MXPA00002910A - Azabenzimidazole-based compounds for modulating serine/threonine protein kinase function - Google Patents

Abstract

The present invention is directed in part towards methods of modulating the function of serine/threonine protein kinases with azabenzimidazole-based compounds. The methods incorporate cells that express a serine/threonine protein kinase, such as RAF. In addition, the invention describes methods of preventing and treating serine/threonine protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to azabenzimidazole compounds and pharmaceutical compositions comprising these compounds.

Description

COMPOUNDS BASED ON AZABENCI IDAZQL FOR MODULAR THE FUNCTION OF SERINE / TREONINE PROTEIN-KINASES Background of the Invention The following description of the background of the invention is provided to aid understanding of the invention, but it is not admitted that it is the prior art to the invention. The transduction of cellular signals is a fundamental mechanism by which external stimuli that regulate diverse cellular processes are delayed into the cells. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins, which allows the regulation of the activity of mature proteins by altering their structure and function. The best characterized protein kinases in eukaryotes are the phosphorylate proteins in the alcoholic portion of the serine, threonine and tyrosine residues. These kinases fall greatly into two groups, those specific for phosphorylation of serine and threonine, and those specific for phosphorylation of tyrosine. Some kinases, also referred to as "dual specificity" kinases, are capable of phosphorylating tyrosine as well as serine / t reonin residues. Protein kinases can also be characterized by their location within cells. Some kinases are transmembrane receptor proteins capable of binding to ligands external to the cell membrane. The binding of the ligands alters the catalytic activity of the receptor protein kinases. Others are non-receptor proteins that lack a transmembrane domain. Non-receptor protein kinases can be found in a variety of cellular compartments from the outer surface of the cell membrane to the nucleus. Many kinases are comprised in regulatory cascades where their substrates may include other kinases whose activities are regulated by their phosphorylation status. Finally, the activity of an effector in the 3 'direction is modulated by the phosphorylation resulting from the activation of this route. The serine / t reonin kinase family includes members that regulate many steps of the signaling cascades, including cascades that control cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, synthesis of cellular proteins, and regulation of the cell cycle. An example of a non-receptor protein kinase that phosphorylates protein targets in serine and threonine residues is RAF. RAF modulates the catalytic activity of other protein kinases, such as the protein kinase that phosphorylates, and thus activates, the mitogen-activated protein kinase (MAPK). The RAF itself is activated by the membrane-bound RAS protein, which in turn is activated in response to activated tyrosine receptor kinases, such as the epidermal growth factor receptor (EGFR) receptor. of platelet-derived growth factor (PDGFR). The biological importance of RAF in the control of cellular events is accentuated by the finding that altered forms of RAF cause cancer in organisms. Evidence of the importance of RAF in malignancies is provided in Monia et al., 1996, Nature Medicine 2: 668, incorporated herein by reference in its entirety including all figures and tables. In an effort to discover new treatments for cancer and other diseases, biomedical and chemical researchers have designed, synthesized and tested molecules that inhibit the function of protein kinases. Some small organic molecules form a class of compounds that modulate the function of protein kinases. Examples of molecules that have been reported to inhibit the function of protein kinases are monocyclic, bicyclic or heterocyclic bis-aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808), 1 -cyclopropyl-4-pyridyl-quinolones (U.S. Patent No. 5,330,992), styryl compounds (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No 0 566 266 al), seleoindoles and selenides (PCT WO 94/03427), polyhydroxylic compounds, tricyclics (PCT WO 92/21660), and benzylphosphonic acid compounds (PCT WO 91/15495).

Compounds that can cross cell membranes and are resistant to acid hydrolysis are potentially advantageous therapeutic products since they become highly bioavailable after they are orally administered to patients. However, many of these protein kinase inhibitors only weakly inhibit the function of protein kinases. In addition, many exhibit a variety of protein kinases, and therefore, will cause multiple side effects as therapeutic products for diseases.

Brief Description of the Invention - The present invention is directed in part towards methods for modulating the function of serine / threonine protein kinases with azabenzimidazole-based compounds. The methods incorporate cells that express a serine / threonine protein kinase, such as RAF. In addition, the invention describes methods for preventing and treating abnormal conditions related to serine / threonine protein kinases in organisms with a compound identified by the invention. Additionally, the invention relates to pharmaceutical compositions comprising compounds identified by the methods of the invention.

I. Methods for Detecting Compounds That Modulate the Function of Serine / Threonine Protein kinases The methods of the present invention provide means for modulating the function of the serine / threonine protein kinases both receptor and cytosolic. These methods provide means to modulate the enzymes both in vitro and in vivo. For in vitro applications, the methods of the invention relate in part to a method for identifying compounds that modulate the function of the serine / threonine protein kinases. Thus, in a first aspect, the invention incorporates a method for modulating the function of a serine / threonine protein kinase with a compound based on azabenzimidazole. The azabenzimidazole compound is optionally substituted with organic groups. The method comprises the new contact cells expressing the serine / threonine protein kinase in the compound. The term "function" refers to the role cell of a serine / threonine protein kinase. The family of serine / threonine protein kinases includes members that regulate many steps in signaling cascades, including cascades that control cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis , and regulation of the cell cycle. The term "modulates" refers to the ability of a compound to alter the function of a protein kinase. A modulator preferentially activates the catalytic activity of a protein kinase, more preferably activates or inhibits the catalytic activity of a protein kinase depending on the concentration of the compound exposed to the protein kinase, or more preferably inhibits the activity of the protein kinase. catalytic activity of a protein kinase. The term "catalytic activity", in the context of the invention, defines the rate at which a protein kinase phosphorylates a substrate. The catalytic activity can be measured, for example, by determining the amount of substrate converted to a product as a function of the weather. Phosphorylation of a substrate occurs at the active site of a protein kinase. The active site is usually a cavity in which the substrate binds to the protein kinase and phosphorylates. The term "substrate" as used herein refers to a molecule phosphorylated by a serine / threonine protein kinase. The substrate is preferably a peptide and more preferably a protein. In relation to protein kinase, RAF, the preferred substrates are MEK and the substrate of MEK, MAPK. The term "active" refers to the increase in cellular function of a protein kinase. The function of the protein kinase is preferably the interaction with a natural binding partner and more preferably the catalytic activity. The term "inhibits" refers to the decrease in cellular function of a protein kinase. The function of the protein kinase is preferably the interaction with a natural binding partner and more preferably the catalytic activity. The term "modulates" also refers to the alteration of the function of a protein kinase by increasing or decreasing the probability that it becomes complexed between a protein kinase and a natural binding partner. A modulator preferentially increases the likelihood that this complex forms between the protein kinase and the natural binding partner, more preferably increasing or decreasing the likelihood that a complex is formed between the protein kinase and the natural binding partner. depending on the concentration of the compound exposed to the protein kinase, and more preferably decreases the likelihood that a complex is formed between the protein kinase and the natural binding partner. The term "complex" refers to a assembly of at least two molecules bound together. Signal transduction complexes frequently contain at least two protein molecules linked together. For example, a receptor protein-protein kinase tyrosine, GRB2, SOS, RAF and RAS are assembled to form a signal transduction complex in response to a mitogenic ligand. The term "natural binding partner" refers to polypeptides that bind to a protein- kinase in the cells. Natural binding partners can play a role in the propagation of a signal in a signal transduction process of protein kinases. A change in the interaction between a protein kinase and a natural binding partner can manifest itself as an increased or decreased probability that the interaction is formed, or an increased or decreased concentration of the prot-eina-kinase / binding partner complex. natural . The natural binding partner of the protein kinase can bind to the intracellular region of the protein kinase with high affinity. High affinity represents an equilibrium binding constant in the order of 10 ~ 6 M or less. In addition, a natural binding partner can also interact transiently with a cellular region of the protein kinase and modify it chemically. The natural binding partners of the protein kinases are chosen from a group that includes, but is not limited to, domains of homology 2 (SH2) or 3 (SH3) of SRC other domains binding to fos foryl-tyrosine ( PTB), guanine nucleotide exchange factors, protein-phosphatases, and other protein kinases. Methods for determining changes in interactions between protein kinases and their natural binding partners are readily available in the art. The term "serine / threonine protein kinase" refers to an enzyme with an amino acid sequence with at least 10% amino acid identity to other enzymes that phosphorylate proteins in the serine and threonine residues. A serine / threonine protein kinase catalyzes the addition of phosphate to proteins in the serine and threonine residues. Serine / threonine protein kinases may exist as membrane bound proteins or cytosolic proteins. The term "contacting" as used herein refers to the mixing of a solution comprising an azabenzimidazole compound of the invention with a liquid medium that damages the cells of the methods. the solution comprising the compound may also comprise another component, such as dimethylsulfoxide (DMSO), which facilitates the admission of the azabenzimidazole compound or compounds into the cells of the methods. The solution that comprising the azabenzimidazole compound can be added to the medium that damages the cells by using a dispensing apparatus, such as a pipette-based device or syringe-based device. The term "azabenzimidazole-based compound" refers to an organic azabenzimidazole compound substituted by chemical substituents. The azabenzimidazole compounds on the general structure: The term "substituted" with reference to the invention refers to the azabenzimidazole compound that is derivatized with any number of chemical substituents. In a preferred embodiment, the invention relates to the method for modulating the function of a serine / threonine protein kinase, where the protein kinase is RAF. The protein kinase RAF phosphorylates the protein targets in the serine or threonine residues. A protein goal is protein- kinase (MEK) that phosphorylates and activates mitogen-activated protein kinase (MEK). The RAF itself is activated by the membrane-bound guanine triphosphate that hydrolyzes the RAS enzyme in response to the mitogen-stimulated receptor-protein kinase-t-irosine kinases, such as the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR). The methods of the present invention can detect compounds that modulate the function of the protein kinase RAF in cells. RAF phosphorylates a protein kinase (MEK) which in turn phosphorylates mitogen-activated protein kinase (MAPK). The assays that monitor only the phosphorylation of MEK by RAF are not sensitive because the levels of MEK phosphorylation are not significant. To overcome this sensitivity dilemma, the phosphorylation of both MEK and MAPK that follows in the assays in the present invention. The MAPK phosphorylation signal amplifies the phosphorylation signal of MAPK and allows RAF-dependent phosphorylation, such as enzyme-linked immunosorbent assays, to be followed in assays.

Additionally, the assay of the invention is performed in a high performance format such that they can be rapidly monitored in many compounds in a short period of time. In another aspect, the invention describes a method for identifying compounds that modulate the function of the serine / threonine protein kinase, which comprises the steps of contacting the cells expressing the serine / threonine protein kinase with the compound, and monitor an effect on the cells. The term "monitor" refers to the observation of the effect of adding the compound to the cells of the method. The effect can be manifested in a change in cell phenotype, cell proliferation, protein kinase kinase activity, or in the interaction between a protein kinase and a natural binding partner. The term "effect" describes a change or absence of a change in the cellular phenotype or cell proliferation. "Effect" can also describe a change or an absence of a change in the catalytic activity of the protein kinase. The "effect" can also describe a change or absence of a change in an interaction between the protein kinase and a natural binding partner. A preferred embodiment of the invention relates to the method for identifying compounds that modulate the function of the serine / threonine protein kinase, where the effect is a change or an absence of a change in the cellular phenotype. The term "cell phenotype" refers to the external appearance of a cell or tissue or the function of the cell or tissue. Examples of the cellular phenotype are cell size (reduction or enlargement), cell proliferation (increased or decreased numbers of cells), cell differentiation (a change or absence of a change in cell shape), cell survival, apoptosis (cell death) ), or the use of a metabolic nutrient (for example, glucose intake). Changes or absence of changes in the cell phenotype are easily measured by techniques known in the art. In another preferred embodiment, the invention relates to the method for identifying compounds that modulate the function of the serine / threonine protein kinase, where the effect is a change or an absence of a change in cell proliferation. The term "cell proliferation" is refers to the number in which a group of cells is divided. The number of cells growing in a container can be quantified by a person skilled in the art when that person visually counts the number of cells in a volume identified using a common light microscope. Alternatively, cell proliferation rates can be quantified by laboratory apparatus that optically or conductively measure cell density in an appropriate medium. In another preferred modality, the invention relates to the method for identifying compounds that modulate the function of the serine / threonine protein kinase, where the Affect is a change or an absence of a change in the interaction between the serine / threonine protein kinase with a natural union partner. The term "interaction", in the context of the invention, describes a complex formed between an intracellular region of the protein kinase and a natural binding partner or compound. The term "interaction" may also extend to a complex formed between a compound of the invention with intracellular regions and regions extracellular proteins of the kinase under study. Although a cytosolic protein kinase will have no extracellular region, a receptor protein kinase will have both an extracellular and an intracellular region. The term "intracellular region" as used herein refers to the portion of a protein kinase that exists within a cell. The term "extracellular region" as used herein refers to a portion of a protein kinase that exists outside the cell. In a preferred embodiment, the invention relates to the method for identifying compounds that modulate the function of the serine / threonine protein kinase which additionally comprises the following steps: (a) lysing the cells to deliver a Used that comprises the protein kinase of serine / threonine; (b) absorbing the serine / threonine protein kinase to an antibody; (c) incubating the absorbed serine / threonine protein kinase with a substrate or substrates; and (d) absorbing the substrate or substrates to a solid support or antibody. The step of monitoring the effect on the cells comprises measuring the phosphate concentration of substrate or substrates.

The term "lysing" as used herein refers to a method for disrupting the integrity of a cell such that its inner contents are released. Cell lysis is achieved by many techniques known to a person skilled in the art. The method is preferably achieved by treatment with sound or cellular tightening techniques and more preferably by techniques with detergents. The term "antibody" as used herein refers to a protein molecule that binds specifically to the protein kinase. An antibody binds preferentially to a protein kinase class and more preferably binds specifically to the protein kinase RAF. The term "binds specifically" as used herein refers to an antibody that binds to a protein kinase with higher affinity than another protein kinase or cellular protein. An antibody that binds specifically to a protein kinase will bind to a higher concentration of the protein kinase specific than any other protein kinase or cell protein. The term "adsorb" as used in the present refers to the binding of a molecule to the surface and an antibody or solid support. Examples of solid supports are chemically modified cellulose, such as phosphocellulose, and nylon. The antibodies can be bound to solid supports on techniques well known to those skilled in the art. See, for example, Harlo & Lane, Antibodies, A. Laboratory Manual, 1989, Cold Spring Harbor Laboratories. The term "measure phosphate concentration" as used herein refers to techniques commonly known to persons skilled in the art. These techniques may comprise quantifying the concentration of phosphate concentrations within a substrate or determining the relative amounts of phosphate within a substrate. These techniques may include adsorbing the substrate to a membrane and detecting the amount of phosphate within the substrate by radioactive measurements. In another preferred embodiment, the invention relates to the method of identifying compounds that modulate the function of the serine / threonine protein kinase which additionally comprises the following steps: (a) lysing the cells for supply a Used that comprises RAF; (b) adsorbing the RAF to an antibody; (c) incubating the absorbed RAF with MEK and MAPK; and (d) adsorbing the MEK and MAPK to a solid support or antibody or antibodies. The step of measuring the effect in cells comprises monitoring the phosphate concentration of MEK and MAPK. In a preferred embodiment, the invention relates to the method of identifying compounds that modulate the function of serine / threonine protein kinase, wherein the azabenzimidazole-based compound has an exposed structure in Formula I, II, or III as defined in the present or any of the subgroups thereof set forth herein. The term "compound" refers to the compound or salt, ester, amide, prodrug, isomer or pharmaceutically acceptable metabolite thereof. The term "pharmaceutically acceptable salt" refers to the formulation of a compound that does not nullify the biological activity of compound properties. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. The term "prodrug" refers to an agent that becomes the parent drug in vivo. Prodrugs may be easier to administer than the parent drug in some situations. For example, the prodrug may be bioavailable for oral administration, but the origin may not, or the prodrug may improve the solubility to allow intravenous administration. In another preferred embodiment, the invention relates to the method for identifying compounds that modulate the function of the serine / threonine protein kinase, wherein the azabenzimidazole-based compound has a structure set forth in formula I, II or III, wherein the compound of azabenzimidazole is selected from the group consisting of SABI compounds. The term "SABI compounds" refers to the group of azabenzimidazole-based compounds having a structure set forth in Formula A or B, and numbered A-1 through A-198 in the following table: II. Methods for Preventing or Treating Abnormal Conditions In another aspect, the invention incorporates a method for preventing or treating an abnormal condition in an organism by administering a compound of the invention, as specified herein by Formula I, II or II, with any of the coercions provided herein, to an organism. The term "organism" refers to any living entity that comprises at least one cell. An organism can be as simple as a eukaryotic cell or as complex as a mammal. In preferred embodiments, an organism refers to humans or mammals. The term "prevent" refers to the method of the invention that decreases the probability, or that eliminates the possibility of an organism contracting or developing the abnormal condition. The term "treat" refers to the method of the invention which has a therapeutic effect and at least partially mitigates or cancels the abnormal condition in the organism. The term "therapeutic effect" refers to the inhibition of cell growth that causes or contributes to an abnormal condition. The term "therapeutic effect" also refers to the inhibition of growth factors that cause or contribute to the abnormal condition (for example, cancer). A therapeutic effect alleviates to some degree one or more of the symptoms of the abnormal condition. In reference to the treatment of a cancer, a therapeutic effect refers to one or more of the following: (a) a reduction in tumor size; (b) inhibition (i.e., identification or arrest) of the tumor metastasis; (c) inhibition of tumor growth; and (d) relief to some degree from one or more of the symptoms associated with the abnormal condition. Compounds that demonstrate efficacy against leukemia can be identified as described herein, except that instead of inhibiting the metastasis, the compounds can actually encourage or decrease cell proliferation or cell growth. The term "abnormal condition" refers to a function in the cells or tissues of an organism that deviates from its normal functions in that organism. An abnormal condition can be related to cell proliferation, cell differentiation, or cell survival. Abnormal, proliferative cell conditions include cancers such as fibrotic and mesanguial disorders, abnormal angiogenesis and vasculogenesis, wound healing, psoriasis, diabetes mellitus, and inflammation. Abnormal differentiation conditions include, but are not limited to, neurodegenerative disorders, slow rates of wound healing, and tissue grafting techniques. Abnormal cell survival conditions are related to conditions in which programmed cell death (apoptosis) is activated or nullified. A number of protein kinases is associated with the pathways of apoptosis. Aberrations in the function of any of the protein kinases could lead to to cellular immortality or premature cell death. Cell proliferation, differentiation and survival are phenomena measured simply by methods in the art. These methods may comprise observing the number of cells or the appearance of cells under a microscope with respect to time (e.g., days). The term "administer" refers broadly to the provision to an organism and more specifically to a method for incorporating a compound into cells or tissues of an organism. The abnormal condition can be prevented or treated when the cells or tissues of the organism exist inside the organism or outside the organism. Cells that exist outside the body can be maintained or cultured in tissue culture boxes. For the cells that are inside the organism, there are many techniques for administering compounds, including (but not limited to) oral, parenteral, dermal, injection and aerosol applications. For cells outside the organism, there are multiple techniques for administering the compounds, including (but not limited to) cellular microinjection, transformation techniques and techniques with carriers. In a preferred embodiment, the invention relates to a method for preventing or treating an abnormal condition in an organism, wherein the azabenzimidazole-based compound has a structure set forth in Formula I, II, or II as defined herein or any of the subgroups of the same exposed in the present. In another preferred embodiment, the invention relates to a method for preventing or treating an abnormal condition in an organism, wherein the azabenzimidazole compound is selected from the group consisting of SABI compounds. In another preferred embodiment, the invention relates to a method for preventing or treating a normal condition in an organism, wherein the organism is a mammal. The term "mammal" refers preferably to organisms such as mice, rats, rabbits, guinea pigs and goats, more preferably to monkeys and apes, more preferably to humans. In another preferred embodiment, the invention relates to a method for preventing and treating an abnormal condition in an organism, where the Abnormal condition is cancer or a fibrotic disorder. In yet another preferred embodiment, the invention relates to a method for preventing or treating an abnormal condition in an organism, wherein the cancer is selected from the group consisting of lung cancer, ovarian cancer, breast cancer, cancer brain, intra-axial brain cancer, colon cancer, prostate cancer, sarcoma, Kaposi's sarcoma, melanoma and glioma. In yet another preferred embodiment, the invention relates to a method for preventing or treating an abnormal condition in an organism, wherein the method applies to an abnormal condition associated with an aberration in the signal transduction pathway characterized by an interaction between a protein - serine / threonine kinase and a natural binding partner. The term "signal transduction path" refers to the propagation of a signal. In general, an extracellular signal is transmitted through the cell membrane to become an intracellular signal. This signal can then stimulate a cellular response. The term it also encompasses signals that propagate completely within a cell. The polypeptide molecules comprised in signal transduction processes are typically receptor and non-receptor protein kinases, receptor and non-receptor protein phosphatases, nucleotide exchange factors, and transcription factors. The term "aberration", in conjunction with a signal transduction process, refers to a protein kinase that is over- or under-expressed in an organism, mutated such that its catalytic activity is less or greater than the activity of the wild-type protein kinase, mutated such that it can no longer interact with a natural binding partner, is no longer modified by another protein-kinase or protein-phosphatase, or does not interact for longer with a natural binding partner . The term "promoting or disrupting the abnormal interaction" refers to a method that can be achieved by administering a compound of the invention to cells or tissues in an organism. A compound can promote an interaction between a protein kinase and natural binding partners at form favorable interactions with multiple atoms of the complex shell. Alternatively, a compound can inhibit an interaction between a protein kinase and natural binding partners by compromising the favorable interactions formed between atoms in the complex shell. In another preferred embodiment, the invention relates to a method for learning to treat an abnormal condition in an organism, wherein the serine / threonine protein kinase is RAF.

III. Compounds and Pharmaceutical Compositions of the Invention In another aspect, the invention incorporates azabenzimidazole compounds having the structures set forth in Formula I, II or III: where (a) Ri, R2, R3 and R4 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated and unsaturated alkyl; (iii) NX2X, wherein X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (iv) halogen or trihalomethyl; (v) a ketone of the formula -C0-X4, wherein X are selected from the group consisting of hydrogen, alkyl and homocyclic or heterocyclic ring portions; (vi) a carboxylic acid of the formula - (X5) n -COOH or ester of the formula - (Xe) n -COO-X-7, where X5, Xβ, and X are independently selected from alkyl and homocyclic or heterocyclic ring portions and where n is 0 or 1; (vii) an alcohol of the formula (Xg) n-OH, or an alkoxy portion of the formula - (X8) n-0-X9, wherein Xs and Xg are independently selected from the group consisting of hydrogen, saturated alkyl or unsaturated, and homocyclic or heterocyclic ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester, and wherein n is 0 or 1; (viii) an amine of the formula NHCOXio, wherein Xio are selected from the group consisting of alkyl, hydroxyl, and heterocyclic or ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the a group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester; (ix) -S02NXnX? 2, where Xn and X? 2 are selected from the group consisting of hydrogen, alkyl and homocyclic or heterocyclic ring portions; (x) a homocyclic or heterocyclic ring portion optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester moieties; (xi) an aldehyde of the formula -CO-H; and (xii) a sulfone of the formula -S02-X13, wherein X? 3 are independently selected from the group consisting of saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (b) Zi and Z2 are independently selected from the group consisting of nitrogen, sulfur, oxygen, NH and NR4, with the proviso that if one of Zx and Z is nitrogen, NH, or NR4 then the other of Zx and Z2 is nitrogen, sulfur, oxygen, NH, or NR; and (c) Z2 and Xi are independently selected from the group consisting of nitrogen, sulfur and oxygen. The term "saturated alkyl" refers to an alkyl portion that does not contain any alkene or alkyne portion. The alkyl portion it can be branched or unbranched. The term "unsaturated alkyl" refers to an alkyl portion that contains at least one alkene or alkyne portion. The alkyl portion may be branched or unbranched. The term "amine" refers to a chemical moiety of the formula NR? R2, where Ri and R2 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and heterocyclic or heterocyclic ring portions., wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro and ester portions. The term "aryl" refers to an aromatic group having at least one ring having a conjugated pi electron system and includes both aryl carboxylic groups (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term "carbocyclic" refers to the compound that contains one or more covalently closed ring structures, and that the atoms that make up the ring structure are all carbon atoms. The term distinguishes from this the carboxylic rings of heterocyclics in which the ring structure contains at least one atom that is different from carbon. The term "heteroaryl" refers to an aryl group that contains at least one heterocyclic ring. The term "halogen" refers to an atom selected from the group consisting of fluorine, chlorine, bromine and iodine. The term "ketone" refers to a chemical moiety with the formula - (R) -n-CO-R ', where R and R' are selected from the group consisting of saturated or unsaturated alkyl and homocyclic ring portions or heterocyclics and wherein n is 0 or 1. The term "carboxylic acid" refers to a chemical moiety with the formula - (R) n -COOH, wherein R is selected from the group consisting of saturated or unsaturated alkyl and ring heterocyclic or heterocyclic, where n is 0 or 1. The term "ester" refers to a chemical portion with the formula: - (R) n-COOR ', where R and R' are independently selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring portions and where n is 0 or 1. The term "alcohol" refers to a chemical substituent the formula: -ROH ,, where R is selected from the group consisting of hydrogen, saturated or unsaturated alkyl , and homocyclic or heterocyclic ring portions, wherein the ring portion is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, carboxylate, nitro and ester portions. The term "amide" refers to a chemical substituent of the formula -NHCOR, wherein R is selected from the group consisting of hydrogen, alkyl, hydroxyl, and heterocyclic and heterocyclic ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, thalhalomethyl, carboxylate, nitro, or ester. The term "alkoxy moiety" refers to a chemical substituent of the formula -OR, where R is hydrogen or a saturated alkyl moiety or unsaturated The term "aldehyde" refers to a chemical moiety with the formula - (R) n-CHO, wherein R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring portions and where n is 0 or 1. The term "sulfone" refers to a chemical moiety with the formula -S02-R, wherein R is selected from the group consisting of saturated or unsaturated alkyl and homocyclic or heterocyclic ring portions. In another preferred embodiment, the invention relates to an azabenzimidazole-based compound having an exposed structure in formula I, II or III, wherein Zi and Z2 are independently selected from the group consisting of nitrogen and NH. In yet another preferred embodiment, the invention relates to an azabenzimidazole-based compound having an exposed structure in formula I, II or III, wherein Ri, R2, R3 and R are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl optionally substituted with a homocyclic or heterocyclic ring portion, in wherein the ring portion is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, hydroxy, alkoxy, carboxylate, nitro, and ester moieties, and a portion of homocyclic or heterocyclic ring optionally substituted with one, two or three substituents selected independently from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, hydroxy, alkoxy, carboxylate, nitro and ester portions. In other preferred embodiments, the invention relates to a compound based on azabenzimidazole having an exposed structure in formula I, II or III, wherein R2 and R3 are hydrogen. In another preferred embodiment, the invention relates to an azabenzimidazole-based compound having the structure set forth in formula I, II or III, wherein Ri is phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro or ester portions. In yet another preferred embodiment, the invention relates to an azabenzimidazole-based compound having a structure set forth in formula I, II or III, wherein Ri is selected from the group consisting of substituents in SABI. The term "SABI" refers to a group of substituents consisting of phenyl, 2-nitophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-chloro nyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl), 4 - (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxy phenyl, 4-methoxyphenyl, 2-carboxyphenyl, 3-carboxyphenyl, and 4-carboxyphenyl. In other preferred embodiments, the invention relates to a compound based on azabenzimidazole having a structure set forth in formula I, II or III, wherein Xi is sulfur. In another preferred embodiment, the invention relates to an azabenzimidazole-based compound having a structure set forth in formula I, II or III, where Xi is oxygen. In still another preferred embodiment, the invention relates to a compound based on azabenzimidazole having an exposed structure in formula I, II or III, wherein Z3 is oxygen. In other preferred embodiments, the invention relates to an azabenzimidazole-based compound having an exposed structure in formula I, II or III, wherein R is selected from the group consisting of methyl and ethyl. In another preferred embodiment, the invention relates to a compound based on azabenzimidazole having an exposed structure in formula I, II or III, wherein the azabenzimidazole compound is selected from the group consisting of SABI compounds. In another aspect, the invention incorporates a pharmaceutical composition comprising a compound of the invention, as specified herein, or its salt, and a physiologically acceptable carrier or diluent. In another aspect, the invention relates to a pharmaceutical composition comprising a compound having a structure in formula I, II or III as defined herein or any of the subgroups of the same exposed in the present. In another preferred embodiment, the invention relates to a pharmaceutical composition, wherein the azabenzimidazole compound is selected from the group consisting of SABI compounds. The term "pharmaceutical composition" refers to a mixture of an azabenzimidazole compound of the invention with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques for administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. The pharmaceutical compositions can also be obtained by reacting the contexts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methansulonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term "physiologically acceptable" defines a carrier or diluent that does not cancel the biological activity and the properties of the compound The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethylsulfoxide (DMSO) is a commonly used carrier since it facilitates the admission of many organic compounds into the cells or tissues of an organism. The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are used as diluents in the art. A commonly used buffered solution is phosphate buffered saline because it mimics the saline conditions of human blood. Since the buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modified the biological activity of a compound.

IV. Methods of Synthesis of the Invention In another aspect, the invention relates to a method for synthesizing an azabenzimidazole compound of the formula I, II or III, comprising the steps of: (a) reacting the 2-amino- 6- chloro-3-nitropyridine with a second reagent in a solvent to produce the first intermediate, wherein the second reagent is a substituted aryl ring; (b) reducing the first intermediate compound in the presence of a catalyst and a reducing agent to produce the second intermediate; (c) reacting the second intermediate compound with a third reagent; and (d) purifying the compounds of the invention. In a preferred embodiment, the invention relates to the method for synthesizing a compound of the invention, wherein the substituted aryl ring is a substituted phenol, substituted thiophenol, and substituted aniline. In another preferred embodiment, the invention relates to the method for synthesizing a compound of the invention, wherein the substituted phenol, substituted thiophenol, and substituted aniline are selected from the group consisting of SABI reagents. The term "SABI reagents" refers to the group of reagents consisting of the sodium salt of phenol, 2-nitophenol, 3-nitrophenol, 4-nitrophenol, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol, 2-cresol, 3-cresol, 4-cresol, 2-fluorophenol, 3-fluorophenol, 4 - . 4 - . 4-fluorophenol, 2- (Tri fluorometi 1) phenol, 3- (Trif luoromet il) phenol, 4 - (Trifluoromet il) phenol, 2-methoxyphenol, 3-methoxy phenol, 4-methoxyphenol, 2-hydroxybenzoic acid, 3 -hydroxybenzoic acid, 4-hydroxybenzoic acid, thiophenol, 2-nitropyriophenol, 3-nitrothiophenol, 4-nitrothiophenol, 2-chlorothiophenol, 3-chlorotrophenol, 4-chlorotophenol, 2-thiocresol, 3-thiocresol, 4-thiocresol, 2 Fluorothiophenol, 3-fluorothiophenol, 4-fluoro-thiophenol, 2- (trifluoromethyl) thiophenol, 3- (trifluoromethyl) thiophenol, 4- (trifluoromethyl) thiophenol, 2-methoxybenzene-1-ol, 3-methoxybenzenethiol, 4-methoxybenzene-1-ol, 2- mercaptobenzoic acid, 3-mercaptobenzoic acid, acid 4-mercaptobenzoic, aniline, 2-nitroaniline, 3-n-t roaniline, 4 -nit roaniline, 2-chloroaniline, 3-chloroaniline, 4-chloroaniline, 2-toluidine, 3-toluidine, 4-toluidine, 2 -fluoroaniline, 3-f luoroaniline, 4 -fluoroaniline, 2- (Trifluoromethyl) aniline, 3- (Trifluoromethyl) aniline, 4- (Trifluoromet il) aniline, 2-anisidine, 3-anisidine, 4-anisidine, 2-aminobenzoic acid, 3-aminobenzoic acid and 4-aminobenzoic acid. In a preferred embodiment, the invention relates to the method of synthesizing a compound of the invention wherein the solvent is n-propanol. In another preferred embodiment, the invention relates to the method of synthesizing a compound of the invention, wherein the reducing agent is hydrogen. In still another preferred embodiment, the invention relates to the method of synthesizing a compound of the invention, wherein the catalyst is Raney nickel. In yet another preferred embodiment, the invention relates to the method of synthesizing a compound of the invention, wherein the third reagent is O-methylisourea. In another preferred embodiment, the invention relates to the method of synthesizing a compound of the invention, wherein the third reagent is the product of the reaction of S-methylisothiouronium sulfate and alkyl chloroformate. In yet another preferred embodiment, the invention relates to the method of synthesizing a compound of the invention, wherein the alkyl chloroformate is methyl chloroformate. In yet another preferred embodiment, the invention relates to the method of synthesizing a compound of the invention, wherein the alkyl chloroformate is ethyl chloroformate. The brief description of the invention described above is not limiting and other features and advantages of the invention will be apparent from the following description of the preferred embodiments, and from the claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is directed in part towards methods for modulating the function of serine / threonine protein kinases with azabenzimidazole-based compounds. In addition, the invention relates in part to methods for identifying compounds that modulate the function of the serine / threonine protein kinases. The methods incorporate cells that express a serine / threonine protine kinase, such as RAF. RAF is a non-receptor protein kinase which binds to the cell membrane when bound to the activated RAS, a guanine triphosphate hydrolyzing enzyme. RAS is activated when an activated, activated receptor tyrosine kinase, such as EGFR or PDGFR, binds to an adapter protein, GRB2, and a guanine nucleotide exchange factor, SOS. The SOS removes the guanine diphosphate from the RAS, replaces it with a guanine triphosphate, and thus activates the RAS. The RAS then joins RAF and consequently activates the RAF. The RAF can then phosphorylate other protein targets in the serine and threonine residues, such that the kinase (MEK) phosphorylates and consequently activates the mitogen-activated protein kinase (MAPK). In this way, the RAF serves as an intermediate control factor in signal transduction activated by mitogen. Due to the important regulatory role of RAF in cells, modifications to the amino acid sequence of RAF can alter its function and consequently modify cellular behavior. The role of RAF in cell proliferation is accentuated by the observation that mutations to the amino acid sequence of RAF have been associated with tumors and cancers. Because the mutations to RAF that cause cancer in cells lead to RAF molecules that exhibit unregulated catalytic activity, the RAF inhibitors can mitigate or even cancel the cell proliferation that leads to cancer in this cell. The methods of the present invention can detect compounds that modulate the function of the protein kinase RAF in cells. The RAF phosphorylates a protein kinase (MEK) which in turn phosphorylates the mitogen-activated protein kinase (MAPK). The assays that monitor only the phosphorylation of MEK by RAF are not sensitive because the MEK phosphorylation levels are not significant. To overcome this sensitivity dilemma, the phosphorylation of both MEK and MAPK are followed in the assays of the present invention. The MAPK phosphorylation signal amplifies the MEK phosphorylation signal and allows RAF-dependent phosphorylation to be followed in immunosorbent assays linked to enzymes. In addition, the assay of the invention is preferably carried out in a high format such that many compounds can be easily monitored in a short period of time.

The methods of the present invention have identified compounds that inhibit the function of the protein kinase RAF. These compounds are derivatives based on azabenzimidazole. Although azabenzimidazole-based derivatives have been tested for their ability to inhibit enzymes comprised of nucleotide synthesis in bacteria, many of these compounds have not yet been explored in any significant way with respect to protein kinase inhibition. Because the RAF exhibits significant amino acid homology to other protein serine / threonine kinases, the azabenzimidazole-based compounds of the invention can also inhibit serine / threonine protein kinases other than RAF. In this manner, the methods of the invention also relate to serine / threonine protein kinases different from RAF, including the serine / threonine receptor and non-receptor protein kinases. The methods of the invention are also suitable for other compounds that modulate the function of RAF in cells since the high throughput aspect of the methods allows a wide array of molecules to be tested in a short time frame. Therefore, the methods of the invention can identify the existing molecules, not described in the present invention, that modulate the STK function.

I. Biological activity of azabenzimidazole-based compounds The azabenzimidazole-based compounds of the present invention were tested for their ability to inhibit the function of the protein kinase RAF. The biological assays and the results of these inhibition studies are reported here. The methods used to measure the modulation of the azabenzimidazole-based compound of the protein kinase function are similar to those described in U.S. Patent Application Serial No. 8 / 702,232, by Tang et al., And entitled " Indolinone Combinatorial Librarles and Related Products and Methods for the Treatment of Disease, "(Lyon &; Lyon document number 221/187), filed on August 23, 1996, regarding the high performance aspect of the method. The application 08/702, 232 'is incorporated herein by reference in its entirety, including any of the drawings. 11 • Target diseases to be treated by the azabenzimidazole-based compounds The methods, compounds, and pharmaceutical compositions described herein are designed to inhibit cell proliferation disorders by modulating the function of the protein kinase RAF. Proliferative disorders result in unwanted cell proliferation of one or more subsets of cells in a multicellular organism, resulting in damage to the organism. The methods, compounds and pharmaceutical compositions described herein may also be useful for treating and preventing other disorders in organisms, such as disorders related to premature cell death (i.e., neurological diseases) or inflammation. These disorders can be the result of RAF molecules that function inappropriately or the result of protein-kinase molecules related to RAF that function inappropriately. Alterations in the function of the protein kinase RAF or protein kinases related to RAF can lead to conditions of cellular proliferation, improved or diminished, evident in certain diseases. Abnormal cell proliferation conditions include cancers, fibrotic disorders, mesangial disorders, abnormal angiogenesis and vasculogenesis, wound healing, psoriasis, restenosis and inflammation. Fibrotic disorders are related to the abnormal formation of the extracellular, cellular matrix. An example of a fibrotic disorder is liver cirrhosis. Liver cirrhosis is characterized by an increased concentration of constituents of the extracellular matrix resulting in the formation of a hepatic scar. Liver cirrhosis can cause diseases such as cirrhosis of the liver. Mesanguial cell proliferative disorders occur due to abnormal proliferation of mesangial cells. Mesanguial proliferative disorders include several human kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrolesclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies. Preferred types of cancers that can be treated by the methods and compounds of the invention are lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, sarcoma of Kaposi, melanoma, and glioma. The evidence that the compounds and methods of the invention can be used effectively to lower and reverse the proliferation of cancer cells is provided herein as a reference. Angiogenic and vasculogenic disorders result from the excessive proliferation of blood vessels. The proliferation of blood vessels is necessary in a variety of normal physiological processes such as embryonic development, the formation of corpora lutea, wound healing and organ regeneration. However, the proliferation of blood vessels is also essential in the development of cancer tumors. Other examples of blood vessel proliferative disorders include arthritis, where new capillary blood vessels invade the joint and destroy the cartilage. In addition, proliferative diseases of blood vessels include ocular diseases, such as diabetic retinopathy, where new capillaries in the retina invade the vitreous body, bleed and cause blindness. Conversely, disorders related to shrinkage, contraction or closure of blood vessels, such as restenosis, are also implicated in the adverse regulation of protein kinases. In addition, vasculogenesis and angiogenesis are associated with the growth of solid, malignant and metastatic tumors. A tumor of vigorous growth cancer requires nutrients and a blood supply rich in oxygen to continue growing. As a consequence, an abnormally large number of capillary blood vessels frequently grows according to the tumor and acts as delivery lines to the tumor. In addition to supplying nutrients to the tumor, new blood vessels embedded in the tumor provide a gateway for tumor cells to enter the circulation and metastasize to distant sites in the body. Folkman, 1990, Na t i. Can cer Ins t. 82: 4-6. Inappropriate activity of RAF can stimulate cell proliferation disorders. Molecules specifically designed to modulate the function of the RAF protein kinase have been shown to inhibit cell proliferation. Specifically, anti-sense nucleic acid molecules, which are designed both to bind messenger RNA that encodes protein kinase RAF, and to block the translation of that messenger, effectively reversed the transformation of A549 cells in vi t ro Monia et al., 1996, Na ture Medi cine 2: 688, incorporated herein by reference in its entirety including all figures and tables. A549 cells are malignant or bad cells. These anti-sense studies directed to RAF provide evidence that the azabenzimidazole molecules of the invention, which modulate the function of the protein kinase RAF, can lower and probably reverse the proliferation of malignant cells in an organism. These azabenzimidazole compounds can be tested in the in vi tro methods provided herein by way of example. Additionally, the azabenzimidazole compounds can be tested for their effect on tumor cells in vivo by the xenograft methods also provided herein as examples. There are at least two ways in which the inappropriate activity of RAF can stimulate the undesired cell proliferation of a particular type of cells: (1) directly stimulate the growth of the particular cell or (2) increase the vascularization of a particular area, such as tumor tissue, thereby facilitating tissue growth. The use of the present invention is facilitated by first identifying whether the cell proliferation disorder is driven by RAF. Once these disorders are identified, patients suffering from this disorder can be identified by analysis of their symptoms using well-known procedures for practitioners or veterinarians skilled in the art. These patients can then be treated as described herein. The determination if the cell proliferation disorder is activated by RAF can be achieved by first determining the level of RAF that occurs in the cell or at a particular location in a patient's body. For example, in the In the case of cancer cells, the level of one or more RAF activities can be compared for cancers not activated by RAF of cancers activated by RAF. If the cancer cells have a higher level of RAF activity than the RAF-activated cancers, preferably equal to or greater than RAF-activated cancers, then they are candidates for treatment using the modulation methods of RAF and compounds of the invention . In the case of cell proliferation disorders that arise due to the undesired proliferation of non-cancer cells, the level of activity of RAF is compared to that of the level that occurs in the general population (for example, the average level that occurs in the general population of people or animals including those people or animals suffering from a cell proliferative disorder). If the undesired cell proliferation disorder is characterized by a higher level of RAF occurring in the general population, then the disorder is a candidate for treatment using the described RAF modulation methods and compounds of the invention.

III. Pharmaceutical compositions and administration of azabenzimidazole-based compounds Methods for preparing pharmaceutical formulations of the compounds, methods for determining the amounts of the compounds to be administered to a patient, and ways of administering the compounds to an organism, are described in U.S. Patent Application Serial No. 08 / 702,232, by Tang et al., and entitled "Indolinone Combinatorial Libraries and Related Products and Methods for the Treatment of Disease," (Lyon &Lyon Document Number 221/187), filed on August 23, 1996, international patent publication number WO 96/22976 of Buzzetti et al., entitled "Hydrosoluble 3-Arylidene-2-Oxindole Derivatives as Tyrosine Kinase Inhibitors", published August 1, 1996, both of which are incorporated herein by reference in their entirety, including any of the drawings. Those skilled in the art will appreciate that these descriptions are applicable to the present invention and can be easily adapted to it.

Examples The examples below are non-limiting and only representative of the various aspects and features of the present invention. The examples describe methods for synthesizing compounds of the invention and methods for measuring the effect of a compound on the function of the protein kinase RAF. The cells used in the methods are commercially available. Nucleic acid vectors carried by the cells are also commercially available and the gene sequences for the various protein kinases are readily accessible in the sequence data banks. In this way, a person skilled in the art can easily recreate cell lines in a timely manner by combining commercially available cells, commercially available nucleic acid vectors and protein kinase genes using techniques readily available to persons skilled in the art. technique.

Example 1: Procedures for synthesizing azabenzimidazole compounds of the invention The invention will be illustrated in the following non-limiting examples in which, unless stated otherwise: (i) the evaporations were carried out by a rotary operation under vacuum; (ii) the operations were carried out under an atmosphere of inert gas such as nitrogen; (iii) High performance liquid chromatography (HPLC) was performed on Merck LiChrosorb inverted phase RP-18 silica obtained from E.

Merck, Darmstadt, Germany. (iv) returns are given by illustration only and are not necessarily the maximum achievable; (v) the melting points are not corrected and were determined using the HWS Mainz SG 2000 digital melting point apparatus; (vi) the structures of all the compounds of formula I, II and III of this invention were confirmed by proton magnetic resonance spectroscopy in a Bruker AMX500-NMR spectrophotometer, by elemental analysis and, in certain cases, by spectroscopy of dough; (vii) the purity of the structures is performed by thin layer chromatography (TLC) using silica gel (Merck 60 F254 silica gel) or by HPLC; and (viii) the intermediates were not characterized completely completely and the purity was assessed by thin layer chromatography (TLC) or by HPLC.

Synthetic Procedures Compound or A-90 2-Oxycarbonylamino- (6-phenylimcapto-3H-imidazo [4, 5-J] pyridine 2-amino-3-nitro-6- (phenylmercapto) pyridine was prepared by heating 2-amino-6 -chloro-3-nit ropyridine (84.0 g, 0.484 mol) and thiophenolate sodium (Fluka) (72.0 g, 0.545 mol) in 2-propanol (1500 mL) under reflux for 2 hours.After cooling to room temperature, the The suspension was diluted with water (100 ml), the solid was collected by vacuum filtration, washed with water and 2-propanol, dried at 50 ° C under vacuum to give 109.1 g (95% yield) of 2-amino -3-nitro-6- (phenylmercapto) pyridine, mp 148-152 ° C). 2, 3-diamino-6- (phenylmercapto) pyridine was prepared by hydrogenating 2-amino-3- nitro-6- (phenylmercapto) pyridine (107.1 g, 0.433 mol) under 5 atmospheres of H2 in the presence of 30 g of Raney nickel in 1,200 mL of 2-propanol at 70 ° C. After 4 hours (29.1 L of hydrogen) the reaction mixture was cooled to 4 ° C while stirring continuously. The precipitate was collected by vacuum filtration, washed with 2-propanol and dried at 50 ° C under vacuum. The combined filtrates were concentrated under reduced pressure and recrystallized from 2-propanol. After washing the hydrogenation apparatus twice with 1,000 mL of THF, evaporating under reduced pressure and recrystallizing from 2-propanol, the precipitate was collected and dried at 50 ° C under vacuum to give 80.4 g (87.1%) of yield) of 2,3-diamino-6- (phenylmercapto) pyridine, mp 119-122 ° C). The 2-methoxycarbonylamino-6-phene Imercapto-3 H-imidazo [4, 5-b] pyridine was prepared by adding methyl chloroformate (34 mL, 0.44 mol) dropwise to a cold solution (5-15 ° C) of S-metilisot iouronium sulfate (53 g, 0.19 mol) (Aldrich) in 68 L of water, while the temperature was kept below 20 ° C. Subsequently, aqueous sodium hydroxide was added carefully (116 g, 25% NaOH) and a white precipitate appeared. After 20 minutes, water was added (210 mL) and the pH was adjusted to 4.0 with acetic acid (glacial, 34 mL). To this mixture was added dropwise the solution of 2,3-diamino-6- (phenylmercapto) pyridine (37.8 g, 0.174 mol) in 210 mL of ethanol, it was heated at 85-90 ° C for two hours. After cooling the reaction mixture overnight, the precipitate was isolated by precipitation, washed with hot water (1000 mL), dried and recrystallized from acetic acid and ethanol at 4 ° C. The precipitate was collected by filtration, washed with methanol and dried at 50 ° C under vacuum to give 30 g (57.4% yield) of 2-methoxycarbonylamino-6-phenylmercapto-3ff-imidazo [4,5-b] pyridine. , pf 269-274 ° C (decomposition).

Compound A-3: 2-Methoxycarbonylamino- (6-phenoxy) -3H-imidazo [4-5-J] pyridine Substituting sodium phenolate for sodium thiophenolate in Example A-90, the identical process gives the 2-methoxycarbonylamino- (6-phenoxy) -3-7-imidazo [4 -5-¿> ] pyridine, p.f > 280 ° C (decomposition).

Compound A-4: 2-Ethoxycarbonylamino-6-phenoxy) -3H-imidazo [4-5-2?] Pyridine Substituting the ethyl chloroformate for methyl chloroformate in Example A-3, the identical process gives 2 -ethoxycarbonylamino- (6-phenoxy) -3i? -imidazo [4-5-j] pyridine, mp > 280 ° C (decomposition).

Compound Al: 2 -Oxo-6-phenoxy-35-imidazo [4-5-b] pyridine When reacting O-methylisourea directly with 2,3-diamino-6- (phenamercapto) pyridine instead of the product of the reaction of S-methylisothiouronium sulfate and methyl chloroformate in Example A-3, the identical process gives 2 -oxo- (6-phenoxy-3 H-imidazo [4 -5-j] pyridine, mp 277-278 ° C .

Compound A-2: 2-Oxo-6-phenyl-mercapto-3H-imidazo [4-5-Jb] pyridine By substituting sodium thiophenolate for sodium phenolate in Example Al, the identical process gives 2 -oxo- (6 phenyl-mercapto-3-fimidazo [4 -5-jpyridine, mp 253-254 ° C.

Compounds A-5 A-25 Substituting the appropriate phenolate for sodium phenolate in Example A-1, the identical process gives the following examples. For examples A-23, A-24, and A-25, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl, or other suitable ester and then deprotected in the last step to give the compounds.

A-5 2-Oxo-6- (2-nitrofenoxi) -3H-imidazo [4, 5-j] pyridine A- 6 2-Oxo-d- (3-nitrophenoxy) -3H-imidazo [4, 5 > ] pyridine A-7 2-Oxo-6- (4-n-trofenoxy) -3H-imidazo [4, 5-b] pyridine A- 8 2 -Oxo- 6- (2-chloro-enoxy) -3 fimidazo [4,5-b] pyridine A-9 2-Oxo-6- (3-chlorophenoxy) -3H-imidazo [4, 5-b] pyridine A-10 2-Oxo-6- (4-chlorophenoxy) -3H - imidazo [4, 5-b] pyridine A-ll 2-Oxo-6- (2-methylphenoxy) - 3 H- imidazo [4, 5-b] pyridine A-12 2-Oxo-6- (3-methylphenoxy) -3H- imidazo [4, 5-b] pyridine A- 13 2-0xo-6- (4-methyl-enoxy) -3 H- imidazo [4,5- b] pyridine A- 14 2-Oxo-6- ( 2-fluorophenoxy) -3 H- imidazo [4,5-b] pyridine A- 15 2-Oxo-6- (3-fluorophenoxy) -3 H- imidazo [4, 5-b] pyridine Al 6 2-Oxo- 6- (4-fluorophenoxy) -3 H- imidazo [4, 5 b] pyridine A- 17 2-0XO-6- [2- (trifluoromethyl) phenoxy] -3 H- imidazo [4, 5-b] pyridine A- 18 2-Oxo-6- [3- (trifluoromethyl) phenoxy] -3 H - imidazo [4, 5-Jb] pyridine A- 19 2-0xo-6- [4- (trifluoromethyl) phenoxy] -3 H- imidazo [4, 5-b] pyridine A-20 2-Oxo-6- ( 2-methoxyphenoxy) -3 H- imidazo [4,5-?] Pyridine A-21 2-Oxo-6- (3-methoxyphenoxy) -3 H- imidazo [4, 5-jb] pyridine A-22 2- Oxo-6- (4-methoxyphenoxy) -3 H- imidazo [4, 5-jb] pyridine A-23 2-Oxo-d- (2-carboxyphenoxy) -3 H- imidazo [4, 5-Jb] pyridine A -24 2-Oxo-6- (3-carboxyphenoxy) -3 H- imidazo [4, 5-b] pyridine A-25 2-Oxo-6- (4-carboxyphenoxy) -3 H- imidazo [4,5- b] pyridine Compounds A-26 A-46 By substituting the appropriate thiophenolate for thiophenolate sodium in Example A-2, the identical process gives the following examples. For examples A-44, A-45, and A-46; the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl, or another suitable ester and then deprotected in the last step to give the compounds.

A-26 2-0xo-6- (2-nitrophenylmercapto) -3 H- imidazo [4,5- b] pyridine A- 21 2-0xo-6- (3-nitrophenylmercapto) -3 H- imidazo [4, 5 - b] pyridine A-28 2-0xo-6- (4-nitrophenylmercapto) -3 H- imidazo [4, 5-b] iridine A-29 2-Oxo-6- (2-chloro-phenylmercapto) -3 H- imidazo [4, 5-b] pyridine A- 3 O 2 -Oxo-6- (3-chlorophenylmercapto) -3 H-imidazo [4,5- b] iridine A- 31 2-Oxo-d- (4-chlorophenyl mercapto) ) -3 H-imidazo [4, 5-jb] pyridine A-32 2-Oxo-6- (2-methylphenumereapto) -3i-imidazo [4, 5-eq. ] pyridine A- 33 2-Oxo-6- (3-methyl-phenylmercapto) -3H-imide zo [4, 5-jb] pyridine A-34 2-Oxo-6- (4-methylphenumereapto) -3 H- imidazo [ 4, 5- jb] pyridine A-35 2-Oxo-6- (2-fluorophenylmercapt o) - 3 H- imidazo [4, 5-¿> ] pyridine A-36 2-Oxo-d- (3-fluorophenylmercapto) -3 H- imidazo [4,5-jb] pyridine A- 31 2-Oxo-d- (4-fluorophenylmercapto) -3 H- imidazo [4, 5- £ > ] pyridine A-38 2-Oxo-6- [2- (trifluoromethyl) phenylmercapto] - 3 H- imidazo [4, 5-b] pyridine A- 39 2-Oxo-6- [3- (trifluoromethyl) phenylmercapto] - 3-imidazo [4, 5-jb] pyridine A-40 2-Oxo-β- [4- (trifluoromethyl) phenylmercapto] -3 H- imidazo [4, 5 -b] pyridine A-41 2-Oxo-6 - (2-methoxy phenylmercapto) -3 H- imidazo [4, 5-jb] pyridine A-42 2-Oxo-6- (3-methoxy pheni lmercapto) -3H-imidazo [4, 5 -jb] pyridine A- 43 2-Oxo-6- (4-methoxyphenylmercapto) -3 H- imidazo [4, 5-jb] pyridine A-44 2-Oxo-6- (2-carboxyphenylmercapto) -3 H- imidazo [4, 5-b ] pyridine A-45 2-Oxo-6- (3 -carboxy phenylmercapto) -3 H- imidazo [4, 5-jb] pyridine A-46 2-Oxo-6- (4-carboxyphenylmercapto) -3 H- imidazo [ 4, 5 -.ib] pyridine Compounds A-47 A-68 By substituting the appropriate aniline salt for sodium phenolate in Example A-1, the identical process gives the following examples. For the Examples A-66, A-67, and A-68, carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl or other suitable ether then deprotected in the last step to give the compounds.

A- 47 2 -Oxo- 6-phenylamino-3? -imidazo [4, 5-b] pyridine A-48 2-Oxo-6- (2-nitrophenylamino) -3 H-imidazo [4,5- j] pyridine A- 49 2-Oxo-6- (3-nitrophenylamino) -3 H-imidazo [4, 5-jb] pyridine A-50 2-Oxo-6- (4-nitrophenylamino) -3 H-imidazo [4 , 5- jb] pyridine A- 51 2-Oxo-6- (2-chloro-phenylamino) -3 H- imidazo [4, 5-jb] pyridine A-52 2 -Oxo- 6- (3-chloro-phenylamino) - 3 H- imidazo [4, 5-jb] pyridine A-53 2-Oxo-d- (4-chlorophenylamino) -3 H- imidazo [4, 5-jb] pyridine A-54 2-Oxo-d- (2 -methyl phenylamino) -3 H- imidazo [4, 5-jb] pyridine A-55 2-Oxo-6- (3-methylphenylamino) -3 H- imidazo [4, 5-jb] pyridine A-56 2-Oxo -β- (4-methylphenylamino) -3 H- imidazo [4,5- j] pyridine A-57 2-Oxo-6- (2-fluorophenylamino) -3 H-imidazo [4, 5-jb] pyridine A-58 2-Oxo-6- (3-fluorophenylamino) -3 H-imidazo [4, 5 - 2?] Pyridine A-59 2-Oxo-d- (4-fluorophenylamino) -3 H- imidazo [4, 5 j] pyridine A- 60 2-Oxo-6- [2- (trifluoromethyl) phenylamino] - 3H- imidazo [4, 5-jb] pyridine A- 61 2-Oxo-6- [3 (trifluoromethyl) phenylamino] -3 H- imidazo [4, 5-jb] pyridine A- 62 2-OXO-6- [ 4- (trifluoromethyl) phenylamino-3 H- imidazo [4, 5-b] pyridine A- 63 2-Oxo-6- (2-methoxy phenylamino) -3 H- imidazo [4,5- jb] pyridine A-64 2-Oxo-6- (3-methoxyphenylamino) -3 H- imidazo [4, 5 jb] 'pyridine A-65 2-Oxo-6- (4-methoxyphenylamino) -3 H- imidazo [4, 5 b ] pyridine A-66 2-Oxo-d- (2-carboxy-phenylamino) -3H-imidazo [4, 5-> ] pyridine A- 61 2-Oxo-d- (3-carboxyphenylamino) -3 H- imidazo [4, 5-b] pyridine A- 68 2-Oxo-6- (4 -carboxy-phenylamino) -3 H- imidazo [4,5- jb] pyridine Compounds A-69 A-89 Substituting the appropriate phenolate for sodium phenolate in Example A-3, the identical process gives the following examples. For examples A-87, A-88, and A-89, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl, or other suitable ester and then deprotected in the last step to give the compounds.

A-69 2-Methoxycarbonylamino-6- (2-nitrophenoxy) - 3 - Timo z or [4, 5-b] pyridine A-70 2-Methoxycarbonylamino-β- (3-nitrophenoxy) -3 H -imidazo [4,5-jb] pyridine A- 1 2-methoxycarbonylamino- 6- (4-nitrophenoxy) -3H - imidazo [4, 5-jb] pyridine A-72 2-Methoxycarbonylamino-6- (2-chlorophenoxy) - 3 H- imidazo [4, 5-jb] pyridine A-73 2-Methoxycarbonylamino-β- (3-chlorophenoxy) ) - 3 H- imidazo [4, 5-b] pyridine A- 1 4 2-methoxycarbonylamino-6- (4-chlorophenoxy) -3H-imidazo [4, 5-jb] pyridine A-75 2-methoxycarbonylamino-6 (2-methylphenoxy) - 3 H- imidazo [4, 5 -jb] pyridine Al 6 2-Methoxycarbonylamino-6- (3-methylphenoxy) -3-imidazo [4,5-jb] pyridine A-77 2-methoxycarbonylamino- 6 - (4-methylphenoxy) -3 H- imidazo [4, 5 -b] pyridine A-78 2-Methoxycarbonylamino-6 - (2-fluorophenoxy) -3-imidazo [4, 5 &] pyridine A- 1 9 2-Methoxycarbonylamino-6- (3-fluorophenoxy) -3- imidazo [4, 5-jb] pyridine A-80 2-methoxycarbonylamino- 6 - (4-fluorophenoxy) -3 H- imidazo [4, 5-b] pyridine A-81 2-methoxycarbonylamino-6-12 - (trifluoromethyl) phenoxy] -3 H- imidazo [4, 5-b] pyridine A-82 2-Methoxycarbonylamino-6 - [3- (trifluoromethyl) phenoxy] -3 H- imidazo [4, 5-b] pyridine A-83 2- Methoxycarbonylamino-6 - [4- (trifluoromethyl) phenoxy] -3 H- imidazo [4, 5-jb] pyridine A-84 2-Methoxycarbonylamino-β - (2-methoxyphenoxy) - 3 H- imidazo [4,5-jb ] pyridine A-85 2-Methoxycarbonylamino-6 - (3-methoxyphenoxy) -3-imidazo [4, 5-jb] pyridine A-86 2-Methoxycarbonylamino-6 - (4-methoxyphenoxy) - 3 H- imidazo [4, 5-b] pyridine A-87 2-Methoxycarbonylamino-6- (2-carboxyphenoxy) -3 H- imidazo [4, 5-jb] pyridine A-88 2-Methoxycarbonylamino-6- (3-carboxyphenoxy) -3 H- imidazo [4, 5 -jb] pyridine A-89 2-Methoxycarbonylamino-6- (4-carboxyphenoxy) -3 H- imidazo [4,5-b] pyridine Compounds A-91-A-III When substituting the appropriate thiophenolate for thiophenolate sodium in Example A-90, the identical process gives the following examples. For examples A-109, A-110, and A-III, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl, or other suitable ester and then deprotected in the last step to give the compounds.

A-91 2-Methoxycarbonylamino-6- (2-nitrophenylmercapto) -3 H- imidazo [4, 5-jb] pyridine A-92 2-Methoxycarbonylamino-6- (3-nitrophenyl mercapto) -3 H- imidazo [4, 5 -jb] pyridine A- 93 2-methoxycarbonylamino- 6- (4-nitrophenyl mercapto) -3 H- imidazo [4,5-b] pyridine A- 94 2-methoxycarbonylamino -6- (2-chlorophenyl mercapto) - 3 H- imidazo [4,5-ib] pyridine A-95 2-Methoxycarbonylamino-6- (3-chlorophenyl mercapto) -3 H- imidazo [4, 5-ib] pyridine A-96 2-methoxycarbonylamino-6- (4-chlorophenyl mercapto) -3 H- imidazo [4 , 5 -ib] pyridine A-97 2-Methoxycarbonylamino-6- (2-methyl phenylmercapto) -3? - imidazo [4, 5 -b] pyridine A-98 2-Methoxycarbonylamino-6- (3-methyl-phenyl-mercapto) - 3 H- imidazo [4, 5-b] pyridine A-99 2-methoxycarbonylamino-6- (4-methyl-phenyl-mercapto) -3 H- imidazo [4,5-b] pyridine A-100 2-methoxycarbonylamino- 6- ( 2-f-fluorophenyl mercapto) -3-fimidazo [4, 5-b] pyridine A-101 2-methoxycarbonylamino-6- (3-fluorophenyl mercapto) -3 H-imidazo [4, 5-¿> ] pyridine A-102 2-Methoxycarbonylamino-6- (4-fluoro-phenylmercapto) -3 H- imidazo [4, 5-jb] pyridine A-103 2-methoxycarbonylamino-6- [2- (trifluoromethyl-phenylmercapto] -3-imidazo [4,5-Ib] pyridine A-104 2-Methoxycarbonylamino-6- [3 (trifluoromethyl) • phenylmercapto] -3 H- imidazo [4, 5-ib] pyridine A-105 2-Methoxycarbonylamino-6- [4 (trifluoromethyl) • phenylmercapto] - 3 H- imidazo [4, 5-ib] pyridine A-106 2-Methoxycarbonylamino-6- (2-methoxyphenylmercapto) -3 H- imidazo [4,5-b] pyridine A-107 2 -Metoxicarbonylamino- 6- (3-methoxyphenylmercapto) -3 H- imidazo [4, 5-ib] pyridine A-108 2-methoxycarbonylamino-6- (4-methoxyphenyl mercapto) -3 H- imidazo [4 , 5-Ib] pyridine A-109 2-methoxycarbonylamino- 6- (2-carboxyphenylmercapto) -3 H- imidazo [4, 5-b] pyridine A-110 2-methoxycarbonylamino- 6- (3-carboxyphenyl mercapto) -3 H - imidazo [4, 5 -ib] pyridine A-III 2-methoxycarbonylamino-6- (4-carboxymethylmercapto) -3 H- imidazo [4, 5-ib] pyridine Compounds A-112-A-133 When replacing the appropriate aniline salt with sodium phenolate in Example A-3, the identical process gives the following examples. For examples A-131, A-132, and A-133, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl, or other suitable ester and then deprotected in the last step to give the compounds.

A- 112 2-Methoxycarbonylamino-6-phenylamino-3H-i idazo [4, 5-A-112 A- 113 2-Methoxy carbonylamino- 6- (2-nitrophenylamino) 3 H- imidazo [4, 5-ib] pyridine A-114 2-Methoxycarbonylamino-6- (3-nitrophenylamino) -3 H- imidazo [4, 5-jb] pyridine A-115 2-Methoxycarbonylamino-6- (4-nitrophenylamino 3 H- imidazo [4, 5-ib ] pyridine A-116 2-Methoxycarbonylamino-6- (2-chlorophene lamino-3 H- imidazo [4, 5-ib] pyridine A-117 2-Methoxycarbonylamino-6- (3-chlorophenylamino) -3-imidazo [4, 5-Ib] pyridine A-118 2-Methoxycarbonylamino-6- (4-chlorophenylamino) -3-imidazo [4,5-? G] pyridine A-119 2-methoxycarbonylamino-6- (2-methylphenylamino) -3,5 imidazo [4,5-IbJpyridine A-120 2-Methoxycarbonylamino-β- (3-methylphenylamino) -3-imidazo [4, 5-Ib] pyridine A-121 2 -Met oxycarbonylamino- 6- (4-methyphenylamino) - 3 H- imidazo [4, 5-Ib] pyridine A-122 2-Methoxycarbonylamino-6- (2-fluorophenylamino) 3 H-imidazo [4, 5-Ib] pyridine A-123 2-Methoxycarbonylamino-6- (3 - fluorophenylamino) - 3 H-imidazo [4, 5-ib] pyridine A-124 2-Methoxycarbonylamino-6- (4-fluoro-phenylamino) -3i'-imidazo [4,5-b] pyridine A-125 2-methoxycarbonylamino- d- [2 - (trifluoromethyl) phenylamino] -3 H- imidazo [4, 5-b] pyridine A-126 2-Methoxycarbonylamino-6- [3 - (trifluoromethyl) -phenylamino] -3 H- imidazo [4, 5-b] pyridine A-127 2-Methoxycarbonylamino-6- [4 - (trifluoromethyl) -phenylamino] - 3 H- imidazo [4,5-b] pyridine A-128 2-Methoxycarbonylamino-6- (2-methoxyphenylamino) -3 H- imidazo [4, 5-Ib] pyridine A-129 2-Methoxycarbonylamino-6- (3 -methoxyphenylamino) -3 H-imidazo [4, 5-b] pyridine A-130 2-Methoxycarbonylamino-6- (4-methoxyphenylamino) -3 H- imide zo [4, 5-ib] pyridine A-131 2-Methoxycarbonylamino -6- (2-Carboxyphenylamino) -3 H- imidazo [4,5-ib] pyridine A-132 2-methoxycarbonylamino-6- (3-carboxy-phenylamino) -3 H-imidazo [4, 5-ib] pyridine A -133 2-Methoxycarbonylamino-6- (4-carboxyphenylamino) -3 H-imidazo [4, 5-ib] pyridine Compounds A-134-A-154 By substituting the appropriate phenolate for sodium phenolate in Example A-4, the identical process gives the following examples. For examples A-152, A-153, and A-154, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl ester, or other suitable ester and then deprotected in the last step to give the compounds A-134 2-Ethoxycarbonylamino-6 - (2-nitrophenoxy) -3 H- imidazo [4, 5-ib] pyridine A-135 2-Ethoxycarbonylamino- 6 - (3-nitrophenoxy) -3 H- imidazo [4, 5 -ib] pyridine A-136 2-Ethoxycarbonylamino- 6 - (4-nitrophenoxy) -3 H- imidazo [4, 5-a] pyridine A-137 2-Ethoxycarbonylamino-6 - (2-chlorophenoxy) -3H-imidazo [ 4,5-b] pyridine A-138 2-Et oxycarbonylamino-6 - (3-chlorophenoxy) -3 H- imidazo [4, 5-ib] pyridine A-139 -2-Ethoxycarbonylamino-6-chlorophenoxy) -3 H- imidazo [4,5-b] pyridine A-140 2-Ethoxycarbonylamino-6 - (2-methyl-phenoxy) -3 H- imidazo [4, 5-Ib] pyridine A-141 2-Ethoxycarbonylamino- 6 3-met ilfenoxi) - 3 H- imidazo [4, 5-ib] pyridine A-142 2-Ethoxycarbonylamino-6 - (4-methylphenoxy) -3 H- imidazo [4, 5-ib] pyridine A-143 2-Ethoxycarbonylamino-6 - (2-fluorophenoxy) -3 H- imidazo [4, 5-Ib] pyridine A-144 2-Ethoxycarbonylamino-6 - (3-fluorophenoxy) -3H-imidazo [4, 5-ib] pyridine A-145 2-Ethoxycarbonylamino-6- (4-fluorophenoxy) -3 H- imidazo [4, 5-Ib] pyridine A-146 2-Ethoxycarbonylamino-6- [2- (trifluromethyl) phenoxy] - 3 H- imidazo [4, 5-b] pyridine A-147 2-Ethoxycarbonylamino-6- [3- (trifluoromethyl) phenoxy] -3 H- imidazo [4, 5-b] pyridine A-148 2-Ethoxycarbonylamino-6- [4 - trifluoromethyl) phenoxy] -3H-imidazo [4,5- b] pi ridine A-149 2-Ethoxycarbonylamino-6- (2-methoxyphenoxy) -3 H- imidazo [4, 5-b] pyridine A-150 2-Ethoxycarbonylamino -6- (3-methoxyphenoxy) -3 H- imidazo [4, 5-ib] pyridine A-151 2-Ethoxycarbonylamino-6- (4-methoxyphenoxy) -3H-imidazo [4, 5-ib] pyridine A-152 2-Ethoxycarbonylamino-β- (2-carboxyphenoxy) -3 if-imidazo [4,5-ib] pyridine A-153 2-Ethoxycarbonylamino-β- (3-carboxyphenoxy) -3H-imidazo [4,5-jb] pyridine A-154 2-Ethoxycarbonylamino-6- (4-carboxyphenoxy) - 3 H- imidazo [4, 5-ib] pyridine Compounds A-155-A-176 When substituting the appropriate thiophenolate for sodium phenolate in Example A-4, the identical process gives the following examples. For examples A-174, A-175, and A-176, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl ester, or other suitable ester and then deprotected in the last step to give the compounds .

A-155 2-Ethoxycarbonylamino-6-phenylmercapto) -3 H- imidazo [4, 5-ib] pyridine A-156 2-Ethoxycarboni lamino-6- (2-nitrophenylmercapto) -3 H- imidazo [4,5-ib ] pyridine A-157 2-Ethoxycarbonylamino-6- (3-nitrophenylmercapto) -3 H-imidazo [4, 5-ib] pyridine Al 58 2 -ethoxycarbonylamino- 6- (4-nitrophenyl mercapto) -3 H-imidazo [4, 5-Ib] pyridine A-159 2-Ethoxycarbonylamino- 6- (2-chlorophenyl mercapto) -3 H- imidazo [4, 5-ib] pyridine A-160 2-Ethoxycarbonylamino-6- (3-chlorophenyl mercapto) -3ii- imidazo [4,5-Ib] pyridine Al 61 2-Ethoxycarbonylamino- 6- (4-chlorophenyl mercapto) -3 H- imidazo [4,5-ib] pyridine A-162 2-Ethoxycarbonylamino-6- (2-methylphenyl mercapto) -3 H-imidazo [4, 5-ib] pyridine A-163 2-Ethoxycarbonylamino-6- (3-methylphenyl mercapto) -3 iimidazo [4,5-Ib] pyridine A-164 2-Ethoxycarbonylamino -6- (4-methyl-phenoxy) -3-yl-imidazo [4, 5-ib] pyridine A-165 2-Ethoxycarbonylamino-6- (2-fluorophenyl mercapto) ) -3 H- imidazo [4, 5-ib] pyridine A-166 2-Ethoxycarbonylamino-6- (3-fluorophenyl mercapto) -3iimidazo [4, 5-jb] pyridine A-167 2-Ethoxycarbonylamino-6 - (4-fluorophenyl mercapto) -3 H- imidazo [4, 5-Ib] pyridine A-168 2-Ethoxycarbonylamino-6- [2- (trifluromethyl) phenylmercapto] -3 H- imidazo [4, 5 b] pyridine A-169 2-Ethoxycarbonylamino-6- [3 - (trifluoromethyl) phenylmercapto] -3H-imidazo [4, 5-ib] pyridine A-170 2-Ethoxycarbonylamino-6- [4- (trifluoromethyl) phenylmercapto] -3H- imidazo [4, 5-Ib] pyridine A-171 2-Ethoxycarbonylamino -6- (2-methoxyphenyl-ercapto) -3 H- imidazo [4, 5-ib] pyridine A-172 2-Ethoxycarbonylamino- 6- (3 - methoxy phenylmercapto) - 3 H- imidazo [4, 5 -ib] pyridine A-173 2-Ethoxycarbonylamino-6- (4-methoxyphenylmercapto) -3 H- imidazo [4, 5-ib] pyridine A-174 2-Ethoxycarbonylamino-6- (2-carboxyphenylmercapto) -3 H- imidazo [4, 5 -ib] pyridine A-175 2-Ethoxycarbonylamino-β- (3-carboxyphenylmercapto) -3 H- imidazo [4, 5-jb] pyridine A-176 2-Ethoxycarbonylamino-6- (4-carboxy phenylmercapto) -3 H- imidazo [4, 5-ib] pyridine Compounds A-177-A-198 When replacing the appropriate aniline salt with sodium phenolate in Example A-4, the identical process gives the following examples. For examples A-196, A-197, and A-198, the carboxy groups are protected by a methyl, ethyl, benzyl, t-butyl ester, or other suitable ester and then deprotected in the last step to give the compounds .

A1-Ethoxycarbonylamino-6-phenylamino-3H-imidazo [4,5-b] pyridine A-178 2-Ethoxycarbonylamino-6- (2-nitrophenylamino-3iT-imidazo [4, 5-Ib] pyridine A- 179 2-Ethoxycarbonylamino-6- (3-nitrophenylamino-3? - imidazo [4, 5-ib] pyridine A-180 2-Ethoxycarbonyl-amino-6- (4-nitrophenylamino-3-yl-imidazo [4, 5-ib] pyridine A-181 2-Ethoxycarbonylamino- 6- (2-chlorophenylamino-3i? -imidazo [4,5-ib] pyridine A-182 2-Ethoxycarbonylamino-6- (3-chlorophenylamino-3iT-imidazo [4, 5-ib] pyridine A-183 2-Ethoxycarbonylamino-6- (4-chlorophenylamino-3-yl-idazo [4,5-ib ] pyridine A-184 2-Ethoxycarbonylamino-6- (2-methyl-1-phenylamino-3-yl-imidazo [4, 5-b] pyridine A-185 2-Ethoxycarbonylamino-6- (3-methyl-phenylamino-3-yl-imidazo [4, 5 -b] pyridine A-186 2-Ethoxycarbonylamino-6- (4-methyl-phenoxy) -3 H- imidazo [4, 5-jb] pyridine A-187 2-Ethoxycarbonylamino-6- (2-fluorophenylamino-3-yl-imidazo [ 4,5-Ib] pyridine A-188 2-Ethoxycarbonylamino-6- (3-fluorophenylamino-3-yl-imidazo [4, 5-jb] pyridine A-189 2-Ethoxycarbonylamino-6- (4-fluorophenylamino-3i? Imidazo [4,5-Ib] pyridine A-190 2-Ethoxycarbonylamino-6- [2- trifluoromethyl) phenylamino] -3iimidazo [4,5- b] pyridine A-191 2-Ethoxycarbonylamino-6- [3-trifluoromethyl) phenylamino] -3-imidazo [4, 5-b] pyridine A-192 2-Ethoxycarbonylamino-6- [4-trifluoromethyl) phenylamino] -3 H-imidazo [ 4,5-b] pyridine A-193 2-Ethoxycarbonylamino-6- (2-methoxyphenylamino) -3 H-imidazo [4, 5-ib] pyridine A-194 2-Ethoxycarbonylamino-6- (3-methoxyphenylamino) -3 H- imidazo [4, 5-Ib] pyridine Al 95 2-Ethoxycarbonylamino-6- (4-methoxy phenylamino) -3 H- imidazo [4, 5-ib] pyridine A-196 2-Ethoxycarbonylamino- 6- (2 - carboxyphenylamino) -3 H- imidazo [4,5-b] pyridine A-197 2-Ethoxycarbonylamino-β- (3-carboxyphenylamino) -3 H-imidazo [4, 5-b] pyridine A1 98 2-Ethoxycarbonylamino-6- (4-carboxy phenylamino) -3-imidazo [4,5-b] pyridine Example 2: Test that measures the phosphorylation function of RAF The following assay reports the amount of phosphorylation characterized by RAF of its MEK target protein as well as the target MAPK of MEK. The gene sequence of RAF is described in Bonner et al. al., 1985, Mol ec. Cel l. Bi ol. 5: 1400-1407, and is easily accessible in multiple gene sequence data banks. The construction of the nucleic acid vector and the cell lines used for this portion of the invention are fully described in Morrison et al., 1988, Proc. Na ti. Aca d. Sci. USA 85: 8855-8859.

Materials and Reagents 1. Sf9 cells (Spodop t was frugiperda); GIBCO-BRL, Gaithersburg, MD. 2. RIPA shock absorber. 20 mM Tris / HCl pH 7.4, 137 mM NaCl, 10% glycerol, 1 M PMSF, Aprotenin 5 mg / L, 0.5% Triton X-100. 3. Tioredoxin-MEK fusion protein (T-MEX): The expression and purification of T-MEK by affinity chromatography was performed according to the manufacturer's procedures. Catalog number K 350-01 and R 350-40, Invitrogen Corp., San Diego, CA, 4. His-MAPK (ERK 2): MAPK is labeled with His expressed in XL1 Blue cells transformed with the pUC18 vector encoding for His-MAPK. His-MAPK was purified by Ni affinity chromatography. Catalog number 27-4949-01, Pharmacia, Alameda, CA, as described herein. 5. IgG sheep anti-mouse: Jackson laboratories, West Grove, PA. Catalog number 515-006-008, Lot 28563. 6. Specific protein kinase antibody RAF-1: URP 2653 from UBI. 7. Coating shock absorber. PBS; phosphate-motivated saline solution, GIBCO-BRL, Gaithersburg, MD. 8. Washing shock absorber: TBST - Tris / HCL 50 mM'pH 7.2, 150 mM NaCl, 0.1% Triton X-100. 9. Block absorber: TBST, 0.1% ethanolamine pH 7.4 10. DMSO, Soma, St. Louis, MO 11. Kinase buffer (KB): Hepes / HCl mM pH 7.2, 150 mM NaCl, 0.1% Triton X-100, 1 mM PMSF, Aprotenin 5 mg / L, 75 mM sodium ortho-vanadate, 0.5 mM DTT and 10 mM MgCl2. 12. ATP mixture: 100 mM MgCl 2, 300 mM ATP, 10 mCi g-33P (Dupont-NEN) / mL. 13. Detention solution: 1% phosphoric acid; Fisher, Pittsburg, PA. 14. Cellulose phosphate filter mats Wallac, Turku, Finland. 15. Filter wash solution: acid 1% phosphoric; Fisher Pittsburg, PA. 16. Tomtec plate collector, Wallac, Turku, Finland. 17. Beta plate vector # 1205, Wallac, Turku, Finland. 18. NUNC 96-well V-bottom polypropylene plates for Applied Scientific compounds catalog number AS-72092.

Procedure All the following steps were carried out at room temperature unless otherwise specified. 1. ELISA plate coating: ELISA wells were coated with 100 Lof affinity purified antisera, sheep anti-mouse (1 mg / 100 mL coating buffer) overnight at 4 ° C. ELISA plates can be used for two weeks when stored at 4 ° C. 2. Reverse the plate and remove the liquid. Add 100 mL of blocking solution and incubate for 30 minutes. 3. Remove blocking solution and wash four times with wash buffer. Place the plate on a paper towel to remove excess liquid. 4. Add 1 mg of specific antibody for RAF-1 to each well and incubate for 1 hour. Wash as described in step 3. 5. Thaw the Used from the Sf9 cells infected with RAS / RAF and dilute with TBST at 10 mg / 100 mL. Add 10 mg of the diluted used to the wells and incubate for 1 hour. Shake the plate during incubation. Negative controls do not receive the product used. The Used of the Sf9 insect cells infected with RAS / RAF are prepared after the cells are infected with the recombinant baculoviruses at an MOI of 5 for each virus, and are harvested 48 hours later. The cells are washed once with PBS and lysed in RIPA buffer. The insoluble material is removed by centrifugation (5 min at 10,000 'x g). The aliquots of the Used are frozen in dry ice / ethanol and stored at -80 ° C until use. 6. Remove unbound material and wash as summarized previously (step 3). 7. Add 2 mg of T-MEK and 2 mg of His-MAEPK per well and adjust the volume to 40 mL with kinase buffer. The methods to purify T-MEK and MAPK and from the cell extracts are provided herein by way of example. 8. Pre-dilute the compounds (10 mg / mL concentrated solution of DMSO) or extracts 20 times in TBST plus 1% DMSO. Add 5 mL of pre-diluted compounds / extracts to the wells described in step 6. Incubate for 20 minutes. The controls do not receive a drug. 9. Start the kinase reaction by the addition of 5 mL of ATP mixture; shake the plates on an ELISA plate shaker during incubation. 10. Stop the kinase reaction after 60 minutes by the addition of 30 mL of solution and termination to each well. 11. Place the phosphocellulose mat and the ELISA plate in the Tomtec plate collector. Collect and wash the filter with the filter wash solution according to the recommendation of the manufacturers. Dry the filter mats. Seal the filter mats and place them in the holder. Insert the support in the radioactive detection apparatus and quantify the radioactive phosphorus in the filter mats. Alternatively, they can be transferred aliquots of 40 mL from the individual wells of the assay plate to the corresponding positions in the phosphocellulose filter mats. After air drying the filters, put the filters in a tray. Gently rock the tray, changing the wash solution at 15 minute intervals for 1 hour. Air dry the filter mats. Seal the filter mats and place them in a suitable support to measure the radioactive phosphor in the samples. Insert the support in a detection device and quantify the radioactive phosphorus in the filter mats. The IC50 values were measured according to the protocol for the following azabenzimidazole-based compounds in the ELISA assay with RAF-1: Y An IC50 value is the concentration of the azabenzimidazole-based inhibitor required to decrease the maximum amount of phosphorylated target protein or cell growth by 50%. The IC 50 values measured in the RAF-1 phosphorylation assay are shown in Table 1: TABLE 1 Example 3: Purification of MAPK and MEK MAPK and MEK proteins are readily expressed in cells by subcloning a gene encoding these proteins into a commercially available vector that expresses proteins with a poly-his t idin tag. The genes that code for these proteins are readily available in laboratories that normally work with these proteins or clone these genes from cells that contain cDNA libraries. Libraries are commercially available in an easy manner and one skilled in the art can easily design nucleic acid probes homologous to the cDNA molecules encoding MEK or MAPK from the nucleic acid sequences of MEK and MAPK, available in multiple gene databases such as Genbank. The cloning of a gene can be achieved in a short period of time using techniques currently available to persons skilled in the art. The purification of MEK proteins and MAPK from cell extracts can be achieved using the following protocol, which is adapted from Robbins et al., 1993, J-. Bi ol. . Chem. 268: 5097-5106. 1. Lising cell by treatment with sound, osmotic stress, or French press techniques readily available to persons skilled in the art. A suitable shock absorber for sound treatment is provided later. 2. Balancing a solid support that is conjugated with nickel and cobalt with the equilibrium buffer described later. The poly-his t idine tag binds specifically to the nickel and cobalt atoms in the solid support. The balance can be achieved by washing the resin three times with a volume of the equilibrium buffer equal to ten times the volume of the solid support. The solid support is easily available to persons skilled in the art. 3. Add the used cell to the solid support and equilibrate in a container for a period of time. Alternatively, the solid support can be packed into a protein chromatography column and the Used can be flowed through the solid support. 4. Wash the solid support with the wash buffer described later. 5. Elute the MEK or MAPK protein from the solid support with an amount of elution buffer (given below) that removes a significant portion of the protein from the solid support.

Sonic Treatment Buffer 50 mM Sodium Phosphate, pH 8.0 Sodium chloride 0.3 M 10 mM ß-mercaptoethanol 10 mM NP-40 1% NaF 10 mM Pefablock 0.5 mM Sodium phosphate equilibrium buffer 50 mM, pH sodium chloride 0.3 M 10 mM β-mercaptoethanol 1% NP40 10 mM NaF 1 mM Imidazole Wash buffer 50 mM sodium phosphate, pH 8.0 sodium chloride 0.3 M 10 mM β-mercaptoethanol 1% NP40 10 mM NaF 10 mM Imidazole Sodium phosphate elution cushion 50 mM, pH 8.0 sodium chloride 0.3 M 10 mM ß-mercaptoethanol 1% NP40 10 mM Nafl 10 - 500 mM Imidazole Example 4: Assay Measuring the Function of Phosphorylation of the EGF Receptor The activity of the EGF receptor kinase (EGFR-NIH3T3 assay) in whole whole cells was measured as described in detail in PCT Publication WO9640116, filed June 5 1996 by Tang et al., and entitled "Indolínone Compounds for the Treatment of Disease," incorporated herein by reference in its entirety, including any of the drawings. The IC50 values measured in the EGF receptor phosphorylation assay are shown in Table 2: TABLE 2 Example 5: Test that Measures the Effect of Compounds Based on Azabenzimidazole in the Growth of Ras Expressing Cells The following assay measures growth rates for NIH-3T3 cells expressing Ras. The purpose of the assay is to determine the effects of the compounds on the growth of NIH 3T3 cells that overexpress H-Ras.

Materials 96-well flat bottom sterile plates 96-well sterile bottom plates sterile 25-mL or 100-mL pipettes, multi-channel pipetman sterile pipette tips sterile tubes 15 mL and 50 mL Reagents SRB 0.4% in 1% acetic acid base 10 M Tris 10% TCA 1% acetic acid DMSO sterile (Sigma) compound in DMSO (concentrated solution 100 mM or less) Tripsina-EDTA (GIBCO BRL) Cell line: 3T3 / H-Ras (cells from clone 7 of NIH 3T3 that expresses a genomic fragment of the oncogenic H-Ras). Cells can be constructed using the following protocol: 1. Subcloning a gene fragment encoding Ras into a commercially available vector that will stably transfect NIH-3T3 cells. The fragment is from the genomic transformation allele of cHa-ras. 2. Transfect NIH-3T3 cells with the subcloned vector by a calcium phosphate method. Select cells that express the construction of Ras in a 2% serum in DMEM. Visible foci are observed after two weeks. Mix the transformed cells to generate a stably transformed cell line.

Growth medium: 2% calf serum / DMEM + 2 mM glutamine, Pen / S t rep Protocol: Day 0: Plate Placement of the Cells: This part of the test was carried out in a laminar flow hood. 1. Trypsin cells. Transfer 200 mL in the cell suspension to 10 mL of isotone. Count the cells with a Coulter counter. 2. Dilute the cells in growth medium at 60,000 cells / mL. Transfer 100 mL of cells to each well in a 96 well flat bottom plate to give 6000 / well. 3. Use half of the plate (4 rows) for each compound and quadruple the wells for each concentration of the compound, and a set of four wells for the control of the medium. 4. Gently shake the plates to allow uniform union of the cells. 5. Incubate plates at 37 ° C in an incubator with 10% C02.

Day 1: Addition of Compound: This part of the test is carried out in a laminar flow hood. 1. In a 96 well round bottom plate, add 120 mL of growth medium that contains 2X% final DMSO found at a higher detection concentration of the compound at columns 1 to 11. For example, if the highest concentration is 100 mL, and this is done from a 10MmM concentrated solution, DMSO IX is 0.1% , so DMSO 2X is 0.2%. This plate is used to crush the compound, 4 rows per column. 2. In a sterile 15 ml tube, make a 2X solution of the highest detection concentration of the compound in the growth medium plus 2X DMSO. 1 mL per cell line is needed. The start concentration of the compound is usually 100 mM, but this concentration may vary depending on the solubility of the compound. 3. Transfer 240 mL of the 2X start compound solution to quadruple the wells in column 12 of the 96-well round bottom plate. Make serial 1: 2 dilutions through the plate from left to right by transferring 12 mL from column 12 to column 11, from column 11 to 10 and so on up to column 2. Transfer 100 mL of the dilutions of the compound, and 100 mL of the medium in column 1, on 100 L of the medium in cells in wells corresponding to the 96-well flat bottom plate. The total volume per well should be 200 mL. 4. Return the plate to the incubator and incubate for 3 days.

Day 4: Development of the Essay This part of the trial is carried out in the bank. 1. Aspirate or empty the medium. Add 200 mL of TCA to 10% cold to each well to fix the cells. Incubate the plate for at least 60 minutes at 4 ° c. 2. Discard the TCA and rinse the wells 5 times with tap water. Dry the plates up on paper towels. 3. Stain the cells with 100 mL / well of SRB at 0.4% for 10 minutes. 4. Pour the SRB and rinse the wells 5 times with 1% acetic acid. Dry the plates completely up on paper towels. 5. Solubilize the dye with 100 mL / well of 10 mM Tris base for 5-10 minutes in the agitator. 6. Read the plates in a plate reader Dynatech ELISA at 570 nm with reference to 630 nm. Select compounds that inhibited the growth rate of the cells that over express Ras as illustrated in Table 3.

TABLE 3 Example 6: Test that Measures the Effect of Compounds Based on Azabenzimidazole in the Growth of A549 Cells The following assay measures growth rates for A549 cells. The purpose of the assay is to determine the effects of the compounds on the growth of lung carcinoma cells, human, A549. A549 cells are readily accessible from commercial sources, such as ATCC (CCL185).

Sterile flat bottom 96-well plates sterile 96-well round bottom plates sterile 25 mL or 100 mL reservoir pipettes, multi-channel pipetman sterile pipette tips sterile tubes of 15 mL and 50 mL Reagents SRB 0.4% in 1% acetic acid base 10 mM Tris 10% TCA 1% acetic acid DMSO sterile (Sigma) compound in DMSO (concentrated solution 100 mM or less) Trypsin-EDTA (GIBCO BRL) Cell line and growth medium: Human lung carcinoma cells A549 (ATCC CCL185) 10% fetal calf serum in Ham's F12-K Protocol: Day 0: Plate Placing of the Cells: This part of the test was carried out in a laminar flow hood. 1. Trypsin cells. Transfer 200 μL in the cell suspension to 10 mL of isotone. Tell the cells with a Coulter counter. 2. Dilute the cells in growth medium at 20,000 cells / mL. Transfer 100 mL of cells to each well in a 96 well flat bottom plate to give 2000 cells / well. 3. Use half of the plate (4 rows) for each compound and quadruple the wells for each concentration of the compound, and a set of four wells of the control medium. 4. Gently shake the plates to allow uniform union of the cells. 5. Incubate the plates at 37 ° C in a 10% C02 incubator.

Day 1: Addition of Compound: This part of the test is carried out in a laminar flow hood. 1. In a 96-well round bottom plate, add 120 μL of growth medium containing 2X% final DMSO found at a higher detection concentration of the compound to columns 1 to 11. For example, if the highest concentration is 100 μM, and this is done from a 100 mM concentrated solution, DMSO IX is 0.1%, so that 2X DMSO is 0.2%. This plate it is used to crush the compound, 4 rows per column. 2. In a sterile 15 ml tube, make a 2X solution of the highest detection concentration of the compound in the growth medium plus 2X DMSO. 1 mL per cell line is needed. The starting concentration of the compound is usually 100 μM, but this concentration can vary depending on the solubility of the compound. 3. Transfer 240 μL of the 2X start compound solution to quadruple the wells in column 12 of the 96-well round bottom plate. Make serial 1: 2 dilutions through the plate from left to right by transferring 120 μL from column 12 to column 11, from column 11 to 10 and so on up to column 2. Transfer 100 μL of the dilutions of the compound, and 100 μL of the medium in column 1, on 100 μL of the medium in cells in corresponding wells of the 96-well flat bottom plate. The total volume per well must be 200 μL. 4. Return the plate to the incubator and incubate for 3 days.

Day 5: Development of the Essay This part of the trial is carried out in the bank. 1. Aspirate or empty the medium. Add 200 μL of 10% TCA to each well to fix the cells. Incubate the plate for at least 60 minutes at 4 ° c. 2. Discard the TCA and rinse the wells 5 times with tap water. Dry the plates up on paper towels. 3. Stain the cells with 100 μL / well of SRB at 0.4% for 10 minutes. 4. Pour. SRB and rinse the wells 5 times with 1% acetic acid. Dry the plates completely up on paper towels. 5. Solubilize the dye with 100 μL / well of 10 mM Tris base for 5-10 minutes on the shaker. 6. Read the plates in a Dynatech ELISA plate reader at 570 nm with reference to 630 nm. Select the compounds that inhibited the growth rate of the cells that overexpress Ras as illustrated in Table 4.

TABLE 4 Example 7: Method for Determining the Biological Activity of Raf Modulators in Vivo Xenograft studies can be used to monitor the effect of the compounds of the invention on the inhibition of ovarian, melanoma, prostate, lung and tumor cells. mammary The protocol for the assay is described in detail in PCT publication WO9640116 filed on June 5, 1996, by Tang et al., And entitled "Indolinone Compounds for the Treatment of Disease," incorporated herein by reference in its entirety. , including any of the drawings. The invention described illustratively herein may be practiced in the absence of any element or elements, limitation or limitations that are not specifically described here. The terms and expressions that have been used are used as terms of description and not limitation, and there is no intention that in the use of these terms and expressions any of the equivalents of the characteristics shown and described or portions thereof, are excluded, but it is recognized that various modifications are possible within the scope of the claimed invention. Thus, it should be understood that while the present invention has been specifically described by preferred embodiments and optional features, the modification and variation of the concepts described herein can be embraced by those skilled in the art and that these modifications and variations are they consider that they are within the scope of this invention as defined by the appended claims. One skilled in the art will readily appreciate that the present invention is well suited to carry out the objects and to obtain the purposes and advantages mentioned, as well as those inherent herein. Molecular complexes and methods, procedures, Treatments, molecules, specific compounds described herein are currently representative of the preferred embodiments, are exemplary and are not proposed as limitations on the scope of the invention. Changes in the present and other uses that are presented to those skilled in the art that encompass within the spirit of the invention are defined by the scope of the claims. It will be readily apparent to one skilled in the art that variation of substitutions and modifications can be made to the invention described herein without departing from the scope and spirit of the invention. All patents and publications mentioned in the specification are representative of the levels of those skilled in the art to which the invention corresponds. All patents and publications are hereby incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated as a reference. The invention described illustratively herein may be practiced in an appropriate manner in the absence of any limiting elements or limitation elements or limitations, which are not specifically described herein. Thus, for example, in each case in the present any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with any of the other two terms. The terms and expressions that have been used are used as terms of description and not limitation, and there is no intention that in the use of these terms and expressions of exclusion any of the equivalents of the characteristics shown and described or portions thereof, but it is recognized that various modifications are possible within the claimed invention. Thus, it should be understood that while the present invention has been specifically described by preferred embodiments and optional features, the modification and variation of the concepts described herein can be embraced by any of those skilled in the art, and that these modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

Furthermore, where the features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described in this way in terms of any individual member or group of Markush group members. For example, if X is described as being selected from the group consisting of bromine, chlorine and iodine, the claims for X that are bromine and the claims for X that are bromine and chlorine are fully described. Those references not previously incorporated herein by reference, including both patent and non-patent references, are expressly incorporated herein by reference for all purposes. Other embodiments are within the following claims.

Claims (37)

1. CLAIMS 1. A method for modulating the function of a serine / threonine protein kinase with an azabenzimidazole-based compound, comprising the step of contacting the cells expressing the serine / threonine protein kinase with the compound.
2. 2. The method according to claim 1, wherein the serine / threonine protein kinase is RAF.
3. 3. A method for identifying compounds that modulate the function of the serine / threonine protein kinase, comprising the following steps: (a) contacting the cells expressing the serine / threonine protein kinase with the compound; and (b) monitor an effect on the cells.
4. 4. The method according to claim 3, wherein the effect is a change or an absence of a change in the cellular phenotype.
5. The method according to claim 3, wherein the effect is a change or an absence of a change in cell proliferation.
6. 6. The method according to claim 3, wherein the effect is a change or absence of a change in the catalytic activity of serine / threonine protein kinase.
7. The method according to claim 3, wherein the effect is a change or absence of a change in the interaction between the serine / threonine protein kinase with a natural binding partner, as described herein.
8. The method according to claim 3, comprising the following steps: (a) lysing the cells to produce a Used that understands. the serine / threonine protein kinase; (b) absorbing the serine / threonine protein kinase to an antibody; (c) incubating the serine / threonine protein kinase absorbed with a substrate or substrates; and (d) absorbing the substrate or substrates to a solid support or antibody; wherein the step of monitoring the effect on the cells comprises measuring the concentration of a phosphate of the substrate or substrates.
9. The method according to claim 3, wherein the serine / threonine protein kinase is RAF and comprises the following steps: (a) lysing the cells to produce a Used comprising RAF; (b) absorbing the RAF to an antibody; (c) incubating the absorbed RAF with a MEK and MAPK; and (d) absorbing the MEK and MAPK to a solid support or antibody or antibodies; wherein the step of measuring the effect on the cells comprises monitoring the phosphate concentration of the MEK and MAPK.
10. The method according to claim 1, wherein the azabenzimidazole-based compound has a structure set forth in formula I, II, or III: where (a) Ri, R2, R3 and R4 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated and unsaturated alkyl; (iii) NX2X3, wherein X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (iv) halogen or trihalomethyl; (v) a ketone of the formula -CO-X4, wherein X are selected from the group consisting of hydrogen, alkyl and heterocyclic or heterocyclic ring portions; (vi) a carboxylic acid of the formula - (X5) n -COOH or ester of the formula - (X6) n -COO-X7, where X5, Xß, and X7 and are independently selected from alkyl and portions of homocyclic or heterocyclic ring and wherein n is 0 or 1; (vii) an alcohol of the formula (Xe) n-OH, or an alkoxy portion of the formula - (XgA-O-Xg, where X8 and X9 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and ring portions homocyclic or heterocyclic, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester, and wherein n is 0 or 1; (viii) an amide of the formula NHCOXio, wherein Xio are selected from the group consisting of alkyl, hydroxyl, and heterocyclic or ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester; (ix) -S02NXnX? 2, wherein Xn and Xi2 are selected from the group consisting of hydrogen, alkyl and heterocyclic and heterocyclic ring portions; (x) a homocyclic or heterocyclic ring portion optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester moieties; (xi) an aldehyde of the formula -CO-H; and (xii) a sulfone of the formula -S02-X? 3, wherein X13 are selected from the group consisting of saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (b) Zi and Z2 are independently selected from the group consisting of nitrogen, sulfur, oxygen, NH and NR4, with the proviso that if one of Zi and Z2 is nitrogen, NH, or NR4 then the other of \ y Z is nitrogen, sulfur, oxygen, NH, or NR4; and (c) Z and Xi are independently selected from the group consisting of nitrogen, sulfur and oxygen.
11. The method according to claim 10, wherein the azabenzimidazole compound is selected from the group consisting of SABI compounds, as defined herein.
12. 12. A method for preventing or treating an abnormal condition in an organism, comprising the step of administering an azabenzimidazole-based compound of the formula I, II, or III to the organism. wherein (a) Ri, R2, R3 and R are independently selected from the group consisting of: (i) hydrogen; (ii) saturated and unsaturated alkyl; (iii) NX2X3, wherein X2 and X3 are independently selected from the group consisting of hydrogen, saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (iv) halogen or trihalomethyl; (v) a ketone of the formula -CO-X, wherein X 4 is selected from the group consisting of hydrogen, alkyl and homocyclic or heterocyclic ring portions; (vi) a carboxylic acid of the formula - (X5) n -COOH or ester of the formula - (X6) n -COO-X7, where X5, X6, and X7 and are independently selected from alkyl and portions of homocyclic or heterocyclic ring and wherein n is 0 or 1; (vii) an alcohol of the formula (X8) n-OH, or an alkoxy portion of the formula - (X8) n-0-X9, wherein X8 and X9 are independently selected from the group consisting of hydrogen, saturated alkyl or unsaturated, and heterocyclic or ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro, and ester, and wherein n is 0 or 1; (viii) an amine of the formula NHCOXio, wherein X? 0 are selected from the group consisting of alkyl, hydroxyl, and heterocyclic or ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from starting from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester; (ix) -S02NXnXi2, where Xu and Xi2 are selected from the group consisting of hydrogen, alkyl and heterocyclic or heterocyclic ring portions; (x) a homocyclic or heterocyclic ring portion optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester moieties; (xi) an aldehyde of the formula -CO-H; and (xii) a sulfone of the formula -S02-X13 / wherein X13 are selected from the group consisting of saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (b) Zi and Z2 are independently selected from the group consisting of nitrogen, sulfur, oxygen, NH and NR, with the proviso that if one of Zi and Z2 is nitrogen, NH, or NR4 then the other of Zi and Z2 is' nitrogen, sulfur, oxygen, NH, or NR4; and (c) Z3 and Xi are independently selected from the group consisting of of nitrogen, sulfur and oxygen.
13. The method according to claim 12, wherein the organism is a mammal.
14. The method according to claim 12, wherein the abnormal condition is cancer or a fibrotic disorder.
15. The method according to claim 14, wherein the abnormal condition is a cancer selected from the group consisting of lung cancer, ovarian cancer, breast cancer, brain cancer, intra-axial brain cancer, colon cancer, prostate cancer, sarcoma, Kaposi's sarcoma, malanoma and glioma.
16. The method according to claim 12, wherein the abnormal condition is associated with an aberration in a signal transduction pathway characterized by an interaction between a serine / threonine protein kinase and a natural binding partner.
17. 17. The method according to claim 16, wherein the serine / threonine protein kinase is RAF
18. 18. An azabenzimidazole compound having an exposed structure in formula I, II, or III: wherein (a) Ri, R2 / R3 and R4 are independently selected from the group consisting of: (i) hydrogen; (ii) saturated and unsaturated alkyl; (iii) NX2X3, wherein X2 and X3 are independently selected from the group "consisting of hydrogen, saturated or unsaturated alkyl, and heterocyclic or ring portions, (iv) halogen or trihalomethyl, (v) a ketone of the formula -C0-X4, where X4 are selected from the group consisting of hydrogen, alkyl and portions of homocyclic or heterocyclic ring; (vi) a carboxylic acid of the formula - (X5) n -COOH or ester of the formula - (X6) n -COO-X7, where X5, X6, and X7 and are independently selected from alkyl and portions of ring homocyclic or heterocyclic and where n is 0 or 1; (vii) an alcohol of the formula (X8) n-OH, or an alkoxy portion of the formula - (X8) n_0-Xg, wherein X8 and Xg are independently selected from the group consisting of hydrogen, saturated unsaturated alkyl , and homocyclic or heterocyclic ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester, and wherein n is 0 or 1; (viii) an amine of the formula NHCOXio, wherein Xio are selected from the group consisting of alkyl, hydroxyl, and heterocyclic or ring portions, wherein the ring is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester; (ix) -S02NXnX? 2, wherein X1X and Xi2 are selected from the group consisting of hydrogen, alkyl and homocyclic or heterocyclic ring portions; (x) a homocyclic or heterocyclic ring portion optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro and ester portions; (xi) an aldehyde of the formula -CO-H; and (xii) a sulfone of the formula -S02- X% 3, wherein X? 3 are selected from the group consisting of saturated or unsaturated alkyl, and homocyclic or heterocyclic ring portions; (b) Zi and Z2 are independently selected from the group consisting of nitrogen, sulfur, oxygen, NH and NR, with the proviso that if one of Zi and Z2 is nitrogen, NH, or NR then the other of Zi and Z2 is nitrogen, sulfur, oxygen, NH, or NR4; and (c) Z3 and Xi are selected independently from the group consisting of nitrogen, sulfur and oxygen.
19. 19. The compound according to claim 18, wherein Zi and Z2 are independently selected from the group consisting of nitrogen and NH.
20. 20. The compound according to the claim 19, wherein Ri, R2, R3 and R are independently selected from the group consisting of (i) hydrogen; (ii) saturated or unsaturated alkyl optionally substituted with a homocyclic or heterocyclic ring portion, or a polycyclic ring portion, wherein the ring portion is optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxylate, nitro and ester portions; and (iii) a homocyclic or heterocyclic ring portion, optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, halogen, trihalomethyl, hydroxy, alkoxy, carboxylate, nitro and ester portions.
21. 21. The compound according to claim 20, wherein R2, and R3 are hydrogen.
22. 22. The compound according to claim 21, wherein Ri is phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, carboxylate, nitro or ester portions.
23. 23. The compound according to the claim 22, wherein Ri is selected from the group consisting of SABI substituents.
24. 24. The compound according to the claim 23, wherein Xi is selected from the group consisting of sulfur, oxygen and NH.
25. 25. The compound according to the claim 24, where Z3 is oxygen.
26. 26. The compound according to the claim 25, wherein the R is selected from the group consisting of methyl and ethyl.
27. 27. The compound according to the claim 26, wherein the azabenzimidazole compound is selected from the group consisting of SABI compounds.
28. 28. A pharmaceutical composition that comprises an azabenzimidazole compound of any of claims 18-27, and a physiologically acceptable carrier or diluent.
29. 29. A method for synthesizing a compound of formula (I) of claim 18, comprising the steps of: (a) reacting 2-amino-6-chloro-3-nitropyridine in a second reagent in a solvent, producing a first intermediate compound, wherein the second reagent is a substituted aryl ring; (b) reducing the first intermediate in the presence of a catalyst and a reducing agent, producing a second intermediate; (c) reacting the second intermediate compound with a third reagent; and (d) purifying the compound of claim 18.
30. 30. The method according to claim 29, wherein the solvent is n-propanol.
31. 31. The method according to claim 30, wherein the substituted aryl ring is a substituted phenol, substituted thiophenyl, and substituted aniline.
32. 32. The method according to claim 31, wherein the substituted phenol, substituted thiophenyl and substituted aniline is selected from the group consisting of SABI reagents.
33. 33. The method according to claim 29, wherein the reducing agent is hydrogen.
34. 34. The method according to claim 29, wherein the catalyst is Raney nickel.
35. 35. The method according to claim 29, wherein the third reagent is O-met ilisourea.
36. 36. The method according to claim 29, wherein the third reagent is the product of the reaction of S-met ilisot iouronium sulfate and alkyl chloroformate.
37. 37. The method according to claim 36, wherein the alkyl is methyl or ethyl.