added a solution of cyclohexanemethylamine (0.13 mL, 1.0 mmol) in acetone (1 mL) followed by the addition of NaOH solution (0.0448 g, 1.0 mmol dissolved in 1 mL H 2 O). The reaction mixture is allowed to stir at reflux for about 3 hours. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq) and 5% NaOH (aq) - The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum to give compound 102 (0.29 g, 76% recovery).

EXAMPLE 7

Synthesis of N-(3-Chloro-4-methoxy-phenyl)-N'-cyclohexyl-N"-m^

methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine (103)

To sample 102 (0.286 g, 1.0 mmol) dissolved in 1,4-dioxane (4 mL) was added a solution of N-methyl-4(methylamino)piperidine (0.15 mL, 1.0 mmol) in acetone (1 mL) followed by the addition of NaOH solution (0.0462 g, 1.0 mmol dissolved in 1 mL H2O). The reaction mixture is allowed to stir at about 80 °C for about 2 hours. The reaction mixture was poured over crushed ice and neutralized with 10% HCl (aq.). The resulting solid is collected by vacuum filtration, washed with water and dried under vacuum overnight. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded light purple solid compound 103 (41 mg, 9%), m.p. 84 °C; HPLC: YMC Pack Pro C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 12.7 min, 97% purity); . 3.25 (t, J=6.6Hz, 2H), 3.05 (s, 3H), 2.94 (d, J=11.4 Hz, 2H), 2.31 (s, 3H), 2.15 (S, 2H), 1.86 (dq, J=12, 4.2 Hz, 3H), 1.57-1.78 (m, 8H), 1.15-1.30 (m, 4H), 1.00 (dq, J = 11.4, 3 Hz, 2H), MS (ESI): m/z 476(37.7), 474 (M+H, 100), 410 (1.4).

EXAMPLE 8

Synthesis of 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-(1-propyl-butyl)-[1,3,5]thazin-2,4-diamine (104)

To sample 101 (0.3062 g, 1.0 mmol) dissolved in acetone (4 mL) was added a solution of 4-heptylamine (0.15 mL, 1.0 mmol) in acetone (1 mL) followed by the addition of NaOH solution (0.0410 g, 1.0 mmol dissolved in 1 mL H2O). The reaction mixture was allowed to stir at 30-50 °C for about 3 hours. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq) and 5% NaOH (aq). The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum to give compound 104 (0.363 g, 94% recovery).

EXAMPLE 9

Synthesis of N-(3-Chloro-4-methoxy-phenyl)-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N''-(1-propyl-butyl)-[1,3,5]triazine-2,4,6-triamine (105)

To sample 104 (0.363 g, 1.0 mmol) dissolved in 1,4-dioxane (6 mL) was added a solution of N-methyl-4(methylamino)piperidine (0.15 mL, 1.0 mmol) in acetone (1 mL) followed by the addition of NaOH solution (0.0414 g, 1.0 mmol dissolved in 1 mL H2O). The reaction mixture is allowed to stir at about 80°C for about 2 hours. The reaction mixture was poured over crushed ice and neutralized with 10% NH1 (aq.). The resulting solid is collected by vacuum filtration, washed with water and dried under vacuum overnight. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) yielded a light purple solid compound 105 (97 mg, 20%), m.p. 249°C; HPLC: YMC Pack Pro C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 14.4 min, 98% purity); MS (ESI): m/z 476 (M+H, 100), 412 (2.9), 366 (2.8), 239 (1.9).

EXAMPLE 10

Synthesis of N-(3-Chloro-4-methoxy-phenyl)-N'-isopropyl-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine (105)

To sample 101 (0.6157 g, 2.0 mmol) dissolved in anhydrous 1,4-dioxane (15 mL) was added a solution of isopropylamine (0.17 mL, 2.0 mmol) in anhydrous acetonitrile (1 mL) followed by the addition of N,N-diisopropylethylamine (DIEA) (0.38 mL, 2.2 mmol) in anhydrous acetonitrile (1 mL). The reaction mixture was allowed to stir at room temperature overnight under nitrogen. To this mixture was added DIEA (0.38 mL, 2.2 mmol) in anhydrous acetonitrile (1 mL) followed by the addition of N-methyl-4(methylamino)piperidine (0.29 mL, 2.0 mmol) in anhydrous acetonitrile (1 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed once with brine and dried over anhydrous potassium carbonate. The organic layer was concentrated on a rotary evaporator and allowed to dry overnight under vacuum. Column chromatography (silica gel, 96:3:1 CH2Cl2:CH3OH:conc. NH4OH) yielded light brown solid compound 106 (271 mg, 32%), TLC (silica gel, 96:3:1 CH2Cl2:CH3OH:conc. NH4OH), Rf 0.28; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt4.4 min, 84.8% purity); MS (ESI): m/z 422(26), 420 (M+H, 71.2), 378 (4.2), 231 (100), 211 (40.4), 118 (5.4).

EXAMPLE 11

Synthesis of ^-( S- Chloro^- methoxy- phenylj- t^- isopropyl-^- methyl-^- piperidine-^

yl- 1, 3, 5- triazine- 2, 4, 6- triamine ( 107)

Compound 107 was isolated (0.159 g) as a by-product by column chromatography (silica gel, 96:3:1 CH2Cl2:CH3OH:conc. NH4OH); mp 129°C; TLC (silica gel, 96:3:1 CH2CI2:CH3OH:conc. NH4OH), Rf 0.14; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt4.4 min, 93.5% purity); MS (ESI): m/ z 408 (17.2), 406 (M+H, 46.6), 375 (18.5), 245 (11.9), 224 (100), 204 (13.4).

EXAMPLE 12

Synthesis of 5-{4-(3-Chloro-4-methoxy-phenylamino)-6-[methyl-(1-methyl-piperidin-4-yl)-amino]-[1,3,5]triazin-2-ylamino}-pentan-1-ol (108)

To sample 101 (1.5046 g, 5.0 mmol) dissolved in anhydrous 1,4-dioxane (30 mL) was added a solution of 5-amino-1-pentanol (0.5067 g, 5.0 mmol) in anhydrous acetonitrile (12 mL) followed by the addition of N,N-diisopropylethylamine (DIEA) (0.95 mL, 5.5 mmol) in anhydrous acetonitrile (2 mL). The reaction mixture was allowed to stir at room temperature overnight under nitrogen. To the reaction mixture was added DIEA (0.95 mL, 5.5 mmol) in anhydrous acetonitrile (1 mL) followed by the addition of N-methyl-4(methylamino)piperidine (0.73 mL, 5.0 mmol) in anhydrous acetonitrile (1 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed once with brine and dried over anhydrous potassium carbonate. The organic layers were concentrated on a rotary evaporator and allowed to dry overnight under vacuum. Column chromatography (silica gel, 90:9:1 CH2CI2:CH3OH:conc. NH4OH) yielded light brown solid 108 (300 mg, 13%); TLC (silica gel, 90:9:1 CH2CI2:CH3OH:conc. NH4OH), Rf 0.22; HPLC: YMC Pack Pro C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 3.5 min, 74.8% purity); MS (ESI): m/z 466(24.2), 464

(M+H, 71.5), 378 (5.2), 253 (4.5), 244 (20.5), 233 (100), 216 (33.3), 196 (14.6), 118 (5.1).

EXAMPLE 13

Synthesis of 5-[4-(3-Chloro-4-methoxy-phenylamino)-6-(1-methyl-piperidin-4-yl)-amino)-[1,3,5]triazin-2-ylamino]-pentan-1-ol (109)

Compound 109 was isolated as a by-product (0.820 g) by column chromatography (silica gel, 90:9:1 CH2Cl2:CH3OH:conc. NH4OH), mp 101 °C; TLC (silica gel, 90:9:1 CH2CI2:CH3OH:conc. NH4OH), Rf0.08; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt3.6 min, 95.3% purity); MS (ESI): m/ z 452 (13), 450 (M+H, 35.6), 419 (3.9), 267 (5.1), 246 (100), 226 (21.3), 209 (23.6), 118 (1.1).

EXAMPLE 14

Synthesis of N-Butyl-6-chloro-N'-(3-chloro-4-methoxy-phenyl)-N-propyl-[1,3,5]triazine-2,4-diamine (110)

To sample 101 (1.5334 g, 5.0 mmol) dissolved in acetone (20 mL) was added a solution of N-propyl-butylamine (0.77 mL, 5.0 mmol) in acetone (1 mL) followed by the addition of NaOH (2.0 mL, 2.5 N, 5.0 mmol).

The reaction mixture was allowed to stir at 30-35°C for about 3 hours under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting oil is dried overnight under vacuum. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded light brown compound 110 as a solid (1.4 g, 77% recovery).

EXAMPLE 15

Synthesis of N-Butyl-N'-(3-chloro-4-methoxy-phenyl)-N'-(1-methyl-piperidin-4-yl)-N-propyl-[1,3,5]triazine-2,4,6-triamine (111)

To sample 110 (1.323 g, 3.4 mmol) dissolved in 1,4-dioxane (25 mL) was added a solution of N-methyl-4(methylamino)piperidine (0.4 mL, 3.4 mmol) in 1,4-dioxane (1 mL) followed by addition of NaOH (1.4 mL, 2.5 N, 3.4 mmol). The reaction mixture was allowed to stir at reflux for about 2 hours under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 90:9:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded light brown solid compound 111 (527 mg, 33%), mp 68 °C; TLC (silica gel, 90:9:1 CH2CI2:CH3OH:conc. NH4OH), Rf 0.46; HPLC: ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 41.6 min, 90.8% purity); MS (ESI): m/ z 476 (M+H, 28.5), 261 (20.2), 260 (52.8), 259 (100), 239 (18.6), 239 (50.6).

EXAMPLE 16

Synthesis of N^ Butyl-^^- chloro^-methoxy-phenyl- N^ methyl- N^ piperidin^- yl-N2- propyl- 1, 3, 5- thazin- 2, 4, 6- triamine ( 112)

Compound 112 was isolated as a by-product by column chromatography, an oil (0.112 g); TLC (silica gel, 90:9:1 CH2CI2:CH3OH:conc. NH4OH), Rf0.46; HPLC: ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 266 nm, R, 41.4 min, 97.8% purity); MS (ESI): m/z 464 (11.6), 462 (M+H, 28.9), 431 (15.6), 273 (12.7), 253 (58.8), 252

(100), 232 (25.8), 157 (14.5).

EXAMPLE 17

Synthesis of 2, 4- Dichloro- 6- cyclohexylmethoxy-[ 1, 3, 5] triazine (113)

Ciuric acid chloride (3.76 g, 20.0 mmol) dissolved in toluene (20 mL) was added to potassium bicarbonate (2.80 g, 20 mmol) and 18-crown-6 (0.1614 g, 0.6 mmol) followed by the dropwise addition of cyclohexylmethanol (2.5 mL, 20 mmol) in toluene (15 mL). The reaction mixture was allowed to stir at reflux for about 18 hours under nitrogen. The reaction mixture was passed through a plug of Celite and concentrated using a rotary evaporator and dried overnight under vacuum to give 113 as an oil (5.212 g, 99% recovery).

EXAMPLE 18

Synthesis of (4-Chloro-6-cyclohexylmethoxy-[1,3,5]triazin-2-yl)-(3-fluoro-4-

methoxy-phenyl)-amine ( 114)

To sample 113 (1.011 g, 3.8 mmol) dissolved in acetone (20 mL) was added a solution of 3-fluoro-anisidine (0.541 g, 3.8 mmol) in acetone (10 mL) followed by the addition of NaOH (1.52 mL, 2.5 N, 3.8 mmol) and water (3 mL). The reaction mixture was allowed to stir at reflux for about 3 hours under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting oil is dried overnight under vacuum. Column chromatography (silica gel, 70:30 hexaneethyl acetate) yielded a yellow solid compound 114 (0.581 g, 42%), mp 98°C; TLC (silica gel, 30:70 ethyl acetate hexanes), Rf 0.36; MS (ESI): m/z 369 (39.1), 368 (22.1), 367 (M+H, 100), 273 (3.2), 271 (10.7).

EXAMPLE 19

Synthesis of 6-Cyclohexylmethoxy-N,N'-bis-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4-diamine (115)

Compound 115 was obtained as a by-product (0.159 g) by column chromatography (silica gel, 70:30 hexanes:ethyl acetate), mp 181°C; TLC (silica gel, 30:70 ethylacetate hexanes), R, 0.17; MS (ESI): m/z 472 (M+H, 100), 261 (1.5).

EXAMPLE 20

Synthesis of 6-Cyclohexylmethoxy-N-(1-ethyl-pyrrolidin-2-ylmethyl)-N'. (3-fluoro-4methoxy-phenyl)-[1,3,5]triazine-2,4-diamine (116)

To sample 114 (0.3004 g, 0.82 mmol) dissolved in 1,4-dioxane (15 mL) was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (0.12 mL, 0.82 mmol) in acetone (1 mL) followed by the addition of NaOH (0.33 mL, 2.5 N, 0.82 mmol) and water (1 mL). The reaction mixture was allowed to stir at reflux for about 2 hours under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded a light yellow solid compound 116 (226 mg, 60%); HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 10.5 min, 100% purity); . 3H), 1.02 (s, 1H), 2.26 (apt sextet, J=6.6 Hz, 1H), 2.19 (q, J=9 Hz, 1H), 1.16-1.92 (m, 10H), 1.57 (s, 2H), 1.17-1.32 (m, 3H), 1.05-1.11 (m, 4H); MS (ESI): m/z 459 (M+H, 100), 363 (40.7), 223 (16.1), 202 (4.4), 138 (1.2).

EXAMPLE 21

Synthesis of (4-Chloro-6-cyclohexylmethoxy-[1,3,5]triazin-2-yl)-(3-chloro-4-

methoxy-phenyl)-amine ( 117)

To sample 113 (1.012 g, 3.8 mmol) dissolved in acetone (20 mL) was added a solution of 3-chloro-anisidine (0.605 g, 3.8 mmol) in acetone (10 mL) followed by the addition of NaOH (1.52 mL, 2.5 N, 3.8 mmol) and water (3 mL). The reaction mixture was allowed to stir at reflux for about 3 hours under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting oil is dried overnight under vacuum. Column chromatography (silica gel, 70:30 hexane ethyl acetate) yielded a light peach solid compound 117 (0.547 g, 38%), mp 114°C; TLC (silica gel, 30:70 ethyl acetate/hexanes), Rf 0.44; MS (ESI): m/ z 385 (74.3), 384 (22.9), 383 (M+H, 100), 287 (8.3).

EXAMPLE 22

Synthesis of N,N'-Bis-(3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-1,3,5-triazine-2,4-diamine (118)

Compound 118 was obtained as a by-product (0.178 g) by column chromatography (silica gel, 70:30 hexanes:ethyl acetate), mp 188°C; TLC (silica gel, 30:70 ethylacetate hexanes), Rf0.22; MS (ESI): m/ z 504 (M+H, 100), 379 (1), 338 (1.3).

EXAMPLE 23

Synthesis of N -( 3- chloro- 4- methoxy- phenyl)- 6- cyclohexylmethoxy- N'- methyl- N'-( 1-

methyl-piperidin-4-yl)-[1,3,5]-triazin-2,4-diamine (119)

To sample 117 (0.3007 g, 0.78 mmol) dissolved in 1,4-dioxane (15 mL) was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (0.11 mL, 0.78 mmol) in acetone (1 mL) followed by addition of NaOH (0.31 mL, 2.5 N, 0.78 mmol) and water (1 mL). The reaction mixture was allowed to stir. under reflux for about 2 hours. The reaction mixture was washed with brine and dried over a rotary evaporator. Column chromatography (silica gel, 96:3:1 conc. ammonium hydroxide) gave a light yellow solid. 119 (159 mg, 43%), mp 140°C. HPLC: Inertsil ODS-3VC18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 15.2 min, 99.7% purity); MS (ESI): m/z 475 (M+H, 64.1), 379 (49.5), 231 (48.6), 210 (100), 190 (3.2).

EXAMPLE 24

Synthesis of 6-Chloro-N,N"-bis-(3-chloro-4-methoxy-phenyl)-[1,3,5]-triazine-2,4-diamine (120)

To sample 101 (3.0556 g, 10.0 mmol) dissolved in acetone (25 mL) was added a solution of 3-chloro-anisidine (1.6050 g, 10.0 mmol) in acetone (10 mL) followed by the addition of NaOH (4.0 mL, 2.5 N, 10 mmol). The reaction mixture was allowed to stir at room temperature for about 3 hours under nitrogen. The reaction mixture is poured over crushed ice. The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum to give compound 120 (4.06 g, 95%), mp 213 °C; HPLC: Inertsil ODS-3VC18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 70.0 min, 97.1% purity); MS (ESI): m/z 427 (20.90), 426 (M+H, 99.6), 210 (100), 209 (22.2), 196 (55.3), 169 (25.4).

EXAMPLE 25

Synthesis of N, N"- bis -( 3- chloro- 4- methoxy- phenyl)- N"- methyl- N"-( 4- methyl-

cyclohexyl)- [ 1, 3, 5]- triazine- 2, 4, 6- triamine ( 121)

To a sample of compound 120 (1.5004 g, 3.5 mmol) dissolved in 1,4-dioxane (20 mL) was added a solution of N-methyl-4(methylamino)-piperidine (0.5 mL, 3.5 mmol) in 1,4-dioxane (1 mL) followed by the addition of NaOH (1.4 mL, 2.5 N, 3.5 mmol). The reaction mixture was allowed to stir at reflux for about 2 hours under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded purple solid compound 121 (487 mg, 27%) mp 130°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 8.1 min, 96% purity; 1H NMR (600 MHz, CDCl 3 , 55°C) δ 7.81-7.92 (broad resonance, rotamers, 2H), 7.19-7.30 (broad resonance, 2H), 6.87 (d, J=9 Hz, 2H), 6.72 (s, 2H), 4.60-4.65 (m, 1H), 3.88 (s, 6H), 3.05 (s, 3H), 2.95 (d, J=12 Hz, 2H), 2.32 (s, 3H), 2.19 (t, J=11.4 Hz, 2H), 1.89 (dq, J=12.6, 3.6 Hz, 2H), 1.71 (apt d, J=11.4 Hz, 2H), 1.65 (s, 1H); MS (ESI): m/z 519 (28.3), 518 (M+H, 42.1), 261 (71.9), 260 (100).

EXAMPLE 26

Synthesis of N,N'-Bis-(3-chloro-4-methoxy-phenyl)-N"-cycloheptyl-[1,3,5]-triazine-2,4,6-triamine (122)

To a sample of compound 120 (1.5004 g, 3.5 mmol) dissolved in acetone (20 mL) was added a solution of cycloheptylamine (0.4 mL, 3.5 mmol) in acetone (1 mL) followed by the addition of NaOH (1.4 mL, 2.5 N, 3.5 mmol). The reaction mixture was allowed to stir at reflux for about 2 hours under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% HCl (aq). The resulting solid was collected by vacuum filtration, washed with water, and dried overnight under vacuum to afford a pale yellow solid 122 (1.5 g, 85%), mp 183 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 59 min, 96% purity; MS (ESI): m/z 503 (M+H, 29), 502 (100), 458 (24.2), 425 (17.9), 225 (5.7), 155 (11.3), 114 (27.6).

EXAMPLE 27

Synthesis of N-(3-bromo-4-methoxy-phenyl)-N'- cycloheptyl- N''- methyl- N''-(

Piperidin-4-yl)-[1,3,5]-triazin-2,4,6-triamine (123)

To a solution of 3-bromo-p-anisidine (0.2019 g, 1.0 mmol) in acetonitrile was added to a solution of 3-bromo-p-anisidine (0.2019 g, 1.0 mmol) dissolved in acetonitrile (3 mL) stirred at about -10 °C, followed by the addition of N,N-diisopropylethylamine (DIEA) (0.17 mL, 1.0 mmol) in acetonitrile. The reaction mixture was allowed to stir at about -10 °C for 1 hour under nitrogen. The reaction mixture was then warmed to room temperature and allowed to stir at room temperature for an additional hour under nitrogen. The reaction mixture was added to a solution of cycloheptylamine (0.13 mL, 1.0 mmol) in acetonitrile followed by the addition of DIEA (0.17 mL, 1.0 mmol). The reaction mixture was allowed to stir at reflux overnight under nitrogen. To the reaction mixture was added N-methyl-4(methylamino)piperidine (0.13 mL, 1.0 mmol) in acetonitrile followed by the addition of DIEA (0.17 mL, 1.0 mmol). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture is extracted 3 times with ethyl acetate; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 90:9:1 methylene chloride:methanol:conc. ammonium hydroxide) yielded 0.029 g (6%) of compound 123.<1>H NMR (400 MHz, CDCl3) 5 7.97-8.19 (broad resonance, 1H), 7.12 (broad resonance, 1H), 6.78-6.80 (m, 2H), 4.82 (br s, 1H), 4.58 (br s, 1H), 3.92 (br s, 1H), 3.84 (s, 3H), 2.90-2.98 (m, 5H), 2.29 (s, 3H), 2.17 (broad resonance, 2H), 1.99-2.24 (broad resonance, 4H), 1.72-1.85 (m, 3H), 1.42-1.62 (m, 11H); MS (ESI): m/z 520 (100), 518 (93.9), 458 (10.4), 424 (20.8), 422 (21.1), 261 (67.5), 260 (63.4); 213 (13.9), 212 (13.6).

EXAMPLE 28

Synthesis of 6-Chloro-N-cyclohexylmethyl-N'~(3-fluoro-4-methoxy-phenyl)-[1,3,5]-triazine-2,4-diamine (125)

To sample 124 (40.02 g, 138.4 mmol, prepared as indicated here) dissolved in acetone (300 mL) was added a solution of cyclohexanemethyolamine (18.0 mL, 138.4 mmol) in acetone (30 mL) followed by the addition of NaOH (55.4 mL, 2.5 N, 138.4 mmol) and 130 mL of water. The reaction mixture is allowed to stir at reflux for about 3 hours. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq) and 10% NaOH (aq). The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum. Recrystallization from ethyl acetate afforded light yellow solid compound 125 (32.93 g, 65%), mp 156 °C; HPLC. Inertsil ODS-3V C18, 40:10:50 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt47.9 min, 92% purity; MS (ESI): m/z 366 (M+H, 100).

EXAMPLE 29

Synthesis of N- Cyclohexylmethyl- N'-( 1- ethyl- pyrrolidin- 2- ylmethyl)- N''-( 3- fluoro- 4-

methoxy-phenyl)- [ 1, 3, 5]- triazine- 2, 4, 6- triamine ( 126)

To sample 125 (10.02 g, 27.3 mmol) dissolved in 1,4-dioxane (150 mL) was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (4.0 mL, 27.3 mmol) in acetone (10 mL) followed by the addition of NaOH (11 mL, 2.5 N, 27.3 mmol) and 27 mL of water. The reaction mixture is allowed to stir at reflux for about 2 hours. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded a light yellow solid compound 126 (7.014 g, 56%) mp 72°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt8.5 min, 93.4% purity; MS (ESI): m/z 458 (M+H, 37.3), 362 (4), 250 (100), 230 (15.3), 229 (44.1).

EXAMPLE 30

Synthesis of N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-pyrrolidin-1-yl-[1,3,5]-triazin-2,4-diamine (128)

To a sample of compound 127 (13.24 g, 36.2 mmol, prepared as indicated herein) dissolved in THF (150 mL) was added a solution of pyrrolidine (3.0 mL, 36.2 mmol) in THF (10 mL) followed by the addition of NaOH (14.5 mL, 2.5 N, 36.2 mmol) and 36 mL of water. The reaction mixture was allowed to stir at reflux for about 2.5 hours. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 98:2 dichloromethane:methanol) yielded a light yellow solid compound 128 (3.36 g, 23%) mp 79°C; HPLC: Inertsil ODS-3V C18, 40:10:50 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 24.5 min, 95.5% purity; <1>H NMR (600 MHz, CDCl3, 55°C) 5 7.77 (broad resonance, 1H). 7.01-7.03 (m, 1H), 6.86 (t, J=9 Hz, 1H), 6.62 (s, 1H), 4.80 (s, 1H), 4.02-4.06

(m, 1H), 3.85 (s, 3H), 3.54 (s, 4H), 1.99-2.03 (m, 2H), 1.91-1.93 (m, 3H), 1.47-1.66 (m, 1H); MS (ESI): m/z 402 (30.7), 401 (M+H, 100).

EXAMPLE 31

Synthesis of (4,6-Dichloro-[1,3,5]-triazin-2-yl)-(3-fluoro-4-methoxy-phenyl)-amine

( 124)

Ciuric acid chloride (28.84 g, 156.0 mmol) dissolved in acetone (200 mL) stirred at approximately 0-5°C, a solution of 3-fluoro-p-anisidine (22.16 g, 156.0 mmol) in acetone (200 mL) was added followed by addition of NaOH (63 mL, 2.5 N, 156.0 mmol). The reaction mixture was allowed to stir at approximately 0-5°C for about 2 hours. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq) and 5% NaOH (aq). The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum. Column chromatography (silica gel, 70:30 hexane:ethyl acetate) yielded a light yellow solid compound 124 (29.6 g, 66%) mp 134°C; HPLC: Inertsil 0DS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 20.3 min, 97.7% purity.

EXAMPLE 32

Synthesis of 6-Chloro-N-cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5]-triazine-2,4-diamine (127)

To sample 124 (10.00 g, 34.6 mmol) dissolved in acetone (150 mL) was added a solution of cycloheptylamine (4.4 mL, 34.6 mmol) in acetone (20 mL) followed by the addition of NaOH (13.8 mL, 2.5 N, 34.6 mmol) and 35 mL of water. The reaction mixture is allowed to stir at reflux for about 3 hours. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample was concentrated on a rotary evaporator and the resulting solid was dried overnight under vacuum to give compound 127 (12.4 g, 98% recovery), mp 145 °C; HPLC: Inertsil ODS-3VC18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt104.8 min, 97.3% purity; <1>H NMR (600 MHz, CDCl3, 55°C) 8 7.50-7.64 (m, 1H). 7.02-7.03 (no. resonance, 2H), 6.90 (t, J=8.9 Hz, 1H), 5.35-5.41 (no. resonance, 1H), 3.99 (no. s, 1H), 4.12 (rotamer), 3.87 (s, 3H), 2.01 (no. s, 2H), 1.42-1.67 (m, 11H).

EXAMPLE 33

Synthesis of N-Cycloheptyl-N'-ethyl-N"~(3-fluoro-4-methoxy-phenyl)-[1,3,5]-thazin-2,4-diamine (129)

To compound 127 (11.00 g, 30 mmol) dissolved in THF (150 mL) was added a solution of ethylamine hydrochloride (2.43 mL, 30 mmol) in THF (20 mL) followed by the addition of NaOH (24 mL, 60 mmol) and 30 mL of water. The reaction mixture is allowed to stir at reflux for about 2 hours. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 98:2 dichloromethane:methanol) yielded a light yellow solid compound 129 (4.81 g, 43%) mp 84 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt30.7 min, 94.2% purity; . 1H), 3.85 (s, 3H), 3.38-3.42 (m, 2H), 1.99-2.01 (m, 2H), 1.47-1.67 (m, 11H), 1.19 (t, J=7.2 Hz, 3H); MS (ESI): m/ z 376 (29.5), 375 (M+H, 100).

EXAMPLE 34

Synthesis of N-Cycloheptyl-N'-(1-ethyl-pyrrolidin-2-ylmethyl)-N''-(3-fluoro-4-methoxy)

phenyl)- [ 1, 3, 5]- triazine- 2, 4, 6- triamine ( 130)

To compound 127 (5.009 g, 13.7 mmol) dissolved in THF (80 mL) was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (2.0 mL, 13.7 mmol) in THF (10 mL) followed by addition of NaOH (5.5 mL, 2.5 N, 13.7 mmol) and 13 mL of water. The reaction mixture was allowed to stir at reflux for about 2 hours under N 2 atm. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting solid is dried overnight under vacuum. Column chromatography (silica gel, 90:9:1 methylene chloride:methanol:conc. ammonium hydroxide) afforded light yellow solid compound 130 (3.63 g, 58%), mp 76 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt7.1 min, 97.1% purity; MS (ESI): m/z 459 (16.5), 458 (M+H, 48.7), 362 (31.3), 250 (100), 230 (22.8), 229 (62.7), 222 (17.2), 202 (34).

EXAMPLE 35

Synthesis of 2-[4-chloro-6-(3-chloro-4-methoxy-phenylamino)-[1,3,5]-triazine-2-

ylamino]-propane-1,3-diol (131)

To compound 101 (0.6114 g, 2 mmol) dissolved in acetone (3 mL) was added 2-amino-propane-1,3-diol (0.1818 g, 2 mmol) dissolved in acetone (1 mL) and water (1 mL). Water (1 mL) was then added to the reaction mixture followed by 2.5 N NaOH (water) (0.8 mL, 2 mmol). The reaction mixture was heated at reflux for 3 hours under N 2 atmosphere. The reaction mixture was diluted with ethyl acetate and washed 2x with brine. The organic layer was separated, dried over anhydrous K 2 CO 3 , filtered, and concentrated under reduced pressure to give 0.643 g of an oval solid. The crude material was purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to give a colorless oil 131 (0.124 g, 18%); HPLC: Inertsil ODS-3VC18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 5.7 min, 83.3% purity; MS (ESI): m/ z 360 (M+H, 100), 338 (10.7), 183 (10.3).

EXAMPLE 36

Synthesis of 2- { 4-( 3- chloro- 4- methoxy- phenylamino)- 6-[ methyl-( 1- methyl- piperidine- 4-

yl)-amino]-[1,3,5]triazin-2-ylamino}-propane-1,3-diol (132)

To compound 131 (0.979 g, 0.271 mmol) dissolved in 3 mL of 1,4-dioxane was added methyl-4-(methylamino)piperidine (0.05 mL, 0.34 mmol) dissolved in 2 mL of 1,4-dioxane followed by the addition of 2.5 N NaOH (aq) (0.11 mL, 0.275 mmol). The mixture was heated at reflux for 3 hours 45 minutes, cooled to about room temperature, and then concentrated under reduced pressure. The resulting material is diluted with dichloromethane and filtered. The filtrate was then concentrated to give 56.5 mg of material. The crude material was purified via a silica gel pipette column eluting with 100% methanol to give a white solid compound 132 (21.1 mg, 18%), mp 84°C; MS (ESI): m/ z 454 (34.7), 452 (M+H, 100), 422 (11.3), 248 (25.3), 247 (51.3), 157 (60.3), 129 (27.5).

EXAMPLE 37

Synthesis of N-(1-benzyl-piperidin-4-yl)-N'-(3-chloro-4-methoxy-phenyl)-N"-

cycloneptyl-[1,3,5]-2,4,6-triamine (134)

To compound 133 (0.1252 g, 0.382 mmol, prepared as indicated herein) dissolved in 3 mL of acetonitrile was added N,N-diisopropyl ethyl amine (DIEA) (0.07 mL, 0.382 mmol) followed by 4-amino-1-benzylamine (0.07 mL, 0.382 mmol). The mixture was refluxed overnight under a N 2 atmosphere. The reaction mixture was diluted with methylene chloride and washed with brine. The organic layer was separated, dried over K 2 CO 3 , filtered and concentrated under reduced pressure to give 0.159 g of material. The crude material is purified by silica gel flash column chromatography eluting with 96:3:1 methylene chloride:methanol:conc. ammonium hydroxide and the collected fractions were dried over potassium carbonate, filtered and then concentrated under reduced pressure to give 77 mg of product. A second column under similar conditions is performed to give an additional 30 mg of material for the combined product 134 (103 mg, 50%); HPLC: Inertsil ODS-3VC18, 40:30:30 [KH2PO4

(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 13.7 min, 97.73% purity; MS (ESI): m/z 538 (15.4), 536 (38.2), 448 (19.3), 446 (49.3), 290 (41.4), 289 (84.6), 269 (100), 247 (4.4).

EXAMPLE 38

Synthesis of N2-(3-chloro-4-methoxy-phenyl)-r/-cycloheptyl-N6-piperidin-4-yl-1,3,5-triazin-2,4,6-triamine (135)

To compound 134 (0.0485 g, 0.0867 mmol) in 2 mL of methanol was added 10% Pd/C (0.052 g) followed by aminium formate (0.0646 g, 1.02 mmol). The mixture is heated at reflux for about 1.5 hours under N2 atmosphere. The cooled reaction mixture was vacuum filtered through celite eluting with methylene chloride, and the filtrate was concentrated under reduced pressure to give 36 g of material. The crude material is purified by silica gel flash chromatography eluting with 90:9:1 methylene chloride:methanol:conc. ammonium hydroxide and the collected fractions were dried over potassium carbonate, filtered and then concentrated under reduced pressure to give solid compound 135 (20 mg, 51.8%), mp 167 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt4.6 min, 52.1% (next major peak at Rt7.3 min, 46.9%); MS (ESI): m/z 448 (4.4), 446 (12.5), 412 (22.7), 386

(2.3), 265 (32.9), 248 (42.6), 244 (56.2), 228 (37.1), 227 (100), 207 (6.9).

EXAMPLE 39

Synthesis of ^-( S- chloro^- methoxy- phenylj- r^- cycloheptyl- r^- fl- ethyl- pyrrolidine^-

ylmethyl)- 1, 3, 5- triazine- 2,- 4, 6- triamine (136)

To compound 133 (0.1257 g, 0.382 mmol, prepared as indicated herein) dissolved in 3 mL of acetonitrile was added DIEA (0.07 mL, 0.382 mL) followed by 2-(aminomethyl)-1-ethyl pyrrolidine (0.06 mL, 0.382 mmol). The mixture was refluxed overnight under a N 2 atmosphere. The reaction mixture was diluted with methylene chloride and washed with brine. The organic layer was separated, dried over K 2 CO 3 , filtered and concentrated under reduced pressure to give 0.143 g of material. The crude material is purified by silica gel flash column chromatography eluting with 96:3:1 methylene chloride:methanol:conc. ammonium hydroxide and the collected fractions were dried over approximately 1:1 potassium carbonate:sodium sulfate, filtered, and then concentrated under reduced pressure to give 77 mg of product. A second column under similar conditions was run to give an additional 30 mg of material for a combined 98 mg (54%) of yellow solid compound 136, mp 69-70 °C; HPLC: YMC Pack Pro C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 12.9 min, 96.5% purity; MS (ESI): m/z 476 (16.3), 474 (42.9), 260 (15), 259 (44.2), 258 (100), 238 (56), 216 (5.3), 210 (9.2).

EXAMPLE 40

Synthesis of 2-chloro-4-{4-cycloheptylamino-[methyl-(1-methyl-piperidin-4-yl)-amino3,5-triazin-2-ylamino}-phenol (138)

Under anhydrous conditions, compound 137 (0.1008 g, 0.21 mmol, prepared as described herein) in a dry round-bottom flask

dissolved in anhydrous methylene chloride (3 mL) under N2 atmosphere around 0°C (ice/water bath) slowly added BBr3 (2.1 mL, 2.1 mmol, 1 M in methylene chloride) via syringe. The mixture was stirred for about 2 hours at 0°C and then quenched with water (5 mL). After standing overnight at room temperature, the mixture was diluted with ethyl acetate, water, and 10% NaHCO 3 (water), and the organic layer was separated and then washed with brine. The organic layers were then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.648 g of material. The crude material was purified using silica gel flash column chromatography eluting with 100% methanol to give a white

solid compound 138 (7 mg, 7%); HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt4.9 min, 90.3% purity; . 1H), 2.96-3.0 (m, 5H), 2.32 (s, 3H), 2.13 (s, 2H), 2.03 (s, 2H), 1.86-1.88 (m, 2H), 1.53-1.67 (m, 12H); MS (ESI): m/ z 463 (12.4), 461 (27), 252 (59), 251 (100), 231 (32.3), 224 (1), 203 (9.8).

EXAMPLE 41

Synthesis of N2-cycloheptyl-N4—((S)-1-ethyl-pyrro!idin-2-ylmethyl)-N6-(3-fluoro-4-

methoxyphenyl)- 1, 3, 5- triazine- 2, 4, 6- triamine ( 139)

Stir ciuric acid chloride (0.368 g, 2 mmol) in CH3CN at ca

-10 to -20 °C 3-fluoro-p-anisidine (0.28 g, 2 mmol) in CH 3 CN was added followed by addition of N,N-diisopropylethylamine (DIEA) (0.35 mL, 2 mmol) and stirred for about one hour. The reaction mixture is then allowed to reach room temperature for one hour. The second step proceeds without further purification. Cycloheptylamine (0.25 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were added and the reaction mixture was stirred overnight at room temperature. The third step also proceeds without any further purification. S-(-)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were added and the reaction mixture

reflux overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure to give 0.920 g of crude material. The crude material was purified by column chromatography to yield a white solid compound 139 (0.550 g, 60%), mp 75-77 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN 2 , 264 nm, Rt 7.9 min, 95.9% purity; MS (ESI): m/z 458 (M+H, 100).

EXAMPLE 42

Synthesis of N^cycloheptyl-^-^-l-ethyl-pyrrole^

methoxyphenyl)- 1, 3, 5- triazine- 2, 4, 6- triamine ( 140)

Stir ciuric acid chloride (0.368 g, 2 mmol) in CH3CN at ca

-10 to -20 °C 3-fluoro-p-anisidine (0.28 g, 2 mmol) in CH 3 CN was added followed by addition of N,N-diisopropylethylamine (DIEA) (0.35 mL, 2 mmol) and stirred for about one hour. The reaction mixture is then allowed to reach room temperature for one hour. Cycloheptylamine (0.25 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were added and the reaction mixture was stirred overnight at room temperature. To this mixture was added R-(+)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) and

the reaction mixture is refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure to give 0.920 g of crude material. The crude material was purified by column chromatography to yield a white solid compound 140 (0.500 g, 54.7%), mp 77-79 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 7.9 min, 95.9% purity; MS (ESI): m/z 458 (M+H, 100).

EXAMPLE 43

Synthesis of N^cycloheptyl-N4-^)-1-ethyl-pyrrolidin-2-ylmethyl)-N6~(3-fluoro-4-

methoxyphenyl)- 1, 3, b- thazin- 2, 4, 6- triamine ( 141)

To a mixture of cyuric acid chloride (0.368 g, 2 mmol) in CH 3 CN at about -20 °C was added 3-fluoro-p-anisidine (0.28 g, 2 mmol) in CH 3 CN followed by addition of N,N-diisopropylethylamine (DIEA) (0.35 mL, 2 mmol) and stirred for about an hour. The reaction mixture is then allowed to reach room temperature for one hour. Cycloheptylamine (0.25 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was stirred overnight at room temperature. S-(-)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 96:3:1 methylene chloride:methanol:conc. ammonium hydroxide to yield a white solid compound 141 (0.400 g, 43.7%), mp 68-69°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt8.2 min, 97.1% purity; MS (ESI): m/ z 458 (M+H, 100), 362 (2.8), 230 (85.4).

EXAMPLE 44

Synthesis of N^ cyclohexylmethyl-^-^ RJ- l- ethyl- p^'

4- methoxyphenyl)- 1, 3, 5- triazine- 2, 4, 6- triamine ( 142)

To a mixture of ciuric acid chloride (0.368 g, 2 mmol) in CH 3 CN at about -20 °C was added 3-fluoro-p-anisidine (0.28 g, 2 mmol) in CH 3 CN followed by the addition of DIEA (0.35 mL, 2 mmol) and stirred for about an hour. The reaction mixture is then stirred at room temperature for about 1 hour. Cyclohexylmethyl amine (0.26 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was stirred overnight at room temperature. R-(+)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 96:3:1 methylene chloride:methanol:conc. ammonium chloride to give compound 142 (0.100 g, 10.9%), mp 66-67°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt8.2 min, 96.7% purity; <1>H NMR (600 MHz, CDCl3) 6 7.58-7.73 (broad resonance, 1H). 7.07-7.11 (broad resonance, 1H), 6.82 (t, J=9 Hz, 1H), 5.49-5.65 (broad resonance, 1H), 4.96-5.13 (broad resonance, 1H), 3.82 (s, 3H), 3.54-3.70 (broad resonance, 1H), 3.13-3.20 (br m, 4H), 2.81 (wide resonance, 1H), 2.54 (broad resonance, 11H), 2.05-2.18 (m, 2H), 2.01 (s, 1H), 1.50-1.83 (brm, 9H), 1.05-1.22 (m, 5H), 0.91 (aptq, J=11.4 Hz, 2H); MS (ESI): m/z 458(M+H, 100), 362 (3.8), 230 (99.8), 216 (1), 182 (1.1).

EXAMPLE 45

Synthesis of ({ 4- cycloheptylamino-6-[(( S)-( 1- ethyl-pyrrolidin-2- itmethyl)- amino]-1, 3, 5- triazin-2- yl}- phenyl- amino)- acetonitrile ( 143)

To a mixture of ciyuric acid chloride (0.368 g, 2 mmol) in CH 3 CN at about -20 °C was added N-phenyl glycinonitrile (0.264 g, 2 mmol) in CH 3 CN followed by the addition of DIEA (0.35 mL, 2 mmol) and stirred for about an hour. The reaction mixture is then stirred at room temperature for about 1 hour. Cycloheptylamine (0.25 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was stirred overnight at room temperature. S-(-)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 96:3:1 methylene chloride:methanol:conc. ammonium chloride to yield compound 143 (0.300 g, 33%), mp 53-55°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt6.9 min, 94.1% purity; MS (ESI): m/z 449 (M+H, 100), 381 (1.2), 353 (16.2), 226 (19.9), 225 (54.3), 212 (20.5), 177 (18.3), 164 (9.6).

EXAMPLE 46

Synthesis of ({ 4-cycloheptylamino-6-[((R)-(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-1, 3, 5-triazin-2-yl}-phenyl-amino)-acetonitrile (144)

To a mixture of ciyuric acid chloride (0.368 g, 2 mmol) in CH 3 CN at about -20 °C was added N-phenyl glycinonitrile (0.264 g, 2 mmol) in CH 3 CN followed by the addition of DIEA (0.35 mL, 2 mmol) and stirred for about an hour. The reaction mixture was then stirred at room temperature for about 1 hour. Cycloheptylamine (0.25 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was stirred overnight at room temperature. R-(+)-2-aminomethyl-N-ethyl pyrrolidine (0.29 mL, 2 mmol) and DIEA (0.35 mL, 2 mmol) were then added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 96:3:1 methylene chloride:methanol:conc. ammonium chloride to yield compound 144 (0.300 g, 33%), mp 53-55°C; HPLC: Inertsil ODS-3VC18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 6.8 min, 92.6% purity; MS (ESI): m/z 449 (M+H, 100), 381 (1.4), 353 (11.8), 226 (13), 225 (33.1), 212 (15), 177 (13.5), 164 (7.8).

EXAMPLE 47

Synthesis of N2-cycloheptyl-1^[(1-ethyl-pyrrolidinyl]-r/-(3-fluoro-4-methoxyphenyl)-6-[(S)-2-(methoxymethyl)-1-pyrrolidinyl]-1,3,5-triazine-2,4-diamine (145)

Ciuric acid chloride (11.07 g, 60 mmol) was dissolved in 40 mL of CH3CN and cooled to about -20 °C. To this was added DIEA (11.5 mL, 60 mmol) followed by 3-fluoro-4-methoxyaninline (8.47 g, 60 mmol) in 20 mL CH 3 CN (the reaction was frozen). The reaction was allowed to warm to room temperature after about 1 hour at -20 °C. TLC (2% CH 3 OH/CH 2 Cl 2 ) and mass spectrometry indicated the presence of compound 124. The reaction mixture was cooled to about 0 °C before the addition of DIEA (11.5 mL, 66 mmol). 2-Aminomethyl-1-ethylpyrrolidine (7.77 g, 60 mmol) in CH 3 CN (10 mL) was added. The reaction was allowed to warm to room temperature and stirred overnight. DIEA (11.5 mL, 66 mmol) and S-(+)-2-methoxyethylpyrrolidine (6.91 g, 60 mmol) in 20 mL of 1,4-dioxane were then added. The reaction is heated to about 50 °C overnight. The solvent is removed in vacuo and the resulting residue is purified by flash chromatography on silica gel packed in ethyl acetate. First, impurities are removed, and then the eluent is increased in polarity to 10% CH3OH: ethyl acetate. The material collected from the column was then dissolved in water and extracted with CH 2 Cl 2 (4 times), dried over MgSO 4 , and concentrated to dryness to give dark solid compound 145 (9.7 gm 27.6% yield), 71-72 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 5.37 min, 90.3% purity; <1>H NMR (600 MHz, CDCl3, 55°C) 5 7.69 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.86 (t, J=9 Hz, 1H), 4.29 (s, 1H), 3.90-3.96 (m, 1H), 3.84 (s, 3H), 3.63-3.81 (m, 6H), 3.35 (s, 3H), 3.23-3.25 (m, 1H), 2.85 (wide with, 1H), 2.78 (broad s, 1H), 2.14 (broad s, 2H), 1.89-2.04 (m, 6H), 1.37 (apparent t, J=7.2 Hz, 3H);<13>C NMR (150.8 mHz, CDCl3, 55 °C) 5 165.8, 163.8 (2C). 152.3 (d, Jc.f=243.5 Hz), 143.0 (142, rotamer or diastereomer), 133.7 (133.67, rotamer or diastereomer), 115.0, 114.4, 109.1 (108.9, rotamer or diastereomer), 72.8, 66.6, 59.0, 57.0, 56.6, 53.7, 51.0, 46.8, 42.2, 28.4 (28.2, rotamer or diastereomer), 23.1 (23.0, rotamer or diastereomer), 10.9; MS (ESI): m/ z 460.2 (M+H, 44.7), 251.1 (47.7), 235.1 (27.5), 231.1 (37.4), 230.6 (100), 214.6 (36.5).

EXAMPLE 48

Synthesis of (3-Chloro-4-methoxy-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine

( 101)

To ciuric acid chloride (36.911 g, 200 mmol) dissolved in acetone (250 mL) with stirring at approximately 0-5°C (ice-water bath), a solution of 3-chloro-p-anisidine (31.582 g, 200.0 mmol) in acetone (150 mL) was added followed by the addition of NaOH solution (80 mL, 2.5 N, 200.0 mmol). The reaction mixture is allowed to stir at approximately 0-5°C (ice-water bath) for about 1 hour. The reaction mixture was then poured over crushed ice and neutralized with 10% NH1 (water). The resulting solid was washed with water and dried overnight under vacuum to give compound 101 (58.3 g, 96%), mp 165 °C; HPLC: YMC Pack Pro C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2). CH3OH: CH3CN], 264 nm, Rt24.3 min, 97.8% purity); MS (ESI): m/z 305 (M+H, 100), 283 (26.3), 271 (26.9), 269 (75.2), 139 (16.2).

EXAMPLE 49

Synthesis of 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-[1,3,5Jtriazine-2,4-diamine (133)

To a sample of compound 101 (20.02 g, 65.6 mmol) in acetone (200 mL) was slowly added cycloheptylamine (8.3 mL, 65.5 mmol) in acetone (55 mL) via an addition funnel at room temperature. Water (66 mL) was then added followed by aqueous sodium hydroxide (26.2 mL, 2.5 N, 65.5 mmol) via the addition funnel. The reaction mixture was heated at reflux under a nitrogen atmosphere for about 3 hours. The reaction was cooled, diluted with ethyl acetate, washed once with water, and finally once with brine. The organic layers are separated and dried over potassium carbonate/sodium sulfate. The organic layer is filtered and concentrated in vacuo. The product (24.13 g) was purified by flash column chromatography (silica gel, 1:4 ethyl acetate/hexanes). The fractions were combined and concentrated in vacuo to give compound 133 as a pale yellow solid (17.66 g, 70.5%), mp 146 °C; HPLC: Inertsil ODS-3V C18, 40.10:50 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, R, 58.8 min, 99.9% purity); MS (ESI): m/ z 382 (M+H, 100), 241 (2.83), 226 (8.49), 139 (43.5), 116 (6).

EXAMPLE 50

Synthesis of N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-N''-methyl-N''-(1- met

Piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine (137)

To compound 133 (10.014 g, 26.2 mmol) in 1,4-dioxane (80 mL) was slowly added methyl-(1-methyl-piperidin-4-yl)-amine (3.8 mL, 26.2 mmol) dissolved in 1,4-dioxane (15 mL) via an addition funnel. Aqueous sodium hydroxide (10.5 mL, 2.5 N, 26.2 mmol) was then added via addition funnel followed by water (26 mL). The reaction mixture was heated at reflux for about 2.5 hours under a nitrogen atmosphere. The reaction was cooled and diluted with methylene chloride. The reaction mixture was filtered using vacuum and the white solid compound 147 was removed. The filtrate was then washed once with brine. The aqueous layer is back-extracted once with methylene chloride. The organic layers are combined and dried over potassium carbonate. The organic solution was filtered and concentrated in vacuo to give the crude product (5.89 g). The crude reaction product was purified by flash column chromatography (silica gel) eluting with 96:3:1 methylene chloride:methanol:15 M ammonium hydroxide. Fractions were combined, dried over sodium sulfate/potassium carbonate, filtered, and concentrated in vacuo to give compound 137 as a white solid (3.84 g, 30.9%), mp 104-105 °C; HPLC: YMC Pack Pro C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 13.8 min, 97% purity); MS (ESI): m/z 474(M+H, 41), 408 (2.3), 364 (2.8), 258 (13), 239 (14), 239 (47.5), 238 (100), 127 (5.3).

EXAMPLE 51

Synthesis of N2-(3-chloro-4-methoxy4enyl)-N4-cycloheptyl-N6-methyl-N6-piperidine-4-H-1.3,5-triazine-2,4,6-triamine (146)

Compound 146 is isolated as a by-product by column chromatography (silica gel, 96:3:1 methylene chloride:methanol:conc. ammonium hydroxide, mp 114-116 °C; TLC (silica gel, 90:9:1 CH2CI2:CH3OH:conc. NH4OH), Rf146 0.15; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 10.7 min, 91.18% purity); MS (ESI): m/z 460(M+H, 25.4), 364 (17.9), 292 (2), 273 (17.1), 272 (37.9), 252 (44), 251 (100), 231 (2.2), 157 (10.54), 118 (2.8).

EXAMPLE 52

Synthesis of 4-(3-chloro-4-methoxy-phenylamino)-6-cycloheptylamino-1,3,5-triazin-2-ol (147)

Compound 147 is isolated as a by-product via vacuum filtration prior to isolation of compound 137, white solid, mp>310 °C; MS (ESI); m7z 727 ([2(363)+H], 1.2, 364 (M+H, 100).

EXAMPLE 53

Synthesis of N-(1-Aza-bicyclo[2.22]oct-3-yl)-N'-(3-chloro^

ethyl-pyrrolidin-2-ylmethyl)-[1,3,5]triazine' 2,4,6-triamine (148)

To compound 101 (3.056 g, 10.0 mmol) dissolved in anhydrous acetonitrile (30 mL) at about 0 °C was added a solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.5 mL, 10.0 mmol) in anhydrous acetonitrile (5 mL) followed by the addition of DIEA (1.9 mL, 11.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight under nitrogen. DIEA (1.9 mL) was then added followed by the addition of 3-aminoquinuclidine dihydrochloride (1.962 g, 10 mmol) in 1,4-dioxane (5 mL): The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture was extracted twice with dichloromethane and once with ethyl acetate. The combined organic layers were washed once with brine and dried over anhydrous potassium carbonate. The organic layer is with 20% HCl (water). The aqueous layer was neutralized with 2.5 N NaOH (water) and then extracted 3 times with ethyl acetate. The combined organic layers were washed once with brine, dried over potassium carbonate, concentrated on a rotary evaporator, and allowed to dry overnight under vacuum. Column chromatography (silica gel, 85:14:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded a pale white solid compound 148 (100 mg, 2%), mp 83 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 8.1 min, 71.2% purity); MS (ESI): m/z 488 (M+H, 18.7), 280 (100), 245 ([M+2H] ++ , 37.4), 236 (23.5).

EXAMPLE 54

Synthesis of ^-( S- chloro^- methoxy- phenylj- t^- cycloheptyl-^^ l- ethyl- pyrrolidine-?-

ylmethyl)- 1, 3, 5- triazine- 2, 4, 6- triamine (149)

To a mixture of ciuric acid chloride (1.8 g, 9.7 mmol) in CH3CN at about -20 °C was added 2-chloro-N,N-diethylphenylene-1,4-diamine hydrochloride (2.35 g, 10 mmol) in CH3CN followed by the addition of N,N-diisopropylethylamine (DIEA).

(1.75 mL, 10 mmol) and stirred for one hour. The reaction mixture was then allowed to reach room temperature in about 1 hour. Cycloheptylamine (1.25 mL, 9.8 mmol) and DIEA (1.75 mL, 10 mmol) were then added and the reaction mixture was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer is separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel) eluting with 96:3:1 methylene chloride:methanol:conc. ammonium hydroxide to yield compound 149 (0.800 g, 15%) as a white solid, mp 84-85 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 9.5 min, 96% purity); MS (ESI): m/ z 515 (M+H, 9.4), 259 (16.8), 258 (55.1), 257 (100).

EXAMPLE 55

Synthesis of N2- cycloheptyl- N4-( 2- dimethylamino- ethyl)- N6-( 3- fluoro- 4- methoxy-

phenyl)- 1, 3, 5- triazine- 2, 4, 6- triamine ( 150)

To ciuric acid chloride (1.84 g, 10 mmol) in CH 3 CN (20 mL) cooled to about -10 °C was added 3-fluoro-p-anisidine (1.41 g, 10 mmol) followed by DIEA (1.8 mL, 10 mmol). The reaction is then stirred for about 45 minutes at room temperature under a N 2 atmosphere. Cycloheptylamine (1.26 mL, 10 mmol) was added followed by DIEA (1.8 mL, 10 mmol) and the reaction was stirred at room temperature overnight. N,N-dimethylethylenediamine (1.1 mL, 10 mmol) was added followed by DIEA (1.8 mL, 10 mmol) and the mixture was heated overnight at reflux under N 2 . The reaction was diluted with ethyl acetate, washed with brine, and dried over anhydrous K 2 CO 3 . The material (1.178 g) was purified by silica gel column chromatography to give solid compound 150 (1.178 g, 28%), mp 73-76 °C; HPLC: Inertsil ODS-3VC18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 10.8 min, 95.1% purity; MS (ESI): m/z 418 (M+H, 100), 373 (11.9), 322 (7.8), 277 (6.8), 162 (3.6).

EXAMPLE 56

Synthesis of ({4-cycloheptylamino-6-[1-ethyl-pyrrolidin-2-ylmethyl)-amino]-1,3,5-triazin-2-yl}-phenyl-amino)-acetonitrile (151)

To ciuric acid chloride (1.84 g, 10 mmol) in CH 3 CN (20 mL) at about -10 to -20 °C was added DIEA (1.75 mL, 10 mmol) and N-phenyl glycinonitrile (1.3 g, 10 mmol), and stirred for about 1 hour. The reaction mixture is then allowed to reach room temperature for one hour. To this reaction mixture was added DIEA (1.75 mL, 10 mmol) and cycloheptylamine (1.25 mL, 10 mmol) and the reaction mixture was stirred overnight at room temperature. DIEA (1.75 mL, 10 mmol) and 2-aminomethyl-N-ethylpyrrolidine (1.45 mL, 10 mmol) were then added and the reaction mixture was refluxed overnight. The reaction mixture was worked up, isolated, and then purified by column chromatography (silica gel) eluting with 96:3:1 methylene chloride:methanol:conc-ammonium hydroxide to yield compound 151 (3 g, 66%), mp 52-54 °C; MS (ESI): m/ z 449 (M+H, 100), 225 [(M+2H)<2+>, 22.3].

EXAMPLE 57

Synthesis of N-Azepan-1-yl-6-chloro-N'-(3-chloro-4-methoxy-phenyl)-[1,3,5-triazine-2,4-diamine (152)

To compound 101 (6.03 g, 20.0 mmol) dissolved in acetone (75 mL) was added a solution of 1-aminohomopiperidine (2.3 mL, 20.0 mmol) in acetone (10 mL) followed by addition of NaOH (8.0 mL, 2.5 N NaOH solution, 20.0 mmol) and 20 mL of water. The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting oil is dried overnight under vacuum. Column chromatography (96:3:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded light purple solid 152 (1.2 g, 16%), mp 139 °C; TLC (silica gel, 96:3:1, CH2Cl2, CH3OH, conc. NH4OH), Rf 0.31; HPLC: Inertsil ODS-3VC18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt52.5 min, 94.9% purity); MS (ESI): m/ z 383 (M+H, 100).

EXAMPLE 58

Synthesis of N"-(3-chloro-4-methoxy-phenyl}-N,N'-bis-perhydro-azepin-1-yl-1,3,5-triazin-2,4,6-triamine (153)

Compound 153 was isolated as a by-product (2.3 g) by column chromatography (silica gel, 96:3:1, CH2Cl2, CH3OH, conc. NH4OH), mp 199°C; TLC (silica gel, 96:3:1, CH2Cl2, CH3OH, conc. NH4OH), Rf 0.11; HPLC: Inertsil ODS 3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt15 min, 86% purity); MS (ESI): m/z 461 (M+H, 100), 366 (19.7), 365 (19.6), 232 (11), 231 (27.3).

EXAMPLE 59

Synthesis of N-Azepan-1-yl-N'-(3-chloro-4-methoxy-phenyl)-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine (154)

To compound 152 (0.2007 g, 0.5 mmol) dissolved in THF (10 mL) was added a solution of N-methyl-4(methylamino)piperidine (0.07 mL, 0.5 mmol) in THF (1 mL) followed by the addition of DIEA (1.0 mL, 0.55 mmol) in acetonitrile (1 mL). The reaction mixture was allowed to stir at reflux overnight under nitrogen. The reaction mixture is extracted 3 times with dichloromethane; the combined organic layers are washed with brine and dried over potassium carbonate. The sample is concentrated on a rotary evaporator and the resulting oil is dried overnight under vacuum. Column chromatography (90:9:1 dichloromethane:methanol:conc. ammonium hydroxide) afforded bright yellow compound 154 as a solid (65 mg, 27%), mp 100 °C; TLC (silica gel, 90:9:1, CH2CI2, CH3OH, conc. NH4OH), Rf0.36; MS (ESI): m/ z 475 (M+H, 23.2), 378 (11.6), 258 (68.9), 239 (52.2), 238 (100).

EXAMPLE 60

Synthesis of N4-(3-chloro-4-methoxy-phenyl)-N6-methyl-N2' perhydro-azepin-1-yl- i^-

Piperidin-4-yl-1,3,5-triazin-2,4,6-triamine (155)

Compound 155 was obtained as a by-product (50 mg) of the reaction via column chromatography (90:9:1 dichloromethane:methanol:conc. ammonium hydroxide), mp 81 °C; TLC (silica gel, 90:9:1, CH2CI2, CH3OH, conc. NH4OH), Rf0.25; MS (ESI): m/z 461 (M+H, 20.3), 430 (2.8), 273 (11.8), 272 (25.5), 251 (100), 236 (4.6), 215 (4.7).

EXAMPLE 61

Synthesis of N, N'- di- n- propyl- N"-( 3- fluoro- 4- methoxy- phenyl)- 1, 3, 5- triazine- 2, 4, 6-

triamine ( 156)

To ciuric acid chloride (0.368 g, 2 mmol) in CH 3 CN at about -20°C was added 3-fluoro-p-anisidine (0.28 g, 2 mmol) in CH 3 CN followed by the addition of DIEA (0.39 mL, 2.2 mmol) and stirred for about 1 hour. The reaction mixture is then stirred at room temperature for about 1 hour. Then n-propylamine (1.64 mL, 19.9 mmol) and DIEA (0.39 mL, 2.2 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture is worked up as usual, diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over sodium sulfate, filtered, concentrated under reduced pressure, and compound 156 was purified by silica gel column chromatography, mp 53-55°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 12.6 min, 93.7% purity); MS (ESI): m/z 335 (M+H, 100), 331 (1.5), 126 (1).

EXAMPLE 62

Synthesis of N,N'-dicyclopropyl-N"-(3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine (157)

To ciuric acid chloride (0.368 g, 2 mmol) in CH 3 CN at about -20°C was added 3-fluoro-p-anisidine (0.28 g, 2 mmol) in CH 3 CN followed by the addition of DIEA (0.39 mL, 2.2 mmol) and stirred for about 1 hour. The reaction mixture is then stirred at room temperature for about 1 hour. Cyclopropylamine (1.39 mL, 20 mmol) and DIEA (0.39 mL, 2.2 mmol) were then added and the reaction mixture was stirred overnight at room temperature. The reaction mixture is worked up as usual, diluted with ethyl acetate and washed with brine. The organic layer was separated and dried over sodium sulfate, filtered, concentrated under reduced pressure, and compound 157 was purified by silica gel column chromatography (200 mg, 30%), mp 91-92°C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt8.6 min, 99.1% purity); MS (ESI): m/ z 331 (M+H, 100), 305 (0.8), 151 (3).

EXAMPLE 63

Synthesis of N^Cycloheptyl-fr-fi-fluoro-^methoxy-phenyO-N6^ 1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine (158)

To ciuric acid chloride (0.180 g, 1 mmol) in 1,4-dioxane (1 mL) at about -10 to -20 °C was added N,N-diisopropylethylamine (DIEA) (0.19 mL, 1 mmol) in CH3CN (1 mL) and 3-fluoro-p-anisidine (0.14 g, 1 mmol) in CH3CN (1 mL) and stirred for about 1 hour. The reaction mixture is then stirred at room temperature for about 1 hour. A solution of cycloheptylamine (0.13 mL, 1 mmol) and DIEA (0.19 mL, 1 mmol) in CH 3 CN (0.5 mL) was then added and the reaction mixture was stirred overnight at room temperature. N-methyl-4(methylamino)piperidine (0.15 mL, 1 mmol) and DIEA (0.19 mL, 1 mmol) in CH 3 CN (0.5 mL) were then added and the reaction mixture was refluxed overnight. The reaction mixture is made using saturated sodium bicarbonate and brine. The organic layers are separated and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane:methanol:conc. ammonium hydroxide) to give compound 158 (0.130 g, 28%); TLC (silica gel, 90:9:1, CH2Cl2, CH3OH, conc. NH4OH), Rf 0.26); 4.55 (s, 1H), 3.98 (s, 1H), 3.82 (s, 3H), 2.97 (s, 3H), 2.94 (br d, J=11.9 Hz, 2H), 2.29 (s, 3H), 2.06-2.10 (m, 2H), 1.93-1.97 (m, 2H), 1.84-1.90 (m, 2H), 1.44-1.66 (m, 12H).

EXAMPLE 64

Synthesis of rf-cycloheptyl-N4-(3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-piperidin-4-yl-1,3,5-triazin-2,4,6-triamine (159)

Compound 159 is isolated as a by-product (55 mg) by column chromatography (silica gel 90:9:1 dichloromethane:methanol:conc. ammonium hydroxide); TLC (silica gel, 90:9:1, CH2CI2, CH3OH, conc. NH4OH), Rf 0.1); HPLC: Inertsil ODS-3VC18, 40:30:30 [KH2PO4(0.01 M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt8.3 min, 93.5% purity); MS(ESI): m/z 443 (M+H, 100).

EXAMPLE 65

Synthesis of N^cycloheptyl-N4-(3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methylpiperidin-4-yl)-1,3,5-thazin-2,4,6-triamine, hydrogen chloride salt (160)

To compound 171 in dry methanol (1 mL, prepared according to parallel synthesis procedure C using the appropriate monomers as disclosed herein) was added HCl (0.3 mL, 0.3 mmol, 1 M in diethyl ether) via syringe under N 2 atmosphere. The mixture was stirred for 10 min at room temperature, concentrated and dried in vacuo overnight to give a white solid 160 (0.131 g) which was soluble in water, mp 189-190 °C (at 160 °C the sample turned brown); HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 7.3 min, 89.1% purity.

EXAMPLE 66

Synthesis of [N-(3-Chloro-4-methoxy-phenyl)-N'-cycloheptyl-N"- m^

Piperidin-4-yl)-[1,3,5]-triazin-2,4,6-triamine (161)

To compound 137 (0.473 g, 1.0 mmol) dissolved in methanol (5 mL) was added 1.0 M hydrochloric acid in diethyl ether (1.0 mL, 1 mmol). The reaction mixture was allowed to stir for about 1 hour at room temperature. The reaction mixture was then concentrated on a rotary evaporator. The resulting solid was dissolved in water, filtered, and concentrated on a rotary evaporator. The sample was dried below °C under vacuum and solid compound 161 (359.1 mg, 70%) was collected, mp 173-176 °C.

EXAMPLE 67

Synthesis of ^-(S- chloro^- diethylamino- phenylO- rS- cycloheptyl- N6^ 1- ethyl- pyrrolidin-2- ylmethyl)- 1, 3, 5- triazin- 2, 4, 6- triamine, hydrogen chloride salt ( 163)

To compound 162 (1.0 g, 2 mmol, prepared according to parallel synthesis procedure A with the appropriate monomers as disclosed herein) in methanol (10 mL) was added HCl (2.5 mL, 2.5 mmol, 1 M) in diethyl ether and stirred. The reaction mixture evaporates. It was then dissolved in water, filtered, evaporated in vacuo, and dried overnight under vacuum to give solid compound 163 (1.1 g, 93%).

EXAMPLE 68

Synthesis of N^cycloheptyl-N4-(1-ethyl-pyrrolidin-2-ylmethyl)-N6-methyl-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazin-2,4,6-triamine, hydrogen chloride salt (164)

To compound 130 (2.285 g, 5 mmol) in dry methanol (10 mL) was added HCl (5 mL, 5 mmol, 1 M in diethyl ether) and stirred at room temperature for about 1 hour. The reaction was evaporated in vacuo, dissolved in water, filtered, evaporated and then dried under vacuum overnight to give solid compound 164 (2.396 g, 97%), tt 131-133°C, HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 7.9 min, 98.2% purity.

EXAMPLE 69

Synthesis of N^ cyclohexylmethyl- rf- tfl- ethyl^- pyrom^

methoxyphenyl)- 1, 3, 5- triazine- 2, 4, 6- triamine, hydrogen chloride salt ( 165)

To compound 136 (0.457 g, 1 mmol) in dry diethyl ether was added HCl (1 mL, 1 mmol, 1 M in diethyl ether). The sediment is formed instantly. The mixture is stirred at room temperature for about 1 hour, and then concentrated in vacuo. The resulting material was dissolved in water, filtered, evaporated, and dried overnight in vacuo to give solid compound 165 (0.400 g, 81%), mp 85 °C; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 8.2 min, 89.6% purity.

EXAMPLE 70

Synthesis of ({4-cycloheptylamino-6-[1-ethyl-pyrrolidin-2-ylmethyl)-amino3,5-triazin-2'yl}-phenyl-amino)-acetonitrile hydrochloride salt (166)

To compound 151 (0.448 g, 1 mmol) in dry diethyl ether (2 mL) was added HCl (1 mL, 1 mmol, 1 M in diethyl ether). The mixture is stirred at room temperature for about 1 hour, and then concentrated in vacuo. The resulting material was dissolved in water (5-10 mL), filtered, evaporated, and dried overnight under vacuum to give solid compound 166 (0.418 g, 86%), mp 125-127°C; HPLC: Inertsil ODS-3VC18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 6.9 min, 73.4% purity.

EXAMPLE 71

Synthesis of N2- cycloheptyl- r^-( 3- fluoro- 4- methoxy- phenyl)- N6- methyl- N^

Piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, maleate salt (167)

Compounds 158 (100.3 mg, 0.219 mmol) and maleic acid (25.4 mg, 0.219 mmol) were dissolved in CH 3 OH (2 mL) and stirred at room temperature under N 2 for about 75 min. The reaction mixture was filtered through a cotton plug and concentrated in vacuo to give solid compound 167, 0.1239 g, mp 99-100°C. In a qualitative test, this material is soluble in water. HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 7.7 min, 87.9% purity.

EXAMPLE 72

Synthesis of N2-cycloheptyl-N4-(3-fluoro-4-methoxy-phen^^^

piperidin-4-yl))-1! 3, 5- triazine- 2, 4, 6- thamine, citrate salt (168)

Compound 158 (100 mg, 0.219 mmol) and citric acid (42.1 mg, 0.219 mmol) were dissolved in CH 3 OH (2 mL) and stirred at room temperature under N 2 atmosphere for about 75 min. The reaction mixture was filtered through a cotton plug and concentrated in vacuo to give solid compound 168 (0.1387 g), mp 125 °C. In a qualitative test, this material is insoluble in water. HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, Rt 7.7 min, 90.1% purity.

EXAMPLE 73

Synthesis of /V2-c/Wo/?epf/7-/V4-f3-//uora-4-mero/(s/-phen/7J-/V6-m

Piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, succinate salt (169)

Compounds 158 (101.5 mg, 0.219 mmol) and succinic acid (24.8 mg, 0.219 mmol) were dissolved in CH 3 OH (2 mL) and stirred at room temperature under N 2 for about 75 min. The reaction mixture was filtered through a cotton plug and concentrated in vacuo to give solid compound 169 (0.1248 g), mp 81 °C. In a qualitative test, this material is soluble in water. HPLC: Inertsil ODS-3V C18, 40:30:30 [KH 2 PO 4 (0.01 M, pH 3.2): CH 3 OH: CH 3 CN], 264 nm, R, 7.6 min, 89.8% purity.

EXAMPLE 74

Synthesis of N-(3-Bromo-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]-triazin-2,4,6-triamine, hydrogen chloride salt (170)

To compound 123 (1.0 mmol) dissolved in methanol (5 mL) was added 1.0 M hydrochloric acid in diethyl ether (1.0 mL, 1 mmol). The reaction mixture was allowed to stir for about 1 hour at room temperature. The reaction mixture is then concentrated on a rotary evaporator. The resulting solid is dissolved in water, filtered and concentrated on a rotary evaporator. The sample was dried below 0°C under vacuum and solid compound 170 (70%) was collected.

EXAMPLE 75

An alternative synthetic route to tris(amino) 1, 3, 5-triazine compounds

The following reaction scheme presents proposed and alternative synthetic routes to 1,3,5-triazines.

This scheme represents a modification of the synthetic route described in the patent to prepare tris-amino substituted 1,3,5-triazines. Alternative leaving groups, X, can be used compared to ciyuric acid chloride (X=CI) in the SNAr reaction with sequential addition of a nucleophilic amine in the presence of an acidic (proton) additive to give a tris-substituted 1,3,5-triazine with the desired combination of amino groups.

EXAMPLE 76

An alternative synthetic route to tris(amino) 1, 3, 5-triazine compounds

The following reaction scheme presents proposed and alternative synthetic routes to 1,3,5-triazines.

This scheme represents a modification of the synthetic route described in the patent text to prepare tris-amino substituted 1,3,5-triazines. Bases, including an excess of the amino reagent R2NH, can be used as acid (proton) additives as an alternative to Hunig's base (iPr2Net) which is routinely used in our procedure. These bases may include organic tertiary amino bases or ionic, inorganic bases. A strong base (NaH, KH, or R1) can be used to first deprotonate the amino monomer via addition to the ciurin-X substrate. Additionally, they can be used with a solid base carrier (eg, resin-NR2, modified Hunig's base) as a proton additive. This potentially allows for an easier isolation procedure and cleaner reaction products. Logically, an appropriate solvent or combination of solvents compatible with the base chosen for this procedure is used.

EXAMPLE 77

An alternative synthetic route to tris(amino) 1, 3, 5-triazine compounds

The following reaction scheme presents proposed and alternative synthetic routes to 1,3,5-triazines.

This scheme represents a modification of the synthetic route described in the patent to prepare tris-amino substituted 1,3,5-triazines. Using melamine as a starting material, the indicated procedure introduces three sequential reductive amination procedures. By controlling the addition, temperature, and pH, choice of aldehyde or ketone, tris-amino substituted triazines with the desired combination of amino groups can be prepared.

EXAMPLE 78

An alternative synthetic route to tris(amino) 1, 3, 5-triazine compounds

The following reaction scheme presents proposed and alternative synthetic routes to 1,3,5-triazines.

This scheme represents a solid phase synthetic approach to the preparation of symmetrically or asymmetrically substituted tris-amino substituted 1,3,5-triazines. The resin should have ready-to-use linker groups (L) and leaving groups (G) to attach the amino group. The scheme outlines the synthesis by initial attachment of a simple amino group, NH2, by reacting the resin with ammonia. Using a standard, SNAr hernia for substitution of perhalogenated 1,3,5-triazines, the triazine can be attached to the aminated resin. Sequential halogen substitutions on the triazine core with functionalized amines in the presence of an acidic additive produce the desired di-amino substituted 1,3,5-triazines. Cleavage of the triazine from the tetra resin gives the tris-amino substituted triazine product. The free NH2 residue of the triazine can be further alkylated or functionalized using standard techniques such as reductive amination or N-alkylation to give the fully functionalized tris-amino substituted 1,2,5-triazine.

EXAMPLE 79

An alternative synthetic route to tris(amino) 1, 3, 5-triazine compounds

The following reaction schemes (Schemes A and B) represent proposed and alternative synthetic routes to 1,3,5-triazines.

These schemes represent variations on the use of Suzuki coupling to synthesize tris-amino substituted 1,3,5-triazines. As illustrated in Scheme A, one can sequentially react the amino groups of melamine with an alkyl or aryl derivative of boric acid in the presence of a suitable palladium catalyst, additive and solvent to give symmetrical or asymmetrical tris-amino substituted 1,3,5-triazines similar to the previously described examples. In Scheme B, the tris-boronic acid 1,3,5-triazine can be prepared from ciuric acid chloride or bromide. This derivative can then be coupled with an aryl or alkyl amine, as illustrated in the preceding descriptions of amine monomers, in the presence of a suitable metal catalyst (eg, Cu or Pd catalyst), additive and solvent to give symmetrical or asymmetrical tris-amino substituted 1,3,5-triazines.

EXAMPLE 80

Proteoglycan induction

Smooth muscle cells achieve quiescence during serum starvation resulting in a blockage of DNA synthesis. To demonstrate the role of perlecan (an example of a proteoglycan) in SMC quiescence, cells were starved by removing serum from the medium. The cells used in this Example and other examples provided herein are human aortic SMCs, which are cultured in basal medium supplemented with growth factors, bFGF and epidermal growth factor (EGF) (Clonetics, San Diego,

CA).

SMC secretion of total PGs (proteoglycans) as well as perlecan is determined in the presence or absence of one or more compounds of the present invention. PGs were radiolabeled with (<35>S)sulfate by incubating cells with (<35>S)sulfate for 2 to 6 hours. PGs medium is collected and purified by DEAE-cellulose chromatography. Cell-associated PGs are assessed by extracting cells with 50 mM Tris buffer pH 7.4 containing 4 M urea, 1% Triton X-100, 0.1 mM EDTA, and 1 mM PMSF. Aqueous solutions of (<35>S)sulfate and (<3>H)leucine were obtained from Amersham. Control cells have no compounds added while treated cells have one or more compounds of the present invention added.

To determine changes in PG levels, DEAE-cellulose chromatography is performed. The DEAE-cellulose column is equilibrated with 50 mM Tris buffer pH 7.4 containing 4 M urea, 0.1 M NaCl, 0.1 mM EDTA, 1 mM PMSF, and 1% 3[3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The column is washed with the same buffer and buffer containing 0.25 M NaCl and PG is eluted with the same buffer containing 0.5 M NaCl. Fractions containing radioactivity (<35>SO 4 ) are pooled and dialyzed against MEM overnight and counted.

To determine the relative proportion of HSPG and chondroitin sulfate/dermatasulfate proteoglycan (CS/DS PG), an aliquot of the pool fraction was incubated in 50 mM sodium acetate buffer pH 5.2 with one unit/mL each of heparanase and hepartinase or with 0.5 unit of chondroitin ABC lyase for 16 hours at 37 °C. Chondroitin ABC refers to different isomeric types of chondroitin, e.g. chondroitin A, chondroitin B and chondroitin C. The reaction mixture is precipitated with either 0.5 volumes of 1% cetyl pyridinium chloride or 3 volumes of ethanol to precipitate undigested glycosaminoglycans. The radioactivity of the surface layer and the pellet is determined.

To determine changes in perlecan protein in response to the presence of compounds, cells were grown in serum-free or serum-containing medium in the presence of (<3>H)leucine for 24 hours (steady state). Cells are plated at low density (8 x 10<4>/well per 48-well plate, 30-40% confluence) and cultured for 24 hours. The wells are then refilled with fresh medium containing no serum or 10% fetal bovine serum (FBS). After a further 24 hours of incubation, cells are labeled with (<3>H)thymidine for 6 hours and radioactivity incorporated into DNA is determined by trichloroacetic acid (TCA) precipitation of the cell lysate. (<3>H)thymidine from NEN. Purified PG (0.5 M eluate) is immunoprecipitated by incubation with anti-perlecan antibody (100-fold dilution9 followed by precipitation with protein A-Sepharose. Immunoprecipitates are analyzed by 5% SDS-PAGE. Perlecan (Mr>550 kDa) is identified by autoradiography. Control cells have no compounds added while treated cells have one or more compounds of the present invention added.

EXAMPLE 81

Inhibition of smooth muscle cell proliferation

Purified perlecan is obtained from SMC medium with DEAE-cellulose chromatography using the procedures of Example 1, and tested for its antiproliferative effects on SMC.

Addition of perlecan to serum-containing medium inhibited SMC growth by 70%. Subconfluent SMCs (40-50% confluence) are incubated in serum-free medium or medium containing 10% serum with or without purified perlecan for 24 hours. DNA synthesis is then determined by incubating cells for the next 5 hours in medium containing (<3>H)thymidine. The number of precipitable thymidine TCA (DNA) is determined and expressed as a percentage of DNA synthesis in cells grown in 10%FBS.

An experiment can be used to show the effect of a compound on perlecan first directly by incubating the compound in perlecan and then performing the experiment. Alternatively, cells may be pretreated with at least one compound of the present invention to demonstrate an indirect effect. Control cells have no compounds added while treated cells have one or more compounds of the present invention added.

EXAMPLE 82

Triazine compounds in the smooth muscle cell proliferation assay

Human aortic smooth muscle cells (Clonetics) are used. Cells are grown in basal medium containing 5% fetal bovine serum supplemented with growth factors, basal growth factor, epidermal growth factor, and insulin. To determine the effects of the triazine compounds of the present invention on SMC proliferation, cells were plated at low density (4000 cells per well in a 96-well plate) and cultured for 24 hours. The cells are then starved of serum for 24 hours to induce quiescence. Fresh growth medium containing no compound or 10 µM compound is then added and further incubated for 24 hours. Cell numbers are determined using a cell proliferation assay kit (Celltiter96 AqUeous from Promega).

The effects of various triazine compounds on smooth muscle cell proliferation are shown in Figure 53. Many of the triazine compounds inhibited SMC proliferation by more than 70%.

EXAMPLE 83

Induction and measurement of endothelial heparanase protein

Experiments are performed on human microvascular endothelial cells (HMVEC) grown in 48-well plates (-90% confluence). To induce heparanase activity, the culture medium is replaced with 200 uL of Dulbecco's Modified Eagle's medium (DMEM) supplemented with 1% bovine serum albumin (BSA) and with or without stimulants (5 ng/mL TGF-alpha, 1 ng/mL IL 1alpha, 200 ng/mL VEGF or other stimulants, cytokines, or elicitors as required). Secreted proteins are analyzed by SDS/PAGE and heparanase protein is detected by immunoblotting using a polyclonal anti-human heparanase antibody. The induction and measurement of endothelial heparanase proteins provided in the Tables herein are performed according to this Example.

EXAMPLE 84

Preparation of biotinylated HS

Heparan sulfate (HS) is biotinylated using biotin with extended spacer arms using succinimidyl-6-(biotinamido) hexanoate (NHS-LC-Biotin) obtained from Pierce. About 0.5 mL of HS solution (2 mg/mL in NaHCO 3 , pH 8.5) is mixed with 0.05 mL of freshly prepared solution of NHS-LC-Biotin in dimethyl sulfoxide. The mixture is incubated at room temperature for 1 hour. Unconjugated biotin is removed by centrifugation (10,000 rpm) through a Microcon-3 filter (Millipore) followed by dilution with phosphate buffered saline (PBS). This procedure is repeated five times to ensure complete removal of free biotin. Unwanted aldehydes in the reaction are then quenched by incubation with one milliliter of Tris-glycine buffer (25 mM-183 mM, pH 8.3) at room temperature for 20 minutes. The mixture is subjected to three rounds of microfiltration as described above. Biotinylated HS (5 mg/mL in PBS) is placed as an aliquot and stored at -20°C- To obtain maximum Biotinylation, a 25-fold molar excess of biotin is used. Using the HABA reagent, it was determined that the ratio of HS to biotin is 1:2.

The extent of biotinylation of HS is determined using Avidin-HABA (Pierce Chemical Co). The HABA assay can be applied over a wide range of pH values and salt concentrations. HABA (4-hydroxyazobenzene-2'-carboxylic acid) is a dye that binds to vaidin and can serve as an indicator of unoccupied binding sites. Avidin combines stoichiometrically with biotin, making it possible to use any physiochemical difference between avidin and the avidin-biotin complex as the basis of a qualitative and quantitative test procedure for any component.

When HABA binds to avidin, there is a wide range of changes in HABA color. A new absorption layer appears at 500 nm, which is characteristic of the quinoid form of the dye. The avidin-biotin complex does not bind HABA and because the dissociation constant of the complex is so low, the dye is stoichiometrically displaced by biotin. Consequently, the HABA test can be the basis for both colorimetric and titimetric tests. The amount of avidin can be calculated directly from the increased absorbance at 500 nm, or the color can be used as an indicator in a spectrophotometric titration with biotin.

The absorption layer resulting from the avidin-HABA complex decreases proportionally with the addition of biotin. Because biotin has such a high affinity for avidin, it displaces the HABA dye. The unknown amount of biotin can be determined by preparing a standard curve using known amounts of biotin to displace HABA bound to avidin,

and plotting against absorbance at 500 nm.

A HABA solution is prepared by adding 24.2 mg of HABA (Pierce) to 9.9 mL of H 2 O, and then adding 0.1 mL of 1 M NaOH. Avidin-HABA reagent is prepared by adding 10 mg of avidin and 600 gL of HABA solution to 19.4 mL of phosphate-buffered saline. To 1 mL of Avidin-HABA reagent in a cuvette, 100 µL of biotinylated HS is added, and the optical density is measured at 500 nm in a spectrophotometer. The standard curve is determined using known amounts of HABA. A decrease in the optical density of HABA was determined, followed by the addition of biotinylated HS.

EXAMPLE 85

Heparanase assay

Biotin-labeled HS prepared as described above with heparanase, under both control and treatment conditions, and a reaction containing non-degraded and degraded HS is run in a biotin-binding plate. Enzyme-conjugated streptavidin is added to the binding plate. By quantifying the color reaction, the amount of available biotin binding sites is measured. Decrease in color from known amount of reflectance HS digestion by heparanase. Control conditions have no added compounds of the present invention and treated conditions have added compounds of the present invention.

Lyophilized heparanase powder (heparanase III obtained from Seikagaku) containing 0.1 unit of enzyme activity was hydrated in 100 µL of Reaction Buffer (3.33 mM calcium acetate pH 7.0, containing 0.1 mg/mL BSA). This solution is then diluted to a working concentration of heparanase solution (0.01 microunits per 1 milliunit) in Reaction Buffer. Enzyme activity is defined by the manufacturer of heparanase (Seikagaku) as follows: one unit of enzyme activity is defined as the amount required to generate 1 micromole of ascorbic acid per minute. Biotin-HS is diluted to the desired concentration in the Reaction Buffer.

To determine heparanase activity, 10 µL of heparanase solution, with or without at least one compound of the present invention, is mixed with 200 µL of biotin-HS substrate in a 96-well plate. The reaction is incubated at 43°C for 1 hour. One hundred microliters of the reaction mixture was added to hydrated biotin-binding plates (Chemicon) and incubated at 37°C for 30 minutes. Biotin binding plates are hydrated with 200 µL of 1x Assay Buffer (Chemicon). The wells are washed five times with 1x Assay buffer and incubated with 100 µL of 1:3000 diluted Streptavidin-Enzyme Conjugate (Chemicon) for 30 minutes at 37°C. The wells are washed five times with 1x Assay Buffer and incubated for 20 minutes with 100 µL of Substrate Solution (Chemicon). Color development in the wells is assessed by measuring the optical density at 450 nm on a microplate reader (Labssystems, Muliskan Ascent model). Plots between control and treated conditions indicate the modulatory activity of the added compound or added compounds on heparanase

EXAMPLE 86

AGE-induced inflammatory response with IL-6 ELISA

Human aortic endothelial cells (HAEC, Clonetics) were cultured according to the manufacturer's instructions in growth medium (Clonetics): basal medium containing human epidermal growth factor, hydrocortisone, vascular endothelial growth factor, heparin-binding growth factor-B, long R3-insulin-like growth factor-1, ascorbic acid, gentamicin/amphotericin, and 5% FBS. These cells were allowed to reach at least 90% confluence before being subjected to experimental treatments. Glycated human serum albumin (G-HSA) was from US biologicals. Tumor necrosis factor a is from R&D Systems.

Endothelial cells are treated with control medium or medium containing 10 to 100 ng/mL of TNF or 300 µg/mL of glycated-HAS (treated cells or treatments) for 24 hours, in control and duplicates with compound added, containing 10 µM of compound. All compound-spiked and control treatments were performed in serum-free medium containing 0.2% albumin. Media from all conditions are pooled and used for the IL-6 ELISA. The IL-6 ELISA is performed using the human IL-6 DuoSet ELISA development kit as described by the manufacturer (R&D Systems). Mouse anti-human IL-6 was used as capture antibody (2 µg/mL) and biotinylated goat anti-human IL-6 (200 ng/mL) was used as detection antibody. Culture media are incubated with captured antibody (in 96 wells) for 2 hours at room temperature. Wells are washed three times with wash buffer (0.05% tween-20 in phosphate buffered saline (PBS) pH 7.4) followed by incubation with detection antibody for 2 hours at room temperature. After three washes, the wells are incubated with Streptavidin-HRP for 20 minutes. Color development is read at 450 nm in a microplate reader.

The effects of compounds of the present invention on G-HSA induced IL-6 are shown in Figure 54. G is G-HSA and C is control, no treatment with the compounds or G-HSA. Endothelial cells under basal conditions secrete about 25 pg/mL of IL-6. Incubation of endothelial cells with G-HSA causes a 3-fold increase in IL-6 secretion by endothelial cells. Addition of a compound of the present invention, as indicated for each compound number, to medium containing G-HSA significantly reduces endothelial secretion of IL-6. These inhibitory effects vary, the most effective compounds showing an 80% reduction in IL-6 secretion. These data indicate that the compounds of the present invention have anti-inflammatory activity.

EXAMPLE 87

Cytotoxicity/lactate dehydrogenase test

Appropriate numbers of cells are plated in 96-well plates, one plate for "day 0" and three plates for days 1-3. Cells are treated with at least one compound of the present invention at various concentrations with or without the apoptosis inducer cisplatin (2 µM)("+cis" or "-cis"). Untreated cells are also tested with or without cisplatin. After changing the infection, the plates are incubated at 37°C overnight.

Appropriate numbers of cells are plated in 96-well plates, one plate for "day 0" and three plates for days 1-3. Cells are treated with at least one compound of the present invention at various concentrations. Negative control cells have normal medium conditions, a duplicate set of wells is treated with a composition in which the compound is provided but no compound is added and positive control cells are treated with the apoptosis inducer cisplatin (2 µM). All cells were transformed by infection with a vector carrying a promoter responsive to apoptotic conditions. When apoptosis occurs, the promoter is turned on and the lactic dehydrogenase gene is activated and an enzyme protein is produced that is active. Activity is easily detected by a hint of color. After transfection, plates are incubated at 37 °C overnight.

About 8 mL of warmed alpha MEM LDH lysis buffer (2% Triton X100) and about 8 mL of culture medium (1/2 dilution) are combined. Two plates of 96 v-bottom wells are prepared, one labeled "lysis" and one labeled "surface layer". To lyse the cells, about 200uL of Alpha MEM lysis buffer (diluted Vi) is added to one test plate from which the supernatant is removed and added to the plate labeled supernatant. After mixing, about 200 µL of lysed cells are transferred to a lysis plate. Both plates and the lysate and supernatant are centrifuged at about 1600 rpm for about 10 minutes. After centrifugation, about 100 µL of both the supernatant and the lysate are transferred to appropriate flat-bottom 96-well plates.

The cytotoxicity assay uses the Cytotoxicity Detection Kit (LDH) from Roche Diagnostics Corp.

(Indianapolis, IN). Using the instructions provided, the dye solution is mixed and added to each well of the lysate and supernatant plates and incubated for up to 20-25 minutes at 15-25°C in the dark.

The difference in the amount of lactate dehydrogenase released from cells in untreated cells compared to cells treated with cisplatin or compounds of the present invention having cytotoxic activity indicates the cytotoxic activity of the tested compounds.

Claims (8)

1. Compound of the formula Or their ene, diene, triene, or yne derivative; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is at each occurrence independently selected from -H; alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkadienyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 12 carbon atoms and including linear or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, or heterocyclic derivatives thereof; arilla; heteroaryl; aryloxy; arylthio; halogen; or amino; G is selected from NR<1> or O; E is selected from CH or N; z is an integer from 0 to 3; X<1>is selected from R<1>, NR<1>3\CN, N02, CO2R<1>, C(0)NR<1>2, CH=CR<1>2,C=CR<1>, C(0)R<1>, SO2R<1>, SO2OR<1>, or NC(0)R<1>, or X<1>and X<2> are fused together with aryl, pyridine, dioxane, pyrrole, pyrrolidine, furan, thiophene ring; provided that the R<1>residue of the C(0)R<1>substituent in the X<1>position excludes amino or dialkylamino when X<1>C(0)R<1>; X<2> is selected from R<1>; CXXH3_X, where X is halogen and x is an integer from 1 to 3;OR1;SR<1>; NR<1>2; CN; C(0)OR<1>;4-morpholinyl; 4-methyl-1-piperizinyl;OR<2>, wherein R<2>is selected from CH2OCH3, CH2OCH2OCH3, CH2OCH2CH2OCH3, or C(0)R<1>;SR<3>, wherein R<3>is selected from CH2OCH3, CH2OCH2CH2OCH3, CH2OCH2CH(CH3)2, CH2NHC(0)CH3, or SR<1>; OM or SM, wherein M is selected from Li, Na, K, Mg, or Ca; AY<1>is halogen, or A is selected from NR<1>or O, and Y<1>is selected from R<1>; CR<4>3;NR<4>2; OR<4>; or SR<4>; wherein n is an integer from 0 to 8, m is an integer from 1 to 8, Z<1>is independently selected from CR<1>or N, Z2 is independently selected from CR<1>2, NR<1>, O, or S, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z2 residues are NR1; R<4> is at each occurrence independently selected from linear or branched alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 10 carbon atoms, -H, aryl, heteroaryl, aryloxy, arylthio, halogen, amino, their NR<1>2-substituted derivatives, or their halogen-substituted derivatives; and DY<2>is halogen, or D is selected from NR<1>wherein R<1>is defined as above, and Y2 is selected from R<1>, , or , wherein Z<1>is independently selected from N or CR<4>andZ<2>is independently selected as defined above, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z<2>residues are NR<1>; and with the further proviso that the compound turns it off N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-ε-morpholine^-or-N'-naphthalene^-yl-fl.S.Sltriazin^^-diamine; N-Cycloheptyl-N'-(3-flu oro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-6-morpholin-4-yl-N,-phenyl-[1,3,5]triazine-2,4-diamine; N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Benzyl-N'-cycloheptyl-N<M->(4-methoxy-phenyl)-N-methyl-[1,3,5]triazine-2,4,6-triamine; N-(2-[1,3lDioxolane-24l-ethyl)-N'-methyl-N41-methyl-pipedin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N''-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine. 2. The compound according to Claim 1, indicated by the fact that it is a compound: N<2->(4-bromo-naphthyl)- N<4->cycloheptyl- N<6>[(1-ethyl-2-pyrroidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->(4-chloro-1-naphthyl)- N<4->cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(3-quinolinyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(6-quinolinyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(8-quinolinyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->[1-(2-naphthyl)ethyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->(3,4-dichlorophenyl)- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->(3,4-difluorophenyl)-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]- N6-[4-(trifluoromethoxy)phenyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4>"-[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(4-fluorophenyl)- 1,3,5-triazine-2.4.6- triamine, 4-[(4-cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)amino]benzonitrile, N<2->(4-chlorophenyl)-N<4->cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, N<2->(4-bromophenyl)-N<4->cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, Ethyl 4-[(4-cycloheptylamino)-6-{ -ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]benzoate, N<2->(1,1'-biphenyl-4yl) N<4>"cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazin-2,4,6-triamine, N<2->cycloheptyl-N<4>"-[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(4-fluorophenyl)- 1,3,5-triazine-2,4,6-triamine, N<2->(3-chlorophenyl)-N<4->cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-(3-bronophenyl)-N4-cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazin-2,4,6-triamine, Ethyl 3-[(4-cycloheptylamino)-6-{[(1 -ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]benzoate, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(2-fluorophenyl) 1,3,5-triazine-2,4,6-triamine, N<2->(2-chlorophenyl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->(2-bromophenyl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, N<2->(1]3benzodioxol-5-yl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazin-2,4,6-triamine, N<2->cycloheptyl-N<4->(2,3dihydro-1,4-benzodioxin-6-yl)-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[4- (dimethylamino)phenyl]-N6-[(1 -ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-[3-chloro-4-(diethylamino)phenyl]-N4- cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl]-1.3.5- triazine-2,4,6-triamine, N2-cycloheptyl-N4-[(1 -ethyl-2-pyrrolidinyl)methyl]-N6-[4-(4-morpholinyl)phenyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->[4-(4-methyl-1-peperazinyl)phenyl]- 1,3,5-triazine-2,4,6-triamine, N-{4-[(4-(cycloheptylamino)-6^ 2-yl)-amino]phenyl}acetamide, N-{3-[(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]phenyl}acetamide, N2-cycloheptyl-N4-[(1 -ethyl-2-pyrrolidinyl)methyl]-N6-(3-methoxyphenyl)-1,3,5-triazin-2,4,6-triamine, N<2->cycloheptyl-N<4->(4-ethoxyphenyl)-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2.4.6-triamine, N2-cycloheptyl-N4-[(1 -ethyl-2-pyrrolidinyl)methyl]-N6- [4-(methylthio)phenyl]-1,3,5-triazine-2,4.6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(2-pyridinyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(2-methylphenyl)-1,3,5-triazine-2,4,6-triamine N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(4-phenoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-methylphenyl)-1,3,5-triazine-2,4,6-triamine N<2->cyclohepti[-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(4-methylphenyl)-1,3,5-triazine-2,4,6-triamine, 2- [(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]-4-rmethyl-3-thiophenecarboxamide, N2-(4-chlorophenyl)-N4-cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl]triazine-2,4,6-triamine, 3- [(4-(cycloheptylamino^ yl)-(phenyl)amino]propanenitrile, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(4-methoxyphenyl)-N6-m 1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-(2,4-difluorophenyl)-N6-[(1-ethyl-2-pyrrolidinyl)methyl]-N6- N<4->methyl-1,3,5-triazine-2,4,6-triamine, [(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-(phenyl)amino]acetonitrile, N2-(3-chlorophenyl)-N4-cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl) triazine-2,4,6-triamine,N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->methyl-N<6->[2-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->methyl-N<6->[4-(trifluoromethoxy)phenyl]-1,3,5-triazine-2,4,6-triamine, N2-(3-chloro-4-methoxyphenyl)-N4-cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl] 1,3,5-triazin-2,4,6-triamine, N-benzoyl-4-[(4-(cyclohep^1,3,54riazin-2-yl)-amino]benzenesulfonamide, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(2-naphthyl)]-1,3,5-triazine-2,4,6-triamine, N2-ethyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(34fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-(tert-butyl)- N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->benzyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cyclooctyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cyclohexyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cyclopentyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-6-(1-pyrrolidinyl)-1,3,5-triazine-2,4-diamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-6-(1-pyrrolidinyl)-1,3,5-triazine-2,4-diamine, H-azepin-1-yl-1,3,5-triazin-2,4-diamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)- N<6->octahydro-1 (2H-quinolinyl-1,3,5-triazin-2,4-diamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-(4-methylcyclohexyl)-1,3,5-triazine-2,4,6-triamine, N2-[(1-ethyl-2-pyrrolidin-24lmethyl]-N4-(3-fluoro-4-methoxyphenyl)-6-((S)-2-methoxymethyl-pyrrolidin-1-yl)-1,3,5-triazin-2,4-diamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)-6-(4-m piperazinyl)-1,3,5-triazine-2,4-diamine, 6-(4-acetyl-1-piperazinyl)-N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4-diamine, Ethyl 4-{4-{[(1 -ethyl-2-pyrrolidinyl)methyl]amino}-N6-(3-fluoro-4-methoxyphenyl)amino]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate, N2-(cyclohexymethyl)-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazin-2-yl}-1-piperazinecarboxylate, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)- N<6->(2-furylmethyl)-1,3,5-triazine-2,4,6-triamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-(2,2,2-trifluoroethyl)-1,3,5-triazine-2,4,6-triamine, N2-[2-(dimethylamino)ethyl]- N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine. -piperazinyl}-1,3,5-triazine-2,4-diamine, N<2>,N<4->bis[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)- 1,3,5-triazine-2,4,6-triamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-N<6->[2-(1-piperidinyl)ethyl]-1,3,5-triazine-2,4,6-triamine, N<6->[4-(1,3-benzodioxo-5-ylmethyl)-1-piperazinyl]-N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)-1,3,5-triazin-2,4-diam N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-[4-(2-pyridinyl)-1-piperazinyl]-1,3,5-triazine-2,4-diamine, 1-[3-({4-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-6[(3-fluoro-4-methoxyphenyl)am 1.3.5-triazin-2-yl}amino)propyl]-2-pyrrolidinone, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)- N<6->[3-(1H-imidazol-1-yl)propyl]-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-ethyl- N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-(tert-butyl)- N4-cycloheptyl-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2.4.6-triamine, N<2>"benzyl-N<4->cycloheptyl-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->cyclohexyl-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->cyclopentyl-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-6-(1-pyrrolidinyl)- 1,3,5-triazin-2,4-diamine, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-6-hexahydro-1H-azepin-1-yl-1.S.S-triazin^^-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-octahydro-1(2H)-quinolinyl-1,3,5-triazine-2,4-diamine, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-N6-(4-methylcyclohexyl)-1,3,5-triazine-2,4-diamine, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-6-[(2S)-2-(methoxy pyrrolidinyl]-1,3,5-triazine-2,4-diamine, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-1,3,5-triazine-2,4-diamine, 6-(4-acetyl-1-piperazinyl)-N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4-diamine, Ethyl-4-{4-(cycloheptylamino)-6[(3-fluoro-4-methohyphenyl)amino]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate, N<2->cycloheptyl- N<4->(cyclohexymethyl)-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-N<6->(furanylmethyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-N<6->(2,2,2-trifluoroethyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[2-(dimethylamino)ethyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-{4-[2-oxo-(1-pyrrolidinyl)ethyl]-1-piperazinyl}-1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)- N<6->[2-(1-piperidinyl)ethyl]- 1,3,5-triazine-2,4,6-triamine, 6[4-(1,3-benzodioxol-5-ylmethyl)1-piperazinyl]- N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-1,3,5-triazin-2,4-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-[4-(2-pyridinyl)-1-piperazinyl]-1,3,5-triazine-2,4,6-triamine, 1-[3-({4-(cyclohptylamino)-6-[(3-fluoro-4-methoxyphenyl)amino]-1,3,5-triazin-2-yl}amino)propyl]-2-pyrrolidinone, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)- N6-[3-(1 H-imidazol-1-yl)propyl]-1,3,5-triazin-2,4,6-triamine, (3-Chloro-4-methoxy-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-arryine, 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-cyclohexylmethyl- [1,3,5]triazine-2,4-diamine, N-(3-Chloro-4-methoxy-phenyl)-N'-cyclohexylmethyl-N<M>methyl-N<M->(1-methylpiperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine, 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-(1-popyl-butyl)-[1,3,5] triazine-2,4-diamine, N-(3-Chloro-4-methoxy-phenyl)-N'-N"methyl-N'-(1 -methyl-piperidin-4-yl) N"-(1 -popyl-butyl)-[1,3,5] triazine-2,4,6-triamine, N-(3-Chloro-4-methoxy-phenyl)-N'-4isopropyl-N"-(1-methyl-piperidin-4-yl)-[1,3,5] triazine-2,4,6-triamine ]triazine-2,4,6-triamine, N<2->(3- chloro-4-methoxy-phenyl)-N<4->isopropyl-N<6->methyl- N<6->piperidin-4-yl-1,3,5-triazin-2,4,6-triamine, 5-{4-(3-Chloro-4-methoxy-phenylamino)-6-[methyl-(1-methyl-piperidin-4 [1,3,5] triazin-2-ylamino}-pentan-1-ol, 5-[4-(3-chloro-4-methoxy-phenylamino)-6-(methyl-(1-methyl-piperidin-4-yl-amine 1,3,5-triazin-2-ylamino]-pentan-1-ol, N-Butyl-6-chloro-N'-(3-chloro-4-methoxy-phenyl)-N-propyl-[1,3,5] triazine-2,4-diamine, N-Butyl-N'-(3-chloro-4-methoxy-phenyl)-N"-methyl-N"-(1-methyl-piperidin-4-yl)-N-propyl- [1,3,5] triazine-2,4,6-triamine, N<2->Butyl-N<4->(3-chloro-4-methoxy-phenyl)- N<6->methyl-N<6>-piperidin-4-yl- N<2->propyl-1,3,5-triazine-2,4,6-triamine, 2,4-Dichloro-6-cyclohexylmethoxy-[1,3,5] triazine, (4-Chloro-6- cyclohexylmethoxy-[1,3,5] triazin-2-yl)-(3-fluoro-4-methoxy-phenyl)-amine, 6-Cyclohexylmethoxy-N-N'-bis-(3-fluoro-4-methoxy-phenyl) )-1,3,5 triazine-2,4-diamine, 6-Cyclohexylmethoxy-N-(1-ethyl-pyrrolidin-2-ylmethyl)-N'-)-(3-fluoro-4-methoxy-phenyl)-[1,3,5] triazine-2,4-diamine, (4-Chloro-6-Cyclohexylmethoxy-[1,3,5] triazin-2-yl)-(3-chloro-4-methoxy-phenyl)-amine, N,N'-Bis-(3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-1,3,5 triazine-2,4-diamine, N-(3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-N'-methyl-N'-(1-methylpiperidin-4-yl)-[1,3,5] triazine-2,4-diamine, 6-Chloro-N,N"bis-(3-chloro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine, N,N'-Bis-(3-chloro-4-methoxy-phenyl)-N"-methyl-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine, N,N'-Bis-(3-chloro-4-methoxy-phenyl)-N"-cycloheptyl-[1,3,5]triazine-2,4,6-triamine, N-(3-Bromo-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine, (4,6-Dichloro-[1,3,5] triazin-2-yl)-( 3-fluoro-4-methoxy-phenyl)-amine, 6-Chloro-N-cyclohexymethyl-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5] triazine-2,4-diamine, N-cyclohexymethyl-N,-(1-ethyl-pyrrolidin-2-ylmethyl)-N"-( 3-fluoro-4-methoxy-phenyl)-[1,3,5]triazin-2,4,6-triamine, 6-Chloro-N-cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5] triazine-2,4-diamine, N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-pyrrolidin-1-yl-[1,3,5] triazine-2,4-diamine, N-Cycloheptyl-N'-ethyl-N"-( 3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine, N-Cycloheptyl-N'-(1-ethyl-pyrrolidin-2-ylmethyl)-N"-( 3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4,6-triamine, 2-[4-chloro-6-(3-chloro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-propane-1,3-diol, 2-{4-(3-chloro-4-methoxy-phenylamino)-6-[methyl-(1-methyl-piperidine [1,3,5]triazin-2-ylamino)-propane-1,3-diol, 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-[1,3,5] triazine-2,4-diamine, N-(1-benzyl-piperidine-44l)-N'-(3-chloro-4-methoxy-phenyl)-N"-cyclohexatriazine-2,4,6-triamine, N<2->(3-chloro-4-methoxy-phenyl)- N<4->cycloheptyl-N<6->piperidin-4-yl-1,3,5- triazin-2,4,6-triamine, N2-(3-chloro-4-methoxy-phenyl)- N4-cycloheptyl-N6-(1-ethyl-pyrrolidini-2-ylmethyl)-1,3,5- triazin-2,4,6-triamine, N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-NM-(1-methyl-piperidine-[1,3,5]triazine-2,4,6-triamine, 2-chloro-4-{4-cycloheptylamino-6-[methyl-(1 -methyl-piperidin-4-yl-amino] -[1,3,5] triazin-2-ylamino}-phenol, N2-cycloheptyl-N4-((S)-1-ethyl-pyrrolidin-2-ylmethyl)- N6-( 3-fluoro-4-methoxyphenyl)-1,3,5- triazine-2,4,6-triamine, N2-cycloheptyl-N4-((S)-1-ethyl-pyrrolidin-2-ylmethyl)- -ethyl-pyrrolidin-2-ylmethyl)- N<6->( 3-fluoro-4-methoxyphenyl)-1,3,5- triazine-2,4,6-triamine, N2-cyclohexylmethyl-N4-((S)-1 -ethyl-pyrrolidin-2-ylmethyl)- N<6->( 3-fluoro-4-methoxyphenyl)-1,3,5- triazine-2,4,6-triamine, N2-cyclohexylmethyl-N4-((R)-1-ethyl-pyrrolidin-2-ylmethyl)- N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, ({4-cycloheptylamino-6-[((S)-1-ethyl-pyrrolidin-2-ylmethyl)-amino]-1,3,5-triazin-2-yl}-phenyl-amino)-acetonitrile, ({4-cycloheptylamino-6-[((R)-1-ethyl-pyrrolidin-2-ylmethyl)-amino]-1,3,5-triazin-2-yl}-phenyl-amino)-acetonitrile, N2-[(1-ethyl-pyrrolidinyl]- N4-(3-fluoro-4-methoxyphenyl)-6-[(S)-2-(methoxymethyl)-1-pyrrolidine-1,3,5-triazine-2,4-diamine, N2-(3-chloro-4-methoxy-phenyl)-N4-cycloheptyl-N6-methyl-N6-piperidin-4-yl-1,3,5-triazine-2,4,6-triamine, 4-(3-Chloro-4-methoxy-phenylamino)-6-cycloheptylamino-1,3,5-triazin-2-ol, N-(1-aza-bicyclo[2.2.2]oct-3-yl)-N'(3-chloro-4-methoxy-phenyl)-N"-(1-ethyl-pyrrolidin-2-ylmethyl)-[1,3,5]triazin-2,4,6-triamine, N2-(3-chloro-4-diethylamino-phenyl)-N4-cycloheptyl-N6-(1-ethyl-pyrrolidin-2-ylm 1.3.5-triazin-2,4,6-triamine, N<2->cycloheptyl-N<4->(2-dimethylamino-ethyl)- N<6->( 3-fluoro-4-methoxy-phenyl)-1,3,5-triazine-2,4,6-triamine, ({4-cycloheptylamino-6-[1-ethyl-pyrrolidin-2-ylmethyl)-amino] -1,3,5- triazin-2-yl}-phenyl-amino)-acetonitrile, N-Azepan-1-yl-6-chloro-N'-(3-chloro-4-methoxy-phenyl)- [1,3,5]triazine-2,4-diamine, N"-(3-chloro-4-methoxy-phenyl)-N,N'-bis-pehydro-azepin-1-yl-1,3,5-triazin-2.4.6-triamine, N-Azepan-1-yl-N'-(3-chloro-4-methoxy-phenyl)-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine, N<4->(3-chloro-4-methoxy-phenyl)- N<6->methyl-N<2>-perhydro-azepin-1-yl-N<6->piperidin-4-H-1,3,5-triazine-2,4,6-triamine, N,N'-di-n-propyl-N"-(3-fluoro-4-methoxy-phenyl)-1,3,5- triazine-2,4,6-triamine, N,N'-dicyclopropyl-N"-( 3-fluoro-4-methoxy-phenyl)- 1,3,5- triazine-2,4,6-triamine, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl- N<6->(1-methyl-piperidin-4-yl)-1,3,5- triazine-2,4,6-triamine, N2-Cycloheptyl-N4-(3-fluoro-4-methoxy-phenyl)-N5-methyl- N6-piperidin-4-yl-1,3,5- triazine-2,4,6-triamine, N<2->Cycloheptyl-N<4->( 3-fluoro-4-methoxyphenyl)-N<6->methyl- N6-(1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, salt hydrogen chloride, [N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-N"-(1-methyl-piperidin-4-yl)- [1,3,5]triazin-2,4,6-triamine, hydrogen chloride salt, N<2->(3-chloro-4-diethylamino-phenyl)-N<4->cycloheptyl-N<6->(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5- triazin-2,4,6-triamine, N<2->(3-chloro-4-diethylamino-phenyl)-N<4->cycloheptyl-N<6->(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5- triazin-2,4,6-triamine hydrochloride salt, N2-Cycloheptyl-N4-(1-ethyl-pyrrolidin-2-ylmethyl)-N6-( 3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine hydrochloride salt, N<2->(cyclohexylmethyl)-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(4-fluoro-3-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine hydrochloride salt, ({4-cycloheptylamino-6- [(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-[1,3,5] triazin-2-yl}-phenyl-amino)-acetonitrile hydrochloride salt, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5- triazin-2,4,6-triamine maleic acid salt, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5- triazine-2,4,6-triamine salt of citric acid, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5- triazine-2,4,6-triamine salt succinic acid, or N-(3-Bromo-4-methoxy-phenyl,3,5]triazine-2,4,6-triamine hydrochloride salt, 3. The compound of the formula or an ene, diene, triene, or yne derivative thereof, a saturated derivative thereof, a stereoisomer thereof; or its salt; indicated by the fact that; R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from F, m-C1, m-Br, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, or X<1> and X<2> are fused together a benzene, pyridine, or dioxane ring; X2 is selected from p-OR<1>, p-SR<1>, p-NR<1>2, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; in the normal chain or branched alkyl of up to 10 carbon atoms; CH2R<2>, wherein R<2> is cycloalkyl with up to 10 carbon atoms; or where n is 1 or 2; AY2 is selected from halogen or OR<1>, or A is NR<1>and Y2 is selected from R1, 4. Compound of the formula or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; E is CH or N; n is an integer from 0 to 3; X<1> is selected from -H,m- F, m- C1, m- Br, m- J,m-CN, m-NO2, m-SO2R<1>, or /77-SO2OR<1>, or X<1> and X<2> are fused together a benzene or pyridine ring; X<2> is selected from -H, o-CI, o-Br, p-OR<1>, p-SR<1>, p-NR<1>2, p-Cl p-Br, p-CF3, p-C(0)OR<1>, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; A is selected from NR<1> or O, wherein Y<1> is selected from cycloalkyl of up to 10 carbon atoms, normal chain or branched alkyl with up to 10 carbon atoms, or when A is NR<1>, and wherein Y1 is selected from R<1>or CH2R<1> when A is O; or AY<1>is selected from halogen, DY<2>is halogen, or DNR<1>and Y<2>is selected from or (CHR<1>)xNR<1>2, where x is an integer from 1 to 6. 5. A compound of the formula or their ene, diene, triene, or yne derivative; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; arilla; or (CH2)XCN, where x is an integer from 0 to 6; E is CH or N; n is an integer from 0 to 3; X<1>is selected from -H,m- F, m- C\,m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, m-NC(0)R<1>, or o-F, or X<1>and X<2> are fused together a benzene, pyridine, or dioxane ring; X2 is selected from -H, o-CI, o-Br, o-CF3, o-R<1>, p-OR<1>, p-SR<1>, p-NR<1>2, p-F, p-CI p-Br, p-CF3, p-CN, p-C(0)OR<1>, p-NC(0)R<1>, p-(4-morpholinyl), or p-(4-methyl-1-piperidinyl); AY<1>is halogen, or A is NR<1>or O and Y<1>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, (CHR<1>)yOR<1>, where y is an integer from 1 to 6, or AY<1> together where x is an integer from 3 to 5; and DY<2>is halogen, or D is NR<1>and Y<2>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in a straight chain or branched alkyl with up to 10 carbon atoms, CH2R<1>, where x is an integer number from 3 to 5, CH2CF3, (CHR<1>)ZZ<1>, where z is whole a number from 1 to 6, and Z<1>is selected from NR<1>2, at where x is an integer from 3 to 5, or is NY2R1 together selected from where Z2 is selected from R<1>, C(0)R<1>, C(0)OR<1>, pyridinyl, aryl, li where Y is an integer from 0 to 6. 6. Compound of the formula: or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>; X2 is selected from o-R<1>, p-OR<1>, p-SR<1>, p-NR<1>2,<p->OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1>is selected from cycloalkyl of up to 10 carbon atoms or Y<2>is selected from straight-chain or branched alkyl of up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms, or and R<2> is -H; or NY<2>R<2>are jointly selected from where x is an integer number from 3 to 5, where q is an integer from 0 to 6, or wherein Z2 is selected from R<1>or 7. Compound of the formula or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is at each occurrence independently selected from -H; in the normal chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is at each occurrence independently selected from -H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>; X2 is at each occurrence independently selected from o-CH3, p-OR<1>, p-SR<1>, p-NR<1>2, or p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; where n is 1 or 2; or Y2 is selected from 8. A composition comprising a compound of the formula Or an ene, diene, triene, or yne derivative thereof; its saturated derivative; its stereoisomer; or its salt; characterized in that: R<1> is at each occurrence independently selected from -H; alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkadienyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 12 carbon atoms and including linear or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, or heterocyclic derivatives thereof; arilla; heteroaryl; aryloxy; arylthio; halogen; or amino; G is selected from NR<1> or O; E is selected from CH or N; z is an integer from 0 to 3; X<1>is selected from R<1>, NR<1>3<+>, CN, N02, C02R<1>, C(0)NR<1>2, CH=CR<1>2,C=CR<1>, C(0)R<1>, S02R<1>, S02OR<1>, or NC(0)R<1>, or X<1>and X<2> are fused together with aryl, pyridine, dioxane, pyrrole, pyrrolidine, furan, thiophene ring; provided that the R<1>residue of the C(0)R<1>substituent in the X<1>position excludes amino or dialkylamino when X<1>C(0)R<1>; X<2> is selected from R<1>; CXXH3.X, where X is halogen and x is an integer from 1 to 3;OR1;SR<1>; NR<1>2; CN; C(0)OR<1>; 4-morpholinyl; 4-methyl-1-piperizinyl; OR<2>, wherein R<2>is selected from CH2OCH3, CH2OCH2OCH3, CH2OCH2CH2OCH3, or C(0)R<1>;SR<3>, wherein R<3>is selected from CH2OCH3, CH2OCH2CH2OCH3, CH2OCH2CH(CH3)2,CH2NHC(0)CH3, or SR<1>; OM or SM, wherein M is selected from Li, Na, K, Mg, or Ca; AY<1>is halogen, or A is selected from NR<1>or O, and Y<1>is selected from R<1>;CR43;NR<4>2; OR<4>; or SR<4>; wherein n is an integer from 0 to 8, m is an integer from 1 to 8, Z<1>is independently selected from CR<1>or N, Z<2>is independently selected from CR<1>2, NR<1>, 0, or S, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z2 residues are NR1; R<4> is at each occurrence independently selected from in the normal sequence or branched alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, acylthio, alkylamino, or dialkylamino, each containing up to 10 carbon atoms, -H, aryl, heteroaryl, aryloxy, arylthio, halogen, amino, their NR<1>2-substituted derivatives, their OR<1->substituted derivatives; their SR<1->substituted derivatives; or their halogen-substituted derivatives; and DY2 is halogen, or D is selected from NR<1>or O where R<1> is as defined above, and Y2 is selected from R<1>, , or wherein Z<1>is independently selected from N or CR<4>and Z<2>is independently selected as defined above, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z<2>residues are NR<1>. 9. Composition according to claim 8, characterized in that the compound is selected from: N<2->(4-bromo-naphthyl)- N<4->cycloheptyl- N<6>[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->(4-chloro-1-naphthyl)- N<4->cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(3-quinolinyl)- 1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(6-quinolinyl)- 1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(8-quinolinyl)- 1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->[1-(2-naphthyl)ethyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->(3,4-dichlorophenyl)- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl- N<4->(3,4-difluorophenyl)-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4"-[(1-ethyl-2-pyrrolidinyl)methyl]- N6-[4-(trifluoromethoxy)phenyl]-1.3.5- triazine-2,4,6-triamine, N<2->cycloheptyl-N<4>"-[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(4-fluorophenyl)- 1,3,5-triazin-2.4.6- triamine, 4-[(4-cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)amino]benzonitrile, N<2->(4-chlorophenyl)-N<4->cycloheptyl- N6-[(1-ethyl-2-pyrrolidinyl)methyl]amino}- 1,3,5-triazine-2,4,6-triamine, N<2->(4-bromophenyl)-N<4->cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, Ethyl 4-[(4-cycloheptylamino)-6-{[(1 -ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]benzoate, N<2->(1,1'-biphenyl-4yl) N<4>cycloheptyl- N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4>"-[(1-ethyl-2-pyrrolidinyl)methyl]- N<6->(4-fluorophenyl)-1,3,5-triazine-2,4,6-triamine, N<2->(3-chlorophenyl)-N<4->cycloheptyl- N6-[(1 -ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, N<2->(3-bromophenyl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]- 1,3,5-triazine-2,4,6-triamine, Ethyl 3-[(4-cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]. -ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]benzoate, N2-cycloheptyl-N4-[(1 -ethyl-2-pyrrolidinyl)methyl]-N6-(2-fluorophenyl) 1,3,5-triazin-2,4,6-triamine, N<2->(2-chlorophenyl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->(2-bromophenyl)-N<4->cycloheptyl- N6-[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-(1,3benzodioxol-5-yl)-N4-cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazin-2,4,6-triamine, N<2->cycloheptyl-N<4->(2,3dihydro-1,4-benzodioxin-6-yl)-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[4- (dimethylamino)phenyl]-N6-[(1 -ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-[3-chloro-4-(diethylamino)phenyl]-N4- cycloheptyl-N6-[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-[4-(4-morpholinyl)phenyl]- 1,3,5-triazine-2,4,6-triamine,N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->[4-(4-methyl-1-peperazinyl)phenyl]-1,3,5-triazine-2,4,6-triamine, N-{4-[(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]phenyl}acetamide, N-{3-[(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)amino]phenyl}acetamide, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(4-ethoxyphenyl)-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-[(1 -ethyl-2-pyrrolidinyl)methyl]-N6- [4-(methylthio)phenyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(2-pyridinyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(2-methylphenyl)-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)rmethyl]-N6-(4-phenoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-methylphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(4-methylphenyl)-1,3,5-triazine-2,4,6-triamine 2-[(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-amino]-4-methyl-3-thiophenecarboxariide, N<2->(4-chlorophenyl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-N<2->methyl-1,3,5-triazine-2,4,6-triamine, 3- [(4-(cycloheptylamino)-6-{[(1 -ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-(phenyl)amino]propanenitrile, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(4-methoxyphenyl)-N<6->methyl-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-(2,4-difluorophenyl)-N6-[(1 -ethyl-2-pyrrolidinyl)methyl]- N<4->methyl-1,3,5-triazine-2,4,6-triamine, [(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-1,3,5-triazin-2-yl)-(phenyl)amino]acetonitrile, N<2->(3-chlorophenyl)-N<4->cycloheptyl-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-N<2->methyl-1,3,5-triazine-2,4,6-triamine,N<2-> cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->methyl-N<6->[2-(trifluoromethyl)phenyl]-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->methyl-N<6->[4-(trifluoromethoxy)phenyl]-1,3,5-triazine-2,4,6-triamine, N<2->(3-chloro-4-methoxyphenyl)-N<4->cyclohepti[-N<6->[(1-ethyl-2-pyrrolidinyl)methyl]-1,3,5-triazine-2,4,6-triamine, N-benzoyl-4-[(4-(cycloheptylamino)-6-{[(1-ethyl-2-pyrrolidinyl)methyl]amin 1,3,54riazin-2-yl)-amino]benzenesulfonamide, N2-cycloheptyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(2-naphthyl)]-1,3,5-triazine-2,4,6-triamine, N<2->ethyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-(tert-butyl)- N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-benzyl-N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cyclooctyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cyclohexyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cyclopentyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-6-(1-pyrrolidinyl)-1,3,5-triazine-2,4-diamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)-6-(1-pyrrolidinyl)-1,3,5-triazine-2,4-diamine, H-azepin-1-yl-1,3,5-triazin-2,4-diamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)- N<6->octahydro-1 (2H-quinolinyl-1,3,5-triazine-2,4-diamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-(4-methylcyclohexyl)-1,3,5-triazine-2,4,6-triamine, N<2->[(1-ethyl-2-pyrrolidin-2-ylmethyl]-N<4->(3-fluoro-4-methoxyphenyl)-6-((S)-2-methoxymethyl-pyrrolidin-1 -yl)-1,3,5-triazin-2,4-diamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-1,3,5-triazine-2,4-diamine, 6-(4-acetyl-1-piperazinyl)-N<2->[(1-ethyl!-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-rnethoxyphenyl)-1,3,5-triazine-2,4-diamine, Ethyl 4-{4-{[(1 -ethyl-2-pyrrolidinyl)methyl]amino}-N6-(3-fluoro-4-methoxyphenyl)amino]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate, N<2->(cyclohexymethyl)-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-(2-furylmethyl)-1,3,5-triazine-2,4,6-triamine, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-(2,2,2-trifluoroethyl)-1,3,5-triazine-2,4,6-triamine, N2-[2-(dimethylamino)ethyl]- N4-[(1-ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triarryine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-N<6->{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}-1,3,5-triazine-2,4-diamine, N2,N4-bis[(1 -ethyl-2-pyrrolidinyl)methyl]-N6-(3-fluoro-4-methoxyphenyl)- 1,3,5-triazine-2,4,6-triamine, N<2->[(1-ethyl-2-pyrrolidinyl)methyl]-N<4->(3-fluoro-4-methoxyphenyl)-N<6->[2-(1-piperidinyl)ethyl]-1,3,5-triazine-2,4,6-triamine, N6-[4-(1,3-benzodioxo-5-ylmethyl)-1 -piperazinyl]-N2-[(1 -ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)-1,3,5-triazin-2,4-diam -piperazinyl]-1,3,5-triazin-2,4-diamine, 1-[3-({4-{[(1-ethyl-2-pyrrolidinyl)methyl]amino}-6[(3-fluoro-4-methoxyphenyl)amirio-1.3.5-triazin-2-yl}amino)propyl]-2-pyrrolidinone, N2-[(1-ethyl-2-pyrrolidinyl)methyl]-N4-(3-fluoro-4-methoxyphenyl)- N6-[3-(1H-imidazol-1 -yl)propyl]-1,3,5-triazin-2,4,6-triamine, N2-cycloheptyl-N4-ethyl- N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-(tert-butyl)- N4-cycloheptyl-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2.4.6-triamine, N<2>"benzyl-N<4->cycloheptyl-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-cyclooctyl-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->cyclohexyl-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->cyclopentyl-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)-6-(1 -pyrrolidinyl)- 1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-hexahydro-1H-azepin-1-yl-1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-octahydro-1(2H)-quinolinyl-1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-N<6->(4-methylcyclohexyl)-1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]-1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-(4-methyl-1-piperazinyl)-1,3,5-triazine-2,4-diamine, 6-(4-acetyl-1 -piperazinyl)-N2-cycloheptyl-N4-(3-fluoro-4-methoxyphenyl)- 1,3,5-triazine-2,4-diamine, Ethyl-4-{4-(cycloheptylamino)-6[(3-fluoro-4-methohyphenyl)amin yl}-1 -piperazinecarboxylate, N2-cycloheptyl- N4-(cyclohexymethyl)-N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-N<6->(furanylmethyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-N<6->(2,2,2-trifluoroethyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->[2-(dimethylamino)ethyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-{4-[2-oxo-(1-pyrrolidinyl)ethyl]-1-piperazinyl}-1,3,5-triazine-2,4-diamine, N<2->cycloheptyl-N<4->[(1-ethyl-2-pyrrolidinyl)methyl]-N<6->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-N<6->[2-(1-piperidinyl)ethyl]- 1,3,5-triazin-2,4,6-triamine, 6[4-(1,3-benzodioxol-5-ylmethyl)1-piperazinyl]- N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4-diamine,N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)-6-[4-(2-pyridinyl)-1-piperazinyl]-1,3,5-triazine-2,4-triamine, 1-[3-({4-(cycloheptylamino)-6-[(3-fluoro-4-methoxyphenyl)amino]-1,3,5-triazin-2-yl}amino)propyl]-2-pyrrolidinone, N<2->cycloheptyl-N<4->(3-fluoro-4-methoxyphenyl)- N<6->[3-(1 H-imidazol-1 -yl)propyl]-1,3,5-triazin-2,4,6-triamine, (3-Chloro-4-methoxy-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine, 6-Chloro-N-(3- chloro-4-methoxy-phenyl)-N'-cyclohexylmethyl- [1,3,5] triazine-2,4-diamine, N-(3-Chloro-4-methoxy-phenyl)-N-(3-chloro-4-methoxy-phenyl)-N'-cyclohexylmethyl- [1,3,5] triazine-2,4-diamine, piperidin-4-yl)-[1,3,5 ]triazin-2,4,6-triamine, 6-Chloro-N-(3- chloro-4-methoxy-phenyl)-N'-(1 -popyl-butyl)-[1,3,5] triazin-2,4-diamine, N-(3-Chloro-4-methoxy-phenyl)-N,-N-(1 -methyl-piperidin-4-yl)-N'-(1 -methyl-4-yl) popyl-butyl)-[1,3,5]triazine-2,4,6-triamine, N-(3-Chloro-4-methoxy-phenyl)-N'4isopropyl-NMmethyl-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine, N<2->(3- chloro-4-methoxy-phenyl)-N<4->isopropyl-N<6->methyl-N<6>-piperidin-4-yl-1,3,5-triazin-2,4,6-triamine, 5-{4-(3-Chloro-4-methoxy-phenylamino)-6-[methyl-(1-methyl-piperidin-4-yl)-am[1,3,5]triazin-2-ylamino}-pentan-1-ol, 5-[4-(3-chloro-4-methoxy-phenylamino)-6-(methyl-(1-methyl-piperidine-^ 1,3,5- triazin-2-ylamino]- pentan-1-ol, N-Butyl-6- chloro-N'-(3-chloro-4-methoxy-phenyl)-N-propyl-[1,3,5] triazin-2,4-diamine, N-Butyl-N'-(3-chloro-4-methoxy-phenyl)-N"-methyl-N"-(1-methyl-piperidin-4-yl)-N-propyl-[1,3,5] triazine-2,4,6-triamine, N<2->Butyl- N<4->(3-chloro-4-methoxy-phenyl)-N<6->methyl-N<6>-piperidin-4-yl- N<2->propyl-1,3,5- triazine-2,4,6-triamine, 2,4-Dichloro-6-cyclohexylmethoxy-[1,3,5] triazine, (4-Chloro-6-triamine) cyclohexylmethoxy-[1,3,5] triazin-2-yl)-(3-fluoro-4-methoxy-phenyl)-amine, 6-Cyclohexylmethoxy-N-N'-bis-(3-fluoro-4-methoxy-phenyl) )-1,3,5 triazin-2,4-diamine, 6-Cyclohexylmethoxy-N-(1-ethyl-pyrrolidin-24lmethyl)-N'-)-(3-fluoro-4-methoxy-phenyl)-[1,3,5] triazine-2,4-diamine, (4-Chloro-6-Cyclohexylmethoxy-[1,3,5] triazin-2-yl) -(3-chloro-4-methoxy-phenyl)-amine, N,N'-Bis-(3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-1,3,5-triazine-2,4-diamine, N-(3-chloro-4-methoxy-phenyl)-6-cyclohexylmethoxy-N'-methy-N'-(1-m piperidin-4-yl)-[1,3,5] triazine-2,4-diamine, 6-Chloro-N,N"bis-(3-chloro-4-methoxy-phenyl)-[1,3,5] triazine-2,4-diamine, N,N'-Bis-(3-chloro-4-methoxy-phenyl)-NM-methyl-NM-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine, N,N'-Bis-(3-chloro-4-methoxy-phenyl)-N"-cycloheptyl-[1,3,5]triazine-2,4,6-triamine, N-(3-Bromo-4-methoxy-phenyl)-N'-cycloheptyl-N<n->methyl-N"-(1-methyl!-piperidin-4-yl)-[1,3,5] triazine-2,4,6-triamine, (4,6-Dichloro-[1,3,5] triazin-2-yl)-(3-fluoro-4-methoxy-phenyl)-amine, 6-Chloro-N-cyclohexyl-N'-( 3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine, N-cyclohexymethyl-N'-(1-ethyl-pyrrolidin-2-ylmethyl)-N"-( 3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4,6-triamine, 6-Chloro-N-cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl) -[1,3,5] triazine-2,4-diamine, N-Cycloheptyl-N'-( 3-fluoro-4-methoxy-phenyl)-6-pyrrolidin-1-yl-[1,3,5] triazine-2,4-diamine, N-Cycloheptyl-N'-ethyl-N" -( 3-fluoro-4-methoxy-phenyl)-[1,3,5] triazine-2,4-diamine, N-Cycloheptyl-N'-(1-ethyl-pyrrolidin-2-ylmethyl)-N"-( 3-fluoro-4-methoxy-phenyl)-[1,3,5] triazine-2,4,6-triamine, 2-[4-chloro-6-(3-chloro-4-methoxy-phenylamino)-[1,3,5] triazin-2-ylamino]-propane-1,3-diol, 2-{4-(3-chloro-4-methoxy-phenylamino)-6-[methyl-(1-methyl-piperid [1,3,5]triazin-2-ylamino}-propane-1,3-diol, 6-Chloro-N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-[1,3,5]triazine-2,4-diamine, N-(1-benzyl-piperidin-44l)-N'-(3-chloro-4-methoxy-phenyl)-NM-cycloheptyl-[1,3,5] triazine-2,4,6-triamine, N<2->(3-chloro-4-methoxy-phenyl)- N<4->cycloheptyl-N<6->piperidin-4-yl-1,3,5-triazine-2,4,6-triamine, N2-(3-chloro-4-methoxy-phenyl)- N4-cycloheptyl-N6-(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5- triazin-2,4,6-triamine, N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-N"-(1-methyl-piperidin-4^ -[1,3,5]triazine-2,4,6-triamine, 2-chloro-4-{4-cycloheptylamino-6-[methyl-(1-methyl-piperidin-4-yl-am -[1,3,5] triazin-2-ylamino}-phenol, N2-cycloheptyl-N4-((S)-1-ethyl-pyrrolidin-2-ylmethyl)- N6-(3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-cycloheptyl-N4-((R)-1-ethyl-pyrrolidin-2-ylmethyl)- N<6->( 3-fluoro-4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine, N2-cyclohexylmethyl-N4-((S)-1-ethyl-pyrrolidin-2-ylmethyl)- N<6->( 3-fluoro-4-methoxyphenyl)-1,3,5- triazine-2,4,6-triamine, N2-cyclohexylmethyl-N4-((R)-1-ethyl-pyrrolidin-2-ylmethyl)- N<6->( 3-fluoro-4-methoxyphenyl)-1,3,5- triazine-2,4,6-triamine, ({4-cycloheptylamino-6- [((S)-1-ethyl-pyrrolidin-2-ylmethyl)-amino] -1,3,5-triazin-2-yl}-phenyl-amino)-acetonitrile, ({4-cycloheptylamino-6- [((R)-1-ethyl-pyrrolidin-2-ylmethyl)-amino]-1,3,5-triazin-2-yl}-phenyl-amino)-acetonitrile, N2-[(1-ethyl-pyrrolidinyl]- N4-(3-fluoro-4-methoxyphenyl)-6-[(S)-2-(methoxymethyl)-1-pyrrolidinyl]-1,3,5-triazine-2,4-diamine, N2-(3-chloro-4-methoxy-phenyl)- N4-cycloheptyl-Ns-methyl-N6-piperidin-4-yl-1,3,5-triazin-2,4,6-triamine, 4-(3-chloro-4-methoxy-phenylam N-(1-aza-bicyclo[2.2.2]oct-3-yl)-N'(3-chloro-4-methoxy-phenyl)-N"-(1-ethyl-pyrrolidin-2-ylmethyl)-[1,3,5] triazin-2,4,6-triamine, N<2->(3-chloro-4-diethylamino-phenyl)-N<4->cycloheptyl-N<6->(1-ethyl-pyrrolidin-2-ylmethyl)-1.3.5- triazin-2,4,6-triamine, N<2->cycloheptyl-N<4->(2-dimethylamino-ethyl)- N<6->(3-fluoro-4-methoxy-phenyl)-N<6-> 1,3,5-triazin-2,4,6-triamine, ({4-cycloheptylamino-6-[1-ethyl-pyrrolidin-2-ylmethyl)-amino] -1,3,5- triazin-2-yl}-phenyl-amino)-acetonitrile, N-Azepan-1 -yl-6-chloro-N'-(3-chloro-4-methoxy-phenyl)- [1,3,5]triazine-2,4-diamine, N<n->(3-chloro-4-methoxy-phenyl)-N,N'-bis-pehydro-azepin-1-yl-1,3,5- triazine-2.4.6- triamine, N-Azepan-1 -yl-N'-(3-chloro-4-methoxy-phenyl)-N"-(1 -methyl-piperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine, N<4->(3-chloro-4-methoxy-phenyl)- N<6->methyl-N<2->perhydro-azepin-1-yl-N<6->piperidin-4-H-1,3,5- triazine-2,4,6-triamine, N,N'-di-n-propyl-N"-( 3-fluoro-4-methoxy-phenyl)-1,3,5- triazine-2,4,6-triamine, N,N'-dicyclopropyl-N"-( 3-fluoro-4-methoxy-phenyl)- 1,3,5- triazine-2,4,6-triamine, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl- N6-(1-methyl-piperidin-4-yl)-1,3,5- triazine-2,4,6-triamine, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl- N<6->piperidin-4-yl-1,3,5- triazine-2,4,6-triamine, N<2->Cycloheptyl-N<4->( 3-fluoro-4-methoxyphenyl)-N<6->methyl- N6-(1-methyl-piperidin-4-yl)-1,3,5-triazin-2,4,6-triamine, hydrogen chloride salt, [N-(3-chloro-4-methoxy-phenyl)-N'-cycloheptyl-N"-methyl-N"-(1-methyl-piperidin-4-yl)- [1,3,5]triazin-2,4,6-triamine, hydrogen chloride salt, N<2->(3-chloro-4-diethylamino-phenyl)-N<4->cycloheptyl-N<6->(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5- triazin-2,4,6-triamine, N<2->(3-chloro-4-diethylamino-phenyl)-N<4->cycloheptyl-N<6->(1-ethyl-pyrrolidin-2-ylmethyl)-1,3,5- triazine-2,4,6-triamine hydrochloride salt, N2-Cycloheptyl-N4-(1-ethyl-pyrrolidin-2-ylmethyl)-N6-( 3-fluoro-4-methoxyphenyl)-1,3,5- triazine-2,4,6-triamine hydrochloride salt, N<2->(cyclohexylmethyl)-N<4->[(1 -ethyl-2-pyrrolidinyl)methyl]- N<6->(4-fluoro-3-methoxyphenyl)-1,3,5- triazin-2,4,6-triamine hydrochloride salt, ({4-cycloheptylamino-6- [(1-ethyl-pyrrolidin-2-ylmethyl)-amino] -[1,3,5] triazin-2-yl}-phenyl-amino)-acetonitrile hydrochloride salt, N<2->Cycloheptyl-N<4->( 3-fluoro-4-methoxy-phenyl)-N<6->methyl-N<6->(1-methyl-piperidin-4-yl)-1,3,5- triazine-2,4,6-triamine salt of maleic acid, N2-Cycloheptyl-N4-( 3-fluoro-4-methoxy-phenyl)-N6-methyl-N6-(1-methyl-piperidin-4-yl)-1,3,5- triazine-2,4,6-triamine salt of citric acid, N2-Cycloheptyl-N4-( 10 The composition according to Claim 8, characterized in that it further contains: a pharmaceutically acceptable carrier; an optional, pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable condom; and optionally, a pharmaceutically acceptable inert filler.; 11. Composition according to Claim 8, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, an anti-inflammatory agent, an anti-rheumatic agent, a cardiovascular agent, a toxin, or any combination thereof.;12. The composition according to Claim 8, indicated by the fact that it is a composition in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.; 13. A composition containing a compound of the formula or its en, diene, triene, or en derivative; its saturated derivative; its stereoisomer; or his salt; indicated by the fact that; R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from m-F, m-Cl, m-Br, m-J, m-CN, m-NO2,m-SO2R<1>, or m-SO2OR<1>, or X1 and X2 are fused together a benzene, pyridine, or dioxane ring; X2 is selected from p-OR<1>, p-SR<1>, p-NR<1>2, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; in the normal chain or branched alkyl of up to 10 carbon atoms; CH2R<2>, where R<2> is cycloalkyl sa up to 10 carbon atoms; or wherein n is 1 or 2; AY2 is selected from OR1, or A is NR1 and Y2 is selected from R1, ;14. The composition according to Claim 13, characterized in that it further contains: a pharmaceutically acceptable carrier; an optional, pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable condom; and optionally, a pharmaceutically acceptable inert filler.; 15. Composition according to Claim 13, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, a toxin, or any combination thereof.;16. The composition according to Claim 13, indicated by the fact that it is a composition in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.; 17. A composition containing a compound of the formula: or an en, diene, triene, or en derivative thereof; their saturated derivative; their stereoisomer; or their salt; wherein: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; or aryl; E is CH or N; n is an integer from 0 to 3; X<1> is selected from -H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, or X<1> and X<2> are fused together a benzene or pyridine ring; X2 is selected from -H, o-CI, o-Br, p-OR<1>, p-SR<1>, p-NR<1>2, p-Cl p-Br, p-CF3, p-C(0)OR<1>, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; A is selected from NR<1>or O, wherein Y<1>is selected from cycloalkyl of up to 10 carbon atoms, with a normal chain or branched alkyl of up to 10 carbon atoms, or <.>and when A is NR<1>, and wherein Y<1>is selected from R<1>or CH2R<1>when A is O; or AY<1>is selected from halogen, DY<2>is halogen, or D is NR<1>and Y<2>is selected from , or (CHR<1>)XNR<1>2, wherein x is an integer from 1 to 6.;18. The composition according to Claim 17, characterized in that it further contains: a pharmaceutically acceptable carrier; an optional, pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable condom; and optionally, a pharmaceutically acceptable inert filler.; 19. Composition according to Claim 17, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, an anti-inflammatory agent, an anti-rheumatic agent, a cardiovascular agent, a toxin, or any combination thereof.;20. The composition according to Claim 17, indicated by the fact that it is a composition in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.; 21. A composition containing a compound of the formula: or an en, diene, triene, or en derivative thereof; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is in each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; arilla; or (CH2)XCN, where x is an integer from 0 to 6; Eje CH or N; n is an integer from 0 to 3; X<1> is selected from -H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, m-NC(0)R<1>, or o-F, or X<1> and X<2> are fused together with a benzene, pyridine, or dioxane ring; X2 is selected from -H, o-CI, o-Br, o-CF3, o-R1, p-OR<1>, p-SR<1>, p-NR<1>2,<p->F, p-CI p-Br, p-CF3, p-CN, p-C(0)OR<1>, p-NC(0)R<1>, p-(4-morpholinyl), or p-(4-methyl-1-piperizinyl); AY<1>is halogen, or A is NR<1>or O and Y<1>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, (CHR<1>)yOR<1>, where y is an integer from 1 to 6, or AY<1>together where x is an integer from 3 to 5; and DY<2>is halogen, or DNR<1>and Y<2>is selected from , cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, ) x, where x is an integer from 3 to 5, CH2CF3, (CHR<1>)2Z<1>, wherein z is an integer from 1 to 6, and Z1 is selected from NR<1>2, wherein x is an integer from 3 to 5, or NY2R1 is together selected from wherein Z<2>is selected from R<1>, C(0)R\ C(0)OR<1>, pyridinyl, aryl, , or where q is an integer from 0 to 6.;22. The composition according to Claim 21, characterized in that it further contains: a pharmaceutically acceptable carrier; an optional, pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable condom; and optionally, a pharmaceutically acceptable inert filler.; 23. Composition according to Claim 21, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, a toxin, or any combination thereof.;24. The composition according to Claim 21, indicated by the fact that it is a composition in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.; 25. A composition containing a compound of the formula or an ene, diene, triene, or ene derivative thereof; their saturated derivative; their stereoisomer; or their salt; characterized in that: R<1> is in each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR1; X2 is selected from o-R<1>, p-OR<1>, p-SR<1>, p-NR<1>2, p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms or Y2 is selected from straight-chain or branched alkyl of up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms, or and R<2>is -H; or NY<2>R<2> are together selected from where x is an integer from 3 to 5, wherein q is an integer from 0 to 6, or wherein Z2 is selected from R<1>or ;26. The composition according to Claim 25, characterized in that it further contains: a pharmaceutically acceptable carrier; an optional, pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable condom; and optionally, a pharmaceutically acceptable inert filler.; 27. Composition according to Claim 25, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, a toxin, or any combination thereof.;28. The composition according to Claim 25, indicated by the fact that the composition is in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.; 29. A composition containing a compound of the formula or an ene, diene, triene, or ene derivative thereof; their saturated derivative; their stereoisomer; or their salt; indicate that: R<1> is in each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is at each occurrence independently selected from -H,m-F, m- C1,m- Br,m-J, m-CN, m-NO2, m-SO2R1, or m-SO2OR<1>; X<2> is at each occurrence independently selected from o-CH3, p-OR<1>, p-SR<1>, p-NR12, or p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; where n is 1 or 2; or and Y2 is selected from ;30. The composition according to Claim 29, characterized in that it further contains: a pharmaceutically acceptable carrier; an optional, pharmaceutically acceptable excipient; optionally, a pharmaceutically acceptable condom; and optionally, a pharmaceutically acceptable inert filler.;31. The composition according to Claim 29, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, an anti-inflammatory agent, an antirheumatic agent, a cardiovascular agent, a toxin, or any combination thereof.;32. The composition according to Claim 29, indicated by the fact that it is a composition in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.;33. A composition, characterized in that it contains a triazine compound selected from: N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-6-morpholin-4-yl-N'-naphthalen-2-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-ε-morpholine^-or-N'-phenyl-1.S.S.Triazine^^-diamine; N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Benzyl-N'-cycloheptyl-N"-(4-methoxy-phenyl)-N-methyl-[1,3,5]triazine-2,4,6-triamine; N-(2-[1.Sj-Dioxolan-yl-ethyl-N'-methyl-N'-Cl-methyl-piperidin-1-N'-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-N''-naphthalen-2-yl.; 34. The composition according to Claim 33, further comprising: a pharmaceutically acceptable excipient; an optional, pharmaceutically acceptable filler.; 35. The composition according to Claim 33, characterized in that it further contains an agent selected from a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic agent, a radioactive isotope, a receptor, an enzyme that activates a pro-drug, anti-inflammatory agent, anti-rheumatic agent, cardiovascular agent, toxin, or any combination thereof.;36. The composition according to Claim 33, characterized by the fact that it is a composition in the form of a tablet, capsule, stamp, powder, granule, solution, suspension, emulsion, large pill, diamond-shaped tablet, uterine plug, tampon, cream, gel, paste, foam, spray, aerosol, microcapsule, liposome, trandermal patch, lozenge, paste or mouthwash.; 37. A method of treating unwanted cell proliferation, a disease mediated by inflammation, a hyperproliferative disease, or modulating a glycosidase enzyme in a human or animal, which consists of administering to a human or an animal a therapeutically effective amount of a composition, indicated by the fact that it contains a compound of the formula Or their ene, diene, triene, or yne derivative; their saturated derivative; their stereoisomer; or their salt; wherein: R<1> is at each occurrence independently selected from -H; alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkadienyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 12 carbon atoms and including linear or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, or heterocyclic derivatives thereof; arilla; heteroaryl; aryloxy; arylthio; halogen; or amino; G is selected from NR<1> or O; E is selected from CH or N; z is an integer from 0 to 3; X<1>is selected from R<1>, NR<1>3<+>, CN, N02, CO2R<1>, C(0)NR12, CH=CR<1>2,C=CR<1>, C(0)R<1>, SO2R<1>, SO2OR<1>, or NC(0)R<1>, or X<1> and X<2> are joined together with an aryl, pyridine, dioxane, pyrrole, pyrrolidine, furan, thiophene ring; provided that the R<1>residue of the C(0)R<1>substituent in the X<1>position excludes amino or dialkylamino when X<1>C(0)R<1>; X<2> is selected from R<1>; CXXH3. X, where X is halogen and x is an integer from 1 to 3; OR<1>; SR<1>; NR<1>2; CN; C(0)OR<1>; 4-morpholinyl; 4-methyl-1-piperizinyl; OR<2>, wherein R<2> is selected from CH2OCH3, CH2OCH2OCH3, CH2OCH2CH2OCH3, or C(O)R<1>; SR<3>, wherein R<3> is selected from CH2OCH3, CH2OCH2CH2OCH3, CH2OCH2CH(CH3)2, CH2NHC(0)CH3, or SR<1>; OM or SM, wherein M is selected from Li, Na, K, Mg, or Ca; AY<1>is halogen, or A is selected from NR<1>or O, and Y<1>is selected from R<1>;CR<4>3; NR<4>2; OR<4>; or SR<4>; wherein n is an integer from 0 to 8, m is an integer from 1 to 8, Z is independently selected from CR or N, Z is independently selected from CR<1>2, NR<1>, O, or S, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z2 residues are NR1; R 4 at each occurrence is independently selected from in the normal sequence or branched chain alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, acylthio, alkylamino, or dialkylamino, each of which contains up to 10 carbon atoms, -H, aryl, heteroaryl, aryloxy, arylthio, halogen, amino, their NR<1>2-substituted derivatives, their OR<1->substituted derivatives; their SR<1->substituted derivatives; or their halogen-substituted derivatives; and DY2 is halogen, or D is selected from NR<1> or O where R<1> is defined as above, and Y2 is selected from R<1>, or wherein Z<1> is independently selected from N or CR<4> and Z2 is independently selected as defined above, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z<2> residues are NR<1>.;38. Procedure according to Request 37, indicated by the fact that further comprising triazine compounds selected from; N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'^S-fluoro^-methoxy-phenyO-N'-methyl-N'-CI-methylpiperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-6-morpholin-4-yl-N'-naphthalen-2-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-e-morpholine^-or-N'-phenyl-t^. Triazine^^-diamine; N-Cycloheptyl-N'-(4-methoxy-4-enyl)-6-morpholin-4-yl-[1,3,5]triazin-2,3-diamine; N-Benzyl-N'-cycloheptyl-Nn-(4-methoxy-phenyl)-N-methyl41,3,5]triazine-2,4,6-triamine; N-(2-[1,3]Dioxolane-24l-ethyl)-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N naphthalene-2-ii-[1,3,5]triazine-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N,,-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine, or any combination thereof.;39. A method of treating unwanted cell proliferation in a human or animal that consists of administering to a human or an animal a therapeutically effective amount of a composition, indicated by the fact that it contains a compound of the formula or its ene, diene, triene, or yne derivative, its saturated derivative, its stereoisomer; or its salt; wherein: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl of up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from m-F, m- C1, m-Br, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, or X<1> and X<2> are fused together a benzene, pyridine, or dioxane ring; X<2> is selected from p-OR<1>, p-SR<1>, p-NR<1>2, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms; in the normal chain or branched alkyl of up to 10 carbon atoms; CH2R<2>, wherein R<2> is cycloalkyl with up to 10 carbon atoms; or wherein n is 1 or 2; AY2 is selected from halogen or OR<1>, or A is NR1 and Y2 is selected from R1, ;40. A method of modulating the enzyme glycosidase in a human or animal, which consists of administering to the human or animal a therapeutically effective amount of the composition, indicated by the fact that it contains a compound of the formula: or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt; wherein: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; X<1> is selected from H, m-F, m-Cl, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR1; X2 is selected from o-R1, p-OR1, p-SR1, p-NR12, p-OM, p-SM, wherein M is selected from Li, Na, K, Mg, or Ca; Y<1> is selected from cycloalkyl of up to 10 carbon atoms or Y2 is selected from straight-chain or branched alkyl of up to 10 carbon atoms; cycloalkyl with up to 10 carbon atoms, or and R<2>is -H; or NY<2>R<2> are together selected from wherein x is an integer from 3 to 5, or wherein q is an integer from 0 to 6, or wherein Z2 is selected from R<1>or ;41. A procedure for treating an inflammation-mediated disease in a human or animal, which consists of administering to the human or animal a therapeutically effective amount of the composition, indicated by the fact that it contains a compound of the formula: or their ene, diene, triene, or ene derivative; their saturated derivative; their stereoisomer; or their salt; wherein: R<1> is at each occurrence independently selected from -H; straight-chain or branched alkyl with up to 10 carbon atoms; or cycloalkyl with up to 10 carbon atoms; arilla; or (CH2)XCN, where x is an integer from 0 to 6; Eje CH or N; n is an integer from 0 to 3; X<1> is selected from -H, m-F, m- C\, m-Br, m-J, m-CN, m-NO2, m-SO2R<1>, or m-SO2OR<1>, m-NC(0)R<1>, or o-F, or X<1> and X<2> are fused together with a benzene, pyridine, or dioxane ring; X2 is selected from -H, o-CI, o-Br, o-CF3, o-R<1>, p-OR<1>, p-SR<1>, p-NR<1>2,<p->F, p-CI p-Br, p-CF3, p-CN, p-C(0)OR<1>, p-NC(0)R<1>, p-(4-morpholinyl), or p-(4-methyl-1-piperidinyl); AY<1>is halogen, or A is NR<1>or O and Y<1>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in the normal sequence or branched alkyl of up to 10 carbon atoms, CH2R<1>, (CHR<1>)yOR<1>, where y is an integer from 1 to 6, or AY<1>together where x is an integer from 3 to 5; and DY<2>is halogen, or D is NR<1>and Y<2>is selected from cycloalkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms substituted by R<1>, in a straight chain or branched N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N<n->methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-6-morpholin-44l-N'-naphthalen-2-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-6-morpholine-44l-N'-phenyl-[1,3H5]triazine-2,4-diamine; N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Benzyl-N'-cycloheptyl-N<M->(4-methoxy-phenyl)-N-methyl-[1,3,5]triazine-2,4,6-triamine; N-(2-[1,3]Dioxolane-24l-ethyl)-N'-methyl-N^1-methyl-piperidin-4-yl)-NM-naphthalene-24l-[1,3,5]triazine-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine, or any combination thereof.; 43. A procedure for the treatment of a hyperproliferative disease in a human or an animal which consists of administering to a human or an animal a therapeutically effective amount of the composition, indicated by the fact that it contains a compound of the formula: alkyl with up to 10 carbon atoms, CH2R<1>, wherein x is an integer from 3 to 5, CH2CF3, (CHR<1>)ZZ<1>, wherein z is an integer from 1 to 6, and Z1 is selected from NR<1>2, wherein x is an integer from 3 to 5, ; or NY<2>R<1> is together selected from Dri wherein Z2 is selected from R<1>, C(0)R<1>, C(0)OR<1>, pyridinyl, aryl, , or where q is an integer from 0 to 6.;42. The process according to Claim 41, further comprising triazine compounds selected from: N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; or an ene, diene, triene, or yne derivative thereof; a saturated derivative thereof; a stereoisomer thereof; or a salt thereof; wherein: R<1> is in each independently selected from -H; or branched alkyl with up to 10 carbon atoms; X<1> is an integer from -H, m-Br, m-J, m-NO2, or m-SO2OR<1> X<1>i X<2>a fused benzene or pyridine ring; X2 is selected from -H, o-CI, o-Br, p-OR<1>, p-SR<1>, p-NR<1>2, p-Cl p-Br, p-CF3, p-C(0)OR<1>, p-OM, or p-SM, wherein M is selected from Li, Na, K, Mg or Ca; A is selected from NR<1> or O, wherein Y1 is selected from cycloalkyl of up to 10 carbon atoms, with a normal chain or branched alkyl of up to 10 carbon atoms, or when A is NR<1>, and wherein Y is selected from R' or CH2R' when A is O; or AY is selected from halogen, DY<2>is halogen, or DNR<1>and Y<2>is selected from or (CHR<1>)XNR<1>2, wherein x is an integer from 1 to 6.;44. Medically a device, indicated by, consisting of: a drug delivery or elution member; and the composition according to Claim 8 exposed on or within the member for drug delivery or elution.;45. A medical device, indicated by, consisting of: a drug delivery or elution member; and the composition according to Claim 13 exposed on or within the article for drug delivery or elution.;46. Medical device according to Claim 45, characterized in that the stent is a member for drug delivery or elution.; 47. A medical device according to claim 45, characterized in that the drug delivery or elution member is selected from a drain, a colostomy bag attachment device, an ear drainage tube, a pacemaker guide, an implantable defibrillator guide, a suture, a driver, a coupling device, a vertebral disc, a bone pin, a suture lenger, a hemostatic barrier, a clip, a screwdriver, a plate, a clip, a vascular implant, tissue adhesives, tissue closure, tissue lifters, bone substitutes, intraluminal device, stent, or vascular carrier.;48. A medical device, indicated by, consisting of: a drug delivery or elution member; and the composition according to Claim 17 exposed on or within the member for drug delivery or elution.;49. Medical device according to claim 48, characterized in that the drug delivery member or the eluting member is a stent.; 50. A medical device according to claim 48, characterized in that the drug delivery or elution member is selected from a drain, a colostomy bag hanging device, an ear drainage tube, a pacemaker guide, an implantable defibrillator guide, a suture, a driver, a coupling device, a vertebral disc, a bone pin, a suture lenger, a hemostatic barrier, a clip, a screwdriver, a plate, a clip, a vascular implant, tissue adhesives, fastener for tissue, tissue lifter, bone substitute, intraluminal device, stent, or vascular carrier.;51. A medical device, indicated by, consisting of: a drug delivery or elution member; and the composition according to Claim 21 exposed on or within the member for drug delivery or elution.;52. Medical device according to Claim 51, characterized in that the drug delivery member or eluting member is a stent.; 53. A medical device according to Claim 51, characterized in that the drug delivery or elution member is selected from a drain, a colostomy bag hanging device, an ear drainage tube, a pacemaker guide, an implantable defibrillator guide, a suture, a driver, a coupling device, a vertebral disc, a bone pin, a suture lenger, a hemostatic barrier, a clip, a screwdriver, a plate, a clip, a vascular implant, tissue adhesives, tissue closure, tissue lifter, substitutes for bone, intraluminal device, stent, or vascular carrier.;54. Medical device, indicated by, which consists of: a member for drug delivery or elution; and composition according to Claim 25 exposed on or within the member for drug delivery or elution.;55. Medical device according to Claim 54, characterized in that the drug delivery member or eluting member is a stent.; 56. A medical device according to claim 54, characterized in that the drug delivery or elution member is selected from a drain, a colostomy bag hanging device, an ear drainage tube, a pacemaker guide, an implantable defibrillator guide, a suture, a driver, a coupling device, a vertebral disc, a bone pin, a suture lenger, a hemostatic barrier, a clip, a screwdriver, a plate, a clip, a vascular implant, tissue adhesive, tissue closure, tissue lifter, bone substitute, intraluminal device, stent, or vascular carrier.;57. A medical device, indicated by, consisting of: a drug delivery or elution member; and the composition according to Claim 29 exposed on or within the member for drug delivery or elution.;58. Medical device according to Claim 57, characterized in that the drug delivery member or eluting member is a stent.; 59. A medical device according to Claim 57, characterized in that n for drug delivery or elution is selected from a drain, a colostomy bag hanging device, an ear drainage tube, a pacemaker guide, an implantable defibrillator guide, a suture, a driver, a coupling device, a vertebral disc, a bone pin, a suture lenger, a hemostatic barrier, a clip, a screwdriver, a plate, a clip, a vascular implant, tissue adhesive, tissue fastener, tissue lifter, bone substitute, intraluminal device, stent, or vascular carrier.; 60. A medical device, indicated by, consisting of: a drug delivery or elution member; and an article according to Claim 33 exposed on or within the article for drug delivery or elution.; 61. A medical device according to Claim 60, characterized in that the drug delivery member or eluting member is a stent.; 62. A medical device according to Claim 60, characterized in that n for drug delivery or elution is selected from a drain, a colostomy bag hanging device, an ear drainage tube, a pacemaker guide, an implantable defibrillator guide, a suture, a driver, a coupling device, a vertebral disc, a bone pin, a suture lenger, a hemostatic barrier, a clip, a screwdriver, a plate, a clip, a vascular implant, tissue adhesive, tissue closure, tissue lifter, bone substitute, intraluminal device, stent, or vascular carrier.;63. A microarray, characterized in that it consists of: a gene expression profile generated from a cell type treated with a compound of the formula Or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt; wherein: R<1> is at each occurrence independently selected from -H; alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkadienyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 12 carbon atoms and including linear or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, or heterocyclic derivatives thereof; arilla; heteroaryl; aryloxy; arylthio; halogen; or amino; G is selected from NR<1> or O; E is selected from CH or N; z is an integer from 0 to 3; X<1>is selected from R<1>, NR<1>3<+,>CN, N02, C02R<1>, C(0)NR<1>2, CH=CR<1>2,C^CR<1>, C(0)R<1>, S02R<1>, S02OR<1>, or NC(0)R<1>, or X<1>and X<2> are fused together with aryl, pyridine, dioxane, pyrrole, pyrrolidine, furan, thiophene ring; provided that the R<1>residue of the C(0)R<1>substituent in the X<1>position excludes amino or dialkylamino when X<1>C(0)R<1>; X<2> is selected from R<1>; CXXH3_X, where X is halogen and x is an integer from 1 to 3;OR1;SR<1>; NR<1>2; CN; C(0)OR<1>;4-morpholinyl; 4-methyl-1-piperizinyl; OR<2>, wherein R<2>is selected from CH2OCH3, CH2OCH2OCH3, CH2OCH2CH2OCH3, or C(0)R<1>;SR<3>, wherein R<3>is selected from CH2OCH3, CH2OCH2CH2OCH3, CH2OCH2CH(CH3)2,CH2NHC(0)CH3, or SR<1>; OM or SM, wherein M is selected from Li, Na, K, Mg, or Ca; AY<1>is halogen, or A is selected from NR<1>or O, and Y<1>is selected from R<1>;CR<4>3; NR<4>2; OR<4>; or SR<4>; wherein n is an integer from 0 to 8, m is an integer from 1 to 8, Z is independently selected from CR or N, Z is independently selected from CR<1>2, NR1, O, or S, provided that two O or S atoms are not located adjacent to each other, and provided that no more than two Z2 residues are NR<1>; R 4 at each occurrence is independently selected from in the normal sequence or branched alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, acylthio, alkylamino, or dialkylamino, each containing up to 10 carbon atoms, -H, aryl, heteroaryl, aryloxy, arylthio, halogen, amino, their NR<1>2-substituted derivatives, their OR<1->substituted derivatives; their SR<1->substituted derivatives; or their halogen-substituted derivatives; and DY2 is halogen, or D is selected from NR<1> or O where R<1> is defined as above, and Y2 is selected from R<1>, , or where Z<1>is independent selected from N or CR<4> and Z<2> is independently selected as defined above, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z<2> residues are NR<1>.;64. A microarray according to Claim 63, characterized in that the compound further comprises a triazine compound selected from: N-Cycloheptyl-N'-methyl-N,-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazine-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-6-morpholin-4-yl-N'-naphthalen-2-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-6-morpholin-4-yl-N'-phenyl-[1,3,5]triazine-2,4-diamine; N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Benzyl-N'-cycloheptyl-N"-(4-methoxy-phenyl)-N-methyl-[1,3,5]triazine-2,4,6-triamine; N-(2-[1,3]Dioxolan-2-yl-ethyl)-N'-methyl-N,-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazine-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine, or any combination thereof.; 65. The microarray of Claim 63, characterized in that the cell type is selected from the group of cells comprising coronary artery endothelium, umbilical artery endothelium, umbilical vein endothelium, aortic endothelium, myometrial microvascular endothelium, kerationocyte epithelium, bronchial epithelium, mammary epithelium, prostate epithelium, renal cortical epithelium, renal proximal tubule epithelium, small airway epithelium, renal epithelium, umbilical artery smooth muscle, neonatal dermal fibroblast, pulmonary artery smooth muscle, dermal fibroblast, neural progenitor cells, skeletal muscle, bronchial smooth muscle, uterine smooth muscle, fibroblast lungs, osteoblasts or stromal cells prostate;66. A database expression profile, indicated by, consisting of: a reference identifying the patient; and an expression profile for the patient generated by administering to the patient a compound of the formula Or an ene, diene, triene, or yne derivative thereof; their saturated derivative; their stereoisomer; or their salt; wherein: R<1> is at each occurrence independently selected from -H; alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkadienyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, alkylthio, alkylamino, or dialkylamino, each having up to 12 carbon atoms and including linear or branched derivatives thereof, cyclic derivatives thereof, substituted derivatives thereof, heteroatom derivatives thereof, or heterocyclic derivatives thereof; arilla; heteroaryl; aryloxy; arylthio; halogen; or amino; G is selected from NR<1> or O; E is selected from CH or N; z is an integer from 0 to 3; X<1>is selected from R<1>, NR<1>3<+>, CN, N02, C02R<1>, C(0)NR<1>2, CH=CR<1>2,C=CR<1>, C(0)R<1>, S02R<1>, S02OR<1>, or NC(0)R<1>, or X<1>and X<2> are fused together with aryl, pyridine, dioxane, pyrrole, pyrrolidine, furan, thiophene ring; provided that the R<1>residue of the C(0)R<1>substituent in the X<1>position excludes amino or dialkylamino when X<1>C(0)R<1>; X<2> is selected from R<1>; CXXH3_X,<p>where X is halogen and x is an integer from 1 to 3; OR<1>; SR<1>; NR<1>2; CN; C(0)OR<1>; 4-morpholinyl; 4-methyl-1-piperizinyl; OR<2>, wherein R<2>is selected from CH2OCH3, CH2OCH2OCH3, CH2OCH2CH2OCH3, or C(0)R<1>;SR<3>, wherein R<3>is selected from CH2OCH3, CH2OCH2CH2OCH3, CH2OCH2CH(CH3)2,CH2NHC(0)CH3, or SR<1>; OM or SM, wherein M is selected from Li, Na, K, Mg, or Ca; AY<1>is halogen, or A is selected from NR<1>or O, and Y<1>is selected from R<1>;CR<4>3; NR<4>2; OR<4>; or SR<4>; where n is an integer from 0 to 8, m is an integer from 1 to 8, Z<1>is independently selected from CR<1>or N, Z<2>is independently selected from CR<1>2, NR<1>, O, or S, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z2 residues are NR1; R 4 at each occurrence is independently selected from in the normal sequence or branched alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, alkoxy, acylthio, alkylamino, or dialkylamino, each containing up to 10 carbon atoms, -H, aryl, heteroaryl, aryloxy, arylthio, halogen, amino, their NR<1>2-substituted derivatives, their OR<1->substituted derivatives; their SR<1->substituted derivatives; or their halogen-substituted derivatives; and DY2 is halogen, or D is selected from NR<1> or O where R<1> is defined as above, and Y2 is selected from R<1>, or wherein Z<1>is independently selected from N or CR<4>and Z2 is independently selected as defined above, provided that no two O or S atoms are located adjacent to each other, and provided that no more than two Z<2>residues are NR<1>.;67. The database expression profile of Claim 66, further comprising a triazine compound selected from: N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-6-morpholin-4-yl-N'-naphthalen-2-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-6-morpholin-4-yl-N'-phenyl-[1,3,5]triazine-2,4-diamine; N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Benzyl-N'-cycloheptyl-N"-(4-methoxy-phenyl)-N-methyl-[1,3,5]triazine-2,4,6-triamine; N-(2-[1,3]Dioxolan-2-yl-ethyl)-N,-methyl-N<*->(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine, or any combination thereof. 68. A method of treating inflammation-mediated diseases in a human or an animal, characterized by administering to a human or an animal a therapeutically effective amount of a composition containing a triazine compound selected from: N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methylpiperidin-4-yl)-[1,3,5]triazin-2,4,6-triamine; [4-(4-Benzyl-piperazin-1-yl)-6-morpholin-4-yl]-(4-methoxy-phenyl)-amine; N-Cycloheptyl-6-morpholin-4-yl-N'-naphthalen-2-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Cycloheptyl-6-morpholin-4-yl-N'-phenyl-[1,3,5]triazine-2,4-diamine; N-Cycloheptyl-N'-(4-methoxy-phenyl)-6-morpholin-4-yl-[1,3,5]triazin-2,4-diamine; N-Benzyl-N'-cycloheptyl-N"-(4-methoxy-phenyl)-N-methyl-[1,3,5]triazine-2,4,6-triamine; N-(2-[1,3]Dioxolan-2-yl-ethyl)-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cyclopropyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine, or any combination thereof. 69. The method according to Claim 37, characterized in that the compound is present in the composition in an amount effective when given in a daily dose, a daily sub-dose, or any fraction thereof to a human or an animal to reduce the effects of a disease or to modulate the glucosidase enzyme. 70. The method according to Claim 39, characterized in that the compound is present in the composition in an amount effective when given in a daily dose, a daily sub-dose, or any fraction thereof to a human or an animal to reduce the effects of unwanted cell proliferation. 71. The method according to Claim 37, characterized in that the compound is present in the composition in an amount effective when administered in a daily dose, daily sub-dose, or any fraction thereof to a human or animal to modulate the glycosidase enzyme. 72. The method according to Claim 37, characterized in that the compound is present in the composition in an amount effective when given in a daily dose, a daily sub-dose, or any fraction thereof to a human or an animal to reduce the effects of inflammation-mediated diseases. 73. The method according to Claim 37, characterized in that the compound is present in the composition in an amount effective when given in a daily dose, a daily sub-dose, or any fraction thereof to a human or an animal to reduce the effects of a hyperproliferative disease. 74. The method according to Claim 39, characterized in that the compound further comprises: N-Cycloheptyl-N,-methyl-N'-(1-methyl-piperidin-4-yl)-N''-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl!)-N"-methyl-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine; or a combination thereof. 75. A method of treating unwanted cell proliferation in a human or animal, characterized by administering to the human or animal a therapeutically effective amount of a composition containing a triazine compound selected from: N-Cycloheptyl-N'-methyl-N'-(1-methyl-piperidin-4-yl)-N"-naphthalen-2-yl-[1,3,5]triazin-2,4,6-triamine; N-Cycloheptyl-N'-(3-fluoro-4-methoxy-phenyl)-N"-methyl-N"-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine; or a combination thereof.