CROSS-REFERENCE TO RELATED APPLICATION 0001 This application claims the benefit of U.S. Provisional Patent Application No. 60/137,810, filed Jun. 4, 1999.

FIELD OF THE INVENTION 0002 This invention is directed to diaminothiazole compounds that modulate and/or inhibit the activity of certain protein kinases, and to pharmaceutical compositions containing such compounds. The invention is also directed to the therapeutic or prophylactic use of such compounds and compositions, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, by administering effective amounts of such compounds.

BACKGROUND OF THE INVENTION 0003 Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxy group of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation dramatically perturbs the function of the protein, and thus protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolisim, cell proliferation, cell differentiation, and cell survival. Of the many different cellular functions in which the activity of protein kinases is known to be required, some processes represent attractive targets for therapeutic intervention for certain disease states. Two examples are angiogenesis and cell-cycle control, in which protein kinases play a pivotal role; these processes are essential for the growth of solid tumors as well as for other diseases. 0004 Angiogenesis is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is fairly limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. See Merenmies et al., Cell Growth & Differentiation, 8, 3-10 (1997). On the other hand, unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (solid tumors). Folkman, Nature Med., 1, 27-31 (1995). Protein kinases which have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family: VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK-1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2). 0005 VEGF-R2, which is expressed only on endothelial cells, binds the potent angiogenic growth factor VEGF and mediates the subsequent signal transduction through activation of its intracellular kinase activity. Thus, it is expected that direct inhibition of the kinase activity of VEGF-R2 will result in the reduction of angiogenesis even in the presence of exogenous VEGF (see Strawn et al., Cancer Research, 56, 3540-3545 (1996)), as has been shown with mutants of VEGF-R2 which fail to mediate signal transduction. Millauer et al., Cancer Research, 56, 1615-1620 (1996). Furthermore, VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF. Therefore, a selective inhibitor of the kinase activity of VEGF-R2 would be expected to exhibit little toxicity. 0006 Similarly, FGF-R binds the angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction. Recently, it has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). Unlike VEGF-R2, however, FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. Nonetheless, systemic administration of a small-molecule inhibitor of the kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. Mohammadi et al., EMBO Journal, 17, 5896-5904 (1998). 0007 TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only on endothelial cells which has been shown to play a role in angiogenesis. The binding of the factor angiopoietin-1 results in autophosphorylation of the kinase domain of TEK and results in a signal transduction process which appears to mediate the interaction of endothelial cells with peri-endothelial support cells, thereby facilitating the maturation of newly formed blood vessels. The factor angiopoietin-2, on the other hand, appears to antagonize the action of angiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997). 0008 As a result of the above-described developments, it has been proposed to treat angiogenesis by the use of compounds inhibiting the kinase activity of VEGF-R2, FGF-R, and/or TEK For example, WIPO International Publication No. WO 97/34876 discloses certain cinnoline derivatives that are inhibitors of VEGF-R2, which may be used for the treatment of disease states associated with abnormal angiogenesis and/or increased vascular permeability such as cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restinosis, autoimmune diseases, acute inflammation and ocular diseases with retinal vessel proliferation. 0009 In addition to its role in angiogenesis, protein kinases also play a crucial role in cell-cycle control. Uncontrolled cell proliferation is the insignia of cancer. Cell proliferation in response to various stimuli is manifested by a de-regulation of the cell division cycle, the process by which cells multiply and divide. Tumor cells typically have damage to the genes that directly or indirectly regulate progression through the cell division cycle. 0010 Cyclin-dependent kinases (CDKs) are serine-threonine protein kinases that play critical roles in regulating the transitions between different phases of the cell cycle. See, e.g., the articles compiled in Science, 274, 1643-1677 (1996). CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific phases of the cell cycle. 0011 It is CDK4 complexed to the D cyclins that plays a critical part in initiating the cell-division cycle from a resting or quiescent stage to one in which cells become committed to cell division. This progression is subject to a variety of growth regulatory mechanisms, both negative and positive. Aberrations in this control system, particularly those that affect the function of CDK4, have been implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, particularly familial melanomas, esophageal carcinomas, and pancreatic cancers. See, e.g., Kamb, Trends in Genetics, 11, 136-140 (1995); Kamb et al., Science, 264, 436-440 (1994). 0012 The use of compounds as anti-proliferative therapeutic agents that inhibit CDKs is the subject of several patent publications. For example, U.S. Pat. No. 5,621,082 to Xiong et al. discloses nucleic acid encoding an inhibitor of CDK6, and European Patent Publication No. 0 666 270 A2 describes peptides and peptide mimetics that act as inhibitors of CDK1 and CDK2. WIPO International Publication No. WO 97/16447 discloses certain analogs of chromones that are inhibitors of cyclin-dependent kinases, in particular of CDK/cyclin complexes such as CDK4/cyclin D1, which may be used for inhibiting excessive or abnormal cell proliferation, and therefore for treating cancer. WIPO International Publication No. WO 99/21845 describes 4-aminothiazole derivatives that are useful as CDK inhibitors. 0013 There is still a need, however, for small-molecule compounds that may be readily synthesized and are effective in inhibiting one or more CDKs or CDK/cyclin complexes. Because CDK4 may serve as a general activator of cell division in most cells, and complexes of CDK4 and D-type cyclins govern the early G1 phase of the cell cycle, there is a need for effective inhibitors of CDK4, and D-type cyclin complexes thereof, for treating one or more types of tumors. Also, the pivotal roles of cyclin E/CDK2 and cyclin B/CDK1 kinases in the G1/S phase and G2/M transitions, respectively, offer additional targets for therapeutic intervention in suppressing deregulated cell-cycle progression in cancer. 0014 Another protein kinase, CHK1, plays an important role as a checkpoint in cell-cycle progression. Checkpoints are control systems that coordinate cell-cycle progression by influencing the formation, activation and subsequent inactivation of the cyclin-dependent kinases. Checkpoints prevent cell-cycle progression at inappropriate times, maintain the metabolic balance of cells while the cell is arrested, and in some instances can induce apoptosis (programmed cell death) when the requirements of the checkpoint have not been met. See, e.g., O'Connor, Cancer Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997); Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al., Science, 246, 629-634 (1989). 0015 One series of checkpoints monitors the integrity of the genome and, upon sensing DNA damage, these DNA damage checkpoints block cell-cycle progression in G1 and G2 phases, and slow progression through S phase. O'Connor, Cancer Surveys, 29, 151-182 (1997); Hartwell et al., Science, 266, 1821-1828 (1994). This action enables DNA repair processes to complete their tasks before replication of the genome and subsequent separation of this genetic material into new daughter cells takes place. Importantly, the most commonly mutated gene in human cancer, the p53 tumor-suppressor gene, produces a DNA damage checkpoint protein that blocks cell-cycle progression in G1 phase and/or induces apoptosis (programmed cell death) following DNA damage. Hartwell et al., Science, 266, 1821-1828 (1994). The p53 tumor suppressor has also been shown to strengthen the action of a DNA damage checkpoint in G2 phase of the cell cycle. See, e.g., Bunz et al., Science, 282, 1497-1501 (1998); Winters et al., Oncogene, 17, 673-684 (1998); Thompson, Oncogene, 15, 3025-3035 (1997). 0016 Given the pivotal nature of the p53 tumor suppressor pathway in human cancer, therapeutic interventions that exploit vulnerabilities in p53-defective cancer have been actively sought. One emerging vulnerability lies in the operation of the G2 checkpoint in p53 defective cancer cells. Cancer cells, because they lack G1 checkpoint control, are particularly vulnerable to abrogation of the last remaining barrier protecting them from the cancer-killing effects of DNA-damaging agents: the G2 checkpoint. The G2 checkpoint is regulated by a control system that has been conserved from yeast to humans. Important in this conserved system is a kinase, CHK1, which transduces signals from the DNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2 kinase, which promotes mitotic entry. See, e.g., Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997). Inactivation of CHK1 has been shown to both abrogate G2 arrest induced by DNA damage inflicted by either anticancer agents or endogenous DNA damage, as well as result in preferential killing of the resulting checkpoint defective cells. See, e.g., Nurse, Cell, 91, 865-867 (1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell, 5, 147-160 (1994). 0017 Selective manipulation of checkpoint control in cancer cells could afford broad utilization in cancer chemotherapeutic and radiotherapy regimens and may, in addition, offer a common hallmark of human cancer genomic instability to be exploited as the selective basis for the destruction of cancer cells. A number of factors place CHK1 as a pivotal target in DNA-damage checkpoint control. The elucidation of inhibitors of this and functionally related kinases such as Cds1/CHK2, a kinase recently discovered to cooperate with CHK1 in regulating S phase progression (see Zeng et al., Nature, 395, 507-510 (1998); Matsuoka, Science, 282, 1893-1897 (1998)), could provide valuable new therapeutic entities for the treatment of cancer. 0018 Integrin receptor binding to ECM initiates intracellular signals mediated by FAK (Focal Adhesion Kinase) that are involved in cell motility, cellular proliferation, and survival. In human cancers, FAK overexpression is implicated in tumorigenesis and metastatic potential through its role in integrin mediated signaling pathways. 0019 Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). At least one of the non-receptor protein tyrosine kinases, namely, LCK, is believed to mediate the transduction in T-cells of a signal from the interaction of a cell-surface protein (Cd4) with a cross-linked anti-Cd4 antibody. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8, 2025-2031 (1993), which is incorporated herein by reference 0020 In addition to the protein kinases identified above, many other protein kinases have been considered to be therapeutic targets, and numerous publications disclose inhibitors of kinase activity, as reviewed in the following: McMahon et al, Oncologist, 5, 3-10 (2000); Holash et al., Oncogene, 18, 5356-62 (1999); Thomas et al., J. Biol. Chem., 274, 36684-92 (1999); Cohen, Curr. Op. Chem. Biol., 3, 459-65 (1999); Klohs et al., Curr. Op. Chem. Biol., 10, 544-49 (1999); McMahon et al., Current Opinion in Drug Discovery & Development, 1, 131-146 (1998); Strawn et al., Exp. Opin. Invest. Drugs, 7, 553-573 (1998). WIPO International Publication WO 00/18761 discloses certain substituted 3-cyanoquinolines as protein kinase inhibitors. As is understood by those skilled in the art, it is desirable for kinase inhibitors to possess both high affinity for the target kinase as well as high selectivity versus other protein kinases.

SUMMARY OF THE INVENTION 0021 The present invention relates to compounds falling within formula I below which modulate and/or inhibit the activity of protein kinases, as well as to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof (such compounds, prodrugs, metabolites and salts are collectively referred to as agents). The invention is also directed to pharmaceutical compositions containing such agents and their therapeutic use in treating diseases mediated by kinase activity, such as cancer, as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis and psoriasis. Further, the invention is related to methods of modulating and/or inhibiting the kinase activity associated with VEGF-R, FGF-R, CDK complexes, TEK, CHK1, LCK, and FAK. 0022 In one general aspect, the invention relates to protein kinase inhibitors of the Formula I: 1

0023 wherein: 0024 R1 is hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or a group of the formula R6CO or R6CS where R6 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, or NR7R8 where R7R8 are each independently hydrogen or substituted or unsubstituted alkyl, aryl, or heteroaryl; 0025 R2 is hydroxy, halo, cyano, or nitro, or substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or 0026 a group of the formula (A) 2

0027 where Ra is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or 0028 a group of the formula (B) 3

0029 where Ra is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or 0030 a group of the formula (C) 4

0031 where Rb and Rc are independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or 0032 a group of the formula (D) 5

0033 where Rd is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, or acylamino, and Re is hydrogen, alkyl, cycloalkyl heterocycloalkyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino, or 0034 a group of the formula (E) 6

0035 where Rf is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or 0036 a group of the formula (F) 7

0037 where Rg and Rh are each independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or 0038 a group of the formula (G) 8

0039 where Ri is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a group of formula (A), formula (B), formula (C), formula (H), or formula (I) as defined herein, or 0040 a group of the formula (H) 9

0041 where Rj is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, or a group of formula (A), formula (B), formula (C) or formula (D) as defined herein, and Rk is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a group of formula (A), formula (B), formula (C), formula (D), formula (E), or formula (F) as defined herein, or 0042 a group of the formula (I) 10

0043 where R1 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a group of formula (C) as defined herein, 0044 or R2 is a substituted or unsubstituted cycloalkyl, heterocycloalkyl, or aryl that is fused to Q; 0045 X is C or N; and 0046 Q is a divalent radical having 2 or 3 ring atoms (in the ring formed by Q together with X, C* and N* in Formula I) each independently selected from C, N, O, S, CR5and NR5, where R5is alkyl, aryl, heteroaryl, alkoxy, hydroxy, halo, cyano, or amino, which together with C* and N* (in Formula I) form a five- or six-membered aromatic or nonaromatic ring. 0047 The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula I. 0048 In a preferred general embodiment, the invention relates to compounds having the Formula II: 11

0049 wherein: 0050 R1 is substituted or unsubstituted aryl or heteroaryl, or a group of the formula R6CO or R6CS where R6 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl alkenyl, aryl, heteroaryl, alkoxy, or NR7R8 where R7R8 are each independently hydrogen or a substituted or unsubstituted alkyl, aryl, or heteroaryl; 0051 R2 is as defined above; 0052 X is C or N; and 0053 Y and Z are each independently C, N, S, O, CR5 or NR5 where R5 is as defined above; 0054 and pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof. Advantageous methods of making the compounds of the Formula II are also described. 0055 More preferably, the invention is directed to compounds of Formula II wherein: R1 is substituted or unsubstituted aryl or heteroaryl, or R6CO or R6CS where R6 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, alkenyl, aryl, heteroaryl, alkoxy, or NR7R8 where R7R8 are each independently hydrogen or substituted or unsubstituted alkyl, aryl, or heteroaryl; R2 is substituted or unsubstituted aryl or heteroaryl; X and Y are each independently C or N; and Z is S or O. In another preferred embodiment of compounds of the Formula II, R1 and R2 are each independently substituted aryl, X is C, Y is C or N, and Z is S or O. More preferably, R1 is a substituted or unsubstituted alkyl, R2 is a substituted aryl, X is C, Y is C or N, and Z is S or O. 0056 In another preferred general embodiment, the invention relates to compounds of Formula III: 12

0057 wherein: 0058 R1 is substituted or unsubstituted aryl or heteroaryl, or R6CO or R6CS where R6 is a substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl, alkoxy, or NR7R8 where R7R8 are each independently hydrogen, alkyl, aryl, or heteroaryl; 0059 R3 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, or NR7R8 where R7R8 are each independently hydrogen, alkyl, aryl, or heteroaryl; 0060 R4 is hydrogen, hydroxy, lower alkyl, halo, lower alkoxy, amino, nitro, or trifluoromethyl; and 0061 Y and Z are each independently C, N, S, O, CR5 or NR5 where R5 is unsubstituted or substituted alkyl or aryl; 0062 as well as pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof. 0063 Especially preferred are compounds of Formula IV: 13

0064 wherein: 0065 R1 is substituted or unsubstituted aryl or heteroaryl, or R6CO where R6 is a substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl, alkoxy, cycloalkyl, heterocycloalkyl, or NR7R8 where R7R8 are each independently hydrogen, alkyl, aryl, or heteroaryl; 0066 R3 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, or NR7R8 where R7R8 are each independently hydrogen, alkyl, aryl, or heteroaryl; 0067 R4 is independently selected from hydrogen, hydroxy, lower alkyl, halo, lower alkoxy, amino, nitro, and trifluoromethyl; 0068 Y is C or N; and 0069 Z is S or O; 0070 as well as pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof. 0071 More preferably, the invention is directed to compounds of Formula IV, wherein: 0072 R1 is substituted or unsubstituted aryl or heteroaryl, or R6CO where R6 is NR7R8 where R7R8 are each independently hydrogen, alkyl, aryl, or heteroaryl; R3 is substituted or unsubstituted alkyl, aryl, heteroaryl, or alkoxy; R4(a) and R4(b) are independently hydrogen, lower alkyl, or halo; Y is C or N; and Z is S or O. Even more preferred are compounds of Formula IV, wherein: R1 is substituted or unsubstituted aryl or heteroaryl, or R6CO where R6 is NR7R8 where R7R8 are each independently hydrogen, alkyl, aryl, or heteroaryl; R3 is substituted or unsubstituted aryl, heteroaryl, or alkoxy; R4(a) is chloro, fluoro, or methyl; R4(b) is fluoro; Y is N; and Z is O. 0073 The invention also relates to a method of modulating and/or inhibiting the kinase activity of VEGF-R, FGF-R, TEK, a CDK complex, CHK1, TEK, LCK, and/or FAK by administering a compound of the formula I or a pharmaceutically acceptable prodrug, pharmaceutically active metabolites, or pharmaceutically acceptable salt thereof. There is also provided compounds of the present invention that have selective kinase activityi.e., they possess significant activity against one specific kinase while possessing less or minimal activity against a different kinase. In one preferred embodiment of the invention, compounds of the present invention are those of Formula I possessing substantially higher potency against VEGF receptor tyrosine kinase than against FGF-R1 receptor tyrosine kinase. The invention is also directed to methods of modulating VEGF receptor tyrosine kinase activity without significantly modulating FGF receptor tyrosine kinase activity. 0074 The invention also relates to pharmaceutical compositions each comprising: an effective amount of an agent selected from compounds of Formula I and pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs thereof; and a pharmaceutically acceptable carrier or vehicle for such agent. The invention further provides methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, comprising administering effective amounts of such agents to a patient in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 0075 The inventive compounds of the Formula I, II, III, and IV are useful for mediating the activity of protein kinases. More particularly, the compounds are useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases. 0076 The term alkyl as used herein refers to straight- and branched-chain alkyl groups having one to twelve carbon atoms. Exemplary alkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. The term lower alkyl designates an alkyl having from 1 to 8 carbon atoms (a C1-8-alkyl). Suitable substituted alkyls include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like. 0077 The term alkenyl refers to straight- and branched-chain alkenyl groups having from two to twelve carbon atoms. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like. 0078 The term cycloalkyl refers to partially saturated or unsaturated carbocycles having from three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. 0079 A heterocycloalkyl is intended to mean a partially saturated or unsaturated monocyclic radical containing carbon atoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur. 0080 The terms aryl (Ar) and heteroaryl refer to monocyclic and polycyclic unsaturated or aromatic ring structures, with aryl referring to those that are carbocycles and heteroaryl referring to those that are heterocycles. Examples of aromatic ring structures include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl), and the like. Such moieties may be optionally substituted by one or more suitable substituents, for example, a substituent selected from a halogen (F, Cl, Br or I); lower alkyl; OH; NO2; CN; CO2H; O-lower alkyl; aryl; aryl-lower alkyl; CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3; and the like. Such moieties may also be optionally substituted by a fused-ring structure or bridge, for example OCH2O. 0081 The term alkoxy is intended to mean the radical O-alkyl. Illustrative examples include methoxy, ethoxy, propoxy, and the like. The term lower alkoxy designates an alkoxy having from 1 to 8 carbon atoms 0082 The term aryloxy represents O-aryl, where aryl is defined above. 0083 The term halogen represents chlorine, fluorine, bromine or iodine. The term halo represents chloro, fluoro, bromo or iodo. 0084 In general, the various moieties or functional groups for variables in the formulae may be optionally substituted by one or more suitable substituents. Exemplary substituents include a halogen (F, Cl, Br, or I), lower alkyl, OH, NO2, CN, CO2H, O-lower alkyl, -aryl, -aryl-lower alkyl, CO2CH3, CONH2, OCH2CONH2, NH2, SO2NH2, haloalkyl (e.g., CF3, CH2CF3), O-haloalkyl (e.g., OCF3, OCHF2), and the like. 0085 The terms comprising and including are used in an open, non-limiting sense. 0086 Compounds of the invention are encompassed by Formula I. Although Formula I depicts a double bond between C* and N*, the artisan will understand that when Q together with C* and N* form a five- or six-membered aromatic ring, the presence of the double bond is not necessarily between C* and N*, as other canonical forms of the aromatic ring exist. It is therefore understood that all possible canonical forms of the aromatic ring formed by Q together with C* and N* are also intended to be covered by Formula I. The compounds of the invention are preferably those of the Formula II, more preferably those of the Formula III, and even more preferably those of the Formula IV. 0087 Some of the inventive compounds may exist as single stereoisomers (i.e., essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds that are optically active are used in optically pure form. 0088 As generally understood by those skilled in the art, an optically pure compound having one chiral center (i.e., one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric excess (e.e.) or diastereomeric excess (d.e.)), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.). 0089 Additionally, the formulas are intended to cover solvated as well as unsolvated forms of the identified structures. For example, Formula I includes compounds of the indicated structure in both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. 0090 In addition to compounds of the Formula I, II, III, and IV, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds. 0091 A pharmaceutically acceptable prodrug is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound. 0092 A pharmaceutically active metabolite is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. 0093 A pharmaceutically acceptable salt is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, -hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. 0094 If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydrozy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. 0095 If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. 0096 In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas. 0097 Therapeutically effective amounts of the agents of the invention may be used to treat diseases mediated by modulation or regulation of protein kinases. An effective amount is intended to mean that amount of an agent that, when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease mediated by the activity of one or more protein kinases, such as tryosine kinases. Thus, e.g., a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of one or more protein kinases such that a disease condition which is mediated by that activity is reduced or alleviated. The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Treating is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of one or more protein kinases, such as tyrosine kinases, and includes: preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition. 0098 The inventive agents may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. 0099 In one general synthetic process, compounds of Formula I are prepared according to the following reaction scheme: 14

0100 A solution of an isothiocyanate, e.g., R1NCS and cyanamide is reacted with 1.1 to 1.5 molar equivalents of 1,8-diazabicylclo5.4.0undec-7-ene (DBU) in a suitable solvent, such as acetonitrile, at an appropriate temperature (preferably room temperature) for approximately 40-80 minutes, generating intermediate V. Without isolation, intermediate V is further allowed to react with a compound of Formula VI, where LG is a suitable leaving group such as chloro, bromo, or mesyloxy, under the same conditions for an additional 0.5 to 24 hours (h) to yield a compound of Formula VII. 0101 In some instances, the compound of Formula VII is not isolated, but is directly converted to the compound of Formula I by continued reaction at a temperature between room temperature and 80 C., preferably 50 C., for 1 to 24 h. Conventional work-up and purification yields final compound I. Alternatively, a compound of Formula VII is isolated and purified, and then is converted to a compound of Formula I by treatment with a suitable base, such as potassium t-butoxide, lithium hexamethyldisilazide, or lithium diisopropylamide, in an appropriate solvent, such as THF, for 0.5 to 24 h at a temperature between 78 C. and room temperature. Various compounds of Formula VI are commercially available or known, for example, 2-(chloromethyl)benzimidazole, 2-(chloromethyl)quinoline, 2-picolyl chloride, 2-acetamido-4-(chloromethyl)thiazole, 6-(chloromethyl)-2-isopropylpyrimidin-4-ol, 4-chloromethyl-2-(4-chlorophenyl)thiazole, 3-(chloromethyl)-1,2,4-oxadiazole, 3-(chloromethyl)-5-(3,5-dimethylisoxazol-4-yl)-1,2,4-oxadiazole, 3-bromomethyl-6,7-dimethoxy-1-methyl-2(1h)-quinoxalinone, 2-chloromethyl-5-methoxybenzimidazole, 5-(tert-butyl)-3-(chloromethyl)-1,2,4-oxadiazole, 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, 3-(chloromethyl)-5-(3-thienyl)-1,2,4-oxadiazole, 5-4-(chloromethyl)-1,3-thiazol-2-ylisoxazole, 5-(chloromethyl)-3-3,5-di(trifluoromethyl)styryl-1,2,4-oxadiazole, 5-chloro-4-(chloromethyl)-1,2,3-thiadiazole, 5-(chloromethyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole, 3-chloro-2-(chloromethyl)-5-(trifluoromethyl)pyridine, 5-(chloromethyl)-3-(2-pyridylsulfonyl)methyl-1,2,4-oxadiazole, 3-(chloromethyl)-5-methylisoxazole, 2-chloromethyl-4,6-dimethoxypyrimidine, 3-(chloromethyl)-5-(4-chlorophenyl)-4H-1,2,4-triazole, 2-(chloromethyl)-5-(4-chlorophenyl)-1,3,4-oxadiazole, 4-chloromethyl-5-methyl-2-phenyl-oxazole, 3-(chloromethyl)-1-(3,5-dichlorophenyl)-5-methyl-1h-pyrazole, and 3-(chloromethyl)-5-(1,2,3-thiadiazol-4-yl)-1,2,4-oxadiazole. Compounds of Formula VI may also be prepared by methods known to those skilled in the art. See, e.g., Mylari et al., J. Med. Chem., 35, 457-465 (1992); Baiocchi et al., Heterocyclic Chem., 16, 1469-1474 (1979), which are incorporated by reference herein. 0102 A compound of Formula VIII may be prepared by conventional acylation of 3-aminobenzonitrile, followed by heating at 60-100 C. with hydroxylamine in a suitable solvent, such as ethanol or isopropanol, for 1 to 24 hours. A compound of Formula VI(a) may be prepared by treatment of a compound of Formula VIII with chloroacetyl chloride and a suitable base, such as diispropylethylamine (DIEA), in an appropriate solvent, such as dichloromethane. Conventional aqueous work-up provides a crude intermediate, which is further heated at 100 C. in a suitable solvent, such as dioxane, for 0.5 to 4 hours, to yield, after conventional isolation and purification, a compound of Formula VI(a). 15

0103 Compounds of Formula II, where X is C and Y and Z are independently C, N, or O, may also be prepared by the above described general procedure. To an R1-isothiocyanate solution in acetonitrile is added cyanamide, followed by the addition of DBU, while maintaining the internal temperature of the reaction at approximately 15-30 C. After stirring 1-2 hours, a suitable reactant that allows for the cyclization and formation as described above of a compound of Formula II is added in the presence of a catalytic amount of tetra-butylammonium iodide. For example, the reaction of 3-chloromethyl-5-R2-1,2,4oxadiazole (VI(a)) with compound VII for about two hours at approximately 50 C. provides after purification the cyclized compound II(a). 16

0104 Inventive compounds of Formulas II, III, and IV may also be prepared by other processes, including the general procedure shown in the following reaction scheme. 17

0105 A compound of Formula II, where X and Y are C and Z is S, may be prepared by adding DBU to a solution of R1-isothiocyanato and cyanamide in a suitable solvent at an appropriate temperature, preferably acetonitrile at room temperature for approximately 40-80 minutes. To this reaction mixture is added bromo-acetonitrile and additional DBU, to yield, after conventional work-up and purification, an intermediate 2-R1-amino-4-amino-thiazole-5-carbonitrile intermediate IX. The reaction of intermediate IX with dihydrogen sulfide in triethylamine/pyridine at about 0 C. provides intermediate X. Intermediate X is converted to a compound II(b) by stirring a solution of compound X and 2-bromo-1-R2-ethanone in methanol overnight at room temperature. After removal of the methanol, the crude compound II(b) is worked up using conventional isolation techniques and purified using silica column chromatography. 0106 Compounds of Formula II(c) may also be prepared directly from compound X by reacting it with a -bromo-acetic acid ester or a -bromolactone under the same conditions as described in the preparation of compounds II(b). 18

0107 By treating compound IX with a suitable 2-amino-alcohol and a catalytic amount of ZnCl2, a compound of Formula II(d) is produced after standard acid work-up and purification by silica chromatography. Compounds of Formula II(e) may also be prepared from compounds IX by refluxing in a suitable aprotic solvent, such as toluene, a solution of IX, TMSN3, and a catalytic amount of Bu2SnO. After refluxing, the solvent is removed and the residue is redissolved in ethyl acetate, washed with a appropriate aqueous acid solution, and dried over a suitable drying agent. After the removal of the solvent, the residue is triturated in ethyl ether and compound II(e) is collected by filtration. 19

0108 Compounds of Formula III may also be prepared directly from compound II(b) where R2 is 3-nitrophenyl by reducing the nitro group with a suitable reducing agent to form the amino substituted phenyl (II(f)). Preferably, a solution of compound II(b) where R2 is 3-nitrophenyl and stannous chloride is dissolved in dimethylformamide (DMF) under inert atmosphere conditions and stirred at between 40-60 C. until II(f) is formed. 0109 The intermediate II(f) may be reacted with a suitable acylating agent under standard acylating conditions to form a compound of the Formula III(a). A preferable acylating procedure involves dissolving compound II(f) in DMF and tetrahydrofuran (THF) and adding pyridine and a suitable acid chloride or acyl chloroformate at 30 to 0 C. The reaction is quenched with a proton source (e.g., methanol) and purified by preparative C-18 reverse phase HPLC to provide compound III(a). 20

0110 Other compounds of Formula I may be prepared in manners analogous to the general procedures described above or the detailed procedures described in the examples herein. The affinity of the compounds of the invention for a receptor may be enhanced by providing multiple copies of the ligand in close proximity, preferably using a scaffolding provided by a carrier moiety. It has been shown that provision of such multiple valence compounds with optimal spacing between the moieties dramatically improves binding to a receptor. See for example, Lee et al., Biochem, 23, 4255 (1984). The multivalency and spacing can be controlled by selection of a suitable carrier moiety or linker units. Such moieties include molecular supports which contain a multiplicity of functional groups that can be reacted with functional groups associated with the compounds of the invention. Of course, a variety of carriers can be used, including proteins such as BSA or HAS, a multiplicity of peptides including, for example, pentapeptides, decapeptides, pentadecapeptides, and the like. The peptides or proteins can contain the desired number of amino acid residues having free amino groups in their side chains; however, other functional groups, such as sulfhydryl groups or hydroxyl groups, can also be used to obtain stable linkages. 0111 Compounds that potently regulate, modulate, or inhibit the protein kinase activity associated with receptors, FGF, CDK complexes, TEK, CHK1, LCK, and FAK, among others, and which inhibit angiogenesis and/or cellular profileration is desirable and is one preferred embodiment of the present invention. The present invention is further directed to methods of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an inventive agent. The activity of the inventive compounds as modulators of protein kinase activity, such as the activity of kinases, may be measured by any of the methods available to those skilled in the art, including in vivo and/or in vitro assays. Examples of suitable assays for activity measurements include those described in Parast C. et al., BioChemistry, 37, 16788-16801 (1998); Jeffrey et al., Nature, 376, 313-320 (Jul. 27, 1995); WIPO International Publication No. WO 97/34876; and WIPO International Publication No. WO 96/14843. These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below. 0112 The active agents of the invention may be formulated into pharmaceutical compositions as described below. Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I, II, III or IV and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of protein kinases. By efficacious levels is meant levels in which the effects of protein kinases are, at a minimum, regulated. These compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g., parenteral or oral administration. 0113 An inventive agent is administered in conventional dosage form prepared by combining a therapeutically effective amount of an agent (e.g., a compound of Formula I) as an active ingredient with appropriate pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. 0114 The pharmaceutical carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like. 0115 A variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. 0116 To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, gylcerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution. 0117 It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated. Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent. For oral administration, an exemplary daily dose generally employed is from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Administration of prodrugs are typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form. 0118 The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e.g., using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. 0119 Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. 0120 For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. 0121 Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents. 0122 Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. 0123 For administration intranasally or by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. 0124 The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. 0125 Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. 0126 For administration to the eye, a compound of the Formula I, II, III, or IV is delivered in a pharmaceutically acceptable ophthalmic vehicle such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, including, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, vegetable oil, or an encapsulating material. A compound of the invention may also be injected directly into the vitreous and aqueous humor. 0127 Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g, containing conventional suppository bases such as cocoa butter or other glycerides. 0128 In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously, intramuscularly, or intraocularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. 0129 A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) cotains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose. 0130 Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. 0131 The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. 0132 Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counter ions. Pharmaceutically compatible salts may be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free-base forms. 0133 The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other protein kinase inhibitors of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

EXAMPLES 0134 In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further purification unless otherwise indicated. Tetrahydrofuran (THF) and N,N-dimethylforamide (DMF) were purchased from Aldrich in Sure seal bottles and used as received. All solvents were purified using standard methods readily known to those skilled in the art, unless otherwise indicated. 0135 The reactions set forth below were done generally under a positive pressure of nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed on glass-backed silica gel 60 F 254 plates Analtech (0.25 mm) and eluted with the appropriate solvent ratios (v/v), and are denoted where appropriate. The reactions were assayed by TLC and terminated as judged by the consumption of starting material. 0136 Visualization of the tip plates was done with a p-anisaldehyde spray reagent or phosphomolybdic acid reagent (Aldrich Chemical 20 wt % in ethanol) and activated with heat. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume unless otherwise indicated. Product solutions were dried over anhydrous Na2SO4 prior to filtration and evaporation of the solvents under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography (Still et al., J. Org. Chem., 43, 2923 (1978)) was done using Baker grade flash silica gel (47-61 m) and a silica gel: crude material ratio of about 20:1 to 50:1 unless otherwise stated. Hydrogenolysis was done at the pressure indicated in the examples or at ambient pressure. 0137 1H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and 13C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDCl3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD3OD (3.4 and 4.8 ppm and 49.3 ppm), or internally tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz). 0138 Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR Spectrometer as neat oils, as KBr pellets, or as CDCl3 solutions, and when given are reported in wave numbers (cm1). The mass spectra were obtained using LSIMS or electrospray. All melting points (mp) are uncorrected.

EXAMPLE A(1) 0139 4-(4-Amino-4-phenyl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 21

0140 The starting material was prepared using Steps (i) and (ii) described below. 0141 Step (i): To a solution of 4-(aminosulfonyl)phenylisothiocyanate (1.12 g, 5.0 mmol) and cyanamide (0.23 g, 5.5 mmol) in acetonitrile (50 ml) was added DBU (0.83 g, 5.5 mmol), and the resulting mixture was stirred at room temperature for 60 minutes. To the reaction mixture was added bromo-acetonitrile (0.66 g, 5.5 mmol) followed by DBU (0.83 g, 5.5 mmol) 30 minutes afterward. The reaction mixture was stirred overnight at room temperature, the solvent was removed at the reduced pressure, and the residue was dissolved in EtOAc (200 ml). The EtOAc solution was washed with 0.1 N HCl (150 ml3) and brine and dried with MgSO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc) to provide 0.73 g (48%) of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbonitrile. 0142 Step (ii): To a solution of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbonitrile (0.59 g, 2 mmol) in 20% triethylamine/pyridine (50 ml) was bubbled H2S gas at ice-water temperature for 30 minutes. Then the reaction solution was sealed and stirred at room temperature overnight. Argon gas was bubbled through the reaction solution for 60 minutes to replace the H2S, and then the solvents were removed at reduced pressure. The residue was dissolved in EtOAc, and the EtOAc solution was then washed with 5% citric acid (50 ml3) followed by brine. The solvent was removed in vacuo and the residue was triturated in Et2O. The product 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbothioamide was collected by filtration (0.56 g, 95%). To prepare the title compound, a solution of 2-(4-aminosulfonylphenyl)amino-4-amino-thiazole-5-carbothioamide (164 mg, 0.5 mmol) and -bromoacetophenone (110 mg, 0.55 mmol) in MeOH (20 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (50 ml). The EtOAc solution was washed with saturated NaHCO3 (10 ml), followed by brine. Purification of the residue by silica gel chromatography provided 4-(4-amino-4-phenyl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide. Mp 233-235 C. (decomp.). 1H NMR (CD3OD): 7.96 (s, 1H), 7.82 (s, 4H), 7.44-7.25 (m, 4H). ESIMS (MH): 430; (MH): 428. Anal. Calcd for C18H15N5O2S3: C, 50.33; H, 3.52; N, 16.30; S, 22.39. Found: C, 50.62; H, 3.54; N, 16.03; S, 22.12. In a manner similar to that used to prepare Example A(1), the following Examples A(2) through A(71) were prepared.

EXAMPLE A(2) 0143 4-4-Amino-4-(4-methoxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 22

0144 mp 195-198 C. 1H NMR (CD3OD): 7.78 (d, J8.80 Hz, 2H1), 7.75 (s, 4H), 7.13 (s, 1H), 6.88 (d, J8.86 Hz, 2H), 3.75 (s, 3H). FABMS (MH): 460. Anal. Calcd for C18H15N5O2S3: C, 50.33; H, 3.52; N, 16.30; S, 22.39. Found: C, 50.62; H, 3.54; N, 16.03; S, 22.12.

EXAMPLE A(3) 0145 4-4-Amino-4-(2-methoxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 23

0146 mp 231-235 C. (decomp). Rf (75% EtOAc/Hex)0.56. 1H NMR (CD3OD): 8.10 (dd, J7.79, 1.73 Hz, 1H), 7.79-7.70 (m, 4H), 7.57 (s, 1H), 7.25-7.19 (m, 1H), 7.03-6.93 (m, 2H), 3.84 (s, 3). FABMS (MH): 460.

EXAMPLE A(4) 0147 4-4-Amino-4-(2,4-difluoro-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 24

0148 mp 233-238 C. 1H NMR (CD3OD): 8.26-8.21 (m, 1H), 7.88 (s, 4H), 7.47 (s, 1H), 7.14-7.07 (m, 2). ESIMS (MH): 466; MH: 464. Anal. Calcd for C18H13F2N5O2S3.0.4 H2O: C, 45.73; H, 2.94; N, 14.82; S, 20.35. Found: C, 45.82; H, 2.78; N, 14.77; S, 20.38.

EXAMPLE A(5) 0149 4-4-Amino-4-(4-fluoro-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 25

0150 mp 254-257 C. 1H NMR (CD3OD): 8.01-7.91 (m, 2H), 7.88-7.76 (m, 4H), 7.35 (s, 1H), 7.20-7.09 (m, 2H). Anal. Calcd for C18H14FN5O2S3: C, 48.31; H, 3.15; N, 15.65; S, 21.49. Found: C, 48.40; H, 3.26; N, 15.44; S, 21.68.

EXAMPLE A(6) 0151 4-4-Amino-4-(2,4-dichloro-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 26

0152 mp 173-175 C. (decomp). 1H NMR (CD3OD): 7.97-7.93 (m, 1H), 7.87-7.81 (m, 4H), 7.67-7.59 (m, 1H), 7.57 (s, 1H), 7.45-7.39 (m, 1H). FABMS (MH): 498. Anal. Calcd for C18 H13Cl2N5O2S3: C, 43.38; H, 2.63; N, 14.05; S, 19.30. Found: C, 43.32; H, 2.78; N, 13.84; S, 19.06%.

EXAMPLE A(7) 0153 4-4-Amino-4-(3-chloro-5-fluoro-4-methyl-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 27

0154 mp 208-212 C. 1H NMR (DMSO-d6): 10.63 (s, NH), 7.95 (t, J8.42 Hz, 1H), 7.73 (q, J9.00 Hz, 4H), 7.55 (d, J2.32 Hz, 1H), 7.35 (d, J8.55 Hz, 1H, 7.17 (s, NH2), 6.96 (s, NH2), 2.28 (s, 3H). ESIMS (MH): 496. Anal. Calcd for C19H15ClFN5O2S3: C, 46.01; H, 3.05; N, 14.12; S, 19.12. Found: C, 45.93; H, 3.23; N, 13.86; S, 19.47.

EXAMPLE A(8) 0155 4-4-Amino-4-(4-hydroxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 28

0156 mp 168-170 C. (decomp). 1H NMR (CD3OD): 7.83 (s, 4H), 7.79-7.76 (d, J8.59 Hz, 2H), 7.16 (s, 1H), 6.85-6.82 (d, J8.46 Hz, 2H). FABMS (MH): 446. Anal. Calcd for C18H15N5O3S3.0.5 H2O: C, 47.56; H, 3.55; N, 15.41; S, 21.16. Found: C, 47.87; H, 3.59; N, 15.09; S, 21.11.

EXAMPLE A(9) 0157 4-(2,4-Difluoro-phenyl)-N2-(3,4,5-trimethoxy-phenyl)-2,5bithiazolyl-2,4-diamine 29

0158 mp 180-183 C. (decomp). 1H NMR (CD3OD): 8.26-8.23 (m, 1H), 7.41 (d, J2.2 Hz, 1H), 7.13-7.05 (m, 2H), 7.02 (s, 2H), 3.90 (s, 6H), 3.78 (s, 3H). FABMS (MH): 476. Anal. Calcd for C21H18F2N4O3S2: C, 52.93; H, 3.81; N, 11.76; S, 13.46. Found: C, 52.81; H, 3.72; N, 11.58; S, 13.45.

EXAMPLE A(10) 0159 4-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenol 30

0160 mp 129-133 C. (decomp). 1H NMR (CD3OD): 7.80 (d, J8.09 Hz, 2H), 7.16 (s, 1H), 7.02 (s, 2H), 6.86 (d, J8.09 Hz, 2H), 3.90 (s, 6H), 3.78 (s, 3H). ESIMS (MH): 457; (MH): 455. Anal. Calcd for C21H20N4O4S2.1.0 Et2O: C, 56.58; H, 5.70; N, 10.56; S, 12.08. Found: C, 56.27; H, 5.48; N, 10.69; S, 12.00.

EXAMPLE A(11) 0161 4-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-benzoic acid ethyl ester 31

0162 mp 240-245 C. (decomp). 1H NMR (CD3OD): 8.18-8.16 (d, J8.46 Hz, 2H), 8.09-8.06 (d, J8.09 Hz, 2H), 7.06 (s, 1H), 4.38 (q, J7.35 Hz, 2H), 3.85 (s, 6H), 3.68 (s, 3H), 1.41-1.37 (t, J6.99 Hz, 3H). FABMS (MH): 513. Anal. Calcd for C22H20N4O5S2.0.3 Et2O: C, 56.59; H, 5.09; N, 10.48; S, 11.99. Found: C, 56.24; H, 4.83; N, 10.26; S, 11.86.

EXAMPLE A(12) 0163 4-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-benzene-1,2-diol 32

0164 mp 132-137 C. (decomp). 1H NMR (CD3OD): 7.42-7.41 (d, J2.20 Hz, 1H), 7.32-7.28 (dd, J7.65, 1.84 Hz, 1H), 7.11 (s, 1H), 7.07 (s, 2H), 6.85-6.82 (d, J8.45 Hz, 1H), 3.90 (s, 6H), 3.78 (s, 3H). FABMS (MH): 473.

EXAMPLE A(13) 0165 4-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-2-methoxyphenol 33

0166 mp 202-203 C. 1H NMR (CD3OD): 7.42 (s, 1H), 7.39 (d, J2.11 Hz, 1H), 7.15 (s, 1H), 6.99 (s, 2H), 6.97 (d, J2.10 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 6H), 3.76 (s, 3H). FABMS (MH): 487. Anal. Calcd for C22H22N4O5S2: C, 54.31; H, 4.56; N, 11.51; S, 13.18. Found: C, 54.52; H, 4.70; N, 11.26; S, 13.32.

EXAMPLE A(14) 0167 4-4-Amino-4-(4-fluoro-phenyl)-5-methyl-2,5bithiazolyl-2-ylamino-benzenesulfonamide 34

0168 mp 145-148 C. (decomp). 1H NMR (CD3OD): 7.90-7.82 (m, 4H), 7.76-7.70 (m, 2H), 7.22-7.17 (m, 2H), 2.56 (s, 3H). HRFABMS: Calcd. for C19H16FN5O2S3(MH): 461.0450. Found: 461.0466.

EXAMPLE A(15) 0169 4-4-Amino-5-(4-fluoro-benzyl)-4-methyl-2,5bithiazolyl-2-ylamino-benzenesulfonamide 35

0170 mp 130-135 C. (decomp). 1H NMR (CD3OD): 7.76-7.68 (m, 4H), 7.17-7.12 (m, 2H), 6.97-6.90 (m, 2H), 3.97 (s, 2H), 2.23 (s, 3H). Anal. Calcd for C20H18FN5O2S3: C, 50.51; H, 3.81; N, 14.73; S, 20.23. Found: C, 50.40; H, 3.73; N, 14.64; S, 20.37.

EXAMPLE A(16) 0171 4-4-Amino-4-(3-hydroxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 36

0172 mp 205-209 C. (decomp). 1H NMR (CD3OD): 7.94-7.81 (m, 4H), 7.43-7.39 (m, 2H), 7.33 (s, 1H), 7.24 (t, J8.17 Hz, 1H), 6.80-6.75 (m, 1H). FABMS (MH): 445. Anal. Calcd for C18H15N5O3S3: C, 48.53; H, 3.39; N, 15.72; S, 21.59. Found: C, 48.74; H, 3.47; N, 15.44; S, 21.31.

EXAMPLE A(17) 0173 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenol 37

0174 mp 226-230 C. 1H NMR (CD3OD): 7.43-7.41 (m, 2H), 7.31 (s, 1H), 7.28-7.23 (m, 1H), 7.02 (s, 2H), 6.80-6.77 (m, 1H), 3.90 (s, 6H), 3.78 (s, 3H). FABMS (MH): 456. Anal. Calcd for C21H20N4O4S2: C, 55.25; H, 4.42; N, 12.27; S, 14.05. Found: C, 55.39; H, 4.56; N, 12.07; S, 14.05.

EXAMPLE A(18) 0175 5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-benzene-1,3-diol 38

0176 mp 198-202 C. 1H NMR (CD3OD): 7.21 (s, 1H), 6.99 (s, 2H), 6.91 (d, J2.06 Hz, 2H), 6.27 (t, J2.03 Hz, 1H), 3.88 (s, 6H), 3.77 (s, 3H). FABMS (MH): 473. Anal. Calcd for C21H20N4O5S2.0.5 H2O: C, 52.38; H, 4.40; N, 11.63; S, 13.32. Found: C, 52.53; H, 4.44; N, 11.83; S, 13.47.

EXAMPLE A(19) 0177 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-5-methoxyphenol 39

0178 mp 208-210 C. 1H NMR (CD3OD): 7.14 (s, 1H), 6.89-6.86 (m, 2H), 6.85 (s, 2H), 6.23 (t, J2.06 Hz, 1H), 3.75 (s, 6H), 3.69 (s, 3H), 3.63 (s, 3H). FABMS (MH): 486. Anal. Calcd for C22H22N4O5S2.0.5 H2O: C, 54.20; H, 4.57; N, 11.49; S, 13.16. Found: C, 54.02; H, 4.71; N, 11.09; S, 13.56.

EXAMPLE A(20) 0179 4-4-Amino-4-(4-hydroxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 40

0180 mp 200-203 C. (decomp). 1H NMR (CD3OD): 7.30 (s, 1H), 6.98 (s, 2H), 6.83 (d, J2.93 Hz, 1H), 6.56 (d, J2.93 Hz, 1H), 3.88 (s, 6H), 3.81 (s, 3H), 3.76 (s, 3H); FABMS (MH): 565/567. Anal. Calcd for C22H21BrN4O5S2.0.5 H2O: C, 46.00; H, 3.86; N, 9.75; S, 11.16. Found: C, 46.26; H, 3.69; N, 9.55; S, 11.09.

EXAMPLE A(21) 0181 3-4-Amino-2-(4-sulfamoyl-phenylamino)-2,5bithiazolyl-4-yl-benzoic acid 41

0182 1H NMR (DMSO-d6): 10.94 (s, OH), 8.46 (s, 1H), 8.18 (d, J7.80 Hz, 1H), 7.92 (d, J7.80 Hz, 1H, 7.78 (m, 4H), 7.56 (t, J7.80 Hz, 1H), 7.22 (brd, NH2), 7.04 (brd, NH2). Anal. Calcd for C19H15N5O4S3.0.3 EtOAc: C, 48.52; H, 3.51; N, 14.01; S, 19.24. Found: C, 48.37; H, 3.67; N, 13.97; S, 19.24.

EXAMPLE A(22) 0183 5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-2-chloro-phenol 42

0184 mp 235-238 C. 1H NMR (CD3OD): 7.61 (d, J1.92 Hz, 1H), 7.47-7.39 (m, 2H), 7.37 (s, 1H), 7.05 (s, 2H), 3.94 (s, 6H), 3.82 (s, 3H). FABMS (MH): 490. Anal. Calcd for C21H19ClN4O4S2: C, 51.37; H, 3.90; N, 11.41; S, 13.06. Found: C, 51.38; H, 3.95; N, 11.32; S, 12.72.

EXAMPLE A(23) 0185 2-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenol 43

0186 mp 186-190 C. (decomp). 1H NMR (CD3OD): 7.88 (dd, J7.99, 1.61 Hz, 1H,), 7.62 (s, 1H), 7.27-7.20 (m, 1H), 7.04 (s, 2H), 6.98-6.91 (m, 2H), 3.92 (s, 6H), 3.80 (s, 3H). FABMS (MH): 457. Anal. Calcd for C21H20N4O4S2: C, 55.25; H, 4.42; N, 12.27; S, 14.05. Found: C, 55.28; H, 4.62; N, 11.96; S, 13.72.

EXAMPLE A(24) 0187 4-(4-Amino-4-p-tolyl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 44

0188 1H NMR (DMSO): 7.92-7.84 (m, 4H), 7.32 (m, 3H), 7.11 (s, 2H), 2.39 (s, 3H). FABMS (M): 443; (MNa): 466.

EXAMPLE A(25) 0189 2-(4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-benzene-1,4-diol 45

0190 mp 208-212 C. (decomp).; 1H NMR (CD3OD): 7.56 (s, 1H), 7.31 (d, J2.80 Hz, 1H), 7.00 (s, 2H), 6.77 (d, J8.69 Hz, 1H), 6.68 (dd, J8.72, 2.87 Hz, 1H), 3.89 (s, 6H, 3.77 (s, 3H). ESIMS (MH): 473. Anal. Calcd for C21H20N4O5S2.0.4 H2O: C, 52.47; H, 4.38; N, 11.66; S, 13.34. Found: C, 52.77; H, 4.48; N, 11.23; S, 12.98.

EXAMPLE A(26) 0191 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-4-bromophenol 46

0192 mp 214-216 C. 1H NMR (CD3OD): 7.47 (d, J8.67 Hz, 1H), 7.38 (s, 1H), 7.26 (d, J3.02, 1H), 7.07 (s, 2H), 6.72 (dd, J8.69, 3.07 Hz, 1H), 3.89 (s, 6H), 3.76 (s, 3H). FABMS (MH): 535/537. Anal. Calcd for C21H19BrN4O4S2: C, 47.11; H, 3.58; N, 10.46; S, 11.85. Found: C, 47.31; H, 3.65; N, 10.26; S, 11.85.

EXAMPLE A(27) 0193 2-(4-Amino-4-benzobthiophen-3-yl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 47

0194 mp 155-160 C. (decomp). 1H NMR (CD3OD): 8.39 (d, J7.94 Hz, 1H), 8.01 (s, 1H), 7.96 (d, J7.72 Hz, 1H), 7.86 (s, 4H), 7.50-7.39 (m, 3H). FABMS (MH): 485.

EXAMPLE A(28) 0195 4-4-Amino-4-4-(2,4-dichloro-phenyl)-furan-2-yl-2,5bithiazolyl-2-ylamino-benzenesulfonamide 48

0196 mp 225-230 C. (decomp). 1H NMR (CD3OD): 8.00 (d, J8.62, 1H), 7.86 (s, 4H), 7.58 (d, J2.10, 1H), 7.45 (dd, J8.60, 2.12 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J3.61 Hz, 1H), 6.97 (d, J3.59, 1H). FABMS (MH): 564/566.

EXAMPLE A(29) 0197 3-(4-Amino-2-propylamino-2,5bithiazolyl-4-yl)-phenol 49

0198 1H NMR (CD3COCD3): 8.43 (s, 1H), 7.50 (d, 1H), 7.43 (d, 1H), 7.30-7.20 (m, 3H), 6.55 (s, 2H), 3.40 (t, 2H), 1.69 (sextet, 2H), 0.97 (t, 3H). ESIMS (MH): 333; (MNa): 355; (MH): 331.

EXAMPLE A(30) 0199 3-(4-Amino-2-methylamino-2,5bithiazolyl-4-yl)-phenol 50

0200 1H NMR (CD3COCD3): 8.40 (s, 1H), 7.50 (d, 1H), 7.43 (d, 1H), 7.31-7.15 (m, 3H), 6.63 (s, 2H), 3.00 (d, 3H). ESIMS (MH): 305; (MH): 303.

EXAMPLE A(31) 0201 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-N-phenethyl-benzamide 51

0202 ESMS (MH): 588. Anal. Calcd for C30H29N5O4S2: C, 61.31; H, 4.97; N, 11.92; S, 10.91. Found: C, 61.02; H, 4.86; N, 11.72; S, 10.83.

EXAMPLE A(32) 0203 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-N-benzyl-benzamide 52

0204 ESMS (MH): 574.

EXAMPLE A(33) 0205 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-N-phenyl-benzamide 53

0206 ESMS (MH): 560. Anal. Calcd for C28H25N5O4S2.0.8 H2O: C, 58.58; H, 4.67; N, 12.20; S, 11.17. Found: C, 58.68; H, 4.49; N, 12.23; S, 11.33.

EXAMPLE A(34) 0207 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-N-(4-isopropyl-3-methyl-phenyl)-benzamide 54

0208 ESMS (MH): 616. Anal. Calcd for C32H33N5O4S2.0.4 H2O: C, 61.69; H, 5.47; N, 11.24; S, 10.29. Found: C, 61.76; H, 5.26; N, 11.08; S, 10.18.

EXAMPLE A(35) 0209 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-N-(2-methyl-quinolin-6-yl)-benzamide 55

0210 ESMS (MH): 625. Anal. Calcd for C32H28N6O4S2.0.2 H2O: C, 58.41; H, 4.36; N, 12.65; S, 9.66. Found: C, 58.40; H, 4.31; N, 12.28; S, 9.54.

EXAMPLE A(36) 0211 3-(4-Amino-2-p-tolylamino-2,5bithiazolyl-4-yl)-phenyl-carbamic acid benzyl ester 56

0212 1H NMR (CD3COCD3): 8.85 (s, 1H), 8.21 (s, 1H), 7.70-7.25 (m, 14H), 6.52 (s, 2H), 5.30 (s, 2H), 2.41 (s, 3H). ESIMS (MH): 514; (MH): 512.

EXAMPLE A(37) 0213 N-3-4-Amino-2-(3-diethylamino-propylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 57

0214 1H NMR (DMSO-D6): 10.39 (s, 1H), 9.12 (s, 1H, 8.35 (s, 2H), 7.96 (m, 3H), 7.79 (m, 1H), 7.69-7.39 (m, 6H), 3.36 (m, 2H), 3.12 (m, 6H), 2.93 (m, 2H), 1.20 (m, 6H). ESIMS (MH): 507.

EXAMPLE A(38) 0215 N-3-(4-Amino-2-phenethylamino-2,5bithiazolyl-4-yl)-phenyl-benzamide 58

0216 1H NMR (DMSO-D6): 10.39 (s, 1H), 8.42-7.15 (m, 16H), 6.85 (s, 1H), 5.20 (broad s, 2H), 2.90 (m, 2H), 3.50 (m, 2H). ESIMS (MH): 498.

EXAMPLE A(39) 0217 3-4-Amino-4-(3-benzoylaminophenyl)-2,5bithiazolyl-2-ylamino-benzoic acid methyl ester 59

0218 1H NMR (DMSO-D6): 10.39 (s, 1H), 10.38 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 8.18 (d, 1H), 7.98 (d, 2H), 7.84 (d, 1H), 7.70 (d, 1H), 7.65-7.39 (m, 8H), 7.10 (broad s, 2H), 3.89 (s, 3H). ESIMS (MH): 528; (MNa): 550; (MH): 526.

EXAMPLE A(40) 0219 3-4-Amino-4-(3-benzoylaminophenyl)-2,5bithiazolyl-2-ylamino-benzoic acid ethyl ester 60

0220 1H NMR (DMSO-D6): 10.80 (s, 1H), 10.38 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 8.15 (d, 2H), 8.00 (d, 2H), 7.88 (d, 1H), 7.75-7.40 (m, 8H), 7.10 (broad s, 1H), 4.38 (quartet, 2H), 1.39 (t, 3H). ESIMS (MH): 542; (MNa): 564.

EXAMPLE A(4 1) 0221 N-3-4-Amino-2-(benzo1,3dioxol-5-ylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 61

0222 1H NMR (DMSO-D6): 10.41 (m, 2H), 8.35 (s, 1H), 8.00-6.88 (m, 14H), 6.10 (s, 2H). ESIMS (MH): 514; (MH): 512.

EXAMPLE A(42) 0223 N-3-4-Amino-2-(3,5-dimethylphenylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 62

0224 1H NMR (CD3OD): 8.36-6.79 (m, 16H), 6.68 (s, 1H) 2.28 (s, 6H). ESIMS (MW)*: 993; (MNa)*: 1015.

EXAMPLE A(43) 0225 N-3-4-Amino-2-(indan-5-ylamino)-2,5bithiazolyl-2-ylamino-phenyl-benzamide 63

0226 1H NMR (CD3OD): 8.50-7.15 (m, 17H), 2.95 (m, 4H), 2.15 (m, 2H). ESIMS (MH): 510; (MNa): 532; (MH): 508.

EXAMPLE A(44) 0227 3-(4-Amino-2-m-tolylamino-2,5bithiazolyl-4-yl)-phenyl-benzamide 64

0228 1H NMR (CD3OD): 8.25-6.81 (m, 18H), 2.29 (s, 3H). ESIMS (MH): 484; (MNa): 506.

EXAMPLE A(45) 0229 N-3-4-Amino-2-(2,3-dihydro-benzo1,4dioxin-6-ylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 65

0230 1H NMR (CD3OD): 8.42-6.83 (m, 17H), 4.29 (m, 4H). ESIMS (MH): 528; (MNa): 550.

EXAMPLE A(46) 0231 N-3-4-Amino-2-(3-methylsulfanyl-phenylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 66

0232 1H NMR (DMSO-D6): 10.39 (s, 1H), 8.89 (d, 2H), 8.51-6.91 (m, 18H). ESIMS (MH)*: 1029.

EXAMPLE A(47) 0233 N-3-4-Amino-2-(3,4-dimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 67

0234 1H NMR (CD3OD): 8.32 (s, 1H), 7.98 (d, 2H), 7.78-6.91 (m, 14H), 3.88 (s, 3H), 3.81 (s, 3H). ESIMS (MH): 530; (MNa): 552.

EXAMPLE A(48) 0235 N-3-2-(3-Acetylamino-4-methyl-phenylamino)-4-amino-2,5bithiazolyl-4-yl-phenyl-benzamide 68

0236 1H NMR (CD3OD): 8.32 (s, 1H), 7.98 (d, 2H), 7.72-7.15 (m, 15H), 2.22 (s, 3H), 1.98 (s, 3H). ESIMS (MH): 541; (MNa): 563; (MK): 579; (MH): 539.

EXAMPLE A(49) 0237 N-3-4-Amino-2-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazin-6-ylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 69

0238 1H NMR (DMSO-D6): 11.11 (s, 1H), 10.39 (s, 1H), 8.35-7.10 (m, 17H). ESIMS (MNa): 576; (MH): 552.

EXAMPLE A(50) 0239 3-4-Amino-4-(3-benzoylamino-phenyl)-2,5bithiazolyl-2-ylamino-benzoic acid 70

0240 1H NMR (DMSO-D6): 10.79 (s, 1H), 10.39 (s, 1H), 8.35 (s, 1H), 8.18-7.34 (m, 16H). ESIMS (MH): 514; (MNa): 536; (MH): 512.

EXAMPLE A(51) 0241 4-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-ethylbenzoate 71

0242 1H NMR (d6-DMSO): 1.2 (t, 3H), 4.3 (q, 2H), 7.4 (t, 1H), 7.5-8.0 (m, 14H), 8.35 (s br, 1H), 10.4 (s, 1H), 10.95 (s, 1H). ESIMS (MH): 542; (MH): 540.

EXAMPLE A(52) 0243 4-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-methoxyphenyl 72

0244 1H NMR (CD3OD): 2.6 (s, 3H), 7.2-7.8 (m, 11H), 8.35 (s br, 1H), 7.9 (d, 2H), 8.2 (s br, 1H). ESIMS (MH): 500; (MNa): 522; (MK): 538.

EXAMPLE A(53) 0245 3-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-pyridine 73

0246 1H NMR (d6-DMSO): 7.1 (s br, 1H), 7.4 (t, 1H), 7.5-7.7 (m, 7H), 7.85 (m, 1H), 8.0 (m, 2H), 8.25-8.4 (m, 3H), 9.0 (d, 1H), 10.4 (s, 1H), 10.95 (s, 1H). ESIMS (MNa): 493; (M-H): 469.

EXAMPLE A(54) 0247 2-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-thiophene carboxylic acid methyl ester 74

0248 1H NMR (d6-DMSO): 3.8 (s, 3H), 7.0 (s br, 2H), 7.4 (t, 1H), 7.5-7.7 (m, 6H), 7.85 (m, 1H), 8.0 (m, 3H), 8.15 (d, 1H), 8.35 (m, 1H), 10.4 (m, 1H). ESIMS (MH): 534; (MNa): 556; (MH): 532.

EXAMPLE A(55) 0249 4-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-phenylsulfonylpiperidine 75

0250 1H NMR (d6-DMSO): 1.2-1.6 (m, 6H), 3.1 (m, 4H), 7.3-8.5 (m, 14H), 8.9 (d, 1H), 10.4 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H). ESIMS (MH): 617; (MH): 615.

EXAMPLE A(56) 0251 4-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-nitrophenyl 76

0252 1H NMR (d6-DMSO): 7.2-7.9 (m, 13H), 8.2 (d, 2H), 8.3 (s, 1H), 10.3 (s, 1H), 11.2 (s, 1H). ESIMS (MH): 515; (MH): 513.

EXAMPLE A(57) 0253 4-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-trans-benzoyl-DL-homoserine lactone 77

0254 1H NMR (d6-DMSO): 2.5 (m, 1H, 2.7 (m, 1H), 4.35 (m, 1H), 4.5 (m, 1H), 4.8 (m, 1H), 7.2 (m, 1H), 7.45 (m, 3H), 7.55 (m, 4H), 7.75 (m, 5H), 7.85 (m, 3H), 8.0 (m, 3H), 8.35 (m, 1H). ESIMS (MH): 597; (MNa): 619.

EXAMPLE A(58) 0255 4-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-acetophenone 78

0256 1H NMR (d6-DMSO): 2.5 (s, 3H), 7.1 (s br, 1H), 7.42 (t, 1H), 7.5-7.7 (m, 6H), 7.8 (m, 4H), 8.0 (m, 5H), 8.35 (t br, 1H). ESIMS (MH): 512; (MNa): 534; (MH): 510.

EXAMPLE A(59) 0257 (4-Amino4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-cyclohexane 79

0258 1H NMR (CDCl3): 1.0-2.0 (m, 10H), 3.2 (m br, 1H), 5.2 (s, 2H), 7.0 (d, 1H), 7.4-8.0 (m, 11H). ESIMS (MH): 506; (MH): 504.

EXAMPLE A(60) 0259 3-(4-Amino-4-(3-benzamidophenyl)-2,5bithiazolyl-2-ylamino)-methoxypropane 80

0260 1H NMR (CDCl3): 1.5 (m, 1H), 1.8 (m, 1H), 2.0 (m, 2H), 3.1 (s, 3H), 3.3 (m, 2H), 5.0 (s, 2H), 7.2-7.4 (m, 12H). ESIMS (MH): 496; (MH): 494.

EXAMPLE A(61) 0261 4-4-Amino-4-(3-benzyloxy-5-hydroxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 81

0262 mp 185-187 C. (decomp). 1H NMR (CD3OD): 7.88 (s, 4H), 7.56-7.32 (m, 6H), 7.10-7.03 (m, 2H), 6.45 (t, J2.23 Hz, 1H), 5.13 (s, 2H). ESIMS (MH): 552; (MH):; 550. Anal. Calcd for C25H21N5O4S3..0.3 EtOAc: C, 54.43; H, 4.08; N, 12.12; S, 16.64. Found: C, 54.54; H, 4.00; N, 12.06; S, 16.59.

EXAMPLE A(62) 0263 4-4-(3-Allyloxy-5-hydroxyphenyl)-4-amino-2,5bithiazolyl-2-ylamino-benzenesulfonamide 82

0264 mp 200-202 C. 1H NMR (CD3OD): 11.12 (s, NH), 9.81 (s, NH2), 8.07-8.00 (m, 4H), 7.86 (s, NH2), 7.48 (s, 1H), 7.30-7.23 (m, 2H), 6.57 (s, 1H), 6.34-6.23 (m, 1H), 5.68-5.52 (m, 2H), 5.32-5.28 (m, 2H). ESIMS (MH): 502; (MH): 501. Anal. Calcd for C21H19N5O4S3: C, 50.29; H, 3.82; N, 13.96; S, 19.18. Found: C, 50.31; H, 3.93; N, 13.74; S, 19.05.

EXAMPLE A(63) 0265 4-(4-Amino-4-styryl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 83

0266 mp 140-143 C. (decomp). 1H NMR (CD3OD): 7.80-7.72 (m, 4H), 7.50-7.46 (m, 1H), 7.38-7.06 (m, 6H), 6.95 (s, 1H). FABMS Calcd for C20H17N5O2S3: 455.0544. Found 455.0529.

EXAMPLE A(64) 0267 4-4-Amino-4-2-(4-hydroxy-phenyl)-vinyl-2,5bithiazolyl-2-ylamino-benzenesulfonamide 84

0268 mp 138-140 C. (decomp). 1H NMR (CD3OD): 10.90 (s, NH), 7.73 (q, J15.32 Hz, 4H), 7.36 (d, J8.75 Hz, 2H), 7.22 (d, J15.80 Hz, 1H), 7.18 (s, NH2), 7.06 (s, 1H), 6.90 (d, J16.1 Hz, 1H), 6.84 (s, NH2), 6.70 (d, J8.62, 2H). FABMS Calcd for C20H17N5O3S3: 471.0494. Found: 471.0502.

EXAMPLE A(65) 0269 4-4-Amino-4-2-(3-hydroxy-4-methoxy-phenyl)-ethenyl-2,5bithiazolyl-2-ylamino-benzenesulfonamide 85

0270 mp 190-193 C. (decomp). 1H NMR (CD3OD): 10.71 (s, NH2), 9.83 (s, NH2), 7.63 (q, J15.40, 4H), 7.10-7.03 (m, 2H), 6.98 (s, 1H), 6.86 (s, NH2), 6.83-6.72 (m, 3H, NH2), 3.60 (s, 3H). ESIMS (MNa): 524. Anal. Calcd for C21H19N5O4S3.0.4 EtOAc: C, 50.56; H, 4.17; N, 13.05; S, 17.92. Found: C, 50.50; H, 4.35; N, 12.75; S, 17.88.

EXAMPLE A(66) 0271 4-4-Amino-4-(4-phenyl-buta-1,3-dienyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 86

0272 mp 193-195 C. (decomp). 1H NMR (CD3OD): 10.92 (s, NH), 7.82 (q, J15.92, 4H), 7.53 (d, J7.42, 2H), 7.36 (t, J7.41 Hz, 2H), 7.28-7.06 (m, 2H, 2NH2), 6.77 (m, 2H). ESIMS (MH): 482.

EXAMPLE A(67) 0273 4-(4-Amino-4-benzoyl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 87

0274 mp 255-260 0C (decomp). 1H NMR (CD3OD): 10.99 (s, 1H), 8.12 (s, 1H), 8.04-8.02 (m, 2H), 7.78 (q, J12.1 Hz, 4H), 7.72-7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.26 (s, NH2), 7.05 (br, NH2). ESIMS (MNa): 480; (MH): 456.

EXAMPLE A(68) 0275 Ethyl 4-amino-2-(4-sulfamoyl-phenylamino)-2,5bithiazolyl-4-carboxylate 88

0276 1H NMR (DMSO-D6): 11.0 (s, NH, 8.12 (s, H), 7.80 (m, 4H), 7.32 (s, NH2), 7.08 (br, NH2), 4.35 (q, J8.7 Hz, 2H), 1.30 (t, J8.7 Hz, 3H). FABMS Calcd for C15H6N5O4S3(MH): 426.0364. Found: 426.0356.

EXAMPLE A(69) 0277 4-4-Amino-4-(4-chloro-3-hydroxy-phenyl)-2,5bithiazolyl-2-ylamino-benzenesulfonamide 89

0278 1H NMR (CD3OD): 7.97 (s, 4H), 7.63 (s, 1H), 7.58-7.46 (m, 3H). FABMS (MH): 480.

EXAMPLE A(70) 0279 4-(4-Amino-4-biphenyl-4-yl-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 90

0280 1H NMR (CD3OD): 8.09-8.00 (m, 1H), 7.88 (s, 4H), 7.72-7.63 (m, 3H), 7.51-7.40 (m, 3H), 7.38-7.29 (m, 1H). EIMS (MH): 504. Anal. Calcd for C24H19N5O2S3: C, 57.01; H, 3.79; N, 13.85; S, 19.02. Found: C, 56.87; H, 3.81; N, 13.57; S, 19.16.

EXAMPLE A(71) 0281 4-(4-Amino-4-benzoyl-2,5bithiazolyl-2-ylamino)-N-(2-dimethylamino-ethyl)-benzenesulfonamide 91

0282 1H NMR (CD3OD): 7.88 (s, 1H), 7.84-7.78 (m, 2H), 7.69-7.47 (m, 5H), 7.40-7.34 (m, 2), 2.63 (t, J6.70 Hz, 2H), 2.06 (t, J6.60 Hz, 2H), 1.84 (s, 6H). FABMS Calcd for C23H24N6O3S3: 529.1150. Found: 529.1158.

EXAMPLE A(72) 0283 4-4-Amino-4-(3-amino-benzoyl)-2,5bithiazoyl-2-ylamino-benzenesulfonamide 92

0284 1H NMR (DMSO): 10.91 (s, 1H), 7.99 (s, 1H), 7.86-7.84 (m, 4H), 7.27 (s, 2H), 7.23-7.06 (m, 5H), 6.81-6.90 (m, 1H), 5.38 (s, 2H). HRFABMS (MNa): Calcd.: 495.0344. Found: 495.0330.

EXAMPLE A(73) 0285 4-Amino-5-benzyl-2-(4-sulfamoyl-phenylamino)-2,5bithiazolyl-4-carboxylic acid ethyl ester 93

0286 1H NMR (CD3OD): 7.76 (s, 4H), 7.18 (m, 5H), 4.40 (s, 2H), 4.30 (q, J7.8 Hz, 2H), 1.26 (t, J7.8 Hz, 3H).

EXAMPLE B(1) 0287 (3-5-4-Amino-2-(trityl-amino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-carbamic acid tert-butyl ester 94

0288 The starting material for use in preparing the title compound was prepared according to the following Steps (i) and (ii). 0289 Step (i): To a solution of 3.15 g (26.7 mmol, 1.0 eq.) of 3-aminobenzonitrile in 10 mL of CH2Cl2 was added a solution of 6.4 g (29.4 mmol, 1.1 eq.) of di-tertbutyl dicarbonate in 10 mL of CH2Cl2, followed by 320 mg (2.7 mmol, 0.1 eq.) of DMAP and 8 mL (80.1 mmol, 3.0 eq.) of pyridine. CO2 evolved and the reaction was followed by TLC until completion. The solvent was pumped off, the residue was taken up in EtOAc, and washed with 1N HCl and brine. The organic layer was dried over NA2SO4 and the solvent was removed. The crude product was purified on SiO2 (2% Et2OCH2Cl2 eluant) to yield 5.4 g of 3-(t-butoxycarbamoyl)benzonitrile (yield 93%). Rf0.9 (10% Et2OCH2Cl2). 1H NMR (CDCl3): 1.5 (s, 9H), 6.6 (s br, 1H), 7.35 (m, 2H), 7.55 (m, 1H), 7.82 (m, 1H). 0290 Step (ii): To a solution of 2 g (9.17 mmol, 1.0 eq.) of 3-(t-butoxycarbamoyl)benzonitrile in 25 mL of EtOH was added 0.84 mL (13.76 mmol, 1.5 eq.) of 50% aqueous solution of NH2OH. The reaction was placed in an oil bath at 80 C. and heated to 85 C. for 4 h. The solvent was removed in vacuo, and residual water was removed by azeotroping the residue with THF-toluene. Without purification, the crude hydroxyamidine (Rf0.1 in 10% Et2OCH2Cl2) was dissolved in 45 mL of DMF and 2.1 mL (12 mmol, 1.3 eq.) of diisopropylethyl amine and 110 mg (0.92 mmol, 0.1 eq.) of DMAP were added. The mixture was cooled to 50 C., and a solution of 0.88 mL (11 mmol, 1.2 eq.) of chloroacetyl chloride in 15 mL of CH2Cl2 (or DMF) was added dropwise, under argon. The reaction was stirred at 50 C. for 1 h, and then poured into EtOAc and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 and the solvent was removed. The residue was taken up in 50 mL of dioxane and placed in an oil bath at 110 C. for about 1 h. The solvent was removed and the residue was purified on SiO2 (Et2O-hexane eluant) to yield 2 g of 5-chloromethyl-3-(3-(t-butoxy-carbamoyl)phenyl)-1,2,4-oxadiazole as a white solid (70% overall yield for three steps). Rf0.9 (10% Et2OCH2Cl2). 1H NMR (CDCl3): 1.5 (s, 9H), 4.75 (s, 2H), 6.62 (s br, 1H), 7.45 (dd, 1H), 7.62 (d br, 1H), 7.75 (m, 1H), 8.05 (m, 1H). 0291 The title compound was prepared as follows. To a solution of tritylisothiocyanate (5.0 mmol) and cyanamide (5.5 mmol) dissolved in anhydrous THF (10 mL) was added 1,8-diazabicyclo 5.4.0undec-7-ene (5.5 mmol). After stirring for 2 hours, the reaction was diluted with acetonitrile (15 mL) and then treated with 5-chloromethyl-3-(3-(t-butoxy-carbamoyl)phenyl)-1,2,4-oxadiazole (2.5 mmol) and 1,8-diazabicyclo 5.4.0undec-7-ene (2.75 mmol). The product was isolated after 1 hour by concentrating the crude reaction in vacuo, and chromatographing the resulting oil (gradient elution, 20% EtOAc/hexane to 40% EtOAc/hexane), giving 1.30 g of product (84% yield). 1H NMR (CDCl3): 7.79 (1H, s), 7.60 (2H, m), 7.24 (16H, m), 6.91 (1H, s), 6.48 (1H, s), 5.77 (2H, s), 1.52 (3H, s), 1.46 (6H, s). ESIMS (MH): 617. 0292 The following Examples B(2) through B(36) were prepared in a similar fashion to Example B(1).

EXAMPLE B(2) 0293 3-(3-tert-Butyloxycarboxy-aminophenyl)-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 95

0294 1H NMR (d6-acetone): 1.5 (s, 9H), 3.7 (s, 3H), 3.85 (s, 6H), 7.0 (s br, 2H), 7.05 (s, 2H), 7.4 (t, 1H), 7.75 (d, 2H), 8.35 (s, 1H), 8.6 (s br, 1H), 9.7 (s br, 1H). ESIMS (MH): 541; (MH): 539. Anal. Calcd for C25H28N6O6S: C, 55.54; H, 5.22; N, 15.55; S, 5.93. Found: C, 56.45; H, 5.67; N, 14.88; S, 5.58.

EXAMPLE B(3) 0295 5-3-(4-tert-Butyl-phenyl)-1,2,4oxadiazol-5-yl- N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 96

0296 MS (FAB) m/z Calc'd: 481. Found 481. Anal. Calc'd: C, 59.86; H, 5.65; N, 14.54; S, 6.66. Found: C, 58.36; H, 5.53; N, 13.95; S, 6.36.

EXAMPLE B(4) 0297 5-3-(3-Methoxymethoxy-phenyl)-1,2,4oxadiazol-5-yl- N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 97

0298 1H NMR (300 MHz, DMSO-d6): 3.41 (s, 3H), 3.64 (s, 3H), 3.81 (s, 6H), 5.29 (s, 2H), 7.01 (s, 2H), 7.22 (m, 1H), 7.34 (br s, 2H), 7.47 (m, 1H), 7.70 (m, 2H), 10.76 (s, 1H). Anal. Calcd for C22H23N5O6S.H2O: C, 52.48; H, 5.00; N, 13.91. Found: C, 52.47; H, 4.98; N, 13.75.

EXAMPLE B(5) 0299 3-(3-(tert-butyloxycarboxyamino)-6-fluoro-phenyl)-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 98

0300 1H NMR (CDCl3): 1.5 (s, 9H), 3.7 (s, 3H), 3.85 (s, 6H), 6.6 (s br, 2H), 6.7 (s br, 1H), 7.05 (t, 1H), 7.55 (m br, 1H), 7.85 (m, 1H). ESIMS MH: 559.

EXAMPLE B(6) 0301 3-(2-methyl-5-(tert-butyloxycarboxyamino)-phenyl)-5-2-(3,4,5 trimethoxyphenyl)-amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 99

0302 1H NMR (CDCl3): 1.5 (s, 9H), 2.55 (s, 3H), 3.85 (s, 3H), 3.87 (s, 6H), 6.65 (s br, 2H), 7.22 (d br, 1H), 7.28 (s, 1H), 7.55 (d br, 1H), 7.85 (m br, 1H). ESIMS MH: 555.

EXAMPLE B(7) 0303 3-3-(3-methoxybenzoyl)amino-6-methyl-phenyl-5-2-4-(N,N-dimethylaminophenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 100

0304 1H NMR (d6-DMSO): 2.55 (s, 3H), 2.9 (s, 6H), 3.85 (s, 3H), 6.75 (m, 2H), 7.18 (m, 3H), 7.35-7.6 (m, 6H), 7.95 (dd, 1H), 8.35 (d, 1H), 10.3 (s br, 1H), 10.4 (s br, 1H). ESIMS MH: 542, MNa: 564. Anal. Calcd. for C28 H27 N7 O3 S: C, 58.22; H, 5.41, N, 16.97; S, 5.55. Found: C, 58.01; H, 5.54, N, 16.13; S, 5.22.

EXAMPLE B(8) 0305 3-3-(1-ethyl-3-methyl-1H-Pyrazole-5-carboxy)-amino-6-methylphenyl-5-2-(3-hydroxymethylphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 101

0306 1H NMR (MeOD): 1.4 (t, 3H), 2.3 (s, 3H), 2.6 (s, 3H), 4.5 (q, 2H), 4.65 (s, 2H), 6.75 (s, 1H), 7.1 (d br, 1H), 7.35 (m, 2H), 7.55 (m, 1H), 7.65 (m br, 1H), 7.8 (dd, 1H), 8.25 (d, 1H). ESIMS MH: 531.

EXAMPLE B(9) 0307 3-3-(1-ethyl-3-methyl-1H-Pyrazole-5-carboxy)-amino-6-methylphenyl-5-2-(3-methylpyrrolidinephenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 102

0308 1H NMR (MeOD): 1.4 (t, 3H), 1.8 (m br, 4H), 2.3 (s, 3H), 2.6 (s br, 7H), 3.7 (s, 2H), 4.5 (q, 2H), 6.75 (s, 1H), 7.18 (m, 3H), 7.35 (m, 2H), 7.55 (m br, 1H), 7.65 (s br, 1H), 7.8 (dd, 1H), 8.28 (d, 1H). ESIMS MH: 584.

EXAMPLE B(10) 0309 3-3-(1-ethyl-3-methyl-1H-Pyrazole-5-carboxy)-amino-6-methylphenyl-5-2-(4-methylpyrrolidinephenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 103

0310 1H NMR (d6-DMSO): 1.32 (t, 3H), 1.7 (m br, 4H), 2.2 (s, 3H), 2.6 (s, 3H), 3.3 (m, 4H), 3.6 (s, 2H), 4.45 (q, 2H), 6.85 (s, 1H), 7.3 (m, 5H), 7.6 (d, 2H), 7.92 (dd, 1H), 8.28 (d, 1H), 10.25 (s, 1H), 10.8 (s br, 1H). ESIMS MH: 584. Anal. Calcd. for C30 H33 N9 O2 S: C, 61.73; H, 5.70, N, 21.60; S, 5.49. Found: C, 61.52; H, 5.61, N, 21.52; S, 5.46.

EXAMPLE B(11) 0311 (R,S)-3-3-(2-hydroxy-4-methyl pentanoyl)amino-6-methylphenyl-5-2-(3-methylpyrrolidinephenyl)amino-4-amino-5-thiazolyl-1,2,4 oxadiazole 104

0312 1H NMR (MeOD): 1.0 (dd, 6H), 1.65 (m, 3H), 1.9 (m, 4H), 2.6 (s, 3H), 2.8 (m br, 4H), 3.85 (s, 2H), 4.2 (dd, 1H), 7.13 (d br, 1H), 7.35 (m, 3H), 7.56 (m br, 1H), 7.72 (m br, 2H), 8.28 (d, 1H).

EXAMPLE B(12)N 0313 (3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazoyl-4-chloro-phenyl)-carbamic acid tert-butyl ester 105

0314 1H-NMR (d6-acetone): 9.71 (s, 1H), 8.71 (s, 1H), 8.20 (m, 1H), 7.78 (m, 1H), 7.52 (m, 1H), 7.06 (s, 2H), 6.95 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 1.50 (s, 9H). ESIMS: (MH): 575(100%), 577(30%).

EXAMPLE B(13) 0315 (5-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-carbamic acid tert-butyl ester 106

0316 1H-NMR (d6-acetone) 9.71 (s, 1H), 8.68 (m, 1H), 8.24 (m, 1H), 7.28 (m, 1H), 7.04 (s, 2H), 6.99 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 1.51 (s, 9H). ESIMS (MH): 577.

EXAMPLE B(14) 0317 (5-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-chloro-2-fluoro-phenyl)-carbamic acid tert-butyl ester 107

0318 1H-NMR (d6-acetone): 9.72 (s, 1H), 8.68 (m, 1H), 7.49 (m, 1H), 7.07 (s, 2H), 6.97 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 1.51 (s, 9H). ESIMS(MH): 593(100%), 595(30%).

EXAMPLE B(15) 0319 (5-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-dichloro-phenyl)-carbamic acid tert-butyl ester 108

0320 1H-NMR (d6-acetone): 9.73 (s, 1H), 8.71 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.07 (s, 2H), 6.98 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 1.52 (s, 9H). ESIMS(MH): 609(100%), 611 (60%).

EXAMPLE B(16) 0321 N-(3-5-4-Amino-2-(3,4,5-methylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl-carbamic acid tert-butyl 109

0322 1H-NMR (d6-acetone): 8.48 (s, 1H), 8.20 (m, 1H), 7.69 (m, 1H), 7.55 (m, 1H), 7.28 (m, 1H), 6.77 (s, 2H), 3.02 (d, 3H), 2.55 (s, 3H), 1.55 (s, 9H). ESIMS: (MH): 403, (MNa): 425.

EXAMPLE B(17) 0323 N-(3-5-4-Amino-2-(3,4,5-methylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl-3-methoxy-benzamide 110

0324 1H-NMR (d6-dmso): 10.33 (s, 1H), 8.59 (m, 1H), 8.35 (m, 1H), 7.95 (m, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.36 (m, 1H), 7.19 (m, 2H), 3.88 (s, 3H), 2.91 (m, 3H), 2.50 (s, 3H). ESIMS: (MH):437, (MNa): 459.

EXAMPLE B(18) 0325 N-(5-5-4-Amino-2-(6-morpholin-4-yl-pyridin-3-ylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 111

0326 1H-NMR (d6-dmso): 10.62 (s, 1H), 10.27 (s, 1H), 8.39 (m, 1H), 8.33 (m, 1H), 7.85 (m, 1H), 7.63 (m, 3H), 7.48 (m, 1H), 7.30 (s, 2H), 7.20 (m, 1H), 6.88 (m, 1H), 3.85 (s, 3H), 3.70 (m, 4H), 3.42 (m, 4H). ESIMS: (MH): 607.

EXAMPLE B(19) 0327 N-5-5-(4-Amino-2-isopropylamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 112

0328 1H-NMR (d6-acetone): 9.37 (s, 1H), 8.70 (m, 1H), 7.65-7.60 (m, 3H), 7.45 (m, 1H), 7.34 (m, 1H), 7.18 (m, 1H), 6.78 (s, 2H), 3.96 (m, 1H), 3.90 (s, 3H), 1.30 (d, 6H). ESIMS: (MH): 487.

EXAMPLE B(20) 0329 N-(5-5-4-Amino-2-(pyridin-3-ylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide-TFA salt 113

0330 1H-NMR (d6-acetone and d6-dmso): 11.07 (s, 1H), 9.94 (s, 1H), 8.98 (m, 1H), 8.54 (m, 1H), 8.30 (m, 2H), 7.64 (m, 3H), 7.48-7.36 (m, 4H), 7.18 (m, 2H), 3.89 (s, 3H). ESIMS: (MH): 522.

EXAMPLE B(21) 0331 5-5-(4-Amino-2-isopropylamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl-carbamic acid tert-butyl ester 114

0332 1H-NMR (d6-acetone): 8.42 (s, 1H, 8.18 (m, 1H), 7.70 (m, 1H), 7.67 (m, 1H), 7.26 (m, 1H), 6.73 (s, 2H), 3.97 (m, 1H), 2.54 (s, 3H), 1.50 (s, 9H), 1.29 (d, 6H). ESIMS: (MH): 431.

EXAMPLE B(22) 0333 N-3-5-(4-Amino-2-isopropylamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-4-methyl-phenyl-3-methoxy-benzamide 115

0334 1H-NMR (d6-acetone): 9.59 (s, 1H), 8.42 (m, 1H), 8.03 (m, 1H), 7.57 (m, 2H), 7.43-7.7.37 (m, 3H), 7.14 (m, 1H), 6.73 (s, 2H), 3.97 (m, 1H), 3.88 (s, 3H), 2.60 (s, 3H), 1.29 (d, 6H). ESIMS: (MH): 465.

EXAMPLE B(23) 0335 3-5-(4-Amino-2-phenyl-thiazol-5-yl)-1,2,4oxadiazol-3-yl-4-methyl-phenyl-carbamic acid tert-butyl ester 116

0336 1H-NMR (d6-acetone): 9.78 (s, 1H), 8.44 (s, 1H), 7.72 (m, 3H), 7.42 (m, 2H), 7.39 (m, 1H), 7.11 (m, 1H), 6.91 (s, 2H), 2.57 (s, 3H), 1.51 (s, 9H). ESIMS: (MH): 465.

EXAMPLE B(24) 0337 (3-5-4-Amino-2-(1H-benzoimidazol-5-yl)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl)-carbamic acid tert-butyl ester

EXAMPLE B(25) 0338 (3-5-4-Amino-2-(3,4,5-trimethoxy-phenyl)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl)-carbamic acid tert-butyl ester 117

0339 1H-NMR (d6-acetone): 9.62 (s, 1H), 8.23 (m, 1H), 8.09 (m, 1H), 7.15-7.05 (m, 2H), 7.39 (m, 3H), 6.82 (s, 2H), 6.91 (s, 2H), 4.07-3.85 (s, 9H), 3.76 (s, 3H), 1.49 (s, 9H). ESIMS: (MH): 571.

EXAMPLE B(26) 0340 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid 3-5-(4-amino-2-phenyl-thiazol-5-yl)-1,2,4oxadiazol-3-yl-4-methyl-phenyl-amide 118

0341 1H-NMR (d6-acetone): 10.75 (s, 1H), 9.42 (m, 1H), 8.38 (m, 1H), 7.99 (m, 1H), 7.20 (m, 2H), 7.45-7.35 (m, 3H), 7.12 (m, 1H), 6.90 (s, 2H), 6.74 (s, 1H), 4.55 (quartet, 2H), 2.62 (s, 3H), 2.21 (s, 3H), 1.39 (t, 3H). ESIMS: (MH): 500, (MNa): 523.

EXAMPLE B(27) 0342 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid 3-(5-4-amino-2-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl-thiazol-5-yl-1,2,4oxadiazol-3-yl)-4-methyl-phenyl-amide 119

0343 1H-NMR (CD3OD): 8.37 (m, 1H), 8.25 (m, 1H), 7.89 (m, 1H), 7.77 (m, 1H), 7.34 (m, 1H), 6.87 (m, 1H), 6.73 (m, 1H), 4.51 (quartet, 2H), 3.58 (m, 4H), 2.72 (m, 4H), 2.58 (s, 3H), 2.46 (s, 3H), 2.28 (s, 3H), 1.42 (t, 3H). ESIMS: (MH): 600.

EXAMPLE B(28) 0344 N-5-(5-4-Amino-2-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl-thiazol-5-yl-1,2,4oxadiazol-3-yl)-2-chloro-4-methyl-phenyl-3-methoxy-benzamide 120

0345 1H-NMR (d6-acetone and d6-dmso): 10.51 (s, 1H) 9.89 (s, 1H), 8.47 (m, 2H), 7.91 (m, 1H), 7.70-7.51 (m, 3H), 7.45 (m, 1H), 7.20-7.14 (m, 3H), 6.89 (m, 1H), 3.91 (s, 3H), 3.58 (m, 4H), 2.67 (s, 3H), 2.58 (m, 4H), 2.36 (s, 3H). ESIMS: (MH): 632.

EXAMPLE B(29) 0346 2-Hydroxy-4-methyl-pentanoic acid 3-(5-4-amino-2-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl-thiazol-5-yl-1,2,4oxadiazol-3-yl)-4-methyl-phenyl-amide 121

0347 1H-NMR (CD3OD): 8.47 (m, 1H), 8.28 (m, 1H), 8.01 (m, 1H), 7.68 (m, 1H), 7.32 (m, 1H), 7.00 (m, 1H), 4.20 (m, 1H), 3.41-3.31 (m, 7h), 2.99 (m, 4H), 2.59 (s, 3H), 1.93 (m, 1H), 1.65 (m, 2H), 1.10 (d, 6H). ESIMS: (MH): 578.

EXAMPLE B(30) 0348 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (3-5-4-amino-2-(4-hydroxy-phenyl)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl)-amide 122

0349 1H-NMR (d6-acetone): 9.77 (s, 1H), 9.43 (s, 1H), 8.36 (m, 1H), 7.98 (m, 1H), 7.66 (m, 2H), 7.41-7.36 (m, 3H), 6.90 (s, 2H), 6.75 (s, 1H), 4.64 (m, 2H), 4.54 (quartet, 2H), 4.14 (m, 1H), 2.61 (s, 3H), 2.20 (s, 3H), 1.39 (t, 3H). ESIMS: (MH): 531.

EXAMPLE B(31) 0350 (Z)-2-Methyl-but-2-enoic acid 3-(5-4-amino-2-4-(4-methyl-piperazin-1-yl)-phenyl-thiazol-5-yl-1,2,4oxadiazol-3-yl)-4-methyl-phenyl-amide 123

0351 1H-NMR (d6-acetone): 10.55 (s, 1H), 9.92 (s, 1H), 8.60 (m, 1H), 8.24 (m, 1H), 7.81 (m, 2H), 7..31 (m, 1H), 7.22 (s, 2H), 6.87 (m, 1H), 5.61 (m, 1H), 3.45 (m, 4H), 2.50 (s, 3H), 2.40 (m, 4H), 2.22 (s, 3H), 1.92 (s, 3H), 1.72 (d, 3H). ESIMS: (MH): 546.

EXAMPLE B(32) 0352 (Z)-2-Methyl-but-2-enoic acid (3-5-4-amino-2-(3-pyrrolidin-1-ylmethyl-phenyl)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl)-amide 124

0353 1H-NMR (CD3OD): 8.31 (m, 1H), 7.80 (m, 2H), 7.68 (m, 1H), 7.50 (m, 2H), 7.32 (m, 1H), 5.70 (m, 1H), 4.33 (s, 2H), 2.59 (s, 3H), 2.16 (s, 3H), 2.10 (m, 4H), 1.99 (m, 4H), 1.80 (m, 3H). ESIMS: (MH): 530.

EXAMPLE B(33) 0354 (3-5-4-Amino-2-(3-pyrrolidin-1-ylmethyl-phenyl)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-methyl-phenyl)-carbamic acid tert-butyl ester 125

0355 1H-NMR (d6-acetone): 10.48 (s, 1H), 8.61 (m, 1H), 8.47 (m, 1H), 8.23 (m, 1H), 7.74 (m, 1H), 7.63 (m, 1H), 7.38-7.28 (m, 5H), 4.33 (s, 2H), 3.47 (m, 4H), 2.80 (m, 4H), 2.58 (s, 3H), 1.51 (s, 9H), ESIMS: (MH): 548.

EXAMPLE B(34) 0356 (3-5-4-Amino-2-(3-pyrrolidin-1-ylmethyl-phenyl)-thiazol-5-yl-1,2,4oxadiazol-3-yl4-methyl-phenyl)-carbamic acid isobutyl ester 126

0357 1H-NMR (d6-acetone): 10.46 (s, 1H), 8.75 (m, 1H), 8.52 (m, 1H), 8.26 (m, 1H), 7.74 (m, 1H), 7.63 (m, 1H), 7.36-7.27 (m, 3H), 7.22 (s, 2H), 4.29 (s, 2H), 3.92 (d, 2H), 3.22 (m, 4H), 3.09 (m, 4H), 2.57 (s, 3H), 1.98 (m, 1H), 0.97 (d, 6H), ESIMS: (MH):548. 127

0358 1H-NMR (d6-acetone): 9.79 (s, 1H), 8.45 (s, 1H), 8.11-8.15 (m, 2H), 7.71 (m, 1H), 7.64 (m, 1H) 7.39 (m, 1H), 7.29 (m, 1H), 6.79 (s, 2H), 2.57 (s, 3H), 1.51 (s, 9H). ESIMS: (MH): 505.

EXAMPLE B(35) 0359 3-3-(3-methoxybenzoyl)amino-6-methyl-phenyl-5-(2-phenylamino)-4-amino-5-thiazolyl-1,2,4-oxadiazole 128

0360 1H NMR (d6-DMSO): 2.55 (s, 3H), 3.85 (s, 3H), 7.1 (m, 1H), 7.18 (m, 1H), 7.2 (s br, 2H), 7.4 (m, 2H), 7.45 (m, 2H), 7.55 (m, 2H), 7.7 (dd, 2H), 7.95 (dd, 1H), 8.35 (d, 1H), 10.35 (s br, 1H), 10.85 (s br, 1H). ESIMS MH: 499. Anal. Calcd. for C26 H22 N6 O3 S: C, 62.64; H, 4.45, N, 16.86; S, 6.43. Found: C, 62.41; H, 4.54, N, 16.72; S, 6.30.

EXAMPLE B(36) 0361 3-3-(3-methoxybenzoyl)amino-6-methyl-phenyl-5-2-3-amino-6-(4-morpholinyl)-pyridinyl-4-amino-5-thiazolyl-1,2,4-oxadiazole 129

0362 1H NMR (d6-DMSO): 2.55 (s, 3H), 3.4 (m, 4H), 3.7 (m, 4H), 3.85 (s, 3H), 6.9 (d, 1H), 7.15 (m, 1H), 7.22 (s br, 1H), 7.35 (d, 1H), 7.45 (m, 1H), 7.55 (m, 2H), 7.85 (dd, 1H), 7.95 (dd, 1H), 8.4 (dd, 2H), 9.75 (s br, 1H), 10.35 (s br, 1H), 10.7 (s br, 1H). ESIMS MH: 585.

EXAMPLE B(37) 0363 5-3-3-(5-Methyl-2H-1,2,4triazol-3-yl)-phenyl-1,2,4-oxadiazol-5-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 130

0364 (A) To 1 (6.0 g, 37.5 mmol) in 120 mL EtOH was added hydrazine (6.24 mL, 200 mmol, 5.3 eq.) dropwise. The resulting solution was placed in a 90 C. oil bath. The reaction was allowed to stir until 1 disappeared by TLC (2 h). The reaction was allowed to cool, the solvent was reduced to 50 mL by rotary evaporation, and 2 precipitated as a white solid. The solid was collected by filtration. The volume of the filtrate was further reduced to 20 mL and diluted with ether (10 mL) allowing a second crop of 2 to be collected. The two crops were combined after 1H NMR showed them to be equally pure (yield: 5.07 g, 83%). Rf 10.8 (25%CH2Cl2-EtOAc), Rf 20.2 (25%CH2Cl2-EtOAc). 2: 1H-NMR (d6-dmso): 9.98 (s, 1H), 8.21 (m, 1H), 8.14 (m, 1H), 8.00 (m, 1H), 7.71 (m, 1H), 4.60 (s, 2H). 131

0365 (B) To a solution of acetamidine HCl (2.3 g, 24.6 mmol, 1 eq) in 20 mL anhydrous ethanol was added NaOEt (24.6 mL, 1 M in EtOH, 1 eq) under argon. After 30 min. the cloudy solution was filtered through a fritted funnel packed with celite. To the resulting clear solution was added 2. Upon addition of 2 the reaction turns yellow and cloudy. The solution clears after 5 min. of stirring and then a heavy precipitate forms. The reaction is allowed to stir until 2 disappears by TLC (3 h). Rf 20.75 (30%EtOH: 30%CHCl3: 40%EtOAc), Rf of uncyclized intermediate0.2 (30%EtOH: 30%CHCl3: 40%EtOAc). The reaction was stirred on ice for 30 min. and then filtered to yield a white solid (2.125 g, 85%). 2.07 g of this intermediate was dissolved in 10 mL xylenes and 0.52 mL 1-octanol and placed in a 150 C. oil bath. After 15 h full conversion to 3 was observed by TLC and white crystals had precipitated. The reaction was placed in an ice-MeOH bath for 15 min. and then filtered. The crystals were washed with cold xylenes and then dried to yield 1.636 g 3 (83%). Rf 30.6 (30%EtOH: 30%CHCl3: 40%EtOAc). 3: 1H-NMR (d6-dmso): 13.89 (s, 1H), 8.27 (m, 2H), 7.86 (m, 1H), 7.67 (m, 1H), 2.43 (s, 3H). 132

0366 Compound 3 was further reacted in a similar manner according to the procedure of B(1) to form Example B(37). 1H-NMR (d6 acetone): 8.85 (m, 1H), 8.26 (m, 1H), 8.15 (m, 1H), 7.63 (m, 1H), 7.09 (s, 2H), 7.01 (s, 2H), 3.86 (s, 6H), 3.72 (s, 3H), 2.49 (s, 3H). ESIMS: (MH): 507. 0367 Examples B(38) and B(39) are formed in a similar manner to the procedure described in B(37).

EXAMPLE B(38) 0368 5-3-3-(5-isopropyl-2H-1,2,4triazol-3-yl)-phenyl-1,2,4oxadiazol-5-yl-N2-(3.4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 133

0369 1H-NMR (d6-acetone): 13.79 (s, 1H), 10.78 (s, 1H), 8.63 (m, 1H), 8.15 (m, 2H), 7.63 (m, 1H), 7.36 (s, 2H), 7.02 (s, 2H), 3.81 (s, 6H), 3.72 (s, 3H), 3.13 (septet, 1H), 1.33 (d, 6H). ESIMS: (MH): 535.

EXAMPLE B(39) 0370 5-(3-5-5-Isobutyl-2H-1,2,4triazol-3-yl)-phenyl-1,2,4oxadiazol-5-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 134

0371 1H-NMR (d6-acetone): 12.75 (s, 1H), 9.68 (s, 1H), 8.81 (m, 1H), 8.23 (m, 1H), 8.11 (m, 1H), 7.58 (m, 1H), 7.02 (s, 2H), 6.93 (s, 2H), 3.77 (s, 6H), 3.67 (s, 3H), 2.51 (d, 2H), 2.01 (m, 1H), 0.98 (d, 6H). ESIMS: (MH): 549. 135

0372 A solution of (3-nitrophenyl)-N2-trimethoxyphenyl-2,5bithiazolyl-2,4-diamine (1 mmol), prepared as in Example A(1), and stannous chloride (3 mmol) in DMF (3 mL), under an argon atmosphere, was stirred at 50 C. (internal temperature) for 2.5 h. The resulting dark-brown solution was diluted with ethyl acetate (10 mL) and NaHCO3 (10 mL), causing formation of a precipitate, which was removed by filtration and rinsed with 50% DMF/ethyl acetate (20 mL) until the filtrate was nearly colorless. The filtrate was then washed with NaHCO3 (30 mL), brine (30 mL), dried over MgSO4, filtered, stripped of solvent, and purified by flash chromatography (gradient elution, 10% acetone/CH2Cl2 to 40% acetone/CH2Cl2) to give 4-(3-aminophenyl)-N2-(3,4,5-trimethoxyphenyl)-2,5bithiazolyl-2,4-diamine. Mp 205-210 C. (decomp). 1H NMR (DMSO-d6): 10.35 (br d, NH2), 7.41 (s, 1H), 7.18 (s, 1H), 7.07 (d, 1H, J4.82 Hz, 1H), 7.00 (s, 2H), 6.95 (s, 1H), 6.57-6.52 (m, 1H), 5.13 (br d, NH2), 3.80 (s, 6H), 3.65 (s, 3H). FABMS (MH): 456. Anal. Calcd for C21H21N5O3S2: C, 55.37; H, 4.65; N, 15.37; S, 14.08. Found: C, 55.59; H, 4.72; N, 15.11; S, 13.92.

EXAMPLE C(2) 0373 3-3-Aminophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 136

0374 A solution of 267 mg (0.49 mmol) of 3-(3-t-butyloxycarboxy-aminophenyl)-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole (prepared according to Example B(2)) in 3 mL of 50% trifluoroacetic acid in dichloromethane was stirred for 60 minutes at ambient temperature and then poured onto ice. 3N NaOH was added dropwise until the solution was basic, and the mixture was extracted with EtOAc. The organic layer was washed with NaHCO3 and brine, and dried over Na2SO4. The solvent was removed to yield 204 mg (95% yield) of the title compound as a light yellow solid. 0375 1H NMR (d6-acetone): 3.6 (s, 3H), 3.75 (s, 6H), 4.8 (s br, 2H), 6.75 (m, 1H), 6.85 (s br, 2H), 6.95 (s, 2H), 7.1 (t, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 9.6 (s br, 1H). ESIMS (MH): 441; (MH): 439. Anal. Calcd for C20H20N6O4S: C, 54.53; H, 4.58; N, 19.08; S, 7.28. Found: C, 54.79; H, 4.59; N, 18.81; S, 7.09.

EXAMPLE C(3) 0376 4-4-Amino-4-(3-amino-phenyl)-bithiazolyl-2-ylamino-benzenesulfonamide 137

0377 In a similar manner to that described above for Examples C(1) and C(2), the title compound was prepared. 0378 1H NMR (CD3OD): 7.88 (s, 4H), 7.42 (s, 1H), 7.40-7.29 (m, 2H), 7.25-7.18 (m, 1H), 6.80-6.72 (m, 1H). FABMS (MH): 445.

EXAMPLE C(4) 0379 3-3-amino-6-fluorophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 138

0380 1H NMR (CDCl3MeOD 10:1): 3.85 (s, 3H), 3.95 (s, 6H), 6.75 (m, 2H), 7.1 (m, 2H), 7.7 (s br, 1H). ESIMS MH: 459.

EXAMPLE C(5) 0381 3-2-fluoro4-methoxy-5-aminophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 139

0382 1H NMR (d6-DMSO): 3.6 (s, 3H), 3.8 (s, 6H), 4.0 (s, 3H), 6.95 (s br, 2H), 7.2 (m, 3H), 8.65 (d, 1H), 9.05 (s br, 1H). ESIMS MH: 489.

EXAMPLE C(6) 0383 3-(3-amino-6-methyl-phenyl)-5-2-(3,4,5 trimethoxyphenyl)-amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 140

0384 1H NMR (CDCl3): 2.05 (s, 3H), 3.8 (s, 9H), 6.2 (s br, 2H), 6.6 (s br, 2H), 6.8 (m br, 1H), 7.05 (m br, 1H), 7.45 (s br, 1H). ESIMS MH: 455.

EXAMPLE C(7) 0385 5-3-(5-Amino-2-chloro-phenyl)-1,2,4oxadiazol-5-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 141

0386 1H-NMR (d6-acetone): 9.58 (s, 1H), 7.13 (m, 2H), 6.92 (s, 2H), 6.78 (s, 2H), 6.70 (m, 1H), 4.91 (s, 2H), 3.78 (s, 6H), 3.58 (s, 3H). ESIMS:(MH): 475 (100%), 477 (30%.)

EXAMPLE C(8) 0387 5-3-(5-Amino-2,4,-difluoro-phenyl)-1,2,4oxadiazol-5-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 142

0388 1H-NMR (d6-acetone): 9.72 (s, 1H), 7.63 (m, 1H), 7.09 (m, 1H), 7.05 (s, 2H), 6.94 (s, 2H), 4.83 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H). ESIMS (MH): 477.

EXAMPLE C(9) 0389 5-3-(5-Amino-2-chloro-4-fluoro-phenyl)-1,2,4oxadiazol-5-yl-N-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 143

0390 1H-NMR (d6-dmso) 10.76 (s, 1H), 7.36 (m, 2H), 7.18 (s, 2H), 6.93 (s, 2H), 5.60 (s, 2H), 3.86 (s, 6H), 3.73 (s, 3H). ESIMS (MH) 493(100%), 495(30%).

EXAMPLE D(1) 0391 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenylacetamide 144

0392 Acetic anhydride (21.3 L, 0.2250 mmol) was added to a solution of 4-(3-aminophenyl)-N2-(3,4,5-trimethoxyphenyl)-2,5bithiazolyl-2,4-diamine (50.0 mg, 0.1125 mmol), prepared as described in Example C(1), dissolved in pyridine (28.5 L, 0.352 mmol), DMF (70 L), and THF (700 L) at 15 C. (bath temperature). After 30 minutes, the reaction was quenched with MeOH (0.5 mL), concentrated, and purified by preparative C-18 reverse-phase HPLC (gradient elution, 95% H2O/0.1% TFA/CH3CN to 5% H2O/0.1% TFA/CH3CN), giving 46 mg (82% yield) of N-3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenylacetamide. 0393 1H NMR (CDCl3): 7.97 (s, 1H), 7.56 (d, J7.7 Hz, 1H), 7.44 (d, J7.8 Hz, 1H), 7.30 (t, J7.6 Hz, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 6.55 (s, 2H), 5.90-6.10 (bs, 1H), 3.82 (s, 6H), 3.78 (s, 3H), 2.14 (s, 3H). ESIMS (MH): 498. Anal. Calcd. for C23H23N5O4S2.(0.5 H2O, 0.5 acetone): C, 54.93; H, 5.08; N, 13.08; S, 11.97. Found: C, 54.73; H, 4.80; N, 13.21; S, 11.98. 0394 In a manner analogous to that described for Example D(1), the following Examples D(2) through D(57) were prepared.

EXAMPLE D(2) 0395 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-C-phenyl-methanesulfonamide 145

0396 1H NMR (CDCl3): 7.61 (s, 1H), 7.55 (d, J7.9 Hz, 1H), 7.32 (d, J7.9 Hz, 1H), 7.26-7.16 (m, 5H), 7.03 (s, 1H), 7.00 (s, 2H), 6.51 (s, 2H), 6.42 (s, 1H), 5.90-6.00 (bs, 2H), 4.26 (s, 2H), 3.78 (s, 6H), 3.74 (s, 3H). ESIMS (MH): 610. Anal. Calcd. for C28H27N5O5S3.0.3 H2O: C, 54.67; H, 4.52; N, 11.39. Found: C, 54.70; H, 4.52; N, 11.04.

EXAMPLE D(3) 0397 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-methanesulfonamide 146

0398 1H NMR (CDCl3): 7.81 (s, 1H), 7.69 (d, J7.8 Hz, 1H), 7.45 (t, J7.9 Hz, 1H), 7.26 (s, 1H), 7.24 (s, 1H), 6.73 (bs, 1H), 6.70 (s, 2H), 3.92 (s, 6H), 3.89 (s, 3H), 3.12 (s, 3H). ESIMS (MH): 534. Anal. Calcd. for C22H23N5O5S3.0.9 TFA: C, 44.92; H, 3.79; N, 11.01; S, 15.12. Found: C, 44.94; H, 3.87; N, 11.12.

EXAMPLE D(4) 0399 3-4-Amino2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid phenyl ester 147

0400 1H NMR (CDCl3): 8.04 (s, 1H), 7.64 (t, J7.2 Hz, 1H), 7.46-7.38 (m, 5H), 7.28-7.18 (m, 4H), 7.14 (s, 1H), 7.05 (s, 1H), 6.64 (s, 2H), 6.09 (bs, 1H), 3.91 (s, 6H), 3.87 (s, 3H). ESIMS (MH): 576. Anal. Calcd. for C28H25N5O5S2.0.3 DMF: C, 58.08; H, 4.57; N, 12.42; S, 10.73. Found: C, 58.33; H, 4.39; N, 11.53; S, 10.68.

EXAMPLE D(5) 0401 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-2-phenyl-acetamide 148

0402 1H NMR (CDCl3): 7.89 (s, 1H), 7.64 (d, J7.4 Hz, 1H), 7.47-7.32 (m, 7H), 7.14 (s, 1H), 7.10 (s, 1H), 6.64 (s, 2H), 6.06 (bs, 2H), 3.91 (s, 6H), 3.87 (s, 3H), 3.79 (s, 2H). ESIMS (MH): 574. Anal. Calcd. for C29H27N5O4S2: C, 60.71; H, 4.74; N, 12.21; S, 11.18. Found: C, 60.88; H, 4.78; N, 12.00; S, 11.14.

EXAMPLE D(6) 0403 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid methyl ester 149

0404 1H NMR (CDCl3): 8.14 (s, 1H), 7.82 (d, J6.9 Hz, 1H), 7.59 (m, 3H), 7.34 (s, 1H), 6.90 (s, 1H), 6.85 (s, 2H), 6.40-6.20 (bs, 1H), 4.12 (s, 6H), 3.78 (s, 3H), 2.14 (s, 3H). ESIMS (MH): 514. Anal. Calcd. for C23H23N5O5S2.0.305 H2O: C, 53.13; H, 4.60; N, 13.47; S, 12.34. Found: C, 53.10; H, 4.58; N, 13.34; S, 12.11.

EXAMPLE D(7) 0405 1-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-methyl-urea 150

0406 1H NMR (CDCl3): 8.63 (bs, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 7.49 (d, J8.0 Hz, 1H), 7.39 (d, J8.2 Hz, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.75 (s, 2H), 6.00-6.10 (bs, 1H), 5.35 (bs, 1H), 3.87 (s, 6H), 3.81 (s, 3H), 2.80 (d, J4.3 Hz, 3H). ESIMS (MH): 513. Anal. Calcd. for C23H24N6O4S2.0.4 H2O: C, 53.14; H, 4.81; N, 16.17; S, 12.34. Found: C, 53.15; H, 4.75; N, 16.12; S, 12.46.

EXAMPLE D(8) 0407 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-propionamide 151

0408 1H NMR (CDCl3): 8.27 (s, 1H), 7.85 (d, J7.5 Hz, 1H), 7.74 (d, J8.0 Hz, 1H), 7.59 (t, J7.9 Hz, 1H), 7.41 (s, 1H), 7.33 (s, 1H), 6.84 (s, 2H), 6.20-6.35 (bs, 1H), 4.11 (s, 6H), 4.07 (s, 3H), 2.64 (q, J7.6 Hz, 2H), 1.50 (t, J7.5 Hz, 3H). ESIMS (MH): 512. Anal. Calcd. for C24H25N5O4S2: C, 56.34; H, 4.93; N, 13.69; S, 12.54. Found: C, 56.22; H, 5.01; N, 13.48; S, 12.73.

EXAMPLE D(9) 0409 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-isobutyramide 152

0410 1H NMR (CDCl3): 9.16 (s, 1H), 8.54 (s, 1H), 8.06 (s, 1H), 7.57 (d, J8.1 Hz, 1H), 7.53 (d, J7.8 Hz, 1H), 7.27 (t, J8.0 Hz, 1H), 7.03 (s, 1H), 6.77 (s, 2H), 6.00-6.20 (bs, 1H), 3.81 (s, 6H), 3.75 (s, 3H), 2.18 (m, 3H), 0.95 (d, J6.3 Hz, 6H). ESIMS (MH): 540. Anal. Calcd. for C26H29N5O4S2.0.5 H2O: C, 56.91; H, 5.51; N, 12.76; S, 11.69. Found: C, 57.33; H, 5.57; N, 12.28; S, 11.64.

EXAMPLE D(10) 0411 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid isopropyl ester 153

0412 1H NMR (CDCl3): 7.93 (s, 1H), 7.60 (d, J6.9 Hz, 1H), 7.40 (m, 3H), 7.13 (s, 1H), 6.65 (s, 2H), 6.62 (s, 1H), 6.08 (bs, 2H), 5.06 (m, J6.4 Hz, 1H), 3.92 (s, 6H), 3.87 (s, 3H), 1.33 (d, J6.4 Hz, 6H). ESIMS (MH): 542. Anal. Calcd. for C25H27N5O5S2: C, 55.44; H, 5.02; N, 12.93; S, 11.84. Found: C, 55.15; H, 5.14; N, 12.46; S, 11.75.

EXAMPLE D(11) 0413 4-Chloro-pyridine-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 154

0414 HRFABMS: Calcd. for C27H23ClN6O4S2 (MH): 594.0911. Found: 594.0927. Anal. Calcd for C27H23ClN6O4S2: C, 54.94; H, 3.90; N, 14.12; S, 10.78. Found: C, 54.43; H, 3.87; N, 14.01; S, 10.92.

EXAMPLE D(12) 0415 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid benzyl ester 155

0416 1H NMR (CDCl3): 7.93 (s, 1H), 7.61 (d, J7.0 Hz, 1H), 7.40 (m, 7H), 7.12 (s, 1H), 6.76 (s 1H), 6.64 (s, 2H), 6.07 (bs, 2H), 5.25 (s, 2H), 3.91 (s, 6H), 3.87 (s, 3H). ESIMS (MH): 590. Anal. Calcd. for C29H27N5O5S2: C, 59.07; H, 4.62; N, 11.88; S, 10.88. Found: C, 58.84; H, 4.64; N, 11.71; S, 11.07.

EXAMPLE D(13) 0417 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-2,2,2-trifluoro-acetamide 156

0418 1H NMR (CDCl3): 8.14 (s, 1H), 7.96 (bs, 1H), 7.79 (d, J6.4 Hz, 1H), 7.48 (d, J8.0 Hz, 1H), 7.17 (s, 1H), 6.65 (s, 2H), 6.05 (bs, 2H), 3.92 (s, 6H), 3.87 (s, 3H). ESIMS (MH): 552. HRMS (FAB), m/z Calcd. for C23H20F3N5O4S2 (MH): 552.0987. Found: 552.0981.

EXAMPLE D(14) 0419 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-2,2-difluoro-acetamide 157

0420 1H NMR (CDCl3): 8.15 (s, 1H), 7.98 (bs, 1H), 7.75 (d, J7.5 Hz, 1H), 7.61 (d, J8.1 Hz, 1H), 7.46 (t, J8.0 Hz, 1H), 7.17 (s, 1H), 6.66 (s, 2H), 6.08 (bs, 2H), 3.93 (s, 6H), 3.89 (s, 3H), 3.52 (s, 1H). ESIMS (MH): 534. HRMS (FAB), m/z Calcd. for C23H21F2N5O4S2 (MCs): 666.0057. Found: 666.0032.

EXAMPLE D(15) 0421 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-2-phenoxy-acetamide 158

0422 1H NMR (CDCl3): 8.27 (s, 1H), 8.06 (s, 1H), 7.63 (d, J7.8 Hz, 1H), 7.51 (d, J8.0 Hz, 1), 7.32 (m, 4H), 7.07 (s, 1H), 6.56 (s, 2H), 6.01 (bs, 2H), 4.58 (s, 2), 3.82 (s, 6H), 3.78 (s, 3H). ESIMS (MH): 590. Anal. Calcd. for C29H27N5O5S2.(0.7 H2O, 0.2 EtOAc): C, 57.73; H, 4.88; N, 11.30; S, 15.74. Found: C, 57.97; H, 4.59; N, 11.08; S, 10.33.

EXAMPLE D(16) 0423 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-phenyl-propionamide 159

0424 1H NMR (CDCl3): 7.97 (s, 1H), 7.63 (d, J8.0 Hz, 1H), 7.46 (d, J7.9 Hz, 1H), 7.40 (m, 3H), 7.12 (s, 1H), 7.06 (s, 1H), 6.64 (s, 2H), 6.07 (bs, 1H), 3.91 (s, 6H), 3.87 (s, 3H), 3.11 (t, J7.5 Hz, 2H), 2.72 (t, J7.5 Hz, 2H). ESIMS (MH): 588. Anal. Calcd. for C30H29N5O5S2: C, 61.31; H, 4.97; N, 11.92; S, 10.91. Found: C, 60.67; H, 5.09; N, 11.77; S, 10.69.

EXAMPLE D(17) 0425 3-4-Amino-2-(2,4-dimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid benzyl ester 160

0426 1H NMR (CDCl3): 7.65 (s, 1H), 7.48 (d, J9.4 Hz, 1H), 7.37 (d, J7.3 Hz, 1H), 7.16 (m, 7H), 6.85 (s, 1H), 6.54 (s, 1H), 6.31 (m, 3H), 6.00-5.70 (bs, 2H), 5.00 (s, 2H), 3.65 (s, 3H), 3.60 (s, 3H). ESIMS (MH): 560. Anal. Calcd. for C28H25N5O4S2.0.7 H2O: C, 59.14; H, 4.61; N, 12.32; S, 11.28. Found: C, 59.51; H, 4.41; N, 11.82; S, 10.90.

EXAMPLE D(18) 0427 3-4-Amino-2-(2,5-dimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid benzyl ester 161

0428 1H NMR (CDCl3): 7.91 (s, 1H), 7.65 (d, J9.4 Hz, 1H), 7.37 (d, J7.3 Hz, 1H), 7.16 (m, 7H), 6.85 (s, 1H), 6.54 (s, 1H), 6.31 (m, 3H), 6.00-5.70 (bs, 2H), 5.00 (s, 2H), 3.65 (s, 6H), 3.60 (s, 3H). ESIMS (MH): 560. Anal. Calcd. for C28H25N5O4S2: C, 60.09; H, 4.50; N, 12.51; S, 11.46. Found: C, 60.52; H, 4.64; N, 12.00; S, 10.96.

EXAMPLE D(19) 0429 3-4-Amino-2-(4-phenoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid benzyl ester 162

0430 1H NMR (CDCl3): 7.90 (s, 1H), 7.61 (d, J7.4 Hz, 1W, 7.46 (m, 10H), 7.11 (m, 8H), 6.81 (s, 1H), 6.08 (bs, 2H), 5.25 (s, 2H). ESIMS (MH): 592. Anal. Calcd. for C32H25N5O3S2: C, 64.96; H, 4.26; N, 11.84; S, 10.84. Found: C, 64.68; H, 4.36; N, 11.58; S, 10.65.

EXAMPLE D(20) 0431 3-(4-Amino-2-phenylamino-2,5bithiazolyl-4-yl)-phenyl-carbamic acid benzyl ester 163

0432 1H NMR (CDCl3): 7.81 (s, 1H), 7.55 (d, J7.3 Hz, 1H), 7.30 (m, 12H), 7.10 (m, 1H), 7.02 (s, 1H), 6.68 (s, 1H), 6.10-5.90 (bs, 2H), 5.15 (s, 2H). ESIMS (MH): 500. HRMS (FAB), m/z Calcd. for C26H21N5O2S2 (MH): 500.1215. Found: 500.1232.

EXAMPLE D(21) 0433 Benzofuran-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 164

0434 ESMS (MH): 600. Anal. Calcd for C30H25N5O5S2.0.75 H2O: C, 58.76; H, 4.36; N, 11.42; S, 10.46. Found: C, 58.74; H, 4.08; N, 11.46; S, 10.41.

EXAMPLE D(22) 0435 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid naphthalen-1-yl ester 165

0436 ESMS (MH): 626. Anal. Calcd for C32H27N5O5S2.0.7 H2O: C, 60.21; H, 4.48; N, 10.97; S, 10.05. Found: C, 60.24; H, 4.31; N, 10.72; S, 10.03.

EXAMPLE D(23) 0437 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid 1-R-phenyl-ethyl ester 166

0438 ESMS (MH): 604. Anal. Calcd for C30H29N5O5S2.0.4 H2O: C, 58.98; H, 4.92; N, 11.46; S, 10.50. Found: C, 58.93; H, 4.90; N, 11.41; S, 10.27.

EXAMPLE D(24) 0439 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-benzamide 167

0440 ESMS (MH): 560. Anal. Calcd for C28H25N5O4S2: C, 60.09; H, 4.50; N, 12.51; S, 11.46. Found: C, 60.07; H, 4.54; N, 12.45; S, 11.42.

EXAMPLE D(25) 0441 3-4-Amino-2-(4-sulfamoyl-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid benzyl ester 168

0442 ESMS (MH): 579.

EXAMPLE D(26) 0443 4-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenylcarbamoyloxymethyl-benzoic acid methyl ester 169

0444 ESMS (MH): 648. Anal. Calcd for C31H29N5O7S2: C, 57.48; H, 4.51; N, 10.81; S, 9.90. Found: C, 57.66; H, 4.52; N, 10.64; S, 10.08.

EXAMPLE D(27) 0445 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-isopropyl-benzamide 170

0446 ESMS (MH): 602. Anal. Calcd for C31H31N5O4S2: C, 61.88; H, 5.19; N, 11.64; S, 10.66. Found: C, 61.45; H, 5.38; N, 11.30; S, 10.38.

EXAMPLE D(28) 0447 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-4-fluoro-benzamide 171

0448 ESMS (MH): 578. Anal. Calcd for C28H24N5O4S2.0.3 H2O: C, 57.68; H, 4.25; N, 12.01; S, 11.00. Found: C, 57.64; H, 4.32; N, 11.79; S, 10.97.

EXAMPLE D(29) 0449 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-bromo-benzamide 172

0450 ESMS (MH): 638/640. Anal. Calcd for C28H24BrN5O4S2: C, 52.67; H, 3.79; N, 10.97; S, 10.04. Found: C, 52.49; H, 3.99; N, 10.36; S, 9.71.

EXAMPLE D(30) 0451 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-4-chloro3-methyl-benzamide 173

0452 ESMS (MH): 608/610. Anal. Calcd for C29H26ClN5O4S2.0.6 H2O: C, 56.27; H, 4.43; N, 11.32; S, 10.36. Found: C, 56.36; H, 4.38; N, 11.14; S, 10.14.

EXAMPLE D(3 1) 0453 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3,4-dimethyl-benzamide 174

0454 ESMS (MH): 588.

EXAMPLE D(32) 0455 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-methoxy-4-methyl-benzamide 175

0456 ESMS (MH): 604. Anal. Calcd for C30H29N5O5S2.0.6 H2O: C, 58.52; H, 5.07; N, 11.08; S, 10.14. Found: C, 58.48; H, 5.03; N, 10.75; S, 9.95.

EXAMPLE D(33) 0457 2,4-Dimethyl-thiazole-5-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 176

0458 ESMS (MH): 595. Anal. Calcd for C27H26N6O4S3.0.2 H2O: C, 54.22; H, 4.77; N, 13.08; S, 14.97. Found: C, 54.59; H, 4.89; N, 12.61; S, 14.73.

EXAMPLE D(34) 0459 5-Methyl-thiophene-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 177

0460 ESMS (MH): 580. Anal. Calcd for C27H25N5O4S,: C, 55.94; H, 4.35; N, 12.08; S, 16.59. Found: C, 55.78; H, 4.26; N, 11.80; S, 16.58.

EXAMPLE D(35) 0461 5-Chloro-thiophene-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 178

0462 ESMS (MH): 600/602. Anal. Calcd for C26H22ClN5O4S3: C, 52.03; H, 3.69; N, 11.67; S, 16.03. Found: C, 51.61; H, 3.82; N, 11.46; S, 16.01.

EXAMPLE D(36) 0463 5-Bromo-thiophene-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 179

0464 ESMS (MH): 644/646. Anal. Calcd for C26H22BrN5O4S3.0.8 H2O: C, 47.39; H, 3.61; N, 10.63; S, 14.60. Found: C, 47:31; H, 3.51; N, 10.57; S, 14.70.

EXAMPLE D(37) 0465 5-Bromo-furan-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 180

0466 ESMS (MH): 628/630. Anal. Calcd for C26H22BrN5O5S2.0.5 H2O: C, 48.98; H, 3.64; N, 10.99; S, 10.06. Found: C, 48.98; H, 3.43; N, 10.79; S, 9.80.

EXAMPLE D(38) 0467 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-methyl-benzamide 181

0468 ESMS (MH): 574. Anal. Calcd for C29H27N5O4S2.0.5 H2O.0.5 CH2Cl2: C, 56.67; H, 4.68; N, 11.20; S, 10.26. Found: C, 56.76; H, 4.39; N, 11.04; S, 10.12.

EXAMPLE D(39) 0469 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-ethyl-benzamide 182

0470 ESMS (MH): 588. Anal. Calcd for C30H29N5O4S2.0.4 H2O: C, 60.56; H, 5.05; N, 11.77; S, 10.78. Found: C, 6063; H, 4.87; N, 11.57; S, 10.65.

EXAMPLE D(40) 0471 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-chloro-benzamide 183

0472 ESMS (MH): 594/596. Anal. Calcd for C28H24ClN5O4S2.0.5 H2O.0.3 CH2Cl2: C, 54.07; H, 4.11; N, 11.14; S, 10.20. Found: C, 54.16; H, 3.88; N, 10.95; S, 10.10.

EXAMPLE D(41) 0473 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-3-methoxy-benzamide 184

0474 ESMS (MH): 590. Anal. Calcd for C29H27N5O5S2.0.85 H2O: C, 57.57; H, 4.78; N, 11.58; S, 10.60. Found: C, 57.62; H, 4.58; N, 11.40; S, 10.53.

EXAMPLE D(42) 0475 5-Methyl-thiazole-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 185

0476 ESMS (MH): 581. Anal. Calcd for C26H24N6O4S3: C, 53.78; H, 4.17; N, 14.47; S, 16.57. Found: C, 53.57; H, 4.24; N, 14.23; S, 16.47.

EXAMPLE D(43) 0477 3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-carbamic acid tert-butyl ester 186

0478 ESMS (MH): 556. Anal. Calcd for C26H29N5O5S2.0.4 H2O: C, 55.48; H, 35.34; N, 12.44; S, 11.39. Found: C, 55.33; H, 5.28; N, 12.55; S, 11.12.

EXAMPLE D(44) 0479 3-3-Benzyloxycarboxy-aminophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 187

0480 1H NMR (d6-acetone): 3.7 (s, 3H), 3.85 (s, 6H), 5.2 (s, 2H), 6.95 (s br, 2H), 7.05 (s, 2H), 7.4 (m, 6H), 7.8 (d, 2H), 8.35 (s, 1H), 8.95 (s br, 1H), 9.7 (s br, 1H). ESIMS (MH): 575; (MH): 573.

EXAMPLE D(45) 0481 3-3-Acetamidophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 188

0482 1H NMR (d6-DMSO): 2.0 (s, 3H), 3.6 (s, 3H), 3.75 (s, 6H), 6.95 (s, 2H), 7.25 (s br, 2H), 7.4 (t, 1H), 7.75 (m, 2H), 8.2 (s, 1H), 10.1 (s br, 1H), 10.7 (s br, 1 H). ESIMS (MNa): 505; (MH): 481.

EXAMPLE D(46) 0483 3-3-Benzamidophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 189

0484 1H NMR (d6-acetone): 3.7 (s, 3H), 3.85 (s, 6H), 7.0 (s br, 2H), 7.05 (s, 2H), 7.6 (m, 4H), 7.9 (m, 1H), 8.05 (m, 2H), 8.1 (m, 1H), 8.6 (m br, 1H), 9.75 (s br, 1H). ESIMS (MH): 545; (MNa): 567; (MH): 543.

EXAMPLE D(47) 0485 3-3-(3-Methylbenzamido)phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 190

0486 1H NMR (d6-acetone): 2.2 (s, 3H), 3.5 (s, 3H), 3.65 (s, 6H), 6.75 (s br, 2H), 6.85 (s, 2H), 7.2 (d, 2H), 7.3 (t, 1H), 7.65 (m, 3H), 7.95 (d, 1H), 8.35 (s br, 1H), 9.5 (s br, 2H). ESIMS (MH): 559; (MNa): 581; (MH): 557. Anal. Calcd for C28H26N6O5S: C, 60.20; H, 4.69; N, 15.04; S, 5.74. Found: C, 60.34; H, 4.82; N, 14.39; S, 5.50.

EXAMPLE D(48) 0487 3-3-(3-Methoxybenzamido)phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 191

0488 1H NMR (d6-acetone): 3.7 (s, 3H), 3.85 (s, 6H), 3.9 (s, 3H), 7.0 (s br, 2H), 7.1 (s, 2H, 7.15 (m, 1H), 7.45 (t, 1H), 7.55 (t, 1H), 7.65 (m, 2H), 7.9 (m, 1H), 8.15 (m, 1H), 8.6 (m, 1H), 9.7 (d br, 2H). ESIMS (MH): 575; (MNa): 597; (MH): 573. Anal. Calcd for C28H26N6O6S: C, 58.53; H, 4.56; N, 14.63; S, 5.58. Found: C, 58.89; H, 4.78; N, 13.88; S, 5.35.

EXAMPLE D(49) 0489 3-3-(3-Trifluoromethylbenzamido)phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 192

0490 1H NMR (d6-DMSO): 3.65 (s, 3H), 3.85 (s, 6H), 7.0 (s, 2H), 7.25 (s br, 2H), 7.55 (t, 1H), 7.8 (m, 2H), 8.0 (d, 1H), 8.1 (d, 1H), 8.32 (d, 1H), 8.35 (d, 1H), 8.45 (s br, 1H), 10.7 (s, 1H), 10.8 (s, 1H). ESIMS (MH): 613; (MNa):; 635; (MH): ;611. Anal. Calcd for C28H23F3N6O5S: C, 54.90; H, 3.78; F, 9.30; N, 13.72; S, 5.23. Found: C, 53.55; H, 3.95; N, 12.24; S, 4.67.

EXAMPLE D(50) 0491 3-3-(3-Chlorobenzamido)phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 193

0492 1H NMR (d6-acetone): 3.6 (s, 3H), 3.75 (s, 6H), 6.85 (s br, 2H), 6.95 (s, 2H), 7.45 (m, 3H), 7.75 (d, 1H), 7.9 (d, 1H), 8.0 (m, 2H), 8.45 (s, 1H), 9.6 (s br, 1H), 9.7 (s br, 1H). ESIMS (MH): 579/581; (MH): 577/579. Anal. Calcd for C27H23ClN6O5S: C, 56.01; H, 4.00; Cl, 6.12; N, 14.51; S, 5.54. Found: C, 55.53; H, 4.23; Cl, 6.31; N, 14.00; S, 5.33.

EXAMPLE D(51) 0493 3-3-(2-Carboxy-5-methylthiazolyl)-aminophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 194

0494 1H NMR (d6-DMSO): 2.6 (s, 3H), 3.65 (s, 3H), 3.85 (s, 6H), 7.0 (s, 2H), 7.38 (s br, 2H), 7.55 (t, 1H), 7.85 (m, 2H), 8.05 (m, 1H), 8.65 (m, 1H), 10.75 (s, 1H), 10.95 (s, 1H). ESIMS (MNa): 588; (MH): 564. Anal. Calcd for C25H23N7O5S2: C, 53.09; H, 4.10; N, 17.33; S, 11.34. Found: C, 50.46; H, 4.39; N, 16.10; S, 10.47.

EXAMPLE D(52) 0495 3-3-(3-Chlorobenzamido)phenyl-5-2-(3-aminopyridyl)-4-amino-5-thiazolyl-1,2,4-oxadiazole 195

0496 1H NMR (d6-DMSO): 7.42 (m, 3H), 7.57 (m, 2H), 7.7 (m, 1H), 7.85 (m, 1H), 7.98 (m, 1H), 8.07 (m, 2H), 8.2 (m, 1H), 8.3 (m, 1H), 8.48 (m, 1H), 8.88 (d br, 1H), 10.6 (s br, 1H), 11.1 (s br, 1H). ESIMS (MH): 490/492; (MH): 577/579. Anal. Calcd for C23H16ClN7O2S: C, 56.38; H, 3.29; N, 20.01; S, 6.54. Found: C, 53.07; H, 3.41; N, 18.01; S, 5.90.

EXAMPLE D(53) 0497 2-Methyl-thiazole-5-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 196

0498 ESMS (MH): 581. Anal. Calcd for C26H24N6O4S3.0.5 H2O: C, 52.95; H, 4.27; N, 14.25; S, 16.31. Found: C, 52.99; H, 4.27; N, 14.21; S, 16.39.

EXAMPLE D(54) 0499 6-Chloro-pyridine-2-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 197

0500 ESMS (MH): 595/597. Anal. Calcd for C27H23ClN6O4S2.(0.5 H2O, 0.5 CH2Cl2): C, 51.08; H, 3.90; N, 13.00; S, 9.92. Found: C, 51.04; H, 3.65; N, 12.54; S, 9.63.

EXAMPLE D(55) 0501 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4 yl-phenyl-2-chloro-isonicotinamide 198

0502 HRFABMS: Calcd. for C27H23ClN6O4S2 (MNa): 617.0808. Found: 617.0832. Anal. Calcd for C27H23ClN6O4S2.0.6 H2O: C, 53.52; H, 4.03; N, 13.87; S, 10.58. Found: C, 53.53; H, 3.85; N, 13.39; S, 10.42.

EXAMPLE D(56) 0503 N-(3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-3,5-dimethyl-benzamide trifluoroacetate salt 199

0504 1H NMR (CD3COCD3): 9.65 (s, 1H), 8.56 (s, 1H), 8.13 (d, 1H), 7.88 (d, 1H), 7.67 (s, 2H), 7.53 (m, 1H), 7.24 (s, 1H), 7.07 (s, 3H), 3.86 (s, 6H), 3.75 (s, 3H), 2.39 (s, 6H). ESIMS: (MH): 573; (MNa): 595; (MH): 571.

EXAMPLE D(57) 0505 N-(3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3- yl-phenyl)-2-methyl-benzamide trifluoroacetate salt 200

0506 1H NMR (CD3COCD3): 9.58 (s, 1H), 8.60 (s, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.67 (s, 2H), 7.56 (m, 2H), 7.36 (m, 3H), 7.07 (s, 3H), 3.86 (s, 6H), 3.73 (s, 3H), 2.49 (s, 3H). ESIMS: (MH): 559; (MNa): 581; (MH): 557.

EXAMPLE D(58) 0507 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-4-hydroxy-3,5-dimethyl-benzamide 201

0508 A solution of 4-(3-aminophenyl)-N2-(3,4,5-trimethoxyphenyl)-2,5bithiazolyl-2,4-diamine (100 mg, 0.2195 mmol) from example C(1), 4-hydroxy-3,5-dimethylbenzoic acid (38.3 mg, 0.2305 mmol), triethylamine (64 L, 0.4609 mmol), and DMF (1.0 mL) were treated with HATU (O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate) (87.6 mg, 0.2305 mmol), and stirred for 30 minutes at room temperature. The crude product was purified by preparative C-18 reverse phase HPLC (gradient elution, 95% H2O/0.1% TFA/CH3CN to 5% H2O/0.1% TFA/CH3CN), giving 33 mg (25% yield) of title compound as a yellow powder. 0509 Anal. Calcd. for C30H29N5O5S2.0.5 H2O: C, 58.81; H, 4.94; N, 11.43; S, 14.36. Found: C, 58.81; H, 4.87; N, 11.50; S, 10.50. ESIMS (MNa): 626. 0510 The following examples D(59) through D(61) were prepared in manner analogous to D(58).

EXAMPLE D(59) 0511 N-3-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-2-bicyclo2.2.1hept-2-yl-acetamide 202

0512 Anal. Calcd. for C30H33N5O4S2.0.8 H2O: C, 59.44; H, 5.75; N, 11.55; S, 10.58. Found: C, 59.43; H, 5.55; N, 11.40; S, 10.54. ESIMS (MH): 592.

EXAMPLE D(60) 0513 Quinoline-3-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 203

0514 Anal. Calcd. for C31H26N6O4S2.0.3 H2O: C, 60.43; H, 4.35; N, 13.64; S, 10.41. Found: C, 60.49; H, 4.36; N, 13.77; S, 10.40. ESIMS (MH): 611.

EXAMPLE D(61) 0515 5-Phenyl-oxazole-4-carboxylic acid 3-4-amino-2-(3,4,5-trimethoxy-phenylamino)-2,5bithiazolyl-4-yl-phenyl-amide 204

0516 ESIMS (MH): 627. In a manner analogous to that described for Example D(1), the following Examples D(62) through D(77) were prepared.

EXAMPLE D(62) 0517 Hex-5-ynoic acid (3-5-4-amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-amide 205

0518 1H-NMR (d6-acetone): 9.72 (s, 1H), 9.35 (s, 1H), 8.39 (m, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.46 (m, 1H), 7.06 (s, 2H, 6.98 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 2.57 (s, 2H), 2.33 (t, 2H), 1.93 (m, 3H). ESIMS: (MH): 535, (MH): 533.

EXAMPLE D(63) 0519 N-3(5-4-Amino-2-3-(2H-tetrazol-5-yl)-phenylamino-thiazol-5-yl-1,2,4oxadiazol-3-yl)-phenyl-3-chloro-benzamide 206

0520 1H-NMR (d6-dmso): 11.04 (s, 1H), 10.59 (s, 1H), 8.46 (s, 1H), 8.17 (m, 1H), 8.11 (m, 2H), 7.98 (m, 1H), 7.83 (m, 2H), 7.69 (m, 2H), 7.56 (m, 3H), 7.42 (m, 3H). ESIMS: (MH): 557(100%), 559(30%).

EXAMPLE D(64) 0521 N-(3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-,2,4oxadiazol-3-yl-4-chloro-phenyl)-3-chloro-benzamide 207

0522 1H-NMR (d6-DMSO): 10.79 (s, 1H), 10.66 (s, 1H), 8.39 (m, 1H), 8.06 (m, 3H), 7.68 (m, 1H), 7.65 (m, 2H), 7.33 (s, 2H), 7.02 (s, 2H), 3.81 (s, 6H), 3.65 (s, 3H). ESIMS: (MH): 613 (100%), 615 (60%).

EXAMPLE D(65) 0523 N-(3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazyl-4-chloro-phenyl)-3-methoxy-benzamide 208

0524 1H-NMR (d6-DMSO): 10.79 (s, 1H), 10.53 (s, 1H), 8.40 (m, 1H), 8.07 (m, 1H), 7.66 (m, 1H), 7.55 (m, 3H), 7.33 (s, 2H), 7.19 (m, 1H), 6.96 (s, 2H), 3.85 (s, 3H), 3.81 (s, 6H), 3.65 (s, 3H). ESIMS: (MH): 609 (100%), 611 (30%).

EXAMPLE D(66) 0525 N-(5-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino )-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-chloro-benzamide 209

0526 1H-NMR (d6 acetone) 9.73 (s, 1H), 9.58 (s, 1H), 8.73 (m, 1H), 8.07 (m, 1H), 8.02 (m, 1H), 7.65 (m, 2H), 7.42 (m, 1H), 7.06 (s, 2H), 6.98 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H). ESIMS: (MH): 615(100%), 617(30%).

EXAMPLE D(67) 0527 N-(5-5-4-Amino-2-(3,4,5-trimethoxy-pheny-1-amino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 210

0528 1H-NMR (d6 acetone): 9.71 (s, 1H), 9.41 (s, 1H), 8.73 (m, 1H), 7.61 (m, 2H), 7.47 (m, 1H), 7.37 (m, 1H), 7.21 (m, 1H), 7.06 (s, 2H), 6.98 s, 2H), 3.90 (s, 3H), 3.85 (s, 6H), 3. 72 (s, 3H). ESIMS: (MH): 611.

EXAMPLE D(68) 0529 N-(3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-yl-phenyl)-3-cyano-benzamide 211

0530 1H-NMR (d6-acetone): 9.91 (s, 1H), 9.73 (s, 1H), 8.55 (m, 1H), 8.45 (m, 1H), 8.38 (m, 1H), 8.13 (m, 1H), 8.03 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.56 (m, 1H), 7.07 (s, 2H), 7.00 (s, 2H), 3.86 (s, 6H), 3.73 (s, 3H). ESIMS: (MH): 570.

EXAMPLE D(69) 0531 N-(5-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-chloro-2-fluoro-phenyl)-3-chloro-benzamide 212

0532 1H-NMR (d6-acetone: 9.73 (s, 1H), 9.63 (s, 1H), 8.74 (m, 1H), 8.07 (m, 1H), 8.03 (m, 1H), 7.68 (m, 2H), 7.63 (m, 1H), 7.07 (s, 2H), 6.98 (s, 2H), 3.86 (s, 6H), 3.73 (s, 3H). ESIMS: (MH): 631(100%), 633(60%), 635(10%).

EXAMPLE D(70) 0533 N-(5-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-4-chloro-2-fluoro-phenyl)-3-methoxy-benzamide TFA salt 213

0534 1H-NMR (d6-acetone): 9.74 (s, 1H), 9.45 (s, 1H), 8.74 (m, 1H), 7.61 (m, 2H), 1.46 (m, 1H), 7.19 (m, 1H), 7.06 (s, 3H), 6.97 (s, 2H), 3.89 (s, 3H), 3.85 (s, 6H), 3.72 (s, 3H). ESIMS: (MH): 627(100%), 629(30%).

EXAMPLE D(71) 0535 N-(3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-3-carboxyimido-benzamide 214

0536 1H-NMR (d6-acetone): 9.91 (s, 1H), 9.73 (s, 1H), 8.58 (m, 2H), 8.21 (m, 1H), 8.15 (m, 2H), 7.85 (m, 1H), 7.66 (m, 2H), 7.57 (m, 1H), 7.06 (s, 2H), 7.00 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H). ESIMS: (MH): 588.

EXAMPLE D(72) 0537 Example: 3-2-fluoro-5-(3-methoxybenzoyl)amino-phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 215

0538 1H NMR (d6-DMSO): 3.7 (s, 3H), 3.85 (s, 6H), 3.9 (s, 3H), 7.05 (s, 2H), 7.25 (m, 1H), 7.6 (m, 6H), 8.15 (m, 1H), 8.55 (m, 1H), 10.5 (s, 1H), 10.85 (s, 1H). ESIMS MH: 593. Anal. Calcd: C, 56.75; H, 4.25; F, 3.21, N, 14.18; S, 5.41. Found: C, 56.55; H, 4.48, N, 13.20; S, 5.39.

EXAMPLE D(73) 0539 3-3-(3-chlorobenzoyl)amino)-6-fluoro-phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 216

0540 1H NMR (d6-DMSO): 3.7 (s, 3H), 3.85 (s, 6H), 6.95 (s, 2H), 7.05 (s, 2H), 7.35 (t, 1H), 7.6 (m, 2H), 8.0 (m, 2H), 8.15 (m, 1H), 8.55 (m, 1H), 9.7 (s br, 1H), 9.85 (s br, 1H). ESIMS MH: 597, 599.

EXAMPLE D(74) 0541 3-3-(3-methoxybenzoyl)amino-6-methyl-phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 217

0542 1H NMR (MeOD): 2.6 (s, 3H), 3.75 (s, 3H), 3.85 (s, 6H), 3.9 (s, 3H), 7.0 (s, 2H), 7.15 (m, 1H), 7.35 (d, 1H), 7.45 (t, 1H), 7.55 (m, 2H), 7.8 (m, 1H), 8.35 (d, 1H). ESIMS MH: 589. Anal. Calcd. for C29 H28 N6 O6 S: C, 59.17; H, 4.79, N, 14.28; S, 5.45. Found: C, 60.07; H, 5.30, N, 13.69; S, 5.07.

EXAMPLE D(75) 0543 3-3-(3-chlorobenzoyl)amino-6-methyl-phenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 218

0544 1H NMR (MeOD): 2.6 (s, 3H), 3.75 (s, 3H), 3.85 (s, 6H), 7.0 (s, 2H), 7.35 (m, 1H), 7.57 (m, 2H), 7.8 (m, 1H), 7.9 (m, 1H), 8.0 (m, 1H), 8.35 (d, 1H). ESIMS MH: 593, 595. Anal. Calcd. for C28 H25 Cl N6 O5 S: C, 56.71; H, 4.25, N, 14.17; S, 5.41. Found: C, 56.66; H, 4.38, N, 13.54; S, 4.89.

EXAMPLE D(76) 0545 3-3-(4-morpholinylmethyl)benzoylaminophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 219

0546 1H NMR (d6-acetone): 2.6 (m, 4H), 3.7 (s, 2H), 3.8 (m, 4H), 3.9 (s, 3H), 4.0 (s, 6H), 7.1 (s, 2H), 7.2 (s, 2H), 7.65 (m, 3H), 8.0 (d br, 1H), 8.15 (d, 2H), 8.3 (d br, 1H), 9.8 (s br, 1H), 10.05 (s br, 1H). ESIMS MH: 644.

EXAMPLE D(77) 0547 3-3-4-(4-methyl-1-piperazinyl)methyl-benzoylaminophenyl-5-2-(3,4,5-trimethoxyphenyl)amino-4-amino-5-thiazolyl-1,2,4-oxadiazole 220

0548 1H NMR (d6-acetone): 2.6 (m br, 8H), 3.5 (s br, 2H), 3.6 (s, 3H), 3.7 (s, 6H), 6.8 (s, 2H), 6.9 (s, 2H), 7.4 (m, 3H), 7.75 (m, 1H), 7.9 (d, 2H), 8.0 (m, 1H), 8.4 (m, 1H), 9.55 (s br, 1H), 9.65 (s br, 1H). ESIMS MH: 657.

EXAMPLE D(78) 0549

221

EXAMPLE E(1) 0550 3-5-(2,4-Diaminothiazol-5-yl)-1,2,4oxadiazol-3-yl-phenyl-carbamic acid tert-butyl ester 222

0551 A solution of 1.3 mmol of (3-5-4-amino-2-(trityl-amino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-carbamic acid tert-butyl ester, prepared as described in Example B(1), dissolved in 8 ml of 1:1 formic acid/diethyl ether was stirred at room temperature until the starting material had been consumed by TLC (typically 5 h). The resulting light yellow solution was stripped of all solvent in vacuo, heated gently under high vacuum to remove residual formic acid, and then recrystallized from methylene chloride, giving 255 mg of the title compound (53% yield) as a light-yellow powder. 0552 1H NMR (DMSO-d6): 9.54 (s, 1H), 8.177 (s, 1H), 8.07 (s, 2H), 7.65-7.59 (m, 3H), 7.39 (t, 1H), 7.12 (bs, 2H), 1.49 (s, 9H). ESMS (MH): 375. Anal. Calcd for C19H15ClN6O2S3: C, 46.48; H, 3.08; N, 17.12; S, 19.59. Found: C, 46.47; H, 3.21; N, 17.10; S, 19.43.

EXAMPLE E(2) 0553 N-3-(2 ,4-Diamino-2,5bithiazolyl-4-yl)-phenylbenzamide 223

0554 A solution of 4-amino-2-(trityl-amino)-thiazole-5-carbothioic acid amide (304 mg, 0.73 mmol) and N-(3-Bromoacetyl-phenyl)-benzamide (300 mg, 0.94 mmol) in MeOH (30 ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 ml). The EtOAc solution was washed with a saturated aqueous solution of NaHCO3 (325 ml). The organic layer was separated, dried over MgSO4, and concentrated. Purification of the residue was achieved by silica gel chromatography (75% EtOAc/DCM) providing N-3-(2,4-diamino-2,5bithiazolyl-4-yl)-phenyl-benzamide (110 mg, 39% yield). mp 159-163 C. (decomp). 1H NMR (CD3OD): 8.33 (s, 1H), 8.00-7.97 (m, 2H), 7.75-7.71 (m, 2H), 7.64-7.52 (m, 3H), 7.43 (t, J7.74 Hz, 1H), 7.33 (s, 1H). FABMS Calcd for C19H15N5OS2: 394.0796. Found: 394.0802.

EXAMPLE E(3) 0555 N-3-(2,4-Diamino-2,5bithiazolyl-4-yl)phenyl-5-chloro-thiophene-2-carboxamide 224

0556 Starting material was prepared following Steps (i) and (ii) described below. 0557 Step (i): Oxalyl chloride (4.9 mL, 56.00 mmol) was added to solution of 5-chloro-thiophene-2-carboxylic acid (4.78 g, 29.40 mmol), DMF (0.25 mL), and CH2Cl2 (50 ml) at room temperature. After stirring overnight, the reaction was stripped of solvent and unreacted oxalyl choride in vacuo, giving a colorless oil. The oil was dissolved in CH2Cl2 (50 mL), and treated with 3-aminoacetophenone (3.78 g, 28.00 mmol) and triethylamine (4.68 mL, 33.60 mmol). After stirring for 1 h, the mixture was diluted with 800 mL of ethyl acetate, extracted with 1N HCl, 1N NaHCO3, brine, and dried over MgSO4. The resulting solution was concentrated in vacuo to a volume of 100 mL, giving 5-chloro-thiophene-2-carboxylic acid (3-acetyl-phenyl)-amide as a white powder, which was collected by filtration and dried under high vacuum (8.12 g, 81% yield). 0558 Step (ii): A solution of 5-chloro-thiophene-2-carboxylic acid (3-acetyl-phenyl)-amide (2.0 g, 7.17 mmol) and CuBr2 (3.19 g, 14.34 mmol) in EtOAc (100 ml) was heated to reflux. Progress of the reaction was monitored every 30 minutes by TLC. After 2.5 h, starting material was still present, so additional CuBr2 (0.75 g) was added. After an additional 1.5 h, TLC indicated that all starting material had been consumed. The reaction was reduced in volume by 50% in vacuo, diluted with CH2Cl2 (50 mL), filtered through a plug of silica, which was eluted with 40% ethyl acetate/CH2Cl2 (300 mL). The resulting solution was concentrated in vacuo, giving a colorless oil, which was taken up in CH2Cl2 (2 mL) and precipitated with diethyl ether (10 mL), giving 5-chloro-thiophene-2-carboxylic acid (3-bromoacetyl-phenyl)-amide (2.06 g, 80% yield) as white powder. 0559 The title compound was prepared as follows. To a solution of 1.07 g (3.0 mmol) of 4-amino-2-(trityl-amino)-thiazole-5-carbothioic acid amide (prepared analogously to the starting material described in step (ii) of Example A(1)) dissolved in DMF (12 mL), was added 5-chloro-thiophene-2-carboxylic acid (3-bromoacetyl-phenyl)-amide. After 15 minutes, the reaction was diluted with MeOH (12 mL), treated with TFA (4 mL), and stirred overnight. The resulting solution was concentrated in vacuo, diluted with ethyl acetate, extracted with 1M NaHCO3, extracted with brine, dried over MgSO4, concentrated, and purified by flash chromatography (gradient elution: 5% CH3CN/CH2Cl2 to 30% CH3CN/CH2Cl2), giving 0.47 g (36% yield) of N-3-(2,4-diamino-2,5bithiazolyl-4-yl)phenyl-5-chloro-thiophene-2-carboxamide. 0560 1H NMR (DMSO-d6): 10.41 (s, 1H), 8.23 (s, 1H), 7.95 (d, J4.1 Hz, 2H), 7.73-7.65 (m, 4H), 7.48 (s, 1H), 7.41 (t, J8.1 Hz, 1H), 7.29 (d, J4.1 Hz, 1H), 6.90 (s, 2H).

EXAMPLE E(4) 0561 (2,4-Diamino-2,5bithiazolyl-4-yl)-phenyl-methanone 225

0562 The title compound was prepared in a manner similar to Example E(3). 1H NMR (CD3OD): 8.02-7.99 (m, 2H), 7.94 (s, 1H), 7.76 (s, NH2), 7.70-7.64 (m, 1H), 7.57-7.52 (m, 2H), 6.85 (bs, NH2). FABMS (MH): 303. FABMS Calcd for C13H10N4OS2 (MNa): 325.0194. Found: 325.0182.

EXAMPLE F(1) 0563 5-Chloro-thiophene-2-carboxylic acid 3-4-amino-2-(3-methyl-ureido)-2,5bithiazolyl-4-yl-phenyl-amide 226

0564 A solution of N-3-(2,4-diamino-2,5bithiazolyl-4-yl)phenyl-5-chloro-thiophene-2-carboxamide (0.2307 mmol) (prepared as in Example E(3)), dissolved in anhydrous THF (5.0 mL) and anhydrous N-methylpyrolidinone (1.0 mL) at 78 C., was treated phenyllithium (0.2307 mmol), followed by methylisocyanate (0.3461 mmol). After 5 minutes a second portion of phenyllithium (0.2307 mmol) was added slowly. After stirring for an additional 15 minutes, the reaction was quenched with acetic acid (0.6921 mmol), and methanol (0.5 mL), concentrated, and purified by reverse phase HPLC. The major component was collected, dissolved in ethyl acetate, extracted with NaHCO3, brine, dried over MgSO4, concentrated until a precipitate formed, and filtered. Mass of the resulting light-yellow powder after drying under high vacuum was 46 mg (41% yield). 0565 ESMS (MH): 491/493. Anal. Calcd for C19H15ClN6O2S3: C, 46.48; H, 3.08; N, 17.12; S, 19.59. Found: C, 46.47; H, 3.21; N, 17.10; S, 19.43. 0566 In an analogous manner to that described in Example F(1), the following Examples F(2) through F(15) were prepared.

EXAMPLE F(2) 0567 N-3-(2-Acetylamino-4-amino-2,5bithiazolyl-4-yl)-phenyl-5-chloro-thiophene-2-carboxamide 227

0568 ESMS (MH): 476/478. Anal. Calcd for C19H14N5O2S3: C, 47.94; H, 2.96; N, 14.17; S, 19.46. Found: C, 47.66; H, 3.39; N, 13.87; S, 19.21.

EXAMPLE F(3) 0569 (4-Amino-4-3-(5-chloro-thiophene-2-carbonyl)-amino-phenyl-2,5bithiazolyl-2-yl)-carbamic acid methyl ester 228

0570 ESMS (MH): 492/494.

EXAMPLE F(4) 0571 N-3-5-(2-Acetylamino-4-amino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-phenyl-3-chloro-benzamide 229

0572 1H NMR (CD3COCD3/DMSO-d6): 10.55 (s, 1H), 8.60 (m, 1H), 8.20 (m, 2H), 8.15 (m, 1H), 8.19 (m, 1H), 7.66-7.50 (m, 4H), 7.12 (s, 2H), 2.22 (s, 3H). ESIMS: (MNa): 477; (MH): 453.

EXAMPLE F(5) 0573 Thiophene-2-carboxylic acid (4-amino-5-3-3-(3-chloro-benzoylamino)-phenyl-1,2,4oxadiazol-5-yl-thiazol-2-yl)-amide 230

0574 1H NMR (DMSO-d6): 13.19 (s, 1H), 10.60 (s, 1H), 8.52 (s, 1H), 8.32 (m, 1H), 8.09-7.88 (m, 5H), 7.72-7.56 (m, 3H), 7.29 (m, 1H), 7.22 (s, 2H). ESIMS: (MH): 523; (MNa): 545; (MH): 521.

EXAMPLE F(6) 0575 N-3-5-(4-Amino-2-propionylamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-phenyl-3-chloro-benzamide 231

0576 1H NMR (DMSO-d6): 12.41 (s, 1H), 10.57 (s, 1H), 8.48 (s, 1H), 8.06 (m, 2H), 7.96 (m, 1H), 7.85 (m, 1H), 7.70 (m, 1H), 7.67-7.55 (m, 2H), 7.15 (s, 2H), 2.46 (q, 2H), 1.09 (t, 3H). ESIMS: (MNa): 491; (MH): 467.

EXAMPLE F(7) 0577 N-3-5-(4-amino-2-benzoylamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-phenyl-3-chloro-benzamide 232

0578 1H NMR (DMSO-d6): 13.08 (s, 1H), 10.57 (s, 1H), 8.50 (s, 1H), 8.43-8.10 (m, 4H), 8.07 (m, 1H), 7.97 (m, 1H), 7.86 (m, 1H), 7.71-7.52 (m, 6H), 7.14 (s, 2H). ESIMS: (MH): 517; (MNa): 539; (MH): 515.

EXAMPLE F(8) 0579 N-(3-5-4-Amino-2-(3-methyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-3-methyl-benzamide 233

0580 ESMS (MH): 450. Anal. Calcd for C21H19N7O3S: C, 56.11; H, 4.26; N, 21.81; S, 7.13. Found: C, 55.97; H, 4.39; N, 21.54; S, 6.89.

EXAMPLE F(9) 0581 N-3-(2-Acetylamino-4-amino-2,5bithiazolyl-4-yl)-phenylbenzamide 234

0582 1H NMR (CD3OD): 8.27-8.24 (m, 1H), 7.89-7.85 (m, 2H), 7.67-7.61 (m, 2H), 7.51-7.31 (m, 5H), 2.14 (s, 3H). ESIMS (MH): 436; (MH): 434.

EXAMPLE F(10) 0583 N-3-4-Amino-2-(3-methyl-ureido)-2,5bithiazolyl-4-yl-phenyl-3-chloro-benzamide 235

0584 Anal. Calcd. for C21H17ClN6O2S2.1.0 H2O: C, 50.14; H, 3.81; N, 16.71; S, 12.75. Found: C, 51.12; H, 3.64; N, 16.96; S, 12.87. ESIMS (MH): 485/487.

EXAMPLE F(11) 0585 N-3-4-Amino-2-(3-methyl-ureido)-2,5bithiazolyl-4-yl-phenyl-3-methoxy-benzamide 236

0586 Anal. Calcd. for C22H20N6O3S2.0.7 H2O: C, 53.58; H, 4.37; N, 17.04; S, 13.00. Found: C, 53.60; H, 4.34; N, 17.04; S, 12.93. ESIMS (MH): 479.

EXAMPLE F(12) 0587 N-(3-5-4-Amino-2-(3-phenyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl -phenyl)-3-methyl-benzamide 237

0588 Anal. Calcd. for C26H21N7O3S: C, 61.04; H, 4.14; N, 19.17; S, 6.27. Found: C, 60.78; H, 4.18; N, 19.05; S, 6.08. ESIMS (MH): 512.

EXAMPLE F(13) 0589 N-(3-5-4-Amino-2-(3-isopropyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-3-methyl-benzamide 238

0590 Anal. Calcd. for C23H23N7O3S: C, 57.85; H, 4.85; N, 20.53; S, 6.71. Found: C, 57.65; H, 4.97; N, 20.47; S, 6.64. ESIMS (MH): 478.

EXAMPLE F(14) 0591 N-(3-5-4-Amino-2-(3-benzyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenyl)-3-methyl-benzamide 239

0592 Anal. Calcd. for C27H23N7O3S.0.9 H2O: C, 59.85; H, 4.61; N, 18.10; S, 5.92. Found: C, 59.86; H, 4.55; N, 17.86; S, 5.78. ESIMS (MH): 526.

EXAMPLE F(15) 0593 N-3-5-(4-Amino-2-methanesulfonylamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-phenyl-3-methyl-benzamide 240

0594 ESIMS (MNa): 493.

EXAMPLE F(16) 0595 N-(4-Amino-4-benzoyl-2,5bithiazolyl-2-yl)-acetamide 241

0596 1H NMR (CD3OD): 6.81-6.69 (m, 2H), 6.41-6.18 (m, 3H), 6.07-5.91 (m, 1H), 0.93 (s, 3H). FABMS Calcd for C15H12N4O2S2Na: 367.0299. Found: 367.0991.

EXAMPLE G(1) 0597 5-Pyridin-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 242

0598 3,4,5-Trimethoxyphenyl isothiocynate (250 mg, 1.11 mmol, 1 equiv.) and cyanamide (56 mg, 1.33 mmol, 1.2 equiv.) were taken up in acetonitrile-tert-butanol (1:1, 10 mL) at 23 C. To this was added KO-t-Bu (286 mg, 2.55 mmol, 2.3 equiv.) and 2-chloromethylpyridine hydrochloride (182 mg, 1.11 mmol, 1.00 equiv.). The reaction mixture was allowed to stir for 1.5 h at 23 C. The mixture was diluted with water (20 mL) and the white solids were filtered, washed with ether and dried (257 mg). The dried residue (60 mg, 0.167 mmol, 1.00 equiv.) was dissolved in THF (3 mL), cooled to 78 C. and was treated with n-butyllithium (0.261 mL, 1.6 M, 2.5 equiv.). The mixture was allowed to warm to 23 C., was quenched with saturated sodium bicarbonate, and organics were extracted into ethyl acetate. The concentrated residue was purified by silica gel chromatography (ethyl acetate/hexane: 1:1, 48.3 mg, 80%). 0599 MS (FAB) m/z Calcd: 359. Found: 359. MS (FAB) m/z Calcd: 357. Found: 357. Anal. Calcd: C, 56.97; H, 5.06; N, 15.63; S, 8.95. Found: C, 56.18; H, 5.10; N, 15.31; S, 8.68. 0600 The following Examples G(2) through G(9) were prepared in a similar manner to Example G(1).

EXAMPLE G(2) 0601 N2-Phenyl-5-pyridin-2-yl-thiazole-2,4-diamine 243

0602 MS (FAB) m/z Calcd: 269. Found: 269. Anal. Calcd: C, 62.66; H, 4.51; N, 20.88; S, 11.95. Found: C, 62.71; H, 4.46; N, 20.76; S, 11.91.

EXAMPLE G(3) 0603 N2-(2,3-Dihydro-benzo1,4dioxin-6-yl)-5-pyridin-2-yl-thiazole-2,4-diamine 244

0604 MS (FAB) m/z Calcd: 327. Found: 327. Anal. Calc'd: C, 58.88; H, 4.32; N, 17.17; S, 9.82. Found: C, 59.00; H, 4.29; N, 16.92; S, 9.58.

EXAMPLE G(4) 0605 N2-(3,4-Dimethoxy-phenyl)-5-pyridin-2-yl-thiazole-2,4-diamine 245

0606 MS (FAB) m/z Calcd: 329. Found: 329. Anal. Calcd: C, 58.52; H, 4.91; N, 17.06; S, 9.76. Found: C, 58.43; H, 4.89; N, 17.03; S, 9.67.

EXAMPLE G(5) 0607 5-Quinolin-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 246

0608 MS (FAB) m/z Calcd: 408. Found: 408. Anal. Calcd: C, 61.75; H, 4.94; N, 13.72; S, 7.85. Found: C, 61.96; H, 4.80; N, 13.05; S, 7.54.

EXAMPLE G(6) 0609 5-(6-Bromo-pyridin-2-yl)-2-N-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 247

0610 1H NMR (300 MHz, CDCl3): 7.35 (t, 1H), 6.98 (d, 1H), 6.76 (d, 1H), 6.62 (s, 2H), 3.85 (s, 6H), 3.82 (s, 3H). MS (FAB) mH/z Calcd: 437. Found: 438. Anal. Calcd: C, 46.69; H, 3.92; N, 12.81; S, 7.33. Found: C, 46.66; H, 3.84; N, 12.68; S, 7.25.

EXAMPLE G(7) 0611 5-(5-Thiophen-3-yl-1,2,4oxadiazol-3-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 248

0612 MS (FAB) m/z Calcd: 431. Found: 431. Anal. Calcd: C, 50.10; H, 3.97; N, 16.23; S, 14.86. Found: C, 50.45; H, 3.96; N, 15.31; S, 14.46.

EXAMPLE G(8) 0613 4-4-Amino-5-1-(4-chloro-benzyl)-1H-imidazol-2-yl-thiazol-2-ylamino-benzenesulfonamide 249

EXAMPLE G(9) 0614 4-4-Amino-5-(5-nitro-benzothiazol-2-yl)-thiazol-2-ylamino-benzenesulfonamide 250

0615 1H NMR (DMSO-d6): 8.35 (s, 1H), 8.02 (d, J6.5 Hz, 1H), 7.90 (d, J6.5 Hz, 1H), 7.72 (m, 4H), 7.64 (br, NH2), 7.22 (br, NH2).

EXAMPLE H(1) 0616 4-(4-Amino4-hydroxy-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 251

0617 The title compound of this example and Examples H(2) through H(6) were prepared in a manner similar to that described in Example A(1) et seq. from 2-arylaminoamino-thiazole-5-carbothioamides and -bromo esters, -bromo-lactones, or -bromo-nitriles, as appropriate. 0618 1H NMR (DMSO-d6): 7.88 (s, 4H), 7.39 (s, 1H). ESIMS (MH): 370; (MH): 368.

EXAMPLE H(2) 0619 4-4-Amino4-hydroxy-5-(4-hydroxy-phenyl)-2,5bithiazolyl-2-yl-amino-benzenesulfonamide 252

0620 1H NMR (DMSO-d6): 9.52 (s, 1H), 7.83 (m, 4H), 7.32, (s, 2H), 7.06 (d, J8.0 Hz, 2H), 7.42 (d, J8.0 Hz, 2H), 5.38 (s, 1H). ESIMS (MH): 462. Anal. Calcd for C18H15N5O4S3.0.2 H2O.0.2 Et2O: C, 47.04; H, 3.65; N, 14.59; S, 20.04. Found: C, 46.78; H, 3.59; N, 14.36; S, 20.73.

EXAMPLE H(3) 0621 4-Amino-2-(4-dimethylamino-phenylamino)-5-(2-hydroxy-phenyl)-2,5bithiazoly-4-ol 253

0622 1H NMR (DMSO-d6): 7.30 (m, 2H), 7.04 (m, 2H), 6.68 (m, 4H), 2.88 (s, 6H). ESIMS (MH): 426; (MH): 424.

EXAMPLE H(4) 0623 4-4-Amino-4-hydroxy-5-(2-hydroxy-phenyl)-2,5bithiazoly-2-ylamino-benzenesulfonamide 254

0624 1H NMR (CD3OD): 7.82 (m, 4H), 7.02 (m, 2H), 6.62 (m, 2H). ESIMS (MH): 462; (MH): 460.

EXAMPLE H(5) 0625 4-4-Amino-4-hydroxy-5-(2-hydroxy-ethyl)-3H-1-2,5bithiazolyl-2-ylamino-benzenesulfonamide 255

0626 1H NMR (DMSO-d6): 7.83 (s, 4H), 4.72 (m, 1H), 4.26 (m, 1H), 3.52 (m, 2H), 2.30 (m,, 1H), 1.78 (m, 1H). ESIMS (MH): 414; (MH): 412. Anal. Calcd for C14H15N5O4S3: C, 40.67; H, 3.66; N, 16.94; S, 23.26. Found: C, 40.81; H, 3.76; N, 1676; S, 23.02.

EXAMPLE H(6) 0627 4-(4,4-Diamino-2,5bithiazolyl-2-ylamino)-benzenesulfonamide 256

0628 1H NMR (DMSO-D6): 11.0 (s, NH), 8.12 (s, H), 7.80 (m, 4H), 7.32 (s, NH2), 7.08 (br s, NH2), 7.02 (s, NH2). ESIMS (MH): 369; (MH): 367.

EXAMPLE I(1) 0629 S-5-(4-Benzyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxyl-pheny)-thiazole-2,4-diamine 257

0630 A mixture of 4-amino-2-(3,4,5-trimethoxy-phenylamino)-thiazole-5-carbonitrile (153 mg, 0.5 mmol), 2(S)-amino-3-phenyl-propan-1-ol (84 mg, 0.55 mmol), and a catalytic amount of dry ZnCl2 in chlorobenzene (15 ml) was refluxed for four hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 0.1 N HCl, brine and dried with MgSO4. The product (53 mg) was obtained after silica chromatography purification (hexanes/ethyl acetate1/1). 0631 1H NMR (CDCl3): 7.33-7.22 (m, 5H), 6.58 (s, 2H), 4.50 (m, 1H), 4.24 (t, J9.0 H, 1H), 4.01 (t, J9.0 Hz, 1H), 3.86 (s, 6H), 3.82 (s, 3H), 3.11 (m, 1H), 2.70 (m, 1H). ESIMS (MH): 441; (MH): 439. 0632 The following Examples I(2) through I(19) were prepared in a similar manner:

EXAMPLE I(2) 0633 R-5-(4-Benzyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxyl-phenyl)-thiazole-2,4-diamine 258

0634 1H NMR (CDCl3): 7.33-7.22 (m, 5H), 6.58 (s, 2H), 4.50 (m, 1H), 4.24 (t, J9.0 Hz, 1H), 4.01 (t, J9.0 Hz, 1H), 3.86 (s, 6H), 3.82 (s, 3H), 3.11 (m, 1H), 2.70 (m, 1H). Anal. Calcd for C22H24N4O4S: C, 59.98; H, 5.49; N, 12.72; S, 7.28. Found: C, 59.88; H, 5.54; N, 12.67; S, 7.21.

EXAMPLE I(3) 0635 S-5-(4-Isobutyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxyl-phenyl)-thiazole-2,4-diamine 259

0636 1H NMR (CDCl3): 6.57 (s, 2H), 5.71 (brd, NH2), 4.36 (m, 1H), 4.26 (m, 1H), 3.85-3.80 (m, 10H), 1.80 (m, 1H), 1.62 (m, 1H), 1.35 (m, 1H), 0.95 (m, 6H). ESIMS (MH): 407.

EXAMPLE I(4) 0637 5-(4R)-(1R)-Benzyloxy-ethyl-4,5-dihydro-oxazol-2-yl-N2-(3,4,5-trimethoxyl-phenyl)-thiazole-2,4-diamine 260

0638 1H NMR (CDCl3): 7.35-7.25 (m, 5H), 6.58 (s, 2H), 5.70 (brd, NH2), 4.70-4.59 (m, 2H), 4.48 (m, 1H), 4.25 (m, 2H), 3.86 (s, 6H), 3.83 (s, 3H), 3.77 (m, 1H), 1.14 (m, 3H). ESIMS (MH): 485.

EXAMPLE I(5) 0639 S-4-4-Amino-5-(4-phenyl-4,5-dihydro-oxazol-2-yl)-thiazol-2-ylamino-benzenesulfonamide 261

0640 1H NMR (CD3OD): 7.82 (m, 4H), 7.34 (m, 5H), 5.26 (t, J8 Hz, 1H), 4.72 (t, J7.80 Hz, 1H), 4.16 (t, J7.80 Hz, 1H). Anal. Calcd for C18H17N5O3S2.0.5 Et2O: C, 53.08; H, 4.90; N, 15.48; S, 14.17. Found: C, 53.36; H, 4.79; N, 15.66, S, 14.33.

EXAMPLE I(6) 0641 S-5-(4-Phenyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxyl-phenyl)-thiazole-2,4-diamine 262

0642 1H NMR (CDCl3): 7.37-7.26 (m, 5H), 6.59 (s, 2H), 5.80 (brd, NH2), 5.32 (t, J7.80 Hz, 1H), 4.65 (t, J7.80 Hz, 1H), 4.09 (t, J7.80 Hz, 1H). FABMS (MH): 427.

EXAMPLE I(7) 0643 R-5-(4-Phenyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxyl-phenyl)-thiazole-2,4-diamine 263

0644 1H NMR (CDCl3): 7.37-7.26 (m, 5H), 6.59 (s, 2H), 5.80 (brd, NH2), 5.32 (t, J7.80 Hz, 1H), 4.65 (t, J7.80 Hz, 1H), 4.09 (t, J7.80 Hz, 1H). FABMS (MH): 427.

EXAMPLE I(8) 0645 S-5-4-(3-Benzyloxy-phenyl)-4,5-dihydro-oxazol-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 264

0646 1HNMR (300 MHz, CDCl3): 3.83 (s, 3H), 3.87 (s, 6H), 4.08 (dd, J8, 8 Hz, 1H), 4.62 (dd, J8, 10 Hz, 1H), 5.05 (s, 2H), 5.30 (dd, J8, 8 Hz, 1H), 5.80 (s, 2H), 6.59 (s, 2H), 6.90 (m, 3H), 7.33 (m, 6H). HRMS (FAB) (MH)) Calcd: 533.1859. Found: 533.18477.

EXAMPLE I(9) 0647 S-3-2-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-4,5-dihydro-oxazol-4-yl-phenol 265

0648 To a solution of S-5-4-(3-benzyloxyphenyl)-4,5-dihydro-oxazo-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine (prepared as described in Example I(8)) (20 mg, 0.038 mmol) in DMF (0.5 ml), Pd black (10 mg) and ammonium formate (10 mg, 0.14 mmol) were added. The reaction mixture was stirred at room temperature for 42 h. The reaction mixture was diluted with CH2Cl2 (5 ml) and filtered through Celite. The product (4 mg) was obtained after the removing of the solvent. 0649 1HNMR (300 MHz, CD3OD): 3.74 (s, 3H), 3.85 (s, 6H), 4.28 (dd, J8, 8 Hz, 1H), 4.84 (m, 1H), 5.20 (dd, J8, 9 Hz, 1H), 6.74 (m, 3H), 6.93 (s, 2H), 7.18 (dd, J8, 8 Hz, 1H). HRMS (FAB) (MH) Calcd: 443.1389. Found: 443.1377.

EXAMPLE I(10) 0650 S-5-4-(4-Benzyloxy-phenyl)-4,5-dihydro-oxazol-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 266

0651 1HNMR (300 MHz, CDCl3): 3.82 (br s, 9H), 4.06 (dd, J8, 8 Hz, 1H), 4.60 (dd, J9, 9 Hz, 1H), 5.05 (s, 2H), 5.26 (dd, J9, 9 Hz, 1H), 5.89 (br s, 2H), 6.58 (s, 2H), 6.94 (d, J9 Hz, 2H), 7.20 (J9 Hz, 2H), 7.39 (m, 5H). HRMS (FAB) (MH) Calcd: 533.1859. Found: 533.1876.

EXAMPLE I(11) 0652 S-4-2-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-4,5-dihydro-oxazol-4-yl-phenol 267

0653 The title compound was prepared from the compound of Example I(10) in a manner similar to that described for Example 1(9). 0654 1HNMR (300 MHz, CD3OD): 3.73 (s, 3H), 3.80 (s, 6H), 4.12 (dd, J8, 8 Hz, 1H), 4.70 (dd, J9, 9 Hz, 1H), 5.16 (dd, J8, 8 Hz, 1H), 6.70 (d, J8 Hz, 2H), 6.92 (s, 2H), 7.12 (d, J8 Hz, 2H). HRMS (FAB) (MH) Calcd: 443.1389. Found: 443.1377.

EXAMPLE I(12) 0655 (R/S)-5-4-(4-Bromo-phenyl)-4,5-dihydro-oxazol-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 268

0656 MS (FAB) mH/z Calcd: 505. Found: 505. Anal. Calcd: C, 49.91; H, 4.19; N, 11.09; S, 6.34. Found: C, 49.32; H, 4.02; N, 10.59; S, 6.05.

EXAMPLE I(13) 0657 (R/S)-5-4-(2-Bromo-phenyl)-4,5-dihydro-oxazol-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 269

0658 MS (FAB) mH/z Calcd: 505. Found: 505. Anal. Calcd: C, 49.91; H, 4.19; N, 11.09; S, 6.34. Found: C, 49.32; H, 4.02; N, 10.59; S, 6.05.

EXAMPLE I(14) 0659 (R/S)-5-4-(3-Bromo-phenyl)-4,5-dihydro-oxazol-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 270

0660 MS (FAB) mH/z Calcd: 505. Found: 505. Anal. Calcd: C, 49.91; H, 4.19; N, 11.09; S, 6.34. Found: C, 50.16; H, 4.41; N, 9.64; S, 5.4.

EXAMPLE I(15) 0661 (R/S)-5-(4-Methyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 271

0662 MS (FAB) m/z Calcd: 364. Found: 364. Anal. Calcd: C, 52.73; H, 5.53; N, 15.37; S, 8.8. Found: C, 50.58; H, 5.36; N, 13.92; S, 7.84.

EXAMPLE I(16) 0663 5-(4-Methyl-5-phenyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 272

0664 MS (FAB) mH/z Calcd: 441. Found: 441. Anal. Calcd: C, 59.98; H, 5.49; N, 12.72; S, 7.28. Found: C, 59.38; H, 5.49; N, 12.50; S, 7.16.

EXAMPLE I(17) 0665 (R/S)-5-(4-Isopropyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 273

0666 MS (FAB) mH/z Calcd: 393. Found: 393. Anal. Calcd: C, 55.08; H, 6.16; N, 14.28; S, 8.17. Found: C, 55.62; H, 6.33; N, 13.07; S, 7.73.

EXAMPLE I(18) 0667 5-(4(R)-Methyl-5(S)-phenyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 274

0668 MS (FAB) mH/z Calcd: 441. Found: 441. Anal. Calcd: C, 59.98; H, 5.49; N, 12.72; S, 7.28. Found: C, 59.38; H, 5.49; N, 12.50; S, 7.16.

EXAMPLE I(19) 0669 (R/S)-5-(5-Methyl-4,5-dihydro-oxazol-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 275

0670 MS (FAB) mH/z Calcd: 365. Found: 365. Anal. Calcd: C, 52.73; H, 5.53; N, 15.37; S, 8.8. Found: C, 50.91; H, 5.27; N, 14.03; S, 8.09.

EXAMPLE I(20) 0671

276

EXAMPLE J(1) 0672 5-(2H-Tetrazol-5-yl-)-N-(3,4,5-trimethoxyl)-thiazole-2,4-diamine 277

0673 A solution of 4-amino-2-(3,4,5-trimethoxy-phenylamino)-thiazole-5-carbonitrile (110 mg, 0.35 mmol), TMSN3 (115 mg, 1.0 mmol) and catalytic amount of Bu2SnO in toluene was refluxed for four days (additional amounts of TMSN3 and Bu2SnO were added during the reaction). Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 0.1 N HCl, brine and dried with MgSO4. The solvent was removed and the residue was triturated in ethyl ether. The final product (30 mg) was collected by filtration: 0674 1H NMR (CD3OD): 6.99 (s, 2H), 3.89 (s, 6H), 3.77 (s, 3H). ESIMS (MH): 350; (MH): 348. 0675 The following example was prepared in a similar manner:

EXAMPLE J(2) 0676 N-(4-Dimethylamino-phenyl)-5-(2H-tetrazol-5-yl)-thiazole-2,4-diamine 278

0677 1H NMR (CD3OD): 7.38 (d, J5.40 Hz, 2H), 6.85 (d, J5.40 Hz, 2H), 2.95 (s, 6H). ESIMS (MH): 302; (MH): 301.

EXAMPLE K(1) 0678 3-5-4-Amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenol 279

0679 To a solution of 200 mg (0.412 mmol) of 5-3-(3-methoxymethoxy-phenyl)-1,2,4oxadiazol-5-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine (prepared in Example B(4)) in 8 mL of 50% aqueous dioxane was added trifluoroacetic acid (8 mL) with water bath cooling at 15 C. After 2 hours at room temperature, toluene was added, and the solution was concentrated in vacuo with the water bath at 22 C. With five milliliters of solvent left, the solution was poured into cold aqueous sodium bicarbonate. This solution was extracted with two portions of dichloromethane, which was subsequently washed with brine and dried over sodium sulfate. Radial silica chromatography eluting with 5-10% methanol/dichloromethane gave 3-5-4-amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl-1,2,4oxadiazol-3-yl-phenol (60 mg) as a pale-yellow solid. 0680 1HNMR (300 MHz, DMSO-d6): 3.64 (s, 3H), 3.81 (s, 6H), 6.95 (m, 3H), 7.34 (m, 2H), 7.49 (m, 2H), 9.76 (s, 1H), 10.76 (s, 1H). Anal. Calcd for C20H19N5O5S: C, 54.41; H, 4.34; N, 15.86. Found: C, 54.40; H, 4.40; N, 15.86.

EXAMPLE L(1) 0681 5-6-(Furan-2-yl)-pyridin-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 280

0682 To a solution of 5-(6-Bromo-pyridin-2-yl-2-N-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine (prepared as in Example G(6)) (60 mg, 0.137 mmol, 1.0 equiv) in DMF (0.7 mL) was added 2-furantributyltin (130 L, 0.411 mmol, 3.0 equiv), triethylamine (95 L, 0.685 mmol, 5.0 equiv) and dichlorobis(triphenylphosphine)-palladium (19 mg, 0.027 mmol, 0.2 equiv.). The reaction mixture was heated to 85 C. for 18 h, cooled and partitioned between ethyl acetate and sodium bicarbonate. The organic layer was dried over sodium sulfate, decanted and concentrated. The material was purified by silica gel chromatography (1:1 ethyl acetate/hexane) to give 5-6-(furan-2-yl)pyridin-2-yl-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine (30.5 mg, 53% yield). 0683 MS (FAB) m/z Calcd: 424. Found: 424. Anal. Calcd: C, 59.42; H, 4.75; N, 13.20; S, 7.55. Found: C, 59.56; H, 4.71; N, 13.10; S, 7.44. 0684 The following Examples L(2) and L(3) were prepared in a similar fashion as Example L(1).

EXAMPLE L(2) 0685 5-(6-Thiophen-2-yl-pyridin-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 281

0686 MS (FAB) mH/z Calcd: 441. Found: 441. Anal. Calcd: C, 57.25; H, 4.58; N, 12.72; S, 14.56. Found: C, 56.57; H, 4.60; N, 12.47; S, 14.33.

EXAMPLE L(3) 0687 5-(6-Thiophen-3-yl-pyridin-2-yl)-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine 282

0688 MS (FAB) m/z Calcd: 440; Found: 440. Anal. Calcd: C, 57.25; H, 4.58; N, 12.72; S, 14.56. Found: C, 56.57; H, 4.60; N, 12.47; S, 14.33.

EXAMPLE M(1) 0689 4-Benzylsulfanylmethyl-N-(4-isopropyl-phenyl)-2,5bithiazolyl-24-diamine 283

0690 A solution of 204 mg (0.7 mmol) of 4-amino-2-(4-isopropyl-phenylamino)-thiazol-5-carbothioamide (prepared as in Example A(1), Step (ii)) and 1,3-dibromoacetone (154 mg, 0.72 mmol) was stirred in MeOH (10 ml) at room temperature for 2 hours. The resultant reaction mixture was then diluted with ethyl ether (150 ml). A yellow-brown solid was filtered off, rinsed with ethyl ether, and dried in vacuum to give a crude intermediate as brown solid (298 mg, 91% yield). Without further purification, the above intermediate (50 mg, 0.12 mmol) was dissolved in DMF (10 mL) with DIEA (17 mg, 0.14 mmol). Benzyl mercapten (17 mg, 0.14 mmol) was then added. The resultant mixture was stirred at room temperature for 2 hours. Solvent was removed under reduced pressure and the residue was re-dissolved in ethyl acetate (100 mL). The organic solution was extracted with saturated NaHCO3 (320 ml) followed by brine. The organic layer was dried over magnesium sulfate and concentrated to furnish a brown solid. The final product was subsequently purified by preparative HPLC to provide 4-benzylsulfanylmethyl-N-(4-isopropyl-phenyl)-2,5bithiazolyl-24-diamine (9 mg, 18% yield). 1H NMR (DMSO-d6): 7.91 (s, 1H), 7.20-7.38 (m, 9H), 6.65 (s, 1H), 5.98 (s, 2H), 3.73 (s, 1H), 3.63 (s, 2H), 2.9 (heptet, J6.9 Hz, 1H), 1.22-1.24 (d, J6.9 Hz, 6H). FABMS (M): 452; FABMS (MNa): 475.

EXAMPLE N(1) 0691 4-Amino-2-(4-methanesulfonyl-phenylamino)-2,5bithiazoyl-4-carboxylic acid trifluoro-acetic acid salt 284

0692 The title compound was prepared as follows: to a solution of 4-Amino-2-(4-sulfamoyl-phenylamino)-thiazol-5-carbothioic acid amide (164 mg, 0.5 mmol) in DMF, bromopyruvic acid (125 mg, 0.75 mmol) was added, and the resultant mixture was stirred at ambient temperature for 2 hours. Following removal of solvent, the residue was dissolved with ethyl acetate and washed with water and brine, then dried with MgSO4. Purification of the residue by preparative HPLC provided the title compound as a yellow power in 34% yield. 0693 1H NMR (DMSO): 10.08 (s, 1H), 8.04 (s, 1H), 7.88-7.78 (m, 4H), 7.31 (s, 4H). HRFABMS (MH): Calcd.: 398.0051. Found: 398.0059.

EXAMPLE N(2) 0694 4-Amino-2-(4-sulfamoyl-phenylamino)-2,5-bithiazoyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide 285

0695 The title compound was prepared as follows: a mixture of 4-Amino-2-(4-methanesulfonyl-phenylamino)-2,5bithiazoyl-4-carboxylic acid (64 mg, 0.13 mmol), PyBop (81 mg, 0.16 mmol), N,N-dimethylethylenediamine (28 l, 0.25 mmol) and DIEA (65 l, 0.38 mmol) in DMF was stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was extracted with saturated solution of NaHCO3 followed by brine, and dried with MgSO4. Purification of the residue by preparative HPLC provided the title compound as a yellow power in 17% yield. 0696 1HNMR (DMSO): 10.91 (s, 1H), 8.72 (t, 1H, J12.3), 7.80 (dd, 4H, J27.1), 7.73 (s, 1H), 7.28 (s, 2H), 7.20 (s, 2H), 2.61-2.51 (m, 4H), 2.25 (s, 6H). HRFABMS (MH): Calcd.: 468.0946. Found: 468.0955. 0697 In a manner similar to that used to prepare Example N(2), the following Examples N(3) and N(4) were prepared.

EXAMPLE N(3) 0698 4-Amino-2-(4-sulfamoyl-phenylamino)-2,5bithiazolyl-4-carboxylic acid methoxy-methyl-amide 286

0699 mp 195-198 C.; 1H NMR (CD3OD): 9.80 (s, NH), 7.80-7.65 (m, 4H), 7.54 (s, 1H), 6.60 (s, NH2), 6.32 (s, NH2), 3.61 (s, 3H), 3.22 (s, 3H). FABMS (MH): 441.

EXAMPLE N(4) 0700 4-Amino-2-(4-sulfamoyl-phenylamino)-2,5bithiazolyl-4 carboxylic acid phenylamide 287

0701 1H NMR (CD3OD): 7.91 (s, 1H), 7.88-7.71 (m, 4H), 7.40-7.22 (m, 4H), 7.17-7.09 (m, 1H). FABMS Calcd for C19H16N6O3S3: 473.0524. Found: 473.0540.

EXAMPLE O(1) 0702 N-5-(5-4-Amino-2-3-(2-morpholin-4-yl-ethyl)-ureido-thiazol-5-yl-1,2,4oxadiazol-3-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 288

0703 Step(i): A solution of activated carbamate (prepared in step(ii)), amine, and DMF (0.60 mL) were stirred at room temperature for 1 h. The resulting solution was concentrated in vacuo, then purified by Chromatatron radial chromatography (10% methanol/methylene chloride), giving 35 mg (72% yield) of the title compound as a white solid. 0704 Anal. Calcd. for C26H26F2N8O5S.1.2 H2O: C, 50.19; H, 4.60; N, 18.01; S, 5.15. Found: C, 50.16; H, 4.35; N, 17.95; S, 5.22. ESIMS (MH): 601. 289

0705 Step(ii): Preparation of the activated carbamate (4-4-Amino-5-3-(2,4-difluoro-5-1-(3-methoxy-phenyl)-methanoyl-amino-phenyl)-1,2,4oxadiazol-5-yl-thiazol-2-ylcarbamoyloxy-benzoic acid methyl ester). A solution of N-5-5-(2,4-Diamino-thiazol-5-yl)-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl-3-methoxy-benzamide (533 mg, 1.20 mmol) prepared analogously to example E(1), dissolved in anhydrous THF (20.0 mL) and anhydrous N-methylpyrolidinone (1.0 mL) at 78 C., was treated with phenyllithium (0.660 mL, 01.20 mmol), followed by p-carboxymethyl chloroformate (772 mg, 3.60 mmol) dissolved in anhydrous THF (5.0 mL), in one portion (internal temperature rose to 55 C.). After 5 minutes a second portion of phenyllithium (0.660 mL, 1.20 mmol) was added slowly. After stirring for an additional 15 minutes the reaction was quenched with acetic acid (0.30 mL), warmed to room temperature, diluted with ethyl acetate, extracted with 1:1 mixture of brine and sodium bicarbonate solution, dried with magnesium sulfate, and filtered. The resulting solution was concentrated in vacuo until only 50 ml of solvent remained, and a white precipitate had formed. The white solid was collected by filtration, giving 446 mg (60% yield) of the activated carbamate. ESIMS (MNa): 645. 0706 The following examples O(2) through O(32) were prepared in manner analogous to O(1).

EXAMPLE O(2) 0707 N-5-5-(4-Amino-2-3-3-(2-oxo-pyrrolidin-1-yl)-propyl-ureido-thiazol-5-yl)-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 290

0708 Anal. Calcd. for C27H26F2N8O5S.1.5 H2O: C, 50.07; H, 4.57; N, 17.52; S, 5.01. Found: C, 50.60; H, 4.58; N, 17.42; S, 5.17. ESIMS (MH): 613.

EXAMPLE O(3) 0709 N-(5-5-4-Amino-2-(3-carbamoylmethyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 291

0710 Anal. Calcd. for C22H18F2N8O5S.0.6 H2O: C, 47.86; H, 4.05; N, 20.09; S, 5.11. Found: C, 47.92; H, 3.95; N, 20.01; S, 5.44. ESIMS (MNa): 567.

EXAMPLE O(4) 0711 N-(5-5-4-Amino-2-(3-methyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 292

0712 Anal. Calcd. for C21H17F2N7O4S.(0.9 DMF, 0.5 H2O): C, 49.47; H, 4.10; N, 19.23; S, 5.57. Found: C, 49.58; H, 4.24; N, 19.33; S, 5.63. ESIMS (MH): 500.

EXAMPLE O(5) 0713 N-5-(5-4-Amino-2-3-(tetrahydro-furan-2-ylmethyl)-ureido-thiazol-5-yl-1,2,4oxadiazol-3-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 293

0714 Anal. Calcd. for C25H23F2N7O5S.0.5 H2O: C, 51.72; H, 4.17; N, 16.89; S, 5.52. Found: C, 51.61; H, 4.09; N, 16.87; S, 5.57. ESIMS (MNa): 594.

EXAMPLE O(6) 0715 N-5-5-(4-Amino-2-3-2-(2-hydroxy-ethoxy)-ethyl-ureido-thiazol-5-yl)-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 294

0716 Anal. Calcd. for C24H23F2N7O6S.1.0 H2O: C, 48.56; H, 4.25; N, 16.52; S, 5.40. Found: C, 48.67; H, 4.04; N, 16.63; S, 5.50. ESIMS (MH): 574.

EXAMPLE O(7) 0717 N-(5-5-4-Amino-2-(3-isobutyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 295

0718 Anal. Calcd. for C24H23F2N7O4S.0.6 H2O: C, 52.00; H, 4.40; N, 17.69; S, 5.78. Found: C, 52.02; H, 4.29; N, 17.87; S, 5.85. ESIMS (MH): 544.

EXAMPLE O(8) 0719 N-(5-5-4-Amino-2-(3-pyridin-2-ylmethyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 296

0720 Anal. Calcd. for C26H20F2N8O4S.1.0 H2O: C, 52.34; H, 3.72; N, 18.78; S, 5.37. Found: C, 52.24; H, 3.75; N, 18.74; S, 5.32. ESIMS (MH): 579.

EXAMPLE O(9) 0721 N-(5-5-4-Amino-2-(3-pyridin-3-ylmethyl-ureido)-thiazol-5-yl-1,2,4oxadiazol-3-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 297

0722 Anal. Calcd. for C26H20F2N8O4S.0.8 H2O: C, 52.66; H, 3.67; N, 18.90; S, 5.41. Found: C, 52.57; H, 3.99; N, 18.92; S, 5.16. ESIMS (MH): 579.

EXAMPLE O(10) 0723 N-5-(5-4-Amino-2-3-(2-hydroxy-ethyl)-ureido-thiazol-5-yl-1,2,4oxadiazol-3-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 298

0724 Anal. Calcd. for C22H19F2N7O5S: C, 49.72; H, 3.6; N, 18.45; S, 6.03. Found: C, 49.45; H, 3.80; N, 18.30; S, 5.97. ESIMS (MH): 530.

EXAMPLE O(11) 0725 N-5-(5-4-Amino-2-3-(trans-4-hydroxy-cyclohexyl)-ureido-thiazol-5-yl-1,2,4oxadiazol-3-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 299

0726 Anal. Calcd. for C26H25F2N7O5S.2.8 H2O: C, 49.10; H, 4.85; N, 15.42; S, 5.04. Found: C, 49.06; H, 4.71; N, 15.39; S, 4.79. ESIMS (MH): 584.

EXAMPLE O(12) 0727 N-3-(5-4-Amino-2-3-(3-morpholin-4-yl-propyl)-ureido-thiazol-5-yl-1,2,4oxadiazol-3-yl)-phenyl-3-methyl-benzamide 300

0728 Anal. Calcd. for C27H30N8O4S.1.5 H2O: C, 54.99; H, 5.64; N, 19.00; S, 5.44. Found: C, 54.83; H, 45.49; N, 18.50; S, 15.30. ESIMS (MH): 563.

EXAMPLE O(13) 0729 N-5-4-Amino-2-(3-benzyl-ureido)-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 301

0730 Anal. Calcd. for C28H22F2N6O3S2: C, 56.75; H, 3.74; N, 14.18; S, 10.82. Found: C, 56.70; H, 3.85; N, 14.09; S, 10.70. ESIMS (MH): 593.

EXAMPLE O(14) 0731 N-(5-4-Amino-2-3-(2-methoxy-1-methyl-ethyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 302

0732 Anal. Calcd. for C25H24F2N6O4S2: C, 52.25; H, 4.21; N, 14.63; S, 11.16. Found: C, 52.06; H, 4.21; N, 14.55; S, 11.09. MALDI FTMS (MH): 575.1341, Found 575.1342.

EXAMPLE O(15) 0733 N-5-(4-Amino-2-3-3-(2-oxo-pyrolidin-1-yl)-propyl-ureido-2,5bithiazolyl-4-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 303

0734 Anal. Calcd. for C28H27F2N7O4S2.1.1 H2O: C, 51.94; H, 4.55; N, 15.14; S, 9.90. Found: C, 52.38; H, 4.79; N, 14.64; S, 9.48. MALDI FTMS (MNa): 650.1426, Found 650.1344.

EXAMPLE O(16) 0735 N-5-4-Amino-2-(3-pyridin-2-ylmethyl-ureido)-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 304

0736 Anal. Calcd. for C27H21F2N7O3S2: C, 54.63; H, 3.57; N, 16.52; S, 10.80. Found: C, 54.44; H, 3.68; N, 16.33; S, 10.60. MALDI FTMS (MH): 594.1188, Found 594.1191.

EXAMPLE O(17) 0737 N-5-4-Amino-2-(3-pyridin-3-ylmethyl-ureido)-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 305

0738 Anal. Calcd. for C27H21F2N7O3S2.0.5 H2O: C, 53.81; H, 3.68; N, 16.27; S, 10.64. Found: C, 53.95; H, 3.78; N, 16.21; S, 10.68. MALDI FTMS (MH): 594.1188, Found 594.1185.

EXAMPLE O(18) 0739 N-5-4-Amino-2-(3-pyridin-4-ylmethyl-ureido)-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 306

0740 Anal. Calcd. for C27H21F2N7O3S2.0.5 H2O: C, 53.81; H, 3.68; N, 16.27; S, 10.64. Found: C, 53.83; H, 3.60; N, 16.33; S, 10.80. MALDI FTMS (MH): 594.1188, Found 594.1198.

EXAMPLE O(19) 0741 N-(5-4-Amino-2-3-((R)-2-hydroxy-propyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 307

0742 Anal. Calcd. for C24H22F2N6O4S2: C, 51.42; H, 3.96; N, 14.99; S, 11.44. Found: C, 50.95; H, 4.12; N, 14.97; S, 11.22. MALDI FTMS (MH): 561.1185, Found 561.1212.

EXAMPLE O(20) 0743 N-(5-4-Amino-2-3-((S)-2-hydroxy-propyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 308

0744 Anal. Calcd. for C24H22F2N6O4S2.1.0 H2O: C, 49.82; H, 4.18; N, 14.53; S, 11.08. Found: C, 49.77; H, 3.92; N, 14.74; S, 10.96. ESIMS (MNa): 583.

EXAMPLE O(21) 0745 N-(5-4-Amino-2-3-((R)-1-hydroxymethyl-propyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 309

0746 Anal. Calcd. for C25H24F2N6O4S2.0.5 H2O: C, 51.45; H, 4.32; N, 14.40; S, 10.99. Found: C, 51.32; H, 4.30; N, 14.53; S, 11.06. ESIMS (MNa): 597.

EXAMPLE O(22) 0747 N-(5-4-Amino-2-3-((S)-1-hydroxymethyl-propyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 310

0748 Anal. Calcd. for C25H24F2N6O4S2.0.5 H2O: C, 51.45; H, 4.32; N, 14.40; S, 10.99. Found: C, 51.49; H, 4.26; N, 14.66; S, 11.16. ESIMS (MNa): 597.

EXAMPLE O(23) 0749 N-5-(4-Amino-2-3-(S)-1-(tetrahydro-furan-2-yl)methyl-ureido-2,5bithiazolyl-4-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 311

0750 Anal. Calcd. for C26H24F2N6O4S2.0.5 H2O: C, 52.43; H, 4.23; N, 14.11; S, 10.77. Found: C, 52.55; H, 4.29; N, 14.44; S, 10.53. ESIMS (MH): 585.

EXAMPLE O(24) 0751 N-5-(4-Amino-2-3-(R)-1-(tetrahydro-furan-2-yl)methyl-ureido-2,5bithiazolyl-4-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 312

0752 Anal. Calcd. for C26H24F2N6O4S2.0.6 H2O: C, 52.27; H, 4.25; N, 14.07; S, 10.73. Found: C, 52.29; H, 4.33; N, 14.33; S, 10.55. ESIMS (MH): 585.

EXAMPLE O(25) 0753 N-5-4-Amino-2-(3-cyclohexylmethyl-ureido)-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl-3-methoxy-benzamide 313

0754 Anal. Calcd. for C28H28F2N6O3S2.0.5 H2O: C, 55.34; H, 4.81; N, 13.83; S, 10.55. Found: C, 55.26; H, 4.78; N, 14.00; S, 10.56. MALDI FTMS (MH): 599.1705, Found 621.1525.

EXAMPLE O(26) 0755 N-(5-4-Amino-2-3-(2-morpholin-4-yl-ethyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 314

0756 Anal. Calcd. for C27H27F2N7O4S2.1.0 H2O: C, 51.17; H, 4.61; N, 15.47; S, 10.12. Found: C, 51.00; H, 4.39; N, 15.12; S, 9.75. MALDI FTMS (MH): 616.1607, Found 616.1597.

EXAMPLE O(27) 0757 N-(5-4-Amino-2-3-(2-pyrrolidin-1-yl-ethyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 315

0758 Anal. Calcd. for C27H27F2N7O3S2: C, 54.08; H, 4.54; N, 16.35; S, 10.69. Found: C, 53.93; H, 4.66; N, 16.11; S, 10.51. MALDI FTMS (MH): 600.1658, Found 600.1640.

EXAMPLE O(28) 0759 N-5-(4-Amino-2-3-2-(2-hydroxy-ethoxy)-ethyl-ureido-2,5bithiazolyl-4-yl)-2,4-difluoro-phenyl-3-methoxy-benzamide 316

0760 Anal. Calcd. for C25H24F2N6O5S2.1.0 H2O: C, 49.33; H, 4.31; N, 13.81; S, 10.54. Found: C, 49.47; H, 4.08; N, 13.87; S, 10.49. MALDI FTMS (MH): 591.1290, Found 591.1276.

EXAMPLE O(29) 0761 N-(5-4-Amino-2-3-(2-pyridin-2-yl-ethyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 317

0762 Anal. Calcd. for C28H23F2N7O3S2.1.8 H2O: C, 52.54; H, 4.19; N, 15.32; S, 10.02. Found: C, 52.56; H, 4.07; N, 15.54; S, 10.03. MALDI FTMS (MH): 608.1345, Found 608.1346.

EXAMPLE O(30) 0763 N-(5-4-Amino-2-3-(2-pyridin-4-yl-ethyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 318

0764 Anal. Calcd. for C28H23F2N7O3S2.1.0 H2O: C, 53.75; H, 4.03; N, 15.67; S, 10.25. Found: C, 53.32; H, 4.01; N, 15.50; S, 9.90. MALDI FTMS (MH): 608.1345, Found 608.1327.

EXAMPLE O(31) 0765 N-3-4-Amino-5-methyl-2-(3-methyl-ureido)-2,5bithiazolyl-4-yl-phenyl-3-methoxy-benzamide 319

0766 The precursor (N-3-(2,4-Diamino-5-methyl-2,5bithiazolyl-4-yl)-phenyl-3-methoxy-benzamide) to the activated carbamate from which this example was prepared, was synthesized analogously to example E(3) only starting with 3-aminopropiophenone rather than 3-aminoacetophenone. 0767 Anal. Calcd. for C23H22N6O3S2.0.6 H2O: C, 54.66; H, 4.63; N, 16.63; S, 12.69. Found: C, 54.50; H, 4.48; N, 16.77; S, 12.70. ESIMS (MH): 495.

EXAMPLE O(32) 0768 N-(5-4-Amino-2-3-(2-pyridin-3-yl-ethyl)-ureido-2,5bithiazolyl-4-yl-2,4-difluoro-phenyl)-3-methoxy-benzamide 320

0769 Anal. Calcd. for C28H23F2N7O3S2.0.5 H2O: C, 54.53; H, 3.92; N, 15.90; S, 10.40. Found: C, 54.35; H, 4.02; N, 16.05; S, 10.30. ESIMS (MH): 608. The exemplary compounds described above may be tested for their activity as described below.

BIOLOGICAL TESTING; ENZYME ASSAYS 0770 The stimulation of cell proliferation by growth factors such as VEFG, FGF, and others is dependent upon their induction of autophosphorylation of each of their respective receptor's tyrosine kinases. Therefore, the ability of a protein kinase inhibitor to block cellular proliferation induced by these growth factors is directly correlated with its ability to block receptor autophosphorylation. To measure the protein kinase inhibition activity of the compounds, the following constructs were devised. 0771 VEGF-R2 Construct for Assay: This construct determines the ability of a test compound to inhibit tyrosine kinase activity. A construct (VEGF-R250) of the cytosolic domain of human vascular endothelial growth factor receptor 2 (VEGF-R2) lacking the 50 central residues of the 68 residues of the kinase insert domain was expressed in a baculovirus/insect cell system. Of the 1356 residues of full-length VEGF-R2, VEGF-R250 contains residues 806-939 and 990-1171, and also one point mutation (E990V) within the kinase insert domain relative to wild-type VEGF-R2. Autophosphorylation of the purified construct was performed by incubation of the enzyme at a concentration of 4 M in the presence of 3 mM ATP and 40 mM MgCl2 in 100 mM Hepes, pH 7.5, containing 5% glycerol and 5 mM DTT, at 4 C. for 2 h. After autophosphorylation, this construct has been shown to possess catalytic activity essentially equivalent to the wild-type autophosphorylated kinase domain construct. See Parast et al., Biochemistry, 37, 16788-16801 (1998). 0772 FGF-R1 Construct for Assay: The intracellular kinase domain of human FGF-R1 was expressed using the baculovirus vector expression system starting from the endogenous methionine residue 456 to glutamate 766, according to the residue numbering system of Mohammadi et al., Mol. Cell. Biol., 16, 977-989 (1996). In addition, the construct also has the following 3 amino acid substitutions: L457V, C488A, and C584S. 0773 LCK Construct for Assay: The LCK tyrosine kinase was expressed in insect cells as an N-terminal deletion starting from amino acid residue 223 to the end of the protein at residue 509, with the following two amino acid substitutions at the N-terminus: P233M and C224D. 0774 CHK-1 Construct for Assay: C-terminally His-tagged full-length human CHK1 (FL-CHK1) was expressed using the baculovirus/insect cell system. It contains 6 histidine residues (6His-tag) at the C-terminus of the 476 amino acid human CHK1. The protein was purified by conventional chromatographic techniques. 0775 CDK2/Cyclin A Construct for Assay: CDK2 was purified using published methodology (Rosenblatt et al., J. Mol. Biol., 230, 1317-1319 (1993)) from insect cells that had been infected with a baculovirus expression vector. Cyclin A was purified from E. coli cells expressing full-length recombinant cyclin A, and a truncated cyclin A construct was generated by limited proteolysis and purified as described previously (Jeffrey et al., Nature, 376, 313-320 (Jul. 27, 1995)). 0776 CDK4/Cyclin D Construct for Assay: A complex of human CDK4 and cyclin D3, or a complex of cyclin DI and a fusion protein of human CDK4 and glutathione-S-transferase (GST-CDK4), was purified using traditional biochemical chromatographic techniques from insect cells that had been co-infected with the corresponding baculovirus expression vectors. 0777 FAK Construct for Assay. The catalytic domain of human FAK (FAKcd409) was expressed using the baculovirus vector expression system. The 280 amino acid domain expressed comprises residues methionine 409 to glutamate 689. One amino acid substitution exists (P410T) relative to the sequence assession number L13616 published by Whithey, G. S. et al., DNA Cell Biol 9, 823-830, 1993. The protein was purified using classical chromatography techniques. 0778 VEGF-R2 Assay 0779 Coupled Spectrophotometric (FLVK-P) Assay 0780 The production of ADP from ATP that accompanies phosphoryl transfer was coupled to oxidation of NADH using phosphoenolpyruvate (PEP) and a system having pyruvate kinase (PK) and lactic dehydrogenase (LDH). The oxidation of NADH was monitored by following the decrease of absorbance at 340 nm (e3406.22 cm1 mM1) using a Beckman DU 650 spectrophotometer. Assay conditions for phosphorylated VEGF-R250 (indicated as FLVK-P in the tables below) were the following: 1 mM PEP; 250 M NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mM poly(E4Y1); 1 mM ATP; and 25 mM MgCl2 in 200 mM Hepes, pH 7.5. Assay conditions for unphosphorylated VEGF-R250 (indicated as FLVK in the tables) were the following: 1 mM PEP; 250 M NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 20 mM poly(E4Y1); 3 mM ATP; and 60 mM MgCl2 and 2 mM MnCl2 in 200 mM Hepes, pH 7.5. Assays were initiated with 5 to 40 nM of enzyme. Ki values were determined by measuring enzyme activity in the presence of varying concentrations of test compounds. The data were analyzed using Enzyme Kinetic and Kaleidagraph software. 0781 ELISA Assay 0782 Formation of phosphogastrin was monitored using biotinylated gastrin peptide (1-17) as substrate. Biotinylated phosphogastrin was immobilized using streptavidin coated 96-well microtiter plates followed by detection using anti-phosphotyrosine-antibody conjugated to horseradish peroxidase. The activity of horseradish peroxidase was monitored using 2,2-azino-di-3-ethylbenzathiazoline sulfonate(6)diammonium salt (ABTS). Typical assay solutions contained: 2 M biotinylated gastrin peptide; 5 mM DTT; 20 M ATP; 26 mM MgCl2; and 2 mM MnCl2 in 200 mM Hepes, pH 7.5. The assay was initiated with 0.8 nM of phosphorylated VEGF-R250. Horseradish peroxidase activity was assayed using ABTS, 10 mM. The horseradish peroxidase reaction was quenched by addition of acid (H2SO4), followed by absorbance reading at 405 nm. Ki values were determined by measuring enzyme activity in the presence of varying concentrations of test compounds. The data were analyzed using Enzyme Kinetic and Kaleidagraph software. 0783 FGF-R Assay 0784 The spectrophotometric assay was carried out as described above for VEGF-R2, except for the following changes in concentration: FGF-R50 nM, ATP2 mM, and poly(E4Y1)15 mM. 0785 LCK Assay 0786 The spectrophotometric assay was carried out as described above for VEGF-R2, except for the following changes in concentration: LCK60 nM, MgCl20 mM, poly(E4Y1)20 mM. 0787 CHK1 Assay 0788 The production of ADP from ATP that accompanies phosphoryl transfer to the synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK) was coupled to oxidation of NADH using phosphoenolpyruvate (PEP) through the actions of pyruvate kinase (PK) and lactic dehydrogenase (LDH). The oxidation of NADH was monitored by following the decrease of absorbance at 340 nm (3406.22 cm1 mM1) using a HP8452 spectrophotometer. Typical reaction solutions contained: 4 mN PEP; 0.15 mM NADH; 28 units of LDH/ml; 16 units of PK/ml; 3 mM DTT; 0.125 mM Syntide-2; 0.15 mM ATP; 25 mM MgCl2 in 50 mM TRIS, pH 7.5; and 400 mM NaCl. Assays were initiated with 10 nM of FL-CHK1. Ki values were determined by measuring initial enzyme activity in the presence of varying concentrations of test compounds. The data were analyzed using Enzyme Kinetic and Kaleidagraph software. 0789 CDK2/Cyclin A and CDK4/Cyclin D Assays 0790 Cyclin-dependent kinase activity was measured by quantifying the enzyme-catalyzed, time-dependent incorporation of radioactive phosphate from 32PATP into a recombinant fragment of the retinoblastoma protein. Unless noted otherwise, assays were performed in 96-well plates in a total volume of 50 L, in the presence of 10 mM HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid) (pH 7.4), 10 mM MgCl2, 25 M adenosine triphosphate (ATP), 1 mg/mL ovalbumin, 5 g/mL leupeptin, 1 mM dithiothreitol, 10 mM -glycerophosphate, 0.1 mM sodium vanadate, 1 mM sodium fluoride, 2.5 mM ethylene glycol-bis(-aminoethyl ether)-N,N,NN-tetraacetic acid (EGTA), 2% (v/v) dimethylsulfoxide, and 0.03-0.2 Ci 32PATP. The substrate (0.3-0.5 g) was purified recombinant retinoblastoma protein fragment (Rb) (residues 386-928 of the native retinoblastoma protein; 62.3 kDa, containing the majority of the phosphorylation sites found in the native 106-kDa protein, as well as a tag of six histidine residues for ease of purification). Reactions were initiated with CDK2 (150 nM CDK2/Cyclin A complex) or CDK4 (50 nM CDK4/Cyclin D3 complex), incubated at 30 C., and terminated after 20 minutes by the addition of ethylenediaminetetraacetic acid EDTA) to 250 mM. The phosphorylated substrate was then captured on a nitrocellulose membrane using a 96-well filtration manifold, and unincorporated radioactivity was removed by repeated washing with 0.85% phosphoric acid. Radioactivity was quantified by exposing the dried nitrocellulose membranes to a phosphorimager. Apparent Ki values were measured by assaying enzyme activity in the presence of different compound concentrations and subtracting the background radioactivity measured in the absence of enzyme. The kinetic parameters (kcat, Km for ATP) were measured for each enzyme under the usual assay conditions by determining the dependence of initial rates on ATP concentration. The data were fit to an equation for competitive inhibition using Kaleidagraph (Synergy Software), or were fit to an equation for competitive tight-binding inhibition using the software KineTic (BioKin, Ltd.). Measured Ki values for known inhibitors against CDK4 and CDK2 agreed with published IC50 values. The specific activity of CDK4 was the same whether complexed to full-length cyclin D3 or the truncated Cyclin D3 construct; both complexes also yielded very similar Ki values for selected inhibitors. 0791 FAK Assay 0792 FAK HTS utilized the fluorescence polarization assay provided by LJL Biosystems. The kinase reaction contained: 100 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM DTT, 1 mM ATP, and 1 mg/ml poly Glu-Tyr (4:1). The reaction is initiated by the addition of 5 nM FAKcd409. The reaction is terminated by the addition of EDTA followed by addition of fluor-labelled peptide and anti-phosphotyrosine antibody, both provided by LJL Biosystems. Inhibition results are read on a Analyst (LJL) detector. 0793 HUVEC Proliferation Assay 0794 This assay determines the ability of a test compound to inhibit the growth factor-stimulated proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC cells (passage 3-4, Clonetics, Corp.) were thawed into EGM2 culture medium (Clonetics Corp) in T75 flasks. Fresh EGM2 medium was added to the flasks 24 hours later. Four or five days later, cells were exposed to another culture medium (F12K medium supplemented with 10% fetal bovine serum (FBS), 60 g/ml endothelial cell growth supplement (ECGS), and 0.1 mg/ml heparin). Exponentially-growing HUVEC cells were used in experiments thereafter. Ten to twelve thousand HUVEC cells were plated in 96-well dishes in 100 l of rich, culture medium (described above). The cells were allowed to attach for 24 hours in this medium. The medium was then removed by aspiration and 105 l of starvation media (F12K1% FBS) was added to each well. After 24 hours, 15 l of test agent dissolved in 1% DMSO in starvation medium or this vehicle alone was added into each treatment well; the final DMSO concentration was 0.1%. One hour later, 30 l of VEGF (30 ng/ml) in starvation media was added to all wells except those containing untreated controls; the final VEGF concentration was 6 ng/ml. Cellular proliferation was quantified 72 hours later by MTT dye reduction, at which time cells were exposed for 4 hours MTT (Promega Corp.). Dye reduction was stopped by addition of a stop solution (Promega Corp.) and absorbance at 595 was determined on a 96-well spectrophotometer plate reader. 0795 IC50 values were calculated by curve-fitting the response of A595 to various concentrations of the test agent; typically, seven concentrations separated by 0.5 log were employed, with triplicate wells at each concentration. For screening compound library plates, one or two concentrations (one well per concentration) were employed, and the % inhibition was calculated by the following formula:

% inhibition(controltest) divided by (controlstarvation)

0796 where 0797 controlA595 when VEGF is present without test agent 0798 testA595 when VEGF is present with test agent 0799 starvationA595 when VEGF and test agent are both absent. 0800 Cancer Cell Proliferation (MV522) Assay 0801 To determine the whether a protein kinases inhibitor should have therapeutic usefulness in treating cancer, it is important to demonstrate the inhibitor's ability to block cellular proliferation in response to a growth factor that is involved in mediating a proliferative disorder. The protocol for assessing cellular proliferation in cancer cells is similar to that used for assessments in HUVEC cells. Two thousand lung cancer cells (line MV522, acquired from American Tissue Cultural Collection) were seeded in growth media (RPMI1640 medium supplemented with 2 mM glutamine and 10% FBS). Cells are allowed to attach for 1 day prior to addition of test agents and/or vehicles. Cells are treated simultaneously with the same test agents used in the HUVEC assay. Cellular proliferation is quantified by MTT dye reduction assay 72 hours after exposure to test agents. The total length of the assay is 4 days vs. 5 for HUVEC cells because MV522 cells are not exposed to starvation medium. 0802 In Vivo Assay of Retinal Vascular Development in Neonatal Rats 0803 The development of the retinal vascular in rats occurs from postnatal day 1 to postnatal day 14 (P1-P14). This process is dependent on the activity of VEGF (J. Stone, et al, J. Neurosci., 15, 4738 (1995)). Previous work has demonstrated that VEGF also acts as a survival factor for the vessels of the retina during early vascular development (Alon, et. al, Nat. Med., 1, 1024 (1995)). To assess the ability of specific compounds to inhibit the activity of VEGF in vivo, compounds were formulated in an appropriate vehicle, usually 50% polyethylene glycol, average molecular weight 400 daltons, and 50% solution of 300 mM sucrose in deionized water. Typically, two microliters (2 l) of the drug solution was injected into the midvitreous of the eye of rat pups on postnatal day 8 or 9. Six days after the intravitreal injection, the animals were sacrificed and the retinas dissected free from the remaining ocular tissue. The isolated retinas were then subjected to a histochemical staining protocol that stains endothelial cells specifically (Lutty and McLeod, Arch. Ophthalmol., 110, 267 (1992 )), revealing the extent of vascularization within the tissue sample. The individual retinas are then flat-mount onto glass slides and examined to determine the extent of vascularization. Effective compounds inhibit the further development of the retinal vasculature and induce a regression of all but the largest vessels within the retina. The amount of vessel regression was used to assess the relative potency of the compounds after in vivo administration. Vessel regression is graded on subjective scale of one to three pluses, with one plus being detectable regression judged to be approximately 25 percent or less, two pluses being judged to be approximately 25-75% regression and three pluses give to retinas with near total regression (approximately 75% or greater). In the development model, the compound Example B(30) is one of the most effective compounds tested to date, being graded a two plus () when a dose of 2 l of 5 mg/ml initial drug concentration was given. 0804 In Vivo Assay of Retinal Vascular Development in Neonatal Rat Model of Retinopathy of Prematurity 0805 A second model of VEGF dependent retinal neovascularization was employed to evaluate the activities of this series of compounds. In this model (Penn et. al, Invest. Ophthalmol. Vis. Sci., 36, 2063, (1995)), rats pups (n16) with their mother are placed in a computer controlled chamber that regulates the concentration of oxygen. The animals are exposed for 24 hours to a concentration of 50% oxygen followed by 24 hours at a concentration of 10% oxygen. This alternating cycle of hyperoxia followed by hypoxia is repeated 7 times after which the animals are removed to room air (P14). Compounds are administered via intravitreal injection upon removal to room air and the animals are sacrificed 6 days later (P20). The isolated retinas are then isolated, stained mounted and analyzed as detail above in the development model. The effectiveness was also graded as is described for the development model. Example D(74) is the most effective compound tested to date in this model (). 0806 The results of the testing of the compounds using various assays are summarized in the tables below, where a notation of % indicates the percent inhibition at the stated concentration and NI indicates no inhibition. 1TABLE 1HUVECMV522FLVK-PFLVKLCKCHK-1FGF-R KiCDK2CDK4IC50IC50ExampleKi (nM)Ki (nM)Ki (nM)Ki (nM)(nM)Ki (nM)Ki (nM)(nM)(M)A(36)36% 0.05A(37)22% 5A(38)7% 0.05A(39)74% 1A(40)51% 1A(41)70% 1A(42)7.3A(43)68% 1A(44)82% 1A(45)9.7A(46)74% 1A(47)7.9260>10A(48)3.1350>10A(49)49% 1A(50)8.9>700>10A(51)38% 1A(52)75% 1A(53)24370>10A(54)1% 1A(55)14% 1A(56)84A(57)6.7A(58)65% 1MA(59)NI 5A(60)11% 5B(2)16.5>7003.65C(1)300*D(1)46D(10)56*D(11)1.9D(12)22.6160>10D(13)120*D(14)120*D(15)240*D(16)11.8D(17)33% 5D(18)55% 5D(19)38% 5D(2)98D(20)3.7990>10D(21)60*200>10D(22)89*D(23)150130>10D(24)1.82110>10D(25)1745>10D(26)38% 5MD(27)1.882>10D(28)6D(29)1.432>10D(3)63>700>10D(30)2.948>10D(31)4.8D(32)3.959>10D(33)3.83.6120>10D(34)0.85899D(35)1.842>10D(36)243>10D(37)3.4150>10D(38)0.9340>10D(39)1.462>10D(4)7.6*240>10D(40)1.11.439>10D(41)1.937>10D(42)0.340.7753>10D(43)2.9241>10D(44)5.42.1373>10D(45)43% 12350.65MD(46)17.1123>10D(47)1.10.3413>10D(48)4.140>10D(49)1.615>10D(5)63*D(50)1.417>10D(51)32*0.6240>10D(52)27% 50D(53)2.5D(54)6.3D(55)6.3D(56)0.81D(57)18D(6)38% 5; 25*D(7)120*D(8)29*D(9)47*E(2)39038F(1)0.911.429F(2)3.94.7186F(3)80F(4)33% 50F(5)31% 50F(6)34% 50F(7)114F(8)1.922F(9)7.89.612% at21>101 MNotes: * determined with ELISA assay rather than spectrophotometric assay.

0807

2TABLE 2HUVECMV522FLVK-PLCKCHK-1FGF-RCDK2CDK4IC50IC50ExampleKi (M)Ki (M)Ki (M)Ki (M)Ki (M)Ki (M)(M)(M)A(1)1.4*NI 4.620A(10)0.02845% 13.49.15A(11)NI NI 33% 1000100100A(12)0.0341906.72.7A(13)0.81*11% 5A(14)1.9*3.17.0A(15)25*2.77.8A(16)0.022*0.220.98A(17)0.00321% 2.42.129>1.0>101A(18)38% 5A(19)0.0040.39A(2)2.9*1.87.3A(20)0.00724% 4200.71660.580.495A(21)8.8*8.2145A(22)0.02154% 5A(23)0.03934% 47% 55A(24)5.5*3.464% 10A(25)0.10*0.29A(26)0.01452% >1.07.55A(27)38% 3.231100*A(28)131*1324A(29)0.07810% 6.413>1>105A(3)64*2.58.4A(30)0.114.822A(31)31% 5A(32)21% 5A(33)22% 5A(34)43% 5A(35)390*A(4)57% 42% 1010A(5)27% 30% 1010A(6)36% 54% 1010A(61)24%2.7 1A(62)0.534.4A(63)2.020A(64)0.52A(65)0.152.1A(66)1.1NI 1A(67)0.110.0150.67A(68)0.134.5A(69)47.2A(7)25% 28% 1010A(70)NI NI 100100A(71)29190A(72)0.1648% 5 MA(73)36% NI 100 M100 MA(8)0.058*0.800.42A(9)1.9*29% NI 100100B(3)NI 300B(4)0.2G(9)C(2)49% 1C(3)2.74.6D(2)98D(3)0.063E(4)8.821G(1)57*50G(2)18% 5.7100*G(3)13% 6.220*G(4)42% NI 11.4300*100G(5)NI 1000*G(6)NI 100300 MG(7)1.6*21% NI 1010G(8)1831% 100H(1)3.6*0.653.8H(2)10.411H(3)6.1*8.81.7H(4)2.62.1H(5)29% NI 100100H(6)0.21.2I(1)>10061I(10)15% 5I(11)0.53I(12)71% 20I(13)1.25*I(14)1.17*I(15)73*I(16)178*I(17)35*I(18)2.7*I(19)34*I(20)46% 100 MI(2)NI NI 600*100I(3)40% NI 300*100I(4)NI NI 100*100I(5)0.77*NI 47% 40100I(6)0.1NI 2240I(7)5.2*I(8)12% 5I(9)0.083J(1)64*NI 100J(2)53*29% 100K(1)0.00642% 0.626.70.955.41L(1)NI 1000*L(3)NI 300 ML(2)NI 300*M(1)NI NI 100100Note: * determined with ELISA assay rather than spectrophotometric assay

0808

3TABLE 3LCKKi (nM)FGF-PFLVK-PFLVK(%Ki (nM)CDK2CDK4HUVECMV522KiKiinh CHK1(% inh KiKiIC50IC50Example(nM)(nM)1 uMKi (nM)1 uM)(nM)(nM)(nM)(nM)D(67)Slow1134.1>10binderD(70)91% 3.561595.4>1050 nMB(9)0.369178B(34)88% 50 nMB(8)0.1B(27)0.3B(10)0.13B(11)0.7B(30)0.085B(29)0.9B(28)3B(32)1.8B(31)5.1B(33)82%B(26)2.8O(31)0.23N(1)24% NI 27001 M25 MN(2)1201300N(3)1001100N(4)158480D(66)115554.2>10O(4)87% 0.19390.6450 nMO(10)946.7O(3)0.57O(2)0.337280.58, 1.9O(1)0.28O(5)0.22O(6)0.15O(7)0.165.2O(8)0.21O(9)0.424.3O(11)0.4514O(14)Slow01016binderO(24)22% 50 nMO(23)29% 50 nMO(22)1.5O(21)61% 1.150 nMO(20)SlowbinderO(19)SlowbinderO(18)SlowbinderO(17)SlowbinderO(16)11% 50 nMO(15)0.5228O(13)Slow140binderO(30)39% binderO(30)39% 50 nMO(29)SlowbinderO(32)SlowbinderO(28)0.29O(27)1.7O(26)1.4O(25)28% 50 nMD(65)19.3374.32.191D(73)1.2415664.45D(72)0.935NI49NINI4.7>10D(74)91% Slow92615.22.9/1350 nMbinderB(36)0.567223B(35)0.263439B(7)61% 50 nMD(63)51% >1000050 nMD(64)1.43.28410-10029.4D(75)Slow1.1647.80.75/2.0binder97D(76)2.7>1000F(10)0.1442478.50.27/0.74B(14)13% 0.76104611>1050 nMB(12)1.62952153.6D(69)0.57978152.3F(11)0.261525129.6/>10B(16)3% 50 nMB(18)0.9NI8%101.9B(20)80%O(12)0.1921334544F(13)0.25292516F(14)0.36150F(12)2.2>300B(6)0.6156D(61)Slow49165>10binderD(77)2.6D(78)9% 1MD(59)2.84454>1003.1D(60)1.41110>100D(68)0.69>100D(71)4.1D(58)1.42923>100>10B(17)3.4631.3B(23)1.7B(24)2.1B(21)10% 50 nMB(22)54% >100050 nMB(19)36% 50 nMB(25)29B(39)6.3>100B(40)31% 1 MB(41)0% 50 nMB(42)12% 50 nMB(43)11% 50 nMB(37)36% >100050 nMB(38)13% >70050 nMC(8)21% >70050 nMC(7)17300B(13)1.3300B(15)1.7100C(5)15% 50 nMD(62)20% 50050 nMC(6)33300C(9)8300C(4)3% 50 nMB(5)2.3F(15)5% 50 nMF(16)48035% 5 M

0809 CHK1 High-throughput screening results shown in Table 4 4TABLE 4%inhibition Example20 MA410.2A417.9A516.1A525.3A610.2A625.4A716.6A719.3A86.2A857.4H316.9H310.3H40.9H21.7A1635.4A217.2H513.4A703.8G84G84.8G83G83C33.7C32.9C33.7C33.7A694.8A692.7A693.8A693.8A633.8A635.4A639.8A641.1A647.2A648.3A663.6A666.6A669.1A680.7A684.4A686.1A627.4A6212.2H617.4H615.2H66.5A6715.3A676.9A674.2A653.2A652.5A658.2E45E46.4B510.7B51B59.7F164.3F167.6A7314.3A7314.4A737.3N35.2N32N35.8J216J120.8I320.1I419.4I216.1I53.3I69.6A2413.3I74.1I73.1I125.3I120.6A136.6A149.8A22.6A27.6A32.8A31.9A154.1A151.2I1311.3I1411.9I151.5I1514.8I191.3I192.7I1613.7A280.4A289.3I(20)9.4I(20)6.5A275.5A272J1812A98.2A94.9A105.9A1036.2A117A1112.2A127A1224.7A1710.8A1741.4A237.2A234.2C112.4A1860.8D20.8D25D38.6D36.7A2062.7D49.3D51.3D55.3D66.1D618.6A135A1978.5D710.1D714.3D86.6D85.7D93.7D94.3D104D101.5D1211D135.5D130.8D1412.3D140D158.9D151.2D164.1A227.5A2519.7A2642.5D175.3D1719D186.4D1812.1D199D194.2D2013.4A312.5I1016.1I96.9I115.7A323.8A339.6A333.8A344.6A343.4A359.9A352.1D210.7D221.8D232.9D245.4K134.1B46.7A297.1D258.7D2644.7A303.4A362.8A3716D275.1D2712.2D286.7D2826.9D294.3D2919D304.2D3016.4D310.8D318.8D321.7D3213.8A389.1A389.8A392.2A401A413.8A534A562.9A587.2A550.1A522A420.1A433A447.1A451A460.9A576.1A481.3D330.3D340.3D354.5D362.5D374.2D388.4D391.4D4017.7D4112.6F915.3A4914.1D421.8A5030.1B25.9D440D452.4D463.9D471D488.5D494.9D505.6D513.8D5225.9B408D789.4F23.5F13.4F410.3F510.5F68.4D535.1F855.8F821.1F83.4F81.8F81.9D566.5F77.3D557.3D1113.3B54.3C416.9D725.1D735.3D637.4B123.1C735.6D646.4D654.9B133C812.4D663.8D675.6D584D581.7D580.1C98.6C96.5C915.1D606.7D604.1D603.7D6810.2D687D6814.1F1210.3F126.3F1213.2B418.6B417.3B4112.9C54.7C52C53.7F139F1311.3F1312.9B148B141.5B142.8C914.8C95.5C916.5F1414F1410.2F1418.1B159B154.1B159.1B64.6B62.1B61.3C624.5C65.4C64.4D7411.3D743.1D7414.3D759.3D754.9D7518.8B424.7B420.4B429.5B438.1B432.8B4311.8B1682.8B1678.9B1655.4B1638.6B1629.1B1677.5B1682O317.1O324.5B214.5B2120.6B354.4B3514.1B366.2B3615.1B253B2510.3B267.5B2613.3B271.4B271.3

0810 FAK High-throughput screening results shown in Table 5 5TABLE 5Inhibition of FAK at 10 uM compoundIn HTS Delphia assayExample% inhibition ofFAKA46A510A60A72A817H319H46H218A1636A2126H542H517H53H53A7011J27J14I33I45I26I52I612A247I71I123A15A28A39A150I153I1957I197I195A284I202A272A94A104A1115A128A172A234C12A1829D13D226D320A2020D417D57D623A1312A1937D723D88D922D104D1229D1312D1423D1517D1617A2213A2557A2590A2588A2588A2617D1724D1814D197D2025A3127I812I812I926I1118A323A3317A3413A3510D211D222D2312D244K117B449B436B411B446B432A298D256D2651D2619A3016A366A372A3883A3823A3812A3910A406A4197A4118A4112A5310A567A589A5559A5511A5516A529A4215A4319A4415A4513A4614A5718A482D337D349D3519D361D376D3814D3921D406D4119F913A4913D425A5014B217D449D459D4614D4719% inhibitionA47A410A58A510A615A616A710A79A812A814H311H39H42H41H20H25A1694A1696A214A211H54H52A7011A702G816G830C319C30A6940A6915A636A6324A6322A6323A6420A6434A6638A6639A6818A6818A627A626H613H630A6729A6733A6531A6539E49E417B54B513F1613F1616A7323A7330N312N317J22J210J18J113I34I35I411I41I219I26I56I50I66I615A244A2413B330B326I79I719I127I127A14A182A29A25A39A33A159A157I132I137I1424I1423I157I1511I195I194I163I161A2814A288I209I207A2714A2711J183J188A96A95A102A105A118A1110A1216A1216A1733A179A235A236C18C111A1825A1832D12D113D23D27D34D30A2046A2056D43D45D51D517D62D63A137A1327A1976A1986D76D71D85D812D98D910D105D105D127D1210D138D131D149D1410D153D156D162D164A2235A2238A2560A2547A2672A2672D1710D1710D186D189D194D1910D206D2010A316A317I108I101I89I81I945I935I1130I1125A328A3211A332A334A343A348A355A359D210D2110D226D2224D236D231D244D247K192K196B456B443A296A2911D259D251D262D260A303A309A3611A3615A3734A3737D2779D2786D2815D287D292D299D3024D3018D3111D310D3220D3213H36H39A392A397A406A406A416A419A538A5310A568A563A586A580A553A557A521A526A421A428A436A432A445A4410A454A456A462A469A572A577A488A488D333D337D341D345D358D354D3619D366D375D378D382D387D3922D398D402D4010D410D417F924F914A497A4910D421D4210A508A502B213B22D4458D4456D4517D4510D4627D4619D4751D4746D4822D4824D4975D5042D5044D5116D5226D5213B4026B4029D7822D7815F218F215F119F125F410F415F516F510F614F61D5315D532F881F882D5673D5671F72F721D5514D5535D1125D1141B534B533C45C49D7265D7269D7369D7373D63130D63126B1243B1244C755C757D6492D6493D6594D6593B1330B1336C833C835D6679D6773D6775D5814D5812C919C916C6011C609C688C687F129F1214B4128B4126C56C511F1354F1356B1411B1417C919C918F142F142B155B152B611B610C619C611D7496D7494D7592D7591B427B4211B4316B4317O331O342B213B212B3596B3691B3693B256B250B2676B2791B2794

0811 Synthetic Protocol for Combinatorial Examples in Tables A-D 0812 The four library building blocks 2-(4-aminosulfonylphenyl)amino,4-aminoithiazole-5-carbothioamide, 2-(4-dimethylaminophenyl)amino,4-aminoithiazole-5-carbothioamide, 2-(3,4,5-trimethoxylaminosulfonylphenyl)amino,4-aminoithiazole-5-carbothioamide and 2-(4-isopropylphenyl)amino,4-aminoithiazole-5-carbothioamide were synthesized in a manner similar to that of step (i) and (ii) in Example A above. 0813 All the compounds in Table A-D were synthesized by the chemistry similar to that used to prepare Example A(1) except: A stock solution of corresponding 4 above carbothioamides in 10% DMF/methanol was distributed into a 96 deep well plate so that each well contained 5 Moles of material. Then, 5 moles of 63 -halid ketones were added to individual wells of each plate. After the reaction plates were shaken at room temperature for 16 hours, approximately 10 mg of Merrifield resin and 10 mg of N-(2-mercaptoethyl)aminomethyl polystyrene resin were added to each well. The reaction plates were shaken for another 2 hours. The reaction mixture was then filtered and the filtrates of each reaction well were collected individually into a receiving 96-well plate. The compounds were obtained after the removal of solvent. 0814 Table A 6EXAMPLESVEGFaCHK1bCDK2cCDK4d

321

3447.710.365.4

322

39.211.61

323

5746.37.333.1

324

26320.218.3

325

2449.54.835.1

326

382312.431.3

327

2203.55.1

328

193.72.11.9

329

59.94.919.9

330

1811.20.16.9

331

36.112.217

332

4115.3133

333

272.723.24

334

2536.61.911.6

335

815.214.45.6

336

311.74.417.8

337

218.720.44.7

338

1810.315.60.3

339

3231.33.823.7

340

2617.913.619.5

341

2232.95.416

342

5348.3 3532.3

343

422.314.62.2

344

5331.314.324.5

345

2616.5527.6

346

68.86.614.9

347

112.17.331.7

348

6648.3317.5

349

3827.928.47.8

350

5048.810.332.3

351

47121.27.3

352

5941.926.726.4

353

2223.912.314.7

354

2321.10.240.1

355

495611.836.4

356

3434.11913.7

357

5648.77.337.1

358

3829.41.711.7

359

5238.11231

360

1722.44.23.4

361

18.513.917.7

362

2031.97.814.6

363

370.54.621.1

364

310.413.89

365

1121.62.720.2

366

164.723.124

367

1125.35.30.1

368

4614.1118.7

369

3421.20.448.1

370

3541.44.422.8

371

5148.319.850.6

372

142.711.219.9

373

2730.97.58.2

374

30.917.510.4

375

138.911.334.4

376

507.41.68.4

377

2626.264.7

378

6032.512.128.7

379

51.36.34.5

380

4113.29.111.5

381

156.43.929.3

382

325.466.5

383

1913.515.610.5

0815

7TABLE BEXAMPLESVEGFaCHK1bCDK2cCDK4d

384

4928.555.957.2

385

127.825.58.9

386

3426.668.259.6

387

67.960.556.4

388

213.117.628.2

389

23.321.425

390

2118.718.916

391

332.120.59.6

392

33.912.51.2

393

274.418.510.9

394

82.328.441.2

395

486.910.79.3

396

31.129.813

397

4725.655.457.8

398

31127.716.3

399

215.98.328

400

312.311.211.3

401

133.71.3316.3

402

3214.76379.2

403

22.94.53.9

404

2920.121.431.8

405

4333.774.761.2

406

84.420.727

407

1313.614.639.7

408

3817.512.45.3

409

3010.817.828.6

410

911.71.33.1

411

5618.757.951.3

412

2513.440.746

413

1119.866.858

414

500.219.613.5

415

1111.351.665

416

436.837.21.9

417

2311.28.233.4

418

2925.669.562.5

419

1818.345.757.5

420

2328.46759.9

421

1110.754.240.9

422

199.75670.6

423

213.135.931.8

424

24.24.53.6

425

715.356.642.2

426

91.6292.3

427

21.314.13.5

428

39.761.453.4

429

35.69.20.3

430

917.52517

431

3412.360.843.3

432

2315.25.94.2

433

911.452.653.3

434

332977.264.1

435

11.2120.5

436

521.16875

437

50.516.131.3

438

1310.89.97.2

439

337.325.44.8

440

921.753.958

441

4021.674.158.2

442

106.134.829.3

443

100.448.944.1

444

43.323.214

445

413.616.615

446

1516.417.60.3

0816

8TABLE CEXAMPLESVEGFaCHK1bCDK2cCDK4d

447

2831.623.862.7

448

210.717.251.2

449

5027.417.576.5

450

259.22684.7

451

723.514.271.5

452

37.915.149.7

453

1315.66.353.3

454

20.814.255.9

455

101.822.638.2

456

20.210.853.1

457

125.212.279.4

458

194.727.860.9

459

95.71528.7

460

1632.217.763

461

4617.835.6

462

7911.79.1

463

0.93.29.60.7

464

77.15.958.4

465

2321.425.781.4

466

50.911.149.8

467

1423.82250.6

468

4839.816.180.7

469

47.573459

470

2217.61953.3

471

510.921.239.5

472

27.224.735.3

473

40.310.47.9

474

492510.577

475

455.114.174.6

476

3019.312.572.7

477

142.523.350

478

331321.861.8

479

58.821.748

480

4423.342.5

481

5138.931.872.8

482

3918.94.375.5

483

4732.338.679.6

484

1214.238.379

485

4217.83179.9

486

1911.65.274.4

487

43.78.748.3

488

2120.929.159.5

489

74.24.856.1

490

136.56.261.4

491

1514.12685.1

492

54.742.4

493

67.920.946.8

494

220.218.559.4

495

103.81649.3

496

262629.281.6

497

5934.939.984.7

498

134.72.450.4

499

1822.828.288.6

500

5918.526.5

501

140.73.610.3

502

1412.86.644.3

503

3114.82686.2

504

4619.730.691.5

505

95.312.273

506

254.39.372

507

30.710.137.8

508

113.41733.2

509

51214.648.1

0817

9TABLE DEXAMPLESVEGFaCHK1bCDK2cCDK4d

510

3446.516.853

511

519.626.945.5

512

3243.92464.1

513

1822.817.669.1

514

2164.159.8

515

57.617.735.6

516

014.86.48.7

517

1615.217.761.6

518

13.16.735.4

519

102.511.236.5

520

1314.115.668.7

521

132.76.119.1

522

94.513.433.7

523

1739.58.346.2

524

817.822.150.4

525

216.611.715.2

526

12514.512.6

527

118.214.336.4

528

1926.917.376.1

529

258.18.359.8

530

1640.8556.5

531

4141.734.856

532

45.58.749.4

533

2832.531.763.6

534

84.23.38.1

535

613.817.127

536

05.19.26.5

537

4647.126.666.8

538

2427.229.852.4

539

3541.433.364.4

540

210.916.123.3

541

2838.16.369.4

542

1623.30.657.5

543

1713.117.248.3

544

3641.124.169.3

545

2729.338.363.5

546

3141.917.164.3

547

2334.829.883

548

2926.837.365.1

549

1832.93.174.4

550

513.133.460.3

551

2032.72.543.7

552

239.827.148.5

553

1718.820.570.9

554

142624.681.8

555

263.223.312.1

556

637.118.373.2

557

3017.519.765.1

558

107.816.320.3

559

2538.519.845.9

560

333733.962.7

561

50.82429.6

562

9278.276.5

563

12.812.617.5

564

89.5636.2

565

244.627.848.5

566

2637.529.182.6

567

3425.220.364.3

568

1617.414.657.8

569

2212.623.557.7

570

35.236.745.2

571

37.616.929.6

572

1714.22930.1 a. % inhibition at 20 Mb. % Inhibition at 20 Mc. % Inhibition at 1.0 Md. % Inhibition at 1.0 M

0818 Combinatorial procedure for the synthesis of Urea functionalized thiazole derivatives and inhibition of HUVEC Profileration 573

0819 Solutions of 263 amines (1.5 mol), and Et3N (0.1393 L, 1.0 mol), dissolved in DMF (15 L), were distributed in to the wells of a 96-well plate. In cases where the amine was used as a hydrochloride salt, additional Et3N (0.4179 L, 3.0 mol) was added to liberate the free base. Each of the wells was treated with a solution of p-carboxy phenol carbamate (0.5395 mg, 1.0 mol) dissolved in DMF (30 L), then agitated for 24 h at room temperature. The crude reaction mixtures were concentrated using a GeneVac apparatus, and then diluted with DMSO to a final concentration of 10 mM, yielding the examples shown in Table E. 10TABLE EInhibition of HUVEC Proliferation% inhibition% inhibitionMOLSTRUCTURE 10 nM 50 nM

574

2862

575

7126

576

533

577

3839

578

1329

579

580

1983

581

2518

582

4687

583

28123

584

390

585

2225

586

11114

587

1855

588

2223

589

2536

590

621

591

592

3532

593

2015

594

939

595

3449

596

110

597

1967

598

838

599

1752

600

435

601

524

602

15115

603

2077

604

1619

605

1362

606

2324

607

1392

608

1121

609

439

610

2128

611

717

612

842

613

5103

614

3105

615

2116

616

342

617

342

618

815

619

1146

620

143

621

562

622

745

623

1225

624

123

625

3597

626

38No data

627

1923

628

4223

629

1515

630

29108

631

1228

632

1101

633

222

634

967

635

035

636

301

637

768

638

271

639

3224

640

223

641

2117

642

1549

643

986

644

347

645

646

137

647

43252

648

4546

649

30135

650

2445

651

10125

652

2746

653

4434

654

655

143

656

657

1798

658

2636

659

265

660

597

0820

11Inhibition of HUVEC Proliferation% inhibitionMOLSTRUCTURE 50 nM

661

662

111

663

664

665

666

667

668

669

670

105

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

105

691

692

108

693

694

695

696

697

105

698

699

700

118

701

102

702

703

704

705

706

707

708

709

710

711

712

100

713

110

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

100

731

732

733

734

735

736

104

737

120

738

739

740

741

742

743

744

745

746

747

748

0821

12Inhibition of HUVEC ProliferationInhibitionMOLSTRUCTURE 50 nM

749

750

751

752

753

754

755

756

757

107

758

106

759

104

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

105

778

779

780

781

782

783

106

784

785

786

787

788

112

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

104

826

827

828

829

830

831

832

833

834

835

836

0822 Combinatorial Procedure for Examples in Table I 0823 0.1 M Solutions of the acid, the amine template, o-(7-azabenzotriazol-1-yl)-N,N,N,N-tetra-methyluronium hexafluorophosphate and triethylamine were prepared separately in anhydrous DMF. To each tube in an array of 811 culture tubes (1075 mm) was added 110 L (0.011 mmol) of a different acid. To this was added 100 L (0.01 mmol) of the amine solution, 110 L (0.011 mmol) of the triethylamine solution followed by 110 L (0.011 mmol) of the o-(7-azabenzotriazol-1-yl)-N,N,N,N-tetra-methyluronium hexafluorophosphate solution. The reactions were stirred in a heating block at 60 C. for 6 h. The reaction mixtures were transferred to a 1 mL 96-well plate using a liquid handler. The solvents were removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO to give a final theoretical concentration of 10 mM. Screening results are shown in Table I. 13TABLE I% inhibition MOL>MOLSTRUCTURE150 nM

837

838

839

840

841

842

843

844

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

877

878

879

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

936

937

938

939

940

941

942

943

944

945

946

947

948

949

950

951

952

953

954

955

956

957

958

959

960

961

962

963

964

965

966

967

968

969

970

971

972

973

974

975

976

977

978

979

980

981

982

983

984

985

986

987

988

989

990

991

992

993

994

108

995

996

997

998

999

1000

0824 Combinatorial Procedure for Examples in Table II 0825 0.1 M solutions of the acid, the amine template, o-(7-azabenzotriazol-1-yl)-N,N,N,N-tetra-methyluronium hexafluorophosphate and triethylamine were prepared separately in anhydrous DMF. To each tube in an array of 811 culture tubes (1075 mm) was added 105 L (0.0105 mmol) of a different acid. To this was added 100 L (0.01 mmol) of the amine solution, 105 L (0.0105 mmol) of the triethylamine solution followed by 105 L (0.0105 mmol) of the o-(7-azabenzotriazol-1-yl)-N,N,N,N-tetra-methyluronium hexafluorophosphate solution. The reactions were stirred in a heating block at 50 C. for 3 h. The reaction mixtures were transferred to a 1 mL 96-well plate using a liquid handler. The solvents were removed using the SpeedVac apparatus and the crude reaction mixtures were redissolved in DMSO to give a final theoretical concentration of 10 mM. Screening results are shown in Table II. 14TABLE II% inhibition % inhibition STRUCTURE10 nM1 nM

1001

408

1002

145

1003

33183

1004

930

1005

261

1006

4510

1007

218

1008

304

1009

1010

1011

141

1012

4012

1013

212

1014

138

1015

1523

1016

1017

121

1018

1114

1019

258

1020

1632

1021

1217

1022

220

1023

277

1024

1025

105

1026

3125

1027

184

1028

1029

912

1030

1014

1031

113

1032

1033

1034

2518

1035

132

1036

102

1037

2232

1038

3910

1039

1325

1040

6011

1041

175

1042

2747

1043

010

1044

6712

1045

1046

2111

1047

291

1048

616

1049

106

1050

1060

1051

154

1052

432

1053

273

1054

5011

1055

1056

1111

1057

692

1058

202

1059

9749

1060

1061

110

1062

118

1063

625

1064

4234

1065

114

1066

477

1067

2111

1068

1069

1070

8229

1071

1917

1072

1811

1073

012

1074

781

1075

621

1076

1315

1077

122

1078

269

1079

416

1080

4117

1081

2932

1082

421

1083

717

1084

4634

1085

551

1086

4554

1087

1920

1088

2114

0826

15%%inhibitioninhibitionSTRUCTURE 10 nM 1 nM

1089

11125

1090

1091

217

1092

477

1093

283

1094

1095

695

1096

5130

1097

7213

1098

1099

225

1100

165

1101

134

1102

7235

1103

164

1104

616

1105

405

1106

401

1107

2123

1108

1109

118

1110

231

1111

214

1112

597

1113

674

1114

3512

1115

332

1116

2318

1117

9435

1118

1512

1119

187

1120

194

1121

810

1122

117

1123

9925

1124

129

1125

991

1126

10923

1127

1636

1128

4134

1129

12360

1130

3719

1131

1132

7432

1133

4223

1134

3231

1135

1821

1136

344

1137

2018

1138

5926

1139

711

1140

1141

2413

1142

2512

1143

1314

1144

1145

489

1146

827

1147

9335

1148

1121

1149

539

1150

1151

662

1152

147

1153

112

1154

7821

1155

521

1156

659

1157

2430

1158

4312

1159

1136

1160

743

1161

624

1162

6429

1163

2914

1164

945

1165

2423

1166

116

1167

188

1168

444

1169

1134

1170

1816

1171

6311

1172

3113

1173

1818

1174

2127

1175

1110

1176

207

0827 The exemplary compounds described above may be formulated into pharmaceutical compositions according to the following general examples.

EXAMPLE 1 0828 Parenteral Composition 0829 To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula I is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

EXAMPLE 2 0830 Oral Composition 0831 To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula I is mixed with 750 mg of lactose. The mixture is incorporated into an oral dosage unit form, such as a hard gelatin capsule, which is suitable for oral administration.

EXAMPLE 3 0832 Intraocular Composition 0833 To prepare a sustained-release pharmaceutical composition for intraocular delivery, a compound of Formula I is suspended in a neutral, isotonic solution of hyaluronic acid (1.5% conc.) in phosphate buffer (pH 7.4) to form a 1% suspension. 0834 It is to be understood that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, the artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.