Kinase inhibitors

Abstract

The invention relates to inhibitors of enzymes that bind to ATP or GTP and/or catalyze phosphoryl transfer, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating disease or disease symptoms. The invention also provides for methods of making phosphoryl transferase inhibitor compounds, methods of inhibiting phosphoryl transferase activity, and methods for treating disease or disease symptoms.

Description

BACKGROUND OF THE INVENTION

[0002] The invention relates to inhibitors of enzymes that catalyze phosphoryl transfer and/or that bind ATP/GTP nucleotides, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating or modulating disease in which phosphoryl transferases, including kinases, may be involved, symptoms of such disease, or the effect of other physiological events mediated by phosphoryl transferases, including kinases. The invention also provides for methods of making the inhibitor compounds and methods for treating diseases in which one or more phosphoryl transferase, including kinase, activities is involved.

[0003] Phosphoryl transferases are a large family of enzymes that transfer phosphorous-containing groups from one substrate to another. By the conventions set forth by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (RUBMB) enzymes of this type have Enzyme Commission (EC) numbers starting with 2.7.-.- (See, Bairoch A., The ENZYME database in Nucleic Acids Re.s 28:304-305(2000)). Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. The protein kinases constitute the largest subfamily of structurally related phosphoryl transerfases and are responsible for the control of a wide variety of signal transduction processes within the cell. (See, Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, histidine, etc.). Protein kinase sequence motifs have been identified that generally correspond to each of these kinase families (See, for example, Hanks, S. K., Hunter, T., FASEB J., 9:576-596 (1995); Knighton et al., Science, 253:407-414 (1991); Hiles et al., Cell, 70:419-429 (1992); Kunz et al., Cell, 73:585-596 (1993); Garcia-Bustos et al., EMBO J., 13:2352-2361 (1994)). Lipid kinases (e.g. P13K) constitute a separate group of kinases with structural similarity to protein kinases.

[0004] Since the X-ray structure of the catalytic subunit of cAMP-dependent protein kinase (cAPK) was elucidated, approximately two dozen additional protein kinase structures and one lipid kinase structure have been solved as either apo enzymes or binary and ternary complexes (with ATP, ATP analogs, metal ions, ADP, ATP competitive inhibitors in the absence or presence of peptide substrate or peptide inhibitors). These proteins share structurally conserved catalytic domains (kinase domains) comprising two lobes that can be further subdivided into twelve subdomains. The N-terminal portion forms the small lobe (including subdomains I-IV) whose architecture is composed of an antiparallel five-strand β-sheet and one α-helix, while the lower C-terminal domain forms another lobe (including subdomains VIA-XI) containing mostly α-helical architecture. Subdomain V spans the two lobes. The N-terminal domain is thought to participate in orienting the nucleotide (or other binding entity), while the C-terminal domain is thought to be responsible for binding peptide substrate and initiating phosphotransfer to the hydroxyl group of a serine, threonine, or tyrosine residue.

[0005] The N- and C-terminal domains are connected through a single peptide strand, to which the adenine moiety of ATP and/or GTP binds via an eleven membered hydrogen bond cycle, involving the N1 and the N6 amino group, and the backbone carbonyl and NH functions of two nonconsecutive residues. This linker acts as a hinge about which the domains can rotate with respect to each other without disruption of the secondary architecture of the kinase. Several torsion angle changes in the linker backbone allow this movement to occur. The ribose group of ATP is anchored to the enzyme via hydrogen bonds with residues within the ribose-binding pocket. The triphosphate group is held in position via various polar interactions with several variable residues from the glycine rich loop, the conserved DFG motif and the catalytic loop.

[0006] The “kinase domain” appears in a number of polypeptides which serve a variety of functions. Such polypeptides include, for example, transmembrane receptors, intracellular receptor associated polypeptides, cytoplasmic located polypeptides, nuclear located polypeptides and subcellular located polypeptides. The activity of protein kinases can be regulated by a variety of mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, protein-polynucleotide interactions, ligand binding, and post-translational modification.

[0007] Protein and lipid kinases regulate many different cell processes including, but not limited to, proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to targets such as proteins or lipids. Phosphorylation events catalyzed by kinases act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity of (either directly or indirectly) the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.

[0008] Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of oncogene related protein kinases in human proliferative disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.

SUMMARY OF THE INVENTION

[0009] The invention relates to compounds of the formula: 1

[0010] wherein,

[0011] Each R1 and R2 is independently R3; R8; NHR3; NHR5; NHR6; NR5R5; NR5R6; SR5; SR6; SR3; OR5; OR6; OR3; C(O)R3; heterocyclyl optionally substituted with 1-4 independent R4 on each ring; or C1-C10 alkyl substituted with 1-4 independent R4;

[0012] Each R3 is independently aryl; phenyl optionally substituted with 1-5 independent R4 on each ring; or heteroaryl optionally substituted with 1-4 independent R4 on each ring; and the remaining groups are as defined herein. The invention also relates to compositions comprising these compounds, methods of making these compounds, methods of inhibiting enzyme activity, particularly kinase activity, through use of these compounds, and methods of treating disease or disease symptoms in a mammal, particularly where modulation of enzyme activity, and more particularly kinase activity, can affect disease outcome.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The invention provides compounds useful in inhibiting kinase activity and inhibiting kinases or other polypeptides having sequences or subsequences homologous to kinase sequences or subsequences. In one embodiment, the inhibitory compound has the formula: 2

[0014] wherein,

[0015] Each R1 and R2 is independently R3; R8; NHR3; NHR5; NHR6; NR5R5; NR5R6; SR5; SR6; SR3; OR5; OR6; OR3; C(O)R3; heterocyclyl optionally substituted with 1-4 independent R4 on each ring; or C1-C10 alkyl substituted with 1-4 independent R4;

[0016] Each R3 is independently aryl; phenyl optionally substituted with 1-5 independent R4 on each ring; or heteroaryl optionally substituted with 1-4 independent R4 on each ring;

[0017] Each n is independently 1 or 2;

[0018] Each m is independently 0, 1, 2, 3, or 4;

[0019] Each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR5R16; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)nR5; S(O)nNR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5 (COOR5); NR5C(O)R8; NR5S(O)NR5R5; NR5S(O)NR5; NR5; NR5C(O)C(O)NR5R; NR5C(O)C(O)NR5R6; OC(O)NR5R5; OS(O)nNR5R5; NR5S(O)nOR5; P(O)(OR5)2; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8; or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;

[0020] Each R5 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; haloalkyl; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R9 groups; C3-C10 cycloalkyl substituted with 1-3 independent aryl, R7 or R9 groups; or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R9;

[0021] Each R6 is independently C(O)R5, COOR5, C(O)NR5R5C(NR5)NR5R5, or S(O)n R5;

[0022] Each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10) (COOR10), S(O)nNR10R10; NR10S(O)NR10R10; NR10OS(O)nR10; or P(O)(OR5)2;

[0023] Each R8 is independently a 3-8 membered monocyclic, 7-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; S(O)nNR5R5; NR5C(O)NR5R5; NR5C(O)R9; NR5S(O)nNR5R5; NR5S(O)nR9; C1-C10 alkyl substituted with 1-3 independent R7, R9 or aryl; or C2-C10 alkenyl substituted with 1-3 independent R7, R9 or aryl;

[0024] Each R9 is independently a 3-8 membered monocyclic, 7-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; halo; sulfur; oxygen; CF3; haloalkyl; SR10; OR10; NR10OR10; NR10R11; NR11R11; COOR10; NO2; CN; C(O)R10; S(O)nR10; S(O)nNR10R10; or C(O)NR10R10;

[0025] Each R10 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; haloalkyl; C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12; NR12C(O)R12, N(R12)(COOR12), S(O)nNR12R12 or OC(O)R12; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NR12C(O)R12, N(R12)(COOR12), S(O)nNR12R12, or OC(O)R12;

[0026] Each R11 is independently C(O)R10, COOR10, C(O)NR10R10 or S(O)nR10;

[0027] Each R12 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl substituted with 1-3 independent C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NR13C(O)R13, or OC(O)R13; or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NR13C(O)R13, or OC(O)R13;

[0028] Each R13 is independently H; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; C1-C10 alkyl optionally substituted with halo, CF3, OR14, SR14, NR14R14, COOR14, NO2, CN; or phenyl optionally substituted with halo, CF3, OR14, SR14, NR14R14, COOR14, NO2, CN;

[0029] Each R14 is independently H; C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

[0030] Each R15 is independently H; CF3; CN; COOR15; or C1-C10 alkyl substituted with 1-3 independent OR5, SR5, or NR5R5;

[0031] Each R16 is independently H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; COOR5; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)nR5; S(O)nNR5R5; C1-C10 alkyl substituted with 1-3 independent aryl, R7, R8, or phenyl optionally substituted with substituted with 1-4 independent R23; or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;

[0032] Each R17 is independently NR5R16; OR5; SR5; or halo;

[0033] Each R18 is independently C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; COOR5; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)NR5 S(O)nNR5R5; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8; or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;

[0034] Each R19 is independently H or C1-C6 alkyl;

[0035] Each R20 is independently NR5R18; OR5; SR5; or halo;

[0036] Each R21 is independently t-butyl, 4-carboxyphenyl, 4-carbomethoxyphenyl, or furyl substituted with 1-4 independent R4;

[0037] Each R22 is independently C2-C9 alkyl substituted with 1-2 independent aryl, R7, or R8;

[0038] Each R23 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; OC(O)R5; NR5R5; NR5R5; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)nR5; S(O)nNR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)nNR5R5; NR5S(O)nNR5; NR8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; OC(O)NR5R5; OS(O)nNR5R5; NR5S(O)nOR5; P(O)(OR5)2; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8; or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;

[0039] Each R24 is independently selected from C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R9; halo; sulfur; oxygen; CF3; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR6R6; COOR5; NO2; CN; C(O)R5; C(O)NR5R5; S(O)nNR5R5; NR5C(O)NR5R5; NR5C(O)R9; NR5S(O)nNR5R5; NR5S(O)nR9; C1-C10 alkyl substituted with 1-3 independent R7, R9 or aryl; or C2-C10 alkenyl substituted with 1-3 independent R7, R9 or aryl;

[0040] Each X is independently O or S;

[0041] Each V, W, Y, and Z is independently N or CR4;

[0042] Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;

[0043] Each aryl is independently a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; R9; halo; haloalkyl; CF3; OR10; SR10; NR10R10; NR10OR11; COOR10; NO2; CN; C(O)R10; C(O)C(O)R10; C(O)NR10R10; N(R10)C(O)NR10R10; N(R10)C(O)R10; N(R10)S(O)nR10; N(R10)(COOR10); NR10C(O)C(O)R10; NR10C(O)R9; NR10S(O)nNR10R10; NR10S(O)nR9; NR12C(O)C(O)NR12R12; S(O)nR10; S(O)nNR10R10; OC(O)R10; C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR10, SR10, OC(O)R10, NR11R11, NR10R10, NR10R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10OR10, C(O)NR10R10, N(R10)C(O)R10, N(R10) (COOR10), S(O)nNR10R10; R10; or C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR10, SR10, OC(O)R10, NR11R11, NR10R10, NR10OR11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10) (COOR10), S(O)nNR10R10;

[0044] Each heterocyclyl is independently a 3-8 membered nonaromatic monocyclic, 8-12 membered nonaromatic bicyclic, or 11-14 membered nonaromatic tricyclic, ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S; and

[0045] Each heteroaryl is independently a 5-8 membered aromatic monocyclic, 8-12 membered aromatic bicyclic, or 11-14 membered aromatic tricyclic ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S. Unless stated otherwise, the groups referenced in the formulae described herein have the definitions as delineated above.

[0046] In one embodiment, the compound is that of any of the formulae herein wherein,

[0047] Each R1 and R2 is independently R3; NHR3; NHR5; or NHR6;

[0048] In one embodiment, the compound is that of any of the formulae herein wherein,

[0049] R1 is independently R3; and

[0050] R2 is independently NHR3.

[0051] In one embodiment, the compound is that of any of the formulae herein wherein,

[0052] R1 is independently heteroaryl optionally substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H); and

[0053] R2 is independently NHR3.

[0054] In one embodiment, the compound is that of any of the formulae herein wherein,

[0055] R1 is independently phenyl optionally substituted with 1-5 independent R4 ring (and alternatively, wherein at least one R4 is not H); and

[0056] R2 is independently NHR3.

[0057] In one embodiment, the compound is that of any of the formulae herein wherein,

[0058] R1 is independently aryl; and

[0059] R2 is independently NHR3.

[0060] In one embodiment, the compound is that of any of the formulae herein wherein,

[0061] R1 is not phenyl, 4-bromophenyl or 2-hydroxyphenyl.

[0062] In one embodiment, the compound is that of any of the formulae herein wherein,

[0063] Each R1 and R2 is independently NHR3. Alternatively, another embodiment of this embodiment is that wherein in R1 and R2, both R3 groups may not simultaneously be phenyl, 4-chlorophenyl, 3-aminophenyl, 4-aminophenyl, 4-nitrophenyl, 2-methylphenyl, thiazolyl, pyridyl, or 3-methylphenyl; or may not simultaneously be 4-nitrophenyl and 3-nitrophenyl, or 4-aminophenyl and 3-aminophenyl, or phenyl and 3-nitrophenyl; or may not simultaneously be 4-cyanophenyl and any one of the following: 2,4,6-trimethylphenyl, 2,6-dibromo-4-methylphenyl, 2,6-dimethyl-4-bromophenyl, 2,6-dibromo-4-isopropylphenyl, 2,-6-dimethyl-4-t-butylphenyl, or 2,6-dimethyl-4-cyanophenyl.

[0064] In one embodiment, the compound is that of any of the formulae herein wherein,

[0065] Each R1 and R2 is independently NHR3, wherein each R3 may not be 4-cyanophenyl.

[0066] In one embodiment, the compound is that of any of the formulae herein wherein,

[0067] Each R1 and R2 is independently NHR3, wherein each R3 may not be phenyl, pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, or pyridazinyl, either substituted or unsubstituted by additional substituents.

[0068] In one embodiment, the compound is that of any of the formulae herein wherein,

[0069] R1 is independently NHR5; and

[0070] R2 is independently NHR3.

[0071] Alternatively, another embodiment of this embodiment is that wherein in R1 and R2, both R3 and R5 groups may not simultaneously be phenyl, 4-chlorophenyl, 3-aminophenyl, 4-aminophenyl, 4-nitrophenyl, 2-methylphenyl, thiazol-2-yl, pyrid-2-yl, or 3-methylphenyl; or may not simultaneously be 4-nitrophenyl and 3-nitrophenyl, or 4-aminophenyl and 3-aminophenyl, or phenyl and 3-nitrophenyl; or may not simultaneously be 4-cyanophenyl and any one of the following: 2,4,6-trimethylphenyl, 2,6-dibromo-4-methylphenyl, 2,6-dimethyl-4-bromophenyl, 2,6-dibromo-4-isopropylphenyl, 2,-6-dimethyl-4-t-butylphenyl, or 2,6-dimethyl-4-cyanophenyl; or may not simultaneously be. 3

[0072] In one embodiment, the compound is that of any of the formulae herein wherein,

[0073] R1 is independently NHR6; and

[0074] R2 is independently NHR3.

[0075] In another embodiment, the compound is that of any of the formulae herein having the formula: 4

[0076] wherein, R4 and R6 are as defined above.

[0077] In another embodiment, the compound is that of any of the formulae herein having the formula: 5

[0078] wherein, R4 and R5 are as defined above.

[0079] In another embodiment, the compound is that of any of the formulae herein having the formula: 6

[0080] In another embodiment, the compound is that of any of the formulae herein having the formula: 7

[0081] In another embodiment, the compound is that of any of the formulae above wherein,

[0082] R2 is independently NHR3; and

[0083] R1 is one of the following groups: 8

[0084] In another embodiment, the compound is that of any of the formulae above wherein,

[0085] R2 is independently NHR3; and R1 is 9

[0086] In another embodiment, the compound is that of any of the formulae above wherein,

[0087] R2 is independently NHR3; and

[0088] R1 is one of the following groups: 10

[0089] In another embodiment, the compound is that of any of the formulae above wherein,

[0090] R2 is independently NHR3; and

[0091] R1 is independently heteroaryl substituted with 1-4 independent R4 on each ring wherein at least one R4 is not H, and wherein that at least one R4 that is not H is any one of NHR3; NHR5; NR5R6; SR5; SR6; SR3; OR5; OR6; or OR3; and is attached at the ring atom alpha to the ring atom attached to the triazinyl group. Alternatively, the heteroaryl group is monocyclic.

[0092] In another embodiment, the compound is that of any of the formulae above wherein,

[0093] R12 is independently NHR3; and

[0094] R1 is independently heterocyclyl substituted with substituted with 1-4 independent R4 on each ring wherein at least one R4 is not H, and wherein that at least one R4 that is not H is any one of NHR3; NHR5; NR5R6; SR5; SR6; SR3; OR5; OR6; or OR3; and is attached at the ring atom alpha to the ring atom attached to the triazinyl group.

[0095] In another embodiment, the compound is that of any of the formulae above wherein,

[0096] R2 is independently NHR3; and

[0097] R1 is one of the following groups: pyrrazolyl, triazolyl, benzimidazolyl, imidazolyl, or pyrrolyl, each optionally substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H).

[0098] In another embodiment, the compound is that of any of the formulae above wherein,

[0099] R2 is independently NHR3; and

[0100] R1 is one of the following groups: indolyl or tetrahydroquinolinyl, each optionally substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H).

[0101] In other embodiments, the compound is that of the formula first delineated above wherein,

[0102] R1 is independently heterocyclyl optionally substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H), wherein said heterocyclyl is not unsubstituted piperidine; and

[0103] R2 is independently NHR3;

[0104] alternatively wherein,

[0105] Each R1 is independently heteroaryl substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H), wherein said heteroaryl comprises at least one nitrogen heteroatom and said heteroaryl is attached at said nitrogen heteroatom;

[0106] alternatively wherein,

[0107] Each R1 is independently heteroaryl substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H), wherein said heteroaryl comprises at least one nitrogen heteroatom and said heteroaryl is attached at said nitrogen heteroatom; and

[0108] Each R2 is independently NHR3;

[0109] alternatively wherein,

[0110] Each R1 is independently heterocyclyl substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H), wherein said heterocyclyl is not unsubstituted piperidine, and said heterocyclyl comprises at least one nitrogen heteroatom and said heterocyclyl is attached at said nitrogen heteroatom; alternatively wherein,

[0111] Each R1 is independently heterocyclyl substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H), wherein said heterocyclyl is not unsubstituted piperidine, unsubstututed piperazine, 4-ethoxycarbonylpiperazine, or 4-(4-chlorophenyl)piperazine, and said heterocyclyl comprises at least one nitrogen heteroatom and said heterocyclyl is attached at said nitrogen heteroatom;

[0112] alternatively wherein,

[0113] Each R1 is independently heterocyclyl substituted with 1-4 independent R4 on each ring (and alternatively, wherein at least one R4 is not H), wherein said heterocyclyl is not unsubstituted piperidine, and said heterocyclyl comprises at least one nitrogen heteroatom and said heterocyclyl is attached at said nitrogen heteroatom; and

[0114] Each R2 is independently NHR3;

[0115] alternatively wherein,

[0116] Each R2 is independently NHR3; and

[0117] Each R1 is independently of the formula: 11

[0118] alternatively wherein,

[0119] Each R2 is independently NHR3; and

[0120] Each R1 is independently of the formula: 12

[0121] alternatively wherein,

[0122] Each R2 is independently NHR3; and

[0123] Each R1 is independently of the formula: 13

[0124] alternatively wherein,

[0125] Each R2 is independently NHR3; and

[0126] Each R1 is independently of the formula: 14

[0127] alternatively wherein,

[0128] Each R2 is independently NHR3; and

[0129] Each R1 is independently of the formula: 15

[0130] alternatively wherein R2 is independently NHR5;

[0131] alternatively wherein R2 is independently NHR5, wherein R5 may not be C2-C4 alkyl; allyl; ethyl optionally substituted with amino, diethylamino, morpholinyl, or pipridinyl; C(CH3)CH2COOH; CH2CH2COOH; CH2CH(CH3)COOH; C(OH)C(Cl)3; or CH(4-chlorophenyl) CH2CH3;

[0132] alternatively wherein each R1 is independently any one of following formulae: 16

[0133] and alternatively wherein R1 is independently any of of formulae above and R2 is independently NHR5.

[0134] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R1 is independently 17

[0135] wherein each R16 is independently C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8; or alternatively, independently C1-C10 alkyl substituted with 1-3 independent aryl or R8.

[0136] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R1 is independently 18

[0137] wherein each V, W, Y, and Z is each independently N or CR4, alternatively wherein at least one, and alternatively at least two of V, W, Y, and Z is independently N, and alternatively wherein not more than any two of V, W, Y, and Z is independently N.

[0138] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R1 is independently any one of the following groups: 19

[0139] wherein m is 0, 1, 2, 3 or 4; or alternatively m is 1, 2, 3 or 4.

[0140] or alternatively wherein,

[0141] Each R1 is independently any one of the following groups: 20

[0142] wherein m is 0, 1, 2, 3 or 4; or alternatively m is 1, 2, 3 or 4;

[0143] or alternatively wherein,

[0144] Each R1 is independently 21

[0145] wherein at least one R4 is not H;

[0146] or alternatively wherein,

[0147] Each R1 is independently 22

[0148] wherein R19 is independently H or C1-C6 alkyl; or alternatively wherein R19 is H;

[0149] or alternatively wherein,

[0150] Each R1 is independently 23

[0151] or alternatively wherein,

[0152] Each R1 is independently 24

[0153] wherein each R19 is independently H or C1-C6 alkyl; or alternatively wherein R19 is H; and

[0154] Each R21 is independently t-butyl, 4-carboxyphenyl, 4-carbomethoxyphenyl, or furyl substituted with 1-4 independent R4; or alternatively wherein,

[0155] Each R1 is independently 25

[0156] wherein R19 is independently H or C1-C6 alkyl; or alternatively wherein R19 is H;

[0157] or alternatively wherein,

[0158] Each R1 is independently 26

[0159] wherein each R19 is independently H or C1-C6 alkyl; or alternatively wherein R19 is H; and

[0160] Each R21 is independently t-butyl, 4-carboxyphenyl, 4-carbomethoxyphenyl, or furyl substituted with 1-4 independent R4;

[0161] or alternatively wherein,

[0162] Each R1 is independently 27

[0163] or alternatively wherein,

[0164] Each R1 is independently any one of the following groups: 2829

[0165] wherein R19 is independently H or C1-C6 alkyl or alternatively wherein R19 is H; and halo, aryl, m, R4 and R5 are as defined herein.

[0166] In one embodiment, the compound is that of any of the formulae herein wherein,

[0167] R1 is independently SR5; (alternatively where R5 is not H); and

[0168] R2 is independently NHR3.

[0169] In one embodiment, the compound is that of any of the formulae herein wherein,

[0170] R1 is independently OR5; (alternatively where R5 is not H); and

[0171] R2 is independently NHR3.

[0172] In one embodiment, the compound is that of any of the formulae herein wherein,

[0173] R1 is independently SR3; and

[0174] R2 is independently NHR3.

[0175] In one embodiment, the compound is that of any of the formulae herein wherein,

[0176] R1 is independently OR3; and

[0177] R1 is independently NHR3.

[0178] In one embodiment, the compound is that of any of the formulae herein wherein,

[0179] R1 is independently SR9; and

[0180] R2 is independently NHR3.

[0181] In one embodiment, the compound is that of any of the formulae herein wherein,

[0182] R1 is independently OR9; and

[0183] R2 is independently NHR3.

[0184] In one embodiment, the compound is that of any of the formulae herein wherein,

[0185] R1 is independently S-aryl; and

[0186] R2 is independently NHR3.

[0187] In one embodiment, the compound is that of any of the formulae herein wherein,

[0188] R1 is independently O-aryl; and

[0189] R2 is independently NHR3.

[0190] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R2 is independently NHR3; those wherein R2 is independently NHR3 and said R3 is phenyl substituted with 1-4 independent R4 (and alternatively where at least one, alternatively at least two, and alternatively at least three, of said R4 is not H); those wherein R2 is independently NHR3 and said R3 is heteroaryl substituted with 1-4 independent (and alternatively where at least one, alternatively at least two, and alternatively at least three, of said R4 is not H); those wherein each R2 is independently NHR3, wherein said R3 is 3,4,5-trimethoxyphenyl; and those wherein each R2 is independently NHR3, wherein said R3 is carboxymethylphenyl or C(O)NH2-substituted phenyl; those wherein R1 is independently SR3 and said R3 is phenyl substituted with 1-4 independent R4 (and alternatively where at least one, alternatively at least two, and alternatively at least three, of said R4 is not H); those wherein R1 is independently SR3 and said R3 is heteroaryl substituted with 1-4 independent (and alternatively where at least one, alternatively at least two, and alternatively at least three, of said R4 is not H); those wherein R1 is independently OR3 and said R3 is phenyl substituted with 1-4 independent R4 (and alternatively where at least one, alternatively at least two, and alternatively at least three, of said R4 is not H); those wherein R1 is independently OR3 and said R3 is heteroaryl substituted with 1-4 independent (and alternatively where at least one, alternatively at least two, and alternatively at least three, of said R4 is not H).

[0191] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R1 and R2 is independently R3; R8; NHR3; NHR5; NHR6; NR5R5; NR5R6; SR5; SR6; OR5; OR6; C(O)R3; heterocyclyl optionally substituted with 1-4 independent R4 on each ring; or C1-C10 alkyl substituted with 1-4 independent R4;

[0192] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from H, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; aryl; R8; halo; haloalkyl; CF3; SR5; OR5; OC(O)R5; NR5R5; NR5R6; NR5R16; COOR5; NO2; CN; C(O)R5; C(O)C(O)R5; C(O)NR5R5; S(O)nR5; S(O)nNR5R5; NR5C(O)NR5R5; NR5C(O)C(O)R5; NR5C(O)R5; NR5(COOR5); NR5C(O)R8; NR5S(O)nNR5R5; NR5S(O)nR5; NR5S(O)nR8; NR5C(O)C(O)NR5R5; NR5C(O)C(O)NR5R6; C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8; or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8.

[0193] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from halo.

[0194] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8.

[0195] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from C1-C10 alkyl; C2-C10 alkenyl; or C2-C10 alkynyl.

[0196] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from haloalkyl.

[0197] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from SR5.

[0198] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from OR5.

[0199] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from NR5R5.

[0200] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from NR5R6.

[0201] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently any one of COOR5; CN; C(O)R5; or C(O)NR5R5.

[0202] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently any one of NR5C(O)NR5R5; NR5C(O)r5; NR5(COOR5); NR5C(O)R8; NR5S(O)nNR5R5; NR5 S(O)nR5; or NR5S(O)nhu 8.

[0203] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from C1-C10 alkyl substituted with 1-3 independent aryl.

[0204] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from C1-C10 alkyl subsituted with 1-3 independent R7.

[0205] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R4 is independently selected from C1-C10 alkyl substituted with 1-3 independent R8.

[0206] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R7 is independently halo, CF3, SR10, OR10, OC(O)R10, NR10R10, NR10 R11, NR11R11, OOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10)(COOR10), S(O)nNR10R10.

[0207] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R6 is independently C(O)R5, COOR5, C(O)NR5R5, or S(O)n R5;

[0208] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein when any group (e.g., phenyl, benzimidazolyl, heteroaryl, heterocyclyl, and the like) may be substituted, or optionally substituted, with 1-4 (or alternatively 1-5) independent R4, wherein at least one, or alternatively at least two, or alternatively at least three of the independent R4, is not H.

[0209] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each heterocyclyl is independently a 3-8, or alternatively a 5-8, or alternatively a 5-6, or alternatively a 5, or alternatively a 6, membered nonaromatic monocyclic, a 7-12, or alternatively an 8-12, or alternatively an 8-10, membered nonaromatic bicyclic, or 11-14 membered nonaromatic tricyclic, ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, and substituted as delineated herein.

[0210] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein each R8 or R9 is independently a 3-8, or alternatively a 5-8, or alternatively a 5-6, or alternatively a 5, or alternatively a 6, membered monocyclic, a 7-12, or alternatively an 8-12, or alternatively an 8-10, membered bicyclic, or a 10-14, or alternatively 11-14 membered tricyclic, ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, and substituted as delineated herein.

[0211] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein additionally, each R1 group may not simultaneously be the same as each R2 group.

[0212] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein additionally, each R1 and R2 group is not NHC(O)R5, and alternatively, not NHAc.

[0213] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein additionally, each R1 and R2 group is not NH2.

[0214] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein additionally, each R1 and R2 group is not OH, SH, or NH2.

[0215] Alternate embodiments of the invention are those of any of the formulae delineated herein, wherein when both R1 and R2 groups are NHR3, and R3 is pyridyl, or aryl, or phenyl optionally siubstituted with 1-5 R4, each R1 group may not simultaneously be the same as each R2 group.

[0216] The invention also relates to methods of inhibiting enzyme or polypeptide activity, particularly of an enzyme or polypeptide described herein, such as a phosphoryl tranferase, or alternatively a kinase, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein. In one embodiment, the invention relates to a method of inhibiting phosphoryl transferase, alternatively kinase, activity in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any one of the formulae described herein. Preferably, the mammal is a human.

[0217] In another embodiment, the invention relates to a method of inhibiting enzyme activity in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.

[0218] The invention also relates to methods of treating disease and/or disease symptoms, particularly those mediated by an enzyme or polypeptide described herein, such as phosphoryl transferase mediated, or kinase mediated, disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound of any of the formulae described herein or a composition comprising a compound of any of the formulae described herein. Such diseases or disease symptoms are described herein. “Kinase mediated” disease or disease symptoms refers to disease or disease symptoms in which kinase activity is involved. In one embodiment, this invention relates to a method of treating disease or disease symptoms, particularly kinase mediated disease or disease symptoms, in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.

[0219] In an alternate embodiment, this invention relates to a method of treating disease or disease symptoms in a mammal comprising the step of administering to said mammal a compound, or a composition comprising a compound, of any of the formulae described herein. Preferably, the mammal is a human.

[0220] In the compounds described herein, the term “halo” refers to any radical of fluorine, chlorine, bromine or iodine. The terms “alkyl”, “alkenyl” and “alkynyl” refer to hydrocarbon chains that may be straight-chain or branched-chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates the group may have from 1 to 10 (inclusive) carbon atoms in it. The terms “ring” and “ring system” refer to a ring comprising the delineated number of atoms, said atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed. The term “nonaromatic” ring or ring system refers to the fact that at least one, but not necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic.

[0221] Leaving groups are species that may be detached from a molecule during a reaction and are known in the art. Examples of such groups include, but are not limited to, halogen groups (e.g., I, Br, F, Cl), sulfonate groups (e.g., mesylate, tosylate), sulfide groups (e.g., SCH3), and the like. Nucleophiles are species that may be attached to a molecule during reaction and are known in the art. Examples of such groups include, but are not limited to, amines, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.

[0222] In the methods described herein, said mammal is preferably a human. The inhibitors described herein, however, are useful in inhibiting kinase activity in human cells and useful in rodent (e.g., murine) and other species used as surrogates for investigating activity in vitro and in vivo in humans and against human kinases. The inhibitors described herein are also useful for investigating inhibition and activity of kinases originating from species other than humans.

[0223] The compounds and compositions described herein are useful for inhibition of kinase activity of one or more enzymes. Kinases include, for example, protein kinases (e.g., tyrosine, serone/threonine, histidine), lipid kinases (e.g., phosphatidylinositol kinases PI-3, PI-4) and carbohydrate kinases. Further information relating to kinase structure, function and and their role in disease or disease symptoms is available at the Protein Kinase Resource web site (http://www.sdsc.edu/Kinases/pk home.html). Kinases may be of prokaryotic, eukaryotic, bacterial, viral, fungal or archaea origin. Specifically, the compounds described herein are useful as inhibitors of tyrosine, serine/threonine or histidine protein kinases, (including combinations or those of mixed specificity, that is for exmaple, those that phosphorylate both tyrosine and serine/threonine residues) or lipid kinases. Examples of kinases that are inhibited by the compounds and compositions described herein and against which the methods described herein are useful include, but are not limited to, LCK, IRK (=INSR=Insulin receptor), IGF-1 receptor, SYK, ZAP-70, IRAK1, BLK, BMX, BTK, FRK, FGR, FYN, HCK, ITK, LYN, TEC, TXK, YES, ABL, SRC, EGF-R (=ErbB-1), ErbB-2 (=NEU=HER2), ErbB4, FAK, FGF1R (=FGR-1), FGF2R (=FGR-2), IKK-1 (=IKK-ALPHA=CHUK), IKK-2 (=IKK-BETA), MET (=c-MET), NIK, PDGF receptor ALPHA, PDGF receptor BETA, TIE1, TIE2 (=TEK), VEGFR1 (=FLT-1), VEGFR2 (=KDR), FLT-3, FLT-4, KIT, CSK, JAK1, JAK2, JAK3, TYK2, RIP, RIP-2, LOK, TAKI, RET, ALK, MLK3, COT, TRKA, PYK2, Activin-like Kinases (Alk1-7), EPHA(1-8), EPHB(1-6), RON, GSK3(A and B), Ilk, PDK1, SGK, Fes, Fer, MatK, Ark(1-3), Plk(1-3), LimK(1 and 2), RhoK, Pak (1-3), Raf(A, B, and C), PknB, CDK(1-10), Chk(1 and 2), CamK(I-IV), CamKK, CK1, CK2, PKR, Jnk(1-3), EPHB4, UL13, ORF47, ATM, PKA (α, β, and γ), P38(α, β, and γ), Erk(1-3), PKB (including all PKB subtypes) (=AKT-1, AKT-2, AKT-3), and PKC (including all PKC subtypes). The compounds and compositions of the invention are therefore also particularly suited for treatment of diseases and disease symptoms that involve one or more of the aforementioned protein kinases. In one embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by any of LCK, ZAP, LYN, EGFR, ERBB-2, KDR, c-MET, SYK, or IGF-1R. In another embodiment, the compounds, compositions or methods of this invention are particularly suited for inhibition of or treatment of disease or disease symptoms mediated by kinases defined by Hardie & Hanks, ed. supra as in the the Src family (PTK-I), Syk/Zap family (PTK-VI), EGFR family (PTK-X), HGF Family (PTK-XXI), Insulin receptor family (PTK-XVI), Tie/Tek family (PTK-XIII), Platelet-derived growth factor receptor family (PTK-XIV), or Fibroblast growth factor receptor family (PTK-XV), and more particularly, KDR, FLT-1, FLT-3 or RET; or EGFR, c-MET, ErbB2, or IGF-1R. The compounds and compositions are also suited for regulating or modulating signal transduction in signal transduction pathways that involve one or more kinases, thus affecting events in a cell, and are therefor useful in methods for regulating or modulating signal transduction.

[0224] The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a phosphoryl transferase sequence, or alternatively a kinase sequence, including the kinases mentioned herein. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme comprising a subsequence, or variant thereof, of any enzyme that comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with a phosphoryl transferase subsequence, or alternatively kinase subsequence, including subsequences of the kinases mentioned herein. Such subsequence preferably comprises greater than 90%, alternatively greater than 85%, or alternatively greater than 70% sequence homology with the sequence of an active site or subdomain of a phosphoryl transferase, or alternatively kinase, enzyme. The subsequences, or variants thereof, comprise at least about 300, or alternatively at least about 200, amino acids.

[0225] The inhibitors described herein are useful for inhibiting the biological activity of any enzyme that binds ATP and/or GTP and thus for treating disease or disease symptoms mediated by any enzyme that binds ATP and/or GTP. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme that binds adenine or guanine nucleotides. The inhibitors described herein are also useful for inhibiting the biological activity of any enzyme that is involved in phosphotransfer and thus for treating disease or disease symptoms mediated by any enzyme that is involved in phosphotransfer. The inhibitors described herein are also useful for inhibiting the biological activity of a polypeptide or enzyme having sequence homology with a phosphoryl transferase, or alternatively kinase, sequence and thus for treating disease or disease symptoms mediated by such polypeptide or enzyme. Such polypeptides or enzymes may be identified by comparison of their sequence with phosphoryl transferase, alternatively kinase, sequences and phosphoryl transferase, alternatively kinase, catalytic domain sequences. Such sequences may be found, for example, in databases such as GENEBANK, EMBO, or other similar databases known in the art. For example, one method of comparison involves the database PROSITE (http://expasy.hcuge.ch) (See, Hofmann K., Bucher P., Falquet L., Bairoch A., The PROSITE database, its status in 1999, Nucleic Acids Res. 27:215-219(1999)), containing “signatures” or sequence patterns (or motifs) or profiles of protein families or domains. Thus, the inhibitors described herein are useful for inhibiting the biological activity of a polypeptide or enzyme comprising a sequence that comprises a “signature” or sequence pattern or profile derived for, and identified in PROSITE as relating to kinases, and for treating disease or disease symptoms mediated by such polypeptide or enzyme. Examples of such PROSITE motifs or consensus patterns identified as relating to kinases include PS00107, PS00108, PS00109, PS00112, PS00583, PS00584, PS50011, PS50290, PS00915, and PS00916.

[0226] The inhibitors described herein are also useful for inhibiting the biological activity of ATP/GTP binding proteins. Many ATP/GTP binding proteins have consensus motifs that can be used to identify them. For example, PROSITE entry PDOC00017 titled “ATP/GTP-binding site motif A (P-loop)” describes a consensus pattern (called the A consensus sequence or the P-loop) for a large group of nucleotide binding proteins including ATP synthases, DNA and RNA helicases, ABC transporters, Kinesin and kinesin-like proteins, among many others. Other nucleotide binding proteins have motifs similar to this P-loop, but take slightly different forms. Examples of these include tubulins, lipid kinases and protein kinases. The ATP binding motif of protein kinases have also been defined within PROSITE entry PS00107. Yet other AGBPs have nothing similar to the P-loop motif. Examples of these include E1-E2 ATPases and the glycolytic kinases.

[0227] The compounds, compositions and methods described herein are useful in inhibiting kinase activity. As such, the compounds, compositions and methods of this invention are useful in treating kinase-mediated disease or disease symptoms in a mammal, particularly a human. Kinase mediated diseases are those wherein a protein kinase is involved in signaling, mediation, modulation, or regulation of the disease process or symptoms. Kinase mediated diseases are exemplified by the following disease classes: cancer, autoimmunological, metabolic, inflammatory, infection (bacterial, viral, yeast, fungal, etc.), diseases of the central nervous system, degenerative neural disease, allergy/asthma, dermatology, angiogenesis, neovascularization, vasculogenesis, cardiovascular, and the like.

[0228] The compounds, compositions and methods described herein are useful in treating or preventing diseases, including, transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel, skin allografts or xenografts), graft versus host disease, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes, diabetic retinopathy, asthma, allergy, inflammatory bowel disease (Crohn's disease, ulcerative colitis), renal disease, cachexia, septic shock, lupus, diabetes mellitus, myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, Alzheimer's disease, Parkinson's disease, depression, stem cell protection during chemotherapy, ex vivo selection or ex vivo purging for autologous or allogeneic bone marrow transplantation, leukemia (acute myeloid, chronic myeloid, acute lymphoblastic, etc.), cancer (breast, lung, colorectal, ovary, prostate, renal, squamous cell, prostate, glioblastoma, melanoma, pancreatic, Kaposi's sarcoma, etc.), occular disease, retinopathies, (e.g., macular degeneration, diabetic retinopathy), corneal disease, glaucoma, bacterial infections, viral infections, fungal infections and heart disease, including but not limited to, restenosis. In one embodiment, the compositions and methods described herein are useful in treating or preventing rheumatoid arthritis, macular degeneration, diabetic retinopathy, psoriasis, restenosis, Kaposi's sarcoma, or cancer. In another embodiment, the compositions and methods described herein are useful in treating or preventing macular degeneration, retinopathies, ocular disease, or cancer.

[0229] Another embodiment envisioned by this invention relates to the use of the kinase inhibitory compounds described herein for use as reagents that effectively bind to kinases. As reagents, the compounds of this invention, and their derivatives, may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. Such derivatives may be used in purification of enzymes, including phosphoryl transferases and kinases. The compounds of this invention, and their derivatives, may also be modified (e.g., radiolabelled or affinity labelled, etc.) in order to utilize them in the investigation of enzyme or polypeptide characterization, structure, and/or function. Additionally, the compounds described herein are useful as reagents for chemical validation of drug targets. These and other uses that characterize kinase inhibitors will be evident to those of ordinary skill in the art.

[0230] In another embodiment, the inhibitors described herein are useful for crystallizing or co-crystallizing with a protein kinase. Such crystals or crystal complexes may additionally comprise additional peptides and or metal ions. The crystals or crystal complexes may be used for investigation and determination of enzyme characteristics including, for example, structure of the kinase enzyme, enzyme active site domains, and inhibitor-enzyme interactions. This information is useful in developing inhibitor compounds with modified characteristics and for understanding structure-function relationships of the enzymes and their enzyme-inhibitor interactions.

[0231] In an alternate embodiment, the inhibitory compounds described herein may be used as platforms or scaffolds which may be utilized in combinatorial chemistry techniques for preparation of derivatives and/or chemical libraries of compounds. Such derivatives and libraries of compounds have kinase inhibitory activity and are useful for identifying and designing compounds possessing kinase inhibitory activity. Combinatorial techniques suitable for utilizing the compounds described herein are known in the art as exemplified by Obrecht, D. and Villalgrodo, J. M., Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon-Elsevier Science Limited (1998), and include those such as the “split and pool” or “parallel” synthesis techniques, solid-phase and solution-phase techniques, and encoding techniques (see, for example, Czarnik, A. W., Curr. Opini. Chem. Bio., (1997). 1, 60. Thus, one embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing a body comprising a plurality of wells; 2) providing one or more compounds of the formulae described herein in each well; 3) providing an additional one or more chemicals in each well; 4) isolating the resulting one or more products from each well. An alternate embodiment relates to a method of using the compounds described in the formulae herein for generating derivatives or chemical libraries comprising: 1) providing one or more compounds of the formulae described herein attached to a solid support; 2) treating the one or more compounds of the formulae described herein attached to a solid support with one or more additional chemicals; 3) isolating the resulting one or more products from the solid support. In the methods described above, “tags” or identifier or labeling moieties may be attached to and/or detached from the compounds of the formulae herein or their derivatives, to facilitate tracking, identification or isolation of the desired products or their intermediates. Such moieties are known in the art. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. Examples of such chemicals are those that appear in the various synthetic and protecting group chemistry texts and treatises referenced herein.

[0232] The compounds of the formulae herein may be used to study the mechanism and role of enzymes in biological pathways and processes involving kinases. The compounds of the formulae herein may also be used as probes to identify new kinase enzymes or polypeptides with sequence homology to kinases. The inhibitor compounds may be tethered to a support or modified (e.g., tagged, radiolabeled or other identifiable detection method) such that the compound may be detected and isolated in the presence of the kinase enzyme or polypeptide. Thus, another embodiment relates to a method of identifying and/or isolating a kinase enzyme or polypeptide with sequence homology to a kinase enzyme sequence or subsequence, comprising, contacting a tethered or modified compound of any of the formulae herein with one or more polypeptides, isolating a polypeptide/inhibitor complex, and identifying or isolating the sequence of the polypeptide in the polypeptide/inhibitor complex. The identification of the polypeptide sequence may be performed while in the polypeptide/inhibitor complex or after the polypeptide is decomplexed from the tethered or modified compound of any of the formulae herein.

[0233] The compounds are also useful in inhibiting enzymes, including kinases, that play a role in plant metabolism regulation, plant growth or growth inhibition. As such the compounds and compositions of the invention are useful as plant growth regulators, and as herbicides. Such compositions comprise the compounds of the invention as well as any agricultural or other acceptable carrier for dispersal of the active compound.

[0234] Table 1 lists representative individual compounds of the invention and compounds employed in the compositions and methods of this invention.

TABLE 1
1	30	2	31
3	32	4	33
5	34	6	35
7	36	8	37
9	38	10	39
11	40	12	41
13	42	14	43
15	44	16	45
17	46	18	47
19	48	20	49
21	50	22	51
23	52	24	53
25	54	26	55
27	56	28	57
29	58	30	59
31	60	32	61
33	62	34	63
35	64	36	65
37	66	38	67
39	68	40	69
41	70	42	71
43	72	44	73
45	74	46	75
47	76	48	77
49	78	50	79
51	80	52	81
53	82	54	83
55	84	56	85
57	86	58	87
59	88	60	89
61	90	62	91
63	92	64	93
65	94	66	95
67	96	68	97
69	98	70	99
71	100	72	101
73	102	74	103
75	104	76	105
77	106	78	107
79	108	80	109
81	110	82	111
83	112	84	113
85	114	86	115
87	116	88	117
89	118	90	119
91	120	92	121
93	122	94	123
95	124	96	125
97	126	98	127
99	128	100	129
101	130	102	131
103	132	104	133
105	134	106	135
107	136	108	137
109	138	110	139
111	140	112	141
113	142	114	143
115	144	116	145
117	146	118	147
119	148	120	149
121	150	122	151
123	152	124	153
125	154	126	155
127	156	128	157
129	158	130	159
131	160	132	161
133	162	134	163
135	164	136	165
137	166	138	167
139	168	140	169
141	170	142	171
143	172	144	173
145	174	146	175
147	176	148	177
149	178	150	179
151	180	152	181
153	182	154	183
155	184	156	185
157	186	158	187
159	188	160	189
161	190	162	191
163	192	164	193
165	194	166	195
167	196	168	197
169	198	170	199
171	200	172	201
173	202	174	203
175	204	176	205
177	206	178	207
179	208	180	209
181	210	182	211
183	212	184	213
185	214	186	215
187	216	188	217
189	218	190	219
191	220	192	221
193	222	194	223
195	224	196	225
197	226	198	227
199	228	200	229
201	230	202	231
203	232	204	233
205	234	206	235
207	236	208	237
209	238	210	239
211	240	212	241
213	242	214	243
215	244	216	245
217	246	218	247
219	248	220	249
221	250	222	251
223	252	224	253
225	254	226	255
227	256	228	257
229	258	230	259
231	260	232	261
233	262	234	263
235	264	236	265
237	266	238	267
239	268	240	269
241	270	242	271
243	272	244	273
245	274	246	275
247	276	248	277
249	278	250	279
251	280	252	281
253	282	254	283
255	284	256	285
257	286	258	287
259	288	260	289
261	290	262	291
263	292	264	293
265	294	266	295
267	296	268	297
269	298	270	299
271	300	272	301
273	302	274	303
275	304	276	305
277	306	278	307
279	308	280	309
281	310	282	311
283	312	284	313
285	314	286	315
287	316	288	317
289	318	290	319
291	320	292	321
293	322	294	323
295	324	296	325
297	326	298	327
299	328	300	329
301	330	302	331
303	332	304	333
305	334	306	335
307	336	308	337
309	338	310	339
311	340	312	341
313	342	314	343
315	344	316	345
317	346	318	347
319	348	320	349
321	350	322	351
323	352	324	353
325	354	326	355
327	356	328	357
329	358	330	359
331	360	332	361
333	362	334	363
335	364	336	365
337	366	338	367
339	368	340	369
341	370	342	371
343	372	344	373
345	374	346	375
347	376	348	377
349	378	350	379
351	380	352	381
353	382	354	383
355	384	356	385
357	386	358	387
359	388	360	389
361	390	362	391
363	392	364	393
365	394	366	395
367	396	368	397
369	398	370	399
371	400	372	401
373	402	374	403
375	404	376	405
377	406	378	407
379	408	380	409
381	410	382	411
383	412	384	413
385	414	386	415
387	416	388	417
389	418	390	419
391	420	392	421
393	422	394	423
395	424	396	425
397	426	398	427
399	428	400	429
401	430	402	431
403	432	404	433
405	434	406	435
407	436	408	437
409	438	410	439
411	440	412	441
413	442	414	443
415	444	416	445
417	446	418	447
419	448	420	449
421	450	422	451
423	452	424	453
425	454	426	455
427	456	428	457
429	458	430	459
431	460	432	461
433	462	434	463
435	464	436	465
437	466	438	467
439	468	440	469
441	470	442	471
443	472	444	473
445	474	446	475
447	476	448	477
449	478	450	479
451	480	452	481
453	482	454	483
455	484	456	485
457	486	458	487
459	488	460	489
461	490	462	491
463	492	464	493
465	494	466	495
467	496	468	497
469	498	470	499
471	500	472	501
473	502	474	503
475	504	476	505
477	506	478	507
479	508	480	509
481	510	482	511
483	512	484	513
485	514	486	515
487	516	488	517
489	518	490	519
491	520	492	521
493	522	494	523
495	524	496	525
497	526	498	527
499	528	500	529
501	530	502	531
503	532	504	533
505	534	506	535
507	536	508	537
509	538	510	539
511	540	512	541
513	542	514	543
515	544	516	545
517	546	518	547
519	548	520	549
521	550	522	551
523	552	524	553
525	554	526	555
527	556	528	557
529	558	530	559
531	560	532	561
533	562	534	563
535	564	536	565
537	566	538	567
539	568	540	569
541	570	542	571
543	572	544	573
545	574	546	575
547	576	548	577
549	578	550	579
551	580	552	581
553	582	554	583
555	584	556	585
557	586	558	587
559	588	560	589
561	590	562	591
563	592	564	593
565	594	566	595
567	596	568	597
569	598	570	599
571	600	572	601
573	602	574	603
575	604	576	605
577	606	578	607
579	608	580	609
581	610	582	611
583	612	584	613
585	614	586	615
587	616	588	617
589	618	590	619
591	620	592	621
593	622	594	623
595	624	596	625
597	626	598	627
599	628	600	629
601	630	602	631
603	632	604	633
605	634	606	635
607	636	608	637
609	638	610	639
611	640	612	641
613	642	614	643
615	644	616	645
617	646	618	647
619	648	620	649
621	650	622	651
623	652	624	653
625	654	626	655
627	656	628	657
629	658	630	659
631	660	632	661
633	662	634	663
635	664	636	665
637	666	638	667
639	668	640	669
641	670	642	671
643	672	644	673
645	674	646	675
647	676	648	677
649	678	650	679
651	680	652	681
653	682	654	683
655	684	656	685
657	686	658	687
659	688	660	689
661	690	662	691
663	692	664	693
665	694	666	695
667	696	668	697
669	698	670	699
671	700	672	701
673	702	674	703
675	704	676	705
677	706	678	707
679	708	680	709
681	710	682	711
683	712	684	713
685	714	686	715
687	716	688	717
689	718	690	719
691	720	692	721
693	722	694	723
695	724	696	725
697	726	698	727
699	728	700	729
701	730	702	731
703	732	704	733
705	734	706	735
707	736	708	737
709	738	710	739
711	740	712	741
713	742	714	743
715	744	716	745
717	746	718	747
719	748	720	749
721	750	722	751
723	752	724	753
725	754	726	755
727	756	728	757
729	758	730	759
731	760	732	761
733	762	734	763
735	764	736	765
737	766	738	767
739	768	740	769
741	770	742	771
743	772	744	773
745	774	746	775
747	776	748	777
749	778	750	779
751	780	752	781
753	782	754	783
755	784	756	785
757	786	758	787
759	788	760	789
761	790	762	791
763	792	764	793
765	794	766	795
767	796	768	797
769	798	770	799
771	800	772	801
773	802	774	803
775	804	776	805
777	806	778	807
779	808	780	809
781	810	782	811
783	812	784	813
785	814	786	815
787	816	788	817
789	818	790	819
791	820	792	821
793	822	794	823
795	824	796	825
797	826	798	827
799	828	800	829
801	830	802	831
803	832	804	833
805	834	806	835
807	836	808	837
809	838	810	839
811	840	812	841
813	842	814	843
815	844	816	845
817	846	818	847
819	848	820	849
821	850	822	851
823	852	824	853
825	854	826	855
827	856	828	857
829	858	830	859
831	860	832	861
833	862	834	863
835	864	836	865
837	866	838	867
839	868	840	869
841	870	842	871
843	872	844	873
845	874	846	875
847	876	848	877
849	878	850	879
851	880	852	881
853	882	854	883
855	884	856	885
857	886	858	887
859	888	860	889
861	890	862	891
863	892	864	893
865	894	866	895
867	896	868	897
869	898	870	899
871	900	872	901
873	902	874	903
875	904	876	905
877	906	878	907
879	908	880	909
881	910	882	911
883	912	884	913
885	914	886	915
887	916	888	917
889	918	890	919
891	920	892	921
893	922	894	923
895	924	896	925
897	926	898	927
899	928	900	929
901	930	902	931
903	932	904	933
905	934	906	935
907	936	908	937
909	938	910	939
911	940	912	941
913	942	914	943
915	944	916	945
917	946	918	947
919	948	920	949
921	950	922	951
923	952	924	953
925	954	926	955
927	956	928	957
929	958	930	959
931	960	932	961
933	962	934	963
935	964	936	965
937	966	938	967
939	968	940	969
941	970	942	971
943	972	944	973
945	974	946	975
947	976	948	977
949	978	950	979
951	980	952	981
953	982	954	983
955	984	956	985
957	986	958	987
959	988	960	989
961	990	962	991
963	992	964	993
965	994	966	995
967	996	968	997
969	998	970	999
971	1000	972	1001
973	1002	974	1003
975	1004	976	1005
977	1006	978	1007
979	1008	980	1009
981	1010	982	1011
983	1012	984	1013
985	1014	986	1015
987	1016	988	1017
989	1018	990	1019
991	1020	992	1021
993	1022	994	1023
995	1024	996	1025
997	1026	998	1027
999	1028	1000	1029
1001	1030	1002	1031
1003	1032	1004	1033
1005	1034	1006	1035
1007	1036	1008	1037
1009	1038	1010	1039
1011	1040	1012	1041
1013	1042	1014	1043
1015	1044	1016	1045
1017	1046	1018	1047
1019	1048	1020	1049
1021	1050	1022	1051
1023	1052	1024	1053
1025	1054	1026	1055
1027	1056	1028	1057
1029	1058	1030	1059
1031	1060	1032	1061
1033	1062	1034	1063
1035	1064	1036	1065
1037	1066	1038	1067
1039	1068	1040	1069
1041	1070	1042	1071
1043	1072	1044	1073
1045	1074	1046	1075
1047	1076	1048	1077
1049	1078	1050	1079
1051	1080	1052	1081
1053	1082	1054	1083
1055	1084	1056	1085
1057	1086	1058	1087
1059	1088	1060	1089
1061	1090	1062	1091
1063	1092	1064	1093
1065	1094	1066	1095
1067	1096	1068	1097
1069	1098	1070	1099
1071	1100	1072	1101
1073	1102	1074	1103
1075	1104	1076	1105
1077	1106	1078	1107
1079	1108	1080	1109
1081	1110	1082	1111
1083	1112	1084	1113
1085	1114	1086	1115
1087	1116	1088	1117
1089	1118	1090	1119
1091	1120	1092	1121
1093	1122	1094	1123
1095	1124	1096	1125
1097	1126	1098	1127
1099	1128	1100	1129
1101	1130	1102	1131
1103	1132	1104	1133
1105	1134	1106	1135
1107	1136	1108	1137
1109	1138	1110	1139
1111	1140	1112	1141
1113	1142	1114	1143
1115	1144	1116	1145
1117	1146	1118	1147
1119	1148	1120	1149
1121	1150	1122	1151
1123	1152	1124	1153
1125	1154	1126	1155
1127	1156	1128	1157
1129	1158	1130	1159
1131	1160	1132	1161
1133	1162	1134	1163
1135	1164	1136	1165
1137	1166	1138	1167
1139	1168	1140	1169
1141	1170	1142	1171
1143	1172	1144	1173
1145	1174	1146	1175
1147	1176	1148	1177
1149	1178	1150	1179
1151	1180	1152	1181
1153	1182	1154	1183
1155	1184	1156	1185
1157	1186	1158	1187
1159	1188	1160	1189
1161	1190	1162	1191
1163	1192	1164	1193
1165	1194	1166	1195
1167	1196	1168	1197
1169	1198	1170	1199
1171	1200	1172	1201
1173	1202	1174	1203
1175	1204	1176	1205
1177	1206	1178	1207
1179	1208	1180	1209
1181	1210	1182	1211
1183	1212	1184	1213
1185	1214	1186	1215
1187	1216	1188	1217
1189	1218	1190	1219
1191	1220	1192	1221
1193	1222	1194	1223
1195	1224	1196	1225
1197	1226	1198	1227
1199	1228	1200	1229
1201	1230	1202	1231
1203	1232	1204	1233
1205	1234	1206	1235
1207	1236	1208	1237
1209	1238	1210	1239
1211	1240	1212	1241
1213	1242	1214	1243
1215	1244	1216	1245
1217	1246	1218	1247
1219	1248	1220	1249
1221	1250	1222	1251
1223	1252	1224	1253
1225	1254	1226	1255
1227	1256	1228	1257
1229	1258	1230	1259
1231	1260	1232	1261
1233	1262	1234	1263
1235	1264	1236	1265
1237	1266	1238	1267
1239	1268	1240	1269
1241	1270	1242	1271
1243	1272	1244	1273
1245	1274	1246	1275
1247	1276	1248	1277
1249	1278	1250	1279
1251	1280	1252	1281
1253	1282	1254	1283
1255	1284	1256	1285
1257	1286	1258	1287
1259	1288	1260	1289
1261	1290	1262	1291
1263	1292	1264	1293
1265	1294	1266	1295
1267	1296	1268	1297
1269	1298	1270	1299
1271	1300	1272	1301
1273	1302	1274	1303
1275	1304	1276	1305
1277	1306	1278	1307
1279	1308	1280	1309
1281	1310	1282	1311
1283	1312	1284	1313
1285	1314	1286	1315
1287	1316	1288	1317
1289	1318	1290	1319
1291	1320	1292	1321
1293	1322	1294	1323
1295	1324	1296	1325

[0235] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications). Typically, such compounds are stable at a temperature of 40° C. or less, in the absence of excessive moisture for at least one week.

[0236] As used herein, the compounds of this invention, including the compounds of formulae described herein, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A “pharmaceutically acceptable derivative or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.

[0237] Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4+ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0238] The compounds of this invention may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. In general, the compounds of the formulae described herein are conveniently obtained via methods illustrated in General Synthetic Schemes 1-2 and the Examples herein. These general schemes are also exemplified by the specific methods described in the Examples section below. General Synthetic Schemes 1-2 and the examples utilize general chemical group descriptors (e.g., X, R3, R5) that are meant to be representative of any group suitable for synthesis of the compounds delineated herein. Such groups are exemplified by and include, but are not limited to, those defined in the definitions of the groups designated R3, R4, R5, R16, R17, and R20, for example, in the formulae herein.

[0239] Thus, one embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the synthetic schemes herein and then converting that intermediate(s) to a compound of the formulae described herein. Another embodiment relates to a method of making a compound of the formulae described herein, comprising synthesizing any one or more intermediates illustrated in the examples herein and then converting that intermediate(s) to a compound of the formulae described herein. Nucleophilic agents are known in the art and are described in the chemical texts and treatises referred to herein. The chemicals used in the aforementioned methods may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like. The methods described above may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein. 13261327

[0240] In one embodiment, the invention relates to a process for making a compound of any of the formulae described herein, comprising reacting a triazine of one or more of the formulae: 1328

[0241] with an appropriate nucleophilic agent or agents, wherein the groups in said formulae are as defined herein.

[0242] In one embodiment, the invention relates to a process for making a compound of any of the formulae described herein, comprising reacting a triazine of one or more of the formulae: 1329

[0243] with an appropriate nucleophilic agent or agents, wherein L is defined as a leaving group and the groups in said formulae are as defined herein.

[0244] In one embodiment, the invention relates to a process for making a compound of the formula 1330

[0245] wherein

[0246] Each R1 and R2 is independently R3; R8; NHR3; NHR5; NHR6; NR5R5; NR5R6; SR5; SR6; SR3; OR5; OR6; OR3; C(O)R3; heterocyclyl optionally substituted with 1-4 independent R4 on each ring; or C1-C10 alkyl substituted with 1-4 independent R4; or alternatively each R1 and R2 is independently R3; R8; NHR3; NHR5; NHR6; NR5R5; NR5R6; SR5; SR6; OR5; OR6; C(O)R3; heterocyclyl optionally substituted with 1-4 independent R4 on each ring; or C1-C10 alkyl substituted with 1-4 independent R4;

[0247] Each R3 is independently aryl; phenyl optionally substituted with 1-5 independent R4 on each ring; or heteroaryl optionally substituted with 1-4 independent R4 on each ring; and all other substituents are as defined herein; comprising the steps of: 1331

[0248] a) reacting a compound of formula (II) wherein each L is independently a leaving group as defined herein, with a nucleophile of formula H—R1 (or salt thereof) to give a compound of formula (III); and

[0249] b) reacting the compound of formula (III) with a nucleophile of formula H—R2 (or salt thereof) to give a compound of formula (I).

[0250] In another embodiment, the process above is carried out by utilizing a nucleophile H—R2 in step (a), then utilizing a nucleophile H—R1 in step (b), as shown: 1332

[0251] L is defined as a leaving group, and R1 and R2 are as defined herein.

[0252] Alternatively, a compound of any of the formulae delineated herein may be synthesized according to any of the, processes delineated herein. In the processes delineated herein, the steps may be performed in an alternate order and may be preceded, or followed, by additional protection/deprotection steps as necesssary. The processes may further comprise use of appropriate reaction inert solvents, additional reagents, such as bases (e.g., LDA, diisopropylethylamine, pyridine, K2CO3, and the like), catalysts, and salt forms of the above. The intermediates may be isolated or carried on in situ, with or without purification. Purification methods are known in the art and include, for example, crystallization, chromatography (liquid and gas phase, simulated moving bed (“SMB”)), extraction, distillation, trituration, reverse phase HPLC and the like. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.

[0253] As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. Synthetic

[0254] chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the inhibitor compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

[0255] The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0256] The novel compounds of the present invention are excellent ligands for protein kinases, subsequences thereof, and homologous polypeptides. Accordingly, these compounds are capable of targeting and inhibiting kinase enzyme and subsequences thereof. Inhibition can be measured by various methods, including, for example, those methods illustrated in the examples below. The compounds described herein may be used in assays, including radiolabelled, antibody detection, colorimetric, and fluorometric, for the isolation, identification, or structural or functional characterization of enzymes, peptides or polypeptides. Other suitable assays include direct ATP competition displacement assays where no phosphoryl transfer is necessary. Such assays include any assay wherein a nucleoside or nucleotide are cofactors or substrates of the polypeptide of interest, and particularly any assay involving phosphotransfer in which the substrates and or cofactors are ATP, GTP, Mg, Mn, peptides, polypeptides, lipids, or polymeric amino acids.

[0257] Pharmaceutical compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from a kinase inhibitory agent (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate compositions of this invention comprise a compound of the formulae described herein or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such compositions may optionally comprise one or more additional therapeutic agents, including, for example, kinase inhibitory agents (small molecule, polypeptide, antibody, etc.), immunosuppressants, anti-cancer agents, anti-viral agents, antiinflammatory agents, antifungal agents, antibiotics, or anti-vascular hyperproliferation compounds.

[0258] The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0259] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0260] The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0261] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0262] The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[0263] The pharmaceutical compositions of this invention may comprise formulations utilizing liposome or microencapsulation techniques. Such techniques are known in the art.

[0264] The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0265] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.

[0266] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

[0267] Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the kinase inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of kinase mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound.

[0268] When the compositions of this invention comprise a combination of a kinase inhibitor of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the kinase inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

[0269] According to one embodiment, the pharmaceutical compositions of this invention may comprise an additional kinase inhibitory agent. Such additional kinase inhibitory agents are those which may modulate, regulate or otherwise affect kinase enzyme activity. Such effects may lead to modulation of disease pathology and/or symptoms. Kinase inhibitory agents include, for example, small molecules, polypeptides, antibodies (including for example, monoclonals, chimeric, humanized, single chain, immunokines, etc.), and the like. Examples of additional kinase inhibitory small molecule agents include, but are not limited to, SU-6668, SU-5416, ZD-4190, ZD-1839, STI-571, CP-358774, LY-333531 and the like.

[0270] According to one embodiment, the pharmaceutical compositions of this invention comprise an additional immunosuppression agent. Examples of additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.

[0271] According to an alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise antibodies (including for example, monoclonals, chimeric, humanized, single chain, immunokines, etc.), cytotoxic or hormonal anti-cancer agents or combinations thereof. Examples of anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, taxotere, colchicine, phenothiazines, interferons, thioxantheres, anti-estrogens (e.g., tamoxifen), aromatase inhibitors, anti-androgens, LHRH antagonists, progetins, and GnRH antagonists.

[0272] According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an anti-viral agent. Examples of anti-viral agents include, but are not limited to, Cytovene, Ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddI, AZT, amprenavir and acyclovir.

[0273] Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0274] As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0275] In an alternate embodiment, this invention provides methods of treating, preventing, or relieving symptoms of disease in a mammal comprising the step of administrating to said mammal any of the pharmaceutical compositions and combinations described above. Preferably, the mammal is a human. If the pharmaceutical composition only comprises the inhibitor of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an additional therapeutic agent, such as an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, or an anti-vascular hyperproliferation compound. Such additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the inhibitor composition.

[0276] The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, for example, as illustrated below: 1333

[0277] the invention expressly includes all tautomeric forms of the compounds described herein. The compounds may also occur in cis- or trans- or E- or Z-double bond isomeric forms. All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.

[0278] Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to specific atoms, whereby they are intended to be fixed to that atom, or they may be drawn unattached to a specific atom (see below), whereby they are intended to be attached at any available atom that is not already substituted by an atom other than H (hydrogen). For example, a structure drawn as: 1334

[0279] is intended to encompass all of the following structures: 1335

[0280] The compounds of this invention may contain heterocyclic ring systems attached to another ring system (e.g., a triazinylyl core ring, an R8 substituent as defined herein, or a heteroaryl group). Such heterocyclic ring systems may be attached through a carbon atom or a heteroatom in the ring system. In instances wherein a heterocyclic or heteroaryl ring system is stated to be attached at a heteroatom (e.g., nitrogen atom), this refers to the heterocyclic or heteroaryl ring system being attached to the designated functional group at said nitrogen heteroatom. To illustrate, for example, when an R1 or R2 substituent on a triazinyl core is a heteroaryl defined as being attached at a nitrogen atom, this definition includes, but is not limited to, structures such as those exemplified below: 1336

[0281] All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.

[0282] In order that the invention described herein may be more readily understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. NMR and MS spectra obtained for compounds described in the examples below and those described herein are consistent with that of the compounds of the formulae herein.

[0283] Analytical Methods:

[0284] Unless otherwise indicated all HPLC analyses are run on a HP-1050 system with an HP Zorbax SB-C18 (5μ) reverse phase column (4.6×150 mm) run at 30 degrees C. with a flow rate of 1.00 ml/minute.

[0285] The mobile phase used solvent A (water/0.1% trifluoroacetic acid) and solvent B (acetonitrile/0.1% trifluoroacetic acid) with a 20-minute gradient from 10% to 90% acetonitrile. The gradient is followed by a 2-minute return to 10% acetonitrile and a 3 minute flush.

[0286] The peaks of interest eluted on the LC profiles at the times indicated.

[0287] LC-MS method for:

[0288] Method A:

[0289] 1. Samples are run on a HP-100 MSD system with a HP Zorbax SB-C8 (5μ) reverse phase column (4.6×50 mm) run at 30 degrees C. with a flow rate of 0.75 ml/minute.

[0290] 2. The mobile phase used solvent A (water/0.1% acetic acid) and solvent B (acetonitrile/0.1% acetic acid) with a 10-minute gradient from 10% to 90% acetonitrile. The gradient is followed by a 1-minute return to 10% acetonitrile and a 2 minute flush.

[0291] 3. The peaks of interest eluted on the LC profiles at the times indicated.

[0292] Method B:

[0293] 4. Samples are run on an HP-1100 system with an HP Zorbax SB-C8 (5μ) reverse phase column (4.6×50 mm) run at 30 degrees C. with a flow rate of 1.5 ml/minute.

[0294] 5. The mobile phase used solvent A (water/0.1% acetic acid) and solvent B (acetonitrile/0.1% acetic acid) with a 5-minute gradient from 10% to 90% acetonitrile. The gradient is followed by a 0.5-minute return to 10% acetonitrile and a 1.5 minute flush.

[0295] 6. The peaks of interest eluted on the LC profiles at the times indicated.

[0296] Preparative HPLC: Where indicated, compounds of interest are purified via preparative HPLC using a Gilson workstation with a 20×50 mm column at 20 mL/min. The mobile phase used solvent A (water/0.1% trifluoroacetic acid) and solvent B (acetonitrile/0.1% trifluoroacetic acid) with a 10-minute gradient from 5% to 100% acetonitrile. The gradient is followed by a 2-minute return to 5% acetonitrile.

[0297] Proton NMR Spectra:

[0298] Unless otherwise indicated, all 1H NMR spectra are run on a Varian series Mercury 300 MHz instrument. All observed protons are reported as parts-per-million (ppm) downfield from Tetramethylsilane (TMS) or other internal reference in the appropriate solvent indicated.

EXAMPLE A

[0299] Sodium dicyanamide (105.9 g, 1.19 mol) is nearly dissolved into water and added quickly to concentrated hydrochloric acid (530 ml) cooled to about −18° C. The slurry is stirred at −18° C. for about 15 minutes and then warmed to 35° C. before being cooled to 110° C. The white precipitate is then filtered, washed with small amounts of water, and dried under vacuum for twenty hours. About 50 g of N-cyanochloroformamidine is obtained: 1H NMR (DMSO-d6) δ 7.59 (s, 1H). Dimethylformamide (27.3 ml) is dissolved into dichloromethane at room temperature. To this solution is added phosphoryl chloride (27.3 ml) and then, after about 5 minutes, 30 g of N-cyanochloroformamidine. The mixture is stirred overnight at room temperature and then washed 3 times with water and once with brine. The organic layer is then dried over sodium sulfate, filtered, and evaporated under reduced pressure. The white solid (20 g) thus obtained is identified as the 2,4-dichloro-1,3,5-triazine: 1H NMR (CDCl3) δ 8.88 (s, 1H). 1337

EXAMPLE B

[0300] 2,4-Dichloro-1,3,5-triazine (1.054 g, 7.028 mmol) is dissolved into DMF (5 ml) and cooled to 0° C. To this solution are added diisopropylethylamine (1.225 ml, 7.028 mmol) and 3,4,5-trimethoxyaniline (1.185 g, 6.47 mmol). The reaction mixture is kept at 0° C. for 15 to 30 minutes and then at room temperature for 15 minutes to 2 hours. The reaction mixture is then diluted with ethyl acetate and washed with brine. The organic layer is dried over sodium sulfate, filtered, and evaporated in vacuo. The residue is treated with methylene chloride. The product precipitates as a white solid that is filtered and dried under reduced pressure, to give material identified as 924 (711 mg, 37%): 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.59 (br s, 1H), 7.00 (s, 2H), 3.72 (s, 6H), 3.60 (s, 3H); HPLC Rt=11.19 min; MS m/z=279 [M−Cl+OH2]+.

EXAMPLE C

[0301] To a slurry of intermediate 924 (75 mg, 0.253 mmol) in ethanol (5 ml) are added diisopropylethylamine (44 μl, 0.253 mmol) and 4-aminoveratrole (46 mg, 0.253 mmol). The mix is heated at 100° C. for 30 minutes. The solution is then cooled to room temperature and then to 0° C. A violet precipitate falls out of solution. The precipitate is filtered off and dried under reduced pressure to give 69 mg (66%) of 36: MS m/z=32 414[M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.48 (br s, 2H), 8.24 (s, 1H), 7.22 (s, 1H), 7.12 (m, 1H), 7.00 (br s, 2H), 6.82 (d, 1H), 3.68 (s, 6H), 3.57 (m, 9H); HPLC Rt=9.47 min.

[0302] The following compounds are prepared according to the procedure described for compound 36, substituting the appropriate reagents.

Compound	MS m/z	HPLC Rt
27	397	7.58
28	385	9.48
29	446	13.221
33	397	7.86
36	414	9.47
39	355	8.30
40	355	8.27
41	451	12.80
61	406	12.28
62	440	11.36
63	384	9.04
64	368	11.19
65	372	10.77
66	396	12.89
67	368	10.49
68	438	10.33
69	469	12.06
70	394	8.90
72	388	12.10
73	460	13.41
74	378	11.34
75	433	12.15
76	466	9.80
77	404	9.13
78	370	8.81
79	394	8.11
81	425	8.87
82	434	12.44
83	384	9.81
85	370	8.31
86	414	11.02
87	384	10.69
89	384	10.19
90	384	10.71
91	354	10.46
92	369	6.81
93	459	9.93
94	398	9.27
95	442	13.33
96	404	12.32
97	405	10.83
98	404	11.33
99	405	9.19
100	430	13.42
101	439	8.81
104	398	9.09
105	446	13.58
106	398	10.91
135, 290	388	11.95
177	484	11.26
178	483	12.92
183	329	7.75
186	379	12.28
250	438	13.34
251	438	8.22
252	398	10.11
253	415	10.96
254	Nd	6.82
255	475	9.45
300	386	11.85
303	372	10.71
304	372	11.27
305	461	9.35
306	406	12.44
316	390	11.88
334	nd	9.62
562	543.2	7.91
613	483	12.55
614	422	12.23
617	479	9.32
618	4440	12.53
623	503	11.31
624	412	8.82
625	402	11.84
627	418	12.41
629	394	12.01
632	440	14.16
633	521	12.32
636	414	8.14
691	393	(Method A) 7.47
692	554	(Method A) 7.68
693	483	(Method A) 6.26
694	483	(Method A) 6.48
695	405	(Method A) 5.38
696	396	(Method A) 5.05
697	396	(Method A) 6.76
698	396	(Method A) 6.73
699	421	(Method A) 5.2
926	460	13.14
927	384	8.61
928	393	9.57
930	368	11.15
931	400	8.68
932	382	11.38
933	398	9.03
934	412	12.20
935	382	7.81
936	468	13.68
937	386	11.31
1031	438	12.25
1047	nd	6.57
922	475	(Method A)
		8.13

[0303] 1338

[0304] To a slurry of intermediate 924 (79.6 mg, 0.2683 mmol) in isopropanol (2 ml) are added diisopropylethylamine (46.7 μl, 0.2683 mmol) and 4-methoxybenzylamine (37 mg, 0.2683 mmol). The mix is heated at 100° C. from 30 minutes to 40 hours. The solution is then cooled to room temperature and sonicated. The precipitate is filtered and dried under reduced pressure, giving 51.6 mg (48%) of compound 80.

[0305] The following compounds are prepared according to the procedure described for compound 80, substituting the appropriate reagents.

Compound	MS m/z	HPLC Rt
80	398	10.34
103	363	7.47
409	292	7.54
425	397.9	8.95
427	420.5 (M + Na)	8.92
428	393.9	10.71
570	382.3	10.40
570	382.1	10.36
581	394	10.93
619	408	11.40
620	408	11.40
628	382	10.87
630	368	10.25
1002	347	7.98

EXAMPLE 4

[0306] 1339

[0307] Compound 428

[0308] To a solution of dichlorotriazine (75 mg, 0.50 mmol) in dry DMF (3 mL) is added diisopropylethylamine (78 mg, 0.6 mmol) at 0° C. under a nitrogen atmosphere. The resulting yellow solution is stirred at 0° C. for 0.5-1 hour. Aniline (0.05 mmol) is added and the reaction stirred for 1-3 hours at room temperature. Finally, a solution of amine hydrochloride (85 mg, 0.5 mmol) and diisopropylethylamine (156 mg, 1.2 mmol) in dry DMF (1.2 mL) is added and the mixture stirred for a further 10-24 hour. The reaction is quenched in a 1:1 water/brine mixture (5 volumes) and extracted with ethyl acetate (4×10 mL) Combined organic extracts are dried, concentrated in vacuo and the resulting residue purified by column chromatography (EtOAc/nan Hexanes) to give compound 428 as an off-white solid (114 mg, 46%). MS m/z=493; HPLC Rt=8.40 minutes. 1340

EXAMPLE 1

[0309] To a solution of 5 g (27.1 mmol) of cyanuric chloride in 50 mL of dry diethyl ether at −20° C. is added, by slow dropwise addition, 26 mL of a 1M solution (26 mmol) of phenyl magnesium bromide. The reaction is stirred for 1 hour and warmed to 0° C. whereupon it is quenched with cold saturated ammonium chloride and partitioned between ethyl acetate and dilute sodium chloride solution. The organic layer is dried over magnesium sulfate, filtered and evaporated to yield crude product that could be used directly, without further purification, in subsequent reactions.

EXAMPLE 3a

One-Pot Procedure

[0310] To a dry solution of dichlorotriazine (113 mg, 0.50 mmol) in DMF (1.5 mL) is added diisopropylethylamine (0.17 mL, 0.55 mmol) followed by neat o-anisidine (68 mg, 0.55 mmol). The resulting solution is stirred at room temperature under a nitrogen atmosphere for 1-5 h. The reaction is diluted with 2N aqueous HCl (10 mL), brine (5 mL) and extracted with EtOAc (3×6 mL). Combined organics is diluted with MeOH (3 mL) and 10% Pd—C (120 mg) and triethylamine (0.2 mL) added. Hydrogen gas is bubbled through the mixture for 1 h and the mixture allowed to stir at room temperature under a hydrogen atmosphere for 10-30 h. The mixture is filtered through celite and washed with MeOH. The filtrate is concentrated in vacuo and the crude material purified by column chromatography (EtOAc/n-Hexanes) to provide compound 12 (90 mg, 65%) as a yellow solid.

EXAMPLE 3b

[0311] 1341

[0312] To a solution of 441 mg (2.4 mmol) of cyanuric chloride in 5 mL of dry diethyl ether at −20° C. is added, by slow dropwise addition, 2 mL of a 1M solution (2 mmol) of phenyl magnesium bromide. The reaction is stirred for 0.5 hour and warmed to 0° C. whereupon 439 mg (2.4 mmol) of 3,4,5-trimethoxy aniline and 416 μL (2.4 mmol) of diisopropyl ethylamine is added in rapid succession. The resulting solution is warmed to room temperature and stirred for one hour. The reaction is quenched with saturated ammonium chloride and partitioned between ethyl acetate and saturated sodium chloride solution. The organic layer is dried over magnesium sulfate, filtered and evaporated to yield crude product which is recrystallized from methanol to give material identified as the desired compound.

EXAMPLE 3c

[0313] 1342

[0314] To 98 mg (0.37 mmol) of triazine in 2 mL of dimethylformamide is added 45 mg of 10% palladium on carbon. The flask is evacuated and flushed with hydrogen five times. To the sealed reaction flask is then added 517 μL (3.8 mmol) of triethylamine. The reaction is evacuated and flushed two more times and then stirred rapidly for four hours while maintaining an atmosphere of hydrogen. The completed reaction is diluted with ethyl acetate, filtered through celite, and partitioned between ethylacetate and water. The organic layer is washed with saturated brine, dried with magnesium sulfate, and filtered to yield crude product. The crude product is triturated with dichloromethane to give a white solid which can be filtered and dried to provide material identified as pure compound 971.

[0315] The following compounds are prepared according to the procedure outlined for compound 971, substituting the appropriate reagents.

Cmpd #	HPLC Rt	MS
8	8.22	265
11	10.64	264
12	16.05	279
13	14.95	279
14	13.85	280
15	15.17	309
16	6.32	231
17	11.88	274 (M-tBu)
18	11.71	265
19	15.47	308 (M-tBu)
20	15.11	267
151	10.27	291
154	9.63	392
155	13.40	323
163	15.41	307
164	15.21	335
165	11.36	nd
970	13.77	339
971	7.2	231

EXAMPLE 2

[0316] 1343

[0317] Cyanuric chloride (7 mmole) is dissolved into toluene (5 mL) air in a tube under air at room temperature. Pyrrole (7 mmole) is added, the tube is sealed, and the reaction heated to 80° C. for two hours, then cooled to room temperature. This gives a red-brown solid, which gives a series of spots by TLC (50% EtOAc:hexane, silica gel). This material is eluted through a column of silica gel with 100% methylene chloride giving the dichloride intermediate compound. Displacement of the chloride with an appropriate amine under standard conditions (described herein) followed by reduction of the remaining chloride by hydrogenation under standard conditions results in the desired product.

EXAMPLE 5

[0318] 1344

[0319] Compounds may be prepared according to the above scheme: 6-Chloronicotinonitrile (650 mg, 4.7 mmol) is dissolved in 30 ml dry EtOH at 0° C. HCl gas is bubbled through the solution until precipitate is present for 30 min. The vessel is sealed, refrigerated, thoroughly concentrated, and suspended in 30 mL isopropanol. Ammonium acetate (700 mg) is added and stirring continued for about 20 hours. The mixture is concentrated, and the residue is triturated with a small amount of isopropanol and filtered. The resulting amidine is suspended in 10 mL isopropanol with 500 mg solid cyanamide and the stirring solids are dissolved by addition of 30 mL of 5% aqueous NaHCO3. After two days stirring, the white precipitate is collected and washed with a small amount of isopropanol.

[0320] By extension of the methodology of Roger Harris [Synthesis 1980, 841-842], the resulting cyanoamidine 1156 is converted to 2-chloro-4-(6-chloro-pyridin-3-yl)-[1,3,5]triazine 1157: to 555 mg compound 1156 suspended in 20 mL CH2CN at 0° C. is added reagent that is prepared by mixing POCl3 (340 μl, 3.6 mmol) and DMF (280 μl, 3.6 mmol) in 7 mL CH2Cl2 at 0° C. Additional CH2CN (30 ml) allows the thick mixture to stir. After three hours, the now clear solution is concentrated and filtered through a plug of silica, using CH2Cl2/isopropanol as necessary to dissolve, and hexane/tBuOMe to elute. 2-Chloro-4-(6-chloro-pyridin-3-yl)-[1,3,5]triazine 1157: MS m/z=227 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 9.21 (s, 1H), 9.17 (d, J=2.6, 1H), 8.56 (dd, J=8.3, 2.5, 1H), 7.63 (d, J=8.2); HPLC Rt=13.1 min.

[0321] Compound 1157 reacts with an optionally substituted aryl or heterocyclic or heteroaryl amine (where R3 is as defined in the formulae herein) at room temperature to produce the desired adduct. The remaining chloride may then be displaced by reaction with amine (neat or in a small amount of solvent) at elevated temperature. The product may be isolated by filtration, silica gel chromatography, or preparative HPLC. 1345

[0322] Compound 1157 (550 mg, 2.4 mmol) and trimethoxyaniline (530 mg, 2.9 mmol) are stirred in 25 mL isopropanol overnight. Et3N (500 μl) is added to allow the now viscous reaction to proceed to completion. After two hours, the material is filtered and rinsed with isopropanol and t-BuOMe to obtain 870 mg yellow solid 1158. MS m/z=374 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.21 (s, 1H), 9.14 (s, 1H), 8.71 (s, 1H), 8.50 (m, J=8.2, finer coupling, 1H), 7.60 (d, J=8.2), 7.04 (s, 2 3.65 (s, 6H), 3.50 (s, 3H); HPLC Rt=13.2 min.

[0323] Compound 1158 (38 mg, 0.10 mmol) is heated with 500 μl morpholine overnight at 70° C. in a sealed tube. The mixture is triturated with isopropanol and filtered to obtain 434. MS m/z=425 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ (s, 1H), 9.07 (d, J=2.3, 1H), 8.66 (s, 1H), 8.35 (dd, J=9.1, 2.3, 1H), 7.17 (s, 2H), 6.94 (d, J=9.1, 1H), 3.8-3.5 (m, 8H), 3.82 (s, 6H), 3.60 (s, 3H); HPLC Rt=8.96 min.

[0324] The following compounds are prepared according to the procedure outlined for compound 434, substituting the appropriate amine in the second reaction step:

[0325] Compound 448: MS m/z=468 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 9.94 (s, 1H), 8.99 (s, 1H), 8.62 (s, 1H), 8.19 (d, J=8.2, 1H)), 7.35 (m, 1H), 7.18 (s, 2H), 3.76 (s, 6H), 3.60 (s, 3H), 3.32-3.23 (m), 2.45-2.35 (m), 1.66-1.57 (m, 2H), 0.93-0.88 (m, 6H); HPLC Rt=7.47 min.

[0326] Compound 449: MS m/z=383 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 9.97 (s, 1H), 9.06 (d, 2.2, 1H), 8.64 (s, 1H), 8.31 (dd, J=9.1, 2.2, 1H), 7.18 (s, 2H), 6.74 (d, J=8.8, 1H), 3.76 (s, 6H), 3.61 (s, 3H), 3.10 (s, 6H); HPLC Rt=8.32 min.

[0327] Compound 497: MS m/z=413 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 9.94 (s, 1H), 8.98 (s, 1H), 8.62 (s, 1H), 8.18 (d, J=8.5, 1H), 7.31-7.16 (m, 1H), 7.17 (s, 2H), 6.51 (d, J=8.8, 1H), 4.48-4.45 (m, 1H), 3.75 (s, 6H), 3.60 (s, 3H), 3.33-3.27 (m, 2H), 3.47-3.41 (m, 2H), 1.70-1.61 (m, 2H); HPLC Rt=7.86 min.

[0328] The following compounds are prepared according to the procedure outlined for compound 434, substituting the appropriate amine in the second reaction step:

Compound	HPLC ret.	MS m/z
436	7.69 min.	424
446	8.36 min.	452
471	10.37 min.	445
472	7.20 min.	412
1074	7.13 min.	398

EXAMPLE 6

[0329] 1346

[0330] ample 6 may be prepared by a similar process as in Example namide (36 mmol) is dissolved in 100 mL dry EtOH at 0° C. the mixture for three hours and the mixture is sealed and After concentration, the residue is stirred with 5.5 g 0 mL isopropanol. After 12 hours, the pH is adjusted to 9 ated ammonium hydroxide solution, and stirring continued two more days. The mixture is concentrated and purified by flash chromatography (10:1:0.1 CH2Cl2/MeOH/NH4OH). Triturating in hot tBuOMe/isopropanol removes some residual amide side-product to provide 3.6 g white solid amidine.

[0331] Amidine is converted to cyanoamidine as in example 5, with the modification that the bulk of the product is isolated by EtoAc extraction of the aqueous reaction mixture followed by flash chromatography using 95:5:0.5 CH2Cl2/MeOH/NH4OH. Cyanoamidine 1159: MS m/z=181 [M+H]+; HPLC Rt=4.93 min.

[0332] 3.5 g cyanoamidine 1159 is added as a solid to a stirring, 0° C. solution of POCl3 (2.3 ml, 25 mmol) and DMF (1.9 ml, 25 mmol) in 100 ml CH3CN. The clear solution is stirred at room temperature for one hour, concentrated, and immediately filtered through a plug of silica as in Example 5. Concentration provides 3.7 g white solid 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine 1160. MS m/z=227 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 9.29 (s, 1H), 8.50 (m, J=4.8, finer coupling, 1H), 8.20 (m, J=7.2, finer coupling, 1H)), 7.54-7.50 (m, 1H); HPLC Rt=10.69 min. 1347

[0333] Compound 1160 reacts with an optionally substituted aryl or heterocyclic or heteroaryl amine (where R3 is as defined in the formulae herein) at room temperature to produce the desired adduct. The remaining chloride may then be displaced by reaction with neat amine (or in some cases with a small amount of isopropanol as solvent) at elevated temperature. The product may be isolated by filtration or silica gel chromatography.

[0334] Compound 1160 (1.7 g, 7.5 mmol) is stirred overnight at room temperature with 3,4,5-trimethoxyaniline (1.5 g, 8.3 mmol) in 200 mL isopropanol. After addition of 2 ml Et3N, stirring is continued for an additional day. The mixture is concentrated, triturated with t-BuOMe and filtered, rinsing with a small amount of isopropanol. The 2.5 g of compound 1075 obtained contains one equivalent of Et3N salt, but is otherwise pure; this material is used as is or is filtered through a plug of silica. MS m/z=374 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.23 (s, 1H), 8.71 (s, 1H), 8.41-8.38 (m, 1H), 8.7-7.9 (br m, 1H), 7.45-7.41 (m, 1H), 7.00 (s, 2H), 3.57 (s, 6H), 3.45 (s, 3H); HPLC Rt=10.86 min.

[0335] Compound 1075 (31 mg, 0.083 mmol) is stirred in a sealed tube with 250 μl R-(+)-1-phenylethylamine at 88° C. for 8 hours. The mixture is diluted with t-BuOMe, and the resulting white precipitate (chloride salt of the reagent amine) is removed by filtration. The filtrate is concentrated, triturated with isopropanol, and the yellow solid 1110 is obtained by filtration. MS m/z=459 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.02 (s, 1H), 9.47 (br d, J=7.6, 1H), 8.66 (s, 1H), 8.52 (m, J=7.5, finer coupling), 8.03-8.01 (m, 1H), 7.30-7.00 (m, 5H), 6.89 (s, 2H), 6.51 (dd, J=7.6, 4.7, 1H), 5.30-5.20 (br m, 1H), 3.62 (s, 6H), 3.43 (s, 3H), 1.50-1.10 (br m, 3H); HPLC Rt=11.42 min. 1348

[0336] Compound 564 is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Compound 565: MS m/z=473 [M+H]+; HPLC Rt=8.16 min. Compound 564: MS m/z=562 [M+H]+; HPLC Rt=8.82 min. 1349

[0337] Compound 1081 is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 1161: MS m/z=327 [M+H]+; HPLC Rt=7.86 min; Compound 1081: MS m/z=348 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.38 (s, 1H), 9.24 (br s, 1H), 8.71 (s, 1H), 8.53 (d, J=6.4), 8.12 (dd, J=4.5, 1.9, 1H), 7.82-7.55 (m, 5H), 7.14 (br s, 1H), 6.56 (dd, J=7.9, 4.7, 1H), 5.8 (br s, 1H), 4.99 (br d, J=17.3, 1H), 4.89 (br d, J=9.7, 1H), 4.02 (br s, 2H); HPLC Rt=7.23 min. 1350

[0338] Compound 1104 above is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 1162: MS m/z=314 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.36 (s, 1H), 8.74 (s, 1H), 8.42 (dd, J=4.8, 1.9, 1H), 8.08 (br s, 1H), 7.56 (s, 1H), 7.50-7.42 (m, 2H), 7.14 (app t, J=7.8, 1H), 6.909 (d, J=7.6, 1H), 5.07-5.03 (m, 1H), 4.33 (d, J=5.6, 2H); HPLC Rt=8.84 min. Compound 1104: MS m/z=403 [M+H]+; HPLC Rt=9.93 min. 1351

[0339] Compound 1099 is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 1163: MS m/z=342 [M+H]+; HPLC R=9.48 min. Compound 1099: MS m/z=413 [M+H]+: 1H NMR (300 MHz, DMSO-d6) 10.19 (br s, 1H), 9.77-9.53 (br m, 1H), 8.63 (s, 1H), 8.56 (d, J=7.0, 1H), 8.08-8.05 (m, 1H), 7.557.28 (br s, 1H), 7.41 (s, 1H), 7.20-7.03 (m, 7H). 6.84 (d, J=7.6, 1H), 6.54 (dd, J=7.6, 4.8, 1H), 4.74-4.48 (br m, 2H), 3.62 (s, 2H): HPLC Rt=10.18 min. 1352

[0340] Compound 1102 is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 1164: MS m/z=365 [M+H]+; HPLC Rt=9.65 min. Compound 1102: MS m/z=454 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.23, (s, 1H), 9.62 (br s, 1H), 8.64 (s, 1H), 8.51 (br 6, 1H), 8.08 (br d, J=3.4, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.60-7.40 (br m, 1H), 7.44 (s, 1H), 7.29-7.03 (m, 3H), 6.99-6.86 (m, 3H), 6.59 (br 8, 1H), 5.48 (s, 2H), 4.59 (br s, 2H); HPLC Rt=10.50 min. 1353

[0341] Compound 1113 is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 1165: MS m/z=369 [M+H]+; HPLC Rt=8.35 min. Compound 1113: MS m/z=426 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 11.4-11.3 (m, 1H), 10.1-10.0 (m, 1H), 8.70-8.57 (m, 1H), 8.65 (s, 1H), 8.26-8.15 (m, 1H), 7.67 (br d, J=7.5, 1H), 7.42-7.00 (m, 5H), 6.91-6.72 (m, 4H), 3.64-3.54 (m, 4H), 2.96-2.86 (m, 4H); HPLC Rt=9.33 min. 1354

[0342] Compound 1116 is prepared according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 1166: MS m/z=324 [M+H]+; HPLC Rt=8.75 min. Compound 1116: MS m/z=347 [M+H]+; 1H NMR (300 MHz, DMSO-d6) [rotamers] 10.1 (s, 1H), 9.0-8.9 & 8.7-8.4 (br m, 2H), 8.6 (s, 1H), 8.1-7.7 (br m, 2H), 7.9 (s, 1H), 7.5-7.3 (br m2H), 6.5-6.4 (br m, 1H), 4.3-3.9 (br m, 1H), 1.2-1.0 & 0.7-0.5 (br m, 6H); HPLC Rt=8.13 min. 1355

[0343] Compound 1093 is prepared essentially according to the procedure outlined for compound 1110, substituting the appropriate amines in each of the two reaction steps, and adding a final deprotection step to remove the t-butyl carbamate (1:1 CF3COOH/CH2Cl2, 0° C., 1 hour,): Compound 1093: MS m/z=540 [M+H]+; Rt=7.38 min.

[0344] The aniline used in the second reaction step to prepare compound 1093 is prepared as shown below: 1356

[0345] 2-Methoxy-4-nitroaniline (4.2 g, 25 mmol) and 4-bromobutyrylchloride (5.0 g, 27 mmol) are stirred overnight at room temperature in 100 mL CH2Cl2. After addition of 100 mL saturated aqueous NaHCO3 and stirring 30 minutes, the mixture is diluted with 300 mL CH2Cl2, washed with 1 N HCl and brine, and dried with Mg2SO4. Concentration, trituration with t-BuOMe, and filtration provided 7.0 g acylated product 1168. A portion of this material (3.4 g, 11 mmol) and 3.3 g piperazine (38 mmol) are heated together as a melt at 100° C. for 10 minutes. The residue is triturated with MeOH and filtered; the filtrate is concentrated and purified by flash chromatography in 10:1:0.1 CH2Cl/MeOH/NH4OH to provide 2.1 g material, which is stirred with 1.4 g di-t-butyl dicarbonate in 40 mL CH2Cl2 at 0° C. to room temperature for 40 minutes. Chromatography in 1-4% MeOH in CH2Cl2 followed by trituration with t-BuOMe and filtration provides 2.2 g off-white solid. This nitroarene (440 mg, 1.0 mmol) is stirred in 20 mL MeOH at 46° C. under N2 with 380 mg ammonium carbonate and 120 mg Pd/C. After 20 minutes, the mixture is diluted with EtoAC, filtered, and concentrated. Silica gel chromatography in EtOAc→95:5:0.5 CH2Cl2/MeOH/NH4OH followed by concentration from t-BuOMe provided 400 mg of compound 1169 as a pinkish, glassy solid. 1357

[0346] Compounds prepared according to the procedure of Example 6 in which 3-aminobenzyl alcohol is added in the second reaction step may be further modified: the benzylic alcohol may be converted to an intermediate which may be displaced with an appropriate nitrogen, oxygen, sulfur, or carbon nucleophile. 1358

[0347] Compound 1104 (50 mg, 0.12 mmol) is stirred under N2 with 22 μl thionyl chloride (0.31 mmol) and 42 mg imidazole (0.61 mmol) in 4 mL 1:1 CH2Cl2/CH3CN. After 12 hours, 2 ml DMF is added, followed by 120 mg powdered K2CO3, 5 mg t-Bu4N+I−, and 30 mg additional imidazole. The mixture is stirred four hours at 53° C. After concentration, chromatography on silica gel in 2%→4% MeOH in CH2Cl2, trituration with t-BuOMe, and filtration provided 1109 as a white solid. MS m/z=453 [M+H]+; Rt=8.71 min.

[0348] Compounds below are prepared according to the procedure for compound 1110, substituting the appropriate amines in each of the two reaction steps.

Compound	HPLC ret.	MS m/z
828	(Method A) 7.86 min.	456
829	(Method A) 7.71 min.	461
830	(Method A) 8.42 min.	471
831	(Method A) 7.41 min.	473
832	(Method A) 7.44 min.	473
833	(Method A) 7.43 min.	445
834	(Method A) 8.50 min.	479
835	(Method A) 8.92 min.	499
836	(Method A) 8.86 min.	499
837	(Method A) 9.40 min.	500
838	(Method A) 8.77 min.	537
839	(Method A) 8.80 min.	523
840	(Method A) 8.94 min.	523
841	(Method A) 8.03 min.	485
842	(Method A) 8.68 min.	529
843	(Method A) 7.60 min.	459
844	(Method A) 8.14 min.	495
845	(Method A) 8.50 min.	509
846	(Method A) 7.92 min.	471
847	(Method A) 4.93 min.	528
848	(Method A) 6.38 min.	437
849	(Method A) 7.02 min.	439
850	(Method A) 8.24 min.	451
851	(Method A) 8.24 min.	485
890	(Method A) 7.28 min.	473
1076	9.23 min.	396
1077	10.65 min.	446
1078	7.44 min.	412
1079	8.92 min.	466
1080	9.06 min.	446
1082	8.50 min.	398
1083	8.55 min.	404
1084	7.39 min.	350
1085	10.69 min.	475
1086	10.45 min.	475
1087	11.05 min.	463
1088	10.92 min.	463
1089	9.22 min.	397
1090	9.04 min.	474
1091	8.64 min.	355
1092	10.94 min.	431
1094	9.75 min.	399
1095	9.91 min.	422
1096	6.78 min.	506
1097	8.93 min.	365
1098	8.88 min.	388
1100	10.45 min.	431
1101	10.22 min.	436
1103	9.71 min.	385
1105	9.73 min.	440
1106	10.16 min.	458
1107	9.26 min.	395
1108	9.48 min.	413
1111	11.40 min.	459
1112	8.26 min.	392
1114	8.31 min.	337
1115	9.19 min.	371
1117	8.64 min.	381

[0349] 1359

[0350] Compounds in example 7 may be prepared in a similar manner as those described in Example 5: the thioamide of 2-chloroisonicotinamide [prepared according to Libermann, D ; Rist, N.; Grumbach, F.; Cals, S.; Moyeux, M.; Rouaix, A. Memoires Presentes a la Societe Chimique 1958, 694-702] is alkylated with methyl iodide. The resulting thioimidate salt (4.3 g, 13.5 mmol) is stirred overnight in 100 ml isopropanol with 1.7 g ammonium acetate. After concentration and trituration with isopropanol/t-BuOMe, filtration provides the amidine as a solid (2.3 g). This material is stirred overnight with 3.5 g solid NaHCO3, 2.4 ml of a 50% aqueous solution of H2NCN, 40 ml isopropanol, and 1100 ml H2O. The resulting precipitate is triturated with a small amount of isopropanol to obtain 1.6 g cyanoamidine 1170. This material is suspended in CH2Cl2/CH3CN with 1.3 ml POCl3 and 1 ml DMF at 0° C. and the mixture is warmed to room temperature. After several hours, the homogenous solution is poured into a 1:1 mixture of pH 7 buffer and saturated NaHCO3. After extraction with EtOAc and filtration through a plug of silica, 1.6 g of 2-chloro-4-(2-chloro-pyridin-4-yl)-[1,3,5]triazine 1171 is obtained as a white solid. MS m/z=227 [M+H]+; HPLC Rt=13.18 min.

[0351] Compound 1171 reacts with an optionally substituted aryl or heterocyclic or heteroaryl amine (where R3 is as defined in the formulae herein) at room temperature to produce the desired adduct. The remaining chloride may then be displaced by reaction with amine (neat or in a small amount of solvent) at elevated temperature. The product may be isolated by filtration, silica gel chromatography, or preparative HPLC. 1360

[0352] Compound 1171 (250 mg, 1.1 mmol) and 3(1,1,2,2,-tetrafluoroethoxy)aniline (230 μl, 1.5 mmol) are stirred in 2 mL THF overnight. The mixture is diluted with t-BuOMe and filtered; the filtrate is concentrated, triturated with t-BuOMe, filtered, and washed with a small amount of isopropanol to obtain 320 mg compound 330 as an off-white solid. MS m/z=400 [M+H]+; HPLC Rt=16.50 min.

[0353] Compound 330 (27 mg, 0.068 mmol) is stirred under N2 15 hours in 1 mL piperidine at 93-104° C. After concentration and silica gel chromatography in 95:5 CH2Cl2/MeOH and trituration with isopropanol, compound 346 is obtained as a yellow solid. MS m/z=449 [M+H]+; HPLC Rt=12.53 min. 1361

[0354]

[0355] Compound 180 is prepared according to the procedure outlined for compound 346, substituting the appropriate amines in each of the two reaction steps. Intermediate compound 331: MS m/z=374 [M+H]+; HPLC Rt=13.8 min. Compound 180: MS m/z=413 [M+H]+; HPLC Rt=8.18 min.

[0356] Compound 433 is prepared from compound 331 according to the procedure outlined for compound 346, substituting the appropriate amine. Compound 443: MS m/z=468 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.22 (s, 1H), 8.80 (s, 1H), 8.09 (d, J=5.3, 1H), 7.35 (s, 1H), 7.23 (dd, J=5.3, 1.5, 1H), 7.16 (s, 2H), 6.87-6.81 (m, 1H), 3.75 (s, 6H), 3.61 (s, 3H), 3.3-3.2 (m), 2.5-2.3 (m), 1.64-1.58 (m, 2H), 0.90 (t, J=7.0, 6H); HPLC Rt=7.64 min.

[0357] The following compounds are prepared according to the procedure outlined for compound 346, substituting the appropriate amines in each of the two reaction steps:

Compound	HPLC ret.	MS m/z
45	7.26 min.	412
345	9.99 min.	423
372	10.26 min.	439
412	9.03 min.	395

EXAMPLE 8

[0358] 1362

[0359] By a similar procedure to examples 5-7, the commercially available amidinethiophene hydrochloride may be converted to a variety of thiophenyl-[1,3,5]triazin-2-ylamines.

[0360] Amidinethiophene hydrochloride (2.6 g, 16 mmol) and cyanamide (1.3 g, 32 mmol) are stirred at room temperature in 20 ml isopropanol and 80 ml 5% aqueous sodium bicarbonate for five days. The resulting white precipitate is filtered and rinsed with a small amount of H2O and isopropanol to provide the thiophene cyanoamidine intermediate. MS m/z=152 [M+H]+; HPLC Rt=7.58 min. To a 0° C. solution of POCl3 (550 μl, 6.0 mmol) and DMF (460 μl, 6.0 mmol) in 15 ml CH2C2 is added 750 mg (5.0 mmol) of this material. The stirring mixture is allowed to warm to room temperature. After an hour, 40 ml CH3CN is added to better dissolve the suspended solids. After four additional hours, the mixture is concentrated and filtered through silica, the solids are dissolved with CHCl2 and EtOAc and this solution is eluted with 5:1 hexanes/t-BuOMe to provide 860 mg white solid 2-chloro-4-thiophen-2-yl-[1,3,5]triazene 1172. MS m/z=198 [M+H]+; HPLC Rt=13.16 min. 1363

[0361] Compound 1172 (37 mg, 0.19 mmol) and 4-aminopyridine (21 mg, 0.22 mmol) are stirred overnight in 2.5 ml isopropanol at room temperature. 50 μl Et3N is added. After stirring a few hours, the mixture is filtered and rinsed with isopropanol and t-BuOMe to provide compound 363 as a white solid. MS m/z=256 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 9.43 (br s, 1H), 9.33 (s, 1H), 9.24 (d, J=7.9, 2H), 8.41 (dd, J=3.7, 1.2, 1H), 8.12 (dd, J=4.9, 1.2, 1H), 7.36 (dd, J=4.9, 3.7, 1H), 7.06 (d, J=7.9, 2H); HPLC Rt=7.64 min.

[0362] Compound 217 is prepared from compound 1172 according to the procedure outlined for compound 363, substituting the amine 3,4,5-trimethoxyaniline. Compound 217: MS m/z=345 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.15 (br s, 1H), 8.67 (s, 1H), 8.01 (dd, J=3.7, 1.2, 1H), 7.88 (dd, J=4.9, 1.2, 1H), 7.23 (dd, J=4.9, 3.7, 1H), 7.19 (br s, 2H); HPLC Rt=12.98 min.

[0363] Compounds below are prepared from compound 1172 according to the procedure outlined for compound 363, substituting the appropriate amine:

Compound	HPLC ret.	MS m/z
349	9.99 min.	340
350	16.05 min.	371
352	14.69 min.	300
354	9.59 min.	298
355	10.20 min.	312
356	13.90 min.	280
357	12.36 min.	315
358	9.63 min.	298
359	12.33 min.	329
360	16.10 min.	289
361	17.28 min.	361
362	11.73 min.	286
1072	13.47 min.	299
1073	15.01 min.	273

[0364] 1364

[0365] Compound 42 may be obtained by a procedure similar to that described in examples 5-8, and also through a route extending from the work of Baldev Singh [Heterocycles, 34, 1992, 929-935]. 4-Cyanopyridine is converted to imidate 1173 by base-catalyzed addition of methanol as described by Singh. One equivalent of trimethoxyphenylguanidine [Davis, P.; Moffat, D. F. C.; Davis, J. M.; Hutchings, M. C. WO 97/19065, 1997] is added to the methanolic solution, with no consumption of imidate at 42° C. overnight. One equivalent each of NaOMe and dimethylformamide, dimethyl acetal are added along with 1:1 isopropanol and toluene, and the mixture is heated at 65° C. for 1-2 days. After concentration, chromatography on silica gel (CH2Cl2/MeOH/NH4OH), and purification by reverse-phase HPLC, compound 42 is obtained as an orange solid, trifluoroacetic acid salt. MS m/z=340 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.37 (s, 1H), 8.88 (s, 1H), 8.83 (d, J=6.0, 2H), 8.25 (d, J=6.0, 2H), 7.16 (s, 2H); HPLC Rt=9.92 min. 1365

[0366] Preparation of compound 1118: 2-Amino-4-(4-pyridinyl)-1,3,5-triazine (200 mg, 1.2 mmol)[prepared according to B. Singh Heterocycles, 34, 1992, 929-935] is stirred with trimethoxyphenylisocyanate (250 mg, 1.2 mmol) and 60% NaH/oil dispersion (47 mg, 1.2 mmol) in 20 mL DMF overnight. The mixture is concentrated and treated with water; the product is collected and recrystallized from DMSO. Compound 1118: MS m/z=383 [M+H]+; 1H NMR (300 MHz, DMSO-d6) 10.86 (s, 1H), 10.83 (s, 1H), 9.14 (s, 1H), 8.84-8.82 (m, 2H), 8.21-8.19 (m, 2H), 6.93 (s, 2H); HPLC Rt=8.26 min. 1366

[0367] With use of the general procedure outlined in examples 5-8, commercially available 3-Nitroamidine provides entry to a variety of aryl substitutions. Reduction of the nitroarene to the amine may be followed, for example, by acylation, reductive amination, sulfonylation, or urea formation to provide compounds exemplified above with independent R5R16 as defined in the formulae herein. 1367

[0368] By the procedure outlined in examples 5-8,6-chloro-pyridine-2-carbonitrile [Elman, B. Tetrahedron, 1985, 41, 4941-4948] may be functionalized to provide the pyridinyl[1,3,5]triazinylamines exemplified above with independent R5R16 as defined in the formulae herein. 1368

[0369] By the procedure outlined in examples 5-8,2-chloro-4-aryl-3-pyridine-carbonitriles [Church, R.; Trust, R.; Albright, J. D.; Powell, D. W. J. Org. Chem. 1995, 60, 3750-3758] may be functionalized to provide the pyridinyl[1,3,5]-triazinylamines exemplified above with independent R5R16 as defined in the formulae herein. 1369

[0370] By the procedure outlined in examples 5-8,6-chloro-2-methyl-3-pyridinecarbonitrile [Singh, B.; Lesher, G. Y.; Brundage, R. P. Synthesis, 1991, 894-896] may be functionalized to provide the pyridinyl[1,3,5]triazinylamines exemplified above with independent R5R16 as defined in the formulae herein. 1370

EXAMPLE 9

[0371] Compound 218: Compound 924 (214 mg, 0.72 mmol) is dissolved into toluene (25 mL) under air at room temperature. Tetrakis (triphenylphosphine) palladium(0) (25 mg, 0.02 mmol) is added, followed by addition of benzo[b]thiophene-2-boronic acid (141 mg, 0.79 mmol) as a solution in ethanol (2 mL), and sodium carbonate (2 M in water, 0.80 mL, 1.6 mmol). The reaction vessel is purged with argon, fitted with a reflux condenser and covered with aluminum foil to exclude light. The reaction is then heated to reflux for 18 hours, then quenched by cooling it to room temperature and adding excess water. This mixture is then extracted with ethyl acetate (3 times). The ethyl acetate extracts are then washed with brine, combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The recovered material is then eluted through a 20×2.5 cm column of silica gel with a 20%, 40%, and 60% ethyl acetate:hexane step gradient. The recovered material is then applied to two 1000μ preparative TLC plates and developedone time with a 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) solvent system. The material that is recovered from these plates is then triturated with a 1:1 mixture of toluene:methanol giving 21 mg (7%) of a green solid: MS m/z=395 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.31 (br s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.06 (dd, J=13.2, 7.5 Hz, 2H), 7.49 (m, 2H), 7.25 (br s, 2H), 3.87 (s, 6H), 3.67 (s, 3H); HPLC Rt=16.18 min.

[0372] Compound 219: Compound 924 (256 mg, 0.86 mmol) is reacted with 3-pyridyl boronic acid (117 mg, 0.95 mmol) in the manner described for Compound 218, but is kept at reflux under argon for 72 hours. The reaction is then quenched by cooling it to room temperature, diluting it with excess water, and extracting it with ethyl acetate (3 times). The ethyl acetate extracts are then washed with brine, combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The recovered material is purified by applying it to two 1000μ preparative TLC plates and developing one time with a 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) solvent system. The material recovered from these plates is then applied to a set of two 500μ preparative TLC plates and developed one time with a 7:7:7:1 MtBE:CH2Cl2:Hexane:MeOH solvent system. This gives 8 mg (2.7%) of a pale green solid: MS m/z=340 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 9.67 (br s, 1H), 8.90 (br s, 1H), 8.80 (br s, 2H), 7.65 (br s, 1H), 7.39 (br s, 2H), 6.94 (br s, 2H), 3.90 (s, 6H), 3.85 (s, 3H); HPLC Rt=8.21 min.

[0373] Compound 220: Compound 924 (180 mg, 0.61 mmol) is reacted with 3-chlorophenyl boronic acid (104 mg, 0.67 mmol) in the manner described for example 218, but with an air atmosphere instead of argon. The reaction is then quenched by cooling it to room temperature, diluting it with excess water, and extracting it with ethyl acetate (3 times). The ethyl acetate extracts are then washed with brine, combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The recovered material is purified by eluting it through a 17×2.5 cm column of silica gel with a 20%, 40%, and 80% ethyl acetate:hexane step gradient. The material from this column is then further purified by applying it to two 1000μ preparative TLC plates and developing one time with a 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) solvent system. Final purification of the recovered material is accomplished with preparative HPLC giving 4 mg (1.7%) of a green solid: MS m/z 373=[M+H]+; 1H NMR (300 MHz, CDCl3) δ 8.76 (br s, 1H), 8.46 (br s, 1H), 8.33 (br d, J=7.4 Hz, 1H), 7.51 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 6.99 (br s, 2H), 3.92 (s, 6H), 3.84 (s, 3H); HPLC Rt=16.23 min.

[0374] Compound 221: Compound 924 (88 mg, 0.30 mmol) is reacted with 4-methylphenyl boronic acid (44 mg, 0.33 mmol) in the manner described for example 218, but with an air atmosphere instead of argon, and with refluxing for 36 hours. The reaction is then quenched by cooling it to room temperature, diluting it with excess water, and extracting the mixture with ethyl acetate (3 times). The ethyl acetate extracts are then washed with brine, combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The recovered material is then eluted through a 17×2.5 cm column of silica gel with a 20%, 40%, and 80% ethyl acetate:hexane step gradient. The recovered material is recrystallized from ethanol, and the recovered crystals are applied to two 500μ preparative TLC plates and developed one time with a 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) solvent system giving 11 mg (10%) of a white solid: MS m/z=353 [M+H]+; 1H NMR (300 MHz, CD3OD) δ 8.69 (br s, 1H), 8.34 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.7 Hz, 2H), 7.22 (br s, 2H), 3.89 (s, 6H), 3.77 (s, 3H), 2.43 (s 3H); HPLC Rt=14.61 min.

[0375] Compound 222: Compound 924 (106 mg, 0.36 mmol) is reacted with 4-fluorophenyl boronic acid (55 mg, 0.39 mmol) in the manner described for example 218, but with an air atmosphere instead of argon, and with refluxing for 60 hours. The reaction is then quenched by cooling it to room temperature, diluting it with excess water, and extracting the mixture with ethyl acetate (3 times). The ethyl acetate extracts are then washed with brine, combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The recovered material is purified by trituration with diethyl ether, followed by CH2Cl2, followed by toluene, giving 28 mg (21%) of a gray solid: MS m/z=357 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.21 (br s, 1H), 8.82 (s, 1H), 8.45 (dd, J=8.7, 5.9 Hz, 1H), 7.41 (t, J=8.7 Hz, 1H), 7.22 (br s, 2H), 3.80 (s, 6H), 3.65 (s, 3H); HPLC Rt=14.60 min.

[0376] Compound 226: Compound 924 (212 mg, 0.71 mmol) is reacted with 3-thiophene boronic acid (101 mg, 0.78 mmol) in the manner described for example 218, but with refluxing for 36 days. The reaction is then quenched by cooling it to room temperature, diluting it with excess water, and extracting the mixture with ethyl acetate (3 times). The ethyl acetate extracts are then washed with brine, combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The recovered material is purified by elution through a 20×2.5 cm column of silica gel with a 20%, 40%, and 60% ethyl acetate:hexane step gradient, followed by a 2.5% MeOH: CH2Cl2 eluant. The material recovered from this column is then applied to two 500μ preparative TLC plates and developed one time with a 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) solvent system. The material recovered from these plates is then finally purified by trituration with a 1:1 toluene:methanol solvent system giving 35 mg (14%) of a pale green solid: MS m/z=345 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.14 (br s, 1H), 8.76 (s, 1H), 8.49 (m, 1H), 7.79 (dd, J=5.04, 1.01 Hz, 1H), 7.71 (dd, J=5.04, 3.02 Hz, 1H), 7.22 (br s, 2H), 3.80 (s, 6H), 3.65 (s, 3H); HPLC Rt=12.66 min.

[0377] The following compounds are prepared according to Example 9 above:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
230	11.73	399	611	13.91	389
232	14.04	369

EXAMPLE 10

[0378] 1371

[0379] Compound 185: Indole (29 mg, 0.25 mmol) is dissolved into DMF (2 mL) under N2 at room temperature. NaH (10 mg of a 60% suspension of NaH in mineral oil, 0.25 mmol) is added producing a strong gas evolution. This mixture is stirred at room temperature for 30 minutes and Compound 924 (74 mg, 0.25 mmol) is added as a solution in DMF (1 mL), dropwise, via syringe, over a 5 minute period. The reaction is then heated to 100° C. for 7 days in a sealed tube under N2. The reaction is then cooled to room temperature and quenched with water, which causes a precipitate to form. This mixture is then extracted with ethyl acetate (3 times). The ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 17×2.5 cm column of silica gel (15%, 30%, 60% EtOAc: Hexane step gradient, followed with 10% MeOH: CH2Cl2). The material recovered from the column is then further purified by applying it to two 500μ preparative TLC plates and developing one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). This gives 50 mg (53%) of a tan solid: MS m/z=378 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.71 (br s, 1H), 8.65 (br s, 1H), 8.20 (br s, 1H), 7.64 (m, 1H), 7.24 (m, 3H), 7.03 (br s, 1H), 6.83 (d, J=3.7 Hz, 1H), 3.78 (s, 6H), 3.68 (s, 3H); HPLC Rt=16.34 min.

[0380] Compound 198: 5-Chloroindole (38 mg, 0.25 mmol) is dissolved into DMF (2 mL) under air, at room temperature, in a sealed tube. NaH (10 mg of a 60% suspension of NaH in mineral oil, 0.25 mmol) is added producing a strong gas evolution, which is vented to the atmosphere. This mixture is allowed to sit for 15 minutes, then Compound 924 (1 mL of a 0.25 M solution in DMF, 0.25 mmol) is added. The tube is sealed and heated to 100° C. for 3 days. The reaction is then cooled to room temperature, and quenched with saturated NH4Cl(aq). The resulting mixture is diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 25×2.5 cm column of silica gel (20%, 40%, 60% and 80% EtOAc:Hexane step gradient). The material recovered from this column is then triturated with a 1:1 mixture of methanol:toluene giving 53 mg (52%) of a white solid: MS m/z=412 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.33 (br s, 1H), 8.90 (br s, 0.5H), 8.74 (br s, 1H), 8.65 (br s, 0.5H), 8.26 (br s, 1H), 7.74 (s, 1H), 7.50-7.10 (br mn, 2H), 7.02 (br s, 1H), 6.83 (d, J=3.7 Hz, 1H), 3.79 (s, 6H), 3.68 (s, 3H); HPLC Rt=14.57 min.

[0381] Compound 238: 4-Methoxyindole (37 mg, 0.25 mmol) is reacted Compound 924 (1 mL of a 0.25 M solution in DMF, 0.25 mmol) in the manner described for compound 198. The reaction is heated to 100° C. for 3 days, then cooled to room temperature and quenched with saturated NH4Cl(aq). The resulting mixture is diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are washed with water and brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 20×2.5 cm column of silica gel (20%, 40%, 60% and 80% EtOAc: Hexane step gradient). The material recovered from this column is then triturated with a 1:1 mixture of methanol: toluene giving 40 mg (39%) of a white solid: MS m/z=408 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.26 (br s, 1H), 8.71 (br s, 1H), 8.53 (br s, 0.5H), 8.21 (br s, 0.5H), 8.03 (br s, 1H), 7.20 (br m, 2H), 7.01 (br s, 1H), 6.80 (br m, 2H), 3.90 (s, 3H), 3.78 (s, 6H), 3.67 (s, 3H); HPLC Rt=16.23 min.

[0382] Compound 239: 5,6-Dimethoxyindole (44 mg, 0.25 mmol) is reacted Compound 924 (1 mL of a 0.25 M solution in DMF, 0.25 mmol) in the manner described for compound 198. The reaction is heated to 100° C. for 3 days, then cooled to room temperature and quenched with saturated NH4Cl(aq). The resulting mixture is diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are washed with water and brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 25×2.5 cm column of silica gel (20%, 40%, 60% and 80% EtOAc: Hexane step gradient). The material recovered from the column is then further purified by applying it to two 500μ preparative TLC plates and developing one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). This gives 47 mg (43%) of a white solid: MS m/z=438 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.21 (br s, 1H), 8.69 (s, 1H), 8.40 (br s, 0.5H), 8.22 (br s, 0.5H), 8.04 (d, J=3.7 Hz, 1H), 7.17 (s, 1H), 7.06 (br m, 2H), 6.70 (d, J=3.3 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 6H), 3.67 (s, 3H), 3.56 (br s, 3H); HPLC Rt=14.05 min.

[0383] Compound 327: 7-Azaindole (35 mg, 0.30 mmol) is reacted with Compound 924 (1 mL of a 0.30 M solution in DMF, 0.30 mmol) in the manner described for compound 198. The reaction is heated to 100° C. for 3 days, then cooled to room temperature and quenched with saturated NH4Cl(aq). The resulting mixture is diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are washed with water and brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). This gives 39 mg (34%) of a pale yellow solid: MS m/z=379 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.35 (br s, 1H), 8.44 (dd, J=4.7, 1.7 Hz, 1H), 8.26 (d, J=4.0 Hz, 1H), 8.10 (dd, J=7.7, 1.7 Hz, 1H), 7.47 (br s, 2H), 7.33 (dd, J=7.7, 4.7 Hz, 1H), 6.84 (d. J=4.0 Hz, 1H), 3.80 (s, 6H), 3.66 (s, 3H); HPLC Rt=9.26 min.

[0384] Compound 339: Melatonin (46 mg, 0.2 mmol) is reacted with Compound 924 (1 mL of a 0.20 M solution in DMF, 0.20 mmol) in the manner described for compound 198. The reaction is heated to 80° C. for 3 days, then cooled to room temperature and quenched with saturated NH4Cl(aq). A precipitate forms and is recovered by vacuum filtration, washed with cold water, suspended in methanol, vacuum filtered, and rinsed with fresh cold methanol to give 25 mg (25%) of a white solid: MS m/z=493 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.20 (br s, 1H), 8.90-8.40 (br m, 2H), 8.02 (m, 2H), 7.18 (d, J=2.3 Hz, 1H), 7.15-6.70 (br m, 3H), 3.82 (s, 3H), 3.79 (s, 6H), 3.68 (s, 3H), 3.35 (br m, 2H), 2.82 (br t, J=6.7 Hz, 2H), 1.79 (s 3H); HPLC Rt=12.61 min.

[0385] Compound 353: Indole-3-acetamide (35 mg, 0.2 mmol) is reacted with 2-chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (1 mL of a 0.20 M solution in DMF, 0.20 mmol) in the manner described for compound 198. The reaction is heated to 100° C. for 3 days, then cooled to room temperature and quenched with saturated NH4Cl(aq). The resulting precipitate is recovered by vacuum filtration, washed with cold water, then triturated with a 1:1 mixture of methanol: CH2Cl2 and dried under high vacuum giving 16 mg (18%) of a brown solid: MS m/z=435 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.00-8.50 (br m, 2H), 8.12 (s, 1H), 7.80-7.45 (m, 2H), 7.45-6.90 (m, 3H), 3.79 (s, 6H), 3.67 (s, 3H), 3.53 (s, 2H); HPLC Rt=11.46 min.

[0386] Compound 411: Ethyl 3-indole acetate (284 mg, 1.40 mmol) is reacted with Compound 924 (166 mg, 0.56 mmol) in the manner described for compound 198 using 5 mL of DMF, 2.8 mmol of NaH, and adding solid Compound 924 instead of as a solution in DMF. The reaction is heated to 80° C. for 3 days, then cooled to room temperature and quenched with saturated NH4Cl(aq). The resulting mixture is diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate extracts are washed with water and brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 20×2.5 cm column of silica gel (20%, 40%, 60% and 80% EtOAc:Hexane step gradient). The material recovered from the column is then further purified by applying it to two 500μ preparative TLC plates and developing one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). The material recovered from these plates is then applied to a second set of two 500μ preparative TLC plates and developed one time with 7:7:7:1 MtBE:CH2Cl2:Hexane:MeOH. This gives 12 mg (5%) of a brown solid: MS m/z=464 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.00-8.50 (br m, 2H), 8.18 (s, 1H), 7.60 (m, 1H), 7.50-6.90 (m, 4H), 4.11 (q, J=7.0 Hz, 2H), 3.85 (s, 2H), 3.79 (s, 6H), 3.68 (s, 3H), 1.20 (t, J=7.0 Hz, 3H); HPLC Rt=15.88 min.

[0387] The following compounds are prepared according to Example 9 above:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
196	15.88	408	323	17.44	392
200	18.56	484	332	16.06	403
205	13.36	436	333	9.63	479
237	17.40	412	441	15.72	396
240	12.82	379

EXAMPLE 11

[0388] 1372

[0389] Compound 202: Compound 924 (74 mg, 0.25 mmol), 5-hydroxyindole (33 mg, 0.25 mmol), and anhydrous K2CO3 (35 mg, 0.25 mmol) are dissolved in DMF (2 mL) in a sealed tube fitted with a magnetic stirrer, under N2, at room temperature. A catalytic amount of copper(II) oxide is then added and the reaction heated to 120° C. for 18 hours. The reaction is then cooled to room temperature and quenched with water. This mixture is then extracted with ethyl acetate (3 times). The ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 17×2.5 cm column of silica gel (25%, 50% and 100% EtOAc: Hexane step gradient). The material recovered from the column is then triturated with a 1:1 mixture of methanol:CH2Cl2 and dried under high vacuum giving 39 mg (40%) of a brown solid: MS m/z=394 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.18 (br s, 1H), 9.29 (s, 1H), 8.67 (br s, 1.5H), 8.38 (br s, 0.5H), 8.10 (d, J=3.4 Hz, 1H), 7.40-6.69 (m, 4H), 6.67 (d, J=3.7 Hz, 1H), 3.78 (s, 6H), 3.68 (s, 3H); HPLC Rt=12.02 min.

[0390] The following compounds are prepared according to the procedure of Example 11:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
463	12.74	422	464	15.80	396

EXAMPLE 12

[0391] 1373

[0392] Reference: WO 99/10349

[0393] Compound 380

[0394] Oxindole (176 mg, 1.32 mmol) is dissolved into a 1:1 mixture of THF:DMF (4 mL), under N2, at room temperature. NaH (53 mg of a 60% suspension in mineral oil, 1.32 mmol) is added, which produces a vigorous gas evolution. This mixture is stirred for 30 minutes at room temperature, then Compound 924 (156 mg, 0.53 mmol) is added and the reaction heated to 80° C. for 2 hours. The reaction is then cooled to room temperature, partially concentrated under reduced pressure, diluted with ethyl acetate, then extracted with water. The water extract is then back extracted two times with fresh ethyl acetate. All of the ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by preparative HPLC (5 to 100% CH3CN:H2O (0.1% TFA buffer) over 10 minutes at 20 mL/minute). Crystals form in the recovered eluant, which are recovered by vacuum filtration, washed with water, and dried under high vacuum giving 7 mg (7%) of a yellow solid: MS m/z=394 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 13.0 (br s, 1H), 10.34 (s, 1H), 10.29 (s, 1H), 8.39 (br s, 1H), 7.77 (d, J=6.7 Hz, 1H), 7.08 (s, 2H), 6.91 (t, J=7.0 Hz, 1H), 6.81 (m, 2H), 3.80 (s, 6H), 3.69 (s, 3H); HPLC Rt=10.89 min.

[0395] Compound 465

[0396] Compound 924 (130 mg, 0.44 mmol) is reacted with N-methylindolin-2-one (162 mg, 1.1 mmol, prepared according to the procedure of Bordwell, F. G.; Fried, H. E., J. Org. Chem., 1991, 56, 4218-4223, in 51% yield) in the manner described for Compound 380, and kept at 80° C. for 3 hours. The reaction is then cooled to room temperature, partially concentrated under reduced pressure, diluted with ethyl acetate, then extracted with water. The water extract is then back extracted two times with fresh ethyl acetate. All of the ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 17×2.5 cm column of silica gel (20%, 40%, 60% EtOAc:Hexane step gradient, followed by a 5% and 10% MeOH: CH2Cl2 step gradient). The material recovered from the column is then further purified by applying it to two 1000μ preparative TLC plates and developing one time with 7:7:7:1 MtBE: CH2Cl2:Hexane:MeOH. The material recovered from these plates is then applied to a set of two 500μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2: MeOH: NH4OH(aq). This gives 52 mg (29%) of a yellow solid: MS m/z=408 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 13.10 (br s, 1H), 10.33 (s, 1H), 8.41 (s, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.08 (s, 2H), 6.99 (m, 2H), 6.88 (t, J=7.4 Hz, 1H), 3.80 (s, 6H), 3.70 (s, 3H), 3.28 (s, 3H); HPLC Rt=15.92 min.

[0397] Compound 517

[0398] Compound 924 (134 mg, 0.45 mmol) is reacted with 5-chlorooxindole (189 mg, 1.1 mmol) in the manner described for compound 380, and kept at 80° C. for 3 hours. The reaction is then cooled to room temperature, partially concentrated under reduced pressure, diluted with ethyl acetate, then extracted with water. The water extract is then back extracted two times with fresh ethyl acetate. All of the ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered and concentrated. The recovered material is then purified by elution through a 17×2.5 cm column of silica gel (10%, 20%, and 50% acetone: CH2Cl2 step gradient, followed by a 10% and 15% MeOH:CH2Cl2 step gradient). The material recovered from the column is then further purified by trituration with acetone giving 5 mg (2.5%) of a yellow solid: MS m/z=428 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 13.06 (br s, 1H), 10.41 (br s, 2H), 8.41 (s, 1H), 7.64 (s, 1H), 6.93 (s, 2H), 6.90 (m, 1H), 6.79 (d, J=8.0 Hz, 1 H), 3.76 (s, 6H), 3.68 (s, 3H); HPLC Rt=11.47 min. 1374

[0399] Compound 325

[0400] To a solution of 2-hydroxybenzimidazole (788 mg, 6 mmol) in dry DMF (12 mL) at 0° C. and under a nitrogen atmosphere is added NaH (60% in mineral oil, 252 mg, 6.30 mmol). The mixture is stirred at 0° C. for 1.5 h and then a solution of chloride 924 (890 mg, 3.00 mmol) in dry DMF (3 mL) added dropwise. The reaction is allowed to warm to room temperature and then heated at 60-80° C. for 5-18 h. The mixture is poured onto water (15 volumes) and the precipitate collected, washed with water, ether and dried to give compound 325 as a white powder (1.09 g, 92%).

[0401] Compounds below are prepared according to the procedure for compound 325, substituting the appropriate reagents. Purification methods varied.

Compound	MS m/z	HPLC Rt
325	395.1	10.47
423	418.4	13.0
	(M + Na)
424	411.7	13.21
426	491.6	15.12
1032	393.9	11.91
	(M − CO2Me)

EXAMPLE 14a

[0402] 1375

[0403] A mixture of 2,4-dichloro-1,3,5-triazine (0.64, 4.26 mmol) and solid K2CO3 (0.6 g, 4.34 mmol) is suspended in acetonitrile (10 mL) under nitrogen at room temperature followed by addition of 2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester [Meanwell, N. A., Yuen, S. S., Gao, Q., St.Laurent, D. R., Balasubramanian, N., J. Org Chem., 60,1565-82 (1995)] (1.0 g, 4.26 mmol). The mixture is allowed to stir at ambient temperature for 1.5 hours. The mixture is poured onto ice/water and the white solid formed is collected by suction filtration and dried under vacuum to give material identified as N3-[4-(2-Chloro-1,3,5-triazinyl)]-2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester.

[0404] Compound 1277

EXAMPLE 14B

[0405] 1376

[0406] Compound 379

[0407] N3-[4-(2-Chloro-1,3,5-triazinyl)]-2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester Compound 1277 (75 mg, 0.22 mmol) is suspended in isopropanol (2 mL) in a sealed tube under air at room temperature. N,N-Diisopropylethylamine (0.2 mL, 0. mmol) is added, followed by addition of 4-aminophenyloxazole (15 mg, 0.17 mmol). The reaction mixture is then heated to 100° C. for 24 hours, during which everything goes into solution. The reaction is then cooled to room temperature and a white precipitate forms, and is recovered by vacuum filtration and washed with cold isopropanol. HPLC(Method A) Rt=8.49 min.; MS m/z=372; 1H NMR (300 MHz, DMSO-d6) 11.4 (m, 1H), 10.5 (m, 1H), 8.8 (m, 2H), 8.4 (s, 1H), 8.1 (s, 1H), 7.9 (m, 1H), 7.6 (m, 1H), 7.4 (m, 2H), 7.1 (t, 1H), 7.0 (d, 2H);

[0408] In a manner similar to that described in Example C, the following compounds of this example are prepared from the appropriately substituted amine and the chloride Compound 1277.

[0409] Compound 418: HPLC(Method A) Rt=8.47 min.; MS m/z=372; 1H NMR (300 MHz, DMSO-d6) δ 11.3 (s, 1H), 10.6 (s, 1H), 8.8 (s, 1H), 8.4 (s, 1H), 8.2 (m, 3H), 8.0 (bs, 1H), 7.6 (m, 3H), 7.1 (t, 1H), 7.0 (t, 1H)

[0410] Compound 419: HPLC Rt=8.22 min.; MS m/z=348; 1H NMR (300 MHz, DMSO-d6) δ 11.3 (s, 1H), 10.6 (s, 1H), 8.8 (s, 1H), 8.1(d, 3H), 7.8 (d, 3H), 7.0-7.2 (m, 4H)

[0411] Compound 420: HPLC Rt=8.54 min.; MS m/z=348; 1H NMR (300 MHz, DMSO-d6) δ 11.4 (s, 1H), 10.6 (s, 1H), 8.8 (s, 1H), 8.6 (s, 1H), 8.1(d, 1H), 7.9 (s, 2H), 7.6 (s, 1H), 7.4(m, 2H), 7.0-7.2 (m, 3H)

[0412] Compound 422: In a manner similar to that described in Example C, the compound is prepared from the amine that is synthesized as described below. HPLC(Method A) Rt=9.7 min.; MS m/z=505; 1H NMR (300 MHz, DMSO-d6) δ 11.2 (s, 1H), 10.4(m, 2H), 8.7 (s, 1H), 8.3(d, 2H), 8.1 (d, 1H), 7.9 (d, 3H), 6.9-7.1 (m, 5H).

[0413] To a solution of N-(tert butoxycarbonyl)-phenylene-1,4-diamine (1.5 g, 7.20 mmol) and triethylamine (5 mL) in methylene chloride (50 mL) is added 4-nitrobenzene sulfonylchloride. The mixture is allowed to stir at room temperature for 18 hours. The reaction is diluted with methylene chloride and the organics washed with water. The organic extracts are dried over anh. Magnesium sulfate and concentrated under reduced pressure. The crude product is purified via medium pressure liquid chromatography using methylene chloride followed by 1:99 methanol/methylene chloride as the solvent system N1-(tert butoxycarbonyl)-N-4-(4-nitrophenylsulfonyl)-phenylene-1,4-diamine. The compound is dissolved in methylene chloride (15 mL) followed by addition of trifluoroacetic acid (5 mL) and allowed to stir for 2 hours at room temperature. The organics concentrated to dryness and the residue is taken up in a mixture of ethyl acetate and saturated sodium bicarbonate. The organics are separated, dried over anh. Magnesium sulfate and concentrated under reduced pressure to give N-(4-nitrophenylsulfonyl)-phenylene-1,4-diamine.

[0414] Compound 450: HPLC Rt=5.98 min.; MS m/z=316

[0415] Compound 451: HPLC Rt=8.85 min.; MS m/z=384

[0416] Compound 452: HPLC Rt=9.41 min.; MS m/z=42

[0417] Compound 453: In a manner similar to that described in Example C, the compound is prepared from the amine that is synthesized as described below. HPLC(Method A) Rt=9.91 min.; MS m/z=505;

[0418] To a solution of 1,4-phenylenediamine (3.0 g, 27.7 mmol) and triethylamine (10 mL) in methylene chloride (50 mL) is added 4-nitrobenzenesulfonylchloride. The mixture is allowed to stir at room temperature for 18 hours. The reaction is taken up in a mixture of ethyl acetate (1L) and saturated sodium bicarbonate (100 mL). The separated organics are dried over anh. Magnesium sulfate and concentrated under reduced pressure. The crude organics are purified via medium pressure liquid chromatography using methylene chloride followed by 2:98 methanol/methylene chloride followed by 0.5:5:995 Conc. NH4OH/methanol/methylene chloride as the solvent system N3-(4-nitrophenylsulfonyl)-phenylene-1,3-diaamine.

[0419] Compound 454: In a manner similar to that described in Example C, the compound is prepared from the amine that is synthesized as described below. HPLC Rt=9.5 min.; MS m/z=434.

[0420] A mixture of 4-nitrophenylisocyanate (1.0 g, 6.09 mmol) and (S)-(+)-3-Hydroxytetrahydrofuran (1.0 mL, 11.3 mmol) is suspended in toluene (20 mL) under nitrogen. The mixture is allowed to stir at room temperature for 18 hours. The reaction is concentrated under reduced pressure. The crude compound is purified via medium pressure liquid chromatography using methylene chloride followed by 1:99 methanol/methylenechloride as the solvent system to give N-(S)-(+)-3-tetrahydrofuranyloxycarbonyl-4-nitroaniline. The compound is added to a suspension of 10% Pd/C (500 mg) and ethanol (20 mL). The mixture is stirred under a hydrogen gas atmosphere for 24 hours. The catalyst is removed by suction filtration and the organics concentrated under reduced pressure. The crude compound is purified via medium pressure liguid chromatography using methylene chloride followed by 1:99 methanol/methylene chloride followed by 5:95 methanol/methylenechloride as the solvent system to give N-(S)-(+)-3-tetrahydrofuranyloxycarbonyl-1,4 phenylenediamine.

[0421] Compound 455: In a manner similar to that described in Example C, the compound is prepared from amine that is synthesized as described below. HPLC Rt==9.7 min.; MS m/z=434.

[0422] A mixture of 3-nitrophenylisocyanate (1.0 g, 6.09 mmol) and (S)-(+)-3(1.0 hydroxytetrahydrofuran (1.0 mL, 11.3 mmol) is suspended in toluene (20 mL) under nitrogen. The mixture is allowed to stir at room temperature for 18 hours. The reaction is concentrated under reduced pressure. The crude compound is purified via medium pressure liquid chromatography using methylene chloride followed by 1:99 methanol/methylenechloride as the solvent system to give N-(S)-(+)-3tetrahydrofuranyloxycarbonyl-3-nitroaniline. The compound is added to a suspension of 10% Pd/C (500 mg) and ethanol (20 mL). The mixture is stirred under a hydrogen gas atmosphere for 24 hours. The catalyst is removed by suction filtration and the organics concentrated under reduced pressure. The crude compound is purified via medium pressure liquid chromatography using methylene chloride followed by 1:99 methanol/methylenechloride followed by 5:95 methanol/methylenechloride as the solvent system to give N-(S)-(+)-3-tetrahydrofuranyloxycarbonyl-1,3 phenylenediamine.

[0423] The following compounds are synthesized in a manner similar to that described in Example C, substituting the appropriate amine.

Compound	HPLC ret.	MS m/z
456	7.8 min	398
457	(Method B) 3.47 min.	339
458	(Method B) 3.5 min.	339
459	12.5 min.	357
460	(Method B) 3.28 min	329
461	(Method B) 3.79 min.	389
462	(Method B) 3.76 min.	388
467	(Method B) 3.19 min.	350
482	(Method B) 3.0 min.	306
483	(Method B) 3.7 min.	419
484	(Method B) 3.2 min.	339
485	(Method B) 3.1 min.	330
486	(Method B) 3.0 min.	330
487	(Method B) 1.9 min.	306
488	(Method B) 1.5 min.	306
489	(Method B) 2.6 min.	336
490	(Method B) 1.9 min.	307
491	(Method B) 2.5 min.	367
492	(Method B) 2.5 min.	307
493	(Method B) 3.2 min.	349
494	(Method B) 2.7 min.	365
503	14.3 min.	374
504	(Method B) 3.6 min.	374
505	13.4 min.	372
506	(Method B) 4.2 min.	441
508	(Method B) 2.86 min.	356
681	(Method B) 2.39 min.	413
682	(Method B) 2.3 min.	321
683	(Method B) 3.24 min.	355
684	(Method B) 3.56 min.	355
685	8.22 min.	344
686	(Method B) 2.19 min.	356

[0424] Compound 687: HPLC(Method B) Rt=2.28 min.; MS m/z=356; 1H NMR (300 MHz, DMSO-d6) δ 11.2 (s, 1H), 11.0 (s, 1H), 9.6(m, 1H), 9.0 (m, 2 H), 8.7 (s, 1 H), 7.8-8.2(m, 4H), 7.0-7.2 (m, 2H)

[0425] Compound 688 : HPLC(Method B) Rt=3.54 min.; MS m/z=356; 1H NMR (300 MHz, DMSO-d6) δ 11.4 (s, 1H), 10.0 (s, 1H), 9.0(m, 3H), 8.5 (d, 1 H), 8.2 (m, 1 H), 7.7 (m, 3H), 7.0-7.2 (m, 3H)

[0426] Compound 689: HPLC(Method B) Rt=2.39 min.; MS m/z=356; 1H NMR (300 MHz, DMSO-d6) δ 11.8 (s, 1H), 9.2 (s, 1H), 9.0(m, 1H), 8.4 (m, 1 H), 7.7-8.2 (m, 5H), 7.1-7.3 (m, 3H) 1377

EXAMPLE 15

[0427] of chlorotriazine 924 (2.97 g, 10 mmol) and 10 mmol) in dry acetonitrile (100 mL) is added ground 12 mmol). The resulting mixture is heated at 50-90° C. for perature, concentrated in vacuo and purified by column -Hexanes) to provide compound 378 as a white powder

EXAMPLE 16

[0428] de 378 (41 mg, 0.10 mmol), 3-aminobenzamide (14 mg, lethylamine (Hunig's base) (16 mg, 0.12 mmol) in i-PrOH 30° C. for 10-40 h. On cooling a precipitate formed which is OH, ether and dried to give compound 377 as a yellow

[0429] are synthesized according to the procedure outlined for e appropriate reagents.

Compound	MS m/z	HPLC Rt
336	470	12.40
371	484	12.09
375	504	14.37
376	509	11.94
377	513	10.22
378	413	13.48
381	495.0	15.59
382	496.1	13.85
383	528.3	13.18
384	484.0	11.59
385	484.0	12.12
386	483.8	12.49
387	nd	12.19
388	512.2	13.83
389	451.1	8.87
390	514.0	11.10
391	438.0	9.19
392	466.0	9.55
397	500	11.98
398	500	12.42
399	530	12.85
400	530	11.16
401	495[M + Na]+	10.91
402	560	11.61
403	436	10.59
404	510	10.26
405	422	11.40
406	510	10.83
407	450	9.33
413	485	8.50
414	485	9.73
415	500	12.23
416	485	8.53
417	408	9.73
509	498	11.86
510	499	8.60
511	498	12.05
512	502	11.77
513	502	11.93
514	502	11.89
515	498	12.32
516	498	12.45
549	491	10.64
561	500	10.39
569	512.3	12.2
571	568	13.15
572	529	11.88
574	434	10.54
579	526.0	11.28
579	526.0	11.13
583	474	8.96
585	556.2	13.12
586	544.3	12.24
587	524	12.61
587	524.2	12.67
588	521	13.87
591	528.6	11.15
592	512.1	12.34
593	527.1	8.93
595	528.4	11.54
596	544.1	11.19
597	532	12.93
598	552	12.96
605	515	12.05
606	536	12.72
940	563	12.63
941	499	10.27
943	518	12.08
944	518	12.42
945	512	12.58
946	563	12.50
947	499	8.33
948	499	8.36
949	518	12.32
950	490	11.47
951	536	12.52
952	529	11.87
954	524	9.95
1033	498.1	11.85
1034	498.1	11.88
1035	514.2	10.82
1036	514.2	10.85
1037	514.1	11.59
1042	514.0	12.08
1043	524	12.62
1044	510.2	12.20
1045	528.3	11.90
1046	528.3	11.97
1048	498	13.48
1049	512	13.40
1050	554	15.83
1051	513	10.70
1052	ND	16.15
1053	488	14.73
1054/1055	ND	13.94/14.11
1056/1057	ND	12.31/12.63
1058/1059	ND	10.11/10.44
1060/1061	ND	12.39/12.67
1062/1063	539/539	12.16/12.35
1064/1065	554	12.04/12.74
	(M + Na)/532

[0430] Compound 558: HPLC(Method A) Rt=8.43 min.; MS m/z=514; 1H NMR (300 MHz, DMSO-d6) δ 10.8(m, 1H), 10.4 (s, 1H), 8.2-8.7(m, 2H), 8.0-8.1 (m, 2H), 7.2 (d, 1H), 7.0 (m, 2H), 6.7 (m, 3H), 3.5-3.7 (m, 15H)

EXAMPLE 17

[0431] Aminobenzimidazole triazines can be prepared according to Examples B and C, substituting the appropriate amines, and according to the procedure shown below, which describes the preparation of Compound 525. 1378

[0432] To 1.0 g (6.67 mmol) of 2,4-dichloro-1,3,5-triazine in 3 mL of DMF at 0° C. is added 1.16 mL (6.67 mmol) of DIEA. The resulting yellow solution is stirred at 0° C. for 10 min when 888 mg (6.67 mmol) of 2-aminobenzimidazole is added portionwise over 5 min, followed by an additional 1 mL of DMF. The resulting mixture is stirred at 0° C. for 1.9 h, then at RT for 3.25 h. At this point, the mixture is poured into 40 mL of stirring cold water with additional cold water rinses to a total volume of 100 mL. The light yellow solid is isolated by filtration, rinsed with cold water, and dried in vacuo, giving 1.36 g (83%) of 1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzoimidazol-2-ylamine (Compound 1174) as a light yellow solid: MS m/z=246 [M+H]+; HPLC Rt=5.79 min. 1379

[0433] To a suspension of 100 mg (0.405 mmol) 1-(4-chloro-[1,3,5]triazin-2-yl)-1H imidazol-2-ylamine (1174) in 2 mL of i-PrOH at RT in a sealed tube under air is d 0.106 mL (0.608 mmol) of DIEA, followed by 81.7 mg (0.446 mmol) of 4-tert aniline. The resulting mixture is heated to 110° C. for 17 h, then cooled to room rature. The yellowish precipitate is isolated by filtration, rinsed once each with OH and Et2O and dried in vacuo, giving 61.8 mg (56.5%) of Compound 525 as a wish solid: MS m/z=360 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1 .85-8.70 (m, 1H), 8.45 (d, 1H), 8.15-6.70 (m, 9H), 1.30 (m, 9H); HPLC Rt=min.

[0434] following compounds are prepared according to Example 17, substituting the priate amine in the second step, corresponding to Example C:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
289	9.65	394	527	7.13	347
395	7.78	347	528	12.07	372
396	7.77	347	646	6.85	228
438	9.87	371	647	12.03	388
439	9.60	371	648	9.01	335
440	8.69	425	651	10.19	304
285	9.66	364	479	8.58	389
286	8.89	350	480	12.54	380
287	9.87	408	524	9.38	378
299	11.36	392	526	9.95	348
302	9.93	452	654	10.41	334
324	8.89	445	655	11.72	332
445	7.64	493	656	10.16	334
466	7.78	493	657	11.78	332
473	8.50	347	658	6.47	305
474	11.24	338	659	7.39	305
475	8.21	361	662	10.68	318
476	10.55	422	663	10.74	348
477	10.38	364	664	11.52	352
478	11.20	338	923	8.27	383

[0435] Compound 700 is prepared according to Example 17, substituting amine Amine 1175 is prepared by the alkylation of 2-methoxy-5-nitrophenol with 4loroethyl)morpholine hydrochloride using K2CO3 in refluxing acetone/water as in the following scheme. 1380

[0436] Standard acid/base workup give a yellow solid, which is purified by trituration with Et2O. The resulting yellow solid is converted to the amine by standard hydrogenation using 10% Pd—C in MeOH and EtOAc at RT. Filtration through Celite™ and concentration of the filtrate gave the desired amine, which is then reacted with Compound 1174 under the conditions of Example C. Compound 700 is purified using preparative HPLC: MS m/z=463 [M+H]+; HPLC Rt=7.65 min.

[0437] Compound 649 is prepared according to Example 17, substituting the appropriate amine, which is prepared according to the method described for Compound 1175, substituting 2-(diethylamino)ethyl chloride hydrochloride in the alkylation: MS m/z=449 [M+H]+; HPLC Rt=7.91 min.

[0438] Compound 650 is prepared according to Example 17, substituting the appropriate amine, which is prepared according to the method described for Compound 1175, using 4-nitroguaiacol and 4-(2-chloroethyl)morpholine hydrochloride. The final solid is purified using preparative HPLC: MS m/z=463 [M+H]+; HPLC Rt=7.48 min.

[0439] Compound 652 is prepared according to Example 17, substituting the appropriate amine, which is prepared according to the method described for Compound 1175, using 4-nitroguaiacol and 2-(diethylamino)ethyl chloride hydrochloride: MS m/z=449 [M+H]+; HPLC Rt=7.88 min.

[0440] Compound 653 is prepared according Example 17, substituting the addition of potassium phthalimide in PhCH3 and DMF at RT for the second step. Standard aqueous workup followed by flash chromatography (SiO2, elution with EtOAc) gives Compound 653: MS m/z=358 [M+H]+; HPLC Rt=11.14 min.

EXAMPLE 19

[0441] Aminotriazine compounds can be prepared by reacting the appropriate chlorotriazine with ammonia, according to the procedure shown below, which describes the preparation of Compound 1024. 1381

[0442] 1.0 g (3.37 mmol) of 2-chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (Compound 924) in 16.8 mL of NH3 in EtOH (2.0 M) is heated at 100° C. for 22 h, then cooled to 0° C. The white solid is isolated by filtration, rinsed with EtOH, and dried in vacuo, giving 0.46 g (50%) of a white solid, which is N-(3,4,5-trimethoxyphenyl)-[1,3,5]triazine-2,4-diamine (1024): MS m/z=278 [M+H]+; HPLC Rt=6.75 min.

[0443] The following compounds are prepared according to Example 19, substituting the appropriate chlorotriazine:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
665	9.12	318

EXAMPLE 20

[0444] Urea and thiourea compounds can be prepared by reacting the appropriate isocyanate or isothiocyanate with an aminotriazine such as Compound 1024, according to the procedure shown below, which describes the preparation of Compound 852. 1382

[0445] To a slurry of 300 mg (1.08 mmol) of N-(3,4,5-trimethoxy-phenyl)-[1,3,5]triazine-2,4-diamine (1024) in 2.5 mL of PhCH3 at RT in a sealed tube under air is added 0.118 mL (1.08 mmol) of PHNCO. The resulting mixture is heated to 100° C. for 7 days, then cooled to room temperature. The white precipitate is isolated by filtration, rinsed once each with PhCH3 and Et2O and dried in vacuo. The slightly impure white solid is purified by trituration in refluxing i-PrOH, cooled to RT, and isolated by filtration, rinsed once each with i-PrOH and Et2O and dried in vacuo giving 353.9 mg (82.5%) of Compound 852 as a white solid: MS m/z=397 [M+H]+; HPLC Rt=11.44 min; 1H NMR (300 MHz, DMSO-d6) δ 11.15 (br s, 1H), 10.27 (br s, 1H), 10.10 (s, 1H), 8.50 (s, 1H), 7.75-6.90 (m, 7H), 3.73 (br s, 6H), 3.64 (s, 3H).

[0446] The following compounds are prepared according to Example 20, substituting the appropriate amino triazine and either an isocyanate or isothiocyanate:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
21	12.07	427	660	11.09	411
22	12.36	457	661	11.61	425

EXAMPLE 21

[0447] Amide and sulfonamide compounds can be prepared by reacting the appropriate carboxylic acid, acid chloride or sulfonyl chloride with an aminotriazine such as Compound 1024, according to the procedure shown below, which describes the preparation of Compound 679. 1383

[0448] To a solution of 75 mg (0.27 mmol) of N-(3,4,5-trimethoxy-phenyl)-[1,3,5]triazine-2,4-diamine (1024) in 2 mL of pyridine at RT in a sealed tube under air is added 0.0.89 mL (0.68 mmol) of PhCH2COCl. The resulting mixture is heated to 100° C. for 2.5 h, then cooled to room temperature, and poured into a stirring mixture of dil. aq. NaHCO3 and EtOAc. The organic layer is washed with dil. NaHCO3, brine, 1N HCl, brine, dried over Na2SO4 and concentrated. Chromatography (SiO2, elution with 3:1 EtOAc-hexanes) gives 55.8 mg (52.1%) of Compound 679 as a yellowish solid: MS m/z=396 [M+H]+; HPLC Rt=11.08 min; 1H NMR (300 MHz, DMSO-d6) δ 10.93 (br s, 1H), 10.01 (br s, 1H), 8.53 (s, 1H), 7.40-7.20 (m, 7H), 3.80-3.70 (m, 8H), 3.62 (s, 3H).

[0449] Alternatively, amide and sulfonamide compounds can be prepared by reacting the appropriate amide with a. substituted chlorotriazine, according to the procedure shown below, which describes the preparation of Compound 680. 1384

[0450] To a solution of 58.5 mg (0.823 mmol) of acrylamide in 1 mL of DMF at RT is added 32.9 mg (0.823 mmol) of NaH (60% dispersion in oil). The resulting foam is heated to 60° C. for 10 min, then cooled to 0° C. when a solution of 70 mg (0.274 mmol) of Compound 701 in 0.75 mL of DMF is added dropwise via syringe, followed by one 0.25 mL rinse. The resulting mixture is stirred at 0° for 1 h, then quenched with satd aq NH4Cl and diluted with water and EtOAc. The organic layer is washed with brine and the combined aqueous layer and washing is extracted with EtOAc. The combined organics are dried and concentrated. Flash chromatography (SiO2, elution with 3:1 EtOAc-hexanes, then EtOAc) gives 2.9 mg (3.6%) of a slightly impure product. that could be purified to homogeneity by flash chromatography (SiO2, elution with 2:1 EtOAc-hexanes) giving Compound 680: MS m/z=290 [M+H]+; HPLC Rt=10.16 min.

EXAMPLE 22

[0451] Aminoindazole compounds can be prepared according to Examples B and C, substituting the appropriate amines, and according to the procedure shown below, which describes the preparation of Compound 554.

[0452] Preparation of 1-benzyl-1H-indazol-5-ylamine: 1385

[0453] To a solution of 10 g (61.3 mmol) of 5-nitroindazole in 100 mL of DMF is added 12.7 g (91.9 mmol) of K2CO3 and 7.29 mL (61.3 mmol) of PhCH2Br. The resulting mixture is stirred at RT for 3.5 days, then poured into 400 mL of water. The resulting slurry is filtered, rinsed once with water and dried in vacuo giving a beige solid. A 2.5 g portion of this crude material is purified by chromatography (SiO2, elution with 1:2 EtOAc-hexanes) giving 906.4 mg of the faster eluting 1-substituted isomer and 518.4 mg of the slower eluting 2-substituted isomer. 1386

[0454] To 906.4 mg (3.58 mmol) of the 1-substituted isomer in 20 mL of MeOH and 5 mL of EtOAc at RT is added a slurry of 150 mg of 10% Pd—C in 5 mL of MeOH. The resulting slurry is then stirred under a balloon of H2 for 1.2 h, filtered through Celite™, and rinsed with MeOH and EtOAc. Concentration of the filtrate gives 790.3 mg (98.9%) of 1-benzyl-1H-indazol-5-ylamine as a pinkish solid: MS m/z=224 [M+H]+.

[0455] Preparation of Compound 554: 1387

[0456] To 526.1 mg (3.51 mmol) of 2,4-dichloro-1,2,5-triazine in 15 mL of DMF at 0° C. is added 0.733 mL (4.21 mmol) of DIEA. The resulting yellow solution is stirred at 0° C. for 20 min when 783.5 mg (3.51, mmol) of 1-benzyl-1H-indazol-5-ylamine is added in one portion followed by 2×2.5 mL DMF flask rinses. The resulting mixture is stirred at 0° C. for 30 min, at RT for 4.5 h, then diluted with EtOAc. The organic layer is then washed twice with water and once with brine. The aqueous layer and washings are extracted once with EtOAc. The combined organics are dried, concentrated, and purified by chromatography (SiO2, elution with 1:1 EtOAc-hexanes) to give a slightly impure pinkish solid. Trituration with Et2O gives 473 mg (40.1%) of Compound 1176 as a light pink solid: MS m/z=337 [M+H]+; HPLC Rt=13.09 min. 1388

[0457] Compound 554 is prepared using Compound 1176 and 3-bromoaniline wing Example C: MS m/z=473 [M+H]+; HPLC Rt=13.801 min; 1H NMR MHz, DMSO-d6) δ 9.88 (br s, 2H), 8.35 (s, 1H), 8.15-7.90 (m, 4H), 7.70-7.50 H), 7.35-7.10 (m, 5H), 5.64 (br s, 2H).

[0458] The following compounds are prepared according to Example 22, substituting ppropriate amine in the second step. The HPLC method for the compounds in the are analyzed using Method A, except for Compound 553.

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
552	8.60	ND	871	4.31	415
553	12.79	408	872	8.38	497
559	9.15	583	873	6.97	482
726	8.46	530	900	6.41	451
727	7.50	414	901	6.51	486
728	6.56	398	902	7.33	430
729	6.39	479	903	8.26	477
730	6.62	436	904	7.01	424
731	6.60	433	905	6.83	424
732	6.34	468	906	7.91	478
733	4.25	389	907	7.88	478
734	7.02	422	908	6.25	466
735	5.67	477	909	7.86	492
736	6.21	501	910	7.64	434
737	6.56	460	911	8.05	463
738	5.49	396	912	6.94	419

[0459] Compound 676 is prepared according to Example 22 substituting the priate amine, which can be prepared according to Kume, M. et al. J Antibio. 46, 177: MS m/z=475 [M+H]+; HPLC Rt=10.72 min.

EXAMPLE 18

[0460] N-alkylated anilinotriazines can be prepared from the commercially available secondary amines according to Examples B and C, or from the alkylation of chlorotriazine intermediates such as Compound 1176 followed by Example C, according to the procedure shown below, which describes the preparation of Compound 566. 1389

[0461] To 473 mg (1.40 mmol) of 1176 in 7.5 mL of DMF at 0° C. is added 0.262 mL (4.21 mmol) of MeI, followed by 67.4 mg (1.69 mmol) of NaH (60% dispersion in oil). The resulting mixture is stirred at 0° C. for 4.25 h (additional 10 mg NaH added after 3.1 h as TLC indicated remaining starting material). At this point, the reaction mixture is quenched with satd aq NH4Cl and diluted with water and EtOAc. The organic layer is washed with water and brine. The aqueous layer and washings are extracted once with EtOAc. The combined organics are dried, concentrated and purified by chromatography (SiO2, elution with 1:1 EtOAc-hexanes) to give Compound 11.77 as a pale oil: MS m/z=351 [M+H]+. 1390

[0462] Compound 566 is prepared using Compound 1177 and 3,4,5-trimethoxyaniline following Example C: MS m/z=498 [M+H]+; HPLC Rt=12.27 min; 1H NMR (300 MHz, DMSO-d6) δ 9.60 (br s, 2H), 8.40-8.00 (m, 2H), 7.72 (br s, 2H), 7.50-6.60 7 H), 5.68 (s, 2H), 4.00-2.80 (m, 12H).

[0463] The following compounds are prepared according to Example 18, substituting the appropriate amine and alkylating reagent for those used in the preparation of 1177, and the appropriate amine in the second step, following Example C. The preparation of the amines used for Compounds 670, 671, 677 are prepared according to Kume, M. et. al. J. Antibio. 1993, 46, 177 and Koguro, K. et al. Synthesis 1998, 910:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
666	14.42	371	670	10.83	439
667	14.89	487	671	10.92	490
668	13.68	422	677	11.48	489
669	12.12	468	51	15.67	459
972	13.87	428	310	12.95	482
973	14.92	472	309	13.52	512
291	15.63	446(−t − Bu)	320	9.14	426
974	15.34	496(M + Na)	319	9.74	478(M + Na)
56	16.04	504

[0464] The following compounds are prepared according to Examples B and C, substituting the appropriate amines, prepared either from the conversion of the commercially available nitrobenzene derivative to the corresponding aniline, as for Compound 1175, or as described in Examples 17, 18 and 22:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
599	7.75	513	673	13.31	442
600	8.09	499	674	11.4	366
601	7.46	513	675	10.48	366
602	7.82	499	678	11.43	393
557	9.06	408	177	11.79	484
556	8.31	408	555	11.11	484
672	14.12	442

[0465] Compound 539 is isolated during the preparation of Compound 666 resulting from the addition of 2 equivalents of 3-bromoaniline to 2,4-dichloro-1,2,5-triazine: MS m/z=422 [M+H]+; HPLC Rt=15.69 min.

EXAMPLE 23

[0466] 1391

[0467] Compounds 296/297 are prepared by reacting chloride 924 with 2-amino-5-chlorobenzimidazole according to Example C to give a 1:1 mixture of 296/297 as a light brown solid (39%).

[0468] The following compounds are synthesized according to the procedure described in Example C. Purification methods vary. MS is [M+H]+ except where noted. HPLC retention time is in minutes.

Compound	MS m/z	HPLC Rt
289, 575	394	9.58
292, 293	462, 462	11.20, 11.67
294, 295	439.0, 439.0	10.43, 10.77
296, 297	428.2, 428.2	10.46, 10.93
334	Nd	9.62
435	498	11.81
1030	454	9.63

EXAMPLE 24

[0469] 1392

[0470] Compounds of example 24 below are synthesized in the same manner as Example C. Purification methods vary. Retention time is in minutes.

Compound	MS m/z	HPLC Rt
88	358	8.24
102, 447	420	10.53
308	410	9.65
313	399.8	10.05
318	425.9	10.29
367	454	11.9
368	426	12.18
369	420	12.54
393	372	8.19
394	433	11.1
999	454	10.26
470	480	8.65
495	476(M + Na)	11.92
521	434	10.86
523	478	10.46
1000	488	12.1
1001	456(M + Na)	10.99
1003	470	12.15
589	488	12.74

[0471] that described in Example B, 5.20 g (33.7 mmol) of 2,4olved in 75 mL of dry dimethylformamide and cooled to ed diisopropylethylamine (6.46 mL, 37.1 mmol) and 3nyl) pyrazole (7.67 g, 35.3 mmol; prepared as described re is stirred at 0° C. for three hours during which time a he precipitate is filtered under vacuum and washed with de pure product. MS m/z=331[M+H]+; HPLC Rt=

[0472] made in a manner similar to that described above:

		HPLC Rt
Compound	MS m/z	(Method B)
975	253	10.38
976	273	11.08

[0473] thoxyphenyl) pyrazole used in the above example is a solution of 5 grams (24.6 mmol) of methyl 4(cyanoacetyl)benzoate in 125 mL of absolute ethanol in a glass pressure vessel is added 3.8 mL (122 mmol) of hydrazine hydrate. The vessel is sealed and heated at 100° C. for 4.5 hours. After cooling the vessel is opened and cooling is continued at 0° C. for 45 minutes. The precipitate thus formed is filtered and washed with cold diethyl ether and utilized without further purification. Rt=7.33 min.

[0474] The following compounds are synthesized from 2,4-dichloro-1,3,5-triazine using the appropriate aminopyrazolotriazine and reacting it with the appropriate amine in isopropanol under conditions of Example C.

		HPLC Rt
Compound	MS m/z	(Method B)
338	416(M + Na)	9.18
337	402(M + Na)	9.15
340	405	8.55
342	363	7.89
341	385(M + Na)	7.72
344	378	9.84
343	458(M + Na)	11.17
364	376	9.34
366	376	10.95
365	380	10.71
429	350	8.26
430	350	7.85
432	406	10.46
431	449	11.05
499	339	8.64
501	339	8.16
500	353	8.15
502	353	7.83
977	390	9.61
978	404	9.61
979	368	8.96
980	390(M + Na)	8.54
981	388	9.19
982	410(M + Na)	8.94
983	400(M + Na)	8.59
984	378	8.39
985	392(-t-Bu)	11.09
986	459	11.61
987	439	11.25
604	445	9.47
573	387	8.14
577	445	8.99
578	387	8.64
988	418	9.56
989	418	9.3
990	431	9.08
991	470	9.63
992	460	10.07
994	364	9.96
995	335	6.47
996	352	10.18
997	424	9.37
998	476	9.57
481	549	10.73
437	349	6.88
443	391	7.9
821	418	6.96
822	394	5.43
823	408	5.59
824	387	5.52
825	400	4.33
826	377	4.86
827	420	7.20
884	421	4.57
885	435	4.63
886	390	5.24
887	392	5.37
888	427	5.29
889	311	4.12
891	404	6.00
913	362	5.63
914	412	7.12
915	403	5.11
916	371	4.56
917	362	5.61
918	377	5.36
919	356	6.34
920	402	7.13
921	360	6.64
805	392	5.98
806	455	6.30
807	473	5.82
808	425	3.95
809	403	4.42
810	424	6.90
811	457	7.44
812	432	6.67
813	460	6.62
814	420	6.37
815	432	6.41
816	370	5.32
817	446	6.36
818	370	4.78
819	397	4.69
820	424	4.74
877	408	6.18
878	439	5.17
879	432	6.48
880	470	6.03
881		6.02
882	468	5.11
883	495	5.69

[0475] 1393

[0476] a one to one mixture of 1N sodium hydroxide and ound 523. The resulting solution is stirred for one to approximately pH 7 by the addition of 1.5 mL of e is filtered, washed with cold water and dried under nd 1004. MS m/z=464[M+H]+; HPLC Rt=8.81

[0477] (0.18 mmol) of Compound 1004 in 6 mL of dry mg (0.19 mmol) of 1-(3-dimethylaminopropyl)-3 97 μL (0.19 mmol) of dimethylamine (2M solution in dimethylaminopyridine. The reaction is stirred for 3 nd washed with water and dilute brine. The organic um sulfate, filtered and evaporated to dryness. The crude product is then applied to a 1000μ preparative TLC plate and eluted with 10% methanol-dichloromethane. The product band is then scraped from the plate and washed with 10% methanol-dichloromethane. The methanol-dichloromethane wash is evaporated to yield pure 993. MS m/z=491[M+H]+; HPLC Rt=8.86

[0478] The following compounds are made in a manner similar to that described above:

Compound	MS m/z	HPLC Rt
1005	503	8.96
1006	566	11.57

[0479] Compound 642

[0480] Reference: Tet. Lett. 1995, 36, 7115.

[0481] Compound 1004 (109 mg, 023 mmol) is suspended in dioxane (5 mL) and pyridine (0.5 mL) under N2 at room temperature. Di-tert-butyl dicarbonate and ammonium bicarbonate are added and the reaction is vigorously stirred at room temperature for 45 hours. The reaction is quenched with water, and extracted three times with ethyl acetate. The ethyl acetate extracts are washed with brine, combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The recovered material is dissolved into hot methanol to recrystallize. The cyrstals are recovered by vacuum filtration, washed with methanol, and dried under high vacuum giving 26 mg (24%) of a white solid: MS m/z=463 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 12.98 (br s, 1H), 10.10 (br s, 1H), 9.92 (br s, 1H), 8.35 (br s, 1H), 8.20-7.50 (br m, 5H), 7.40 (s, 1H), 7.30-6.80 (br m, 2H), 3.79 (br s, 6H), 3.63 (s, 3H); HPLC Rt=8.01 min.

EXAMPLE 25

[0482] 1394

[0483] To a slurry of intermediate 924 (95.4 mg, 0.3216 mmol) in isopropanol (2 ml) are added diisopropylethylamine (56 ul, 0.3216 mmol) and 2 mg, aminophenylbenzimidazole (67.3 mg, 0.3216 mmol) (2-Aminophenylbenzimidazole is prepared by protecting 2-chlorobenzimidazole with a Boc-group and subsequently displacing the chloride at 100° C. with aniline. The Boc group falls off during the displacement reaction). The mix is heated at 100° C. for 21 hours. The solution is then cooled to room temperature and concentrated under reduced pressure. The crude is eluted on silica gel preparative plate with 5% methanol/dichloromethane. The lower (minor) band is extracted with 15% methanol/dichloromethane and concentrated under reduced pressure, giving 30 mg (20%) of compound 335.

[0484] Compounds below are prepared according to the procedure outlined for compound 335, substituting the appropriate reagents. Purification methods vary. Retention time is in minutes.

Compound	MS m/z	HPLC Rt
256	464	8.54
311	420.4	11.42
312	481.1	12.20
315	418	14.05
317	429	12.0
335	470	10.85
373	484	9.62
374	504	11.85
938	408	9.83
442	383(M + Na)	8.02
444	437	12.35
468	375	8.41
469		11.18

[0485] 1395

EXAMPLE 26

[0486] 2,4-Dichloro-1,3,5-triazine (89.1 mg, 0.5944 mmol) is dissolved into DMF (0.5 ml) and cooled to 0° C. To this solution are added diisopropylethylamine (104 μl,) and a solution of the appropriate aniline TFA salt (264 mg, 0.59 mmol) (The starting aniline for intermediate 1134 is prepared from 5-amino-2-methoxyphenol using known procedures. The amine is Boc-protected, the phenol is alkylated with 2-bromoethylmethylether, and the Boc group is removed with trifluoroacetic acid, leaving the TFA salt of the desired aniline.) and 208 μl of diisopropylethylamine in 1 ml of DMF. The reaction mixture is kept at 0° C. for 15 to 30 minutes and then at room temperature for 15 minutes to 2 hours. The reaction mixture is then diluted with ethyl acetate and washed with brine. The organic layer is dried over sodium sulfate, filtered, and evaporated in vacuo, to give crude material identified as 1134. This intermediate is used as is for the next step. Intermediates 1129, 1131, 1132, 1133, and 1136 are prepared either from commercially available anilines or with anilines synthesized according to readily available literature procedures.

EXAMPLE 27

[0487] To a solution of intermediate 1134 in isopropanol (2 ml) are added diisopropylethylamine (79 ul, 0.453 mmol) and 5-amino-o-cresol (56 mg, 0.453 mmol). The mix is heated at 120° C. for 18 hours. The solution is then cooled to room temperature and sonicated. The precipitate is filtered and then dried under reduced pressure, giving 52.5 mg (22%) of 127.

[0488] Compounds below are prepared according to the procedure outlined for compound 127. Purification methods vary. HPLC retention times is in minutes.

Compound	MS m/z	HPLC Rt
111	338	10.05
113	376	11.68
114	367	7.01
115	363	9.19
116	348	10.78
117	421	12.13
118	403	11.61
119	354	9.35
121	382	11.03
123	398	9.61
125	442	9.72
127	398	9.67
321	451.1	9.41
322	444	11.50
328	468.1	9.53
929	416	12.69
953	503	8.99
181	nd	8.39
1039	494.3	8.45
1040	493.3	8.26
1184	355	10.76

[0489] 1396

[0490] is prepared by reacting dichlorotriazine with 1-Example B. Crude product is purified by column eaxnes) to give chloride 1180 as off-white solid (86%).

[0491] prepared by reacting chloride 1180 with the appropriate C. Product is isolated by filtration, washing with iPrOH and diethylether and finally dried to give compound 1041 as an off-white powder

Compound	MS m/z	HPLC Rt
1180	Nd	12.5
1041	503	8.62
551	Nd	7.48

[0492] 1397

[0493] Compound 153 is prepared by reacting dichlorotriazine with 4benzyloxyaniline according to Example B to give chloride 153 as a light brown solid ( 91%)

[0494] Compound 156 is prepared by reacting chloride 153 with 3,5dimethoxyaniline according to Example C to give compound 156 as a white solid (51%)

Compound	MS m/z	HPLC Rt
153	313	15.41
156	430	14.04
157	430	12.65
158	386	11.44
159	386	11.92
160	400	13.80
161	400	13.30
162	485	14.58
170	458	14.22
171	416	11.86

[0495] 1398

EXAMPLE 28

[0496] The aniline used to prepare intermediate 1141 is prepared by reacting 3-aminophenylacetic acid with acetyl chloride in methanol to afford the corresponding methyl ester HCl salt, (3.09 g, 15.324 mmol) which is dissolved into DMF (5 ml) with diisopropylethylamine (2.67 ml, 15.324 mmol) and cooled to 0° C. To this solution is added dropwise a 0° C. solution of DMF (5 ml) containing 2,4-dichloro-1,3,5-triazine (2.297 g, 15.324 mmol) and diisopropylethylamine (2.67 ml, 15.324 mmol). The reaction is stirred at 0° C. for 15 to 40 minutes and then at room temperature for 15 minutes to 2 hours. The reaction mix is diluted with ethyl acetate and water. The layers are separated, and the aqueous layer is extracted two times with ethyl acetate. The combined organic layers are washed 4 times with brine and dried over sodium sulfate. The crude is then concentrated down and dried under reduced pressure, giving 4.3 g (100%) of intermediate 1141. HPLC Rt=11.71 min.

EXAMPLE 29

[0497] To a mixture of intermediate 1141 (279 mg, 1.001 mmol) in isopropanol (3 ml) are added diisopropylethylamine (175 ul, 1.001 mmol) and 3-bromoaniline (172 mg, 1.001 mmol). The mix is heated at 100-120° C. for 4 to 18 hours. The solution is then cooled to room temperature and sonicated. The precipitate is filtered and then dried under reduced pressure, giving 254 mg (61%) of compound 540.

[0498] Compound 540 (142 mg, 0.3425 mmol) is dissolved into THF (34.5 ml) and 1N lithium hydroxide/water (6.85 ml). The reaction is stirred vigorously at room temperature for 2 to 20 hours. The organic solvent is evaporated off. The aqueous solution is acidified to pH 3, whereupon a white precipitate is formed. The precipitate is filtered and dried under vacuum, giving 130 mg (95%) of Compound 541.

EXAMPLE 28

[0499] 2,4-Dichloro-1,3,5-triazine (173.7 mg, 1.158 mmol) is dissolved into DMF (1 ml). To the stirring solution cooled to 0° C. is added diisopropylethylamine (202 μl, 1.158 mmol). This solution is added dropwise to a 0° C. mix of DMF (1 ml) and 3-aminophenyl acetamide (prepared from 3-nitrophenylacetic acid via literature preparation (Pozdnev, V. F., et al; Tetrahedron Letters; 1995; 36; 7115), followed by reduction of nitro to amine). The reaction is stirred at 0° C. for 15 minutes to 40 minutes and then at room temperature for 20 minutes to 2 hours. The reaction mix is then diluted with ethyl acetate and water. The layers are separated, and the aqueous layer is extracted 2 times with ethyl acetate. The combined organic layer is washed 3 times with brine, dried over sodium sulfate, and concentrated under reduced pressure, giving 175 mg (57%) of compound 1143. HPLC Rt=7.61 min.

EXAMPLE 29

[0500] To a mixture of intermediate 1143 (36.6 mg, 0.1388 mmol) in isopropanol (1 ml) are added diisopropylethylamine (27 ul, 0.1527 mmol) and 3-bromoaniline (26.3 mg, 0.1527 mmol). The mix is heated at 100-120° C. for 4 to 18 hours. The solution is then cooled to room temperature and sonicated. The precipitate is filtered and then dried under reduced pressure, giving 39.1 mg (70%) of compound 966.

[0501] Compound 1147

[0502] 2,4-Dichloro-1,3,5-triazine (405.8 mg, 2.7065 mmol) is dissolved into DMF (2 ml). To the stirring solution cooled to 0° C. is added diisopropylethylamine (471 μl, 2.7065 mmol). This solution is added dropwise to a 0° C. mix of DMF (2 ml) and 471.5 mg (2.7065 mmol) of the appropriate aniline (prepared from 3-nitrobenzylbromide and 1H-1,2,3-triazole, followed by separation of regioisomers and reduction of nitro to amine). The reaction is stirred at 0° C. for 15 minutes to 40 minutes and then at room temperature for 20 minutes to 2 hours. The reaction mix is then diluted with ethyl acetate and water. The layers are separated, and the aqueous layer is extracted 2 times with ethyl acetate. The combined organic layer is washed 3 times with brine, dried over sodium sulfate and concentrated under reduced pressure, giving 696.3 mg (89%) of a white foam named compound 1147. HPLC Rt=9.34 min.

[0503] Compound 961

[0504] To a mixture of intermediate 1147 (64.8 mg, 0.2252 mmol) in isopropanol (1 ml) are added diisopropylethylamine (39 ul, 0.225 mmol) and 3-bromoaniline (38.7 mg, 0.2252 mmol). The mix is heated at 100-120° C. for 4 to 18 hours. The solution is the cooled to room temperature and sonicated. The precipitate is filtered and then dried under reduced pressure, giving 34.3 mg (36%) of 961.

[0505] The following compounds are prepared according to the procedures of examples 28 and 29.

Compound	MS m/z	HPLC Rt
107	294	9.20
108	338	10.65
109	357	14.12
110	nd	10.64
120	318	9.05
540	415	13.01
541	401	10.95
542	366	10.22
543	352	8.68
544	362	9.02
546	376	10.22
955	361	8.13
956	452	7.63
960	385	9.10
961	424	11.44
966	400	9.80
968	374	10.79

[0506] 1399

EXAMPLE 30

[0507] 2,4-Dichloro-1,3,5-triazine (327.5 mg, 2.1845 mmol) is dissolved into DMF (2 ml) and cooled to 0° C. To this solution are added diisopropylethylamine (381 μl, 2.184 mmol) and 2-chlorobenzimidazole (333.3 g, 2.1845 mmol). The reaction mixture is kept at 0° C. for 15 to 30 minutes and then at room temperature for 15 minutes to 2 hours. The crude compound 1145 is used as is for the next step.

EXAMPLE 31

[0508] To crude reaction mix 1145 are added diisopropylethylamine (381 μl, 2.184 mmol) and then a solution of DMF (1 ml) and 382.7 mg (2.1845 mmol) of the appropriate aniline (prepared from 3-nitrophenylacetonitrile according to Koguro, K., et al. (Synthesis; 1998; 910), followed by reduction of nitro to amine). The reaction is heated at 60-75° C. for 4 to 20 hours. The reaction is then cooled to room temperature and concentrated to a small volume. The crude is eluted on a silica gel column with a methanol/dichloromethane elution gradient, giving 120 mg (14%) of intermediate 1146. HPLC Rt=11.43 min.

EXAMPLE 32

[0509] Intermediate 1146 (40 mg, 0.0988 mmol), 4-methoxybenzylamine (19.4 μl, 0.148 mmol), and diisopropylethylamine (17.2 μl, 0.0988 mmol) are combined with isopropanol (1 ml) and heated at 100-120° C. for 30 minutes to 20 hours. The reaction is cooled to room temperature and diluted into water. The aqueous solution is then acidified to pH 3. The precipitate is filtered and dried, giving 33.5 mg (67%) of 959.

Compound	MS m/z	HPLC Rt
957	476	10.74
958	477	8.80
959	506	10.89

[0510] 1400

EXAMPLE 33

[0511] 2,4-Dichloro-1,3,5-triazine (204 mg, 1.362 mmol) is dissolved into DMF (2 mL) and cooled to 0° C. To this solution are added diisopropylethylamine (238 μl, 1.362 mmol) and the appropriate aniline (360 mg, 1.362 mmol) (The aniline is prepared the following way. 2,6-Dimethoxy-4-nitrophenol is prepared according to known sources (Tepe, Jetze J. et al; J. Med. Chem.; 39; 11; 1996; 2188-2196) and then is reacted via Mitsunobu with 2-(1-triazolyl)ethanol (prepared according to Kume, Masaharu et al., Journal of Antibiotics; 1993; 46; 177-195). The Mitsunobu product is then reduced to the aniline via palladium on carbon.) dissolved in DMF (2 mL). The reaction mixture is kept at 0° C. for 15 to 30 minutes and then at room temperature for 15 minutes to 2 hours. The reaction mix is then added to water, whereupon the product precipitates out of solution. The precipitate is filtered and dried under vacuum, giving 425 mg (83%) of 1139. HPLC Rt=9.79 min. Intermediates 1135 and 1136 are prepared in a similar fashion.

EXAMPLE 34

[0512] Intermediate 1139 (407 mg, 1.076 mmol) is combined with 2-chlorobenzimidazole (164 mg, 1.076 mmol) and potassium carbonate (179 mg, 1.292 mmol) in acetonitrile (10 ml) and heated at 65 to 75° C. for 4 to 20 hours. The mix is concentrated down under reduced pressure and treated with water. A white precipitate is formed. The precipitate is filtered and dried under vacuum, giving 393 mg (74%) of intermediate 140. HPLC Rt=12.08 min. Intermediates 1137 and 1138 are prepared in a similar fashion.

EXAMPLE 35

[0513] Intermediate 1140 (377 mg, 0.763 mmol) is combined with 2-aminomethylpyridine (107 mg, 0.993 mmol) and diisopropylethylamine (173 μl, 0.993 mmol) in isopropanol (3 ml). The mix is heated at 100-120° C. for 30 minutes to 20 hours. The reaction mix is cooled to room temperature and added to about 40 ml of water. The precipitate is filtered and dried under vacuum, giving 376 mg (87%) of compound 942.

[0514] The following compounds are prepared according to the method outlined for compound 942.

Compound	MS	HPLC Rt
507	584	7.91
519	584	7.78
942	566	9.02

[0515] 1401

EXAMPLE 37

[0516] Intermediate 1141 (3.530 g, 12.67 mmol) is combined with 2-chlorobenzimidazole (1.933 g, 12.67 mmol) and potassium carbonate (2.101 g, 15.20 mmol) in acetonitrile (50 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is then cooled to room temperature. The inorganic salts are filtered off. The acetonitrile solution is then concentrated down under reduced pressure. The crude is then purified on a silica gel column with an ethyl acetate/hexane elution gradient, giving 530 mg (10%) of intermediate 1142 along with several more grams of product requiring further purification. HPLC Rt=14.52 min.

EXAMPLE 38

[0517] Intermediate 1142 (169.8 mg, 0.4301 mmol), 4-methoxybenzylamine (84 μl, 0.6451 mmol), and diisopropylethylamine (150 μl, 0.8602 mmol) are combined with isopropanol (2 ml) and heated at 100-120° C. for 30 minutes to 20 hours. The reaction mix is cooled to room temperature and added to water. The precipitate is filtered and dried, giving 188 mg (88%) of compound 548.

[0518] Compound 548 (123 mg, 0.248 mmol) is dissolved into THF (25.5 ml) and 1N lithium hydroxide/water (5 ml). The reaction is stirred vigorously at room temperature for 1 to 20 hours. The organic solvent is evaporated off. The aqueous solution is acidified to pH 3, whereupon a white precipitate is formed. The precipitate is filtered and dried under vacuum, giving 120 mg (100%) of compound 534.

[0519] Compound 1144

[0520] Intermediate 1143 (136.5 mg, 0.5177 mmol) is combined with 2-chlorobenzimidazole (86.9 mg, 0.5177 mmol) and potassium carbonate (93 mg, 0.673 mmol) in acetonitrile (5 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is then cooled to room temperature. The inorganic salts are filtered off. The acetonitrile solution is then concentrated down under reduced pressure. The crude is then purified on a silica gel column with an ethyl acetate/hexane to methanol/dichloromethane elution gradient, giving 29 mg (15%) of Compound 1144. HPLC Rt=10.61 min.

[0521] Compound 967

[0522] Intermediate 1144 (27.9 mg, 0.0735 mmol), benzylamine (11 μl, 0.103 mmol), and diisopropylethylamine (20 μl, 0.110 mmol) are combined with isopropanol (1 ml) and heated at 100-120° C. for 30 minutes to 20 hours. The reaction mix is cooled to room temperature and sonicated. The precipitate is filtered and dried, giving 20.7 mg (62%) of compound 967.

[0523] Compound 1148

[0524] Intermediate 1147 (552.7 mg, 1.921 mmol) is combined with 2-chlorobenzimidazole (381 mg, 2.497 mmol) and potassium carbonate (372 mg, 2.689 mmol) in acetonitrile (10 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is then cooled to room temperature and diluted with methanol and dichloromethane. The inorganic salts are filtered off. The organic solution is then concentrated down under reduced pressure. The crude is then treated with 5-8 ml of acetonitrile. The precipitate is filtered and dried, giving 330 mg (42%) of intermediate 1148. HPLC Rt=12.329 min.

[0525] Compound 964

[0526] Intermediate 1148 (62.0 mg, 0.1535 mmol), 3-fluorobenzylamine (24.5 μl, 0.2149 mmol), and diisopropylethylamine (38 μl, 0.2149 mmol) are combined with isopropanol (1 ml) and heated at 100-120° C. for 30 minutes to 20 hours. The reaction mix is cooled to room temperature and sonicated. The precipitate is filtered and dried, giving 43.4 mg (57%) of compound 964.

[0527] Compound 1149

[0528] 2,4-Dichloro-1,3,5-triazine (122.7 mg, 0.8182 mmol) is dissolved into DMF (1 ml). To the stirring solution cooled to 0° C. is added diisopropylethylamine (150 μl, 0.861 mmol). This solution is added dropwise to a 0° C. mix of DMF (2 ml), diisopropylethylamine (150 μl, 0.861 mmol) and 340 mg (0.8182 mmol) of the appropriate aniline (prepared from 3-nitrophenylacetonitrile to yield the imidazoline (Amemiya, Yoshiya et al.; J. Med. Chem.; 1992; 35, 750-755), which is then oxidized to the imidazole (Amemiya, Yoshiya, et al.; Synthetic Communications; 20(16); 2483-2489), trityl-protected and finally reduced from nitro to amine). The reaction is stirred at 0° C. for 15 minutes to 40 minutes and then at room temperature for 20 minutes to 2 hours. The reaction mix is then diluted with ethyl acetate and water. The layers are separated, and the aqueous layer is extracted 2 times with ethyl acetate. The combined organic layer is washed 3 times with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude is eluted on a silica gel column with ethyl acetate:hexane (1:1), giving 333 mg (77%) of a white solid named 1149. HPLC Rt=13.87 min.

[0529] Compound 1150

[0530] Intermediate 1149 (331 mg, 0.6256 mmol) is combined with 2-chlorobenzimidazole (114.6 mg, 0.7508 mmol) and potassium carbonate (190 mg, 1.376 mmol) in acetonitrile (5 ml) and heated at 65-75° C. for 2 to 20 hours. The reaction mix is then cooled to room temperature. The product apparently precipitates out of acetonitrile, which is filtered off. The crude solid is then treated with water. The precipitate is filtered and dried, giving 264 mg (65%) of intermediate 1150. HPLC Rt=15.52 min.

[0531] Compound 969

[0532] Compound 1150 (103.3 mg, 0.1601 mmol), benzylamine (23 μl, 0.208 mmol), and diisopropylethylamine (42 μl, 0.240 mmol) are combined with isopropanol (1 ml) and heated at 100-120° C. for 30 minutes to 20 hours. The reaction mix is cooled to room temperature and sonicated. The precipitate is filtered and dried, giving 69.5 mg (60%) of Compound 1151 PLC Rt=13.53 min.

[0533] Compound 1151 (68 mg, 0.0950 mmol) is heated at 60-75° C. in a mix of methanol (3.8 ml), dichloromethane (1 ml), and acetic acid (0.20 ml) for 1 to 6 hours. The reaction mix is cooled room temperature and concentrated down. The crude is purified on a silica gel column with a methanol/dichloromethane elution gradient, giving about 30 mg (67%) of Compound 969.

Compound	MS m/z	HPLC Rt
531	452	11.26
533	453	9.20
534	482	11.16
545	466	12.64
547	467	10.60
548	496	12.79
962	498[M + Na]+	9.28
963	500	11.31
964	493	11.57
965	475	11.27
967	451	10.21
969	474	9.07
1066	381	14.95
1067	451	13.0
1068	482	12.92
1069	438	11.12
1070	468	11.20
1185	nd	12.05

[0534] 1402

[0535] Compound 1186 is prepared by reacting chlorotriazine with 3-chloroindazole according to Example 39 to give an off-white solid (78%). MS m/z=413[M+H]+; HPLC Rt=16.07 minutes. 1403

[0536] Compound 1071 is prepared by reacting chloride 924 with 2-chloroimidazole (prepared according to literature procedure: “Facile Synthesis of 2-Substituted Imidazoles”, K. L. Kirk, J. Org. Chem. 43 (22), 1978, 4381-4383) according to Example 15 to give compound 1071.

[0537] Compound 1296 is prepared by reacting 1071 with benzylamine according to Example 42 to give Compound 1296

	Compound	MS m/z	HPLC Rt
	1071	363	11.24 min
	1296	434	(Method A)
			7.8 min

[0538] 1404

[0539] A mixture of the compound 2,4-dichloro-1,3,5-triazine (Example A) (2.5 g, 16.7 mmol) and solid K2CO3 (6.9 g, 49.9 mmol) is suspended in acetonitrile (50 mL) under nitrogen at 0° C. followed by addition of N-methyl-3-chloroaniline (2.5 g, 17.7 mmol). The mixture is allowed to stir at 0° C. for 2 hours. The reaction is quenched by pouring onto ice/water. The white solid formed is collected by suction filtration and dried under vacuum to give material identified as N-methyl-2-chloro-4-(3-chloroanilino)-1,3,5-triazine. HPLC(Method A) Rt=8.63 min.; MS m/z=256; 1H NMR (300 MHz, DMSO-d6) δ 8.4 (bs, 1H), 7.1-7.4(m, 5H), 3.2 (s, 3H)

[0540] In a manner similar to that described in Example C, the following compounds of this example are prepared from the appropriately substituted amine and the chloride described in Compound 701.

EXAMPLE 43b

[0541] 1405

[0542] Compound 702: HPLC(Method A) Rt=9.60 min.; MS m/z=361; 1H NMR (300 MHz, DMSO-d6) δ 8.0 (bs, 1H), 7.0-7.3(m, 8H), 3.1 (s, 6H)

[0543] Compound 703: HPLC(Method A) Rt=9.7 min.; MS m/z=365; 1H NMR (300 MHz, DMSO-d6) δ 9.0 (bs, 1H), 8.2 (s, 1H), 7.0 (s, 1H), 7.7 (bs, 1H), 7.0-7.2(m, 5H), 3.1 (s, 3H)

[0544] Compound 705: HPLC(Method A) Rt=7.33 min; MS m/z=370; 1H NMR (300 MHz, DMSO-d6) δ 12.0 (bs, 1H), 9.6 (s, 1H), 8.1 (s, 1H), 7.2-7.4(m, 3H), 6.8 (m, 1H), 6.6 (d, 2H), 6.3 (d, 2H), 4.8 (bs, 1H), 3.1 (s, 3H)

[0545] Compound 706: HPLC(Method A) Rt=7.5 min.; MS m/z=370; 1H NMR (300 MHz, DMSO-d6) δ 11.0 (bs, 1H), 9.5 (s, 1H), 8.0 (s, 1H), 7.0-7.4(m, 6H), 6.9 (s, 1H), 6.8 (s, 1H), 6.2 (s, 1H)

[0546] Compound 707: HPLC(Method A) Rt=10.1 min.; MS m/z=391; 1H NMR (300 MHz, DMSO-d6) δ 9.8 (s, 1H), 8.1 (s, 1H), 7.7 (s, 1H), 6.8-7.4(m, 7H), 3.1 (s, 3H)

[0547] Compound 708: HPLC(Method A) Rt=10.6 min.; MS m/z=381; 1H NMR (300 MHz, DMSO-d6) δ 9.9 (s, 1H), 8.1 (s, 1H), 7.7 (s, 1H), 7.0-7.4(m, 5H), 3.1 (s, 3H)

[0548] Compound 709: HPLC(Method A) Rt=9.6 min.; MS m/z=326; 1H NMR (300 MHz, DMSO-d6) δ 9.5 (s, 1H), 8.1 (s, 1H), 7.0-7.4(m, 6H), 6.8 (m, 1H), 6.6 (m, 1H), 3.1 (s, 3H), 2.0 (s, 3H)

[0549] Compound 711: HPLC Rt=18.36 min.; MS m/z=372; 1H NMR (300 MHz, DMSO-d6) δ 9.9 (s, 1H), 8.2 (s, 1H), 6.8-7.5(m, 7H), 3.2 (s, 3H)

[0550] Compound 712: HPLC Rt=13.86 min.; MS m/z=372; 1H NMR (300 MHz, DMSO-d6) δ 9.5 (s, 1H), 8.0 (s, 1H), 7.0-7.4(m, 4H), 6.7 (s, 2H), 5.9 (s, 1H), 3.5(s, 6H), 3.0(s, 3H)

[0551] Compound 714: HPLC(Method A) Rt=7.14 min.; MS nm/z=351; 1H NMR (300MHz, DMSO-d6) δ 10.7 (s, 1H), 9.4 (s, 1H), 8.1 (s, 1H), 7.6 (s, 1H), 6.9-7.4(m, 6 H), 6.0 (s, 1H), 3.1(s, 3H)

[0552] Compound 716: HPLC(Method A) Rt=6.26 min.; MS tn/z=353; 1H NMR (300MHz, DMSO-d6) δ 9.6 (s, 1H), 8.1 (s, 1H), 7.7 (s, 1H), 7.6 (s, 1H), 7.0-7.4(m, 4H), 3.1 (s, 3H)

[0553] Compound 718: HPLC(Method A) Rt=6.59 min.; MS m/z=352; 1H NMR (300MHz, DMSO-d6) δ 9.7 (s, 1H), 8.1 (s, 1H), 7.8 (s, 1H), 7.7(s, 1H), 7.5 (s, 1 H), 7.0-7.4 (m, 4H), 6.3 (s, 1H), 5.0 (s, 1H), 3.2 (s, 3H)

[0554] Compound 720: In a manner similar to that described in Example C, the compound of this example is prepared from the appropriately substituted amine prepared from 3-nitrophenylacetonitrile according to Koguro, K., et al.(Synthesis; 1998; 910). followed by reduction of nitro to amine. HPLC(Method A) Rt=6.28 min.; MS m/z=394; 1H NMR (300 MHz, DMSO-d6) δ 9.6 (s, 1H), 8.1 (s, 1H), 7.1-7.4(m, 7 H), 6.9 (m, 1H), 6.6 (m, 1H), 4.0 (s, 2H), 3.2 (s, 3H)

[0555] Compound 721: HPLC(Method A) Rt=8.21 min.; MS m/z=455; 1H NMR (300 MHz, DMSO-d6) 6.9.6 (s, 1H), 8.1 (s, 1H), 7.5(m, 1H), 7.1-7.3 (m, 5 H), 7.0 (m, 1 H), 6.2 (m, 1H), 4.9 (m, 2H), 3.8 (m, 2H), 3.6 (m, 4H), 1.6 (m, 1 H)

Compound	HPLC ret.	MS m/z
739	(Method A) 6.48 min.	320
740	(Method A) 4.26 min.	347
741	(Method A) 3.62 min.	342
742	(Method A) 8.56 min.	398
743	(Method A) 7.40 min.	342
744	(Method A) 8.48 min.	380
745	(Method A) 4.19 min.	335
746	(Method A) 5.34 min.	324
747	(Method A) 7.01 min.	416
748	(Method A) 7.66 min	312
749	(Method A) 6.63 min.	390
750	(Method A) 7.80 min.	427
751	(Method A) 6.31 min.	433
752	(Method A) 4.78 min.	409
753	(Method A) 6.70 min.	368
754	(Method A) 8.17 min.	359
755	(Method A) 5.00 min.	395
756	(Method A) 4.24 min.	313
757	(Method A) 5.26 min.	314
804	(Method A) 9.44 min	416
874	(Method A) 8.67 min.	396
875	(Method A) 8.71 min.	396
876	(Method A) 8.58 min.	392

[0556] 1406

[0557] In a manner similar to that described in Example B, the compound of this example is prepared from the appropriately substituted amine and the chloride described in Example A to give material identified as 2-Chloro-4-(3-chloro-4fluoroanilino)-1,3,5-triazine. HPLC Rt=13.89 min.; 1H NMR (300 MHz, DMSO-dd6) δ10.7 (s, 1H), 7.8(m, 1H), 7.4 (s, 1H), 7.3 (s, 1H) In a manner similar to that described in Example C, the following compounds of this example are prepared from the appropriately substituted amine and the chloride described in Compound 704. 1407

[0558] Compound 715 HPLC(Method A) Rt=6.91 min.; MS m/z=355; 1H NMR (300 MHz, DMSO-d6) δ 10.8 (s, 1H), 9.6 (s, 1H), 9.4 (s, 1H), 8.1 (s, 1H), 7.8 (s, 1 N), 7.6 (s, 1 H), 7.4 (s, 1H), 6.9-7.2(m, 6H), 6.2 (s, 1H), 3.1(s, 3H)

[0559] Compound 717 HPLC(Method A) Rt=6.02 min.; MS m/z=356; 1H NMR (300 MHz, DMSO-d6) δ 9.6 (m, 2H), 8.2 (s, 1H), 7.8(s, 3H), 7.3(m, 2H), 7.1 (m, 2 H), 3.1 (s, 3 H)

[0560] Compound 719 HPLC(Method A) Rt=6.37 min.; MS nz/z=356; 1H NMR (300 MHz, DMSO-d6) δ 9.8 (s, 1H), 7.8(m, 2H), 7.5 (m, 2H), 7.2 (m, 2H), 6.3 (m, 2H), 5.0 (m, 2H), 3.1 (s, 3H) 1408

[0561] In a manner similar to that described in Example C, the compound of this example is prepared from the appropriately substituted amine and the following described chloride. HPLC Rt=12.9 min.; MS m/z=420; 1H NMR (300 MHz, DMSO-d6) δ 9.4 (s, 1H), 8.0 (s, 1H), 7.5 (s, 1H), 7.2(m, 2H), 6.8 (s, 2H), 3.5 (s, 6H), 3.4 (s, 3H), 3.1 (s, 3H) 1409

[0562] A mixture of the compound of Compound 704 (1.7 g, 6.56 mmol) and methyl iodide (1.5 mL) in DMF (20 mL) under a nitrogen atmosphere is added sodium hydride (60% dispersion, 0.53 mg, 13.3 mmol). The mixture is allowed to stir for 3 hours. The reaction is quenched by the addition of water and the organic extracts are taken up in ethyl acetate dried over anh. magnesium sulfate and concentrated under reduced pressure. The crude product is purified via medium pressure liquid chromatography using methylene chloride as the solvent system to give N-methyl-2-chloro-4-(3-chloro-4-fluoroanilino)-1,3,5-triazine.

[0563] Compound 713 HPLC Rt=16.1 min.; MS m/z=409; 1H NMR (300 MHz, DMSO-d6) δ 9.7 (s, 1H), 8.1 (s, 1H), 7.7 (bs, 1H), 7.5(m, 1H), 7.2 (m, 3H), 6.9 (m, 2H), 3.1 (s, 3H)

[0564] Compound 722

[0565] In a manner similar to that described in Example C, the compound of this example is prepared from the appropriately substituted amine and the following described chloride. HPLC(Method A) Rt=9.8 min.; MS m/z=398

[0566] Compound 1154

[0567] In a manner similar to that described in Compound 710, the chloride of this example is prepared from the allyl bromide and 2-Chloro-4-(3-chloroanilino)-1,3,5-triazine described in Compound 1153.

[0568] Compound 134

[0569] In a manner similar to that described in Example C, the compound of this example is prepared from the appropriately substituted amine and the chloride described in Compound 1153. HPLC (Method A) Rt=6.00 min.; MS m/z=338; 1H NMR (300 MHz, DMSO-d6) δ 9.8 (s, 1H), 9.7 (s, 1H), 8.2 (s, 1H), 7.9 (s, 1H), 7.8 (s, 1H), 7.7 (s, 1H), 7.2(m, 3H), 7.1 (m, 1H), 6.9 (d, 1H),

[0570] Compound 723 1410

[0571] In a manner similar to that described in Example C, the compound of this example is prepared from the appropriately substituted amine and 2-Chloro-4-(3-chloroanilino)-1,3,5-triazine (Compound 1153). HPLC(Method A) Rt=7.60 min.; MS m/z=358; 1H NMR (300 MHz, DMSO-d6) δ 9.8 (s, 1H), 9.6 (s, 1H), 8.2 (s, 1H), 7.8 (s 1H), 7.5 (s, 1H), 7.2 (t, 1H), 6.9 (d, 1H), 6.8 (s, 2H), 6.1 (s, 1H), 3.6(s, 6H) 1411

[0572] Compound 1153

[0573] In a manner similar to that described in Compound 701, the chloride of this example is prepared from the appropriately substituted amine and the chloride described in Example A to give material identified as 2-Chloro-4-(3-chloroanilino)-1,3,5-triazine

[0574] Compound 724

[0575] In a manner similar to that described in Example B, the compound of this example is prepared from the appropriately substituted amine and Compound 1155. HPLC(Method A) Rt=8.1 min.; MS m/z=386; 1H NMR (300 MHz, DMSO-d6) δ 9.5 (s, 1H), 8.1 (s, 1H), 7.1-7.4(m, 4H), 6.8 (s, 2H), 6.0 (s, 1H), 3.8 (q, 2H), 3.5 (s, 6H), 1.0 (t, 3H)

[0576] Compound 1155

[0577] In a manner similar to that described in Compound 710, the chloride of this example is prepared from ethyl iodide and 2-Chloro-4-(3-chloroanilino)-1,3,5-triazine described in Compound 1153.

[0578] Salts of Compound 414

[0579] Compound 414, Hydrochloric Acid Salt

[0580] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added a saturated solution of HCl in ethanol (1 mL). The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0581] Compound 414, Oxalic Acid Salt

[0582] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added Oxalic acid (18.6 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0583] Compound 414, Methane Sulfonic c Acid Salt

[0584] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added Methane sulfonic acid (19.8 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0585] Compound 414, Fumaric Acid Salt

[0586] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added fumaric acid (24 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0587] Compound 414, Ascorbic Acid Salt

[0588] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added ascorbic acid (36.3 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0589] Compound 414, Citric Acid Salt

[0590] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added citric acid (40.3 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0591] Compound 414, Acetic Acid Salt

[0592] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added acetic acid (18. μL 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min.

[0593] Compound 414, Tartaric Acid Salt

[0594] To a solution od Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added tartaric acid (31 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum.

[0595] Compound 414, Malic acid salt

[0596] To a solution of Compound 414 (100.0 mg 0.21 mmol) in absolute ethanol (2 mL) is added L-Malic acid (28.0 mg 0.21 mmol). The mixture is heated to 60° C. for 3 hours. The solid formed is collected by suction filtration and dried under vacuum. HPLC Rt=9.6 min. 1412

EXAMPLE 46a

[0597] To a stirred mixture of 924 (50 mg, 0.169 mmol) and powdered potassium carbonate (51 mg, 0.37 mmol) in dry DMF (2.0 mL) is added p-methoxyphenol (46 mg, 0.37 mmol). The mixture is stirred at room temperature for 18-24 h, diluted with water (3 volumes) and brine (3 volumes) and extracted with EtOAc (3×10 mL). Combined organic extracts are dried, concentrated in vacuo and the resulting solid purified by column chromatography (EtOAc/n-Hexanes) to provide compound 174 as a white solid 57%).

	Compound	HPLC ret.	MS m/z
	174	12.57 min.	385
	175	14.28 min.	401
	421	9.16 min.	293

EXAMPLE 46b

[0598] 1413

[0599] To a mixture of 4-benzyloxyphenol (200 mg, 1.0 mmol) in DMF under a nitrogen atmosphere is added sodium hydride (60% dispersion, 40 mg, 1.0 mmol). The mixture is allowed to stir for 0.75 hours followed by addition of 2-chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine. The reaction is allowed to stir for 18 hrs, diluted with water and extracted with ethyl acetate (100 mL), dried over anh. magnesium sulfate and concentrated in vacuo. The crude product is purified via medium pressure liquid chromatography using methylene chloride followed by 1:99 methanol/methylenechloride as the solvent system to afford compound 530. HPLC(Method A) Rt=9.12 min.; MS m/z=461; 1H NMR (300 MHz, DMSO-d6) 10.0(s, 1H), &8, 1H), 6.6-7.4 (m, 13H), 4.8 (s, 2H), 3.0-3.6 (m, 9H).

[0600] Compound 1121: HPLC ret time=13.48 min; MS m/z=437; 1H NMR (300 MHz, DMSO-d6) δ 9.9-10.1(broad d, 1H), 8.4 (s, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 6.9 (s, 1H), 6.7 (s, 2H), 3.3-3.5 (m, 9H).

[0601] Compound 1122: HPLC ret time=11.47 min; MS m/z=415; 1H NMR (300 MHz, DMSO-d6) δ 9.83-10.1(broad d, 1H), 8.4 (s, 1H), 6.7-6.9 (m, 4H), 6.6 (d, 1H), 3.3-3.7 (m, 15H).

[0602] Compound 1123: HPLC ret time=13.05 min; MS m/z=431; 1H NMR (300 MHz, DMSO-d6) δ 9.8-10.1(broad s, 1H), 8.26 (s, 1H), 7.0 (s, 2H), 6.9 (s, 2H), 6.7 (s, 1H), 3.34-3.7 (m, 15H).

[0603] Compound 1124: HPLC ret time=9.78 min; MS m/z=398; 1H NMR (300 MHz, DMSO-d6) δ 9.9-10.1(broad d, 1H), 8.4 (s, 1H), 7.03 (t, 1H), 6.94 (broad s, 1H), 6.78 (broad s, 1H), 6.4 (d, 2H), 6.3 (s, 1H) 3.3-3.4 (m, 9H), 2.7 (s, 6H).

Compound	HPLC ret.	MS m/z
1119	13.48 min.	437
1120	9.81 min.	356

EXAMPLE 47

[0604] 1414

[0605] Compound 522

[0606] Compound 924 (300 mg, 1 mmol) is dissolved in hydrazine monohydrate (0.630 mL, 20 mmol) and heated at 120° C. for 25 minutes. The resulting white solid is filtered and dried to provide intermediate 1179. This intermediate (40 mg, 0.14 mmol) is then reacted with benzoyl acetonitrile (20 mg, 0.14 mmol) in refluxing absolute ethanol (1 mL). The resulting product is purified by silica gel chromatography. MS m/z=442[M+Na]+; HPLC Rt=12.25

[0607] Compound 520, the related regioisomer, can be prepared as above by using formyl phenylacetonitrile as the condensing reagent. MS m/z=442[M+Na]+; HPLC Rt=11.76

EXAMPLE 49

[0608] 1415

[0609] 7-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (440 mg, 2.2 mmol) is dissolved into DMF (10 mL) under N2 at room temperature. N,N-Diisopropylethylamine (284 mg, 2.2 mmol) is added, and the reaction solution is cooled to 0° C. 2,4-Dichloro-1,3,5-triazine is then added, and reaction is stirred with gradual warming to room temperature. The reaction is quenched after 3 hours with water, which causes a fine precipitate to form, which is not filterable. This mixture is extracted 3 times with ethyl acetate. The ethyl acetate extracts are then washed brine, combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum giving 800 mg (>100%) of a yellow oil that is used without further purification. 1416

[0610] 2,4-Dichloro-1,3,5-triazine (1.95 g, 13 mmol) is dissolved into DMF (50 mL) under N2 and cooled to 0° C. N,N-Diisopropylethylamine (1.68 g, 13 mmol) is added, followed by the addition of 6-methyl-1,2,3,4-tetrahydroquinoline (1.91 g, 13 mmol). The reaction solution is then stirred with gradual warming to room temperature. The reaction is quenched after 3 hours with water, which causes a sticky precipitate to form. The mixture is extracted 3 times with ethyl acetate. The ethyl acetate extracts are then washed brine, combined, dried over sodium sulfate, filtered, and concentrated, then dried under high vacuum to remove residual traces of DMF. The recovered material is then purified by elution through a 17×2.5 cm column of silica gel (55, 10%, 20% and 40% EtOAc:Hexane step gradient) giving 1.98 g (58%) of a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.57 (d, J=7.7 Hz, 1 H), 7.00 (m, 2 H), 3.93 (t, J=6.7 Hz, 2H), 2.71 (t, J=6.7 Hz, 2H), 1.92 (m, 2H). In a manner similar to that described in Example C, the following compounds of this example are prepared from the appropriately substituted amine and the chloride described previously.

Compound	HPLC ret.	MS m/z
759	(Method A) 6.92 min.	326
760	(Method A) 6.50 min.	375
761	(Method A) 7.16 min.	328
762	(Method A) 6.77 min.	314
763	(Method A) 7.27 min.	374
764	(Method A) 6.93 min.	401
765	(Method A) 7.38 min	397
766	(Method A) 6.31 min	308
767	(Method A) 9.09 min.	382
768	(Method A) 7.81 min	385
769	(Method A) 5.95 min.	333
770	(Method A) 6.81 min.	348
771	(Method A) 7.47 min.	406
772	(Method A) 4.43 min.	350
773	(Method A) 7.50 min.	375
774	(Method A) 7.65 min.	385
775	(Method A) 5.22 min.	347
776	(Method A) 4.38 min.	355
777	(Method A) 5.88 min.	333
778	(Method A) 8.86 min.	366
779	(Method A) 5.50 min.	389
853	(Method A) 6.61 min.	376
854	(Method A) 8.58 min.	382
892	(Method A) 8.59 min.	362
893	(Method A) 8.59 min.	354

[0611] 1417

[0612] 5-triazine (12.6 g, 84 mmol) is dissolved into DMF (100 mL) 0° C. N,N-Diisopropylethylamine (11.7 g, 90 mmol) is added, on of 4-aminoveratrole (13.35 g, 87 mmol). The reaction with gradual warming to room temperature. The reaction is s with water, which causes a gray precipitate to form. This by vacuum filtration, washed with cold water, dried under d through a 28×4.5 cm column of silica gel (0.1% NH4OH(aq) 4%, and 5% MeOH: CH2Cl2 step gradient) giving 4.16 g olid: 1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.57H), 7.14 (br s, 1H), 6.95 (br s, 1H), 3.74 (br s, 6H).

[0613] lar to that described in Example C, the following compounds red from the appropriately substituted amine and the chloride

Compound	HPLC ret.	MS m/z
758	(Method A) 7.53 min.	406
780	(Method A) 5.24 min.	368
781	(Method A) 7.68 min.	359
782	(Method A) 3.41 min.	387
783	(Method A) 6.50 min.	368
784	(Method A) 3.71 min.	333
785	(Method A) 5.48 min.	348
786	(Method A) 1.62 min.	388
787	(Method A) 4.54 min	301
788	(Method A) 4.44 min.	320
789	(Method A) 5.47 min.	416
790	(Method A) 4.81 min.	332
791	(Method A) 6.74 min.	386
792	(Method A) 6.39 min.	372
793	(Method A) 6.74 min.	386
794	(Method A) 6.53 min.	360
795	(Method A) 7.05 min.	372
796	(Method A) 7.01 min.	344
797	(Method A) 6.38 min.	338
798	(Method A) 4.29 min.	418
799	(Method A) 6.82 min.	352
800	(Method A) 6.81 min.	352
801	(Method A) 6.74 min	374
802	(Method A) 4.46 min.	421
803	(Method A) 7.09 min.	366
855	(Method A) 5.76 min.	421
856	(Method A) 5.85 min.	407
857	(Method A) 5.56 min.	366
858	(Method A) 6.57 min.	441
859	(Method A) 7.06 min	420
860	(Method A) 5.43 min.	382
861	(Method A) 3.14 min.	359
862	(Method A) 6.64 min	383
863	(Method A) 6.31 min.	368
864	(Method A) 6.46 min.	396
865	(Method A) 6.77 min.	372
866	(Method A) 7.50 min.	422
867	(Method A) 7.23 min.	422
868	(Method A) 5.76 min.	382
869	(Method A) 3.99 min.	367
870	(Method A) 3.79 min.	361
894	(Method A) 5.41 min.	380
895	(Method A) 5.44 min.	381
896	(Method A) 6.81 min.	364
897	(Method A) 6.01 min.	349
898	(Method A) 7.30 min.	392
899	(Method A) 4.43 min.	407

[0614] 1418

[0615] 2,4-Dichloro-1,3,5-triazine (3 g, 20 mmol) is dissolved into DMF (20 mL) under N2 and cooled to 0° C. N,N-Diisopropylethylamine (2.58 g, 20 mmol) is added, followed by the addition of 3-chloro-6-methylaniline (2.83 g, 20 mmol). The reaction solution is then stirred with gradual warming to room temperature. The reaction is quenched after 3 hours with water, then extracted 3 times with ethyl acetate. The ethyl acetate extracts are then washed brine, combined, dried over sodium sulfate, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (25%, 40%, 60% EtOAc: Hexane step gradient) giving 169 mg (3.3%) of the desired compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.55 (br s, 1H), 7.45 (s, 1H), 7.29 (, 2H), 2.18 (s, 3H). A by-product of the reaction recovered from the silica gel column is the bis-addition product, Example 638, giving 601 mg (11%) of a white solid: MS m/z 360=[M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.24 (s, 1H), 7.45 (s, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 2.19 (s, 6H); HPLC Rt=14.32 min.

[0616] Compound 1291: 1419

[0617] 2-(4-Nitrophenoxy)ethanol (1.83 g, 10 mmol) is dissolved into ethanol (100 mL) under air at room temperature. A catalytic amount of 10% Palladium on carbon is added. The air is then replaced with a H2(g) atmosphere and the reaction is stirred vigorously for 18 hours. The reaction is quenched by filtering it through celite with ethanol. The filtrate is concentrated under reduced pressure and the recovered material purified by eluting it through a 17×2.5 cm column of silica gel (5% and 10% MeOH: CH2Cl2 step gradient) giving 1.18 g (77%) of a black solid: MS m/z 154=[M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 6.64 (d, J=8.7 Hz, 2H), 6.49 (d, J=9.0 Hz, 2H), 4.76 (t, J=5.5 Hz, 1H), 4.58 (br s, 2H), 3.81 (t, J=5.0 Hz, 2H), 3.63 (q, J=5.4 Hz, 2H).

[0618] Compound 1292: 1420

[0619] 6-Methoxyquinoline (1.26 g, 7.9 mmol) is dissolved into glacial acetic acid (20 mL) under N2 at room temperature. Solid sodium cyanoborohydride (2 g, 32 mmol) is then added in small portions over a 45 minute period. The reaction is then heated to 50° C. for 8 hours, then cooled to room temperature and stirred overnight. The reaction is then quenched by cooling it to 0° C., and adjusting the pH of the solution to 14 with 2 N NaOH(aq). This solution is then extracted 3 times with ethyl acetate. The ethyl acetate extracts are then washed brine, combined, dried over sodium sulfate, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (5% and 10% EtOAc:Hexane step gradient) giving 750 mg (58%) of a red oil. This material is then used without further purification.

[0620] Compound 1293:

[0621] Reference: Rauckman, B. S.; Tidwell, M. Y.; Johnson, J. V.; Roth, B. J. Med. Chem., 1989, 32, 1927-1935.

[0622] 5-Chloroquinoline (1.01 g, 6.2 mmol) is dissolved into anhydrous ethanol (30 mL) under N2 at-room temperature. Concentrated hydrochloric acid (2.14 mL, 24.8 mmol) is added, followed by the addition of the sodium cyanoborohydride (1.56 g, 24.8 mmol). This produces a vigorous gas and heat evolution. The reaction is then heated to 60° C. for 2 hours, then cooled and stirred at room temperature for an additonal 18 hours. The reaction is then quenched by adjusting the pH to approximately 9 with 2 N NaOH(aq). This mixture is then extracted 3 times with ethyl acetate. The ethyl acetate extracts are then washed brine, combined, dried over sodium sulfate, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (5%, 10%, 15%, 40% and 50% EtOAc: Hexane step gradient) giving 725 mg (69%) of a green oil: MS m/z 168=[M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 6.83 (t, J=7.9 Hz, 1H), 6.48 (d, J=8.0 Hz, 1H), 6.39 (d, J=8.1 Hz, 1H), 5.99 (br s, 1H), 3.13 (m, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.81 (m, 2H).

[0623] Compound 1294:

[0624] Reference: Rauckman, B. S.; Tidwell, M. Y.; Johnson, J. V.; Roth, B. J. Med. Chem., 1989,32,1927-1935

[0625] 4,7-Dichloroquinoline (1.02 g, 5.1 mmol) is dissolved into anhydrous ethanol (30 mL) under N2 at room temperature. Concentrated hydrochloric acid (1.76 mL, 20.4 mmol) is added, followed by the addition of the sodium cyanoborohydride (1.28 g, 20.4 mmol). This produces a vigorous gas and heat evolution. The reaction is then heated to 60° C. for 2 hours, then cooled and stirred at room temperature for an additonal 18 hours. The reaction is then quenched by adjusting the pH to approximately 9 with 2 N NaOH(aq). This mixture is then extracted 3 times. with ethyl acetate. The ethyl acetate extracts are then washed brine, combined, dried over sodium sulfate, filtered, and concentrated, then eluted through a 30×2.5 cm column of silica gel (3.75% EtOAc: Hexane) giving 134 mg (13%) of an orange solid: MS m/z 168=[M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 6.80 (d, J=8.0 Hz, 1H), 6.42 (s, 1H), 6.36 (d, J=7.7 Hz, 1H), 5.95 (br s, 1H), 3.15 (t, J=5.5 Hz, 2H), 2.60 (t, J=6.2 Hz, 2H), 1.75 (m, 2H).

[0626] Compound 1295: 1421

[0627] 1,2,3,4-Tetrahydroquinoline (1.33 g, 10 mmol) is dissolved into DMF (15 mL) under N2 and cooled to 0° C. N-Chlorosuccinimide (1.35 g, 10 mmol) is dissolved into DMF (10 mL) under N2 and is then added to the tetrahydroquinoline solution dropwise, via pressure equalizing dropping funnel, over a 45 minute period. The reaction is then stirred at 0° C. for 3 hours, then quenched by pouring it into water (100 mL). This mixture is then extracted one time with a 5:1 mixture of ethyl acetate:toluene, then two more times with ethyl acetate. All of the organic extracts are then washed with brine, combined, dried over sodium sulfate, filtered, and concentrated, then eluted through a 17×2.5 cm column of silica gel (5%, 10% and 15% EtOAc:Hexane step gradient) giving 830 mg (49%) of a green oil: 1H NMR (300 MHz, DMSO-d6) δ 6.83 (m, 1H), 6.40 (d, J=9.0 Hz, 1H), 5.81 (br s, 1H), 3.14 (t, J=Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 1.74 (m, 2H).

EXAMPLE 36

[0628] 1422

[0629] Compound 207: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (51 mg, 0.17 mmol) is suspended in ethanol (2 mL) in a sealed tube under air at room temperature. N,N-Diisopropylethylamine (22 mg, 0.17 mmol) is added, followed by addition of piperidine (15 mg, 0.17 mmol). The reaction mixture is then heated to 100° C. for 30 minutes, during which everything goes into solution. The reaction is then cooled to room temperature and a white precipitate forms, and is recovered by vacuum filtration and washed with cold ethanol. The recovered solid is then dissolved into hot ethanol to re-crystallize. The recovered crystals are then applied to two 500μ preparative TLC plates and developed one time with 40% EtOAc:Hexanes giving 12 mg (20%) of a white solid: MS m/z=346 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.48 (br s, 1H), 8.20 (s, 1H), 7.14 (s, 2H), 3.76 (br s, 4H), 3.74 (s, 6H), 3.61 (s, 3H), 1.63 (br s, 2H), 1.52 (br s, 4H); HPLC Rt=10.44 min.

[0630] Compound 208: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (43 mg, 0.14 mmol) is reacted with 4-hydroxypiperidine (15 mg, 0.14 mmol) in the manner described for compound 207, and kept at 100° C. for 4 days. A solid does form when the reaction is cooled to room temperature, and is allowed to settle to the bottom of the reaction vessel and recovered by decantation of the solvent. This solid is then washed with methanol and dried under high vacuum giving 36 mg (72%) of a white solid: MS m/z=362 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.49 (br s, 1H), 8.20 (s, 1H), 7.12 (s, 2H), 4.78 (d, J=4.0 Hz, 1H), 4.20 (br d, J=13.8 Hz, 2H), 3.74 (s, 6H), 3.61 (s, 3H), 3.39 (br m, 2H), 1.75 (br m, 2H), 1.35 (br s, 1H); HPLC Rt=7.50 min.

[0631] Compound 209: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (56 mg, 0.19 mmol) is reacted with morpholine (16 mg, 0.19 mmol) in the manner described for compound 207, and kept at 100° C. for 30 minutes. A white precipitate forms when the reaction is cooled to room temperature and is recovered by vacuum filtration, then washed with cold ethanol. The recovered material is then dissolved into hot ethanol to re-crystallize. The recovered crystals are then applied to two 500μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) giving 31 mg (46%) of a white solid: MS m/z=348 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.55 (br s, 1H), 8.24 (s, 1H), 7.11 (s, 2H), 3.76 (s, 4H), 3.73 (s, 6H), 3.64 (s, 4H), 3.61 (s, 4H); HPLC Rt=8.59 min.

[0632] Compound 211: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (110 mg, 0.37 mmol) is reacted with tert-butyl 1-piperazine carboxylate (69 mg, 0.37 mmol) in the manner described for compound 207, and kept at 100° C. for 3 hours. A white precipitate forms when the reaction is cooled to room temperature and is recovered by vacuum filtration, then washed with cold ethanol and dried under high vacuum giving 43 mg (26%) of a white solid: MS m/z=447 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.57 (br s, 1H), 8.24 (s, 1H), 7.11 (s, 2H), 3.75 (br s, 10H), 3.61 (s, 3H), 3.40 (br s, 4H), 1.42 (s 9H); HPLC Rt=11.99 min.

[0633] Compound 212: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (53 mg, 0.18 mmol) is reacted with 1-methylpiperazine (18 mg, 0.18 mmol) in the manner described for compound 207, and kept at 100° C. for 18 hours. A white precipitate forms when the reaction is cooled to room temperature and is recovered by vacuum filtration, then washed with cold ethanol. The recovered solid is then applied to two 500μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2: MeOH NH4OH(aq) giving 16 mg (25%) of a white solid: MS m/z=361 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.55 (br s, 1H), 8.22 (s, 1H), 7.12 (s, 2H), 3.77 (br s, 4H), 3.74 (s, 6H), 3.61 (s, 3H), 2.36 (br s, 4H), 2.21 (s 3H); HPLC Rt=6.62 min.

[0634] Compound 213: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (62 mg, 0.21 mmol) is reacted with 1-(2-pyridyl)piperazine (34 mg, 0.21 mmol) in the manner described for compound 207, and kept at 100° C. for 1 hour. A white precipitate forms when the reaction is cooled to room temperature and is recovered by vacuum filtration, washed with cold ethanol, then dried under high vacuum giving 61 mg (68%) of a white solid: MS m/z=424 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.56 (br s, 1H), 8.26 (s, 1H), 8.13 (dd, J=5.0, 1.9 Hz, 1H), 7.56 (m, 1H), 7.15 (s, 2H), 6.89 (d, J=8.7 Hz, 1H), 6.67 (dd, J=7.0, 5.0 Hz, 1H), 3.90 (br s, 4H), 3.78 (s, 6H), 3.62 (s, 3H), 3.61 (br s, 4H); HPLC Rt=7.48 min.

[0635] Compound 298: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (56 mg, 0.19 mmol) is reacted with 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (31 mg, 0.19 mmol) in the manner described for compound 207, and kept at 100° C. for 18 hours. The reaction mixture is then cooled to room temperature and concentrated under reduced pressure. The recovered material is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). The recovered material is then applied to two 500μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) giving 38 mg (47%) of a glassy white solid: MS m/z=426 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.64 (br s, 1H), 8.28 (s, 1H), 7.59 (dd, J=9.1, 5.4 Hz, 1H), 7.05 (m, H), 6.99 (t, J=9.0 Hz, 1H), 5.13 (q, J=6.7 Hz, 1H), 3.68 (s, 6H), 3.61 (s, 3H), 2.73 (m, 1H), 2.65 (m, 1H), 2.27 (m, 1H), 1.48 (m, 1H), 1.13 (d, J=6.4 Hz, 3H); HPLC Rt=13.41 min.

[0636] Compound 326: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (54 mg, 0.18 mmol) is reacted with 1,2,3,4-tetrahydroisoquinoline (24 mg, 0.18 mmol) in the manner described for compound 207, and kept at 100° C. for 3 days. A precipitate forms when the reaction is cooled to room temperature and is recovered by vacuum filtration, then washed with cold methanol and dried under high vacuum giving 54 mg (76%) of yellow needles: MS m/z=394 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 9.60 (br s, 1H), 8.26 (br s, 1H), 7.30-7.10 (m, 6H), 4.90 (br d, J=6.6 Hz, 2H), 4.00 (br d, J=5.1 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.63 (s, 3H), 2.89 (m, 2H); HPLC Rt=12.16 min.

[0637] Compound 498: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (74 mg, 0.25 mmol) is reacted with 6-methyl-1,2,3,4-tetrahydroquinoline (44 mg, 0.3 mmol) in the manner described for compound 207, except for using 1.5 equivalents of N,N-diisopropylethylamine, and kept at 100° C. for 3 days. A white precipitate forms when the reaction is cooled to 0° C., and is recovered by vacuum filtration, then washed with cold isopropanol. The recovered solid is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2: MeOH NH4OH(aq). The recovered material is then applied to a set of two 500μ preparative TLC plates and developed one time with 7:7:7:1 MtBE: CH2Cl2: Hexane: MeOH giving 20 mg (20%) of a white solid: MS m/z=408 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.64 (br s, 1H), 8.29 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.10 (s, 2H), 6.97 (s, 1H), 6.93 (d, J=8.7 Hz, 1. H), 3.98 (t, J=6.0 Hz, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 2.71 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.90 (m, 2H); HPLC Rt=12.77 min.

[0638] Compound 518: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (74 mg, 0.25 mmol) is reacted with 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (60 mg, 0.3 mmol) in the manner described for compound 207, except for using 1.5 equivalents of N,N-diisopropylethylamine, and kept at 100° C. for 3 days. A white precipitate forms when the reaction is cooled to 0° C., and is recovered by vacuum filtration, then washed with cold isopropanol. The recovered solid is then applied to two 1000μ preparative TLC plates and developed one time with 7:7:7:1 MtBE:CH2Cl2:Hexane:MeOH. The recovered material is then applied to a set of two 500μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) giving 36 mg (31%) of a white solid: MS m/z=462 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.81 (br s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.38 (m, 2H), 7.09 (s, 2H), 4.04 (m, 2H), 3.65 (s, 6H), 3.61 (s, 3H), 2.83 (m, 2H), 1.90 (m, 2H); HPLC Rt=14.40 min.

[0639] Compound 535: 2-Chloro-4-(3′,4′,-dimethoxyanilino)-1,3,5-triazine (130 mg, 0.49 mmol) is reacted with 7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (98 mg, 0.49 mmol) in the manner described for compound 207, except for using isopropanol (4 mL) as the solvent, then kept at 100° C. 18 hours. A white precipitate forms when the reaction is cooled to room temperature, and is removed by vacuum filtration. The filtrate is then concentrated under reduced pressure, and eluted through a 17×2.5 cm column of silica gel with a 10%, 20%, 40%, 60%, and 80% EtOAc:Hexane step gradient, giving a white solid that is then triturated with methanol giving 58 mg (27%) of a white solid: MS m/z=432 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.73 (br s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.45-7.20 (m, 3H), 7.14 (br s, 1H), 6.81 (br s, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.70 (s, 3H), 3.64 (s, 3H), 2.84 (t, J=6.4 Hz, 2H), 1.94 (m, 2H); HPLC Rt=14.27 min.

[0640] Compound 567: 2-Chloro-4-(6′-methyl-1′,2′,3′,4′-tetrahydroquinolino)-1,3,5-triazine (108 mg, 0.41 mmol) is reacted with 4-aminoveratrole (63 mg, 0.41 mmol) in the manner described for compound 207, except for using isopropanol (4 mL) as the solvent, then kept at 100° C. 18 hours. A white precipitate forms when the reaction is cooled to room temperature, and is recovered by vacuum filtration, washed with cold isopropanol, and dried under high vacuum giving 147 mg (94%) of a white solid: MS m/z=378 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (br s, 1H), 8.29 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.14 (m, 1H), 6.96 (m, 3H), 6.86 (d, J=8.7 Hz, 1H), 3.98 (t, J=6.1 Hz, 2H), 3.73 (s, 3H), 3.65 (s, 3H), 2.72 (t, J=6.7 Hz, 2H), 2.28 (s, 3H), 1.91 (m, 2H); HPLC Rt=12.19 min.

[0641] Compound 582: 2-Chloro-4-(7′-(trifluoromethyl)-1′,2′,3′,4′-tetrahydroquinolino)-1,3,5-triazine (168 mg, 0.53 mmol) is reacted with 3-methylaniline (57 mg, 0.53 mmol) in the manner described for compound 207, except for using isopropanol (5 mL) as the solvent, then kept at 100° C. 18 hours. The reaction is then concentrated under reduced pressure, and applied to two 1000μ preparative TLC plates and developed one time with 7:7:7:1 MtBE: CH2Cl2:Hexane:MeOH. The recovered material is then applied to a second set of two 1000μ preparative TLC plates and developed one time with 30% EtOAc: Hexanes giving 53 mg (25%) of a clear glassy solid: MS m/z=386 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.82 (br s, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.5-7.3 (m, 4H), 7.09 (t, J=7.1 Hz, 1H), 6.80(d,J=7.1 Hz, 1H), 4.01 (t,J=6.2 Hz, 2H), 2.84(t,J=6.2 Hz, 2H), 2.20 (s, 3H), 1.95 (m, 2H); HPLC Rt=16.02 min.

[0642] Compound 609: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (56 mg, 0.19 mmol) is reacted with 1,2,3,4-tetrahydroquinoline (25 mg, 0.19 mmol) in the manner described for compound 207, then kept at 100° C. 15 hours. A white precipitate forms when the reaction is cooled to room temperature, and is recovered by vacuum filtration, washed with cold ethanol, and dried under high vacuum giving 49 mg (65%) of a white solid: MS m/z=394 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.66 (br s, 1H), 8.31 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.18-7.00 (m, 5H), 4.00 (t, J=6.2 Hz, 2H), 3.67 (s, 6H), 3.61 (s, 3H), 2.75 (t, J=6.7 Hz, 2H), 1.92 (m, 2H); HPLC Rt=12.50 min.

[0643] Compound 610: 2-Chloro-4-(3′,4′,-dimethoxyanilino)-1,3,5-triazine (73 mg, 0.25 mmol) is reacted with 2-methylindoline (33 mg, 0.25 mmol) in the manner described for compound 207, except for using isopropanol (4 mL) as the solvent, then kept at 100° C. 3 days. The reaction is cooled to room temperature, and then concentrated under reduced pressure. The recovered material is then eluted through a 17×2.5 cm column of silica gel with a 20%, 40%, 60%, and 80% EtOAc:Hexane step gradient. The material recovered from the column is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq) giving 42 mg (42%) of a white solid: MS m/z=394 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.69 (br s, 1H), 8.42 (s, 1H), 8.31 (br s, 1H), 7.27 (d, J=7.0 Hz, 1H), 7.15 (m, 3H), 7.00 (t, J=7.4 Hz, 1H), 4.96 (br s, 1H), 3.76 (s, 6H), 3.64 (s, 3H), 3.39 (m, 1H), 2.70 (d, J=16 Hz, 1H), 1.27 (d, J=6.0 Hz, 3H); HPLC Rt=12.77 min.

[0644] Compound 621: 2-Chloro-4-(3′,4′,-dimethoxyanilino)-1,3,5-triazine (97 mg, 0.36 mmol) is reacted with 3-chloro-N-methylaniline (51 mg, 0.36 mmol) in the manner described for compound 207, except for using isopropanol (4 mL) as the solvent, then kept at 100° C. 18 hours. The reaction is cooled to room temperature, and then concentrated under reduced pressure. The recovered material is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). The material recovered from these plates is then applied to a second set of two 1000μ preparative TLC plates and developed one time with 7:7:7:1 MtBE:CH2Cl2:Hexane:MeOH giving 80 mg (59%) of a white solid: MS m/z=372 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.62 (br s, 1H), 8.23 (s, 1H), 7.55-7.30 (m, 5H), 7.10 (br s, 1H), 6.78 (br s, 1H), 3.70 (s, 3H), 3.62 (s, 3H), 3.46 (s, 3H); HPLC Rt=11.49 min.

[0645] Compound 631: 2-Chloro-4-(3′,4′,5′-trimethoxyanilino)-1,3,5-triazine (120 mg, 0.40 mmol) is reacted with 6-methoxy-1,2,3,4-tetrahydroquinoline (65 mg, 0.40 mmol) in the manner described for compound 207, except for using isopropanol (6 mL) as the solvent, then kept at 100° C. 3 days. The reaction is cooled to room temperature, and then concentrated under reduced pressure. The recovered material is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH:NH4OH(aq). The material recovered from these plates is then applied to two 500μ preparative TLC plates and developed one time with 7:7:7:1 MtBE:CH2Cl2:Hexane:MeOH giving 15 mg (8%) of a white solid: MS m/z=424 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.65 (br s, 1H), 8.27 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.10 (s, 2H), 6.74 (m, 2H), 3.98 (t, J=6.2 Hz, 2H), 3.74 (s, 6H), 3.67 (s, 3H), 3.61 (s, 3H), 2.73 (t, J=6.4 Hz, 2H), 1.91 (m, 2H); HPLC Rt=12.16 min.

[0646] Compound 640: 2-Chloro-4-(3′-chloro-N-methylanilino)-1,3,5-triazine (175 mg, 0.68 mmol) is reacted with 3,4-diethoxyaniline hydrochloride (149 mg, 0.68mmol) in the manner described for compound 207, except for using isopropanol (4 mL) as the solvent, two equivalents of N,N-diisopropylethylamine, and then heating at 100° C. 3 days. The reaction is cooled to room temperature, and then concentrated under reduced pressure. The recovered material is then applied to two 1000μ preparative TLC plates and developed one time with 95:5:0.5 CH2Cl2:MeOH: NH4OH(aq). The material recovered from these plates is then applied to a second set of two 1000μ preparative TLC plates and developed one time with 7:7:7:1 MtBE: CH2Cl2: Hexane: MeOH. The material isolated from these plates is then applied to a third set of 1000μ preparative TLC plates and developed one more time with 95:5:0.5 CH2Cl2: MeOH:NH4OH(aq). The material from this set of plates is then triturated with diethyl ether giving 25 mg (9%) of a clear, glassy solid: MS m/z=432 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.23 (s, 1H), 7.55-7.30 (m, 5 H), 7.07 (br s, 1H), 6.78 (br s, 1H), 3.94 (q, J=7.0 Hz, 2H), 3.80 (br s, 2H), 3.46 (s, 3 H), 1.28 (m, 6H); HPLC Rt=14.27 min.

[0647] The following compounds are prepared according to Examples B and C according to the procedures shown above:

Cmpd #	HPLC Rt	MS	Cmpd #	HPLC Rt	MS
181	9.02	332	615	ND	445
184	12.72	380	616	11.97	402
187	14.91	425	622	16.66	ND
191	13.81	425	626	12.09	374
214	9.39	425	634	13.24	432
314	13.01	400	635	11.26	400
536	11.30	382	637	9.12	398
537	12.14	396	639	14.47	428
538	12.20	396	641	10.13	372
603	12.15	402	643	14.71	428
607	12.05	418	644	15.86	384
612	12.43	408	645	14.44	428

EXAMPLE 48

[0648] 1423

[0649] Compound 690

[0650] A mixture of 2-pyridylcarbinol (79 mg, 0.72 mmol) in DMF under a nitrogen atmosphere is added sodium hydride (60% dispersion, 30 mg, 0.75 mmol). The mixture is allowed to stir for 0.75 hours followed by addition of the compound of Compound 378. The reaction is quenched by the addition of water and the organics taken up in ethyl acetate (100 mL) dried over anh. Magnesium sulfate and concentrated under reduce pressure. The crude product is purified via medium pressure liquid chromatography using methylene chloride followed by 1:99 methanol/methylenechloride as the solvent system. HPLC(Method A) Rt=6.36 min., MS m/z=486.

EXAMPLE 52

[0651] The inhibitor compounds described herein are screened in the following manner. Kinases suitable for use in the following protocol to determine kinase activity of the compounds described herein include, but are not limited to: Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, EGFR, ErbB2, Kdr, Flt-1, Flt-3, Tek, c-Met, InsR, and AKT.

[0652] Kinases are expressed as either kinase domains or full length constructs fused to glutathione S-transferase (GST) or polyHistidine tagged fusion proteins in either E. coli or Baculovirus-High Five expression systems. They are purified to near homogeneity by affinity chromatography essentially as previously described (Lehr et al., 1996; Gish et al., 1995). In some instances, kinases are co-expressed or mixed with purified or partially purified regulatory polypeptides prior to measurement of activity.

[0653] Kinase activity and inhibition are measured essentially by established protocols (Braunwalder et al., 1996). Briefly, The transfer of 33PO4 from ATP to the synthetic substrates poly(Glu, Tyr) 4:1 or poly(Arg, Ser) 3:1 attached to the bioactive surface of microtiter plates serves as the basis to evaluate enzyme activity. After an incubation period, the amount of phosphate transferred is measured by first washing the plate with 0.5% phosphoric acid, adding liquid scintillant, and then counting in a liquid scintillation detector. The IC50 is determined by the concentration of compound that causes a 50% reduction in the amount of 33P incorporated onto the substrate bound to the plate.

[0654] Other similar methods whereby phosphate is transferred to peptide or polypeptide substrate containing tyrosine, serine, threonine, or histidine, either alone, in combination, or in combination with other amino acids, in solution or immobilized (i.e., solid phase) are also useful. For example, transfer of phosphate to a peptide or polypeptide can also be detected using scintillation proximity (Wu et al., 2000), ELISA (Cleaveland et al., 1990), Fluorescence Polarization (Seethala and Menzel, 1998), and homogeneous time-resolved fluorescence (HTRF, Kolb et al., 1998). Alternatively, kinase activity can be measured using antibody-based methods whereby an antibody or polypeptide is used as a reagent to detect phosphorylated target polypeptide. The compounds of the invention described herein are potent and selective kinase inhibitors as demonstrated by representative compounds described herein that inhibit kinases with IC50 values at between about 10 nM and about 5 μM or greater.

REFERENCES

[0655] Braunwalder A F, Yarwood D R, Hall T, Missbach M, Lipson K E, Sills M A. (1996). A solid-phase assay for the determination of protein tyrosine kinase activity of c-src using scintillating microtitration plates. Anal. Biochem. 234(1):23-26.

[0656] Cleaveland J S, Kiener P A, Hammond D J, Schacter B Z. (1990). A microtiter-based assay for the detection of protein tyrosine kinase activity. Anal Biochem. 190(2):249-53.

[0657] Gish G, McGlone M L, Pawson T, Adams J A. (1995). Bacterial expression, purification and preliminary kinetic description of the kinase domain of v-fps.—Protein Eng. 8(6):609-614.

[0658] Kolb, A. J., Kaplita, P. V., Hayes, D. J., Park, Y.-W., Pernell, C., Major, J. S., Mathis, G. (1998). Tyrosine kinase assays adapted to homogeneous time-resolved fluorescence. Drug Discov. Today. 3:333-342.

[0659] Lehr R V, Ma Y G, Kratz D, Brake P G, Wang S, Faltynek C R, Wang X M, Stevis P E (1996). Production, purification and characterization of non-myristylated human T-cell protein tyrosine kinase in a baculovirus expression system. Gene 169(2):27527-9.

[0660] Seethala R, Menzel R. (1998). A fluorescence polarization competition immunoassay for tyrosine kinases. Anal Biochem. 255(2):257-62.

[0661] Wu J J, Yarwood D R, Sills M A, Chaudhuri B, Muller L, Zurini M, Sills M A. (2000). Measurement of cdk4 kinase activity using an affinity peptide-tagging technology. Comb Chem High Throughput Screen. 3(1):27-36.

EXAMPLE 53

[0662] The cellular activities of the inhibitor compounds described herein may be assessed in a number of assays known to those skilled in the art, some of which are exemplified as described below. Typical sources for cells include, but are not limited to, human bone marrow or peripheral blood lymphocytes, fibroblasts, tumors, immortalized cell lines, in-vitro transformed cell lines, rodent spleen cells, or their equivalents. Tumor cells and transformed cell lines that have been reported as cytokine- and growth factor-dependent cells are available from standard cell banks such as The American Type Culture Collection (Bethesda, Md.). Cells genetically manipulated to express a particular kinase or kinases are also suitable for use in assaying cellular activity and can be made using standard molecular biology methods. These cells are grown in various standard tissue culture media available from suppliers such as GIBCO/BRL (Grand Island, N.Y.) supplemented with fetal bovine serum. Cellular activity may also be measured using bacterial, yeast, or virally infected mammalian cells. Standard inhibitors (or reference compounds) of cellular activities measured in cellular assays, include mycophenolic acid (SIGMA, St. Louis, Mo.), staurosporine (Calbiochem, San Diego, Calif.), wortmannin (Calbiochem), cyclosporine, FK-506, and steroids (e.g., corticosteroids).

[0663] The compound(s) are tested for activity in cellular assays of T or B cell activation. For example, the receptor-induced production of cytokines and/or cell proliferation is a useful measure. This assay is performed similarly to techniques described in the literature (1,2), and involves antibody-, antigen-, mitogen-, or antigen presenting cell-mediated crosslinking of the T cell or B cell receptor with or without engagement of co-stimulatory receptors.

[0664] The compound(s) are tested for activity in cellular assays of allergic mediator release. For example, the receptor-induced degranulation in mast cells or basophils leading to histamine release and the production of cytokines is a useful measure. This assay is performed similarly to techniques described in the literature (3), and involves signalling via specific cell surface receptors for I, E, or other immunoglobulin (e.g., IgG) following crosslinking of antigen-specific IgE on cells or immune complex binding leading to degranulation and or cytokine production.

[0665] The compound(s) are tested for activity in cellular assays of growth factor effects. For example, growth factor receptor-induced signaling in a cell leading to intracellular signaling events such as kinase autophosphorylation, phosphorylation of relevant kinase substrates, phosphorylation of MAP kinases, induction of gene expression, or protein expression. Also, for example, growth factor-induced functional events in cells such as DNA synthesis, proliferation, migration, or apoptosis. These assays are performed similarly to techniques described in the literature (4-7), and involve addition of growth factor to responsive cells followed by monitoring of signaling or functional events.

[0666] The compound(s) are tested for activity in cellular assays of lymphokine, chemokine, cytokine, growth factor, or hormone, activation. For example, cytokine-induced intracellular signaling events and/or DNA synthesis and/or cell proliferation and/or cytokine or chemokine production are a useful measure. These assays are performed similarly to techniques described in the literature (8), and involves addition of cytokine to responsive cells followed by monitoring intracellular signaling events and/or cell proliferation and/or cytokine production.

REFERENCES

[0667] 1. Shuji, K., et al. Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. J. Immunol. 160:4182-4189(1998).

[0668] 2. Satterthwaite, A. B., et al., Independent and opposing roles for Btk and Lyn in B cell and myeloid signaling pathways. J. Exp. Med. 188: 833-844 (1998).

[0669] 3. Stephan, V., et al. FcεRI-induced protein tyrosine phosphorylation of pp72 in rat basophilic leukemia cells (RBL-2H3). J. Biol. Chem. 267 (8): 5434-5441 (1992).

[0670] 4. Olayioye, M. A., et al. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Molecular and Cellular Biology. 18(9): 5042-5051 (1998).

[0671] 5. Buchdunger, E., et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 56;101-104 (1996).

[0672] 6. Yoshida, A. et al., Differential endothelial migration and proliferation to basic fibroblast growth factor and vascular endothelial growth factor. Growth Factors. 13:57-64 (1996).

[0673] 7. Brunet, A., et al., Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 96:857-868 (1999).

[0674] 8. Liu, K. D., et al. Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Current Biology. 7 (11): 817-826 (1997).

[0675] Representative compounds tested under the following example protocols exhibit cellular activities consistent with their observed enzyme inhibition activities.

EXAMPLE 54

[0676] Vascular Endothelial Growth Factor (VEGF)-Induced Kdr Auto-Phosphorylation.

[0677] Human umbilical vein endothelial cells (HUVEC) are plated out in flat-well plates in complete media and allowed to adhere overnight. The cells are then starved in medium containing 0.1% fetal calf serum (FCS), pre-incubated with or without dilutions of compound, then activated for 15 minutes with 50 ng/ml VEGF. The cells are lysed and Kdr is immunoprecipitated using an anti-Kdr antibody. The immunoprecipitated Kdr protein is separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and the level of phosphotyrosine is determined by western blotting with an anti-phosphotyrosine-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

EXAMPLE 55

[0678] Vascular Endothelial Growth Factor (VEGF)-Induced Extra-Cellular Signal Regulated Kinase (Erk) 1/2-phosphorylation.

[0679] Human umbilical vein endothelial cells (HUVEC) are plated out in flat-well plates in complete media and allowed to adhere overnight. The cells are then starved in medium containing 0.1% fetal calf serum (FCS), pre-incubated with or without dilutions of compound, then activated for 15 minutes with 50 ng/ml VEGF. The cells are lysed and proteins are separated by SDS-PAGE. The level of phosphotyrosine on Erk1/2 is determined by western blotting with an anti-phospho-Erk1/2-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

EXAMPLE 56

[0680] Vascular endothelial growth factor (VEGF)-induced proliferation. Human umbilical vein endothelial cells (HUVEC) are plated out in flat-well plates in complete media and allowed to adhere overnight. The cells are then starved in medium containing 0.1% fetal calf serum (FCS), pre-incubated with or without dilutions of compound, then activated for 72 hours with 50 ng/ml VEGF. Proliferation is determined by the level of 3H-thymidine incorporation into DNA. IC50's are determined by comparing the level of thymidine incorporation found in the presence of compound compared to controls.

EXAMPLE 57

[0681] Growth factor-induced DNA synthesis. A rat fibroblast cell line is plated out in flat-well plates in complete medium and allowed to adhere overnight. The cells are then starved in medium containing 0.1% bovine serum albumin (BSA), pre-incubated with or without dilutions of compound, then activated overnight with 50 ng/ml platelet derived growth factor (PDGF), 1 ng/ml epidermal growth factor (EGF), 3 ng/ml fibroblast growth factor (FGF), or 10 ng/ml insulin-like growth factor-I (IGF-1). Proliferation is determined by the level of 3H-thymidine incorporation into DNA. IC50's are determined by comparing the level of thymidine incorporation found in the presence of compound compared to controls.

EXAMPLE 58

[0682] Platelet-derived growth factor (PDGF)-induced PDGF receptor (PDGF-R) auto-phosphorylation. A mouse fibroblast cell line is plated out in flat-well plates in complete-medium and allowed to adhere overnight. The cells are then starved in medium containing 0.1% bovine serum albumin (BSA), pre-incubated with or without dilutions of compound, then activated with 50 ng/ml platelet derived growth factor (PDGF) for 5 minutes. The cells are lysed and proteins are separated by SDS-PAGE. The level of phosphotyrosine on PDGF-R is determined by western blotting with an anti-phosphotyrosine-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

EXAMPLE 59

[0683] Epidermal growth factor (EGF)-induced EGF receptor (EGF-R) auto-phosphorylation. Human epidermoid carcinoma cells (A431) are plated out in flat-well plates in complete media and allowed to adhere overnight. The cells are then starved in medium containing 0.5% fetal calf serum (FCS), pre-incubated with or without dilutions of compound, then activated for 3 minutes with 50 ng/ml EGF. The cells are lysed and proteins are separated by SDS-PAGE. The level of phosphotyrosine on EGF-R is determined by western blotting with an anti-phospho-EGF-R-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

EXAMPLE 60

[0684] Heregulin-β1 (HRG)-induced ErbB2 auto-phosphorylation. Human breast carcinoma cells (ZR-75) are plated out in flat-well plates in complete media and allowed to adhere overnight. The cells are then starved in medium containing 0.5% fetal calf serum (FCS), pre-incubated with or without dilutions of compound, then activated for 5 minutes with 50 ng/ml HRG. The cells are lysed and proteins are separated by SDS-PAGE. The level of phosphotyrosine on ErbB2 is determined by western blotting with an anti-phospho-ErbB2-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

EXAMPLE 61

[0685] Hepatocyte growth factor (HGF) receptor (Met) auto-phosphorylation. Human gastric carcinoma cells (MKN-45), which overexpress and constitutively auto-phosphorylate Met, are plated out in flat-well plates in complete media and allowed to adhere overnight. The cells are then incubated with or without dilutions of compound for 1 hour. The cells are lysed and proteins are separated by SDS-PAGE. The level of phosphotyrosine on Met is determined by western blotting with an anti-phospho-tyrosine-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

EXAMPLE 62

[0686] Anti-CD3/CD28-induced IL-2 secretion and proliferation. Purified T cells are obtained from human peripheral blood lymphocytes. T cells are pre-incubated incubated with or without dilutions of compound for 30 minutes. The T cells and compounds are then transferred to a plate containing captured anti-CD3-specific antibody. Anti-CD28-specific antibody is then added and the cells are incubated for 20 hours. T cell supernatants are measured for the presence of interleukin-2 by commercially available ELISA. IC50's are determined by comparing the level of IL-2 secretion found in the presence of compound compared to controls. The cells are then pulsed with 3H-thymidine and incubated for an additional 24 hours to determine cellular proliferation. IC50's are determined by comparing the level of thymidine incorporation found in the presence of compound compared to controls.

EXAMPLE 63

[0687] Anti-CD3-induced T cell receptor 4-chain (TCR;) phosphorylation. The human T cell line, Jurkat, is pre-incubated with or without compounds, then incubated with anti-CD3-specific antibody at 4° C. Cells are washed, then incubated at 4° C. with a secondary anti-immunoglobulin antibody for crosslinking. Cells are activated by transfer to a 37° C. water bath for 1 minute. The cells are lysed and proteins are separated by SDS-PAGE. The level of phosphotyrosine on TCRζ is determined by western blotting with an anti-phospho-tyrosine-specific antibody. IC50's are determined by comparing the level of phosphotyrosine found in the presence of compound compared to controls.

TABLE 2
Compound Number	EGFR-1	IGFR-1	AKT3-1	Met-1
1014	E	ND	ND	E
1015	E	ND	ND	E
1016	E	ND	ND	E
1017	E	ND	ND	E
1018	E	ND	ND	E
1019	E	ND	ND	E
271	E	ND	ND	E
272	E	ND	ND	E
1020	E	ND	ND	E
1021	E	ND	ND	E
1022	E	ND	ND	E
273	E	ND	ND	E
1023	E	ND	ND	E
1024	E	ND	ND	E
1025	D	ND	E	E
1027	E	ND	ND	E
970	E	E	E	E
36	D	E	E	E
182	E	ND	ND	D
275	E	ND	ND	D
274	E	ND	ND	E
276	E	ND	ND	E
277	E	ND	ND	E
11	E	E	E	E
12	E	E	E	E
13	E	E	E	E
14	E	E	E	E
15	E	E	E	E
17	E	E	E	E
16	E	E	E	E
18	E	E	E	E
19	E	C	E	E
20	E	E	E	E
21	E	B	E	D
8	E	E	E	E
971	E	E	E	E
924	E	E	E	E
925	E	E	E	E
61	A	A	E	E
926	B	E	E	D
29	A	C	E	D
27	C	A	E	D
28	B	B	E	E
852	E	A	E	C
151	E	E	E	E
1028	E	E	E	E
153	E	E	E	E
63	E	E	E	E
62	A	B	E	D
40	E	E	E	E
39	E	E	E	E
65	A	B	E	E
64	A	A	E	C
67	C	D	E	E
66	E	A	E	B
69	E	E	E	E
68	A	A	E	D
927	C	E	E	E
70	B	B	E	E
928	A	A	D	C
232	C	E	E	E
1118	B	E	E	E
77	B	B	E	E
73	E	E	E	E
76	D	B	E	E
72	B	A	E	D
75	A	A	D	D
74	A	A	E	D
33	E	A	E	E
78	A	B	E	E
79	A	A	E	C
80	E	E	E	E
81	E	E	E	E
82	B	B	E	E
83	A	B	E	E
289	E	A	E	B
86	E	A	E	E
85	B	B	E	E
88	D	B	E	B
87	B	A	E	E
90	B	B	E	E
89	B	B	E	E
91	B	B	E	E
92	B	B	D	B
93	E	E	E	E
94	A	C	E	E
95	E	B	E	E
96	B	A	E	E
97	E	E	E	E
98	A	E	E	E
99	B	A	E	D
100	D	C	C	E
101	E	E	E	E
102	B	A	E	A
154	E	B	E	E
155	E	E	E	E
207	E	E	E	E
251	B	E	B	B
22	E	E	E	E
278	E	ND	ND	E
279	E	ND	ND	E
280	E	ND	ND	E
281	E	ND	ND	E
282	E	ND	ND	C
283	E	ND	ND	E
284	E	ND	ND	E
156	A	E	E	D
157	B	E	D	D
158	B	C	B	B
159	A	D	B	B
160	B	E	D	D
161	E	E	C	E
162	E	E	D	E
209	E	E	D	E
183	E	E	E	E
253	C	E	E	E
221	E	A	E	E
252	B	A	E	E
256	E	E	E	E
103	E	C	B	E
104	B	C	E	E
105	B	E	E	B
106	B	C	E	B
220	E	E	E	E
107	A	B	B	C
108	A	C	E	E
109	A	E	E	E
110	A	B	E	D
929	A	D	E	A
111	A	A	E	E
114	E	C	E	E
113	B	A	E	E
116	A	B	E	E
115	A	B	B	E
118	A	B	E	E
41	A	B	E	C
117	C	E	C	D
119	A	C	E	E
163	E	E	E	E
164	E	E	E	E
165	E	E	E	E
1029	E	E	E	E
285	E	A	E	E
299	C	C	B	B
286	C	A	C	B
214	E	E	E	C
213	E	E	E	E
181	E	E	E	E
184	E	E	E	D
255	E	E	E	E
185	E	B	E	D
191	E	E	E	E
211	E	E	E	E
254	E	E	E	E
42	E	E	E	E
922	B	B	B	C
186	D	B	E	B
208	E	E	E	D
121	B	E	E	D
123	A	B	E	E
125	B	B	E	E
127	A	B	E	E
120	A	A	C	C
170	B	E	B	C
171	A	E	B	E
287	D	A	E	E
222	E	E	E	E
51	A	E	E	B
212	E	E	E	E
250	A	A	E	E
200	E	E	E	D
218	E	E	E	E
187	E	E	E	E
930	A	B	E	D
931	A	B	E	E
932	B	B	E	C
933	A	B	E	E
934	B	A	E	E
935	A	B	E	E
1030	E	A	E	A
174	C	E	E	E
175	E	B	E	B
972	A	C	E	B
609	A	E	E	B
936	A	A	E	E
937	A	A	E	C
938	E	C	E	E
135	A	A	E	B
226	E	E	E	E
973	B	E	E	E
291	B	E	E	E
292/293	E	A	E	A
294/295	E	A	E	B
296/297	E	A	B	A
178	A	B	D	C
302	E	A	E	E
300	A	A	E	C
303	B	B	E	E
304	A	A	E	B
305	B	C	E	D
196	D	B	E	E
298	B	C	E	A
306	A	A	E	C
974	A	E	E	E
56	A	D	E	E
310	B	B	E	E
309	C	E	E	E
311	E	E	E	B
312	E	E	E	E
313	B	A	E	A
238	E	E	E	E
239	D	E	E	E
198	E	E	E	E
237	D	A	E	C
240	E	E	E	E
314	A	E	E	B
315	E	E	E	D
316	B	A	E	E
317	E	B	E	B
318	A	A	D	A
308	A	A	D	A
320	B	E	E	C
319	B	E	E	E
321	A	C	E	E
322	E	E	E	E
323	E	E	E	D
324	E	A	E	E
328	B	A	C	A
325	D	E	E	E
327	E	C	E	E
326	E	E	E	E
338	B	A	E	B
337	B	A	E	A
336	E	E	E	E
335	A	E	E	E
334	E	A	C	E
219	E	E	E	E
333	E	E	E	E
332	E	C	E	C
331	E	E	E	E
330	E	D	E	E
339	E	E	E	E
340	C	A	C	A
342	A	B	E	B
341	C	B	E	B
344	E	B	E	B
343	E	B	E	D
345	E	B	E	B
346	E	E	E	E
217	E	E	E	D
1072	E	E	E	D
1073	E	E	E	E
349	E	E	D	D
350	E	E	E	E
352	E	E	E	E
205	E	E	E	E
353	E	E	E	E
354	E	E	E	E
356	E	E	E	E
355	E	E	E	E
358	E	E	E	E
357	E	E	E	E
359	E	E	E	E
360	E	E	E	E
362	E	E	E	E
361	E	E	E	E
363	E	E	E	E
364	B	B	E	B
366	E	B	E	E
365	B	A	C	A
367	C	A	E	A
368	E	E	E	E
369	E	E	E	E
180	E	E	E	E
372	E	E	E	E
373	C	E	E	E
371	C	E	E	E
374	A	E	E	B
375	E	E	E	E
376	D	B	E	C
378	E	B	E	B
377	E	C	E	D
379	E	E	E	E
380	E	C	E	E
382	E	B	E	E
381	E	E	E	D
383	E	E	E	E
384	D	E	E	D
386	E	E	E	E
385	E	E	E	E
387	E	E	E	D
388	E	E	E	E
389	E	A	E	E
390	D	E	B	D
391	E	E	E	E
392	E	E	E	E
393	D	E	E	E
394	D	B	E	E
396	C	A	C	B
395	E	B	D	B
397	E	ND	E	E
398	E	ND	E	E
399	E	ND	D	E
400	E	ND	E	E
402	E	ND	E	E
401	B	ND	E	B
403	E	ND	E	E
404	D	ND	D	E
406	E	ND	E	E
405	E	ND	E	E
407	E	ND	E	E
393	E	ND	E	E
409	E	ND	E	E
45	E	ND	E	E
412	E	ND	E	E
411	E	ND	E	A
413	E	ND	E	E
414	E	E	E	E
416	E	ND	E	E
415	E	ND	E	E
417	E	ND	E	E
418	B	ND	B	E
419	E	ND	E	E
420	E	ND	E	E
422	B	ND	B	E
421	E	ND	E	E
423	B	ND	C	E
424	E	ND	E	E
426	E	ND	E	E
425	B	ND	E	E
427	E	ND	E	E
428	A	B	E	E
202	E	ND	D	B
429	B	ND	B	A
430	B	ND	B	B
432	B	ND	E	B
431	B	ND	C	E
433	E	ND	E	E
434	E	ND	E	E
436	D	ND	E	E
435	E	ND	E	E
437	B	ND	E	B
438	B	ND	C	B
439	B	ND	B	B
440	B	ND	E	B
441	E	ND	E	E
442	E	ND	E	E
443	B	ND	E	B
444	E	ND	E	E
445	E	ND	E	B
446	E	ND	E	E
448	E	ND	E	E
449	E	ND	E	E
450	E	ND	E	E
452	E	ND	E	E
451	E	ND	D	E
453	B	ND	C	C
454	E	ND	E	C
456	E	ND	E	E
455	C	ND	E	E
457	C	ND	E	E
458	E	ND	E	C
459	E	ND	E	C
460	B	ND	E	C
461	E	ND	E	E
462	E	ND	E	D
464	E	ND	E	E
463	E	ND	E	E
465	E	ND	E	E
466	E	ND	E	B
467	E	ND	E	E
468	B	ND	E	E
469	E	ND	E	E
999	E	ND	E	E
470	D	ND	E	E
471	E	ND	E	E
472	E	ND	E	E
1074	E	ND	E	E
473	E	C	E	D
474	B	B	B	B
476	E	B	E	E
475	E	ND	E	C
477	E	ND	E	E
478	B	ND	B	B
479	D	A	E	C
480	B	ND	B	B
481	E	ND	E	E
482	E	ND	E	E
484	B	ND	E	C
483	B	ND	E	E
486	E	ND	E	E
485	E	ND	E	E
487	E	ND	E	E
488	E	ND	E	E
489	E	ND	E	E
490	E	ND	E	E
492	C	ND	E	C
491	E	ND	E	E
493	E	ND	E	D
494	C	ND	E	E
495	B	ND	E	B
923	E	ND	E	B
497	E	ND	E	E
498	A	E	E	A
499	B	ND	E	B
501	B	ND	E	A
500	B	ND	E	B
502	B	ND	B	B
503	E	ND	E	E
504	E	ND	E	E
505	E	ND	E	E
506	E	ND	E	E
508	E	ND	E	E
507	E	ND	E	E
509	B	E	E	E
510	E	E	E	E
511	E	E	E	E
512	E	E	E	E
513	D	D	E	E
514	E	E	E	E
515	E	E	E	E
516	E	E	E	E
517	C	B	E	D
518	A	E	E	E
519	E	B	E	E
520	E	B	E	E
522	C	B	E	C
521	B	A	E	A
523	B	A	E	A
524	E	A	E	C
526	B	ND	C	B
525	E	ND	E	D
528	B	ND	B	B
527	C	ND	E	B
975	E	ND	E	E
976	E	ND	E	E
977	B	A	E	A
978	B	A	E	A
979	B	ND	E	B
980	B	ND	B	D
610	B	B	E	B
681	E	ND	E	E
682	B	ND	E	C
683	E	ND	E	E
684	E	ND	E	E
685	E	ND	E	E
686	E	ND	E	E
687	D	ND	E	E
688	E	ND	E	E
689	B	ND	E	C
1031	A	B	E	E
1032	E	ND	E	E
570	D	ND	E	E
570	A	ND	E	E
1033	C	E	E	E
1034	E	ND	E	D
1035	E	ND	E	E
1036	B	D	E	E
1037	E	E	E	E
700	E	B	E	E
646	E	ND	B	E
611	E	ND	E	E
230	D	ND	E	E
612	B	C	E	A
940	E	ND	E	E
941	E	ND	E	E
942	E	C	E	E
943	E	E	E	E
944	E	D	E	E
1000	C	B	D	C
1001	B	A	E	A
1002	E	ND	E	E
1003	C	ND	E	B
945	E	ND	E	E
946	D	C	E	D
947	E	ND	E	E
948	E	ND	E	E
949	E	D	E	D
981	A	A	E	A
982	B	ND	D	B
983	A	B	D	A
984	A	ND	E	B
1075	E	ND	E	E
1076	E	E	E	E
1077	E	E	E	E
1078	E	ND	E	E
647	B	ND	E	E
1038	E	ND	E	E
177	A	B	C	B
690	E	ND	E	E
648	E	ND	E	E
649	E	A	E	E
650	E	A	E	D
651	E	A	E	B
652	E	A	E	B
691	C	A	E	B
985	B	ND	E	C
986	C	ND	E	B
987	E	ND	E	E
1039	E	ND	E	E
613	B	D	E	E
614	A	A	E	E
950	B	E	E	E
1079	E	ND	E	E
1080	E	ND	E	E
1081	E	ND	E	E
1082	B	C	E	D
653	E	ND	E	E
654	C	A	E	C
655	B	A	E	B
656	C	A	E	B
657	B	B	C	C
615	E	E	E	E
658	C	A	E	E
951	D	E	E	E
952	E	B	E	E
692	B	B	E	C
693	B	ND	E	B
694	B	ND	E	E
695	C	ND	E	E
696	E	ND	E	E
697	B	B	E	E
698	C	ND	E	E
699	B	B	E	E
616	A	B	E	A
1004	B	A	E	A
1083	B	E	E	E
1084	E	E	E	C
1085	E	E	E	E
953	A	C	E	E
954	E	D	E	D
1086	E	E	E	E
1087	E	E	E	E
1088	E	E	E	E
1089	E	E	E	E
1040	C	D	E	E
1041	A	B	E	E
659	E	B	E	E
660	B	E	E	E
661	E	E	E	E
599	D	E	E	E
600	E	E	E	E
601	B	E	E	E
602	B	E	E	E
604	B	B	C	A
603	A	B	E	B
617	C	C	E	E
606	E	D	E	E
605	E	E	E	E
598	E	E	E	E
597	D	D	C	E
607	A	E	E	E
559	A	B	E	E
592	B	E	E	E
591	E	E	E	E
1042	E	D	E	E
593	C	A	E	E
596	C	E	E	E
595	E	E	C	E
1043	D	D	E	E
1044	C	E	E	E
618	A	A	D	C
579	E	E	E	E
579	A	E	E	E
414	E	D	E	E
589	C	A	E	D
583	E	B	E	E
584	C	E	E	D
619	D	E	D	E
620	B	E	E	C
581	B	E	E	E
582	A	E	E	D
585	E	E	E	D
584	E	E	E	E
1045	E	E	E	E
587	C	D	E	D
662	C	D	E	E
663	E	E	E	E
664	B	B	C	B
587	D	E	E	E
573	B	A	C	B
569	E	E	E	E
571	E	E	E	D
1046	E	E	E	E
574	E	B	E	E
572	E	E	E	D
588	E	D	E	E
561	E	E	E	E
577	D	A	E	A
578	A	A	E	A
562	A	C	E	E
563	A	B	E	C
565	E	E	E	E
564	C	E	E	E
566	A	D	E	B
549	C	E	E	E
567	A	E	E	B
621	A	C	E	B
1047	E	E	E	E
551	E	E	E	D
552	E	E	E	E
554	A	E	D	C
553	A	D	C	B
622	C	E	E	E
555	A	A	C	C
557	B	A	E	E
556	B	A	E	E
576	B	A	E	A
558	E	E	E	C
701	E	E	E	E
702	B	E	E	E
703	A	E	E	E
530	E	E	E	E
704	E	E	E	E
665	B	E	E	E
539	A	C	D	D
546	C	A	D	C
540	A	A	E	C
542	B	B	E	D
544	E	A	E	E
541	A	B	E	D
543	A	E	E	E
545	B	E	E	E
547	E	E	E	E
548	E	E	E	E
1007	A	A	E	B
531	A	E	E	D
623	B	B	E	D
533	E	E	E	E
534	E	E	E	E
535	A	E	E	B
536	A	B	E	A
537	A	B	E	B
538	A	A	E	A
666	A	E	E	C
988	B	B	E	B
989	B	D	E	D
990	E	B	E	C
955	E	A	E	B
705	A	E	E	E
706	A	E	E	B
707	A	E	E	E
708	E	E	E	E
709	A	E	E	B
1048	A	E	E	E
1049	E	E	E	B
1050	C	E	E	C
1051	E	C	E	E
1052	E	E	E	E
1005	E	B	E	C
624	A	E	E	E
625	A	B	E	E
626	D	E	E	B
627	B	A	E	D
956	E	A	E	D
710	A	C	E	B
711	A	E	E	E
712	A	E	E	B
713	E	E	E	E
1006	E	A	E	A
628	B	B	E	E
629	B	A	E	C
957	A	B	B	B
958	B	B	C	B
959	B	B	B	B
1053	C	E	E	E
1090	E	D	E	D
1091	E	E	C	D
630	A	D	E	E
714	A	B	E	B
715	A	B	D	C
716	A	A	D	B
717	A	B	E	B
718	A	E	D	E
719	A	E	E	E
631	B	B	E	A
632	A	B	E	E
720	A	E	E	A
721	A	D	E	B
1009	A	A	E	E
1011	B	A	B	B
1012	A	A	B	B
726	A	E	E	E
727	E	E	E	D
728	B	B	E	B
729	A	B	D	B
730	A	B	C	B
731	A	B	D	B
732	D	D	E	E
733	B	E	E	E
734	E	C	E	D
735	A	D	C	D
736	B	B	B	B
737	B	B	D	C
738	B	B	E	E
739	B	E	E	E
740	C	E	E	E
741	A	E	E	E
742	B	E	E	E
743	A	E	E	E
744	B	E	E	E
745	B	E	E	E
746	E	E	E	E
747	C	E	E	E
748	A	C	E	B
749	A	E	E	B
750	A	E	E	C
751	A	E	E	E
752	B	E	E	E
753	A	B	E	B
754	E	E	E	E
755	E	E	E	E
756	A	E	E	B
757	A	E	E	E
758	A	C	E	A
759	E	E	E	E
760	A	E	E	B
761	E	E	E	E
762	D	E	E	E
763	A	E	E	B
764	A	E	E	A
765	E	E	E	E
766	B	B	E	B
767	E	E	E	E
768	E	E	E	C
769	E	E	E	E
770	A	D	E	A
771	E	E	E	E
772	E	E	E	E
773	B	B	E	A
774	A	C	B	A
775	E	E	E	E
776	E	E	E	E
777	E	E	E	E
778	C	E	B	B
779	E	E	E	E
780	D	E	E	E
781	E	E	E	E
782	E	E	E	E
783	E	B	E	E
784	E	E	E	E
785	E	E	E	E
786	E	E	E	E
787	E	E	E	E
788	E	E	E	E
789	E	B	E	E
790	E	E	E	E
791	E	E	E	E
792	B	E	E	E
793	E	E	E	E
794	B	C	E	D
795	A	D	E	A
796	A	E	E	B
797	A	C	E	B
798	E	E	E	D
799	A	B	E	B
800	A	D	E	B
801	A	E	E	B
802	E	E	E	E
803	B	E	E	E
804	E	E	E	E
805	E	C	E	C
806	B	B	E	B
807	D	B	E	A
808	C	E	E	E
809	E	C	D	C
810	E	D	E	E
811	E	C	E	E
812	E	B	E	B
813	E	E	E	E
814	E	E	E	E
815	E	E	E	E
816	E	D	E	E
817	E	E	E	E
818	E	E	E	E
819	E	E	E	E
820	E	D	E	E
821	B	B	C	B
822	B	B	E	C
823	E	C	B	B
824	A	A	A	A
825	A	B	B	B
826	A	B	E	B
827	A	B	D	B
828	E	E	E	E
829	D	E	E	E
830	E	E	E	B
831	E	E	E	C
832	E	E	E	B
833	E	E	E	E
834	E	E	E	E
835	E	E	E	E
836	E	E	E	E
837	E	E	E	E
383	D	E	B	D
839	E	E	E	E
840	E	E	E	E
841	E	E	E	E
842	E	E	E	D
843	E	E	E	E
844	E	C	E	E
845	E	E	B	E
846	C	E	E	E
847	E	E	E	E
848	E	E	E	E
849	D	E	E	E
850	E	E	E	E
851	E	E	E	E
667	A	E	E	D
668	A	E	E	C
669	A	E	E	D
670	A	E	E	A
671	A	C	E	A
633	B	E	E	E
634	A	E	D	C
1013	B	A	B	B
1008	B	A	E	B
635	A	E	E	A
636	B	E	E	E
637	A	E	E	C
960	C	A	E	D
961	A	B	E	E
991	B	B	C	A
992	B	A	C	A
993	B	A	E	A
962	C	D	E	E
963	C	C	D	B
964	B	E	E	E
672	B	E	E	E
673	A	E	E	B
674	A	E	E	B
675	A	C	E	B
1092	E	E	E	E
1093	B	D	E	B
1094	B	E	E	B
1095	E	E	E	E
1096	E	E	D	D
1097	E	E	E	C
1098	C	E	C	C
638	A	D	E	E
994	E	E	E	E
639	A	E	E	A
995	B	C	E	E
996	D	B	E	E
997	E	E	E	E
965	A	E	E	E
966	A	A	E	E
967	A	E	D	C
968	B	D	E	D
1010	B	A	B	A
1099	A	E	E	B
1100	B	E	E	D
1101	B	E	E	C
1102	C	E	E	E
1103	B	E	D	E
1104	E	E	D	E
1105	E	E	E	E
1106	E	E	E	E
1104	B	D	E	E
1108	B	C	B	E
1127	E	A	E	A
1128	D	A	E	B
1109	B	B	E	C
722	A	D	E	B
1054/1055	E	B	E	E
1056/1057	B	E	E	E
1058/1059	E	C	E	E
1060/1061	E	E	E	E
1062/1063	E	A	C	D
1064/1065	C	E	E	E
640	A	E	E	B
641	A	B	E	A
642	B	A	E	A
853	E	E	E	E
854	B	E	E	E
855	E	E	E	E
856	E	C	E	E
857	C	E	E	E
858	C	E	E	E
859	B	C	B	B
860	E	C	E	B
861	E	E	E	E
862	B	E	E	A
863	A	E	E	B
864	E	E	E	A
865	A	E	E	B
866	B	E	E	B
867	B	E	B	A
723	A	A	B	C
134	A	A	B	A
676	A	B	C	B
677	A	C	E	A
1110	B	E	E	E
1111	B	E	E	E
1112	B	E	E	B
1113	B	E	E	B
1114	D	E	E	D
1115	B	E	E	B
1116	B	B	D	B
1117	D	E	E	B
1066	C	E	C	C
1067	B	E	E	E
1068	E	E	E	E
868	B	E	E	E
869	B	E	E	D
870	E	E	E	E
871	E	E	E	E
872	B	B	B	B
873	E	E	E	E
874	B	E	E	E
875	A	E	E	C
876	A	E	E	E
877	C	D	E	B
878	E	C	E	D
879	B	C	E	B
880	B	E	E	B
881	B	B	E	B
882	B	B	C	B
883	C	C	E	A
884	B	B	B	B
885	B	B	D	B
886	A	B	B	A
887	A	A	B	A
888	B	A	B	A
889	B	B	E	B
890	E	E	E	E
891	B	A	B	A
892	A	E	E	B
893	B	E	B	B
894	C	E	E	E
895	B	A	E	E
896	B	B	C	B
897	A	E	E	E
898	C	C	E	E
899	B	C	C	B
900	A	B	A	A
901	A	E	B	B
902	A	C	B	B
903	A	E	E	C
904	A	C	D	B
905	A	E	E	B
906	B	C	B	B
907	A	E	E	C
678	A	E	E	A
643	A	E	E	B
644	B	E	E	B
724	A	B	E	B
645	A	E	E	E
1069	A	E	E	E
1070	E	E	C	E
1071	B	B	E	E
679	B	E	E	E
1125	A	A	E	B
1126	B	A	E	B

[0688]

TABLE 3
Compound Number	KDR-1	Zap-1	Lck-1	Itk-1
1014	E	E	E	E
1015	E	E	E	E
1016	E	E	E	E
1017	E	E	E	E
1018	E	E	E	E
1019	C	E	E	E
271	E	B	E	E
272	E	C	E	E
1020	E	E	E	E
1021	E	E	E	E
1022	E	E	E	E
273	E	E	E	E
1023	C	E	D	C
1024	E	E	E	E
1025	C	D	E	E
1027	E	E	E	E
970	A	E	E	E
36	A	E	B	E
182	A	E	C	E
275	B	E	E	E
274	B	E	E	E
276	B	E	E	E
277	B	E	E	E
11	B	E	C	E
12	D	E	E	E
13	E	E	E	E
14	E	D	E	E
15	E	D	E	E
17	E	E	E	E
16	E	E	E	E
18	C	E	C	E
19	C	C	E	E
20	E	E	E	E
21	B	D	B	E
8	C	E	E	E
971	E	E	E	E
924	B	E	E	E
925	E	E	B	E
61	A	E	A	E
926	A	C	B	E
29	A	E	A	E
27	A	E	B	E
28	A	E	B	E
852	C	D	E	E
151	D	E	E	E
1028	E	E	E	E
153	D	E	E	E
63	B	E	E	E
62	B	E	B	E
40	E	E	E	E
39	E	E	E	E
65	B	E	D	E
64	B	D	B	E
67	B	E	B	E
66	B	C	B	E
69	B	E	B	E
68	A	E	A	E
927	B	E	C	E
70	A	E	B	D
928	A	E	A	C
232	B	E	B	E
1118	E	E	E	E
77	A	E	B	D
73	E	E	E	E
76	B	E	B	E
72	A	E	B	E
75	B	D	B	E
74	B	E	B	E
33	B	E	D	E
78	A	E	B	B
79	A	E	A	A
80	E	E	E	E
81	B	E	B	E
82	A	E	B	E
83	A	E	A	B
289	A	E	A	B
86	A	E	B	E
85	A	E	A	B
88	A	E	B	B
87	B	D	B	E
90	A	E	B	D
89	A	E	B	E
91	B	E	B	E
92	B	D	E	E
93	E	E	E	E
94	A	E	A	E
95	B	D	B	E
96	B	D	B	E
97	A	E	D	E
98	A	E	A	E
99	A	E	B	E
100	B	B	E	E
101	B	E	C	E
102	A	E	A	B
154	B	E	E	E
155	E	E	E	E
207	B	E	D	E
251	A	C	C	E
22	E	E	E	E
278	E	E	E	E
279	E	E	E	E
280	E	E	E	E
281	E	E	E	E
282	E	E	E	E
283	E	E	E	E
284	D	E	E	E
156	C	E	D	E
157	B	C	E	E
158	B	B	D	E
159	C	C	E	E
160	E	E	E	E
161	B	E	E	E
162	C	E	E	E
209	E	E	E	E
183	C	E	E	E
253	B	E	D	E
221	B	E	E	E
252	A	E	A	C
256	D	E	E	E
103	E	E	E	E
104	B	E	C	E
105	B	E	E	E
106	A	E	C	E
220	E	E	E	E
107	B	E	B	B
108	C	E	D	E
109	C	C	E	E
110	A	E	B	C
929	B	C	B	B
111	B	E	B	E
114	A	E	E	E
113	E	E	E	E
116	C	E	D	E
115	B	E	B	D
118	E	E	D	B
41	A	E	C	D
117	B	D	C	E
119	A	E	B	D
163	E	E	E	E
164	E	E	E	E
165	E	E	E	E
1029	D	C	E	E
285	A	E	B	E
299	B	B	D	E
286	A	E	B	B
214	B	E	E	E
213	B	E	E	E
181	E	E	E	E
184	A	E	B	E
255	A	E	E	E
185	A	E	C	E
191	C	E	E	E
211	C	E	E	E
254	E	E	E	E
42	B	E	B	E
922	A	C	B	E
186	A	E	B	E
208	B	E	E	E
121	A	E	B	D
123	A	E	B	C
125	A	E	B	C
127	A	E	B	E
120	B	D	D	C
170	B	C	E	E
171	E	E	E	E
287	A	E	B	C
222	D	E	E	E
51	B	E	B	E
212	E	E	E	E
250	C	E	B	E
200	C	E	D	E
218	E	E	E	E
187	B	E	E	E
930	A	E	B	E
931	A	E	B	E
932	A	E	B	E
933	B	E	B	E
934	B	E	E	E
935	A	E	B	C
1030	A	E	C	B
174	A	E	E	E
175	A	E	B	E
972	A	E	B	E
609	A	E	A	E
936	B	E	B	C
937	A	E	B	E
938	A	E	E	E
135	A	D	B	C
226	C	D	D	E
973	E	E	C	E
291	C	E	C	E
292/293	B	E	B	B
294/295	C	E	C	E
296/297	A	E	B	C
178	B	B	B	E
302	B	E	E	E
300	A	E	B	C
303	B	E	B	E
304	A	E	A	D
305	A	E	B	E
196	A	E	E	E
298	A	D	B	B
306	A	E	B	E
974	B	E	C	E
56	B	E	C	E
310	D	E	B	E
309	D	E	D	E
311	B	E	E	E
312	E	E	E	E
313	B	E	B	C
238	B	E	E	E
239	B	E	E	E
198	B	E	E	E
237	A	D	B	E
240	B	E	B	E
314	A	E	A	B
315	A	D	D	E
316	A	E	E	E
317	B	E	B	E
318	A	E	B	C
308	A	E	B	B
320	C	D	C	E
319	E	E	E	E
321	A	E	D	E
322	B	E	E	E
323	A	D	D	E
324	A	E	E	B
328	A	E	B	B
325	A	E	E	E
327	E	E	B	B
326	E	E	E	E
338	B	E	B	E
337	A	E	B	B
336	A	E	B	E
335	A	E	B	E
334	B	E	D	B
219	B	E	E	E
333	E	E	E	E
332	B	E	D	E
331	E	E	E	E
330	E	E	E	E
339	A	E	E	E
340	A	E	B	E
342	A	E	B	B
341	A	E	C	C
344	A	E	B	E
343	B	E	E	E
345	A	E	B	E
346	B	E	E	E
217	C	E	B	E
1072	C	E	E	E
1073	E	E	E	E
349	D	E	B	E
350	E	E	E	E
352	E	E	E	E
205	C	E	E	E
353	A	E	D	B
354	E	E	E	E
356	E	E	E	E
355	E	E	E	E
358	E	E	E	E
357	E	E	E	E
359	E	E	E	E
360	E	E	E	E
362	E	E	E	E
361	E	E	E	E
363	E	E	E	E
364	A	E	C	C
366	E	C	C	E
365	A	B	B	B
367	A	E	B	B
368	E	E	D	E
369	E	E	C	D
180	B	E	B	E
372	E	E	E	E
373	B	E	E	E
371	A	E	B	E
374	A	E	A	E
375	B	E	C	E
376	A	E	A	B
378	A	E	C	E
377	B	B	B	D
379	D	E	E	E
380	A	E	E	E
382	B	E	B	E
381	C	E	D	E
383	B	E	C	C
384	A	E	A	E
386	A	E	C	E
385	A	E	B	E
387	A	E	B	E
388	B	E	B	E
389	E	E	E	E
390	B	E	A	E
391	B	E	D	E
392	B	E	C	E
393	E	E	B	E
394	A	E	B	E
396	A	E	B	A
395	A	E	C	B
397	A	E	A	E
398	C	E	E	E
399	B	E	D	E
400	A	E	E	E
402	B	E	E	E
401	A	B	B	A
403	A	E	A	E
404	A	E	B	B
406	B	E	B	E
405	B	E	E	E
407	A	E	A	E
393	C	E	E	E
409	E	E	D	E
45	E	E	B	E
412	B	E	A	E
411	A	E	D	E
413	A	E	E	E
414	A	E	E	E
416	A	E	B	E
415	A	E	C	E
417	A	E	A	E
418	A	E	B	D
419	B	E	E	E
420	B	E	E	E
422	B	E	E	E
421	E	E	E	E
423	B	E	B	E
424	C	E	E	E
426	E	E	E	E
425	D	E	E	E
427	E	E	E	E
428	C	E	A	E
202	A	E	A	A
429	A	E	B	B
430	A	E	B	B
432	B	E	E	D
431	B	E	D	C
433	E	E	E	E
434	E	E	E	E
436	D	E	E	E
435	E	E	E	E
437	A	E	B	B
438	B	D	B	B
439	A	C	B	B
440	B	B	B	D
441	A	E	C	E
442	C	E	E	E
443	A	E	E	B
444	E	E	E	E
445	A	E	A	B
446	E	E	E	E
448	C	E	B	E
449	E	E	E	E
450	E	E	E	E
452	B	E	E	E
451	B	E	B	E
453	B	E	E	E
454	B	E	B	E
456	E	E	E	E
455	B	E	E	E
457	B	E	D	E
458	B	E	E	E
459	B	E	E	E
460	B	E	D	E
461	E	E	E	E
462	E	C	D	E
464	B	E	C	E
463	A	E	E	E
465	B	E	E	E
466	A	E	A	C
467	B	C	E	E
468	B	E	E	E
469	B	E	E	E
999	E	E	E	E
470	E	E	C	B
471	E	E	E	E
472	B	E	E	E
1074	B	E	C	E
473	D	D	C	E
474	B	C	B	B
476	D	E	E	E
475	A	E	B	B
477	A	E	B	B
478	B	B	B	B
479	B	E	B	C
480	B	B	B	D
481	B	E	E	D
482	A	E	E	E
484	E	E	E	E
483	B	B	C	E
486	B	E	B	E
485	B	E	E	E
487	E	E	E	E
488	B	E	E	E
489	E	E	E	E
490	E	E	E	E
492	C	D	E	E
491	D	E	E	E
493	E	E	E	E
494	A	E	C	E
495	D	E	C	E
923	A	E	D	B
497	A	E	D	E
498	A	E	A	E
499	B	E	B	B
501	B	E	B	B
500	B	E	B	B
502	B	E	B	B
503	E	D	D	E
504	E	E	E	E
505	E	D	E	E
506	E	E	D	E
508	B	E	B	C
507	A	E	B	E
509	A	E	B	C
510	A	E	B	B
511	A	E	A	E
512	A	E	B	E
513	A	E	B	E
514	A	E	E	E
515	A	E	A	E
516	A	E	C	E
517	A	E	B	D
518	D	E	E	E
519	A	E	B	E
520	E	E	B	B
522	C	E	B	B
521	A	E	A	B
523	E	E	A	D
524	B	E	C	D
526	A	B	B	B
525	C	E	C	C
528	B	B	B	B
527	A	E	B	B
975	E	E	E	E
976	E	C	E	E
977	A	E	A	E
978	B	E	B	C
979	C	E	E	E
980	E	E	E	D
610	A	E	A	B
681	B	E	E	E
682	B	E	C	D
683	E	E	E	E
684	C	E	E	E
685	E	E	E	E
686	E	E	E	E
687	B	E	B	D
688	E	C	E	E
689	C	B	C	E
1031	C	E	B	E
1032	B	E	E	E
570	E	E	E	E
570	E	E	B	E
1033	A	E	A	E
1034	A	E	B	E
1035	A	E	E	E
1036	A	E	A	E
1037	A	E	E	E
700	A	E	B	D
646	B	E	E	C
611	B	E	B	D
230	A	E	B	D
612	A	D	A	B
940	A	E	D	E
941	E	E	E	E
942	A	E	C	E
943	A	C	B	E
944	A	E	E	E
1000	B	E	B	E
1001	B	E	A	B
1002	D	E	E	E
1003	B	C	B	B
945	B	E	D	E
946	B	E	B	E
947	A	E	E	C
948	B	E	C	C
949	A	E	A	E
981	A	E	B	B
982	A	B	B	B
983	A	C	C	B
984	A	D	B	B
1075	D	E	E	E
1076	A	E	A	E
1077	A	E	B	E
1078	B	E	E	E
647	B	E	E	E
1038	E	E	B	E
177	B	C	A	D
690	A	E	E	E
648	B	E	E	E
649	B	E	B	D
650	A	E	B	E
651	A	E	B	B
652	A	E	A	B
691	A	E	B	C
985	B	E	B	C
986	B	E	E	C
987	E	E	B	E
1039	A	E	B	E
613	C	E	B	E
614	D	E	B	E
950	A	E	A	E
1079	E	E	E	E
1080	A	E	C	E
1081	A	E	B	E
1082	A	B	B	E
653	E	E	E	E
654	A	E	B	B
655	A	E	B	B
656	A	E	B	C
657	B	B	C	C
615	E	E	D	D
658	B	E	E	B
951	A	E	B	E
952	A	E	C	D
692	A	B	A	B
693	B	E	B	C
694	B	E	B	C
695	A	E	A	B
696	E	E	E	E
697	B	E	A	E
698	A	E	A	B
699	B	E	A	B
616	A	E	A	E
1004	B	E	A	D
1083	A	E	B	D
1084	B	E	A	C
1085	A	E	B	E
953	B	E	A	D
954	D	E	D	C
1086	A	E	C	E
1087	B	E	C	E
1088	A	E	C	E
1089	A	E	A	C
1040	A	E	B	B
1041	A	E	A	B
659	C	E	C	B
660	E	E	B	E
661	B	E	E	E
599	C	E	B	E
600	B	E	A	E
601	C	E	B	E
602	D	E	B	E
604	B	C	B	B
603	A	E	A	E
617	B	E	B	E
606	A	E	C	E
605	A	E	B	E
598	B	E	E	E
597	B	E	B	E
607	A	E	A	E
559	B	E	A	C
592	A	E	B	E
591	A	E	A	E
1042	A	E	B	E
593	B	E	B	E
596	D	E	E	E
595	B	E	D	E
1043	B	E	C	E
1044	B	E	C	E
618	B	E	B	D
579	B	E	B	E
579	A	E	B	E
414	A	E	B	E
589	B	E	B	C
583	C	E	B	B
584	B	E	B	E
619	C	E	C	E
620	D	D	B	E
581	D	E	B	E
582	C	E	C	E
585	A	E	C	E
584	B	E	D	E
1045	B	E	B	E
587	A	E	B	E
662	B	E	C	E
663	C	E	E	E
664	B	C	B	C
587	B	E	B	E
573	A	C	A	B
569	A	E	A	E
571	E	E	E	E
1046	A	E	E	E
574	A	E	A	E
572	A	E	B	E
588	C	E	E	E
561	A	E	A	E
577	B	E	B	B
578	A	E	A	A
562	C	E	A	E
563	B	E	A	E
565	C	E	B	E
564	A	E	A	E
566	A	E	A	E
549	A	E	B	E
567	A	E	B	E
621	B	E	B	E
1047	E	E	E	E
551	E	E	E	E
552	E	E	E	E
554	B	D	C	E
553	B	C	E	D
622	E	E	E	E
555	B	D	A	D
557	B	E	A	D
556	B	E	A	B
576	A	E	A	B
558	A	C	C	E
701	E	E	E	E
702	E	E	E	E
703	E	E	E	E
530	E	E	E	E
704	E	E	E	E
665	E	E	E	E
539	B	B	D	D
546	A	D	B	B
540	C	E	B	D
542	A	E	B	B
544	A	E	E	E
541	B	E	E	D
543	A	E	C	E
545	A	E	B	E
547	A	E	E	E
548	A	E	E	E
1007	B	E	B	B
531	A	E	B	E
623	B	E	A	B
533	A	E	E	E
534	A	E	D	E
535	B	E	B	E
536	A	E	B	E
537	A	E	A	D
538	A	E	B	D
666	E	E	C	E
988	E	E	C	B
989	D	E	E	D
990	E	E	E	C
955	A	E	B	B
705	D	E	E	E
706	A	E	E	E
707	E	E	E	E
708	E	C	E	E
709	E	E	C	E
1048	A	E	B	E
1049	A	E	B	E
1050	B	E	E	E
1051	A	E	A	C
1052	B	E	E	E
1005	E	E	D	E
624	C	E	B	E
625	B	E	A	E
626	B	E	B	D
627	B	E	A	B
956	A	E	C	B
710	B	E	A	E
711	C	E	E	E
712	B	E	B	E
713	B	E	E	E
1006	E	E	B	C
628	C	E	B	E
629	B	C	A	B
957	A	C	B	B
958	A	C	B	B
959	A	B	B	B
1053	A	E	B	E
1090	A	E	A	E
1091	A	E	B	D
630	C	E	B	E
714	B	E	B	E
715	B	C	E	D
716	B	E	B	B
717	B	B	B	B
718	E	D	E	E
719	B	E	E	E
631	A	E	A	E
632	D	E	B	E
720	B	C	B	E
721	B	E	B	E
1009	E	E	E	B
1011	B	E	B	B
1012	B	D	B	B
726	D	E	E	E
727	D	C	E	E
728	B	B	E	E
729	B	C	B	C
730	B	B	C	B
731	B	C	B	B
732	E	D	E	E
733	E	E	E	E
734	B	C	E	E
735	B	C	E	D
736	B	B	B	B
737	B	D	C	B
738	E	E	E	B
739	E	E	E	E
740	E	E	E	E
741	E	E	C	E
742	E	E	E	E
743	E	E	E	E
744	E	E	E	E
745	E	E	E	E
746	E	E	E	E
747	E	E	E	E
748	C	E	B	E
749	C	E	B	E
750	E	E	B	E
751	B	E	C	E
752	E	E	E	E
753	B	B	B	B
754	E	E	E	E
755	E	E	E	E
756	E	E	B	E
757	E	E	E	E
758	B	E	A	E
759	E	E	E	E
760	B	E	B	E
761	E	E	E	E
762	E	E	E	E
763	B	E	C	E
764	E	E	E	E
765	E	E	E	E
766	B	E	B	A
767	E	E	E	E
768	D	E	E	E
769	E	E	E	E
770	B	E	A	E
771	C	E	E	E
772	E	E	E	D
773	B	E	B	B
774	B	E	B	B
775	E	E	E	E
776	E	E	E	E
777	E	E	E	D
778	C	E	E	E
779	E	E	E	E
780	E	E	C	E
781	E	E	E	E
782	E	E	E	E
783	D	E	B	E
784	E	E	E	E
785	E	E	E	E
786	E	E	E	E
787	E	E	E	E
788	E	E	E	E
789	E	E	B	E
790	E	E	E	E
791	E	E	E	E
792	E	E	B	E
793	E	E	E	E
794	C	D	B	D
795	B	E	B	E
796	D	E	A	C
797	B	E	B	E
798	B	E	E	E
799	B	E	B	E
800	B	E	B	E
801	C	E	B	E
802	E	E	E	E
803	E	E	B	E
804	E	E	E	E
805	E	E	E	C
806	B	E	B	B
807	E	E	E	C
808	E	E	E	E
809	E	E	E	B
810	E	E	E	E
811	E	E	E	E
812	D	E	B	D
813	E	E	E	B
814	E	E	E	E
815	D	E	E	E
816	E	E	E	C
817	E	E	E	E
818	E	E	E	E
819	E	E	E	E
820	E	E	E	D
821	B	B	B	B
822	D	C	E	B
823	B	D	D	B
824	A	B	B	A
825	A	C	D	B
826	A	E	B	B
827	B	B	B	B
828	E	E	E	E
829	A	E	E	E
830	B	E	E	E
831	E	E	E	E
832	B	E	E	E
833	A	E	A	E
834	B	E	E	E
835	E	E	E	E
836	E	E	E	E
837	E	E	E	E
383	A	E	E	E
839	E	E	E	E
840	C	E	E	E
841	E	E	E	E
842	B	D	E	E
843	A	E	A	E
844	A	E	E	E
845	A	E	B	E
846	B	E	B	E
847	E	E	E	E
848	A	E	D	E
849	A	E	E	E
850	B	E	E	E
851	E	E	E	E
667	E	E	E	E
668	C	E	C	E
669	B	E	B	E
670	B	E	B	E
671	B	E	D	D
633	D	E	B	E
634	A	E	B	E
1013	A	C	B	B
1008	B	E	B	B
635	A	D	C	E
636	A	E	A	E
637	B	E	B	E
960	A	E	B	B
961	B	E	C	C
991	C	D	C	C
992	B	B	A	B
993	B	E	A	C
962	A	E	B	E
963	A	D	B	C
964	A	E	C	D
672	E	E	E	E
673	C	D	C	E
674	B	E	B	E
675	B	E	B	E
1092	A	E	E	E
1093	A	E	B	C
1094	A	C	E	E
1095	A	E	E	E
1096	B	E	B	C
1097	B	C	B	E
1098	B	E	B	B
638	D	E	E	E
994	E	E	E	E
639	A	E	B	E
995	C	E	E	D
996	E	E	E	E
997	E	E	E	E
965	A	E	B	C
966	B	E	C	E
967	A	E	A	D
968	A	E	E	E
1010	B	E	B	C
1099	A	E	B	E
1100	A	E	D	E
1101	A	E	C	C
1102	A	D	E	E
1103	A	D	B	E
1104	A	E	E	E
1105	A	E	E	E
1106	B	E	E	E
1104	A	E	B	D
1108	A	C	C	C
1127	E	E	E	E
1128	B	E	B	B
1109	A	C	B	A
722	A	E	B	A
1054/1055	B	E	E	E
1056/1057	A	E	B	E
1058/1059	A	E	B	E
1060/1061	A	E	E	E
1062/1063	A	E	B	E
1064/1065	A	E	B	E
640	B	E	B	E
641	B	E	B	E
642	B	E	A	B
853	E	E	E	E
854	E	E	E	E
855	E	E	E	E
856	E	E	E	E
857	E	E	E	E
858	E	E	E	E
859	C	B	E	B
860	C	E	E	E
861	E	E	E	E
862	E	E	E	E
863	B	E	B	E
864	B	E	E	E
865	C	E	B	E
866	B	E	C	E
867	D	E	B	E
723	B	B	B	D
134	A	B	B	A
676	B	E	B	B
677	A	E	B	C
1110	C	E	A	E
1111	A	E	A	E
1112	A	E	B	D
1113	B	B	C	E
1114	B	D	B	D
1115	A	E	B	E
1116	C	E	B	E
1117	A	E	E	E
1066	C	E	E	E
1067	A	E	E	E
1068	A	E	E	E
868	E	E	E	B
869	D	E	E	C
870	E	E	E	E
871	E	E	E	C
872	B	E	E	B
873	E	E	E	E
874	E	E	E	E
875	C	E	E	D
876	E	E	E	D
877	E	E	E	B
878	E	E	E	D
879	E	E	E	D
880	C	E	E	E
881	B	E	E	B
882	B	E	C	B
883	E	E	E	E
884	A	C	E	B
885	A	C	E	B
886	A	B	B	A
887	A	E	B	C
888	A	E	C	A
889	B	E	E	B
890	D	E	E	E
891	A	B	C	B
892	B	E	B	D
893	E	E	E	E
894	B	E	E	D
895	B	E	B	B
896	C	E	E	C
897	E	E	E	C
898	E	E	E	E
899	B	E	B	B
900	A	C	B	B
901	B	E	B	B
902	E	E	E	E
903	E	E	E	E
904	C	E	B	D
905	B	E	E	B
906	B	E	E	E
907	E	E	E	E
678	B	E	B	B
643	B	E	E	E
644	B	E	E	D
724	B	E	B	B
645	E	E	E	E
1069	A	E	E	E
1070	B	E	E	E
1071	D	E	D	B
679	D	E	B	E
1125	B	E	A	A
1126	C	E	A	B

[0689]

TABLE 4
Compound Number	PDGFRB-1	Tek-1	ErbB2-2
1021	ND	E	ND
1024	ND	E	ND
1025	ND	E	ND
970	C	E	ND
36	A	D	ND
182	E	ND	ND
11	ND	E	ND
12	ND	E	ND
13	ND	E	ND
14	ND	E	ND
15	ND	E	ND
18	ND	E	ND
19	ND	E	ND
61	A	ND	ND
926	A	D	ND
29	B	E	ND
27	E	ND	ND
852	D	ND	C
63	B	E	ND
62	ND	E	ND
65	A	E	ND
64	D	E	B
67	B	E	ND
66	E	C	ND
68	B	E	ND
927	ND	E	ND
70	A	E	ND
928	A	E	A
232	ND	E	ND
77	A	E	ND
76	ND	E	ND
72	A	E	B
75	E	E	ND
74	ND	E	ND
33	D	E	ND
78	A	E	ND
79	B	E	ND
80	ND	E	ND
81	ND	E	ND
82	A	E	ND
83	A	D	A
289	A	B	E
86	B	E	B
85	A	E	ND
88	ND	E	ND
87	A	E	A
90	A	E	ND
89	A	E	ND
91	A	E	B
92	B	C	ND
93	ND	E	ND
94	B	E	ND
95	ND	E	ND
96	B	E	A
97	A	E	E
98	E	E	A
99	B	E	ND
100	ND	E	ND
101	ND	D	ND
102	C	C	B
154	ND	E	ND
155	ND	E	ND
207	E	E	ND
251	E	E	ND
22	ND	D	ND
156	D	E	B
157	ND	C	ND
158	ND	C	ND
159	ND	C	ND
160	ND	E	ND
161	ND	C	ND
252	B	E	ND
256	ND	E	ND
103	ND	E	ND
104	B	E	B
105	ND	E	ND
106	A	E	ND
220	ND	E	ND
107	B	E	ND
108	B	E	ND
109	E	E	C
110	A	E	A
929	E	E	ND
111	ND	E	ND
114	E	E	ND
113	ND	E	ND
116	E	E	ND
115	E	E	ND
118	ND	E	ND
41	B	D	ND
117	ND	E	ND
119	A	E	ND
285	E	E	E
299	ND	C	ND
286	B	B	ND
184	A	E	ND
255	ND	E	ND
185	A	E	E
922	B	B	ND
186	A	D	ND
208	ND	E	ND
121	A	E	ND
123	A	D	ND
125	A	E	ND
127	A	E	ND
120	A	C	B
170	E	C	ND
171	ND	E	ND
287	E	E	ND
222	ND	E	ND
51	ND	B	ND
212	ND	E	ND
250	ND	E	ND
200	B	E	ND
218	ND	E	ND
187	E	E	ND
930	A	E	B
931	A	D	B
932	ND	C	ND
935	A	E	ND
1030	B	E	ND
174	ND	E	ND
175	A	B	ND
972	A	D	ND
609	A	D	ND
936	A	E	ND
937	A	E	ND
938	B	E	ND
135	A	C	A
226	ND	D	ND
973	ND	E	ND
291	ND	D	ND
292/293	B	C	B
294/295	C	D	D
296/297	A	B	ND
178	C	C	A
302	E	E	ND
300	A	D	ND
303	ND	B	ND
304	A	E	B
305	A	E	ND
196	A	E	ND
298	A	B	ND
306	A	E	ND
974	E	E	ND
56	E	E	ND
310	ND	E	ND
309	ND	E	ND
311	E	E	ND
312	ND	E	ND
313	B	E	ND
238	B	E	ND
239	E	E	ND
198	A	E	ND
237	E	E	ND
240	A	E	ND
314	B	B	ND
315	B	E	ND
316	A	E	ND
317	ND	D	ND
318	A	C	ND
308	A	C	ND
320	E	E	ND
319	E	E	ND
321	B	E	B
322	ND	E	ND
323	A	E	ND
324	E	B	ND
328	B	C	ND
325	A	E	ND
337	B	E	ND
336	A	E	ND
335	D	E	ND
334	B	E	ND
339	A	E	ND
340	D	D	ND
342	B	E	ND
341	A	E	ND
344	C	E	ND
353	A	E	ND
364	C	E	ND
366	ND	E	ND
365	C	E	ND
367	E	D	ND
368	ND	E	ND
369	ND	E	ND
180	D	E	ND
372	ND	E	ND
373	ND	B	ND
371	A	E	E
374	B	B	ND
375	ND	E	ND
376	A	B	C
378	B	D	ND
377	A	D	ND
379	ND	E	ND
380	A	E	ND
383	ND	C	ND
384	A	E	ND
386	B	E	ND
385	A	E	ND
387	A	E	ND
388	B	E	ND
389	ND	E	ND
390	B	C	ND
394	B	E	ND
396	B	B	ND
395	B	B	ND
397	A	E	ND
398	ND	D	ND
399	ND	E	ND
400	E	E	ND
402	ND	E	ND
401	A	B	ND
403	A	E	ND
404	A	E	ND
406	B	E	ND
405	ND	E	ND
407	A	E	ND
412	C	E	ND
411	A	E	ND
413	A	E	ND
414	A	E	E
416	A	E	ND
415	A	E	ND
417	A	E	ND
418	ND	D	ND
422	ND	D	ND
425	B	E	ND
427	ND	E	ND
428	B	E	B
202	A	C	ND
429	A	D	ND
430	B	B	ND
432	ND	E	ND
431	ND	C	ND
437	A	C	ND
438	ND	B	ND
439	A	B	ND
440	B	C	ND
441	A	E	ND
442	ND	E	ND
443	B	E	ND
444	ND	E	ND
445	A	D	ND
462	ND	C	ND
464	ND	E	ND
463	A	E	ND
465	ND	E	ND
466	A	D	ND
467	ND	C	ND
473	ND	E	D
474	B	B	B
476	ND	E	C
478	ND	B	ND
479	C	E	C
480	ND	B	ND
483	ND	B	ND
492	ND	C	ND
491	ND	B	ND
493	ND	C	ND
494	ND	E	ND
495	ND	E	ND
923	ND	E	ND
497	ND	E	ND
498	A	D	B
504	ND	B	ND
505	ND	C	ND
506	ND	C	ND
508	ND	C	ND
507	ND	D	ND
509	B	D	C
510	C	E	E
511	A	D	D
512	A	E	C
513	A	E	D
514	A	E	E
515	A	D	E
516	D	E	E
517	B	C	C
518	E	D	B
519	A	E	E
520	E	E	E
522	C	D	D
521	ND	E	B
523	E	E	D
524	ND	E	C
526	ND	B	ND
525	ND	C	ND
528	ND	B	ND
977	E	E	B
978	E	E	B
979	ND	E	ND
980	ND	E	ND
610	A	C	B
689	ND	C	ND
1031	A	E	B
1033	A	E	D
1034	ND	E	ND
1035	ND	E	ND
1036	A	C	B
1037	E	E	E
700	B	B	ND
646	ND	E	ND
611	ND	C	ND
230	ND	D	ND
612	B	B	B
940	ND	E	ND
941	ND	E	ND
942	A	E	E
943	A	D	E
944	B	E	E
1000	ND	E	C
1001	ND	E	B
1002	ND	E	ND
1003	ND	B	ND
945	ND	E	ND
946	A	E	E
947	ND	E	ND
948	ND	E	ND
949	A	E	E
981	B	B	B
982	ND	B	ND
983	B	C	E
984	ND	E	ND
1075	ND	E	ND
1076	A	E	E
1077	A	E	E
1078	ND	E	ND
647	ND	E	ND
1038	ND	E	ND
177	A	B	A
690	ND	E	ND
648	ND	E	ND
649	B	C	ND
650	B	D	ND
651	B	C	ND
652	B	B	C
691	A	E	E
985	ND	C	ND
986	ND	D	ND
613	A	E	A
614	B	D	B
950	A	C	B
1082	B	B	E
653	ND	E	ND
654	B	B	B
655	B	C	B
656	B	B	C
657	C	B	B
615	E	E	E
658	E	E	E
951	A	C	E
952	B	C	C
692	A	B	A
693	ND	E	ND
694	ND	D	ND
695	ND	C	ND
696	ND	E	ND
697	A	D	B
698	ND	D	ND
699	A	D	A
616	A	B	B
1004	B	B	B
1083	B	B	E
1084	B	E	E
1085	B	E	E
953	A	B	B
954	E	E	C
1086	E	D	D
1087	C	E	E
1088	A	E	E
1089	A	E	E
1040	A	E	C
1041	A	B	A
659	E	ND	E
660	E	ND	C
661	E	ND	E
599	B	ND	C
600	B	ND	C
601	B	ND	B
602	B	ND	B
604	B	ND	B
603	B	ND	A
617	B	ND	E
606	B	ND	D
605	A	ND	E
598	E	ND	D
597	C	ND	B
607	B	ND	B
559	A	ND	A
592	A	ND	B
591	A	ND	C
1042	A	ND	E
593	B	ND	C
596	C	ND	B
595	D	ND	B
1043	C	ND	B
1044	D	ND	B
618	B	ND	C
579	E	ND	C
579	E	ND	A
414	A	ND	E
589	E	ND	C
583	B	ND	E
584	E	ND	C
619	E	ND	D
620	E	ND	D
581	C	ND	E
582	E	ND	B
585	B	ND	C
584	E	ND	B
1045	B	ND	E
587	B	ND	B
662	E	ND	C
663	E	ND	E
664	D	ND	B
587	E	ND	C
573	B	ND	C
569	A	ND	E
571	E	ND	C
1046	E	ND	E
574	A	ND	E
572	A	ND	D
588	B	ND	B
561	A	ND	E
577	B	ND	D
578	B	ND	B
562	C	ND	C
563	B	ND	B
565	B	ND	E
564	A	ND	E
566	B	ND	A
549	A	ND	B
567	B	ND	C
621	B	ND	A
1047	E	ND	E
551	E	ND	E
552	E	ND	E
554	D	ND	C
553	B	ND	B
622	D	ND	C
555	B	ND	B
557	A	ND	A
556	A	ND	A
576	E	ND	E
558	B	ND	D
701	E	ND	E
702	E	ND	E
703	E	ND	D
530	E	ND	E
704	E	ND	E
665	E	ND	B
539	D	ND	B
546	B	ND	C
540	D	ND	B
542	B	ND	B
544	B	ND	E
541	B	ND	A
543	B	ND	B
545	A	ND	D
547	E	ND	E
548	E	ND	E
1007	E	ND	B
531	A	ND	A
623	A	ND	B
533	B	ND	E
534	B	ND	E
535	C	ND	A
536	B	ND	B
537	B	ND	B
538	B	ND	B
666	D	ND	B
988	E	ND	B
989	E	ND	E
990	E	ND	E
955	B	ND	B
705	E	ND	B
706	C	ND	A
707	E	ND	E
708	E	ND	E
709	C	ND	B
1048	D	ND	B
1049	B	ND	E
1050	B	ND	C
1051	B	ND	B
1052	C	ND	C
1005	E	ND	E
624	B	ND	A
625	A	ND	A
626	B	ND	E
627	A	ND	B
956	C	ND	E
710	B	ND	A
711	E	ND	E
712	B	ND	A
713	E	ND	E
1006	E	ND	C
628	B	ND	E
629	A	ND	B
957	A	ND	A
958	B	ND	B
959	B	ND	C
1053	A	ND	E
1090	A	ND	E
1091	A	ND	B
630	B	ND	C
714	B	ND	A
715	B	ND	B
716	A	ND	A
717	A	ND	B
718	C	ND	E
719	E	ND	C
631	A	ND	B
632	B	ND	B
720	B	ND	A
721	B	ND	B
1009	D	ND	E
1011	B	ND	B
1012	B	ND	C
726	E	ND	E
727	E	ND	E
728	E	ND	E
729	B	ND	B
730	B	ND	B
731	B	ND	A
732	E	ND	E
733	E	ND	E
734	E	ND	C
735	E	ND	B
736	B	ND	B
737	C	ND	B
738	E	ND	C
739	E	ND	E
740	E	ND	E
741	C	ND	B
742	E	ND	E
743	E	ND	E
744	E	ND	E
745	E	ND	E
746	E	ND	E
747	E	ND	E
748	B	ND	B
749	B	ND	B
750	E	ND	C
751	B	ND	E
752	E	ND	E
753	B	ND	B
754	E	ND	E
755	E	ND	E
756	B	ND	E
757	E	ND	E
758	A	ND	A
759	E	ND	E
760	B	ND	B
761	E	ND	E
762	E	ND	E
763	C	ND	B
764	A	ND	E
765	E	ND	E
766	B	ND	B
767	E	ND	E
768	E	ND	D
769	E	ND	E
770	A	ND	A
771	E	ND	E
772	D	ND	E
773	A	ND	B
774	A	ND	A
775	E	ND	E
776	E	ND	E
777	E	ND	E
778	E	ND	C
779	E	ND	E
780	D	ND	E
781	B	ND	E
782	C	ND	E
783	C	ND	C
784	E	ND	E
785	E	ND	E
786	E	ND	E
787	E	ND	E
788	D	ND	E
789	C	ND	ND
790	D	ND	B
791	E	ND	C
792	E	ND	C
793	E	ND	ND
794	B	ND	B
795	A	ND	A
796	B	ND	C
797	C	ND	B
798	B	ND	E
799	B	ND	B
800	E	ND	B
801	B	ND	D
802	B	ND	E
803	E	ND	C
804	D	ND	E
805	E	ND	E
806	E	ND	B
807	E	ND	B
808	B	ND	E
809	D	ND	D
810	E	ND	E
811	E	ND	E
812	E	ND	C
813	B	ND	E
814	B	ND	E
815	B	ND	B
816	A	ND	C
817	B	ND	B
818	B	ND	E
819	B	ND	E
820	E	ND	E
821	B	ND	B
822	B	ND	C
823	B	ND	C
824	A	ND	A
825	B	ND	B
826	B	ND	B
827	B	ND	A
828	E	ND	E
829	B	ND	B
830	E	ND	E
831	A	ND	E
832	E	ND	E
833	A	ND	E
834	A	ND	E
835	E	ND	E
836	E	ND	E
837	E	ND	E
383	A	ND	C
839	C	ND	B
840	B	ND	B
841	E	ND	E
842	C	ND	D
843	A	ND	D
844	B	ND	B
845	B	ND	C
846	B	ND	C
847	E	ND	E
848	A	ND	E
849	B	ND	B
850	E	ND	E
851	E	ND	E
667	E	ND	B
668	D	ND	A
669	B	ND	A
670	B	ND	A
671	B	ND	A
633	C	ND	B
634	D	ND	B
1013	A	ND	B
1008	E	ND	E
635	B	ND	A
636	A	ND	B
637	C	ND	C
960	D	ND	C
961	D	ND	A
991	B	ND	B
992	B	ND	B
993	B	ND	B
962	A	ND	D
963	A	ND	B
964	A	ND	C
672	C	ND	D
673	B	ND	C
674	B	ND	B
675	B	ND	A
1092	A	ND	E
1093	A	ND	E
1094	A	ND	C
1095	A	ND	E
1096	A	ND	E
1097	A	ND	E
1098	B	ND	E
638	B	ND	D
994	E	ND	E
639	A	ND	C
995	B	ND	E
996	E	ND	E
997	E	ND	E
965	A	ND	B
966	A	ND	E
967	A	ND	B
968	A	ND	C
1010	B	ND	B
1099	A	ND	B
1100	A	ND	B
1101	A	ND	E
1102	A	ND	E
1103	A	ND	D
1104	A	ND	E
1105	A	ND	E
1106	B	ND	E
1104	A	ND	B
1108	A	ND	E
1127	E	ND	E
1128	E	ND	B
1109	A	ND	B
722	B	ND	B
1054/1055	ND	ND	E
1056/1057	ND	ND	B
1058/1059	ND	ND	E
1060/1061	ND	ND	E
1062/1063	ND	ND	C
1064/1065	ND	ND	E
640	ND	ND	A
641	ND	ND	B
642	ND	ND	B
856	ND	ND	B
857	ND	ND	C
858	ND	ND	E
859	ND	ND	B
860	ND	ND	D
861	ND	ND	C
862	ND	ND	E
863	ND	ND	C
864	ND	ND	E
865	ND	ND	B
723	ND	ND	A
134	ND	ND	B
676	ND	ND	A
677	ND	ND	A
1110	ND	ND	E
1111	ND	ND	C
1112	ND	ND	B
1113	ND	ND	B
1067	ND	ND	B
1068	ND	ND	C
868	B	ND	E
869	B	ND	D
870	E	ND	E
871	D	ND	E
872	B	ND	B
873	E	ND	E
874	E	ND	E
875	B	ND	B
876	E	ND	B
877	B	ND	E
878	B	ND	E
879	B	ND	E
880	B	ND	C
881	B	ND	B
882	B	ND	B
883	C	ND	E
884	A	ND	B
885	B	ND	B
886	E	ND	B
887	B	ND	B
888	B	ND	B
889	B	ND	B
890	B	ND	E
891	A	ND	A
892	A	ND	B
893	B	ND	E
894	A	ND	E
895	A	ND	C
896	A	ND	B
897	A	ND	E
898	D	ND	E
899	A	ND	B
900	B	ND	A
901	A	ND	B
902	E	ND	B
903	C	ND	C
904	B	ND	B
905	B	ND	B
906	E	ND	B
907	E	ND	B
678	A	ND	A
643	A	ND	B
644	B	ND	E
724	B	ND	B
645	E	ND	A
1069	A	ND	A
1070	B	ND	E
1071	B	ND	E
679	D	ND	C
1125	B	ND	B
1126	B	ND	B

[0690]

TABLE 5
Compound Number	EPHB4-1	ErbB4-1	FGFR1-1	Flt-1	Fyn-1
970	E	ND	E	C	D
36	D	ND	E	A	E
182	ND	ND	E	E	ND
61	A	E	E	A	A
926	E	E	B	B	C
29	E	B	A	A	A
27	E	ND	B	A	B
28	B	ND	ND	ND	B
852	E	E	E	E	E
62	E	E	ND	ND	ND
40	E	ND	ND	ND	ND
39	E	ND	ND	ND	ND
65	C	E	E	B	E
64	B	E	E	E	B
67	C	ND	E	D	D
66	D	ND	E	E	E
69	E	ND	ND	ND	ND
68	B	E	E	A	E
927	E	ND	ND	ND	ND
70	B	B	B	A	E
928	A	B	B	A	E
232	E	ND	ND	ND	E
1118	E	ND	ND	ND	ND
77	B	ND	B	B	B
73	E	ND	ND	ND	ND
76	B	ND	ND	ND	B
72	B	B	A	A	ND
75	A	E	D	E	B
74	A	E	ND	ND	E
33	E	ND	C	E	C
78	A	B	A	A	A
79	A	B	C	B	B
80	E	ND	ND	ND	ND
81	E	ND	ND	ND	ND
82	B	ND	B	A	ND
83	B	B	A	A	A
289	B	E	A	A	B
86	E	B	E	E	D
85	B	B	A	A	A
88	B	ND	ND	ND	B
87	E	D	C	D	B
90	B	ND	B	B	A
89	E	ND	E	A	B
91	C	ND	C	A	A
92	C	ND	C	C	E
93	E	ND	ND	ND	ND
94	B	B	E	D	A
95	D	ND	ND	ND	B
96	E	B	E	D	D
97	E	E	C	C	C
98	E	E	C	E	B
99	A	ND	B	B	B
100	B	ND	ND	ND	ND
101	E	ND	ND	ND	B
102	A	A	B	A	A
154	D	ND	ND	ND	ND
155	E	ND	ND	ND	ND
207	E	ND	E	B	ND
251	E	ND	E	D	E
22	E	ND	ND	ND	ND
156	E	C	B	C	C
157	B	E	ND	ND	ND
158	B	ND	ND	ND	ND
159	C	E	ND	ND	ND
253	E	ND	ND	ND	E
221	B	ND	ND	ND	ND
252	B	ND	B	A	B
256	E	ND	ND	ND	ND
103	B	ND	ND	ND	ND
104	A	ND	E	B	B
105	E	ND	ND	ND	ND
106	B	C	B	A	ND
220	E	ND	ND	ND	ND
107	B	C	B	A	A
108	E	D	B	E	B
109	E	E	ND	ND	ND
110	D	B	A	A	A
929	E	B	E	E	ND
111	E	E	ND	ND	ND
114	E	ND	E	E	ND
113	C	ND	ND	ND	ND
116	E	E	E	E	E
115	D	E	C	B	C
118	B	E	ND	ND	ND
41	B	E	C	B	B
117	D	ND	ND	ND	ND
119	E	B	B	A	A
285	E	E	D	E	E
299	E	ND	ND	ND	ND
286	C	ND	A	A	E
184	C	ND	C	A	B
255	E	ND	ND	ND	ND
185	E	E	E	B	E
922	C	A	B	C	B
186	E	E	E	B	E
208	E	ND	ND	ND	ND
121	E	B	B	A	A
123	E	B	B	A	B
125	E	D	B	A	B
127	D	B	B	A	A
120	B	B	B	B	B
170	C	D	E	E	E
171	C	E	ND	ND	ND
287	E	E	B	E	E
222	E	ND	ND	ND	ND
51	B	C	ND	ND	ND
212	E	ND	ND	ND	ND
250	E	B	ND	ND	ND
200	E	C	D	E	E
218	E	ND	ND	ND	ND
187	E	C	E	E	E
930	C	B	C	C	A
931	B	B	B	A	A
932	E	B	ND	ND	ND
933	C	B	ND	ND	ND
934	B	E	ND	ND	ND
935	B	B	B	B	A
1030	B	E	C	B	B
174	E	ND	ND	ND	ND
175	B	E	E	C	B
972	B	B	B	B	B
609	E	E	A	A	A
936	A	B	B	B	A
937	B	C	E	D	B
938	E	C	B	B	E
135	A	C	B	E	A
226	E	ND	ND	ND	ND
973	C	ND	ND	ND	ND
291	D	ND	ND	ND	ND
292	B	E	D	B	C
294	B	E	E	E	E
296	A	D	B	B	C
178	C	E	D	D	B
302	E	E	B	E	E
300	B	B	C	E	B
303	D	ND	ND	ND	ND
304	B	A	B	B	A
305	B	B	B	B	A
196	E	E	C	B	E
298	B	B	A	A	B
306	B	E	B	B	B
974	E	E	C	E	E
56	E	E	C	C	E
310	E	ND	ND	ND	ND
309	E	ND	ND	ND	ND
311	E	E	E	E	E
312	E	ND	ND	ND	ND
313	B	A	B	C	B
238	E	E	E	E	E
239	E	E	E	E	E
198	E	E	E	B	E
237	D	E	C	D	E
240	E	E	C	B	B
314	E	B	C	B	B
315	E	B	E	E	E
316	D	E	E	D	D
317	C	ND	ND	ND	ND
318	A	A	B	A	A
308	A	B	A	A	A
320	E	E	E	E	E
319	E	E	E	E	E
321	E	E	E	E	E
322	E	ND	ND	ND	ND
323	E	ND	E	C	E
324	E	ND	A	A	E
328	E	ND	B	A	C
325	E	B	E	A	C
338	C	ND	ND	ND	ND
337	B	B	A	A	B
336	E	E	A	A	E
335	B	E	D	B	E
334	C	E	B	B	E
332	B	ND	ND	ND	ND
330	C	ND	ND	ND	ND
339	E	E	E	E	E
340	B	B	B	A	B
342	B	B	A	A	B
341	B	E	A	A	E
344	B	E	A	C	E
343	B	ND	ND	ND	ND
353	E	E	B	A	D
364	B	E	B	B	E
366	B	ND	ND	ND	ND
365	B	C	B	B	B
367	B	E	C	B	B
368	E	ND	ND	ND	ND
369	E	ND	ND	ND	ND
180	E	E	E	E	C
372	E	ND	ND	ND	ND
373	E	ND	ND	ND	ND
371	A	E	A	A	A
374	A	B	A	B	B
375	E	ND	ND	ND	ND
376	D	D	A	A	B
378	E	E	A	B	C
377	B	E	A	A	E
379	E	ND	ND	ND	ND
380	E	B	A	A	B
382	E	ND	ND	ND	ND
381	B	ND	ND	ND	ND
383	E	ND	ND	ND	ND
384	B	E	B	E	B
386	E	E	A	A	E
385	E	E	A	A	E
387	E	E	B	A	E
388	E	E	C	E	E
390	E	D	C	B	B
394	C	E	B	A	B
396	B	B	A	A	B
395	E	E	A	A	C
397	ND	E	A	A	E
400	ND	E	E	B	E
401	ND	B	A	A	B
403	ND	E	A	B	B
404	ND	E	A	A	B
406	ND	E	A	C	B
407	ND	E	A	A	A
412	ND	E	E	E	E
411	ND	E	A	B	E
413	ND	E	A	B	B
414	ND	E	A	A	B
416	ND	E	A	B	D
415	ND	E	A	B	E
417	ND	E	A	B	C
425	ND	E	C	E	D
428	ND	B	C	E	B
202	ND	B	A	A	A
429	ND	B	A	A	B
430	ND	B	A	B	B
437	ND	B	A	B	B
439	ND	B	A	A	B
440	ND	B	B	B	B
441	ND	E	E	B	B
443	ND	B	B	B	C
445	ND	E	A	A	B
463	ND	E	A	A	A
466	ND	E	A	A	B
479	ND	D	B	B	E
498	ND	B	A	B	A
509	ND	B	B	B	E
510	ND	E	B	B	E
511	ND	B	A	A	E
512	ND	B	A	B	E
513	ND	C	A	A	D
514	ND	E	A	A	E
515	ND	E	A	B	E
516	ND	E	A	C	E
517	ND	E	B	A	C
518	ND	E	E	E	C
519	ND	E	A	B	E
610	ND	B	A	A	B
1031	ND	E	B	E	E
1033	ND	B	A	A	A
1036	ND	C	A	A	B
1037	ND	E	B	C	E
612	ND	B	A	A	B
942	ND	E	A	A	E
943	ND	D	B	B	E
944	ND	E	B	B	E
946	ND	E	A	B	E
949	ND	B	A	A	E
1076	ND	E	B	B	B
1077	ND	E	A	A	E
177	ND	A	C	B	A
652	ND	E	A	B	E
613	ND	B	B	E	E
950	ND	B	A	A	B
1082	ND	B	E	E	E
655	ND	C	B	A	E
656	ND	C	B	B	D
951	ND	E	A	E	E
952	ND	E	B	B	C
616	ND	B	B	B	B
1084	ND	E	E	E	E
953	ND	B	B	B	A
1086	ND	E	E	C	E
1087	ND	E	D	E	E
1088	ND	E	A	E	E
1089	ND	E	E	E	B
1040	ND	C	B	B	B
1041	ND	B	B	C	B
600	ND	B	E	E	B
602	ND	B	E	E	B
603	ND	D	B	B	B
606	ND	E	B	C	E
605	ND	E	A	B	E
607	ND	B	B	D	B
559	ND	A	B	E	A
592	ND	C	A	B	B
591	ND	D	A	A	A
1042	ND	E	A	B	E
579	ND	A	B	B	E
582	ND	E	B	E	E
585	ND	E	A	B	E
587	ND	B	A	B	E

[0691]

TABLE 6
Compound Number	Hck-1	Lyn-1	Ret-1	Src-1
970	E	E	E	E
36	E	E	E	E
61	E	A	E	A
926	E	B	D	B
29	E	A	A	A
27	E	B	B	B
28	E	B	ND	B
852	E	E	C	E
65	E	B	B	B
64	E	A	E	A
67	E	A	E	B
66	E	B	E	A
68	E	A	B	A
70	E	B	B	A
928	E	A	A	A
232	E	E	ND	E
77	E	A	B	B
76	E	B	ND	A
72	ND	ND	A	ND
75	E	A	E	B
74	E	A	ND	B
33	E	B	E	B
78	B	A	A	A
79	E	A	E	A
82	ND	ND	B	ND
83	B	A	A	A
289	E	C	B	B
86	E	E	B	B
85	E	A	B	A
88	D	B	ND	B
87	E	B	B	B
90	B	A	B	B
89	E	B	B	C
91	E	B	B	B
92	E	B	E	D
94	E	A	E	B
95	E	C	ND	E
96	D	B	C	C
97	E	B	B	E
98	E	B	E	E
99	D	D	B	B
101	E	C	ND	B
102	C	A	B	A
251	E	B	E	E
156	E	C	E	E
253	E	E	ND	A
221	ND	ND	ND	ND
252	E	A	E	A
104	E	E	E	C
106	ND	ND	B	ND
107	D	A	B	A
108	E	A	ND	B
110	C	A	B	A
929	ND	ND	C	ND
114	ND	ND	B	ND
116	E	E	E	E
115	E	C	B	C
41	E	A	A	B
119	E	B	A	B
285	E	E	C	E
286	E	E	A	D
184	E	B	E	B
185	E	E	E	E
922	E	A	B	B
186	E	D	E	E
121	E	A	A	A
123	C	A	A	A
125	D	A	B	A
127	B	A	A	A
120	B	A	A	B
170	E	E	ND	E
287	E	E	E	E
200	E	E	E	E
187	E	E	E	E
930	C	A	B	A
931	B	A	A	A
935	C	A	ND	A
1030	E	B	A	B
175	E	C	C	B
972	E	A	ND	B
609	E	A	A	A
936	C	A	ND	A
937	E	A	A	B
938	E	E	E	E
135	E	A	B	A
292	E	B	B	B
294	E	E	B	E
296	E	B	A	B
178	E	A	C	B
302	E	E	E	E
300	E	A	B	A
304	C	A	A	A
305	C	A	A	A
196	E	C	E	E
298	B	A	A	B
306	D	A	A	B
974	E	C	E	E
56	E	B	E	E
311	E	E	E	E
313	C	A	B	A
238	E	E	E	E
239	E	E	E	E
198	E	E	E	E
237	E	C	C	E
240	E	B	C	D
314	C	A	E	B
315	E	E	E	E
316	E	B	B	D
318	B	A	A	A
308	B	A	A	A
320	E	E	E	E
319	E	E	E	E
321	E	A	B	B
323	E	E	E	E
324	E	E	A	E
328	C	B	B	B
325	E	D	E	E
337	E	B	A	B
336	E	B	A	E
335	E	B	A	C
334	E	E	B	E
219	ND	ND	ND	ND
339	E	E	A	E
340	E	B	A	E
342	C	B	A	E
341	E	E	A	E
344	E	E	B	E
353	E	E	A	E
364	E	D	B	E
365	E	A	ND	B
367	E	B	ND	B
180	E	B	ND	E
371	E	A	ND	B
374	D	A	ND	A
376	E	A	ND	E
378	E	B	ND	C
377	E	E	ND	E
379	ND	ND	ND	ND
380	E	B	ND	E
384	E	A	ND	E
386	E	E	ND	E
385	E	B	ND	E
387	E	B	ND	E
388	E	B	ND	E
390	E	B	ND	C
394	E	A	ND	B
396	C	B	ND	E
395	E	D	ND	D
397	E	E	ND	E
400	E	E	ND	E
401	B	B	ND	B
403	E	A	ND	B
404	D	B	ND	C
406	E	B	ND	E
407	E	A	ND	A
412	E	A	ND	E
411	E	B	ND	B
413	E	B	ND	B
414	E	E	ND	E
416	E	B	ND	C
415	E	E	ND	E
417	E	B	ND	B
425	E	A	ND	B
428	E	A	ND	B
202	E	A	ND	A
429	E	A	ND	A
430	E	B	ND	B
437	D	B	ND	B
439	B	B	ND	B
440	C	C	ND	E
441	E	E	ND	E
443	E	B	ND	C
445	E	B	ND	B
463	E	B	ND	B
466	E	A	ND	B
479	E	D	B	E
498	E	A	A	A
509	E	B	A	E
510	E	E	B	E
511	E	B	A	E
512	E	A	A	E
513	E	B	A	D
514	E	E	A	E
515	E	E	A	E
516	E	E	A	E
517	E	D	C	E
518	E	B	D	E
519	E	D	A	E
610	E	A	A	B
1031	E	B	B	C
1033	E	A	A	B
1036	E	A	A	B
1037	E	E	B	E
612	D	B	B	B
942	E	A	A	E
943	E	B	A	E
944	E	C	A	E
946	E	A	B	E
949	E	B	A	E
1076	E	E	A	B
1077	E	B	A	D
177	B	A	A	A
652	E	B	A	B
613	E	C	B	E
950	E	A	A	B
1082	E	C	A	E
655	E	C	A	C
656	C	C	B	C
951	E	E	A	E
952	D	A	A	D
616	C	B	A	A
1084	E	A	A	E
953	B	A	B	A
1086	E	E	D	E
1087	E	E	B	E
1088	E	E	A	E
1089	E	A	A	B
1040	E	E	C	B
1041	B	A	B	A
600	E	A	B	B
602	E	B	E	B
603	D	B	A	B
606	E	C	B	E
605	E	B	A	E
607	B	A	A	B
559	C	A	A	A
592	E	B	A	B
591	B	B	A	A
1042	ND	E	A	E
579	ND	C	A	E
582	ND	E	C	E
585	ND	E	A	E
587	ND	B	A	E
The Tables herein utilize the following designations:
A < 0.4 ug/mL
B > 0.4 and < 2.4 ug/mL
C > 2.4 and < 3.5 ug/mL
D > 3.5 and < 4.5 ug/mL
E > 4.5 ug/mL
ND—Not Determined

[0692] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the products and processes of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. A compound having the formula:

2. The compound of claim 1 wherein, R1 is independently R3; and R2 is independently NHR3.

3. The compound of claim 1 wherein, R1 is independently heteroaryl optionally substituted with 1-4 independent R4 on each ring; and R2 is independently NHR3.

4. The compound of claim 1 wherein, R1 is independently phenyl optionally substituted with 1-5 independent R4; and R2 is independently NHR3.

5. The compound of claim 1 wherein, Each R1 and R2 is independently NHR3.

6. The compound of claim 1 wherein, R1 is independently NHR5; and R2 is independently NHR3.

7. The compound of claim 1 wherein, R1 is independently NHR6; and R2 is independently NHR3.

8. The compound of claim 1 wherein, R1 is independently OR5; and R2 is independently NHR3.

9. The compound of claim 1 wherein, R1 is independently SR5; and R2 is independently NHR3.

10. The compound of claim 1 wherein: R2 is independently NHR3; and R1 is one of the following groups: 1425

11. The compound of claim 1 wherein, R1 is independently heterocyclyl optionally substituted with 1-4 independent R4 on each ring, wherein said heterocyclyl is not unsubstituted piperidine; and R2 is independently NHR3.

12. The compound of claim 1 wherein, Each R1 is independently heteroaryl substituted with 1-4 independent R4 on each ring, wherein said heteroaryl comprises at least one nitrogen heteroatom and said heteroaryl is attached at said nitrogen heteroatom; and Each R2 is independently NHR3.

13. The compound of claim 1 wherein, Each R1 is independently heterocyclyl substituted with 1-4 independent R4 on each ring, wherein said heterocyclyl is not unsubstituted piperidine, and said heterocyclyl comprises at least one nitrogen heteroatom and said heterocyclyl is attached at said nitrogen heteroatom; and Each R2 is independently NHR3.

14. The compound of claim 1 wherein, Each R2 is independently NHR3; and Each R1 is independently of the formula: 1426

15. The compound of claim 1 wherein, Each R2 is independently NHR3; and Each R1 is independently of the formula: 1427

16. The compound of claim 1 wherein, Each R2 is independently NHR3; and Each R1 is independently of the formula: 1428

17. The compound of claim 1 wherein, Each R2 is independently NHR3; and Each R1 is independently of the formula: 1429

18. The compound of claim 1 wherein, Each R1 is independently one of the following groups: 1430wherein m is 0, 1, 2, 3 or 4.

19. The compound of claim 1 wherein, Each R1 is independently 1431wherein m is 0, 1, 2, 3 or 4.

20. The compound of claim 1 wherein, Each R1 is independently one of the following: 1432wherein the groups are as defined in claim 1.

21. The compound of claim 1 wherein, Each R1 is independently 1433wherein R19 is independently H or C1-C6 alkyl.

22. A composition comprising a compound of any of claims 1-21 and a pharmaceutically acceptable carrier.

23. The composition of claim 22, further comprising at least one additional therapeutic agent.

24. A method of treating kinase-mediated disease or disease symptoms in a mammal comprising administration of a composition comprising a compound of any of claims 1-21.

25. A method of inhibiting kinase activity in a mammal comprising administration of a composition comprising a compound of any of claims 1-21.

26. A method of treating disease or disease symptoms in a mammal comprising administration of a composition comprising a compound of any of claims 1-21.

27. A method of inhibiting angiogenesis or vasculogenesis activity in a mammal comprising administration of a composition comprising a compound of any of claims 1-21.

28. A method of making a pharmaceutically useful composition comprising combining a compound of any of claims 1-21 with one or more pharmaceutically acceptable carriers.

29. The method of claim 28, further comprising combining an additional therapeutic agent.

30. A method of making a compound of claim 1 of the formula

31. A method of making a compound of claim 1 comprising reacting a triazine of one or more of the formulae: