60/342,034 filed December 19,2001 and U. S. Provisional Patent Application Serial No.

60/386,482 filed June 5,2002.

The present invention is in the field of novel chalcone derivatives, pharmaceutical compositions and methods for treating a variety of diseases and disorders, including inflammation and cardiovascular disease.

BACKGROUND OF THE INVENTION Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis (including rheumatoid arthritis), asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.

Coronary heart disease (CHD), primarily as a result of atherosclerosis, remains the leading cause of death in industrialized countries. Atherosclerosis is a disease characterized by vascular inflammation, deposition of lipids in the arterial vessel wall and smooth muscle cell proliferation resulting in a narrowing of the vessel passages. In advanced stages of the disease atherosclerotic lesions can become unstable resulting in plaque rupture, thrombosis, myocardial infarction and ischemic heart disease. It is now well accepted that the initiating events in atherosclerosis are local injury to the arterial endothelium that results in the induction of VCAM-1 and recruitment of mononuclear leukocytes that express the integrin counterreceptor, VLA-4, (O'Brien, et al., J. Clin. Invest., 92: 945-951,1993). Subsequent conversion of leukocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help propagate formation of the mature atheromatous plaque by further inducing endothelial activation, leukocyte recruitment, smooth muscle cell proliferation, and extracellular matrix deposition. Pharmacological inhibition of VCAM-1 expression has been shown to inhibit atherosclerosis in several animal models (Sundell et al., Circulation, 100: 42,1999). A monoclonal antibody against VCAM-1 has also been shown to inhibit neointimal formation in a mouse model of arterial wall injury (Oguchi, S. , et al., Arterioscler. Thromb. Vasc. Biol., 20: 1729-1736,2000).

Asthma, which is increasing in prevalence and morbidity world-wide, is a chronic inflammatory disease characterized by lung eosinophilia and bronchial hyperreactivity. The interaction between VCAM-1 on lung endothelial cells and VLA-4, which is the integrin counterreceptor expressed on eosinophils, is thought to be important for selective eosinophil recruitment. Eosinophils have been considered an important effector cell in the pathogenesis of asthma and other allergic diseases. Activated eosinophils release proteins such as major basic protein (MBP) that have been demonstrated to induce bronchial hyperreactivity, one of the defining criteria of asthma (Bousquot, et al., N. Engl. J. Med., 323: 1033-1039,1990). It has been demonstrated that VCAM-1 is markedly upregulated on human bronchial vascular endothelium of subjects with asthma who have air flow limitation, when compared with subjects without asthma (Pilewski, et al., Am. J. Respir. Cell Mol. Biol., 12,1-3, 1995; Ohkawara, Y. , et al., Am. J. Respir. Cell Mol. Biol., 12,4-12, 1995; Gosset, P. , et al., Int. Arch.

Allergy Immunol. 106: 69-77,1995 ; Hacken, N. H. , et al., Clin. Exp. Allergy, 28 (12): 1518- 1525,1998). An elevation in serum soluble VCAM-1 levels has also been demonstrated in

patients undergoing a bronchial asthma attack compared with levels under stable conditions (Montefort, S. , Koizumi, A., Clin. Exp. Immunol., 101: 468-73,1995). Several animal studies further demonstrate a spatial and temporal association between VCAM-1 and asthma. In a mouse model of allergic asthma, VCAM-1 expression was shown to be induced by allergen challenge, and administration of an anti-VCAM-1 antibody was effective in inhibiting eosinophil infiltration that occurred in this model (Metzger, W. J. , et al., J Allergy Clin.

Immunol., 93: 183,1994). Further evidence for the importance of VCAM-1 in allergic asthma comes from work in IL-12 knockout mice. IL-12 knockout mice had fewer eosinophils and VCAM-1 expression than wildtype mice; however, administration of recombinant IL-12 at the time of ova sensitization and challenge restored lung VCAM-1 expression and eosinophilia (Wang, S. , et al., J. Immunol., 166: 2741-2749,2001). There are several examples where blocking the integrin receptors for VCAM-1 have had positive effects on animal models of asthma (Rabb et al., Am. J. Respir. Care Med. 149: 1186-1191,1994 ; Abraham, W, et al., Am.

J. Respir. Crit. Care Med. 156: 696-703.1997) further demonstrating the importance of VCAM-1/VLA-4 interactions in allergic inflammation. Eosinophils are also important effector cells in allergic rhinitis. VCAM-1 has been demonstrated to be upregulated 24 hrs after nasal allergen provocation in patients with seasonal allergic rhinitis but not in normal subjects (Braunstahl, G. J., et al., J. Allergy Clin. Immunol., 107: 469-476, 2001).

Rheumatoid arthritis (RA) is a clinical syndrome of unknown cause characterized by symmetric, polyarticular inflammation of synovial-lined joints. The role of adhesion molecules in the pathogenesis of RA has also been well documented, and VCAM-1 expression on synovial fibroblasts is a clinical hallmark of RA (Li, P. , et al., J. Immunol. 164: 5990-7,2000).

VLA-4/VCAM-1 interactions may be the predominant mechanism for recruitment of leukocytes to the synovium (Dinther-Janssen, et al., J. Immunol. 147: 4207-4210,1991 ; Issekeutz and Issekeutz, Clin. Immunol. Immunopathol. 61: 436-447,1991 ; Morales-Ducret et al. , J. Immunol. 149: 1424-1431,1992 ; Postigo et al., J. Clin. Invest. 89: 1445-1452,1992 ; Matsuyama, T. , et al, Hum. Cell, 9: 187-192,1996). In support of this, increased VCAM-1 expression has been found in RA synovial tissue compared with osteoarthritis and control tissue (Wilkinson et al., Lab. Invest. 69: 82-88,1993 ; Furuzawa-Carballeda, J. , et al., Scand. J.

Immunol. 50: 215-222; 1999). Soluble VCAM-1 is higher in RA patients than in control subjects (Kolopp-Sarda, M. N. , et al., Clin. Exp. Rheumatol. 19: 165-70,2001). Soluble

VCAM-1 has been shown to be chemotactic for T cells (Kitani, A. , et al., J. Immun. 161: 4931- 8,1998), and in addition to being a possible diagnostic marker for RA, may contribute to its pathogenesis by inducing migration and recruitment of T cells. VCAM-1 expressed on fibroblast-like synoviocytes has also been implicated in enhanced survival of activated synovial fluid B cells (Marinova, Mutafcheia, L., Arthritis Rheum. 43: 638-644,2000) that may further contribute to RA pathogenesis.

Chronic inflammation and accompanying vascular complications and organ damage characterize systemic lupus erythematosis (SLE). Recent studies suggest that VCAM-1 plays a role in SLE. Expression of VCAM-1 is increased on dermal vessel endothelial cells in patients with active systematic lupus erythematosus (Jones, S. M., British J. Dermatol. 135: 678-686, 1996) and correlates with increased disease severity (Belmont et al., Arthritis Rheum. 37: 376- 383,1994). SLE muscle samples with perivascular infiltrate have greater endothelial cell expression of VCAM-1 compared with SLE patients without a perivascular infiltrate or with control samples (Pallis et al., Ann. Rheum. Dis. 52 : 667-671,1993). Increased expression of VCAM-1 has also been demonstrated in kidneys of lupus-prone MRL/lpr mice compared to nonautoimmune strains and its expression increased with disease severity (McHale, J. F. , et al., J. Immunol. 163: 3993-4000,1999). VCAM-1 expression on mesangial cells in vitro can be stimulated by IL-1, TNF-a, and INFy exposure as well as by anti-endothelial cell IgG fraction and anti-DNA autoantibodies from SLE patients (Wuthrich, Kidney Int. 42: 903-914,1992 ; Papa, N. D. , et al., Lupus, 8: 423-429,1999 ; Lai, K. N. , et al., Clin Immunol Immunopathol, 81: 229-238,1996). Furthermore, soluble VCAM-1 is higher in SLE patients than in normal subjects (Mrowka, C. , et al., Clin. Nephrol. 43: 288-296,1995 ; Baraczka, K. , et al., Acta.

Neurol. Scand. 99: 95-99,1999 ; Kaplanski, G. , et al., Arthritis Rheumol. 43: 55-64,2000 ; <BR> <BR> <BR> <BR> Ikeda, Y., Lupus, 7: 347-354,1998) and correlates with disease activity (Scudla, V. , Vnitr. Lek, 43: 307-311,1997).

Increased VCAM-1 expression has also been demonstrated in solid organ transplant rejection. Acute transplant rejection occurs when the transplant recipient recognizes the grafted organ as"non-self"and mounts an immune response characterized by massive infiltration of immune cells, edema, and hemorrage that result in the death of the transplanted organ. Acute rejection occurs in a matter of hours or days and has been correlated with increased levels of

VCAM-1 in tissues and in plasma (Tanio et al., Circulation, 89: 1760-1768,1994 ; Cosimi et al., J. Immunol. 144: 4604-4612,1990 ; Pelletier, R. , et al., Transplantation, 55: 315,1992). A monoclonal antibody to VCAM-1 has been shown to inhibit cardiac allograft rejection in mice (Pelletier, R. , J. Immunol., 149: 2473-2481,1992 ; Pelletier, R. , et al., Transplantation Proceedings, 25: 839-841,1993 ; Orosz, C. G. , et al., J. Heart and Lung Transplantation, 16: 889-904,1997) and when given for 20 days can cause complete inhibition of rejection and long-term graft acceptance (Orosz C. G. , et al., Transplantation, 56: 453-460,1993). Chronic graft rejection also known as allograft vasculopathy is distinct from acute transplant rejection and is a leading cause of late graft loss after renal and heart transplantation. Histologically it is characterized by concentric neointimal growth within vessels that is largely due to smooth muscle migration and proliferation. It is thought to be the result of endothelial damage brought about by several factors including: ischemia-reperfusion injury, immune complexes, hypertension, hyperlipidemia and viruses. All of these factors have been associated with induction of VCAM-1 in endothelial cells. There is also a strong correlation of soluble and tissue VCAM-1 levels with chronic rejection (Boratynska, M.,. Pol. Arch. Med. Wewn, 100: 410-410,1998 ; Zembala, M. , et al., Ann. Transplant. 2: 16-9,1998 ; Solez K. , et al., Kidney International., 51: 1476-1480,1997 ; Koskinen P. K. , et al., Circulation, 95: 191-6,1997).

Multiple sclerosis is a common demyelinating disorder of the central nervous system, causing patches of sclerosis (plaques) in the brain and spinal cord. It occurs in young adults and has protean clinical manifestations. It is well documented that VCAM-1 is expressed on brain microvascular endothelial cells in active lesions of multiple sclerosis (Lee S. J. , et al., J.

Neuroimmunol., 98: 77-88,1998). Experimental therapy of experimental autoimmune encephalomyelitis, which is an animal model for multiple sclerosis, using antibodies against several adhesion molecules, including VCAM-1, clearly shows that adhesion molecules are critical for the pathogenesis of the disease (Benveniste et al., J. Neuroimmunol. 98: 77-88, 1999). A time and dose dependent expression of VCAM-1 and release of soluble VCAM-1 were detected in cultures of human cerebral endothelial cells induced by TNFa, but not in peripheral blood mononuclear cells (Kallmann et al., Brain, 123: 687-697,2000). Clinical data also show that adhesion molecules in blood and cerebrospinal fluid are up-regulated throughout the clinical spectrum of multiple sclerosis (Baraczka, K. , et al., Acta. Neurol. Scand. 99: 95-99, 1999; Reickmann, P. , et al., Mult. Scler., 4: 178-182,1998 ; Frigerio, S. , et al., J.

Neuroimmunol., 87: 88-93,1998) supporting the notion that therapies which interfere with cell adhesion molecules such as VCAM-1 may be beneficial in modifying this disease (Elovaara et al., Arch. Neurol. 57: 546-551,2000).

Diabetes mellitus is a metabolic disease in which carbohydrate utilization is reduced and that of lipid and protein is enhanced. Evidence has accumulated that increased levels of adhesion molecules may play a functional pathophysiological role in diabetes (Wagner and Jilma, Hormone and Metabolic Research, 29: 627-630,1997 ; Kado, S., Diabetes Res. Clin.

Pract., 46: 143-8,1999). It is caused by an absolute or relative deficiency of insulin and is characterized by chronic hyperglycemia, glycosuria, water and electrolyte loss, ketoacidosis, and coma. Elevated circulating adhesion molecules including VCAM-1 have been detected in patients with diabetes and in experimental models of diabetes in animals (Lorini et al., Hormone Research, 48: 153,1997 ; Otsuki et al., Diabetologia, 40: A440,1997 ; Hart et al., FASEB J. 11 : A340,1997 ; Albertini et al., Diabetologia, 39: A240,1996 ; Wagner et al., Diabetologia, 39: A205,1996 ; Enghofer et al., Diabetologia, 39: A97,1996 ; Koga M., Diabet.

Med., 15: 661-667,1998). In addition, complications of diabetes often include peripheral vasculopathies such as diabetic retinopathy and diabetic nephropathy. It is believed that adhesion of leukocytes to the peripheral vasculature plays a central role in the vasculopathies often associated with diabetes.

Crohn's disease, also known as regional enteritis, is a subacute chronic inflammatory condition of unknown cause, involving the internal ileum and less frequently other parts of the gastrointestinal tract. It is characterized by patchy deep ulcers that may cause fistulas, and narrowing and thickening of the bowel by fibrosis and lymphocytic infiltration. Ulcerative colitis is a chronic disease of unknown cause characterized by ulceration of the colon and rectum, with rectal bleeding, mucosal crypt abscesses, inflammatory pseudopolyps, abdominal pain, and diarrhea. It has been reported that serum VCAM-1 reflects the grade of intestinal inflammation in patients with Crohn's disease or ulcerative colitis (Jones, et al., Gut, 36: 724- 30,1995 ; Goggins et al., Gastroenterology, 108: A825,1995 ; Goeke and Manns, Gastroenterology, 106: A689,1994 ; Goeke et al., J. Gasterokenterol. 32: 480-486,1997 ; Loftus et al., Gastroenterology, 108: A684,1995 ; Tahami et al., Gastroenterology, 118: A344,2000).

Antibodies to VCAM-1 have been shown to ameliorate experimentally-induced colitis in mice (Soriano, A., Lab. Invest. 80: 1541-1551,2000).

Psoriasis is a chronic skin disease characterized by erythematous scaling plaques as a result of keratinocyte hyperplasia, influx of immune cells and endothelial activation (Nickoloff, B. J. , et al., J. Invest. Dermatol., 127: 871-884, 1991). VCAM-1 is upregulated in psoriatic skin as compared to normal skin (Groves, R. W., J. Am. Acad. Dermatol., 29: 67-72,1993 ; Uyemura, K. , et al., J Invest. Dermatol. 101: 701-705,1993) and levels of circulating VCAM- 1 correlate with disease activity (Schopf, R. E., Br. J. Dermatol., 128: 34-7,1993).

U. S. Patent Nos. 5,750, 351 ; 5,807, 884; 5,811, 449; 5,846, 959; 5,773, 231, and 5,773, 209 to Medford, et al. , as well as the corresponding WO 95/30415 to Emory University indicate that polyunsaturated fatty acids ("PUFAs") and their hydroperoxides ("ox-PUFAs"), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses. As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E- selectin.

WO 98/51662, filed by AtheroGenics, Inc. and listing as inventors Russell M. Medford, Patricia K. Somers, Lee K. Hoong, and Charles Q. Meng, claims priority to provisional application U. S. S. N. 60/047,020, filed on May 14,1997. This application discloses the use of a broad group of compounds as cardiovascular protectants that exhibit at least one, and sometimes a composite profile, of reducing cholesterol, lowering LDL, and inhibiting the expression of VCAM-1.

U. S. Patent No. 5,155, 250 to Parker, et al. discloses that 2, 6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same compounds are disclosed as serum cholesterol lowering agents in PCT Publication No. WO 95/15760, published on June 15,1995. U. S. Patent No.

5,608, 095 to Parker, et al. discloses that alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower plasma cholesterol, and inhibit the expression of VCAM-1, and thus are useful in the treatment of atherosclerosis.

WO 98/51289, which claims priority to provisional application U. S. S. N. 60/047,020, filed on May 14, 1997 by Emory University listing Patty Somers as sole inventor, discloses the use of a group of compounds as cardiovascular protectants and antiinflammatory agents which exhibit at least one, and sometimes a composite profile, of reducing cholesterol, lowering LDL, and inhibiting the expression of VCAM-1 and thus can be used as antiinflammatory and cardivascular treating agents.

U. S. Patent Nos. 5,380, 747; 5,792, 787; 5,783, 596; 5,750, 351; 5,821, 260; 5,807, 884; 5,811, 449; 5,846, 959; 5,877, 203; and 5,773, 209 to Medford, et al. , teach the use of dithiocarbamates of the general formula A-SC (S) -B for the treatment of cardiovascular and other inflammatory diseases. Examples include sodium pyrrolidine-N-carbodithioate, tri- sodium N, N-di (carboxymethyl) -N-carbodithioate, and sodium N, N-diethyl-N-carbodithioate.

The patents teach that the compounds inhibit the expression of VCAM-1.

WO 98/23581 discloses the use of benzamidoaldehydes and their use as cysteine protease inhibitors.

WO 97/12613 of Cornicelli et al. discloses compounds for the inhibition of 15- lipogenase to treat and prevent inflammation or atherosclerosis. Compounds disclosed include benzopyranoindole, benzimidazole, catacholes, benzoxadiazines, benzo [a] phenothiazine, or related compounds thereof.

Japanese Patent No. 06092950 to Masahiko et al. discloses preparation of epoxy compounds wherein electron deficient olefins such as acylstyrene derivatives, styrene derivatives, and cyclohexenone derivatives are efficiently oxidized by a hydrogen peroxide derivative in the presence of a primary or secondary amine in an organic solvent to give said epoxides which are useful intermediates for pharmaceutical and flavoring materials.

U. S. Patent No. 5,217, 999 to Levitzki et al. discloses substituted styrene compound as a method of inhibiting cell proliferation.

Chalcone (1, 3-bis-aromatic-prop-2-en-1-ones) compounds are natural products related to flavonoids. WO 99/00114 (PCT/DK98/00283) discloses the use of certain chalcones, 1,3- bis-aromatic-propan-l-ones (dihydrochalcones), and 1, 3-bisaromatic-prop-2-yn-1-ones for the preparation of pharmaceutical compositions for the treatment of prophylaxis of a number of serious diseases including i) conditions relating to harmful effects of inflammatory cytokines, ii) conditions involving infection by Helicobacter species, iii) conditions involving infections by viruses, iv) neoplastic disorders, and v) conditions caused by microorganisms or parasites.

WO 00/47554 filed by Cor Therapeutics describes a broad class of substituted unsaturated compounds for use as antithrombotic agents.

WO 96/20936 (PCT/KR95/00183) discloses thiazolidin-4-one derivatives of the formula: which act as PAF antagonists or 5-lipoxygenase inhibitors. The compounds are used in the prevention and treatment of inflammatory and allergic disorders mediated by platelet-activating factor and/or leukotrienes.

U. S. Patent No. 4,085, 135 discloses 2'- (carboxymethoxy)-chalcones with antigastric and antiduodenal ulcer activities.

U. S. Patent No. 5,744, 614 to Merkle et al. discloses a process for preparing 3,5- diarylpyrazoles and various derivatives thereof by reacting hydrazine hydrate with 1,3- diarylpropenone in the presence of sulfuric acid and an iodine compound.

U. S. Patent No. 5,951, 541 to Wehlage et al. discloses the use of salts of aromatic hydroxy compounds, such as (hydroxyaryl) alkenone salts, as brighteners in aqueous acidic electroplating baths. In addition the invention discloses that such compounds have a lower

vapor pressure than the known brighteners, as a single substance and in the electroplating baths, in order to avoid losses of substance. They also have high water solubility properties.

Japanese Patent No. 07330814 to Shigeki et al. discloses benzylacetophenone compounds as photoinitiator compounds.

Japanese Patent No. 04217621 to Tomomi discloses siloxane chalcone derivatives in sunscreens.

U. S. Patent No. 4,085, 135 to Kyogoku et al. discloses a process for preparation of 2'- (carboxymethoxy) -chalcones having antigastric and anti duodenal activities with low toxicity and high absorptive ratio in the body. This patent suggests that the high absorptive ratio in the body is due to the 2'-carboxymethoxy group attached to the chalcone derivative.

U. S. Patent No. 4,855, 438 discloses the process for preparation of optically active 2- hydroxyethylazole derivatives which have fungicidal and plant growth-regulating action by reacting an a- (3-unsaturated ketone which could include a chalcone or a chalcone derivative with an enantiomerically pure oxathiolane in the presence of a strongly basic organometallic compound and at temperatures ranging from-80 to 120 °C.

European Patent No 307762 assigned to Hofmann-La Roche discloses substituted phenyl chalcones.

E. Bakhite et al. in J. Chem. Tech. Biotech. 1992,55, 157-161, have disclosed a process for the preparation of some phenyloxazole derivatives of chalcone by condensing 5- (p- acetylphenyl)-2-phenyloxazole with aromatic aldehydes.

Herencia, et al. , in Synthesis and Anti-inflammatory Activity of Chalcone Derivatives, Bioorganic & Medicinal Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone derivatives with anti-inflammatory activity.

Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J. Pharm.

Pharmacol. 2000,52 ; 163-171 describes that certain chalcones have potent antiinflammatory activity.

Zwaagstra, et al., Synthesis and Structure-Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT, (LT4) Receptor Antagonists; J. Med. Chem. , 1997,40,

1075-1089 discloses that in a series of 2-, 3-, and 4- (2-quinolinylmethoxy)- and 3-and 4- [2- (2- quinolinyl) ethenyl]-substituted, 2', 3', 4', or 5'carboxylated chalcones, certain compounds are CysLT, receptor antagonists.

JP 63010720 to Nippon Kayaku Co. , LTD discloses that chalcone derivatives of the following formula (wherein R'and R2 are hydrogen or alkyl, and m and n are 0-3) are 5- lipoxygenase inhibitors and can be used in treating allergies.

JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloses chalcones of the following structure as 5-lipoxygenase inhibitors, wherein R is acyl and Rl-R5 are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and Rl-R5 are hydrogen.

U. S. Patent No. 6,046, 212 to Kowa Co. Ltd. discloses heterocyclic ring-containing chalcones of the following formula as antiallergic agents, wherein A represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a group:

in which X represents a hydrogen or halogen atom or a hydroxyl, lower alkyl or lower alkoxyl group and B represents-CH=CH-,-N (R6)-, R6 is a lower alkyl group or a lower alkoxyalkyl group,-0-or-S- ; W represents-CH=CH-or-CH2O-, and RI-5 is the same or different and each independently represent a hydrogen or halogen atom, a hydroxyl, a lower alkyl, lower alkoxyl, carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, a group-CONHR7 in which R7 represents a hydrogen atom or a lower alkyl group, or a group ~O (CH2) n R8 in which R8 represents a carboxyl, alkyloxycarbonyl or tetrazolyl group and n is from 1 to 4, with the proviso that at least one of the groups RI-5 represents a carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, the group--CONHR7 or the group--O (CH2) nR8 ; or a salt or solvate thereof.

Reported bioactivies of chalcones have been reviewed by Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6,1125-1149 ; Liu et al., Antimalarial Alkoxylated and Hydroxylated Chalones: Structure-Activity Relationship Analysis, J. Med. Chem. 2001,44, 4443-4452; Herencia et al, Novel Anit-inflammatory Chalcone Derivatives Inhibit the Induction of Nitric Oxide Synthase and Cyclooxygenase-2 in Mouse Peritoneal Macrophages, FEBS Letters, 1999,453, 129-134; and Hsieh et al., Synthesis and Anti-inflammatory Effect of Chalcones and Related Compounds, Pharmaceutical Research, 1998, Vol. 15, No. 1, 39-46.

Given that VCAM-1 is a mediator of chronic inflammatory disorders, it is a goal of the present work to identify new compounds, compositions and methods that can inhibit the expression of VCAM-1. A more general goal is to identify selective compounds and methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed. An even more general goal is to identify selective compounds, pharmaceutical compositions and methods of using the compounds for the treatment of inflammatory diseases.

It is therefore an object of the present invention to provide new compounds for the treatment of disorders mediated by VCAM-1.

It is also an object to provide new pharmaceutical compositions for the treatment of diseases and disorders mediated by the expression of VCAM-1.

It is a further object of the invention to provide compounds, compositions, and methods of treating disorders and diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases.

Another object of the invention is to provide compounds, compositions, and method of treating cardiovascular and inflammatory diseases.

It is another object of the invention to provide compounds, compositions and methods to treat arthritis.

Another object of the invention is to provide compounds, compositions and methods to treat rheumatoid arthritis. The inventions compounds, compositions and methods are also suitable as disease modifying anti-rheumatoid arthritis drugs (DMARDs).

It is yet another object of the invention to provide compounds, compositions and methods to treat asthma.

It is another object of the invention to provide compounds, methods and compositions to inhibit the progression of atherosclerosis.

It is still another object of the invention to provide compounds, compositions, and methods to treat or prevent transplant rejection.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of lupus.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of inflammatory bowel disease.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of autoimmune diabetes.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of multiple sclerosis.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic retinopathy.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic nephropathy.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic vasculopathy.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of rhinitis.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of ischemia-reperfusion injury.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of post-angioplasty restenosis.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of chronic obstructive pulmonary disease (COPD).

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of glomerulonephritis.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of Graves disease.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of gastrointestinal allergies.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of conjunctivitis.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of dermatitis.

It is a further object of the present invention to provide compounds, methods and compositions for the treatment of psoriasis.

SUMMARY OF THE INVENTION It has been discovered that particular chalcone derivatives inhibit the expression of VCAM-I, and thus can be used to treat a patient with a disorder mediated by VCAM-1.

Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.

The compounds disclosed herein can also be used in the treatment of inflammatory skin diseases that are mediated by VCAM-I, as well as human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to psoriasis, dermatitis, including eczematous dermatitis, Kaposi's sarcoma, multiple sclerosis, as well as proliferative disorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.

In one embodiment, the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but is not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. The compounds can also be used in the prevention or treatment of graft-versus- host disease, such as sometimes occurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used

in primary treatment of, for example, coronary disease states including atherosclerosis, post- angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.

Compounds of the present invention are of the formula

or its pharmaceutically acceptable salt or ester, wherein the substituents are defined herein.

DETAILED DESCRIPTION OF THE INVENTION It has been discovered that compounds of the invention inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. These compounds can be administered to a host as monotherapy, or if desired, in combination with another compound of the invention or another biologically active agent, as described in more detail below.

In a 1st embodiment, the invention is represented by Formula I

or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R1) 2C (O) OH, -OC (R1) 2C (O) OR2,- OC (R1) 2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7R,-NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, - N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,-NHC (O) NRRB,-NHC (O) N (R2) 2,

thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R') 2C (O) OH, -SC (R1) 2C (O) OR,-SCH2C (O) OH, SCF2C (O) OH,-S02NH2,-SO2NHR2,-SO2N (R2) 2, S02NRR8,-SO2NHC (O) R2,-SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, - C (O) NHR2,-C (O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHS02NHR2,- C (O) NHSO2N (R2), -C(O)NHSO2NR7R8, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,-P02H2,-PO3H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2)2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR'Rg, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R2ß, R3ß, R4ß, R5ß or R6ß, or one of R2α, R3α, R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl; and/or

wherein when one of R2ß, R3ß, R4ß, R5ß or R6ß is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; and/or wherein when one of R2α, R3α, R4α, R5α or R6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; and/or R2a taken together or R3α and Retaken together or R4α and R5α taken together, or R20 and Retaken together or R3ß and R40 taken together or R4ß and Ruß taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo ; and/or R2α and R3α taken together or R3a and Retaken together or R4α and Retaken together or R2ß and Retaken together or R3ß and R40 taken together or R4ß and Rip taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; provided that R2a, R3a, R4α, R'O', R6a WO, R3ß, R4ß Rsß and Ruß cannot be-OC (R') 2C (O) OH; and/or at least one of R2α, R3α, R4α, R5α, R6α or one of R2ß, R3ß, R4ß, R5ß, R6ß must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, <BR> <BR> <BR> -C(O)NHR2, -C(O) N (R2) 2, -C (O) NR7R8, -C (O) NHC (O) NHR2, -<BR> <BR> <BR> <BR> <BR> <BR> C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8,-C (O) NHS02NHR2,-C (O) NHSO2N (R2), - C (O) NHSO2NR7R8, -C (O) NHC (O) R2,-C (O) NHSO2R2,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol,-SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,- SCH2C (O) OH, -SCF2C (O) OH,-SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC (O) NHR2, -SO2NHC (O) N (R2) 2,- S02NHC (O) NR7R8, -OC (R1) 2C (O) OH,-OC (R') 2C (O) OR2,-OC (R') 2C (O) NH2, - OC (R1) 2C (O) NHR2, -OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C(O)NR7R8, amino, -NHR2, N (R2) 2, <BR> <BR> <BR> NR7R8, -NHC (RI) 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,-NHC (O) OR2,

-NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2,-NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and -NHC(O) N (R2) 2 ; wherein all R1, R2, R7 and R substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 2nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R1) 2C (O) NH2,-OC (RI) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NRR, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NRRB,-NHC (R') 2C (O) OH,-NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, -

S02NH2,-SO2NHR2,-S02N (R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2,-S02NHC (O) NR R, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2)2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2),- C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2)2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R2ß, R3ß, R4ß, R5ß or R6ß, or one of R2α, R3α, R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl; and/or wherein when one of R2ß, R3ß, R4ß, R5ß or R6ß is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2α, R3α, R4α, R5α or R6α can be-OCH3 ; and/or

wherein when one of R2α, R3α, R4α, R5α or R6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2ß, R3ß, R4ß, R5ß or R65 can be-OCH3 ; and/or R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together, or R2p and Retaken together or R3ß and Retaken together or R4ß and Retaken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; and/or R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together or R20 and Retaken together or R3ß and Retaken together or R4ß and Ruß taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2)2; provided that R2 «, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß cannot be -OC(R1)2C(O) OH; and/or at least one of R2α, R3α, R4α, or one of R2ß, R3ß, R4ß must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2, - C (O) N (R2) 2, -C (O) NR7R8, -C(O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, - C (O) NHC (O) NR7R,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, - C (O) NHC (O) R2,-C (O) NHS02R2,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4, 5, or 6, thiol,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH,-SO2NH -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, S02NHC (O) NHR2,-SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, -OC (R') 2C (O) OH, - OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2,-OC (R1) 2C (O) NHR2, -OC (R1) 2C (O) N (R2)2, - <BR> <BR> <BR> OC (R') 2C (O) NR7R8, amino, -NHR2, N (R2) 2, NR7R8, -NHC(R1)2C(O) OH, -NHC (R') 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2,-NHSO2NHR2,-NHSO2R2,- NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and- NHC (O) N (R2) 2 ;

wherein all R, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 3d embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (Rl) 2C (O) OR2, - OC (R') 2C (O) NH2,-OC (RI) 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R') 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7R,-NHC (R1) 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R 2) C (O) R2,- NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2,-S02NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid,

sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHSO2NHR2,-C (O) NHS02N (R2),- C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- PO2H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R2ß, R3ß, R4ß, R5ß or R6R must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; and/or R2α and Retaken together or R3α and R4 « taken together or R4α and R5α taken together, or R2ß and Retaken together or R3ß and R4ßtaken together or R4ß and Retaken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected

from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; and/or R2a and R3a taken together or R3α and R4α taken together or R4α taken together or R2ß and Retaken together or R3ß and WO taken together or R4ß and Retaken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; provided that R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß cannot be -OC(R1)2C(O) OH; and/or at least one of R2α, R3α, R4α, R5α, or R6α must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2, -C (O) NH2, -C(O)NHR2, -C(O) N (R2)2, -C(O)NR7R8, - C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8, C (O) NHSO2NHR2,-C (O) NHS02N (R2),-C (O) NHSO2NR7R8, -C(O) NHC (O) R2,- C (O) NHSO2R2,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol, -SC(R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,- S02NHC (O) NR7R8, -OC(R1) 2C (O) OH, -OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2, - OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R') 2C(O)NR7R8, amino, -NHR2, N (R2) 2, NR7R8, -NHC (R') 2C (O) OH,-NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2, -NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR) 2, -NR2SO2R2, - NHC (O) NHR2, -NHC (O) NR7R8, and -NHC(O) N (R2) 2 ; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 4th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle,

cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R1) 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2, -OC (R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R1) 2C (O) OH, -SC (RI) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-S02NHC (O) NHR2,- S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2, -C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2, - C (O) NR7R8, -C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHSO2NHR2,-C (O) NHS02N (R2),- C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- PO2H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2;

R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, Rsß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α OR R6α can be -OCH3 ; and/or R and R3a taken together or R3a and Retaken together or R4α and R5α taken together, or R20 and Retaken together or R3ß and WO taken together or Ruß and Rip taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, -NR7R8, and halo; and/or R2a and R3t taken together or R3α and R4α taken together or R4α and R5α taken together or R2ß and Retaken together or R30 and R4ß taken together or R4ß and Retaken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy,

carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2; provided that R2a, R3α, R4α, R'O', R6a WO, WO, R4ß WO and R6ß cannot be-OC (R1) 2C (O) OH; and/or at least one of R2α, R3α, or R4α must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8, - C (O) NHC (O) NHR2,-C (O) NHC (O) N 9R2) 2, -C (O) NHC (O) NR7R8, -C (O) NHS02NHR2,- C (O) NHS02N (R2),-C (O) NHS02NR7R8,-C (O) NHC (O) R2,-C (O) NHSO2R2,- C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, thiol,-SC (R1) 2C (O) OH, - SC (R') 2C (O) OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2,- <BR> <BR> <BR> S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, -OC(R1) 2C (O) OH, -OC (R') 2C (O) OR2,-<BR> <BR> <BR> <BR> <BR> OC (R') 2C (O) NH2, -OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino,-NHR2, N (R2)2, NR7R8, -NHC(R1) 2C (O) OH, -NHC (R1) 2C (O) OR2, -NHC(O)R2, - N (R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8,- N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,-NHC (O) NR'Rg, and-NHC (O) N (R2) 2; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 5th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (Rl) 2C (O) OR2, - OC (R1) 2C (O) NH2, -OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NRR, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N (R2) 2, -NH7R8, -NHC(R1)2C(O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R 2) 2, - C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHS02NR7R8,-C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- P02H2,-P03H2,-P (R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2)2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NRR8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2a, R3a, or R4a must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2, -C(O)NH2, -C(O)NHR2, - C (O) N (R2) 2,-C (O) NR7R8, -C(O) NHC (O) NHR2, -C(O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8,- C (O) NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(O) NHC (O) R2, - C (O) NHS02R2,-C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, thiol, -SC(R1) 2C (O) OH, -SC (R1) 2C (O) OR2, -SCH2C(O) OH, -SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,- S02NHC (O) NHR2, -SO2NHC (O) N(R2)2, -SO2NHC(O)NR7R8, -OC(R1) 2C (O) OH, OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2, -OC (R1) 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2, - OC (R1) 2C (O) NR7R8, amino, -NHR2, N (R2) 2, NR7R8, -NHC(R1)2C(O) OH, -NHC (R1) 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2,-NHC (O) OR2,-NHC (O) SRz,-NHSO2NHR2,-NHS02R2,- NHSo2NR7R8,-N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and- NHC (O) N (R ?) 2; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 6th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and Ruß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R, R2C(O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2,- OC (R1) 2C (O) NH2, -OC (R') 2C (O) NHR2, -OC(R1)2C(O) N (R2)2, -OC(R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC (R) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) RZ,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2,-C (O) NHR2,-C (O) N (R 2) 2, - C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHSO2NHR2, -C (O) NHSO2N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,-

P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R 2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2a, R3a, or W'must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) Nor 8, and-C (O) N (R2) 2.

In a 7th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R') 2C (O) NH2,-OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC(R1)2C(O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - S02NH2,-SO2NHR2,-SO2N (R2) 2, So2NR7R8,-SO2NHC (O) R2,-SR2,-SO2NHC (O) NHRz,- S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C(O)NHR2, -C(O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2HR2,- C (O) NHS02N (R2),-C (O) NHS02NR7R8,-C (CH3) 2C (O) OH, and -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the

group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (0) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and- C (O) N (R2)2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4ß, Rsß or R65 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4 « must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2.

In an 8th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,-C (O) R2, WC (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (RI) 2C (O) N (R2) 2,-OC (R') 2C (O) NR7R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2)2, -NR7R8, -N(R2) C (O) R2, - NHS02NR7R8,-N (C (O) NHR2) 2, -NHC (O) NR7R8, -NHC(O) N (R2) 2, -SO2NH2, -SO2NHR2, -SO2N(R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC (O) NHR2, -SO2NHC(O) N (R2)2,- S02NHC (O) NR7R8, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,- C (O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R 2) 2, - C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2),- C (O) NHS02NR7R8,-C (CH3) 2C (O) OH, and -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl,

hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,- C (O) NR 7R', and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or Ruß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2.

In a embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy,- (O (CH2) 2),-3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N (R2) 2, - NR7R8, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) N (R2)2, -C(O)NR7R8, - C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8,- C (O) NR7R8, and-C (O) N (R2) 2 ;

R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 8-membered monocyclic or benzofused ring; wherein one of WO, WO or Ruß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4 « must be selected from the group consisting of tetrazol-5-yl, carboxy,-C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6; wherein all R2, R7 and R substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 10th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1-3-0-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy,-C (O) OR2, - C (O) N (R2) 2, and-C (O) NR7R8, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, -NR7R8, -C(O)NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl,- NR7R8, alkoxy, -C(O)NR7R8, and-C (O) N (ruz 2; R7 and R8 are independently alkyl, and linked together forming a 5-to 7-membered monocyclic or benzofused ring;

wherein one of R4ß, R5ß or Ruß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4 « must be selected from carboxy or- C (O) OR2 ; wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, -NR7R8, -C(O)NR7R8, and - C (O) N (R2) 2.

In an 11th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2 2a, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and Ruß are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2), 3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, and carboxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and -C(O) N (R2) 2 ; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6 can be-OCH3 ; with the proviso that at least one of R2α, R3α, or R4α must be carboxy.

In a 12th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, and R6 « are independently selected from the group consisting of hydrogen and carboxy; R2ß, R3R, R4R, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2 ) -3-O-lower alkyl,

heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,- NR7R8, -C(O)NR7R8, and -C(O) N (R2) 2; R is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl; with the proviso that at least one of R2α, R3α, or R4α must be carboxy.

In a 13th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, and R6a are independently selected from the group consisting of hydrogen and carboxy; R2R, R3ß, R4R, R5ß and WO are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy,- (O (CH2) 2) -3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and - C (O) N (R2) 2; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring ; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heteroaryl; with the proviso that at least one of R2α, R3α, or R4 « must be carboxy.

In a 14th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, and R6α arwe independently selected from the group consisting of hydrogen and carboxy; R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2- (1- morpholino) ethoxy, CH30 (CH2) 20 (CH2) 2-, wherein one of R4ß, R5ß or R6ß must be selected from the group consisting of thiophen-s- yl, thiophen-3-yl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol- 2-yl, pyrrol-3-yl, 1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl, N-Boc-indol-3- yl, N-Boc-pyrrol-2'yl, and N-Boc-pyrrol-3-yl ; with the proviso that at least one of R2 «, R3 «, or R4a must be carboxy.

In a 15th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, and R6 « are independently selected from the group consisting of hydrogen and carboxy; R2ß, R3ß, R4R, R5ß and Ruß are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino) propoxy, 2- (l-morpholino) ethoxy, andCH30 (CH2) 20 (CH2) 2; wherein one of R4ß, R5ß or R6R must be selected from the group consisting of thiophen-s- yl, benzo [b] thiophen-2-yl, indol-2-yl, 1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol- 2'yl, and N-Boc-pyrrol-3-yl ; with the proviso that at least one of R2α, R3α, or R4 « must be carboxy.

In a 16'h embodiment, the invention is selected from a compound A compound selected from the group consisting of

4- [3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid ; <BR> 4- [3E- (4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid ;<BR> <BR> 4- [3E- (4-Thiazol-2-yl-phenyl)-acryloyl]-benzoic acid ; 4- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid ; 2- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid ; 4- [3E- (3, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid ; 2- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt; 4- [3E- (4-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4- [3- {4- (thien-2-yt)-phenyt}-3-oxo-E-propenyl]-benzoic acid, sodium salt; 4- [3- {4- (thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid; 4- [3- (2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoic acid; 4- [3E- (4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4-[3E-{4-Fluoro-3-(thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid; 4- (3E- {4-Methoxy-2- [2- (2-methoxyethoxy) ethoxy] -5-thiophen- 2-yl-phenyl}-acryloyl)-benzoic Acid ; 4- [3E- (2-Fluoro-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4- [3E- (2, 4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid; <BR> <BR> 4- [3E- (2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acry loyl]-benzoic acid ; 4- {3E- [5- (3, 5-Dimethyl-isoxazol-4-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid; 4- [3E- (4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 2- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid ; 2- {5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phe nyl}-indole-1-carboxylic acid tert-butyl ester; 4- [3E- (2, 6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4- {3E- [5- (2, 4-Dimethoxy-pyrimidin-5-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid ; 4- [3E- (2, 4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid ; 4- {3E- [2, 4-Dimethoxy-5- (5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic acid; 4- [3E- (4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4- [3E- (3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; <BR> <BR> 3- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid ;<BR> <BR> 4- [3E- (3-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid ;

4- [3E- (2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4- [3E- (2, 4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid; <BR> <BR> 4- {3E- [4- ( 1-Carboxy-I-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl] -acryloyl}-benzoic acid; 2- [3E- (4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4- (3E- {2-Methoxy-4- [2- (2-methoxy-ethoxy)-ethoxy]-5-thi ophen-2-yl-phenyl}-acryloyl)- benzoic acid; 4- {3E- [4- (3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-y l-phenyl]- acryloyl}-benzoic acid; 5-15- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl)-thiophene-2- carboxylic acid methyl ester; 5- {5- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl}-thiophene-2- carboxylic acid; 4- [3E- (4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoi c acid ; 4- [3E- (4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzo ic acid ; 4- [3E- (2, 4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid; 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt ; <BR> <BR> 2- {5- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl}-pyrrole-1-carboxylic acid tert-butyl ester; 4- [3E- (2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzo ic acid ; <BR> <BR> 4-{3E-[2-(1-Carboxy-I-methyl-ethoxy)-4-methoxy-5-thiophen-2- yl-phenyl]-acryloyl}-benzoic acid; <BR> <BR> 4- (3E- [4-Methoxy-2- (2-morpholin-4-yi-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzoic acid, hydrochloride; 2 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-ben zoic acid; 4-{3E-[2-(3,5-Dimethyl-isoxazol-4o-ylmethoxy)-4-methoxy-5-th iophen-2-yl-phenyl]-acryloyl}- benzoic acid; 4- [3E- (2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid; 4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thi ophen-2-yl-phenyl]- acryloyl}-benzoic acid;

4- {3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-ac ryloyl}-benzoic acid, hydrochloride; <BR> <BR> <BR> 4- {3E- [4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl} -benzoic acid, hydrochloride ; 4- [3E- (2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl )-acryloyl]-benzoic acid; 4- [3E- (4-Methoxy-2- {2- [2- (2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)- acryloyl]-benzoic acid; 4- {3E- [2, 4-Dimethoxy-5- (2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoic acid; 4- 3E- [5- (1H-Benzoimidazol-2-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid; 4- [3E- (2-Carbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acrylo yl]-benzoic acid; 4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acry loyl}- benzoic acid; 4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-t hiophen-2-yl-phenyl}-acryloyl)- benzoic acid, hydrochloride; 4-{3E-[2, 4-Dimethoxy-5-(lH-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid; 4- {3E- [2, 4-Dimethoxy-5- (2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid; 4-f 3E- [S- (3H Imidazo [4, 5-b] pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid; 2- {4- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-meth yl-propionic acid ; 4- {3E- [5- (2-Cyclopropyl-1H-imidazol-4-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride ; 4-{3E-[5o-(4-Isobutyl-4H-[1, 2,4] triazol-3-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid ; 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acry loyl}-benzoic acid; and 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloy l]-benzoic acid ethyl ester, or its pharmaceutically acceptable salt or ester.

In a 17th embodiment, the invention is a compound selected from the group consisting of 4- [3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid ; 4- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid ; 4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2- yl-phenyl}-acryloyl)-benzoic Acid; and

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl -phenyl]-acryloyl}-benzoic acid, hydrochloride, or its pharmaceutically acceptable salt or ester.

In an 18th embodiment, the invention is 4- [3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid or its pharmaceutically acceptable salt or ester.

In a 19"embodiment, the invention is 4- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl) - acryloyl]-benzoic acid, or its pharmaceutically acceptable salt or ester.

In a 20"'embodiment, the invention is 4- (3E- {4-Methoxy-2- [2- (2- methoxyethoxy) ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid; and, or its pharmaceutically acceptable salt or ester.

In a 21st embodiment, the invention is 4- {3E- [4-Methoxy-2- (2-morpholin-4-yl- ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride, or its pharmaceutically acceptable salt or ester.

In a 22nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, and R6α are independently selected from the group consisting of hydrogen and carboxy; R2P, R3ß, R4ß, Rsß and WO are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2 ) i-3-0-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,- NR7R8-C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4ß, Rsß or R60 must be a carbon-carbon linked heterocyclic; with the proviso that at least one of R2a, R3 «, or R4 « must be carboxy.

In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R'a, R3a, Wa, RScc, and R6a are independently selected from the group consisting of hydrogen and carboxy; R2ß, R3ß, R4ß, R5ß and WO are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2)1-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,- NR7R8,-C (O) NRR, and-C (O) N (R2) 2; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked tetrahydrofurn-2-yl or dihydrofuran-2-yl; with the proviso that at least one of R2α, R3α, or W'must be carboxy.

In a 24th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2)1- 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2, - OC (R1) 2C (O) NH2, -OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC(R1)2C(O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2, - C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R',-C (O) NHS02R2,-C (O) NHS02NHR2,-C (O) NHSO2N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O)N(R2)2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or Ruß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3, ; with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting of-C (O) NH2,-C (O) NHR2,-C (O) N (R2) 2,-C (o) NR7R8,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSO2NR7R8-C (O) NHC (O) R2,-C (O) NHSO2R2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 25th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß, and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2,

R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R) 2C (O) OR2, - OC (R1) 2C (O) NH2, -OC (R1) 2C (O) NHR2, -OC (R') 2C (O) N (R2) 2,-OC (R') 2C (O) NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino-NHR2, N (R2) 2, -NR7R8, -NHC (R') 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH, - S02NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C(O)NHR2, -C(O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, - C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, and-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R 2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3, ; with the proviso that at least one of R2 «, R3 «, or R4α must be selected from the group consisting of-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,-C (O) NR'Rg,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSO2NR7R8, -C (O) NHC (O) R2, and-C (O) NHSO2R2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 26th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein : R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,-C (O) R2, WC (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) ,-3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy,

heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC (R1)2C(O) N (R2) 2,-OC (R') 2C (O) NR7R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -N (R) C (O) R2,- NHSO2NR7R8, -N (C (O) NHR2) 2,-NHC (O) NR7R8, -NHC(O) N (R 2,-SO2NH2,- S02NHR2,-SO2N (R2) 2, SO2NR7R8,M -SO2NHC (O) R2,-SO2NHC (O) NHR2,-SO2NHC (O) N (R2) 2,-SO2NHC (O) NR7R8, cyano, tetrazol-5-yl,-C (O) OR2,-C (O) NH2,-C (O) NHR2,-C (O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSO2NR7R8, and-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2; Rl is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ;

with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting <BR> <BR> <BR> of-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8, -C (O) NHC (O) NHR2,-<BR> <BR> <BR> <BR> <BR> <BR> C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8,-C (O) NHS02NHR2,-C (O) NHSO2N (R2),- C (O) NHSO2NR7R8, -C (O) NHC (O) R2, and-C (O) NHSO2R2 ; wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2.

In a 27th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R60 are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N (R2) 2, -NR7R8, -N (R2) C (O) R2, -C(O)NH2, -C(O)NHR2, -C(O) N (R2) 2, -C (O) NR7R8, and-C (CH3) 2C (O) OH, - (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, -C (O) NR7R8, and- C (O) N (R) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl,

wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR 7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 8-membered monocyclic or benzofused ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4 « must be selected from the group consisting of-C (O) NH2,-C (O) NHR2,-C (O) N (R2) 2,-C (O) NR7R8,-C (O) NHC (O) R2, and- C (O) NHSO2R2 ; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, -C(O)NR7R8, and -C(O) N (R2) 2.

In a 28th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) l 3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-N (R2) C (O) R, C (O) NH2, and-C (O) NHR2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, and lower alkyl which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl,-NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, heteroaryl, and heterocyclic, wherein all may be substituted by one or more selected

from the group consisting of halo, lower alkyl,-NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2; R7 and R8 are independently alkyl, and linked together forming a 5-to 7-membered monocyclic ring ; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4 « must be selected from the group consisting of-C (O) NH2, -C (O) NHR2,-C (O) NHC (O) R2, and-C (O) NHSO2R2 ; wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, heterocyclic, amino, aminoalkyl, and- NR7R8.

In a 29th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2) 1-3-0-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,-N (R2) C (O) R2,-C (O) NH2, and- C (O) NHR2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R'is hydrogen ; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ;

with the proviso that at least one of W, R, or R4 « must be selected from the group consisting of-C (O) NH2,-C (O) NHR2,-C (O) NHC (O) R2, and-C (O) NHSO2R2 ; wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of heterocyclic, amino, aminoalkyl, and-NR7R8.

In a 30th embodiment, the invention is represented by the following compounds: 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N- (2-morpholin-4-yl-ethyl)- benzamide; 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N- (2, 2,2-trifluoro-ethyl)- benzamide; 4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzamide ; 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzamide ; 4- {3E- [4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyll - benzamide; N-Acetyl-4- [3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzamide ; and 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl-benzamide.

In a 3 embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2 α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy,

arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R') 2C (O) NH2, -OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R') 2C (O) NR7R amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC(R1)2C(O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2, - NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2,-S02NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2, - C (O) NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group

consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) Nk7R', and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or e must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2t, R3a, or W"must be selected from the group consisting of thiol,-SC (R) 2C (O) OH, -SC (R1) 2C (O) OR,-SCH2C (O) OH, SCF2C (O) OH,-SO2NH2,-S02NHR2,-S02N (R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2, -SO2NHC (O) NR7R8 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 32nd embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, 45α, 46α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy,- (O (CH2) 2) 1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,-OC (R') 2C (O) NH2, -OC (R') 2C (O) NHR2, OC (R1) 2C (O) N (P-2) 2,-OC (R1) 2C (O) NR7R89 amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2)2, -NR7R8, -NHC(R1)2C(O) OH, - NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, <BR> <BR> <BR> -NHS02R2,-NHS02NR'R 8,-N (C (O) NHR2) 2,-NWS02R2,-NHC (O) NHR 2,-NHC (O) NkR',- NHC (O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (RI) 2C (O) OH, -SC (R1) 2C (O) OR2, - SCH2C (O) OH,-SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2) 2, S02NR'R8,- S02NHC (O) R2,-SR2,-S02NHC (O) NHR2,-SO2NHC (O) N (R2)2, -SO2NHC(O)NR7R8, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2,-C (O) NHR2,-C (O) N (R2)2, -C(O)NR7R8, - C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, - C (O) NHSO2R2,-C (O) NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, - C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,- NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and- C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2)2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and

heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R 7and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4 must be selected from the group consisting of thiol,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH, SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NRRB,-SO2NHC (O) R2,-SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2, -SO2NHC(O)NR7R8 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 33rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-

OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7R8,-N (R2) C (O) R2, - NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC (O) NHR2,-NHC (O) NR7R8,- <BR> <BR> <BR> NHC (O) N (R2) 2,-SC (R1) 2C (O) OH, -SC (RI) 2C (O) OR2,-SCH2C (O) OH -SO2NH2, -SO2NHR2, -SO2N(R2) 2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, cyano, tetrazol-5-yl, -C(O)OR2, -C(O) NH2, - <BR> <BR> <BR> C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) Nl4w,-<BR> <BR> <BR> <BR> <BR> C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, - C (O) NHSO2N (RZ),-C (O) NHS02NR7R8,-C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,-C (O) NR'R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylarylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4ß, R5ß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ;

with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting of-SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SO2NHC (O) NHR2, -SO2NHC(O) N (P'2) 2, -SO2NHC(O)NR7R8 ; wherein all R', R2, R7 and R substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2.

In a 34th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N (R2)2, -NR7R8, -N(R2) C (O) R2, -SCH2C(O)OH -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, - S02NHC (O) NHR2,-S02NHC (O) N (R2) 2,-S02NHC (O) NR7R8, -C (O) N (R2) 2,-C (O) NR'Rg, and-C (O) NHSO2R2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and -C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, -C (O) NR7R8, and- C (O) N (R2) 2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, -C (O) NR7R8, and -C(O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 8-membered monocyclic or benzofused ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting of-SC (R') 2C (O) OR2,-SCH2C (O) OH,-SO2NH2,-S02NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC(O)R2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,-S02NHC (O) NR 7R' ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, -C(O)NR7R8, and-C (O) N (R2) 2.

In a 35th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, lower alkyl, alkenyl, alkynyl, carbocycle, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, hydroxyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1-3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-N (R2) C (O) R2,-SCH2C (O) OH- SO2NH2, -SO2NHR2, -SO2N (R2) 2, So2NR7R8-SO2NHC (O) R2,-SR2,- S02NHC (O) NHR2, -SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, and-C (O) NHSO2R2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2 ;

R'is independently selected from the group consisting of hydrogen and lower alkyl, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl,-NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl and lower alkyl, which may be substituted by one or more selected from the group consisting of halo, lower alkyl,- NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently alkyl, and linked together forming a 5-to 7-membered monocyclic ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α,R3α,R4α,R5α or R6α can be -OCH3 ; with the proviso that at least one of R2, R, or R4α must be selected from the group consisting of-SC (R') 2C (O) OR2,-SCH2C (O) OH,-SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, and -SO2NHc (O) R2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, -NR7R8, -C(O)NR7R8, and-C (O) N (R2)2.

In a 36th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, carbocycle, heteroaryl, heterocyclic, hydroxyl, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,-N (R2) C (O) R2, -SO2NH2, -SO2NHR2, S02NHC (O) R2, -SR2, S02NHC (O) NHR2, -SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, and-C (O) NHSO2R2, all of which can be optionally substituted by one or more selected from the group consisting of alkenyl, acyl, hydroxy, hydroxyalkyl, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2; R'is hydrogen; R2 is lower;

R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2, R3a, R4a, Rsa or R6a can be-OCH3 ; with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting of-SC (R') 2C (O) OR2,-S02NH2,-S02NRRg, and-SO2NHC (O) R2.

In a 37th embodiment, the invention is represented by the following compound: 4- [3E- (4-Thiophen-2-yl-phenyl)-acryloyl]-benzenesulfonamide ; 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide ; 4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzenesulfonamide ; 2- {5-Methoxy-2- [3-oxo-3- (4-sulfamoyl-phenyl)-E-propenyl]-4-thiophen-2-yl-phenoxy}-2- methyl-propionic acid; <BR> <BR> <BR> <BR> 2- {2, 4-Dimethoxy-5- [3-oxo-3- (4-sulfamoyl-phenyl)-E-propenyl]-phenyl}-indole-l-carboxylic acid tert-butyl ester; 4- {3E- [5- (lH-Indol-2-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide ; 4- {3E- [4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl} - benzenesulfonamide ; 4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thi ophen-2-yl-phenyl]- acryloyl}-benzenesulfonamide ; 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl- benzenesulfonamide ; 4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzenesulfonamide, hydrochloride; 4- 3E-[4-Methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-ph enyl]-acryloyl}- benzenesulfonamide ; 4- [3E- (2, 4-Dimethoxy-5-pyridin-3-yl-phenyl)-acryloyl]-benzenesulfonam ide ; 4- {3E- [4- (3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-y l-phenyl]- acryloyl}-benzenesulfonamide ;

4- {3E- [5- (4-Isobutyl-4H- [1, 2,4] triæol-3-yl)-2, 4-dimethoxy-phenyl]-acryloyl}- benzenesulfonamide ; 4- {3E- [5- (2-Cyclopropyl-1 H-imidazol-4-yl)-2, 4-dimethoxy-phenyl]-acryloyl}- benzenesulfonamide ; 4- {3E- [5- (3H Imidazo [4,5-b] pyridin-2-yl) -2, 4-dimethoxy-phenyl]-acryloyl}- benzenesulfonamide ; 4- 3E- [2- (IH-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phe nyl]-acryloyl}- benzenesulfonamide ; 4-{3E-[4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-phe nyl]-acryloyl}- benzenesulfonamide ; 4- {3E- [2- (Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl] -acryloyl}- benzenesulfonamide ; and 4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acry loyl}-benzenesulfonamide.

In a 38th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and RO are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) -3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,-OC (R') 2C (O) NH2,-OC (R') 2C (O) NHR2, OC (R1) 2C (O) N (R2) 2,-OC (R') 2C (O) Nor',

amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, NHR2, N (R2) 2, -NR7R8, -NHC (R') 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2, N (R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,-NHC (O) NR7R8, -NHC(O)N(R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,-SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2,- <BR> <BR> <BR> C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-<BR> <BR> <BR> <BR> <BR> C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8, -C (O) NHSO2R2,-C (O) NHS02NHR2,- C (O) NHSO2N (R2),-C (O) NHSo2NR7R8,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2, 3,4, 5, or 6,-PO2H2,-PO3H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C9O)NR7R8, and-C (O) N (R2)2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N(R2)2 ;

R 7and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, Rsß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be-OCH3 ; with the proviso that at least one of R2α, R3α, or R4a must be selected from the group consisting of amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O) OH, -NHC (RI) 2C (O) OR2,- NHC (O) R2,-N (R) C (O) R2,-NHC (O) OR2,-NHC (O) SR2,-NHSO2NHR2, -NHSO2R2,- NHS02NR,-N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and- NHC (O) N (R2) 2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2.

In a 39th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and 6Rß are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2) 1-3-0-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, , all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, <BR> <BR> <BR> alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is lower alkyl optionally substituted by alkoxycarbonyl.

R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ;

with the proviso that at least one of R2α, R3α, or R4a must be selected from the group consisting of amino,-N (C (O) NHR2) 2, NR2SO2R2 and-NR2SO2R2 ; wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 40th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (R') 2C (O) OH, -OC (R') 2C (O) OR,-OC (R') 2C (O) NH2, -OC (R') 2C (O) NHR2, OC (R') 2C (O) N (R2) 2,-OC (R1) 2C (O) NOR 8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC(R1)2C(O) OH, - NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2,- NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,- NHC (O) NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio,

heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R1) 2C (O) OH, - SC (R1) 2C (O) OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-S02NHC (O) NHR2, -SO2NHC (O) N (R2 2,- SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2, -C (O) N (R2)2, -C(O)NR7R8, - C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8,- C (O) NHS02R2,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, - C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, -PO2H2, -PO3H2, - P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2)2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ;

with the proviso that at least one of R2α, R3α, or R4α must be selected from the group consisting of-OC (R1) 2C (O) OH, -OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2, OC (R') 2C (O) NHR2,-OC (R1) 2C (O) N (R) 2,-OC (R') 2C (O) NR7R8 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2.

In a 41 st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, - OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8 all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O) N (R2) 2; Ru ils hydrogen or lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, - C (O) Nor 8, and-C (O) N (R2) 2 ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ;

with the proviso that at least one of R2a, R3a, or R4a must be selected from- OC (R') 2C (O) OH ; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 42nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2a, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) z),- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2,- OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2,-NHSO2NHR2,-NHSO2R2,-NHSo2NR7R8-N (C (O) NHR2) 2, -NR2SO2R2,-NHC (O) NHR2,-NHC (o) NR7R8,-NHC (O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl,

haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - S02NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2),- C (O) NHSo2NR7R8,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- PO2H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C9O)NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) Nk7k', ; and -C(O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4ß, R5ß or R6 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; and/or

R2α taken together or R3α and R4α taken together or R4α and R5α taken together, or R2ß and Retaken together or R3ß and R4ß taken together or R4ß and Retaken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; and/or At least one of R2α, R3α, or R4a must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2,-C (O) NHr2, -C(O) N (R2)2, - C (O) NR7R8, -C(O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8, -C (O) NHSO2NHR2, -C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, - C (O) NHC (O) R2,-C (O) NHS02R,-C (CH3) 2C (O) OH,-- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2, -SO2NHC(O)NHR2, -SO2NHC(O0 N (R2) 2,-SO2NHC (O) NR7R8, -OC (R1) 2C (O) OH, OC (R1) 2C (O) OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O) N (R2)2, OC (R') 2C (O) NR2R8, amino, -NHR2, N (R2) 2, NR7R8, -NHC(R1) 2C (O) OH, - NHC (R1) 2C (O) OR2,-NHC (O) R2, -N(R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, - NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2,-NR2SO2R2,- NHC(O)NHR2, -NHC(O)NR7R8, and -NHC(O) N (R2) 2; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2.

In a 42nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O (CH2) 2)1 -3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,

all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, <BR> <BR> <BR> aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently alkyl or lower alkyl ; R7 and R8 are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring; wherein one of R4ß, Rsß or R60 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; and/or R and Retaken together or R4a and R5a taken together, or R3ß and Retaken together or R40 and R5ß taken together form a heterocyclic ring optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.

In a 44"embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and Ruß are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R R'C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (RI) 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R1) 2C (O) NH2,-OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R) 2,-OC (R1) 2C (O) NR7R8,

amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC (R1) 2C (O) OH, -NHC (RI) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2,-SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2)2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, - C (O) NHC (O) NR7R8,-C (O) NHS02R2,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2),- C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- PO2H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R 2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, ; heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4ß, R5ß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α, R3α, R4α, R5α or R6α can be -OCH3 ; and/or R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together or R2ß and Retaken together or R3ß and R4ß taken together or WO and Retaken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N(R2) 2; provided that R2α, R3α, R4α, R5a, R, WO, R3R, Ri, WO and R6ß cannot be-OC (R1) 2C (O) OH; and/or at least one of R2α, R3α, or R4'1 must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2, -C(O) NH2, -C (O) NHR2,-C (O) N (R2)2, - C (O) NR7R8, -C(O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R8, -C (O) NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, - C (O) NHC (O) R2,-C (O) NHS02R2,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol,-SC (R1) 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH, - SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, - S02NHC (O) NHR2,-SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, -OC(R1)2C(O)OH, - OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2,-OC (R') 2C (O) NHR2, -OC(R1) 2C (O) N (R2)2, - . OC (R') 2C (O) NR7R, amino, -NHR2, N (R2) 2, NR7R8, -NHC (R') 2C (O) OH,-NHC (R') 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2, -NHC(O)OR2, -NHC(O)S2, -NHSO2NHR2, -NHSO2R2, - NHSO2NR7R8, -N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2, -NHC(O)NR7R8, and- NHC (O) N (R2) 2, wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O)N(R2) 2.

In a 45th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2a, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and RO are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O (CH2) 2) 3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R 2) 2; R is independently alkyl or lower alkyl ; R7 and R8 are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring; wherein one of R4ß, Rsß or R6ß must be a carbon-carbon linked heterocyclic or heteroaryl, and only one OF R2α, R3α, R4α, R5α or R6α can be -OCH3 ; and/or R and R4"taken together or R4α and R5α taken together or R3ß and R40 taken together or R40 and Rsß taken together form a 5-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of alkyl, lower alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonyl; provided that R2α, R3α, R4α, R5α, R6α, R2ß, R3ß, R4ß, R5ß and R6ß cannot be-OC (R') 2COOH.

In a 46th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2 ß R3ß R4ß Rsß R6 W R3a, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2,

R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2))- 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R1) 2C (O) NH2, -OC (R1) 2C (O) NHR2,-OC (R') 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N (R2) 2,-NR7R',-NHC (R1) 2C (O) OH,-NHC (R') 2C (O) OR2,-NHC (O) R2, -N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R) 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2,-C (O) NHR2,-C (O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, - C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHS02NHR2,-C (O) NHSO2N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2 ; R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl,

heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R2α, R3α, R4α, R5α or R6α, or one of R2ß, R3ß, R4ß, R5ß or R6p must be a carbon-carbon linked heterocyclic or heteroaryl; and/or wherein when one of R2α, R3α, R4α, R5α or R6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2ß, R3ß, R4ß, R5ß or R'P can be-OCH3; and/or wherein when one of R2ß, R3ß, R4ß, R5ß or R6ß is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2α, R3α, R4α, R5α OR R6α can be-OCH3 ; and/or R2R and R30 taken together or R3ß and Retaken together or R4ß and Rip taken together, or R2Q and R3Q taken together or R 3a and R4'taken together or R4α and R5α taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; and/or R2ß and R3ß taken together or R3ß and Retaken together or R4ß and Rsß taken together or R2'and Retaken together or R3α and Retaken together or R4α and R5α taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy,

carboxyalkyl, aloxycarbonyl, -C9O)NR7R8, and-C (O) N (R2) 2; provided that R2ß, R3ß Rap Rsß RP, R2", R3α, R4α, R5α and R6α cannot be -OC(R1) 2C (O) OH; and/or at least one of R2ß, R3ß, R4ß, or one of R2α, R3α, R4α must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2,-C (O) NHR2, - C (O) N (R2) 2, -C (O) NR7R8, -C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, C (O) NHC (O) NR7R8, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, - C (O) NHC (O) R2,-C (O) NHS02R2,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4, 5, or 6, thiol,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, S02NHC (O) NHR2,-SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, -OC (R1) 2C (O) OH,- OC (R') 2C (O) OR2,-OC (R') 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2, OC (R1) 2C (O) NR7R8, amino,-NHR2, N (R2) 2, NR7R8, -NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, - NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC (O) NHR2,-NHC (O) NR'R8, and- NHC (O) N (R2) 2; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2.

In a 47th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R20, RIP, Wo, RIP, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (0) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2, - OC (R1) 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7Rg,-NHC (R') 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R 2) C (O) R2,- NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N (R2) Z,-SOZNHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N ( W) 2, - C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R8, -C (O) NHS02R2,-C (O) NHSO2NHR2,-C (O) NHS02N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R 2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2 ;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R2α, R3α, R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that R20 and R30 taken together or R3ß and WO taken together or R4ß and Retaken together, or R2α and R3α taken together or R3"and R4a taken together or R4a and R5α taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; or R2ß and R30 taken together or R3ß and WO taken together or R4ß and Rsß taken together or R2α and R3α taken together or R3 and R4a taken together or Rua Retaken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) 8, and-C (O) N (R2)2 ; provided that R2ß, R3ß, WO, R5ß, R6ß R2α, R3α, R4α, R5α and e cannot be-OC (R1)2C(O) OH; and with the proviso that at least one of R2ß, R3ß, R4ß, R5ß, or Ruß must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2, -C(O)NH2, -C(O)NHR2, - C (O) N (R2) 2, -C (O) NR7R8,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R8, -C (O) NHSO2NHR2,-C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, - C (O) NHC (O) R2,-C (O) NHSO2R2,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,

5, or 6, thiol,-SC (RI) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH,-SO2NH2, -SO2NHR2, -SO2N(R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, -OC (R1) 2C (O) OH, -OC (R1) 2C (O) OR2,- OC (R') 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R') 2C (O) NR'R8, amino, -NHR2, N (R2)2, NR7R8, -NHC(R1) 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,- N (R2) C (O) R2,-NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, - N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,-NHC (O) NR7R8, and -NHC(O) N (R 2) 2; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 48th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R20, R3P, WO, R 50, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2), _ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2, - OC (R') 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R') 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC(R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,-

NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O)N(R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R',-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, - C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2),- C (O) NHSo2NR7R8,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; Rl is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, : and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R, and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R4α, R5α or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or WO can be-OCH3 ; with the proviso that R20 and R3ß taken together or R3ß and R4ß taken together or R4ß and Ruß taken together, or R2α and R3α taken together or R3α and R4a taken together or R4α and R5α taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; or R2ß and R3ß taken together or R3ß and WO taken together or Wo and Rsß taken together or R2a and Retaken together or R3a and Retaken together or R4α and R5α taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and -C(O) N (R2) 2 ; provided that R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α cannot be -OC(R1)2C(O)OH; and with the proviso that at least one of R2ß, R3ß, or R4ß must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O) N (R2)2, - C (O) NR7R8,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8, - C (O) NHSO2NHR2,-C (O) NHS02N (R2),-C (O) NHSO2NR7R8, -C(O) NHC (O) R2,- C (O) NHSO2R2,-C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol, -SC(R1)2C(O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH,-SO2NH2,- SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2,-S02NHC (O)NR7R8, -OC(R1)2C(O) OH, -OC (R1) 2C (O) OR2, - <BR> <BR> <BR> OC (R1) 2C (O) NH2, -OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8,<BR> <BR> <BR> <BR> <BR> amino, -NHR2, N (R2)2, NR7R8, -NHC(R1)2C(O) OH, -NHC (R') 2C (O) OR2, -NHC(O)R2, - N (R2) C (O) R2,-NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8,- N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,-NHC (O) NR7R8, and-NHC (O) N (R2) 2; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl,

hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2.

In a 49th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R R3ß, R4ß, R5ß, R5p, R2α, R3a, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2))- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2, - OC (R1) 2C (O) NH2,-OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R) 2C (O) NR7 R 8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N (R2) 2, -NR7R8, -NHC(R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHCO)R2, -SR2, -SO2NHC(O)NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, -

C (O) NHC (O) NR7R8,-C (O) NHSO2R2,-C (O) NHSO2NHR2,-C (O) NHS02N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- P02H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R, and-C (O) N (R2)2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2, - <BR> <BR> <BR> C (O) N (R2) 2, -C (O) NR7R8, -C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8,- C (O) NHS02NHR2,-C (O) NHSO2N (RZ),-C (O) NHS02NR'R8,-C (O) NHC (O) R2,- C (O) NHSO2R2, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol, -SC(R1) 2C (O) OH, -SC (R') 2C (O) OR2, -SCH2C(O)OH, -SCF2C(O) OH, -

SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, SO2NHC (O) NHR2,-S02NHC (O) N (R2)2, -SO2NHC(O)NR7R8, -OC(R1) 2C (O) OH, OC (R1) 2C (O) OR2,-OC (R') 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2, - OC (R1) 2C (O) NR7R8, amino,-NHR2, N (R2) 2, NR7R8, -NHC(R1)2C(O) OH, -NHC (R1) 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2,-NHSO2NHR2,-NHS02R2,- NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and- NHC (O) N (R2) 2; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2.

In a 50th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: , R3P, R4ß, R, R6ß R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2, - OC (R1) 2C (O) NH2,-OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N (R2) 2,-NR7R8,-NHC (RI) 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,-

NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N (R2) 2, S02NR7R8,-SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2)2, - C (O) NR7R',-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R8,-C (O) NHSO2R2, -C (O) NHS02NHR2,-C (O) NHSO2N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- P02H2,-P03H2,-P (R2) O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R 2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ;

wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 51 st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1- 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2, - OC (RI) 2C (O) NH2, -OC (R') 2C (O) NHR2,-OC (R1) 2C (O) N (R) 2,-OC (R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7R,-NHC (R') 2C (O) OH,-NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2,-NHSO2NHR2,-NHSO2R2,-NHSo2NR7R8-N (C (O) NHR2) 2,

-NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R1) 2C (O) OH, -SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR S02NHC (O) N (R2) 2,-S02NHC (O) NR7R8, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C(O)NHR2, -C(O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2, - C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, - C (O) NHS02N (R2), -C(O)NHSO2NR7R8, -C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NRR, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, <BR> <BR> <BR> aminoalkyl,-NR7R8, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and- C (O) N (R2)2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6p can be-OCH3 ;

with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2, -C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6; wherein all R, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2)2.

In an 52nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,-C (O) R2, RC (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R1) 2C (O) N (R2)2, -OC (R') 2C (O) NR7R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N (R2) 2,-NR7R8,-N (R2) C (O) R2,- NHS02NR'Rg,-N (C (O) NHR2) 2, -NHC (O) NR7R8, -NHC(O) N (R2) 2,-SO2NH2,-SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,- S02NHC (O) NR7R8, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2,-C (O) NHR2,- C (O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O0NHSO2N(R2), - C (O) NHSo2NR7R8,-C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2;

R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α OR R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2.

In a 53rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2p, RIP, Wo, RIP, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy,- (O (CH2) 2)1-3-O-lower alkyl,

polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N (R2) 2,- NR7R8, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) N (R2) 2, -C (O) NR7R8, - C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8,- C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 8-membered monocyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R4ß must be selected from the group consisting of tetrazol-5-yl, carboxy, -C (O) OR2,-C (CH3) 2C (O) OH, (CH2) yC (O) OH, wherein y is 1, 2,3, 4, 5, or 6; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 54th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5Z, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy,-C (O) OR2,- C (O) N (R2) 2, and-C (O) NRR8, all of which can be optionally substituted by one or more

selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic,-NR7R8,-C (o) NR7R8, and-C (O) N (R2)2 ; R2 is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl,- NR7R8, alkoxy, -C (O) NR7R8, and -C(O) N (R2) 2 ; R7 and R8 are independently alkyl, and linked together forming a 5-to 7-membered monocyclic or benzofused ring; wherein one of R4°, Rs « or R6"must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R40 must be selected from carboxy or- C (O) OR2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, -NR7R8, -C (O) NOR', and- C (O) N (R2)2.

In a 55th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, and carboxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and-C (O) N (R2) 2 ; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or WO can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R4ß must be carboxy.

In a 56th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R, R3R, R4P, R5ß, and Ruß are independently selected from the group consisting of hydrogen and carboxy; R2a, R3c,, Wa, R5a and R6 « are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2) 1-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,- NR7R8, -C (O) NR7R, and-C (O) N (R2) 2 ; * is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4a, Rsa or R6° must be a carbon-carbon linked heterocyclic or heteroaryl; with the proviso that at least one of R2ß, R3ß, or Wo must be carboxy.

In a 57th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, and R6ß are independently selected from the group consisting of hydrogen and carboxy; R2 R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy,- (O (CH2) 2)1-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,-NR7R8,-C (o) NR7R8, and -C (O) N (R2) 2; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4a, Rs° or R6a must be a carbon-carbon linked heteroaryl;

with the proviso that at least one of R2ß, R3ß, or R4ß must be carboxy.

In a 58th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, WO, RIO, R5ß, and R60 are independently selected from the group consisting of hydrogen and carboxy; R2a, R3a, R4α, R5α and Wu are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2- (1- morpholino) ethoxy, CH30 (CH2) 20 (CH2) 2-, wherein one of R4α, R5α or R6α must be selected from the group consisting of thiophen-s- yl, thiophen-3-yl, benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol- 2-yl, pyrrol-3-yl, 1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl, N-Boc-indol-3- yl, N-Boc-pyrrol-2'yl, and N-Boc-pyrrol-3-yl; with the proviso that at least one of R2ß, R3ß, or R4ß must be carboxy.

In a 59th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2P, R3R, WO, R, and R6ß are independently selected from the group consisting of hydrogen and carboxy; R2a, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, methoxy, 3- (1-morpholino) propoxy, 2- (l-morpholino) ethoxy, andCH30 (CH2) 20 (CH2) 2; wherein one of R4α, R5α or R6α must be selected from the group consisting of thiophen-s- yl, benzo [b] thiophen-2-yl, indol-2-yl, 1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol- 2'yl, and N-Boc-pyrrol-3-yl; with the proviso that at least one of R2ß, R3ß, or R4ß must be carboxy.

In a 60th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, and Ruß are independently selected from the group consisting of hydrogen and carboxy; R2α, R3α, R4α, R5α and R6a are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2) -3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,- NR7R8,-C (O) NR7R8, and-C (O) N (R2) 2; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic ; with the proviso that at least one of R2ß, R3ß, or WO must be carboxy.

In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: RP, R3ß, R4ß, R5ß, and R6ß are independently selected from the group consisting of hydrogen and carboxy; R2a, R3a, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2) 3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl,- NR7R8, -C (O) NR7R8, and -C(O) N (R2) 2 ; R2 is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;

wherein one of R4α, R5α or R6 « must be a carbon-carbon linked tetrahydrofurn-2-yl or dihydrofuran-2-yl ; with the proviso that at least one of R2ß, R3ß, or Wu must be carboxy.

Embodiment 6c. Amide Branch In a 61st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,- OC (R1) 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R1) 2C (o) NR7R amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7R8,-NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O0NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH,-SC (R') 2C (O) oR2R-SCH2C (O) OH, -SCF2C (O) OH,-

SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N (R2) 2,-SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, - C (O) NHC (O) NR7R8,-C (O) NHSO2R2, -C (O) NHSO2NHR2,-C (O) NHS02N (R2), - C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6,- PO2H2,-P03H2,-P (R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; Rl is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O) N (R2)2 ; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R4 must be selected from the group consisting of-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8, -C(O) NHC (O) NHR2, -

C (O) NHC (O) N (ruz 2, -C (O) NHC (O) NR7R8,-C (O) NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSO2NR7R8, -C (O) NHC (O) R2,-C (O) NHSO2R2 ; wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 62nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6'1 are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclicloweralkoxy,-OC (R) 2C (O) OH, -OC (R') 2C (O) OR2, - OC (R1) 2C (O) NH2,-OC (R') 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R1) 2C (O) NR, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino-NHR2, N (R2) 2,-NR7R8,-NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC (R1) 2C (O) OH, -SC (RI) 2C (O) OR2,-SCH2C (O) OH, -SCF2C (O) OH, -

SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2,-SO2NHC (0) NR7 R8, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C(O)NHR2, -C(O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR'R8,-C (O) NHS02R2,-C (O) NHS02NHR2,- C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, and-C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, <BR> <BR> <BR> aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4a, R5 or R6 must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of-C (O) NH2, -C (O) NHR2, -C (O) N (R2) 2, -C (O) NR7R8, -C(O)NHC(O)NHR2, -

C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2), - C (O) NHSO2NR7R8, -C (O) NHC (O) R2, and-C (O) NHSO2R2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2.

In a 63rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R1) 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -N(R2) C (O) R2,- NHSo2NR7R8-N (C (O) NHR2) 2, -NHC(O)NR7R8, -NHC(O) N (R2) 2,-SO2NH2,- SO2NHR2, -SO2N (RZ) 2, S02NR7R8,-S02NHC (O) R2,-SO2NHC (O) NHR2,-SO2NHC (O) N (R2) 2,K -SO2NHC(O)NR7R8, cyano, tetrazol-5-yl, -C(O)OR2, -C(O) NH2, -C (O) NHR2,-C (O) N(R2)2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2,- C (O) NHC (O) NR7R8, -C (O) NHSO2R2,-C (O) NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHS02NR7R8, and-C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkhyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2)2;

R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,-C (o) NR7R8,-C (O) NHC (O) NHR2,- C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSO2NR7R8, -C(O) NHC (O) R2, and-C (O) NHSO2R2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,- C (O) Nor 8, and-C (O) N (R2) 2.

In a 64th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2Q, R3Q, Raya, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl,

haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy,- (O (CH2) 2) 13-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N (R2)2, -NR7R8, -N(R2) C (O) R2, -C(O) NH2, -C (O) NHR2,-C (O) N (R2) 2,-C (O) NR7R8, and-C (CH3) 2C (O) OH, - (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R'is. independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, -C (O) NR7R8, and- C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 8-membered monocyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R4ß must be selected from the group consisting of -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, and - C(O)NHSO2R²;

wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, -C(O)NR7R8, and-C (O) N (R2)2.

In a 65th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy,-(O (CH2) 2),. 3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-N (R) C (O) R, C (O) NH2, and-C (O) NHR2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, and lower alkyl which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl,-NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, heteroaryl, and heterocyclic, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl,-NR7R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently alkyl, and linked together forming a 5-to 7-membered monocyclic ring ; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WP must be selected from the group consisting of-C (O) NH2, -C (O) NHR2,-C (O) NHC (O) R2, and-C (O) NHSO2R2 ;

wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, heterocyclic, amino, aminoalkyl, and- NR7R8.

In a 66th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6Q are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,-N (R 2) C (O) R2,-C (O) NH2, and- C (O) NHR2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R 2) 2; Rl is hydrogen; R is lower alkyl ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or Wu must be selected from the group consisting of-C (O) NH2,-C (O) NHR2, -C (O) NHC (O) R2, and-C (O) NHS02R2 ; wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of heterocyclic, amino, aminoalkyl, and NR R.

In a 67th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R30, WO, R5ß, R0, R2t, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl,

heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocycHc tower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2, - OC (R') 2C (O) NH2, -OC (R1) 2C (O) NHR2,-OC (R') 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC (R') 2C (O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH,- S02NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2,- S02NHC (O) N (R2)2, -SO2-NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2) 2,- C (O) NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, C (O) NHC (O) NR7R8,-C (O) NHS02R2,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2),- C (O) NHSO2NR7R8, -C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- P02H2,-P03H2,-P (R2) O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2 ;

R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR'R', and-C (O) N (R2) 2 ; R is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α, or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or Wu must be selected from the group consisting ofthiol,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2, -SCH2C(O)OH, SCF2C (O) OH,-SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,-SO2NHC (O) NR'R8 ; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 68th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R2ß, R3ß, RIP, R5ß, R6ß, Ro, R3Q, R4α, R5α and R6a are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)103-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (R') 2C (O) OH, -OC (R') 2C (O) OR2,-OC (R') 2C (O) NH2,-OC (R') 2C (O) NHR2, OC (R1) 2C (O) N (R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2,-NR7R8,-NHC (RI) 2C (O) OH, - NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (RZ) C (O) R2,-NHC (O) OR2,-NHC (O) SR2,-NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2), -NHC(O)NR7R8, - NHC (O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2,- SCH2C (O) OH, -SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N(R2) 2, SO2NR7R8, - S02NHC (O) R2, -SR2, -SO2NHC (O) NHR2,-SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, cyano, <BR> <BR> <BR> tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2,-C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8,-<BR> <BR> <BR> <BR> <BR> <BR> C (O) NHC (O) R2,-C (O) NHC (O) NHR2, -C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8,- C (O) NHS02R2,-C (O) NHSO2NHR2,-C (O) NHS02N (R2),-C (O) NHSO2NR7R8, - C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-

NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and- C (O) N (R2)2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R', and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R4P must be selected from the group <BR> <BR> <BR> consisting of thiol,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH, SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2) 2, S02NRR8,-SO2NHC (O) R2,-SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2, -SO2NHC (O) NR7R8 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2.

In a 69th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R R3ß, R4ß, RIP, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -N (R2) C (O) R2,- NHSO2NHR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC (O) NHR2,-NHC (O) NR7R8, - <BR> <BR> <BR> NHC (O) N (R2) 2, -SC (R') 2C (O) OH,-SC (R') 2C (O) ORz,-SCH2C (O) OH-SO2NH2,-S02NHR2, -SO2N(R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC (O) NHR2,- S02NHC (O) N (R2) 2-, SO2NHC (O) NR7R8, cyano, tetrazol-5-yl,-C (O) OR2,-C (O) NH2,- <BR> <BR> <BR> C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-<BR> <BR> <BR> <BR> <BR> <BR> <BR> C (O) NHC (O) N (R2) 2, -C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, - C (O) NHS02N (R2),-C (O) NHS02NR7R8,-C (CH3) 2C (O) OH, and- (CH2) yC (O) OH, wherein y is 1,2, 3,4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and -C(O) N (R2)2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylarylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2)2 ;

R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring ; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or WP can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R40 must be selected from the group consisting of-SC (R1) 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH, S02NH2,-SO2NHR2,-SO2N (R2) 2, S02NR7R8,-SO2NHC (O) R2,-SO2NHC (O) NHR2, -SO2NHC(O) N (R2)2, -SO2NHC(O)NR7R8 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2.

In a 70th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R30, R4ß, R5ß, Rp, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1-3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N (R2)2, -NR7R8, -N(R2) C (O) R2, -SCH2C(O)OH -SO2NH2, -SO2NHR2, -SO2N(R2) 2, S02NR7Rg,-So2NHC (O) R2,-SR2,-

SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,-S02NHC (O) NR7R8,-C (O) N (R2) 2, -C (O) NOR', and-C (O) NHSO2R2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and - C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, -C(O)NR7R8, and- C (O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 8-membered monocyclic or benzofused ring; wherein one of R4α, R5α or R"must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or Rip must be selected from the group consisting of-SC (R) 2C (O) OR2,-SCH2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC(O)R2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2)2, -SO2NHC(O)NR7R8 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 71st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6Q are independently selected from the group consisting of hydrogen, halogen, lower alkyl, alkenyl, alkynyl, carbocycle, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, hydroxyl, alkoxy, lower alkoxy,- (O (CH2) 2)1-3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -N(R2) C (O) R2,-SCH2C (O) OH- SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2, S02NHC (O) NHR2,-SO2NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, and-C (O) NHSO2R2, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano,-C (O) NR7R8, and-C (O) N (R2) 2; R'is independently selected from the group consisting of hydrogen and lower alkyl, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl,-NR7R8, alkoxy,-C (o) NR7R8, and-C (O) N (R2) 2; R2 is independently selected from the group consisting of alkyl and lower alkyl, which may be substituted by one or more selected from the group consisting of halo, lower alkyl,- NR7R8, alkoxy,-C (o) NR7R8, and-C (O) N (R2)2; R7 and R8 are independently alkyl, and linked together forming a 5-to 7-membered monocyclic ring ; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of-SC (R') 2C (O) OR,-SCH2C (O) OH,-SO2NH2,-SO2NHR2,-S02N (R2) 2, SO2NR7R8, and -SO2NHC (O) R2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, -NR7R8, -C(O)NR7R8, and-C (O) N (R2)2.

In a 72nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R2ß, R3P R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, carbocycle, heteroaryl, heterocyclic, hydroxyl, lower alkoxy,- (O (CH2) 2) 13-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -N (R2) C (O) R2, -SO2NH2, -SO2NHR2, S02NHC (O) R2,-SR2, S02NHC (O) NHR2, -SO2NHC (O) N (R2) 2,-SO2NHC (O) NR7R8 and-C (O) NHSO2R2, all of which can be optionally substituted by one or more selected from the group consisting of alkenyl, acyl, hydroxy, hydroxyalkyl, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano,- C (O) NR7R8, and-C (O) N (R2) 2 ; R'is hydrogen; R is lower; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R40 must be selected from the group consisting of-SC (R') 2C (O) OR2, -SO2NH2, - SO2NR7R8, and -SO2NHC(O)R2.

In a 73rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R20, R3p, R4ß, RIP, R6ß, R2Q, R3Q, R4Q, R5Q and R6Q are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

alkoxy, lower alkoxy,- (O (CH2) 2) 1-3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (R1) 2C (O) OH, -OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2, -OC (R1) 2C (O) NHR2, OC (R') 2C (O) N (R2) 2,-OC (R') 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, NHR2, N (R2)2, -NR7R8, -NHC(R1)2C(O) OH, -NHC (R') 2C (O) OR2,-NHC (O) R2, N (R2) C (O) R2, -NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC (O) NHR2,-NHC (O) NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2, -SCH2C(O) OH, SCF2C (O) OH, -SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, - C (O) NHR2,-C (O) N (R2) 2, -C (O) NR7R8, -C (O) NHC (O) R2,-C (O) NHC (O) NHR2, - C (O) NHC (O) N (R2) 2,-C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, - C (O) NHS02N (R2),-C (O) NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2) yC (O) OH, wherein y is 1, 2, 3,4, 5, or 6, -PO2H2, -PO3H2, -P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) R2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or R4ß must be selected from the group consisting of amino,-NHR, N (R) 2, NR7R',-NHC (R) 2C (O) OH, -NHC (R') 2C (O) OR2, - NHC (O) R2,-N (R2) C (O) R2, -NHC (O) OR2,-NHC (O) SR2,-NHS02NHR2,-NHSO2R2,- NHSo2NR7R8,-N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2,-NHC (O) NR7R8, and- NHC (O) N (R2) 2 ; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 74th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein :) I,, R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2) 1-3-0-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, , all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R, <BR> <BR> <BR> alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2;

R2 is lower alkyl optionally substituted by alkoxycarbonyl.

R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or WO can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or WO must be selected from the group consisting of amino,-N (C (O) NHR2) 2, NR2SO2R2 and-NR2SO2R2 ; wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8 alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and C (O) N (R2) 2.

In a 75th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R, R30, RIP, R, WO, R2 R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O)CH2)2)103-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,- OC (RI) 2C (O) OH,-OC (R') 2C (O) OR2,-OC (R') 2C (O) NH2, -OC (R') 2C (O) NHR2, OC (R1) 2C (O) N (R2) 2,-OC (R') 2C (O) NR7R8, amino, alkylamino, acylamino, dialkylamino,

cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2)2, -NR7R8, -NHC(R1)2C(O) OH, - NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, - NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2,-NHC(O)NHR2, - NHC (O) NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH,- SC (R1) 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH,-S02NH2,-S02NHR2,-S02N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2,-SO2NHC (O) N (R 2) 2, - S02NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2)2, -C(O)NR7R8, - C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, -C (O) NHC (O) Nor',- C (O) NHSO2R2,-C (O) NHSO2NHR2,-C (O) NHS02N (R2),-C (O) NHSO2NR7R8, - C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,-PO2H2,-PO3H2,- P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2 ; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2 ;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3; with the proviso that at least one of R2ß, R3ß, or R4ß must be selected from the group consisting of-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2,-OC (R1) 2C (O) NH2, OC (R1) 2C (O) NHR2,-OC (R') 2C (O) N (R2) 2,-OC (R1) 2C (O) NR7R8 ; wherein all R, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2.

In a 76th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3P, WO, R5ß, R6ß, R2 R3α, R4α R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy,- (O (CH2) 2),-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy,-OC (R1) 2C (O) OH, - OC (R1) 2C (O) N (R2) 2,-OC (R') 2C (O) NOR 8, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2; R'is hydrogen or lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; R2 is lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,

amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, - C (O) NR7R8, and-C (O) N (R2) 2 ; R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; with the proviso that at least one of R2ß, R3ß, or Rip must be selected from- OC (R1) 2C (O) OH; wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (o) NR7R8, and-C (O) N (R2) 2.

In a 77th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3R, WO, R, RP, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R1) 2C (O) OR2,- OC (R') 2C (O) NH2,-OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2) 2,-OC (R1) 2C(O)NR7R8,

amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclialkylamino, -NHR2, N (R2) 2,-NRR,-NHC (R1) 2C (O) OH, -NHC (R1) 2C (O) OR2,-NHC (O) R2,-N (R2) C (O) R2,- NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R') 2C (O) OR2,-SCH2C (O) OH,-SCF2C (O) OH, - SO2NH2, -SO2NHR2, -SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N (R2) 2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) OR2, -C(O) NH2, -C (O) NHR2, -C(O) N (R2) 2,- C (O) NR7R8,-C (O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2)2, - C (O) NHC (O) NR7R8,-C (O) NHS02R2,-C (O) NHSO2NHR2,-C (O) NHSO2N (R2), - C (O) NHS02NR,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- PO2H2,-P03H2,-P (R2) O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and -C(O) N (R2) 2; R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) (2;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; and/or R2ß and R3P taken together or R3P and Retaken together or Wop and Retaken together, or R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo,-NR7R8, and halo; and/or at least one of R2ß, R2ß, or R4ß must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2)2, - C (O) NR7R8,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (R2) 2, - C(O)NHC(O)NR7R8, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, - C(O)NHC(O)R2, -C(O)NHSO2R2, -C(CH3)2C(O)OH, --(CH2)yC(O)OH, wherein y is 1,2, 3,4, 5, or 6, thiol,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2, -SCH2C (O) OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2) 2, SO2NR7R8, -SO2NHC (O) R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O) N (R2) 2,-SO2NHC (O) NR7R8,-OC (Rt) 2C (O) OH,- OC (R1) 2C (O) OR2,-OC (R') 2C (O) NH2, -OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R) 2, - OC (R1) 2C (O) NR7R8, amino, -NHR2, N (R2)2, NR7R8, -NHC(R1)2C(O) OH, - NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2) C (O) R2,-NHC (O) OR2, -NHC(O)SR2, - NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, - NHC (O) NHR2,-NHC (O) NR7R8, and -NHC(O) N (R2) 2; wherein all R', R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2)2.

In a 78th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R, R3ß, RIP, leo, RIP, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O (CH2) 2),-3-0-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NRR8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2)2 ; R is independently alkyl or lower alkyl ; R7 and R8 are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring; wherein one of R4", Rsa or R6"must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3 ; and/or R3ß and Retaken together or WO and Rip taken together, or R3α and R4α taken together or R4α and R5α taken together form a heterocyclic ring optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.

In a 79th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, Wo, R5p, Ro, R2 R3a, Wa, Rla and R6 « are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S (O)-lower alkyl, lower alkyl-S (O) 2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl,-C (O) R2, R2C (O) alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy,- (O (CH2) 2) 1- 3-0-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy,-OC (R') 2C (O) OH, -OC (R) 2C (O) OR2, - OC (R') 2C (O) NH2,-OC (R1) 2C (O) NHR2,-OC (R1) 2C (O) N (R2)2, -C(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino,-NHR2, N (R2) 2, -NR7R8, -NHC(R1)2C(O) OH, -NHC (R1) 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2, - NHC (O) OR2, - NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N (C (O) NHR2) 2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O) N (R2) 2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,-SC (R') 2C (O) OH, -SC (R1) 2C (O) OR2, -SCH2C(O)OH, -SCF2C(O) OH, - SO2NH2,-SO2NHR2,-SO2N (R2) 2, SO2NR7R8, -SO2NHC (O) R2,-SR2,-SO2NHC (O) NHR2, - S02NHC (O) N (R2) R2, -SO2NHC (O) NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C (O) ORZ,-C (O) NH2,-C (O) NHR2,-C (O) N (R2) 2, -C(O)NR7R8, -C(O) NHC (O) R2,-C (O) NHC (O) NHR2,-C (O) NHC (O) N (P, 2) 2, - C (O) NHC (O) NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), - C (O) NHSo2NR7R8,-C (CH3) 2C (O) OH,- (CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6,- PO2H2,-P03H2,-P (R2) 02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2 ; R'is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O) N (R2) 2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,-C (O) NR7R8, and-C (O) N (R2) 2; R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4-to 12-membered monocyclic, bicylic, tricyclic or benzofused ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or R6ß can be-OCH3; and/or R2ß and R3ß taken together or R3ß and WO taken together or R4ß and Rsß taken together or R2α and R3α taken together or R3α and Retaken together or R4α and R5α taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl,-NR7R8, alkoxy, oxo, cyano, carboxy, <BR> <BR> <BR> carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2 ; provided that R2ß, R3ß, RIP, R5ß, R6ß, R2a, R3α, R4α, Rsa and R6α cannot be -OC(R1)2C(O) OH; and/or at least one of R2ß, R3ß, or WO must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy,-C (O) OR2,-C (O) NH2, -C (O) NHR2,-C (O) N (R2)2, - C (O) NR7R8, -C(O) NHC (O) NHR2,-C (O) NHC (O) N (R 2) 2, - C (O) NHC (O) NR7R8, -C (O) NHSO2NHR2, -C (O) NHSO2N (R2),-C (O) NHSO2NR7R8, - C (O) NHC (O) R2,-C (O) NHS02R2,-C (CH3) 2C (O) OH, -(CH2) yC (O) OH, wherein y is 1, 2,3, 4,5, or 6, thiol,-SC (R1) 2C (O) OH, -SC (R') 2C (O) OR2, -SCH2C (O) OH, - SCF2C (O) OH,-SO2NH2,-SO2NHR2,-SO2N (R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, - S02NHC (O) NHR2,-S02NHC (O) N (R2) 2,-SO2NHC (O) (NR7R8, -OC(R1) 2C (O) OH,- OC (R') 2C (O) OR2, -OC (R1) 2C (O) NH2, -OC (R') 2C (O) NHR2,-OC (R1) 2C (O) N (R2)2, - OC (R1) 2C (O) NR7R8, amino, -NHR2, N (R2) 2, NR7R8, -NHC(R1)2C(O) OH, -NHC (R1) 2C (O) OR2, -NHC(O)R2, -N(R2) C (O) R2,-NHC (O) OR2,-NHC (O) SR2, -NHSO2NHR2, -NHSO2R2, -

NHSo2NR7R8,-N (C (O) NHR2) 2,-NR2SO2R2,-NHC (O) NHR2, -NHC(O)NR7R8, and- NHC (O) N (R2) 2, wherein all Rl, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C (O) NR7R8, and-C (O) N (R2) 2.

In a 80th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O (CH2) 2), -3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and-C (O) N (R2) 2; R is independently alkyl or lower alkyl ; R7 and R8 are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring; wherein one of R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2ß, R3ß, R4ß, R5ß or Ruß can be-OCH3 ; and/or R3ß and le taken together or R4ß and R50 taken together or R3Q and R4Q taken together or R4° and RS"taken together form a 5-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of alkyl, lower alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonyl; provided that R2ß, R3ß, R4ß, R5ß, R6ß, R2α, R3α, R4α, R5α and R6α cannot be -OC(R1)2COOH.

As an 81 embodiment, the invention is a pharmaceutical composition coprising any of the above 80 embodiments or any of the specific Examples below together with one or more pharmaceutically acceptable carriers.

An 82nid embodiment includes embodiments 1-80 above or any of the Examples as a means to treat or prophylactically treat an inflammatory disorder including arthritis, rheumatoid arthritis, asthma, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, systemic lupus erthematosus, atherosclerosis, and restinosis.

A further embodiment includes the intermediates used to make the final compounds of the invention. Said intermediates are useful as starting materials for making the compounds of the invention as well as having pharmaceutical activity alone.

Another embodiment of the invention includes the process for making both the intermediates as well as the final compounds.

Definitions A wavy line used as a bond"N", denotes a bond which can be either the E-or Z- geometric isomer.

When not used as a bond, the wavy line indicates the point of attachment of the particular substituent.

The terms"alkyl"or"alk", alone or in combination, unless otherwise specified, refers to a saturated straight or branched primary, secondary, or tertiary hydrocarbon from I to 10 carbon atoms, including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, and sec-butyl, . The term"lower alkyl"alone or in combination refers to an alkyl having from 1 to 4 carbon atoms. The alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.

The term"alkenyl", alone or in combination, means a non-cyclic alkyl of 2 to 10 carbon atoms having one or more unsaturated carbon-carbon bonds. The alkenyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.

The term"alkynyl", alone or in combination, means a non-cyclic alkyl of 2 to 10 carbon atoms having one or more triple carbon-carbon bonds, including but not limited to ethynyl and propynyl. The alkynyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.

The terms"carboxy","COOH"and"C (O) OH" are used interchangeably.

The terms"alkoxycarbonyl"and"carboalkoxy"are used interchangeably. Used alone or in combination, the terms mean refer to the radical-C (O) OR, wherein R is alkyl as defined herein.

The term"thio", alone or in combination, means the radical-S-.

The term"thiol", alone or in combination, means the radical-SH.

The term"hydroxy", alone or in combination means the radical-OH.

The term"sulfonyl", alone or in combination means the radical-S (O) 2-.

The term"oxo"refers to an oxygen attached by a double bond (=O).

The term"carbocycle", alone or in combination, means any stable 3-to 7-membered monocyclic or bicyclic or 7-to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.

Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

The term"cycloalkyl", alone or in combination, means a saturated or partially unsaturated cyclic alkyl, having from 1 to 10 carbon atoms, including but not limited to mono- or bi-cyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, and cyclohexyl.

The term"aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The"aryl"group can be optionally substituted with one or more of the moieties selected from the group consisting of alkyl, alkenyl, alkynyl, heteroaryl, heterocyclic, carbocycle, alkoxy, oxo, aryloxy, arylalkoxy, cycloalkyl, tetrazolyl, heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halogen, haloalkylthi, haloalkoxy, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, aminoalkyl, aminoacyi, amido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonate, sulfonyl, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, haloalkylsulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide or any other desired functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., "Protective Groups in Organic Synthesis, "John Wiley and Sons, Second Edition, 1999. In

addition, adjacent groups on an"aryl"ring may combine to form a 5-to 7-membered saturated or partially unsaturated carbocyclic, aryl, heteroaryl or heterocyclic ring, which in turn may be substituted as above.

The term"heterocyclic", alone or in combination, refers to a nonaromatic cyclic group that may be partially (containing at least one double bond) or fully saturated and wherein the ring contains at least one heteroatom selected from oxygen, sulfur, nitrogen, or phosphorus.

The terms"heteroaryl"or"heteroaromatic", alone or in combination, refer to an aromatic ring containing at least one heteroatom selected from sulfur, oxygen, nitrogen or phosphorus.

The heteroaryl or heterocyclic ring may optionally be substituted by one or more substituent listed as optional substituents for aryl. In addition, adjacent groups on the heteroaryl or heterocyclic ring may combine to form a 5-to 7-membered carbocyclic, aryl, heteroaryl or heterocyclic ring, which in turn may be substituted as above. Nonlimiting examples of heterocylics and heteroaromatics are pyrrolidinyl, tetrahydrofuryl, tetrahydrofuranyl, pyranyl, purinyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl, pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, or 1,4-dioxanyl. aziridinyl, furyl, furanyl, pyridyl, pyridinyl, pyridazinyl, pyrimidinyl, benzoxazolyl, 1,2, 4- oxadiazolyl, 1,3, 4-oxadiazolyl, 1,3, 4-thiadiazole, indazolyl, triazinayl, 1,3, 5-triazinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, 1, 2,4-thiadiazolyl, isooxazolyl, 1,2, 4- oxadiazolyl, 1,3, 4-oxadiazolyl, pyrrolyl, quinazolinyl, quinoxalinyl, benzoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, pyrazole, imidazole, 1,2, 3- triazole, 1,2, 4-triazole, 1,2, 3-oxadiazole, thiazine, pyridazine, triazolopyridinyl or pteridinyl. wherein said heteroaryl or heterocyclic group can be optionally substituted with one or more substituent selected from the same substituents as set out above for aryl groups. Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired.

Suitable protecting groups can include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

The term"thienyl", alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds.

The term"benzothienyl", alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds fused to a phenyl ring.

The term"aryloxy", alone or in combination, refers to an aryl group bound to the molecule through an oxygen atom.

The term"heteroaryloxy", alone or in combination, refers to a heteroaryl group bound to the molecule through an oxygen atom.

The term"aralkoxy", alone or in combination, refers to an aryl group attached to an alkyl group which is attached to the molecule through an oxygen atom.

The term"heterocyclearalkoxy"refers to a heterocyclic group attached to an aryl group attached to an alkyl-O-group. The heterocyclic, aryl and alkyl groups can be optionally substituted as described above.

The terms"halo"and"halogen", alone or in combination, refer to chloro, bromo, iodo and fluoro.

The terms"alkoxy"or"alkylthio", alone or in combination, refers to an alkyl group as defined above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.

The terms"lower alkoxy"or"lower alkylthio", alone or in combination, refers to a lower alkyl group as defined above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.

The term"acyl", alone or in combination, refers to a group of the formula C (O) R', wherein R'is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.

The term"acetyl", alone or in combination, refers to the radical-C (O) CH3.

The term"amino", alone or in combination, denotes the radical-NH2 or-NH-.

The term"nitro", alone or in combination, denotes the radical-NO2.

The term"substituted", means that one or more hydrogen on the designated atom or substituent is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and the that the substitution results in a stable compound. When a subsitutent is"oxo" (keto) (i. e., =O), then 2 hydrogens on the atom are replaced.

The term"alditol", as referred to herein, and unless otherwise specified, refers to a carbohydrate in which the aldehyde or ketone group has been reduced to an alcohol moiety.

The alditols of the present invention can also be optionally substituted or deoxygenated at one or more positions. Exemplary substituents include hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, amino acid, amino acid esters and amides, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate, . Particular exemplary substituents include amine and halo, particularly fluorine.

The substituent or alditol can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1999, hereby incorporated by reference. The alditol may have 3,4, 5,6 or 7 carbons. Examples of useful alditols are those derived from reduction of monosaccharides, including specifically those derived from the reduction of pyranose and furanose sugars.

The term"carbohydrate", as referred to herein, and unless otherwise specified, refers to a compound of carbon, hydrogen and oxygen that contains an aldehyde or ketone group in combination with at least two hydroxyl groups.. The carbohydrates of the present invention can also be optionally substituted or deoxygenated at one or more positions. Carbohydrates thus include substituted and unsubstituted monosaccharides, disaccharides, oligosaccharides, and polysaccharides. The saccharide can be an aldose or ketose, and may comprise 3,4, 5,6, or 7 carbons. In one embodiment the carbohydrates are monosaccharides. In another embodiment the carbohydrates are pyranose and furanose sugars.

As used herein, the term"patient"refers to warm-blooded animals or mammals, and in particular humans, who are in need of the therapy described herein. The term"host", as used

herein, refers to a unicellular or multicellular organism, including cell lines and animals, and preferably a human.

Synthesis of the Active Compounds The compounds of the present invention can be readily prepared by those skilled in the art of organic synthesis using commonly known methods, many of which are described by J, March, in Advanced Organic Chemistry, 4ti Edition (Wiley Interscience, New York, 1992) and D. N. Dnar in The Chemistry of Chalcones and Related Compounds (Wiley-Interscience, New York, 1981), incorporated herein by reference.

Compounds of the present invention are prepared either by reacting a heteroaryl-or heterocyclic-substituted aryl or heteroaryl ketone with a suitably substituted aryl aldehyde or by reacting a suitably substituted aryl ketone with a heteroaryl-or heterocyclic-substituted aryl or heteroaryl aldehyde. This reaction, which is a condensation reaction, is suitably carried out under base-or acid-catalyzed conditions. The reaction may be suitably carried out in water or protic organic solvents such as lower alcohols (e. g. methanol, ethanol, tert-butanol), lower carboxylic acid (e. g. formic acid, glacial acetic acid, propionic acid), or in aprotic organic solvents such as ethers (e. g. tetrahydrofuran, dioxane, diethyl ether), liquid amides (e. g. dimethylformamide, hexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons (e. g. toluene, benzene), or mixtures of such solvents. When carrying out the reaction under basic conditions, the base may be selected from sodium, lithium, potassium, barium, calcium, magnesium, aluminum, ammonium, or quarternary ammonium hydroxides, lower alkoxides (e. g. methoxides, ethoxides, tert-butoxides), carbonates, borates, oxides, hydrides, or amides of lower secondary amines (e. g. diisopropyl amides, methylphenyl amides). Primary aromatic amines such as aniline, free secondary amines such as dimethyl amine, diethyl amine, piperidine, or pyrrolidine, tertiary amines such as pyridine, as well as basic ion exchange resins may also be used. Alternatively, a phase-transfer catalyst such as cetyl trimethyl ammonium chloride can also be used to facilitate the reaction, particularly when water is the solvent.

Alternatively, the aldol condensation reaction can also be carried out in an aprotic solvent such as tetrahydrofuran (THF) with an organic base. The preferred solvent is THF and

the preferred base is lithium diisopropylamide (LDA). In this manner an aldol reaction may take place first and the subsequent dehydration reaction may take place during an aqueous workup.

Acid catalysts may be selected from hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, sulfonic acids (such as paratoluenesulfonic or methansulfonic acid), lower carboxylic acid (such as formic, acetic, or propionic acid), lower halogenated carboxylic acid (such as trifluoroacetic acid), Lewis acids (such as BF3, POC13, PCIs, FeCI3), or acid ion exchange resins.

The reaction may be carried out at temperatures in the range of-80 °C to +150 °C, preferrably in the range of 0'C to +100 °C, and more preferably at room temperature. The time of reaction may be from 30 minutes to approximately 24 hours.

Compounds of the invention may be isolated as either mixtures of cis (Z) and trans (E) geometric isomers or either pure trans (E) isomers. If desired, either the mixtures or the pure trans isomers may be isomerized to the corresponding predominantly cis (Z) iomers using methods well known in the literature.

In the above reactions, it may be preferred or necessary to protect various sensitive or reactive groups present in the starting materials so as to prevent said groups from interfering with the reactions. Such protection may be carried out in a well-known manner as taught by Theodora W. Green and Peter G. M. Wuts, in Protective Groups in Organic Chemistry Third Edition (Wiley, 1999) or using methods from references cited therein or of the like. The protecting group may be removed after the reaction in a manner known per se.

The following schemes will prove useful to those skilled in the art in manufacturing the compounds of the invention: Legend for all schemes: 1. R, R', R", R"', and R""can be any substitution including H; 2. R, R', R", R"', and R""can be suitabaly functionalized; 3. R, R', R", R"', and R""can represent multiple substitutions; 4. Two adjacent R, R', R", R"', or R""can form a ring; 5. Dashed double bond can be at any location of a ring;

6. Y, Y', Y", and Y"'independently represent N (H), O, or S, 7. X and X'independently represent Cl, Br, or I ; 8. Each R, R', R", R"', R"", Y, Y', Y", Y"', X or X'is independent in each scheme; 9. HetAr represents suitably substituted heterocyclic aryl ; 10. Cy represents cyclohexyl.

Scheme 1 0 R-0 H, Me 0 H mye ° R HO \J' R O, S, NH Tf20 n base Heck cross coupling solvent Pd (0), solvent, heat 0 0 H, Me XCH Me or TfO+, \g X R R HetArB (OH) 2 /HetAr-H or HetAr-BEt2 Suzuki cross coupling 1. Pd [Ph3P] 4, solvent 0 RFt * 2. BEt3 Na2CO3, H20, heat or HetAr-BEt2 2. Pd [t-Bu3P] 2, solvent, KF, heat O 14 XH, Me HetArw R R'O OR' acetone ces acid R' heat H2 0 HetAr-X R'O OR'Pd (0), base sue HetAr X heat 0 (R"') 2BH, Pd (OAc) 2/ Cy2P-biphenyl H, Me base, solvent, heat R'O OR' R R'-OH acid,, solvent MHz R Scheme 2 \1 R'O x + O QH R'°X OH vent 0 base R solvent 0 0 R R'o 0 Xi LAH R'O HO reduction HO Ll Ho Friedel-Crafts acylation R"C (O) CI, AICI3 R solvent \ R"'O ~ R"'O Scheme 3 0 0 H, Me R \ CH, Me zur j R"/N base H solvent R" heat Scheme 4 O O HS \ H'Me R-S \ H Me R \ R'-X, base/R solvent Scheme 5 0 11 H, Me N-S NH \R RW ° CH Me it/0 R \ NH P 0"D \R"base/ solvent Scheme 6 0 0 //H, Me/H, Me R'-X, base-1\ l R solvent, heat \ NU

Scheme 7 HO 0 HO 0 Ho\ H M. romnation or iodination R R HO ? HetAr-B (OH) 2 H, Me Suzuki cross HetAr coupling R O Au0 I H, Me r-X Het R \ R'-X'or R'-OMs base, solvent \heat R'O I H, Me HetA O R HO-1 0 hydrolysis when _ HetAr OEt R II Scheme 8 RXO ISl (NH) R"fl NH2 R \ EtOH\ base or no base S heat zon R". P O 1. TiC4 \ Ru Ci S \ \ H CI'O I ci 0

Scheme 9 R Nu2 (HO) H Y' EtOH AcOH heat po L Y ,. _y| R -Ytpt R 1. TiC) 4 \ p C ! 0 ci y H Cl 0 YY," Scheme 10 0 0 H, Me N-N H, Me X tH X R R 1. NaN3, ZnBr H20, heat \2. acid/ Scheme 11 0 0 0 1 H, Me H, Me HA R' N R R., R Rp\ acylation R NH R" Scheme 12 0 O OH N Y H, Me HA I OH Ho HO OH acid OH OH solvent heat 0 C R'-SO HN I H, Me H, Me base R'-S02 R solvent O O HO OH solvent, heat base \V"'R""NH, EtOH solveny O O 0< ;, 0 0/ R N HN H, Me 0 R R"\ H, Me H, Me N I R'-S02 R Scheme 13

1. hydrazine solvent, heat N N MeO R 2. R'-N=C=S N R solvent, heat R'R 3. Base, solvent heat \ 4. Raney Ni 1. TiC14 EtOH, heat CI 0 ci 0 N. N/H 2. H20 zur R Scheme 14 0 0 0 0 AcCI, AICIg ><R'R \tS R R R R R Scheme 15

0 0 RX + R"'C H R R" R X R" 1. NaOH, DMF, H20 or 2. LiOMe, MeOH, DMF or 3. Surfactant, base, Hz0 O R I v I \ R"' R R" R R" Scheme 16 0 rrTTi HS</8 R"' R R" R R" R R" solvent CTI, R'-S-I I-R-1- R R" R R"

Scheme 17 Scheme 18 0 o R'-S-N-\ I/ R"' R g R 0 R R R" R""-X, base, solvent 0 0 11-H O 11 0 R R" and/or O O. R N- {- J ,-JLR'" R'-S R R" R'-S (0) 2-CI base, solvent 0 o H2N</R"' R R" R'-N=C=O solvent, heat 0 -N \/I R -N-L !) t !. j-R-" R'-NH R R" and/or O O N R, \HN I/I = R R N 0 R R" R'

0 o H2N R R"' R'C (O) OC (O) R or R'C (O) CI base, solvent 0 O// I I R"' R R and/or o WN) =tR"598 R*@ R R" ouzo cfo R P" R' Scheme 19 O H / / R'I R"' R R" R'lu light Sol ry solvent H R'-I R Examples The following examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. All intermediates and final products have

been completely characterized by conventional proton NMR, mass spectral analyses and standard analytical methods known to those skilled in the art.

EXAMPLE 1 1- (2, 2-Bis-hydroxymethyl-benzo [1, 3] dioxol-5-yl)-3E- (3, 4-dimethoxy-5-thiophen-2-yl- phenyl)-propenone Ex-lA: Catechol (2.2 g, 20 mmol) was dissolved in acetone. Diethyl dibromomalonate (7.0 g, 22 mmol) and potassium carbonate (2.76 g) were added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and water was added to the residue. The residue was extracted with dichloromethane, and the organic phase was washed with brine, dried over magnesium sulfate and evaporated. Chromatography (hexanes/ethyl acetate, 4: 1) gave 3.9 g of benzo [1, 3] dioxole-2, 2-dicarboxylic acid diethyl ester.

'H-NMR (CDC13) 8 6.90-6. 97 (m, 4H), 4.37 (q, J = 7 Hz, 4H), 1.32 (t, J = 7 Hz, 6H).

Ex-lB : [Bis (ethoxycarbonyl) methyldenedioxy] benzene obtained from Ex-lA (3.9 g, 14.7 mmol) was dissolved in THF (100 mL) and cooled with ice-water. Lithium aluminum hydride (1 M solution in THF, 44 mL) was added dropwise, and the mixture was stirred overnight. The reaction was carefully quenched with saturated sodium sulfate until there was no further bubbling. The mixture was stirred overnight, then filtered, and the filtrate was dried over magnesium sulfate. Chromatography (dichloromethane/methanol, 10: 1) gave 0.5 g of the desired (2-hydroxymethyl-benzo [1, 3] dioxol-2-yl)-methanol.'H-NMR (CDC13) 8 6.82 (s, 4H), 3.94 (d, J = 7 Hz, 4H), 1.98 (t, J = 7 Hz, 2H).

Ex-lC : Aluminum chloride (1.3 g) was added to nitromethane followed by the addition of acetyl chloride (1.86 g). Then (2-hydroxymethyl-benzo [1, 3] dioxol-2-yl) -methanol obtained from Ex-lB (0.5 g) in nitromethane was added dropwise. The mixture was stirred overnight.

Water was added to the reaction mixture, and it was extracted with dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate and evaporated.

Chromatography gave 0.28 g of 5-acetyl-benzo [1, 3] dioxole-2,2-dicarboxylic acid diethyl ester.

'H-NMR (CDC13) 8 7.56 (d, J = 7 Hz, 1H), 7.43 (s, 1H), 6.85 (d, J = 7 Hz, 1H), 4.42 (s, 4H), 2.53 (s, 3H), 2.05 (s, 6H).

Ex-lD : A solution of 5-bromo-3, 4-dimethoxybenzaldehyde (10.23 g, 41.7 mmol) in 359 mL of ethylene glycol dimethyl ether was purged with nitrogen gas for 30 min. The solution was treated with tetrakis (triphenylphosphine) palladium (0) (5.0 g, 4.3 mmol), thiophene-2-boronic acid (8.01 g, 62.6 mmol), and a solution of 2 N sodium carbonate 72 mL, 3.45 mmol). The reaction was refluxed for 16 h. The reaction mixture was concentrated, diluted with an aqueous solution of saturated sodium bicarbonate (75 mL), and extracted with dichloromethane (2 x 100 mL). The organic layer was dried over sodium sulfate and concentrated to a brown solid. The crude material was purified by silica gel chromatography (1: 1 ethyl acetate/hexanes) to give 9.42 g (90%) of the desired 3, 4-dimethoxy-5- (thien-2-yl) benzaldehyde product.'H-NMR (300 MHz, CDC13) 8 9.94 (s, 1 H), 7.79 (d, 1 H), 7.57 (dd, 1 H), 7.41 (d, 1 H), 7.36 (d, 1 H), 7.13 (dd, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H).

5-Acetyl-benzo [1, 3] dioxole-2, 2-dicarboxylic acid diethyl ester obtained from Ex-lC (0.28 g, 1. 11 mmol) and 3, 4-dimethoxy-5- (thien-2-yl) benzaldehyde obtained from Ex-lD (0.275 g, 1. 11 mmol) were dissolved in ethanol, and 50% sodium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure, and water was added to the remainder. The resulting product was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated. Chromatography gave 0.19 g (38%) of the title compound as a yellow solid, m. p.

74-80 °C.'H-NMR (300 MHz, CDC13) 8 7.74 (d, 1 H), 7.63 (dd, 1 H), 7.49-7. 55 (m, 3 H), 7.38 (d, 1 H), 7.37 (d, 1 H), 7.12 (dd, 1 H), 7.07 (d, 1 H), 6.88 (d, 1 H), 3.99 (s, 4 H), 3.98 (s, 3 H), 3.88 (s, 3 H). Anal. Calculated for C24H2207S : C, 63.42 ; H, 4.88 ; S, 7.06 ; found: C, 63.46 ; H, 5. 11 ; S, 6.55.

EXAMPLE 2

1-(2, 2-Bis-hydroxymethyl-benzoll, 3] dioxol-5-yl)-3E- (4-thiophen-2-yl-phenyl)-propenone Ex-2A: 4- (Thien-2-yl) benzaldehyde was obtained in a similar manner as described in Ex-lD from 4-bromobenzaldehyde.'H-NMR (CDC13) 8 10. 00 (s, 1H), 7. 88 (d, J = 9 Hz, 2H), 7.77 (d, J = 9 Hz, 2H), 7.46 (d, J = 4 Hz, 1H), 7.39-7. 41 (m, 1H), 7.12-7. 15 (m, 1H).

The title compound was obtained when 5-acetyl-benzo [1, 3] dioxole-2,2-dicarboxylic acid diethyl ester from Ex-1C was condensed with 4- (Thien-2-yl) benzaldehyde from Ex-2A in a similar manner as described in Ex-1. Yellow solid, mp 166-168°C, 23.6% yield.'H-NMR (CDCl3) 8 7.77 (d, J = 15Hz, 1H), 7.60-7. 65 (m, 5H), 7.51 (d, J = 2 Hz, 1H), 7.45 (d, J = 15 Hz, 1H), 7.37-7. 38 (m, 1H), 7.32 (d, J = 5 Hz, 1H), 7.09 (dd, J= 4, 5 Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 3.96 (d, J = 7 Hz, 4H). MS m/z = 394 ([M] +, 50%), 363 (100%). HRMS (EI) Calcd. for C22HI805S : 394.0875. Found: 394.0869.

EXAMPLE 3

4- [3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid Ex-3A: A sample of 5-bromo-2, 4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL). Tetrakis (triphenylphosphine) palladium (0) (2.32 g, 2 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min.

Benzo [b] thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonate solution (2 M, 20 mL) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate 2: 1 then 1: 1) gave 4.75 g (83%) of the desired 5- (benzo [b] thien-2-yl) -2,4- dimethoxybenzaldehyde.'H NMR (CDC13) 8 10.36 (s, IH), 8.20 (s, 1H), 7.83-7. 78 (m, 2H), 7.68 (s, 1H), 7.36-7. 27 (m, 2H), 6.54 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H).

An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20 g), benzo [b] thiophene-2- boronic acid (16 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10 g), and Pd (tBu3P) 2 (0.417 g). The solution was immediately heated to 60 °C and aged for 1.5 h.

(Note: The HPLC assay at this point routinely indicated complete consumption of 5-bromo- 2,4-dimethoxybenzaldehyde, < 0.5 area% of benzo [b] thiophene-2-boronic acid along with 0.5 area% of an unknown (0.55 RRT). These impurities are removed during crystallization. ) Upon completion, as determined by HPLC, the reaction was diluted with H20 (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H20 (200 mL). The layers. were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was batch concentrated and solvent switched to 33 wt% 5- (benzo [b] thien-2- yl) -2,4-dimethoxybenzaldehyde in THF in preparation for crystallization. (Note: The internal temperature during batch concentration should be kept above 45 °C to prevent premature crystallization. ) The resulting THF solution of 5- (benzo [b] thien-2-yl) -2,4- dimethoxybenzaldehyde was then charged with heptane (20 mL) and slowly cooled to ambient

temperature. Crystallization was then completed with the slow addition of heptane (175 mL) and cooling to 4 °C. After aging for I h, the batch was filtered and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40 °C, 20 inHg) affording 23.74 g (97% yield) of desired 5-(benzo [b] thien-2-yl)-2, 4-dimethoxybenzaldehyde as a light orange crystalline solid, m. p. 134-136 °C. HPLC assay of this solid indicated > 99.9 LCAP.'H-NMR identical as above.

To a solution of 4-acetylbenzoic acid (1.50 g, 9.1 mmol) and 5- (benzo [b] thien-2-yl) -2,4- dimethoxybenzaldehyde from Ex-3A (3.27 g, 11.0 mmol) in N, N dimethylformamide (76 mL) was added a solution of sodium hydroxide (5 M, 7.3 mL, 36.5 mmol). The reaction mixture was allowed to stir at room temperature for 2 h and was then diluted with water to a volume of 150 mL. The solution was washed with dichloromethane and acidified with concentrated sulfuric acid to pH = 3. The resulting solution was then extracted with dichloromethane. The dichloromethane extract was washed with brine, dried over sodium sulfate and concentrated.

The resulting oily product solidified in ethanol. The solid was further stirred in ethanol for one day and collected by filtration. The solid was washed with ethanol, then dried in vacuo to afford the title compound as a yellow solid (2.2 g, 54%). 1H NMR (300 MHz, DMSO-d6) S 8.36 (s, 1H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H), 7.82 (d, 1H), 7.32 (m, 2H), 6.86 (s, 1H), 4.08 (s, 3H), 4.00 (s, 3H). Anal. Calculated for C26H2o0sS'1/6H20 : C, 69.78 ; H, 4.58 ; S, 7.17 ; found: C, 69.95 ; H, 4.69 ; S, 7.15. HPLC purity: 97.9% (area percentage). <BR> <BR> <P>An alternative procedure: 5- (Benzo [b] thien-2-yl) -2,4-dimethoxybenzaldehyde from. Ex-3A (42.3 g), 4-acetylbenzoic acid (22.1 g), MeOH (250 mL) and DMF (600 mL) were sequentially charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter.

After complete dissolution, LiOMe (10.5 g) was added in one portion and the resulting solution was aged at 40 °C for 2 h. Upon completion, as determined by HPLC, the reaction mixture was transferred to a separatory funnel containing cold H20 (800 mL, precooled to 10 deg C). An additional 400 mL cold H20 was used to rinse the reaction vessel and this rinse was also added to the seperatory funnel. The combined aqueous was washed with iPrOAc (500 mL) and then acidified to a pH of 3 with 6 N HCI (ca. 60 mL). The resulting heterogeneous solution was aged

for 30 min and then the precipitate was filtered, washed with 70% EtOH (100 mL) and dried on the filter funnel under a stream of N2 affording desired acid 5 as a crude yellow solid. The crude dry product and THF (260 mL) were charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter. Heptane (30 mL) was slowly added to the resulting solution over 30 min and then aged resulting in crystallization. Additional heptane (270 mL) was added over 1 h, aged for an additional 1 h and then filtered. The reaction vessel was then rinsed with 70% EtOH (100 mL) and this rinse was added to the filter cake. The wet cake was then transferred to a clean reaction vessel containing 70% EtOH (750 mL) and the resulting heterogeneous mixture was stirred overnight. The product was then filtered, rinsed with fresh 70% EtOH (100 mL) and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40 °C, 20 inHg) affording 52.05 g (87% yield) of desired 4- [3- (5-benzo [b] thiophen-2-yl- 2, 4-dimethoxy-phenyl)-E-acryloyl]-benzoic acid 5 as a yellow crystalline solid, m. p. 231-232 °C (dec. ). HPLC assay of this solid indicated > 99.9 LCAP.'H-NMR identical as above.

EXAMPLE 4 4- [3E- (4-Pyrimidin-5-yl-phenyI)-acryloyll-benzoic acid Ex-4A: 4-Pyrimidin-5-yl-benzaldehyde was obtained pyrimidine-5-boronic acid and 4- bromobenzaldehyde in a similar manner as described in Ex-3A, 88.6% yield.'H-NMR (CDC13) 8 10.11 (s, 1H), 9.28 (s, IH), 9.01 (s, 2H), 8.05 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H).

The title compound was obtained in a similar manner as described in Ex-3 from 4-pyrimidin-5- yl-benzaldehyde (Ex-4A) and 4-acetylbenzoic acid. Yellow solid, mp >260°C, 45% yield.'H- NMR (DMSO-d6) S 9.21 (s, 2H), 9.19 (s, 1H), 8.24 (d, J = 9 Hz, 2H), 8.01-8. 09 (m, 5H), 7.9 (d, J = 6 Hz, 2H), 7. 81 (d, J = 15Hz, H), MS m/z = 330 ([M]+, 100%). HRMS (EI) Calcd. for C20Hs4N203 : 330.1004. Found: 330.1000.

EXAMPLE 5

4- [3E- (4-Thiazol-2-yi-phenyl)-acryloyll-benzoic acid Ex-5A : 4-Thiazol-2-yl-benzaldehyde was prepared from 4-bromobenzaldehyde and thiazole-2- boronic acid in a similar manner as described in Ex-3A, 82% yield. 1H-NMR (CDCl3) # 10.07 (s, 1H), 8.15 (d, J = 8 Hz, 2H), 7.95-7. 98 (m, 3H), 7.45 (d, J = 3 Hz, 1H). HMRS (EI) calcd. for C10H7NOS : 189.0248 ; found: 189.0242.

The title compound was obtained in a similar manner as described in Ex-3 from 4-thiazol-2-yl- benzaldehyde (Ex-5A) and 4-acetylbenzoic acid. Yellow solid, mp 232-235°C, 20% yield. lH- NMR (CDC13) 8 8.24 (d, J = 9 Hz, 2H), 8.11 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 7.93 (d, J = 3 Hz, 1H), 7.86 (d, J = 15 Hz, 1H), 7.74 (d, J = 9Hz, 2H), 7.57 (d, J = 15 Hz, 1H), 7.41 (d, J = 3 Hz, 1H), MS m/z = 335 ([M]+, 100%). HRMS (EI) Calcd. for ClgHI3NO3S : 335.0616.

Found: 335.0618.

EXAMPLE 6 4- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-6A: 5-bromo-2, 4-dimethoxybenzaldehyde (20.3 g), thiophene-2-boronic acid (11.6 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g), and Pd ('Bu3P) 2 (0.424 g). The solution was immediately heated to 60 °C and aged for 1.5 h. The reaction was diluted with H20 (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H20 (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g).

The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness. The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition. The product was filtered and then dried to a constant weight in the vacuum oven (38 °C, 20 inHg) affording 19.32 g (94% yield) of desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde as a light off- white solid, m. p. 125-126°C.'H-NMR (300 MHz, CDC13) : 10.34 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J= 3. 5 and 1.5 Hz), 7.31 (dd, 1 H, J= 5.2 and 1.5 Hz), 7.07 (dd, 1 H, J= 5.2 and 3.5 Hz), 6.51 (s, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H).

2, 4-Dimethoxy-5-thiophen-2-yl-benzaldehyde from Ex-6A (7.81 g), 4-acetylbenzoic acid (4.9 g), MeOH (60 mL) and DMF (150 mL) were sequentially charged into a clean reaction vessel fitted with a stir bar and nitrogen inlet adapter. After complete dissolution LiOMe (4.60 g) was added and the resulting solution was aged for 5 h. The reaction was diluted with H2O (200 mL) and transferred to a separatory funnel containing iPrOAc (100 mL). The layers were cut and the aqueous layer was acidified to a pH of 1 with 3 N HCI. The resulting precipitate was filtered and then dried on the filter funnel under a stream of N2. The crude product was then dissolved in THF (60 mL) and crystallized with the addition of heptane (60 mL). The product was filtered and then dried to a constant weight in the vacuum oven affording 8.9 g (75% yield) of the title compound as a yellow solid, m. p. 213-216°C.'H-NMR (300 MHz, CDC13) : 8.20 (d, 2 H, J= 8.5 Hz), 8.09 (d, 1 H, J= 16.1 Hz), 8.06 (d, 2 H, J= 8. 5 Hz), 7.85 (s, 1 H), 7.52 (d, 1 H, J = 16.1 Hz), 7.40 (m, I H), 7.30 (dd, 1 H, J = 5.2 and 1.7 Hz), 7.08 (dd, 1 H, J = 5.2 and 3.6 Hz), 6.53 (s, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H); EIMS m/z = 394 (M^). Anal. calc. for C22HI805S : C, 66.99 ; H, 4.60 ; S, 8.13 ; found: C, 66.71 ; H, 4.59 ; S, 8.10.

EXAMPLE 7

2- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid The title compound was obtained starting from 5- (benzo [b] thien-2-yl) -2,4- dimethoxybenzaldehyde from Ex-3A and 2-acetylbenzoinc acid in a similar manner as described in Ex-3. Yellow solid, mp 220-223 °C (dec.).'H-NMR (DMSO-d6) 8 8.01 (s, 1H), 7. 88 (d, J = 7.3 Hz, 1H), 7.80-7. 75 (m, 2H), 7.45-7. 24 (m, 7H), 7.11 (d, J = 16.2 Hz, 1H), 6.79 (s, 1H), 4.00 (s, 3H), 3.88 (s, 3H). MS m/z = 445 (M+, 100%).

EXAMPLE 8 4- [3E- (3, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid The title compound was obtained in a similar manner as described in Ex-3 from 3,4- dimethoxy-5- (thien-2-yl) benzaldehyde (Ex-lD) and 4-acetylbenzoic acid. Yellow solid, mp 231°C.'H-NMR (DMSO-d6) 8 8.23 (d, 2H), 8.08 (d, 2H), 7.96 (d, 1H), 7.90 (m, 1H), 7.77 (m, 2H), 7.59 (d, 1H), 7.54 (m, 1H), 7.13 (dd, J= 4,4 Hz, 1H). Mus milz = 395 ([M+H]+, 100%).

EXAMPLE 9

2- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt To a solution of 2-acetyl-benzoic acid (0.75g, 4.6 mmol) and 5-benzo [b] thiophen-2-yl-2, 4- dimethoxy-benzaldehyde (Ex-3A, 1.64g, 5.5 mmol) in N,N-dimethylformamide (38 mL) was added sodium hydroxide (5M, 3.7 mL, 18.5 mmol). The reaction mixture was allowed to stir for 2 hours at ambient temperature and was diluted with water (50 mL) and sodium carbonate (2M, 20 mL). The aqueous solution was extracted with dichloromethane. A yellow precipitate formed in dichloromethane and was collected by filtration, washed with dichloromethane, dried in vacuo to give the title compound as a yellow solid (1.53g, 67 %), mp 214-217 °C (dec).'H- NMR (DMSO-d6) 8 7.93-7. 87 (m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 7.33-7. 26 (m, 4H), 7.09-7. 06 (m, 2H), 7.01 (d, J = 17.0 Hz, 1H), 6.78 (s, 1H), 3.99 (s, 3H), 3.88 (s, 3H). MS nzlz = 467 ( [M + Na] +, 75%), 445 ( [M + H] +, 100%). Anal. (C26H19O5SNa#1.3H2O) Calc. C 63. 55, H 4. 35, S 6.52, found C 63.74, H, 4.44, S 6.55.

EXAMPLE 10 4- [3E- (4-Thiophen-2-yl-phenyl)-acryloyll-benzoic acid The title compound was obtained by condensing 4- (thien-2-yl) benzaldehyde from Ex-2A and 4-acetylbezoic acid in a similar manner as described in Ex-3. Yellow solid, 56% yield, mp >260 °C.'H-NMR (DMSO-d6) 8 8.01-8. 08 (m, 4H), 7.72 (d, J = 8 Hz, 2H), 7.68 (s, 2H), 7.61 (d, J = 8 Hz, 2H), 7.41 (d, J = 4 Hz, 1H), 7. 35 (d, J = 4 Hz, 1H), 7.04 (dd, J = 4,8 Hz, IH). MS

m/z = 334 ([M + Na] +, 100%). Anal. (C22H, 403S) Calc. C 71.84, H 4.22, S 9.59, found C 71.44, H 4.32, S 9.43.

EXAMPLE 11 1-(4-Amino-phenyl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl) -propenone A suspension of 3, 4-dimethoxy-5-(thien-2-yl) benzaldehyde (1. 8 g, 7.4 mmol) from Ex-lD in an aqueous solution of 5 N potassium hydroxide (37 mL) was treated with cetyltrimethyl ammonium chloride (39 mL, 29.6 mmol) and 4-aminoacetophenone (1.0 g, 7.4 mmol). The reaction was stirred for 16 h at room temperature. The reaction mixture was titrated with 6 M H2SO4 to a pH of 7. The mixture was extracted with dichloromethane (2 x 75 mL). The organic layer was washed with aqueous NaHC03 (2 x 25 mL), brine, dried over sodium sulfate, and concentrated to a yellow foam. The crude material was purified by silica gel chromatography (1: 1 ethyl acetate and hexanes) to give 720.0 mg (27%) of the title compound as a yellow solid, mp. 67-71 °C.'H-NMR (300 MHz, CDC13) 8 7.94 (d, 2 H), 7.75 (d, 1 H), 7.54 (s, 1H), 7.53 (s, 1 H), 7.46 (d, 1 H), 7.39 (d, 1H), 7.13 (d, 1H), 7.11 (m, 1H), 6.72 (d, 2H), 4.16 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H). Anal. calculated for C21H19NO3S#1/5 H2O : C, 68.60, H, 5.28, S, 8.72 ; found C: 68. 51, H: 5.40, S: 8.69. MS (Pos. Ion ES): calcd for C21H20NO3S : n2/z = 366 [M+H] +, found: 7n/z = 366 [M+H] +.

EXAMPLE 12

1- (4-Amino-phenyl)-3E- (4-thiophen-2-yl-phenyl)-propenone The title compound was prepared from 4- (thien-2-yl) benzaldehyde (Ex-2A) and 4- aminoacetophenone in a similar manner as described in Ex-11. Yellow solid, 45% yield, mp 185-187°C.'H-NMR (CDCI3) 5 7.95 (d, 2 H), 7.79 (d, 1H), 7.65 (m, 4H), 7.55 (d, 1H), 7.39 (d, 1H), 7. 33 (dd, J=5, 5 Hz, 1H), 7.11 (dd, J= 5, 5 Hz, 1H), 6.71 (d, 2H), 4.16 (s, 2H). MS m/z = 305 ([M]+, 100%). Anal. calculated for ClgHlsNos : C, 74.72, H, 4.95, S, 10.50 ; found C: 74.60, H: 5.05, S: 10.42.

EXAMPLE 13 1- (4-Amino-phenyl)-3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-propenone The title compound was prepared from 5- (benzo [b] thien-2-yl) -2,4-dimethoxybenzaldehyde (Ex-3A) and 4-aminoacetophenone in a similar manner as described in Ex-11. Yellow solid, 24% yield, mp 98-104°C. IH-NMR (CDCI3) 6 8.10 (d, 1 H), 7.95 (m, 3H), 7.82 (m, 2H), 7.67 (s, 1H), 7.60 (d, 1H), 7.32 (dd, J = 8. 8 Hz, 2H), 6.71 (d, 2H), 6. 57 (s, 1H), 4. 11 (br s, 2H), 4.02 (s, 3H), 3.99 (s, 3H). MS m/z = 415 ([M]+, 39%), 384 (100%). Anal. calculated for C25H21NO3S#1/3 H2O : C, 71.24, H, 5.18, S, 7.61 ; found C: 71.63, H: 5.18, S: 7.55.

EXAMPLE 14

N-{4- [3E-(3, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-aclyloyl]-phenyl}-methan esulfonamide Ex-14A: A solution of 1- (4-amino-phenyl)-3E- (3, 4-dimethoxy-5-thiophen-2-yl-phenyl)- propenone (Ex-11,472. 2 mg, 1. 3 mmol) and triethylamine (398. 63 uL, 2.86 mmol) was stirred in 20 mL of anhydrous dichloromethane. The mixture was treated with mesyl chloride (100 pL, 1.3 mmol). The reaction mixture was stirred for 16 hours and heated gently for another 4 hours. The crude material was purified by silica gel chromatography (1 : 3 ethyl acetate/hexane) to give 337.0 mg (quantitative) of 1- [4-bis- (methanesulfonyl) aminophenyl]-3E- [ (3, 4- dimethoxy-5- (thien-2-yl) phenyl]-propenone.'H-NMR (300 MHz, CDECl3) 8 8.06 (d, 2H), 7.76 (d, 1H), 7.53 (m, 2H), 7.49 (d, 2H), 7.38 (m, IH), 7.36 (d, 1H), 7.10 (m, 1H), 7.08 (m, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.42 (s, 6H).

A solution of 1- [4-bis- (methanesulfonyl) aminophenyl]-3E- [ (3, 4-dimethoxy-5- (thien-2- yl) phenyl]-propenone (378.86 mg, 0.73 mmol) from Ex-14A in tetrahydrofuran (6.6 mL) was treated with aqueous IN NaOH (1.4 mL, 1.4 mmol). The reaction was stirred at room temperature for 1 h. The reaction was titrated with 1 N HCl to a pH of 6. The crude material was purified by silica gel chromatography (5% MeOH/CH2CI2 with 1% acetic acid) to give 269.2 mg (83%) of the title compound as a solid, 83% yield, mp. 71-75 °C.'H-NMR (300 MHz, CDC13) 8 8.04 (d, 2H), 7.76 (d, 1H), 7.52 (m, 2H), 7.40 (d, 1H), 7.37 (m, 1H), 7.29 (d, 2H), 7.10 (m, IH), 7.08 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.12 (s, 1H), 3.09 (s, 3H). MS (Pos.

Ion ES): calcd for C22H22NO5S2 : nzlz = 444 [M+H] +, found: mlz = 444 [M+H] +. HRMS m/z: calc. 444.0939, found 444.0953.

EXAMPLE 15

(3- {4- [3E- (4-Thiophen-2-yl-phenyl)-acryloyl]-phenyl}-ureido)-acetic acid ethyl ester A solution of 1- (4-amino-phenyl)-3- (4-thiophen-2-yl-phenyl)-propenone (Ex-12,250 mg, 0.80 mmol) and isocyanato-acetic acid ethyl ester (105.7 mg, 0.80 mmol) in toluene (15 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and the crude product precipitated out of solution. The material was suctioned filtered and dried on hi-vac to give 280.2 mg (79%) of the title compound as a yellow solid, mp 209-212°C.'H-NMR (DMSO-d6) 8 9.29 (br s, 1 H), 8.08 (d, 2H), 7.90 (m, 3H), 7.71 (d, 3H), 7.60 (m, 4H), 7.14 (t, 1H), 6.61 (t, 1H), 4.09 (q, 2H), 3.86 (dd, J= 2,6 Hz, 2H), 1.17 (t, 3H). MS m/z = 435 ([M+H] +, 100%). HRMS m/z: calc. 435.1378, found 435.1375.

EXAMPLE 16 (3- [Ethoxycarbonylmethylaminocarbonyll-3-14- [3E- (3, 4-dimethoxy-5-thiophen-2-yl- phenyl)-acryloyl]-phenyl}-ureido)-acetic acid ethyl ester A solution of 1- (4-aminophenyl)-3E- [ (3, 4-dimethoxy-5- (thien-2-yl) phenyl]-propenone (Ex-11, 500 mg, 1.37 mmol) and ethyl isocyanatoacetate (177 mg, 1.37 mmol) in anhydrous methylene chloride (20 mL) was stirred at room temperature for 5 hours. Due to no reaction, the reaction mixture was concentrated, diluted with toluene (20 mL), treated with ethyl isocyanatoacetate (177 mg, 1.37 mmol), and refluxed for 14 hours. The reaction was concentrated, diluted with

methylene chloride (50 mL), and washed with water (3 x 50 mL). The organic portion was collected, dried over sodium sulfate, and concentrated over silica gel. The crude material was purified by silica gel chromatography (50-75% ethyl acetate/hexanes) to give 178.0 mg (21%) of the title compound as a yellow solid, mp 83-86'C.'H-NMR (CDC13) 8 8.09 (d, 2 H), 7.76 (d, 1H), 7.55 (m, 2H), 7.65 (d, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.11 (m, 2H), 4.17 (q, 4H), 4.01 (d, 4H), 3.97 (s, 3H), 3.88 (s, 3H). MS m/z= 646 ([M+Na] +, 100%). Anal. calculated for C3lH33N309S : C, 59.70, H, 5.33, S, 5.14 ; found C: 60.18, H: 5.38, S: 5.17.

EXAMPLE 17 4- [3- {4- (thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid, sodium salt Ex-17A: 4'-Bromoacetophenone (3.98 g, 20 mmol) was dissolved in ethylene glycol dimethyl ether and then the solution was degassed with nitrogen for 15 minutes.

Tetrakis (triphenylphosphine) palladium (0) (2.31 g, 2 mmol) was added, and the solution was further degassed for 10 minutes. Thiophene-2-boronic acid (3.07 g, 24 mmol) was added followed by the addition of sodium carbonate solution (2 M, 45 mL). The mixture was stirred at reflux under nitrogen overnight. Most of the solvent was removed, and water was added to the remainder. The solid was filtered out and recrystallized from ethanol and water to give 3.85 g of the desired 4'- (thien-2-yl) acetophenone as a solid, 95% yield.'H-NMR (CDC13) 8. 7.97 (d, J = 9 dz, 2H), 7.70 (d, J = 9 Hz, 2H), 7.44 (d, J = 4 Hz, 1H), 7.38 (d, J = 5 Hz, 1H), 7.11-7. 14 (m, 1H), 2.62 (s, 3H). HMRS (EI) calcd. for Cl2HloOS : 202. 0452 ; found: 202.0454.

4'- (Thien-2-yl) acetophenone obtained from Ex-17A (0.81 g, 4 mmol) and 4- carboxybenzaldehyde (0.6 g, 4 mmol) were dissolved in dimethylformamide (20 mL). Sodium hydroxide solution (5 M, 3.2 mL) was added over 30 minutes at room temperature, and the mixture was stirred for another 30 minutes at room temperature. The precipitate was filtered off and recrystallized from hot water to give the title compound as a yellow solid, 29% yield, m. p.

>260 °C.'H-NMR (300 MHz, DMSO-d6) 6 8.17 (d, 2H), 7.89 (d, 1H), 7.87 (d, 2H), 7.81 (d, 2H), 7.76 (d, 2H), 7.72 (d, 1H), 7.69 (d, 1H), 7.64 (d, 1H), 7.17 (dd, 1H). Anal. calculated for C2oH, 303NaS'l/2H20 : C, 65.74 ; H, 3.86 ; S, 8.78, found: C, 65.66 ; H, 4.04 ; S, 9.04.

EXAMPLE 18

4- [3- {4- (thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid The title compound was prepared by acidifying its sodium salt from Ex-17. Yellow solid, mp 260-265°C, 67% yield.'H-NMR (DMSO-d6) 8 8.18 (d, J = 8Hz, 2H), 8.00 (d, J = 15 Hz, I H), 7.91-7. 94 (m, 4H), 7.82 (d, J = 8 Hz, 2H), 7.77-7. 79 (m, 1H), 7.71 (d, J = 3Hz, 1H), 7.66 (d, J =5 Hz, 1H), 7.16-7. 19 (m, 1H), MS nilz = 334 ([M]+, 100%). HRMS (EI) Calcd. for C20Hl403S : 334.0664. Found: 334.0669.

EXAMPLE 19

'4- [3- (2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoic acid- Ex-19A : 1-(2-Methoxy-4-thiophen-2-yl-phenyl)-ethanone was prepared from 4-iodo-2- methoxyacetophenone in a similar manner as described in Ex-17A.'H-NMR (CDC13) 8 7.53 (d, J = 7 Hz, 1H), 7.37 (dd, J = 2,5 Hz, IH), 7.06 (dd, J = 4,6 Hz, 1H), 6.98-7. 00 (m, 1H), 6.88-6. 95 (m, 2H), 3.84 (s, 3H), 2.10 (s, 3H).

The title compound was prepared by condensing 1- (2-methoxy-4-thiophen-2-yl-phenyl)- ethanone (Ex-19A) and 4-carboxybenzaldehyde in a similar manner as described in Ex-17

except an acidic workup. Yellow solid, mp 193-195°C. H-NMR (CDC13) 7. 70 (d, J = 8Hz, 2H), 7.38 (d, J = 8 Hz, 1H), 7.07-7. 16 (m, 4H), 6.75-6. 80 (m, 4H), 6.42 (d, J = 16 Hz, 1H), 3.67 (s, 3H), MS m/z = 364 ([M] +, 100%). Anal. Calculated for C2lHs604S : C, 69.21 ; H, 4.43 ; S, 8.80 ; found: C, 69.02 ; H, 4.56 ; S, 8.75.

EXAMPLE 20 4- [3E- (4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-20A: A solution of 3-bromo-4-flouro-benzaldehyde (5.0 g, 24.6 mmol) and thiophene-2- boronic acid (4.7 g, 37.0 mmol) in ethylene glycol dimethyl ether (100 mL) was stirred at room temperature under nitrogen for 15 min. Then tetrakis (triphenylphosphine)-palladium (0) (2.8 g, 2.42 mmol) and a sodium carbonate solution (2 M, 33 mL) were added, and the resulting mixture was refluxed under nitrogen overnight. Upon cooling to room temperature the reaction was poured into water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure.

Silica gel chromatography (hexane/ethyl acetate, 1 : 1) gave 4.8 g (95%) of the desired 4-fluoro- 3- (thiophen-2-yl)-benzaldehyde product as a yellow oil.'H-NMR (300 MHz, CDCl3) 8 10.0 (s, 1H), 8.18 (dd, 1H, J= 7.3 and 2.4 Hz), 7.80 (m, 1H), 7.56 (dd, 1H, J= 3.7 and 1.7 Hz), 7.44 (d, IH, J= 5. 1 Hz), 7.36 (m, 1H), 7.16 (dd, 1H, J= 5.1 and 3.7 Hz).

Ex-20B: A solution of 4-fluoro-3-(thiophen-2-yl)-benzaldehyde (1. 11 g, 5. 38 mmol) from Ex- 20A and pyrrolidine (13.0 g, 183.0 mmol) in dimethylformamide (30 mL) was treated with solid K2CO3 (1.7 g, 12.3 mmol), and the resulting mixture was stirred at reflux for 1 week.

Upon cooling to room temperature, the reaction was poured into water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate,

2: 1) gave 400 mg (29%) of the desired 4-pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde product as a yellow oil. 'H-NMR (300 MHz, CDC13) 8 9.75 (s, 1H), 7.71-7. 74 (m, 2H), 7.30 (dd, IH, J=5. 1 and 1. 6 Hz), 7.02 (dd, IH, J= 5. 1 and 3. 7 Hz), 6.96 (m, 1H), 6.81 (d, IH, J= 10.1 Hz), 3.15 (m, 4H), 1. 84 (m, 4H).

4-Pyrrolidin-1-yl-3- (thiophen-2-yl)-benzaldehyde (400 mg, 1. 55 mmol) from Ex-20B and 4- acetylbenzoic acid (255 mg, 1.55 mmol) were dissolved in dimethylformamide (30 mL).

Sodium hydroxide solution (5 N, 1.25 mL) was added in one portion, and the mixture was stirred at room temperature overnight. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was acidified with conc. HCI and extracted with ethyl acetate (2 X 100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Silica gel chromatography (100% ethyl acetate) followed by recrystallization from ethanol provided 80 mg (13%) of the title compound as a solid, m. p. 212-214°C with decomposition.'H-NMR (300 MHz, CDC13) 8 8.21 (d, 2H, J= 8. 4 Hz), 7.06 (d, 2H, J= 8. 4 Hz), 7.80 (d, 1 H, J= 15.3 Hz), 7.58 (d, 1H, J= 1. 9 Hz), 7.52 (dd, 1H, J= 8.5 and 1.9 Hz), 7. 33 (m, 1H), 7.32 (d, 1H, 15. 3 Hz), 7.01-7. 06 (m, 2H), 6.82 (d, 1H, 7.9 Hz), 3.12 (m, 4H), 1.84 (m, 4H). MS m/z = 403 ([M]+, 100%). HRMS (EI) Calcd. for C24H2lNO3S : 403.1242. Found: 403. 1251.

EXAMPLE 21 4- [3E- {4-Fluoro-3- (thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid 4-Fluoro-3-thiophen-2-yl-benzaldehyde (1.0 g, 4.85 mmol, from Ex-20A) and 4-acetylbenzoic acid (0.80 g, 4.87 mmol) were dissolved in dimethylformamide (55 mL). Sodium hydroxide solution (5 N, 3.88 mL) was added in one portion, and the mixture was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and washed with ethyl

acetate (100 mL). The aqueous phase was acidified with conc. HCI and extracted with ethyl acetate (2 X 100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethanol provided 0.90 g (53%) of the title compound as a solid, m. p. 242-244 °C.'H-NMR (300 MHz, d6-DMSO) 5 13.31 (bs, 1H), 8.32 (dd, 1H, J= 8. 2 and 2.0 Hz), 8.24 (d, 2H, J= 8.2 Hz), 8.07 (d, 2H, J=7. 9 Hz), 7.98 (d, 1H, J= 16.1 Hz), 7.92 (m, 1H), 7.80 (d, 1H, J= 16.1 Hz), 7.69-7. 73 (m, 2H), 7.41 (dd, 1H, 10.8 and 9.2 Hz), 7.20 (m, 1H). MS m/z = 352 ([M]+, 50%), 343 (100%). HRMS (EI) Calcd. for C20Hl3FO3S : 352.0569. Found: 352.0571.

EXAMPLE 22 1- (4-Mercapto-phenyl)-3E- (4-thiophen-2-yl-phenyl)-propenone To a solution of 4-mercaptoacetophenone (prepared according to European Patent Application 0271307) (0.57 g, 3.74 mmol) and 4- (thien-2-yl)-benzaldehyde (0.70 g, 3.74 mmol, Ex. 2A) in N, N-dimethylformamide (20 mL) was added a solution of sodium hydroxide (5 M, 3 mL). The solution was allowed to stir at room temperature for 3 h. The reaction mixture was then acidified with hydrochloric acid (0. 5 M) to pH 3. The precipitate was collected by filtration, washed with water, and stirred in ethanol overnight. The resulting yellow solid was collected by filtration, washed with ethanol, and dried in vacuo to afford 0.68 g (56%) of the title compound as a solid, m. p. > 110 °C (dec). MS (direct probe) mlz = 322 (M).'H-NMR (CDC13) 8 7.98-8. 01 (d, 1H), 7.90-7. 93 (d, 1H), 7.79-7. 84 (d, 2H), 7.61-7. 66 (m, 3H), 7.33- 7.53 (m, 4H), 7.10-7. 25 (m, 2H).

EXAMPLE 23

{4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-phenylthio}-acetic acid Ex-23A: To a solution of methyl bromoacetate (1.01 mL, 10.7 mmol) in potassium hydroxide (5M, 20 mL) was added benzenethiol (1.0 mL, 9.7 mmol). The reaction mixture was allowed to stir overnight at ambient temperature. The cloudy solution was then acidified to pH 3. The resulting solid was filtered, washed with water and dried in vacuo to obtain phenylthioacetic acid (0.55g). The aqueous filtrate was extracted with dichloromethane. The solution of dichloromethane was washed with brine, dried over sodium sulfate and concentrated to obtain additional phenylthioacetic acid (1. 49g).'H NMR (CDC13) 8 743-7.40 (m, 2H), 7.34-7. 23 (m, 3H), 3.67 (s, 2H).

Ex-23B: To a mixture of alumina chloride (5. 5g, 41. 0 mmol) in carbon disulfide (100mL) was added acetyl chloride (1.17 mL, 16.5 mmol) followed by addition of phenylthioacetic acid (Ex- 23A, 1.38g, 8.2 mmol) and nitromethane (15 mL). The reaction mixture was allowed to stir overnight at ambient temperature and then was poured into ice containing sulfuric acid (6M).

The insoluble solid was filtered, washed with water. After dried in vacuo, the solid was washed with toluene (2 x 60 mL), filtered and dried under reduced pressure to obtain (4- acetylphenylthio) acetic acid (1.28 g, 74%), m. p. 151-153 °C (Lit. 156-158 °C).'H NMR (DMSO-d6) 8 12.80 (bs, 1H), 7.84 (d, J = 9 Hz, 2H), 7.36 (d, J = 9 Hz, 2H), 3.92 (s, 2H), 2.49 (s, 3H).

The title compound was prepared by condensing (4-acetylphenylthio) acetic acid (Ex-23B) and 5- (benzo [b] thien-2-yl) -2,4-dimethoxybenzaldehyde (Ex-3A) in a similar manner as described

in Ex-22. Yellow solid, mp 136-138 °C (dec.). IH-NMR (DMSO-d6) 6 8. 35 (s, 1H), 8.08 (d, J = 7.4 Hz, 2H), 8.03 (d, J = 16. 3 Hz, 1H), 7.93-7. 87 (m, 3H), 7.82 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.37-7. 27 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.93 (s, 2H). MS m/z = 491 ([M+H]+, 100%).

EXAMPLE 24

1- (4-Methylthiophenyl)-3E- (4-thiophen-2-yl-phenyl)-propenone To a mixture of 1- (4-mercapto-phenyl)-3E- (4-thien-2-yl-phenyl)-proenone (Ex-22,0. 33g, 1.02 mmol) and potassium carbonate (0.54g, 3.9 mmol) in N, N-dimethylformamide (15 mL) was added iodomethane (0.32 mL, 5.1 mmol). The reaction mixture was allowed to stir at ambient temperature for 2 hours. The insoluble material was filtered. The solution was diluted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0.5 M), sodium carbonate (2M) and brine, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave the title compound (20 mg, 6%) as a yellow solid, mp 138-140 °C.'H-NMR (CCD13) 8 7.98 (d, J = 7.8 Hz, 2H), 7.89-7. 86 (m, 1H), 7.83 (d, J = 15. 3 Hz, 1H), 7.76 (s, 3H), 7.53 (d, J = 15. 1 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H), 7.35-7. 31 (m, 3H), 7.13-7. 10 (s, 1H), 2.54 (m, 3H). MS m/z= 336 (M+, 100%).

EXAMPLE 25

Difluoro- {4- [3E- (4-thiophen-2-yl-phenyl)-acryloyl]-phenylthio}-acetic acid, sodium salt

Ex-25A: To a solution of 4-mercaptoacetophenone (prepared according to published procedure, European Patent Application 0271307) (1.16g, 7.6 mmol) and ethyl bromodifluoroacetate (1.2 mL, 9.15 mmol) in N, N-dimethylformamide (20 mL) was added potassium carbonate (3.2g, 22.9 mmol). The reaction mixture was allowed to stir overnight at ambient temperature and then was diluted with ethyl acetate. The combined solution of ethyl acetate was subsequently washed with water, hydrochloric acid (0. 5M), brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave (4-acetyl-phenylthio) -difluoro-acetic acid ethyl ester (1.38g, 66%).

'H NMR (CDC13) 8 7. 97 (d, J = 8 Hz, 2H), 7.90 (d, J = 8 Hz, 2H), 4.29 (q, J = 7 Hz, 2H), 2.62 (s, 3H), 1.29 (t, J = 7 Hz, 3H).

The title compound was prepared by condensing (4-acetyl-phenylthio) -difluoro-acetic acid ethyl ester (Ex-25A) and 4- (thien-2-yl) benzaldehyde (Ex-2A) in a similar manner as described in Ex-22. Yellow solid, 3% yield, mp 118-220 °C. IH-NMR (CCDI3) 6 8.11 (d, J = 7. 9 Hz, 2H), 7.95-7. 90 (m, 3H), 7.75-7. 70 (m, 3H), 7.66 (m, 3H), 7.59 (d, J = 5. 0 Hz, 1H), 7.16-7. 13 (m, 1H). MS m/z = 415 ( [M-Na] +, 50%), 321 (100%).

EXAMPLE 26 4- [3E- (4-Thiophen-2-yl-phenyl)-acryloyl]-benzenesulfonamide Ex-26A: To a solution of 4-acetyl-benzenesulfonyl chloride (Hoffinan, R. V. Org. Syn. VII, 508; 4. 18g, 19. 1 mmol) in acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 min. The precipitate was filtered and the residue was washed with water and dried in vacuo to afford 4- acetyl-benzenesulfonamide as a white solid (3.54g, 93%). lH NMR (DMSO-d6) 6 8.10 (d, J = 9 Hz, 2H), 8.03 (d, J = 9 Hz, 2H), 4.86 (bs, 2H), 2.65 (s, 3H).

To a solution of 4-acetyl-benzsulfonamide (Ex-26A, 0.44g, 2.2 mmol) and 4-thiophen-2-yl- benaldehde (Ex-2A, 0. 50g, 2.7 mmol) in DMF (18 mL) was added a solution of NaOH (5 M, 1.77 mL, 8.8 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature. The reaction was quenched after 2 hours with water. The precipitate was filtered, washed with water, dried in vacuo and purified by stirring in aqueous ethanol overnight. The title compound was collected as a yellow solid (0.45g, 55%), mp >245 °C.'H-NMR (DMSO- d6) 8 8.22 (d, J = 8.6 Hz, 2H), 7.96-7. 89 (m, 6H), 7.77-7. 72 (m, 5H), 7.64 (d, J = 4.0 Hz, 1H), 7.60 (d, J = 4.6, 1H), 7. 15 (m, 1H), 6.65 (bs, 1H). MS m/z = 369 ( [M + H] +, 100%).

EXAMPLE 27 3E-(3, 4-Dimethoxy-5-thiophen-2-yl-phenyl>1-(lH-indol-5-yl)-prop enone To a solution of 1-(1H-indol-5-yl)-ethanone (Yang, Y. , et al., Heterocycles, 1992,34 (6), 1169- 1175) (0.26 g, 1.63 mmol) and 3, 4-dimethoxy-5- (thien-2-yl)-benzaldehyde (0.45 g, 1.80 mmol, Ex-lD) in ethanol (30 mL) was added a solution of sodium hydroxide (50%, 0.65 mL, 16 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solution was concentrated. The residue was treated with sulfuric acid (1 M), and the cloudy solution was extracted with dichloromethane. The combined dichloromethane extracts were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc/hexane: 1/3 then 1/1) to give 0.17 g (26%) of the title compound as a yellow solid, m. p. 184. 5-186 °C. MS (direct probe): m/z = 389 (MF). IH-NMR (300 MHz, CDCl3) 8 8.43 (s, 1H), 7.99 (d, 1H), 7.12-7. 83 (m, 10H), 6.73 (s, 1H), 3.99 (s, 3H), 3. 88 (s, 3H).

EXAMPLE 28

3E- (3, 4-Dimethoxy-5-thiophen-2-yl-phenyll- (l-methyl-lH-indol-5-yl)-propenone Ex-28A: To a solution of 1-(1H-indol-5-yl)-ethanone (Yang, Y. et al, Heterocycles, 1992, 34 (6), 1169-1175 ; 0.45g, 2.8 mmol) were added iodomethane (3 mL) and cesium carbonate (2.3g, 7.1 mmol). The reaction mixture was allowed to stir at 55 °C for 1.5 day during which additional iodomethane (11 mL) was added. The reaction was quenched with water. The aqueous solution was extracted with ether. The solution of ether was washed with saturated solution sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave 1-(1-methyl-1H-indol-5-yl)-ethanone (0.25g, 51%).'H NMR (CDC13) 8 8.30 (s, 1 H), 7.91 (dd, J = 1.2, 8.1 Hz, 1 H), 7.34 (d, J=8. 6Hz, lH), 7.12 (d, J=3. 2Hz, IH), 6.61 (d, J = 3.0, 1H), 3.82 (s, 3H), 2.66 (s, 3H).

The title compound was prepared by condensing 1-(1-methyl-lH-indol-5-yl)-ethanone (Ex- 28A) and 3, 4-dimethoxy-5-(thien-2-yl) benzaldehyde (Ex-lD) in a similar manner as described in Ex-27. Yellow solid, 43% yield, mp 70-71 °C. IH-NMR (CDCI3) 6 8.41 (s, 1H), 8.00 (dd, J = 1 Hz, 7 Hz, IH), 7.80 (d, J = 15 Hz, tH), 7.63 (d, J=15. 0 Hz, 1H), 7.58-7. 55 (m, 2H), 7.43- 7.40 (m, 2H), 7.15-7. 12 (m, 3H), 6.66 (d, J = 3 Hz, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H).

Anal. (C24H21NOS#0.25H2O) Calc. C 70.65, H 5.31, N 3.43, S 7.86, found C 70.64, H 5.35, N 3.43, S 7.90.

EXAMPLE 29

4- (3E- {4-Methoxy-2- [2- (2-methoxyethoxy) ethoxy] -5-thiophen- 2-yl-phenyl}-acryloyl)-benzoic Acid Ex-29A: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 °C using an ice-water bath. Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise to the cooled solution and stirred for 2 h at 0 °C. The mixture was warmed to room temperature and stirred for an additional 1 h and the resulting yellow precipitate was collected. Recrystallization (ethyl acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, m. p. 63-64 °C.'H- NMR (300 MHz, CDC13) 5 11.43 (s, 1 H), 9.69 (s, 1 H), 7.68 (s, 1 H), 6.48 (s, 1 H), 3.95 (s, 3 H). Anal. Calcd. for C8H7BrO3 : C, 41.59 ; H, 3.05. Found: C, 41.86 ; H, 3.05.

Ex-29B: 5-Bromo-2-hydroxy-4-methoxybenzaldehyde obtained from Ex-29A (1.5 g, 6.5 mmol) and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis (tri-t-butylphosphine) palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60 °C and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1: 3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde as a yellow solid, m. p.

118-119 °C.'H-NMR (300 MHz, CDC13) 6 11.48 (s, 1 H), 9.79 (s, 1 H), 7.72 (s, 1 H), 7.37 (dd, 1 H), 7.31 (dd, 1 H), 7.08 (dd, 1 H), 6.54 (s, I H), 3.98 (s, 3 H). Anal. Calcd. for C8H703S : C, 61.52 ; H, 4.30 ; S, 13.69. Found: C, 61.12 ; H, 4.34 ; S, 13.56.

Ex-29C: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde from Ex-29B (0. 10 g, 0.43 mmol) in N, N-dimethylforrnamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80°C. Once at 80 °C, 1-bromo-2-(2- methoxyethoxy) ethane (0.24 g, 1.3 mmol) was added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80 °C and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1 x 15 mL), water (1 x 15 mL), and brine (1 x 15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 4: 1) afforded 0.13 g (87%) of 4-methoxy-2- [2- (2- methoxyethoxy) ethoxy] -5-thiophen-2-yl-benzaldehyde as a pale yellow oil.'H-NMR (300 MHz, CDC13) 6 10.38 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H), 7.30 (dd, 1 H), 7.07 (dd, 1 H), 6.57 (s, 1 H), 4.33 (t, 2 H), 4.00 (s, 3 H), 3.94 (t, 2 H), 3.74m, 2 H), 3.59 (m, 2 H), 3.40 (s, 3 H).

HRMS (El) Calcd. for Cl7H20OsS : 336.1031. Found: 336.1027.

4-Methoxy-2- [2- (2-methoxyethoxy) ethoxy] -5-thiophen-2-yl-benzaldehyde obtained from Ex- 29C (0.13 g, 0.37 mmol) and 4-acetylbenzoic acid (0.061 g, 0.37 mmol) were dissolved in a tetrahydrofuran-methanol solution (2 mL, 7: 3). After complete dissolution, lithium methoxide (0.057 g, 1.5 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (3 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected and dried in vacuo to yield 0.14 g (85%) of the title compound as a yellow solid, m. p. 145-146 °C.'H-NMR (300 MHz, DMSO-d6) 8 8.22 (m, 3 H), 8.09 (d, 2 H), 8.01 (d, 2 H), 7.66 (dd, 1 H), 7.52 (d, 1 H), 7.13 (dd, 1 H), 6.88 (s, 1 H), 4.36 (t, 2 H), 4.00 (s, 3 H), 3.88 (t, 2 H), 3.65 (m, 2 H), 3.46 (m, 2 H), 3.22 (s, 3 H). Anal. Calcd. for C26H26NO7S : C, 64. 71 ; H, 5.43 ; S, 6.64. Found: C, 64.64 ; H, 5.44 ; S, 6. 61.

EXAMPLE 30

4- [3E- (2-Fluoro-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-30A: 2-Fluoro-4-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-3A from thiophene-2-boronic acid and 4-bromo-2-fluorobenzaldehide (93% yield). IH-NMR (300 MHz, d6-DMSO): 10.13 (s, I H), 7.81 (d, 1 H, J= 8.0 Hz), 7.76 (m, 1 H), 7.67 (m, 2 H), 7.59 (dd, 1 H J = 8.0 and 2. 1 Hz), 7.17 (dd, 1 H J = 5.2 and 3.7 Hz).

The title compound was prepared by condensing 2-fluoro-4-thiophen-2-yl-benzaldehyde (Ex- 30A) and 4-acetylbezoic acid in a similar manner as described in Ex-3. Yellow solid, 71% yield, m. p. >260°C.'H-NMR (300 MHz, d6-DMSO) : 8.19 (d, 2 H, J= 8.4 Hz), 8.12 (d, 1 H, J = 8 Hz), 8.06 (d, 2 H, J = 8 Hz), 7.95 (d, 1 H, J= 16 Hz), 7.80 (d, I H, J = 16 Hz), 7.71 (d, 1 H, J= 3.5 Hz), 7.62 (m, 2 H), 7.56 (d, 1 H, J= 8 Hz), 7.15 (m, 1 H). MS mlz = 352 ([M]+, 100%).

HRMS (EI) Calcd. for C20Hs3NO3S : 352.0569. Found: 352.0560.

EXAMPLE 31 4- [3E- (2, 4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid Ex-31A: 2, 4-Dimethoxy-5-pyrimidin-5-yl-benzaldehyde was prepared from 5-bromo-2,4- dimethoxybenzaldehyde and pyrimidine-5-boronic acid in a similar manner as described in Ex- 3A, 98% yield. 1H-NMR (CDCl3) # 10.37 (s, 1H), 9.15 (s, 1H), 8.87 (s, 2H) 7.86 (s, 1H), 6.57 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H).

The title compound was prepared by condensing 2,4-dimethoxy-5-pyrimidin-5-yl- benzaldehyde (Ex-31A) and 4-acetylbezoic acid in a similar manner as described in Ex-3.

Yellow solid, mp >260°C, 26% yield. 1H-NMR (DMSO-d6) 8 9.11 (s, 1H), 8.96 (s, 2H), 8.13- 8.16 (m, 3H), 8.01-8. 09 (m, 3H), 7.90 (d, J = 15 Hz, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3. 91 (s, 3H), MS m/z = 391 [(M+H]+, 100%). HRMS (ES+) Calcd. for C22HlgN205 : 391.1294. Found: 391.1295.

EXAMPLE 32 4- [3E- (2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acry loyl]-benzoic acid Ex-32A: 2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-29C from 2-hydroxy-4-methoxy-5-thiophen-2-yl- benzaldehyde (Ex. 29B) and chloromethyl-cyclopropane, 18% yield.'H-NMR (CDC13) 8 10. 41 (s, 1 H), 8.24 (s, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 7.06 (t, 1H), 6.45 (s, 1H), 3.95 (m, 5H), 1.31 (m, 1H), 0.68 (m, 2H), 0.40 (q, 2H).

The title compound was prepared by condensing 2-cyclopropylmethoxy-4-methoxy-5- thiophen-2-yl-benzaldehyde (Ex-32B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 187-191°C. 1H-NMR (DMSO-d6) 8 8.22 (d, 2H), 8.19 (s, 1H), 7.01 (m, 4H), 7.62 (d, 1H), 7.47 (d, 1H), 7.09 (t, 1H), 6.76 (s, 1H), 4.06 (d, 2H), 3.94 (s, 3H), 1.34 (m, 1H), 0.62 (q, 2H), 0.38 (q, 2H). MS m/z = 434 ( [M] +, 82%), 363 (100%). 10 %.

Anal. for C25H22OsS. HRMS m/z: calc. 435.1266, found 435.1266.

EXAMPLE 33

4- {3E- [5- (3, 5-Dimethyl-isoxazol-4-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid Ex-33A: 5- (3, 5-Dimethyl-isoxazol-4-yl)-2, 4-dimethoxy-benzaldehyde was prepared from 5- bromo-2, 4-dimethoxybenzaldehyde and 3,5-dimethyl-isoxazole-4-boronic acid in a similar manner as described in Ex-3A, 75% yield. lH-NMR (CDCI3) 6 10.34 (s, 1H), 7.63 (s, 1H), 6.52 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 2.12 (s, 6H).

The title compound was prepared by condensing 5- (3, 5-dimethyl-isoxazol-4-yl)-2, 4- dimethoxy-benzaldehyde (Ex-33A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp >260°C, 7% yield.'H-NMR (DMSO-d6) 8 8.15 (d, J = 8 Hz, 2H), 8.04 (d, J = 16 Hz, 1H), 8.02 (d, J = 8 Hz, 2H), 7.89 (s, IH), 7. 81 (d, J = 16 Hz, 1H), 6.79 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.23 (s, 3H) 2.05 (s, 3H) MS Sz = 407 ([M]+, 60%), 376 (100%). HMRS (EI) calcd. for C23H21NO6 : 407.1369 ; found: 407.1375.

EXAMPLE 34 4- [3E- (4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-34A: A solution of 2-hydroxy-4-methoxy-benzaldehyde (5.0 g, 32.86 mmol) in dichloromethane (65 mL) was cooled to 0 °C and then pyridine (13.3 mL, 164.4 mmol) was added in 1 portion. Triflic anhydride (14.8 mL, 87.97 mmol) was then added over 2 h while

maintaining an internal temperature below 5 °C. The resulting solution was allowed to warm to room temperature overnight and then was slowly poured into ice water (100 mL). After diluting further with 1 N HCI (100 mL) the solution was extracted with dichloromethane (2 X 100 mL). The organic phase was washed with sat NaHC03 (100 mL) and dried over magnesium sulfate. The solvent was then removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 1: 1) gave 1.65 g (18%) of the desired trifluoro- methanesulfonic acid 2-formyl-5-methoxy-phenyl ester.'H-NMR (300 MHz, CDC13) : 10.12 (s, 1 H), 7.94 (dd, 1 H, J= 8. 7 Hz), 7.03 (dd, 1 H, J= 8.7 and 2.4 Hz), 6. 87 (d, I H, J= 2.4 Hz), 3.92 (s, 3 H).

Ex-34B: A solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (Ex- 34A, 1.6 g, 5.63 mmol) in 1,4-dioxane (15 mL) was stirred at room temperature under nitrogen for 5 min. Thiophene-2-boronic acid (1.08 g, 8.44 mmol), tetrakis (triphenylphosphine)- palladium (0) (0.65 g, 0.56 mmol) and a potassium phosphate (2.2 g, 10.36 mmol) were then added and the resulting mixture was heated to 95 °C under nitrogen overnight. Upon cooling to room temperature the reaction was diluted with EtOAc (25 mL) and water (25 mL) and the layers were cut. The organic phase was concentrated under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 4: 1) gave 1.1 g (90%) of the desired 4-methoxy-2- thiophen-2-yl-benzaldehyde product.'H-NMR (300 MHz, CDCl3) : 10.06 (s, 1H), 8.03 (m, 1H), 7.45 (m, 1H), 7.14 (m, 1H), 7.09 (m, 1H), 7.00 (m, 2 H), 3.91 (s, 3H).

The title compound was prepared by condensing 4-methoxy-2-thiophen-2-yl-benzaldehyde (Ex-34A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 61% yield, m. p. 209-211°C. lH-NMR (300 MHz, d6-DMSO): 8.14 (m, 3 H), 8.04 (d, 2 H, J= 9. 2 Hz), 7.89 (d, 1 H, J = 15. 5 Hz), 7.76 (d, 1 H, J = 15. 5 Hz), 7.70 (d, 1 H, J=5.0 Hz), 7.18 (dd, 1 H, J=5.6 and 3.6 Hz), 7.11 (d, 1 H, J = 2. 1 Hz), 7.05 (dd, 1 H, J=8.8 and 1. 8 Hz), 6.98 (d, 1 H, J= 1.8 Hz), 3.83 (s, 3 H). MS m/z = 364 ([M]+, 100%). HRMS (EI) Calcd. for C21Hl604S : 364.0769. Found: 364.0761.

EXAMPLE 35

2- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid The title compound was prepared by condensing 2, 4-dimethoxy-5- (thiophen-2-yl)- benzaldehyde (Ex-6A) and 2-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, 47 % yield, mp 196-198°C.'H-NMR (DMSO-d6) 8 8.00 (s, 1H), 7.84 (d, 1H), 7.61 (m, 3H), 7.45 (m, 3H), 7.21 (d, 1H), 7.08 (t, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H).

MS m/z = 394 ([M]+, 100%). Anal. calculated for C22H1805S : C, 66.99, H, 4.60, S, 8.13 ; found C: 67.08, H: 4.17, S: 7.97.

EXAMPLE 36 2- {5- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl}-indole-1- carboxylic acid tert-butyl ester Ex-36A: 2-(5-Formyl-2,4-diemthoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester was prepared from 5-brom-2, 4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as described in Ex-3A. Yellow oil, 79% yield.'H-NMR (CDC13) 8 10. 36 (s, 1H), 8.15 (d, J = 8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J = 8 Hz, 3H), 7.27-7. 35 (m, 1H), 7.19-7. 27 (m, IH), 6.52 (s, 1H), 6.47 (s, IH), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).

The title compound was prepared by condensing 2- (5-formyl-2, 4-dimethoxy-phenyl)-indole-1- carboxylic acid tert-butyl ester (Ex-36A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 8% yield, mp 182-183°C. 1H-NMR (CDCl3) # 8.21 (d, J = 8 Hz, 2H), 8.19 (d, J = 13 Hz, 1H), 8.16 (d, J = 7 Hz, 1H), 8.07 (d, J = 8 Hz, 2H), 7.69 (s, 1H), 7.54 (d, J = 7 Hz, 1H), 7.52 (d, J = 13 Hz, 1H), 7.29-7. 35 (m, 1H), 7.23 (d, J = 7 Hz, 1H), 6.55 (s, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H). MS m/z= 528 ([M+H]+, 100%).

Anal. calc. for C31H29NO7H2O : C, 68.25 ; H, 5.73 ; N, 2.56 ; found: C, 68.63 ; H, 5.62 ; N, 2.45.

EXAMPLE 37 4- [3E- (2, 6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-37A: 2, 6-Dimethoxy-4-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-34A and Ex-34B. 75% yield, m. p. 168-170°C.'H-NMR (300 MHz, CDCl3) : 10.48 (s, 1 H), 7.43 (dd, 1 H, J= 3.6 and 1.3 Hz), 7.41 (d, 1 H, J= 5.3 Hz), 7.13 (dd, 1 H, J= 5. 3 and 3. 6 Hz), 6.79 (s, 2 H), 3.96 (s, 6 H).

The title compound was prepared by condensing 2,6-dimethoxy-4-thiophen-2-yl-benzaldehyde (Ex-37A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 79% yield, m. p. 256-258°C.'H-NMR (300 MHz, d6-DMSO): 8.11 (d, 1 H, J= 15.9 Hz), 8.10 (m, 4 H), 8.05 (d, 1 H, J = 15.9 Hz), 7.73 (d, 1 H, J= 3.6 Hz), 7.61 (d, 1 H, J= 5.3 Hz), 7. 16 (dd, 1 H, J= 5. 3 and 3.6 Hz), 6.95 (s, 2 H), 3.98 (s, 6 H). MS nzlz = 394 ([M]+, 100%). HRMS (EI) Calcd. for 228058 : 394.0875. Found: 394.0877.

EXAMPLE 38

4- {3E- [5- (2, 4-Dimethoxy-pyrimidin-5-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid Ex-38A: 5- (2, 4-Dimethoxy-pyrimidin-5-yl)-2, 4-dimethoxy-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 2,4-Dimethoxy-pyrimidin-5-boronic acid in a similar manner as described in Ex-3A, 75% yield.'H-NMR (CDC13) 6 10.34 (s, 1H), 8.13 (s, IH), 7.74 (s, 1H), 6.51 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.95 (s, 3H), 3.88 (s, 3H).

The title compound was prepared by condensing 5- (2, 4-dimethoxy-pyrimidin-5-yl) -2,4- dimethoxy-benzaldehyde (Ex-38A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 203-205°C, 22% yield.'H-NMR (DMSO-d6) 8 8.11-9. 15 (m, 3H), 7.99-8. 06 (m, 3H), 7.88 (s, 1H), 7.76 (d, J = 17 Hz, 1H), 6.76 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H) 3.81 (s, 3H). MS m/z = 451 ([M+H] +). HRMS (ES+) Calcd. for C24H22N207 : 451.1505. Found: 451.1524.

EXAMPLE 39 4- [3E- (2, 4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-39A: 2, 4-Dimethoxy-6-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-34A, 40% yield. lH-NMR (CDCI3) 6 10.02 (s, 1 H), 7.40 (d, 1H), 7.07 (m, 2H), 6.58 (d, 1H), 6.50 (d, 1H), 3.93 (s, 3H), 3.89 (s, 3H).

The title compound was prepared by condensing 2,4-dimethoxy-6-thiophen-2-yl-benzaldehyde (Ex-39A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 61% yield, mp 231 °C (dec.). lH-NMR (DMSO-d6) 6 8.02 (d, 2 H), 7.93 (d, 2H), 7.73 (m, 3H), 7.15 (t, 1H), 7.07 (d, 1H), 6.72 (d, 1H), 6.62 (d, 1H). MS m/z=394 ([M]+, 6%), 245 (100%).

HRMS m/z: calc. 395.0953, found 395.0949.

EXAMPLE 40 4- {3E- [2, 4-Dimethoxy-5- (5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic acid Ex-40A: 2, 4-Dimethoxy-5- (5-methyl-thiophen-2-yl)-benzaldehyde was prepared from 5- bromo-2,4-dimethoxybenzaldehyde and 5-methyl-thiophene-2-boronic acid in a similar manner as described in Ex-3A, 100% yield.'H-NMR (CDC13) 8 10.33 (s, 1H), 8.05 (s, 1H), 7.22 (d, J = 4 Hz, 1 H), 6.72 (d, J = 4 Hz, 1 H), 6.49 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.50 (s, 3H). HMRS (EI) calcd. for C14H14O3S : 262.0664 ; found: 262.0665.

The title compound was prepared by condensing 2, 4-dimethoxy-5- (5-methyl-thiophen-2-yl)- benzaldehyde (Ex-40A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, mp 213-215°C, 27% yield.'H-NMR (DMSO-de) 8 8. 18 (d, J = 7 Hz, 2H), 8.17 (s, 1H), 8.00-8. 06 (m, 3H), 7.85 (d, J = 15Hz, 1H), 7.42 (d, J = 4 Hz, 1H), 6.78 (m, 2H), 3.96 (s, 3H), 3.95 (s, 3H), 2.42 (s, 3H). MS Hz = 408 ([M]+, 100%). HMRS (EI) calcd. for C23H20OsS : 408. 1031 ; found: 408.1023.

EXAMPLE 41

4- [3E- (4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-41A: 4-Methoxy-3-(thiophen-2-yl)-benzaldehyde was prepared from 3-bromo-4- methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex- 3A. Orange oil, 96% yield.'H-NMR (CDC) ) 5 9.94 (s, 1H), 8.16 (d, J = 1. 8 Hz, 1H), 7.80 (dd, J = 2. 4,8. 4 Hz, 1H), 7.57 (dd, J = 1. 8,3. 6 Hz, 1H), 7.38 (d, J = 5. 1 Hz, 1H), 7.12 (dd, J= 3. 6, 5.1 Hz, 1H), 7.09 (d, J = 8. 4 Hz, 1H), 4.02 (s, 3H). HRMS m/z : calc. 218.0402, found 218. 0406.

The title compound was prepared by condensing 4-methoxy-3- (thiophen-2-yl)-benzaldehyde (Ex-41A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 219-220°C, 71 % yield.'H-NMR (DMSO-D6) S 13.36 (br s, 1H), 8.25-8. 31 (m, 3H), 8.11 (d, J = 8 Hz, 2H), 7.85-7. 98 (m, 3H), 7.78-7. 80 (m, 1H), 7.61 (d, J= 5 Hz, 1H), 7.25 (d, J = 9 Hz, 1H), 7.17 (dd, J = 4,6 Hz, 1H), 3.99 (s, 3H). HRMS nzlz = calc. 365.0848, found 365.0833.

EXAMPLE 42 4- [3E- (3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-42A: 3- (Thiophen-2-yl)-benzaldehyde was prepared from 3-bromobenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. Orange oil, 93% yield. 'H-NMR (CDCI3) b 10.06 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 8. 4 Hz, 1H), 7.78 (d, J = 7. 2 Hz,

1H), 7.55 (dd, J = 7.2, 8.4 Hz, 1H), 7.40 (dd, J= 1.5, 3.6 Hz, 1H), 7.34 (dd, J = 1.5, 5.3 Hz, 1H), 7. 11 (dd, J = 3. 6,5. 3 Hz, 1H). HRMS m/z : calc. 188. 0296, found 188.0293.

The title compound was prepared by condensing 3- (thiophen-2-yl)-benzaldehyde (Ex-42A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238°C (dec), 71% yield.'H-NMR (DMSO-D6) 8 13.40 (bs, 1H), 8.29 (d, J = 8 Hz, 2H), 8.22 (s, 1H), 8.13 (d, J = 8 Hz, 2H), 8.04 (s, 1H), 7.87 (s, 1H), 7.83 (d, J = 8 Hz, 1H), 7.73 (d, J = 9 Hz, 1H), 7.69 (d, J = 4 Hz, 1H), 7.63 (d, J = 5 Hz, 1H), 7.52 (t, J = 8 Hz, 1H), 7,20 (dd, J = 4,5 Hz, 1H). HRMS m/z=calc. 335.0742, found 335.0749.

EXAMPLE 43 3- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid The title compound was prepared by condensing 2, 4-dimethoxy-5- (thiophen-2-yl)- benzaldehyde (Ex-6A) and 3-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, 65% yield, mp 179-182 °C.'H-NMR (DMSO-d6) 8 8.54 (s, I H), 8. 39 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.90 (d, 1H), 7.67 (m, 2H), 7.48 (d, 1H), 7.09 (t, 1H), 6.81 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H). MS milz = 394 ([M]+, 72%), 363 (100%). Anal. calculated for C22H1805S : C, 66.99, H, 4.60, S, 8.13 ; found C: 66.80, H: 4.60, S: 8.07.

EXAMPLE 44

4- [3E- (3-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid Ex-44A: 3-Benzo [b] thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde was prepared through Suzuki coupling as described in Ex-3A using 3-bromo-2-hydroxy-4-methoxybenzaldehyde (obtained as a minor product from Ex-29A). IH-NMR (CDCI3) 6 12.08 (s, 1H), 9.80 (s, IH), 7.80-7. 87 (m, 2H), 7.70 (s, 1H), 7.56 (d, J = 9 Hz, 1H), 7.31-7. 35 (m, 2H), 6.71 (d, J = 9 Hz, 1H), 3.97 (s, 3H). HRMS m/z : calc. 284.0507, found 284.0502.

Ex-44B: 3-Benzo [b] thiophen-2-yl-2-hydroxy-4-methoxy-benzaldehyde (Ex-44A, 57.4 mg, 0.202 mmol) was dissolved in acetone (5 mL) and potassium carbonate (31 mg, 0.22 mmol) was added. Methyl iodide (25 uL, 0.40 mmol) was added and the solution was heated to reflux for 3.5 h. After cooling, the crude reaction mix was concentrated on the rotavap. The resulting residue was taken up in 10 mL of a 1: 9 mix of saturated, aqueous NH4C1 to water and extracted with EtOAc (2x15 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to provide 58.5 mg of 3-benzo [b] thiophen-2-yl-2, 4-dimethoxy-benzaldehyde as an orange, oily residue which was used without further purification, 97% yield.'H-NMR (CDCl3) 8 10.31 (s, 1H), 7.92 (d, J = 9 Hz, 1H), 7.81-7. 88 (m, 2H), 7.56 (d, 1H), 7.33-7. 39 (m, 2H), 6. 88 (d, J = 9 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H).

The title compound was prepared by condensing 3-benzo [b] thiophen-2-yl-2,4-dimethoxy- benzaldehyde (Ex-44B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, mp 237°C (dec. ), 64% yield.'H-NMR (DMSO-d6) 8 13.37 (bs, 1H), 8.20-8. 25 (m, 3H), 8.11 (d, J = 8 Hz, 2H), 8.02 (d, J = 8 Hz, 1H), 7.96 (d, J = 9 Hz, 2H), 7.88-7. 91 (m, 1H), 7.65 (s, 1H), 7.35-7. 43 (m, 2H), 7.14 (d, J = 9 Hz, 1H), 3.90 (s, 3H), 3.53 (s, 3H). HRMS m/z = calc. 445. 1110, found 445.1112.

EXAMPLE 45

4- [3E- (2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-45A: 2-Methoxy-5- (thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2- methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex- 3A.'H NMR (CDCl3) S 10.49 (s, 1H), 8.07 (d, J = 3 Hz, 1H), 7.79 (dd, J = 3,9. 0 Hz, 1H), 7. 28-7. 26 (m, 2H), 7.09-7. 06 (m, 1H), 7.02 (d, J = 9 Hz, 1H), 3.97 (s, 3H).

The title compound was prepared by condensing 2-methoxy-5- (thiophen-2-yl)-benzaldehyde (Ex-45A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 195-196 °C.'H-NMR (DMSO-d6) 8 8.23-8. 20 (m, 3H), 8.08-7. 96 (m, 4H), 7.67 (dd, J = 2. 1, 6.8 Hz, 1H), 7.55 (d, J = 3.8 Hz, 1H), 7.49 (d, J = 5.1 Hz, 1H), 7.16-7. 11 (m, 2H), 3.90 (s, 3H).

MS m/z = 364 (MF, 100%).

EXAMPLE 46 4- [3E- (2, 4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid Ex-46A: 5-Bromo-2, 4-dimethoxybenzaldehyde (4.92 g, 20.1 mmol) was dissolved in benzene (41 mL). Ethylene glycol (3 mL, 54 mmol) and p-toluenesulfonic acid (25 mg, 0.13 mmol) were added and the solution was refluxed with a Dean-Stark trap attached. After 6 h, the reaction was cooled and washed with water (1x20 mL), saturated, aqueous NaHC03 (1x20

mL), and water (1x20 mL). The organic phase was dried over sodium sulfate, filtered, concentrated, and dried to provide 5.32 g of 2- (5-bromo-2, 4-dimethoxy-phenyl)- [1, 3] dioxolane as a faint yellow oil which solidified upon standing (92% yield).

'H-NMR (CDC13) 8 7.67 (s, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 4.11-4. 13 (m, 2H), 3.98-4. 03 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H). HRMS (ES+) Calcd. for CllHl3BrO4 : 289.0075. Found: 289.0077.

Ex-46B: 2- (5-Bromo-2, 4-dimethoxy-phenyl)- [1, 3] dioxolane (Ex-46A, 4.78 g, 10.5 mmol) was dissolved in dioxane (75 mL) and the solution was purged with nitrogen for 15 min. Pd (OAc) 2 (188 mg, 0.84 mmol), Et3N (6.91 mL, 49.6 mmol), and 2- (dicyclohexylphosphino) biphenyl (1.16 g, 3.31 mmol) were added. 4,4, 5, 5-Tetramethyl- (1, 3,2] dioxaborolane (3.6 mL, 24.8 mmol) was added slowly, accompanied by gas evolution and the darkening of the reaction solution. The solution was heated at reflux for 2.5 h and then cooled. Saturated, aqueous NH4CI (60 mL) and water (20 mL) were added and the solution extracted with EtOAc (1x100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a dark oil.

The oil was purified via silica gel chromatography (1: 1 EtOAc/hexanes after a column pre- wash of 5% Et3N in 1 : 1 EtOAc/hexanes) to provide 3.27 g of 2- (5- [1, 3] dioxolan-2-yl-2,4- dimethoxy-phenyl) -4,4, 5, 5-tetramethyl- [1, 3,2] dioxaborolane as a yellow solid (with some starting borolane present), 59% yield.'H-NMR (CDC13) 8 7.85 (s, 1H), 6.39 (s, 1H), 6.07 (s, 1H), 4.13-4. 18 (m, 2H), 3.98-4. 02 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 1.33 (s, 9H).

Ex-46C: 2- (5- [1, 3] Dioxolan-2-yl-2, 4-dimethoxy-phenyl) -4,4, 5,5-tetramethyl- [1, 3,2] dioxaborolane (Ex-46B, 2.22 g, 6.60 mmol, containing borolane impurity) was dissolved in DME (60 mL) and 2-iodopyrazine (0.59 mL, 6.0 mmol) was added. 2M aqueous Na2C03 (17.8 mL, 35. 6 mmol) was added and the mixture was purged with nitrogen for 20 min.

Tetrakis (triphenylphosphine) palladium (0) (0.69 g, 0.60 mmol) was added and the mixture was heated at reflux for 2.5 h. After cooling, water (50 mL) was added and the mixture was extracted with CH2CI2 (2x30 mL). The organic phase was washed with brine (1x20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the resulting yellow-orange solids via silica chromatography (50-80% EtOAc/hexanes) provided 1.02 g of 2- (5- [1, 3] dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine as a yellow solid (59% yield).'H-NMR

(CDCI3) å 9.10 (d, J = 2 Hz, 1H), 8.61 (m, 1H), 8. 39 (d, J = 3 Hz, 1H), 8.07 (s, 1H), 6. 57 (s, 1H), 6.14 (s, 1H), 4.13-4. 18 (m, 2H), 4.01-4. 05 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H).

Ex-46D: 2- (5- [1, 3] Dioxolan-2-yl-2, 4-dimethoxy-phenyl) -pyrazine (1.02 g, 3.54 mmol) was dissolved in acetone and p-toluenesulfonic acid (100 mg, 0.53 mmol) and water (5 mL) were added. The solution was stirred for 3 h at room temperature, then concentrated on the rotavap.

The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3x100 mL).

The organic phase was washed with 25% saturated aqueous NaHC03, dried over sodium sulfate, filtered, and concentrated. Drying gave 0.30 g of 2, 4-dimethoxy-5-pyrazin-2-yl- benzaldehyde as a yellow solid (18% yield).'H-NMR (CDC13) 8 10.35 (s, 1H), 9.06 (d, J = 2 Hz, 1H), 8.63-8. 65 (m, 1H), 8.45 (d, J = 2 Hz, 1H), 8.39 (s, 1H), 6.56 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). HRMS m/z : calc. 244.0848, found 244.0853.

The title compound was prepared by condensing 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde (Ex-46D) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238°C (dec. ), 4% yield.'H-NMR (DMSO-D6) 8 9.04 (d, J = 2 Hz, 1H), 8.75-8. 76 (m, 1H), 8.56 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J = 9 Hz, 2H), 8.05-8. 11 (m, 3H), 7.83 (d, J = 16 Hz, 1H), 6.90 (s, 1H), 4.05 (s, 3H), 4.00 (s, . 3H). HRMS m/z = calc. 391.1294, found 391.1313.

EXAMPLE 47 4-{3E-14-(1-Carboxy-l-methyl-ethoxy)-2-methoxy-5-thiophen-2- yl-phenyl]-acryloyl}- benzoic acid Ex-47A: 5-Bromo-4-hydroxy-2-methoxy-benzaldehyde was prepared in an analogous fashion as described in Ex-29A using 4-hydroxy-2-methoxybenzaldehyde. The crude solid was slurried in water to remove residual HBr and dried in vacuo to give the bromide as an off-white solid

(98%), mp 199-201 °C.'H-NMR (300 MHz, DMSO-d6) 8 11. 58 (s, 1H), 10.07 (s, 1H), 7.75 (s, 1H), 6.69 (s, 1H), 3.87 (s, 3H). MS (EI) m/z = 230 ([M] +, 100%). Anal. Calcd. for CsH7Br03-'4H20 : C, 40.79 ; H, 3. 21. Found: C, 40.66 ; H, 3.01.

Ex-47B: 4-Hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in an analogous fashion as described in Ex-29B. Silica gel chromatography (ethyl acetate/hexanes, 2: 1) gave the expected product as a solid (85%), mp 200 °C (dec.).'H-NMR (300 MHz, CDCl3) 8 10.31 (s, 1 H), 7.89 (s, 1H), 7.42 (dd, 1H, J= 4. 8, 1. 2 Hz), 7.14-7. 19 (m, 2H), 6.59 (s, 1H), 6.14 (brs, 1H), 3.94 (s, 3H). MS (EI) m/z : 234 ([M]+, 100%). Anal. Calcd. for C12H10O3S#H2O : C, 57.13 ; H, 4.79 ; S, 12. 71. Found: C, 57.16 ; H, 4.47 ; S, 12.48.

Ex-47C: 2- (4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid ethyl ester was prepared in an analogous fashion as described in Ex-29C using ethyl 2- bromoisobutyrate. Silica gel chromatography (ethyl acetate/hexanes, 1 : 1) gave the expected product as a solid (82%), mp 111-113 °C.'H-NMR (300 MHz, CDC13) 8 10.32 (s, 1H), 8.14 (s, 1H), 7.45 (dd, IH, J= 3. 7,1. 3 Hz), 7. 30 (dd, 1H, J= 5. 2,1. 3 Hz), 7.07 (dd, 1H, J=5. 2,3. 7 Hz), 6.35 (s, 1H), 4.25 (q, 2H, J= 7.2 Hz), 3.85 (s, 3H), 1. 76 (s, 6 H), 1.23 (t, 3H, J= 7.2 Hz).

MS (EI) m/z = 348 ([M]+, 100%). Anal. Calcd. for C18H2005S : C, 62.05 ; H, 5.79 ; S, 9.20.

Found: C, 61. 81 ; H, 5. 81 ; S, 9.12.

Ex-47D: To a solution of 2- (4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl- propionic acid ethyl ester (0.29 g, 0.83 mmol) in a mixture of tetrahydrofuran, water and methanol (9 mL, 4: 1: 1) was added lithium hydroxide (0.10 g, 2.49 mmol) and the resulting yellow slurry was stirred at rt for 5 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (I x 5 mL). The aqueous layer was acidified with a 1 N HCI solution and extracted with ethyl acetate (3 x 15 mL). The combined organic layers was dried over sodium sulfate and concentrated to afford 0.13 g (87%) of 2- (4-formyl-5-methoxy-2-thiophen-2-yl- phenoxy) -2-methyl-propionic acid as a pale green solid, mp 183-184 °C.'H-NMR (300 MHz, CDCl3) 8 10.32 (s, 1H), 8.12 (s, 1H), 7.40 (d, 1H, J= 3.6 Hz), 7.32 (d, 1H, J = 4.8 Hz), 7.08

(dd, 1H, J= 4. 8,3. 6 Hz), 6.47 (s, 1H), 3.86 (s, 3H), 1.78 (s, 6 H). MS (EI) mlz = 320 ([M]+, 100%). Anal. Calcd. for C 16H I 605S : C, 59.99 ; H, 5.03 ; S, 10. 01. Found: C, 60.04 ; H, 5.26 ; S, 9.70.

2- (4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid (Ex-47D, 0.23 g, 0.72 mmol) and 4-acetylbenzoic acid (0.12 g, 0.72 mmol) were dissolved in a dimethylformamide-methanol solution (5 mL, 7: 3). After complete dissolution, lithium methoxide (0.11 g, 2.9 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (4 x 25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in a tetrahydrofuran-heptane solution (5 mL, 10: 1) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.30 g (90%) of the title compound as a dark yellow solid, mp 135-137 °C.'H-NMR (300 MHz, DMSO-d6) 8 8.32 (s, 1H), 8.23 (d, 2H, J= 8.4 Hz), 8.10 (d, 2H, J= 8. 4 Hz), 7.99 (d, 2H, J= 15.6 Hz), 7.71 (d, 1 H, J = 3. 0 Hz), 7.54 (d, lH, J=5. 1 Hz), 7.14 (dd, 1H, J=5. 1,3. 0 Hz), 6.49 (s, 1H), 3.85 (s, 3H), 1.69 (s, 6H). MS (ESI) m/z = 467 ([M+H]+, 100%). Anal. Calcd. for C2sH2808S-EtOH : C, 63.27 ; H, 5.51 ; S, 6.26. Found: C, 63.40 ; H, 5.19 ; S, 6.38.

EXAMPLE 48 2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid The title compound was prepared by condensing 4-methoxy-3- (thiophen-2-yl)-benzaldehyde (Ex-41A) and 2-acetylbenzoic acid in a similar manner as described in Ex-3. Beige solid with green tint, mp 79-81°C, 44% yield. lH-NMR (DMSO-D6) 8 8.07 (d, J = 2 Hz, 1H), 7.91 (d, J =

8 Hz, 1H), 7.73 (dd, J = 2,4 Hz, 1H), 7.67-7. 70 (m, 2H), 7.63 (dd, J = 2,7 Hz, 1H), 7.57 (dd, J = 2, 5 Hz, I H), 7.50 (d, J= 8 Hz, 1H), 7.22 (d, J = 2 Hz, 2H), 7.19 (d, J = 8 Hz, 1 H), 7.12 (dd, J = 4,5 Hz, 1H), 3.96 (s, 3H). HRMS m/z = calc. 365.0848, found 365.0853.

EXAMPLE 49 4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxyl-5-thiophen- 2-yl-phenyl}-acryloyl)- benzoic acid Ex-49A: To a solution of 4-hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-47B, 0.50 g, 2.14 mmol) and tri (ethylene glycol) monomethyl ether (0.38 g, 3.2 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (0.84 g, 3.2 mmol) and the resulting mixture was cooled to 0 °C. Diethyl azodicarboxylate (0.55 g, 3.2 mmol) was then added drop wise, stirred at 0 °C for 30 min, and allowed to warm to rt. The solution was stirred for an additional 24 and concentrated under reduced pressure to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 8: 1) afforded 0.31 g (45%) of the expected 2-methoxy-4- [2- (2-methoxy- ethoxy) -ethoxy] -5-thiophen-2-yl-benzaldehyde as a viscous clear oil. 1H-NMR (300 MHz, CDC13) 8 10.34 (s, 1H), 8.13 (s, 1H), 7.48 (d, 1H, J= 3.6 Hz), 7.30 (t, 1H, J= 5.1 Hz), 7.06 (dd, IH, J= 5. 1,3. 6 Hz), 6.56 (s, IH), 4.34 (t, 2H, J=5. 1 Hz), 3.94 (t, 2H, J = 5.1 Hz), 3.96 (s, 3H), 3.72-3. 75 (m, 2H), 3.56-3. 59 (m, 2H), 3.39 (s, 3H). MS (ESI) m/z = 337 ([M+H]+, 100%).

HRMS (EI) Calcd. for CoOsS : 336.1031. Found: 336.1028.

The title compound was prepared by condensing 2-methoxy-4- [2- (2-methoxy-ethoxy)-ethoxy]- 5-thiophen-2-yl-benzaldehyde (Ex-49A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 174-175 °C, 61% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.28 (s, 1H), 8.23 (d, 2H, J= 8.1 Hz), 8.05-8. 11 (m, 3H), 7.91 (d, 1H, J= 15. 3 Hz), 7.72 (d, 1H, J= 2.7 Hz), 7.52 (d, 1H, J= 4.2 Hz), 7.11-7. 15 (m, 1H), 6.86 (s, 1H), 4.39 (t, 2H, J= 3.9

Hz), 3.99 (s, 3H), 3.89 (t, 2H, J= 3.9 Hz), 3.64 (t, 2H, J= 3.9 Hz), 3.48 (t, 2H, J= 3. 9 Hz), 3.25 (s, 3H). MS (ESI) m/z = 483 ([M+H] +, 100%). Anal. Calcd. for C26H2607S : C, 64. 71 ; H, 5.43 ; S, 6.64. Found: C, 64.43 ; H, 5.34 ; S, 6.54.

EXAMPLE 50 4- {3E- [4- (3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-y l-phenyl]- acryloyl}-benzoic acid Ex-50A : To a solution of 3- (tert-butyl-dimethyl-silanyloxy)-2- (tert-butyl-dimethyl- silanyloxymethyl)-propan-l-ol (25.0 g, 74.3 mmol) and triethylamine (22.6 g, 223 mmol) in dichloromethane (150 mL) at 0 °C. was added mesyl chloride (12.8 g, 111 mmol) and the resulting slurry was stirred at 0 °C for 15 min and allowed to warm to rt. The solution was stirred for an additional 3 h at rt and diluted with water (130 mL) and ethyl acetate (350 mL).

The layers were separated and the aqueous was extracted with ethyl acetate (1 x 150mL). The combined organic extracts were washed with a saturated sodium bicarbonate (1 x 200 mL), a 50% sodium chloride solution (2 x 200 mL), dried over sodium sulfate and concentrated to afford 29.5 g (97%) of the expected methanesulfonic acid 3- (tert-butyl-dimethyl-silanyloxy)-2- (tert-butyl-dimethyl-silanyloxymethyl) -propyl ester as a yellow oil, 97% yield. 1H-NMR (300 MHz, CDC13) 8 4.29 (d, 2H, J= 5.7 Hz), 3.61-3. 68 (m, 4H), 2.99 (s, 3H), 2.04-2. 11 (m, l. H), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for Cl7H40OsSSi2 : 413.2213. Found: 413.2226.

Ex-SOB : 4- [3- (tert-Butyl-dimethyl-silanyloxy)-2- (tert-butyl-dimethyl-silanyloxymethyl)- propoxy] -2-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in an analogous fashion as described in EX-29C using methanesulfonic acid 3- (tert-butyl-dimethyl-silanyloxy)-2- (tert- butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-50A). Silica gel chromatography (ethyl acetate/hexanes, 1 : 6) gave the expected product as a pale green solid, 90% yield.'H-NMR (300

MHz, CDCl3) 8 10.34 (s, 1H), 8.13 (s, IH), 7.41 (dd, 1H, J= 3.6, 1.2 Hz), 7.28 (dd, 1H, J= 5.1, 1.2 Hz), 7.05 (dd, 1H, J= 5.1, 3.6 Hz), 6.54 (s, 1H), 4.22 (d, 2H, J= 5.7 Hz), 3.96 (s, 3H), 3.80 (d, 4H, J= 5.7 Hz), 2.33 (pentet, 1H,J= 5.7 Hz), 0.88 (s, 18H), 0. 012 (s, 12H). MS (ESI) m/z=551 ([M+H]+, 100%). HRMS (EI) Calcd. for C28H4605SSi2 : 550.2604. Found: 550.2593.

Ex-50C : To a solution of 4- [3- (tert-butyl-dimethyl-silanyloxy)-2- (tert-butyl-dimethyl- silanyloxymethyl)-propoxy]-2-methoxy-5-thiophen-2-yl-benzald ehyde (Ex-50B, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at rt for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed with a 50% ammonium chloride solution (1 x 30 mL), water (2 x 30 mL), brine (I x 30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of the expected 4- (3- hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-b enzaldehyde as a pale yellow solid, 90% yield, mp 144-145 °C..'H-NMR (300 MHz, CDC13) 8 10.33 (s, 1H), 8.10 (s, 1H), 7. 38 (dd, 1H, J=3. 6,1. 5Hz), 7. 30 (dd, lH, 7=5. 1,1. 5 Hz), 7.07 (dd, IH, J=5. 1,3. 6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J= 6.0 Hz), 4.02 (t, 4H, J= 4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J = 6.0 Hz), 1.89 (t, 2H, J= 4.8 Hz). MS (ESI) mlz = 323 ([M+H]_, 100%). Anal. Calcd. for C16H18O5 S : C, 59.61 ; H, 5.63 ; S, 9.95. Found: C, 59.34 ; H, 5.75 ; S, 9.82.

The title compound was prepared by condensing 4- (3-hydroxy-2-hydroxymethyl-propoxy)-2- methoxy-5-thiophen-2-yl-benzaldehyde (Ex-SOC) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 199-201 °C, 60% yield.'H-NMR (300 MHz, DMSO- d6) 8 8.31 (s, 1H), 8.23 (d, 2H, J= 8.7 Hz), 8.06-8. 11 (m, 3H), 7.93 (d, 1H, J= 15. 0 Hz), 7.71 (d, 1H, J= 3.3 Hz), 7.54 (d, 1H, J= 5.1 Hz), 7.13-7. 16 (m, 1H), 6.87 (s, 1H), 4.62 (brs, 2H), 4.27 (d, 2H, J= 5.1 Hz), 4.00 (s, 3H), 3.62 (brs, 4H), 2.11-2. 15 (m, 1H). MS (ESI) m/z = 469 ([M+H]+, 100%). Anal. Calcd. for C25H2407S''/4H2O : C, 63.48 ; H, 5.22 ; S, 6.78. Found: C, 63.45 ; H, 5.29 ; S, 6.61.

EXAMPLE 51

5- {5- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl}-thiophene-2- carboxylic acid methyl ester Ex-51A : 5- (5-Formyl-2, 4-dimethoxy-phenyl)-thiophene-2-carboxylic acid methyl ester was prepared starting from 5-bromo-thiophene-2-carboxylic acid methyl ester in a similar manner as described in Ex-46A through-46D. Yellow solid, 18% yield.'H-NMR (CDC13) 8 10.32 (s, 1H), 8.16 (s, 1H), 7.74 (d, J = 4.4 Hz, 1H), 7.42 (d, J = 4.4 Hz, 1H), 6.51 (s, 1 H), 4.05 (s, 3H), 3.98 (s, 3H), 3.90 (s, 3H). HRMS (ES+) Calcd. for Cl5Hl405S : 307.0640. Found: 307.0630.

4-Acetylbenzoic acid (24 mg, 0.15 mmol) and 5- (5-formyl-2, 4-dimethoxy-phenyl)-thiophene- 2-carboxylic acid methyl ester (Ex-51A, 46 mg, 0.15 mmol) were dissolved in DMF (4 mL).

Lithium methoxide, 1M in methanol (0.29 mL) was added and the solution stirred at room temperature overnight. The reaction solution was poured into cold IN HCl (3 mL) and extracted with EtOAc (3x20 mL); the organic phase was washed with brine (1x10 mL), dried over sodium sulfate, filtered, and concentrated. The resulting orange residue was purified via silica gel chromatography (0-10% MeOH/CH2CI2) to provide 89 mg of yellow solid which still contained DMF. The solid was slurried in EtOH for several hours, filtered, and dried to provide 31 mg of final product as a yellow solid (47% yield).'H-NMR (DMSO-d6) 8 8.47 (s, 1 H), 8.23 (d, J = 9 Hz, 2H), 8.01-8. 11 (m, 4H), 7.89 (d, J = 4 Hz, 1 H), 7.82 (d, J = 4 Hz, 1H), 6.90 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 3.84 (s, 3H). HRMS (ES+) Calcd. for C24H2007S : 453.1008. Found: 453.1020.

EXAMPLE 52

5- {5- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl}-thiophene-2- carboxylic acid The title compound was prepared through routine hydrolysis of 5- {5- [3- (4-Carboxy-phenyl)-3- oxo-propenyl]-2, 4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester (Ex-51).

Orange solid, mp >260°C, 43% yield.'H-NMR (DMSO-de) 8 8.43 (s, 1H), 8.26 (d, J = 8 Hz, 2H), 8.01-8. 12 (m, 4H), 7.82 (d, J = 4 Hz, 1H), 7.71 (d, J = 4 Hz, 1H), 6.89 (s, 1H), 4.08 (s, 3H), 4.03 (s, 3H).

EXAMPLE 53 4- [3E- (4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoi c acid Ex-53A: Reaction of 4-hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-47B) and (2- ethoxymethyl-5-hydroxymethyl- [1, 3] dioxolan-4-yl) methanol was preformed under the Mitsunobu condition using triphenylphosphine and diethyl azodicarboxylate in THF. However, the expected product, 4- (2-ethoxymethyl-5-hydroxymethyl- [1, 3] dioxolan-4-ylmethoxy)-2- methoxy-5-thiophen-2-yl-benzaldehyde, was not obtained. Instead, 4-ethoxy-2-methoxy-5- thiophen-2-yl-benzaldehyde was formed via cleavage of the cyclic ethyl orthoformate group under the reaction conditions. Silica gel chromatography (ethyl acetate/hexanes, 1 : 2) gave 0.16

g (90%) of 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde, mp 101-103 °C.'H-NMR (300 MHz, CDCl3) 5 10.33 (s, IH), 8.15 (s, 1 H), 7.48 (d, IH, J= 3.6 Hz), 7.29 (d, 1H, J= 5.2 Hz), 7.07 (dd, 1H, J= 5.2, 3.6 Hz), 6.50 (s, 1H), 4.25 (q, 2H, J= 7.2 Hz), 3.97 (s, 3H), 1.59 (t, 3H, J = 7.2 Hz). MS (EI) m/z=262 ([M]+, 100%). HMRS (EI) Calcd. for Cl4Hs403S : 262.0664.

Found: 262.0667.

The title compound was prepared by condensing 4-ethoxy-2-methoxy-5-thiophen-2-yl- benzaldehyde (Ex-53A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, mp 210-212 °C, 76% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.31 (s, 1H), 8.23 (d, 2H, J= 9. 0 Hz), 8.06-8. 11 (m, 3H), 7.92 (d, 1H, J= 16. 2 Hz), 7.71 (d, 1H, J= 3. 9 Hz), 7.52 (d, 1H, J= 5. 1 Hz), 7.13 (dd, 1H, J= 5.1, 3.9 Hz), 6.82 (s, 1H), 4.33 (q, 2H, J= 6.1 Hz), 3.99 (s, 3H), 1.48 (t, 3H, J = 6.1 Hz). MS (ESI) mlz = 409 ([M+H]+, 100%). Anal. Calcd. for C23H20O5S#½H2O : C, 66.17 ; H, 5.07 ; S, 7.68. Found: C, 65.88 ; H, 5.24 ; S, 7.36.

EXAMPLE 54 4- [3E- (4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzo ic acid 4-Hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-47B, 0.30 g, 0.86 mmol) and 4- acetylbenzoic acid (0.13 g, 0.86 mmol) were dissolved in a dimethylformamide-methanol solution (6 mL, 7: 3). After complete dissolution, lithium methoxide (0.12 g, 3.3 mmol) was added and the resulting red slurry was stirred in the dark at room temperature for 18 h. The mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (4 x 25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was subjected to silica gel chromatography (CH2CI2 : MeOH, 20: 1) to yield an orange solid containing residual amounts of starting acid. The solid was taken up in ethyl alcohol (5 mL) to remove acid impurity and the

resulting precipitate was collected on filter paper and dried in vacuo to yield 0. 010 g (5%) of the title compound as an orange solid, mp 243 °C (dec).'H-NMR (300 MHz, DMSO-d6) 8 8.18-8. 23 (m, 3H), 8.06-8. 09 (m, 2H), 8.02 (s, 1H), 7.85 (d, IH, J= 15.6 Hz), 7.68 (d, 1H, J= 3.6 Hz), 7.47 (d, 1H, J= 5. 1 Hz), 7.11 (dd, 1H, J= 5.1, 3.6 Hz), 6.67 (s, 1H), 4.13 (s, 1H), 3.89 (s, 3H). MS (ESI) m/z= 381 ([M+H]+, 100%). HRMS (ESI) Calcd. for C2 I H I 605S : 381. 0796.

Found: 381.0800.

EXAMPLE 55 4- [3E- (2, 4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid Ex-55A : 2, 4-Dimethoxy-5-thiazol-2-yl-benzaldehyde was prepared from 2-bromothiazole in a similar manner as described in Ex-46A through-46D. Off-white solid, 83% yield.'H-NMR (CDC13) 5 10. 34 (s, 1H), 8.86 (s, 1H), 7.89 (d, J=3. 6 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 6.56 (s, 1H), 4.12 (s, 3H), 4.02 (s, 3H). HRMS m/z : calc. 249.0460, found 249.0461.

The title compound was prepared by condensing 2, 4-dimethoxy-5-thiazol-2-yl-benzaldehyde (Ex-55A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp >260°C, 65% yield.'H-NMR (DMSO-d6) 5. 13. 33 (bs, 1H), 8.74 (s, 1H), 8.22 (d, J = 8 Hz, 2H), 8.04-8. 12 (m, 3H), 7.95 (d, J = 2 Hz, 1H), 7.82 (d, J = 16 Hz, 1H), 7.76 (d, J = 3 Hz, 1H), 6.94 (s, 1H), 4.14 (s, 3H), 4.05 (s, 1H). HRMS m/z = calc. 396.0906, found 396.0903.

EXAMPLE 56

4- 3E- (5-Benzo [bJthiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt To a solution of 4- [3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzoic acid (5.77g, 13.0 mmol) in tetrahydrofuran (50 mL) was added sodium methoxide (0.70g, 12.3 mmol). The reaction mixture was allowed to stir for 2 hours at ambient temperature. The precipitate was then filtered, washed with tetrahydrofuran and dried in vacuo to give the title compound (5.13g, 85%) as a yellow solid, mp > 235 °C.'H-NMR (DMSO-d6) 8 8.35 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.00-7. 89 (m, 4H), 7.82 (d, J = 7.6 Hz, 1H), 7.35-7. 29 (m, 4H), 6.85 (s, 1 H), 4.02 (s, 3H), 3.99 (s, 3H). MS m/z = 443 (M+, 100%).

EXAMPLE 57 2- {5- [3- (4-Carboxy-phenyl)-3-oxo-E-propenyl]-2, 4-dimethoxy-phenyl}-pyrrole-1- carboxylic acid tert-butyl ester Ex-57A: 2- (5-Formyl-2, 4-dimethoxy-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester was prepared from pyrrole-I-carboxylic acid ter-butyl ester-2-boronic acid in a similar manner as described in Ex-3A, 81% yield.'H-NMR (CDCI3) 5 10.32 (s, 1H), 7.76 (s, 1H), 7.31-7. 33 (m,

1H), 6.43 (s, 1H), 6.22-6. 24 (m, 1H), 6.14-6. 16 (m, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 1.40 (s, 9H).

HRMS (EI) Calcd. for C, 8H2, NOs : 331.1420. Found: 331.1421.

The title compound was prepared by condensing 2- (5-formyl-2, 4-dimethoxy-phenyl)-pyrrole-1- carboxylic acid tert-butyl ester (Ex-57A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 205-207°C, 6% yield.'H-NMR (DMSO-d6) 5 8.19 (d, J = 5 Hz, 2H), 8.00-8. 10 (m, 3H), 7.87 (s, 1H), 7.80 (d, J = 16 Hz, 1H), 7.27-7. 28 (m, 1H), 6.71 (s, 1H), 6.22-6. 23 (m, 1H), 6.14-6. 16 (m, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 1.29 (s, 9H). MS m/z= 476 ( [M-H] +). HMRS (El) calcd. for C27H27NO7 : 477.1788 ; found: 477.1793.

EXAMPLE 58 4- [3E- (2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzo ic acid 2-Hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-29B, 0.10 g, 0.43 mmol) and 4- acetylbenzoic acid (0.070 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2.8 mL, 7: 3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting red slurry was stirred in the dark at room temperature for 18 h. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature.

Note: the compound appears to decompose with heating. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.025 g (15%) of the title compound as a dark yellow solid, mp 125 °C (dec). 1H-NMR (300 MHz, DMSO-d6) 8 10.73 (s, 1 H), 8.18-8. 22 (m, 3 H), 8.09 (d, 2 H, J= 8.1 Hz), 8.05 (s, I H), 7.87 (d, 1 H, J= 14.7 Hz), 7.60 (d, 1 H, J= 3.0 Hz), 7.49 (d, 1H, J= 4.2 Hz), 7.11 (dd, 1 H, J=4. 2,3. 0 Hz), 6.67 (s, 1 H), 3.90 (s, 3 H). MS (ESI) m/z = 381 ( [M+H] +, 100%). Anal. Calcd. for C21HI605S-EtOH : C, 64.77 ; H, 5.20 ; S, 7.52. Found: C, 64.68 ; H, 5.00 ; S, 7.77.

EXAMPLE 59

4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2- yl-phenyl]-acryloyl}- benzoic acid Ex-59A: 2- (2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid ethyl ester was prepared in an analogous fashion as described in Ex-29C using ethyl 2- bromoisobutyrate. Silica gel chromatography (ethyl acetate/hexanes, 1: 2) gave the expected product as a dark yellow solid (97%), mp 87-88 °C.'H-NMR (300 MHz, CDC13) 8 10.37 (s, 1H), 8.14 (s, 1H), 7.45 (dd, 1H, J= 3. 6,1. 2 Hz), 7. 30 (d, 1H, J= 5. 4 Hz), 7.07 (dd, 1H, J= 5. 1, 3.6 Hz), 6.42 (s, 1H), 4.25 (q, 2H, J= 6.9 Hz), 3.90 (s, 3H), 1.72 (s, 6H), 1.26 (t, 3H, J= 6. 9 Hz). MS (ESI) m/z = 349 ([M+H]+, 100%). Anal. Calcd. for ClsH2005S : C, 62.05 ; H, 5.79 ; S, 9.20. Found: C, 62.15 ; H, 5.82 ; S, 9.06.

Ex-59B: 2- (2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid was prepared in an analogous fashion as described in Ex-47D. The crude solid was dried in vacuo to afford the product as a pale yellow solid (98%), mp 187-188 °C.'H-NMR (300 MHz, CDCl3) # 9. 33 (s, lH), 7.99 (s, 1H), 7.47 (dd, IH, J= 3. 6,1. 5 Hz), 7.37 (d, 1H, J= 4. 8 Hz), 7.11 (dd, 1H, J= 4. 8,3. 6 Hz), 6.67 (s, 1H), 4.00 (s, 3H), 1.75 (s, 6H). MS (ESI) m/z = 321 ([M+H]+, 100%). Anal. Calcd. for C16H16O5S : C, 59.99 ; H, 5.03 ; S, 10.01. Found: C, 59.80 ; H, 5.12 ; S, 9.87.

2- (2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid (Ex-59B, 0.12 g, 0.39 mmol) and 4-acetylbenzoic acid (0.064 g, 0.39 mmol) were dissolved in a

dimethylformamide-methanol solution (2.7 mL, 7: 3). After complete dissolution, lithium methoxide (0.060 g, 1.6 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 2 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.15 g (85%) of the title compound as a dark yellow solid, mp 223-225 °C.'H-NMR (300 MHz, DMSO-d6) 8 8.31 (s, 1H), 8.23 (d, 2H, J= 8.1 Hz), 8.10 (d, 2H, J= 8. 1 Hz), 8.06 (s, 1H), 7.95 (d, 1H, J= 16.2 Hz), 7.69 (d, 1H, J= 3.0 Hz), 7. 55 (d, 1H, J=5. 1 Hz), 7.14 (dd, 1H, J= 5.1, 3.0 Hz), 6. 58 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z = 467 ([M+H]+, 100%). Anal. Calcd. for C2sH2207S-'/3H20 : C, 63.55 ; H, 4.84 ; S, 6.79. Found: C, 63.39 ; H, 5.02 ; S, 6.53.

EXAMPLE 60 4- {3E- [4-Methoxy-2- (2-morpholin-4-yt-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzoic acid, hydrochloride Ex-60A: 4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzal dehyde was prepared in an analogous fashion as described in Ex-29C using 4- (2-chloroethyl) morpholine. Silica gel chromatography (80 to 100% ethyl acetate/hexanes then 5% methanol/methylene chloride) gave of the expected product as a off-white solid (81%). 1H-NMR (300 MHz, CDCl3) 8 10.36 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J= 3. 6,1. 5 Hz), 7.30 (dd, 1H, J= 5. 1,1. 5 Hz), 7.07 (dd, 1H, J= 5.1, 3.6 Hz), 6.53 (s, 1H), 4.27 (t, 2H, J= 6.3 Hz), 4.00 (s, 3H), 3.72-3. 76 (m, 4H), 2.89

(t, 2H, J= 6.3 Hz), 2.60-2. 63 (m, 4H). MS (ESI) mlz = 348 ( [M+H] +, 100%). HRMS (EI) Calcd. for Cl8H2lNO4S : 347.1191. Found: 347. 1188.

4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzal dehyde (Ex-60A, 0.15 g, 0.43 mmol) and 4-acetylbenzoic acid (0.071 g, 0.43 mmol) were dissolved in a dimethylformamide- methanol solution (3.0 mL, 7: 3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 2 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with an ethyl acetate: tetrahydrofuran mixture (1: 1,6 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude solid was slurried in ethyl alcohol (5 mL) to remove residual impurities and the resulting solid was collected on filter paper and dried in vacuo to yield 0.21 g (98%) of the title compound as a dark yellow solid, mp: 255 °C (dec).'H-NMR (300 MHz, DMSO-d6) 8 8.34 (s, 1H), 8.26 (d, 2H, J= 8.7 Hz), 8.11 (d, 2H, J= 8.7 Hz), 8.08 (s, 1H), 7.95 (d, 1H, J= 15.9 Hz), 7.71 (d, 1H, J= 3.3 Hz), 7. 55 (d, 1H, J= 4. 5 Hz), 7.15 (dd, 1H, J= 4.5, 3.3 Hz), 6.94 (s, 1H), 4.68 (brs, 2H), 4.04 (s, 3H), 3.98 (brs, 2H), 3.81-3. 88 (brm, 2H), 3.70 (brs, 2H), 3.54-3. 58 (brm, 2H), 3.29 (brs, 2H). MS (ESI) m/z = 494 ([M+H] +, 100%). Anal. Calcd. for C27H28ClNO6S : C, 61.18 ; H, 5.32 ; Cl, 6.69 ; N, 2.64 ; S, 6.05.

Found: C, 61.18 ; H, 5. 41 ; Cl, 6.16 ; N, 2.73 ; S, 5.87.

EXAMPLE 61 2 4-13E- [5- (lH-Indol-2-yi)-2, 4-dimethoxy-phenyl]-acryloyl)-benzoic acid Ex-61A: 2- (5-Formyl-2, 4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex- 36A, 2. 0g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu4NF (6.86g, 26 mmol) was

added. The reaction mixture was stirred at room temperature overnight. No reaction occured at this condition. Then, Bu4NF (6.86g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction was about 50 % completion (HPLC). The reaction mixture was poured into CH2CI2, and washed with water and brine. The organic phase was dried over MgS04, and concentrated. The residue was purified by column chromatography (EtOAc: Hex, 2: 1) to give 0.45 g (30 %) of5-(lH-indol-2-yl)-2, 4-dimethoxy-benzaldehyde. lH- NMR (CDCI3) 8 10. 37 (s, 1H), 9.25 (br, 1H), 8.28 (s, IH), 7.63 (d, J = 8 Hz, 1H), 7.39 (d, J = 8 Hz, 1H), 7.08-7. 20 (m, 2H), 6.92 (d, J = 2 Hz, 1H), 6.56 (s, 1H) 4. 11 (s, 3H), 4.00 (s, 3H).

HMRS (EI) calcd. for C17HIsN03 : 281.1052 ; found: 281.1049.

The title compound was prepared by condensing 5-(1H-indol-2-yl)-2, 4-dimethoxy- benzaldehyde (Ex-61A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 210-212°C, 66% yield.'H-NMR (Aceton-d6) 8 10.53 (br, s, 1H), 8.32 (s, 1H), 8.14- 8.21 (m, 5H), 7.89 (d, J = 15 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7. 38 (d, J = 7 Hz, 1H), 6.97- 7.07 (m, 3H), 6.87 (s, 1H), 4.07 (s, 3H), 4.02 (s, 3H), MS m/z=427 ([M]+). HMRS (EI) calcd. for C26H21NO5 : 427.1420 ; found: 427.1435.

EXAMPLE 62 4- 3E- [2- (3, 5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-p henyl]- acryloyl}-benzoic acid Ex-62A: 2- (3, 5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-b enzaldehyde was prepared in a similar manner as described in Ex-29C using 4-chloromethyl-3,5-dimethyl- isoxazote.'H-NMR (CDCb) 5 t0. 26 (s, 1H), 8.14 (s, 1H), 7.45 (d, J = 6 Hz, 1H), 7.32 (d, J = 5 Hz, 1H), 7.07-710 (m, 1H), 6.58 (s, 1H), 4.96 (s, 2H), 4.04 (s, 3H), 2.46 (s, 3H), 2.32 (s, 3H).

The title compound was prepared by condensing 2- (3, 5-dimethyl-isoxazol-4-ylmethoxy) -4- methoxy-5-thiophen-2-yl-benzaldehyde (Ex-62A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 213-215°C. IH-NMR (CDCI3) 6 8.20 (d, J = 9 Hz, 2H), 7.88-8. 03 (m, 4H), 7.58 (d, J = 16 Hz, 1H), 7.44 (d, J = 4 Hz, 1H), 7.34 (d, J = 5 Hz, 1H), 7.12 (dd, J = 4,5 Hz, 1H), 6.63 (s, 1H), 4.97 (s, 2H), 4.01 (s, 3H), 2.46 (s, 3H), 2.34 (s, 3H). MS m/z= 490 ([M+H] +). HRMS (ES+) Calcd. for C27H22NO6S : 490.1324. Found: 490.1321.

EXAMPLE 63 4-13E-(2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-b enzoic acid Ex-63A: A solution of 2-fluoro-5-thiophen-2-yl-benzaldehyde (1.42g, 6.89 mmol) in pyrrolidine was refluxed (10 mL). After 4.5 days the reaction mixture was cooled and diluted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0. 5M) sodium carbonate (2M) and saturated solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (20%, v/v, in hexane) afforded 2-pyrrolidin-I-yl-5-thiophen-2-yl- benzaldehyde (0. 5g, 32%).'H NMR (CDC13) 8 10.14 (s, 1H), 7.94 (d, J = 2 Hz, 1H), 7.62 (dd, J = 2.7, 9 Hz, 1H), 7.22-7. 20 (m, 2H), 7.07-7. 04 (m, 1H), 6.86 (d, J=9 Hz, 1H), 3.41 (m, 4H), 2.01 (m, 4H).

The title compound was prepared by condensing 2-pyrrolidin-1-yl-5-thiophen-2-yl- benzaldehyde (Ex-63A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 208-209 °C.'H-NMR (DMSO-) S 12.50 (bs, 1H), 8.22 (d, J = 8. 5 Hz, 2H), 8.09- 7.99 (m, 4H), 7.73 (d, J = 15. 5 Hz, 1H), 7.52-7. 41 (m, 3H), 7.10-7. 07 (m, 1H), 6.93 (d, J=9. 0 Hz, 1H), 3.28 (m, 4H), 1.87 (m, 4H).

EXAMPLE 64

4-{3E-12-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thi ophen-2-yl-phenyl]- acryloyl}-benzoic acid Ex-64A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (10.0 g, 42.7 mmol) in N, N-dimethylformamide (100 mL) was added potassium carbonate (11.8 g, 85.4 mmol) and the resulting yellow slurry was heated to 80 °C. Once at 80 °C, methanesulfonic acid 3- (tert-butyl-dimethyl-silanyloxy)-2- (tert-butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-50A, 19.5 g, 46.9 mmol) was added dropwise and the reaction was stirred for an additional 24 h at 80 °C and cooled to room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers was sequentially washed with a saturated sodium bicarbonate solution (1 x 150 mL), water (1 x 150 mL), and brine (1 x 150 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (100% ethyl acetate to 10% ethyl acetate/hexanes) gave 19.0 g (81%) of2- [3- (tert-butyl-dimethyl-silanyloxy)-2- (tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-4- methoxy-5-thiophen-2-yl-benzaldehyde as an off-white solid, mp 91-92 °C.'H-NMR (300 MHz, CDCI3) 8 10.37 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J= 3.6, 1. 2 Hz), 7.29 (d, 1H,J= 5.1 Hz), 7.07 (dd, 1H,J= 5.1, 3.6 Hz), 6.54 (s, 1H), 4.19 (d, 2H, J = 6.0 Hz), 3.99 (s, 3H), 3.72- 3.82 (m, 4H), 2.28 (pentet, 1H, J= 6.0 Hz), 0.88 (s, 18H), 0.048 (s, 12H). MS (EI) m/z = 550 ([M]+, 100%). Anal. Calcd. for C28H46O5SSi2 : C, 61.05 ; H, 8.42 ; S, 5.82. Found: C, 61.20 ; H, 8.74 ; S, 5.69.

Ex-64B: 2- (3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-y l-benzaldehyde was prepared in an analogous fashion as described in Ex-50C. Silica gel chromatography (ethyl acetate/hexanes, 1: 9) gave the expected product as an off-white solid.'H-NMR (300 MHz, CDCl3) 8 10.17 (s, 1H), 8.03 (s, 1H), 7.43 (dd, 1H,J= 3.6, 1.2 Hz), 7.31 (d, 1H,J= 5. 1 Hz),

7.08 (dd, 1H, J= 5. 1,3. 6 Hz), 6.58 (s, 1H), 4.32 (d, 2H, J= 6.0 Hz), 4.01 (s, 3H), 3.95-3. 99 (m, 4H), 2.51 (t, 2H, J=5. 1 Hz), 2. 33 (pentet, lH, J= 5.4 Hz). MS (EI) m/z=322 ([M]+, 100%).

HRMS (EI) Calcd. for Cl6H, 805S : 322.0875. Found: 322.0873.

The title compound was prepared by condensing 2- (3-hydroxy-2-hydroxymethyl-propoxy)-4- methoxy-5-thiophen-2-yl-benzaldehyde (Ex-64B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Light orange solid, mp 219-220 °C, 61% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.36 (s, 1H), 8.20 (d, 2H, J= 7.5 Hz), 8.05-8. 11 (m, 3H), 7.93 (d, 1H, J= 16.2 Hz), 7.67 (d, 1H, J= 3. 0 Hz), 7.52 (d, lH, J=5. 1 Hz), 7. 13 (dd, 1H, J=5. 1,3. 0 Hz), 6.88 (s, 1H), 4.66 (brs, 2H), 4.23 (d, 2H, J= 6.3 Hz), 4.01 (s, 3H), 3.55-3. 66 (m, 4H), 2.09-2. 14 (m, 1H). MS (ESI) m/z = 469 ([M+H]+, 100%). Anal. Calcd. for C25H2407S-H20 : C, 61.72 ; H, 5.39 ; S, 6.59. Found: C, 61.93 ; H, 5.30 ; S, 7.06.

EXAMPLE 65 4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]- acryloyl}-bernzoic acid hydrochloride Ex-65A: 2- (3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-60A, 80% yield.'H-NMR (DMSO-D6) 8 10.36 (s, 1 H), 7.90 (dd, J = 3, 5 Hz, 1H), 7.82 (d, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.25 (d, 1H), 7.09 (t, 1H), 4.18 (t, 2H), 3.53 (m, 4H), 3.28 (br s, 2H), 2.43 (m, 4H), 1.89 (q, 2H).

The title compound was prepared by condensing 2- (3-morpholin-4-yl-propoxy)-5-thiophen-2- yl-benzaldehyde (Ex-65A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, 67% yield, mp 234-236 °C.'H-NMR (DMSO-d6) 8 13.32 (br s, 1 H), 11.10 (br s, 1H), 8.21 (m, 3H), 8.02 (m, 3H), 7.67 (dd, J= 2,2 Hz, 1H), 7.56 (d, 1H), 7.50 (d, 1H), 7.14 (m,

2H), 4. 21 (t, 2H), 3.86 (m, 4H), 3.23 (m, 6H), 2.29 (q, 2H). MS m/z = 478 ([M+H]+, 100%). Anal. calculated for C27H28Clno5s#3/2 H2O : C, 59.94, H, 5.78, S, 5.93 ; found C: 60.20, H: 5.65, S: 5.94 EXAMPLE 66 4- {3E- [4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl} - benzoic acid, hydrochloride Ex-66A: 4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-60A, 78% yield.'H-NMR (DMSO-D6) 8 10.21 (s, 1 H), 7.88 (s, 1H), 7.46 (m, 2H), 7.06 (t, 1H), 6.82 (s, 1H), 4.24 (t, 2H), 4.00 (s, 3H), 3.53 (m, 4H), 3.28 (m, 2H), 2.34 (m, 4H), 1.93 (q, 2H).

The title compound was prepared by condensing 4-methoxy-2- (3-morpholin-4-yl-propoxy)-5- thiophen-2-yl-benzaldehyde (Ex-66A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 72% yield, mp 188-191°c (dec).'H-NMR (DMSO-d6) 5 12.63 (br s, 1 H), 11.08 (br s, 1H), 8.33 (s, 1H), 8.22 (d, 2H), 8.05 (m, 3H), 7.89 (d, 1H), 7.65 (d, 1H), 7.49 (d, 1H), 7.10 (t, 1H), 6.84 (s, 1H), 4.30 (t, 2H), 3.98 (s, 3H), 3.84 (m, 4H), 3.21 (m, 6H), 2.28 (q, 2H). MS m/z = 508 ([M+H]+, 100%). Anal. calculated for C28H32CN07S' H20 : C, 59.83, H, 5.74, S, 5. 70 ; found C: 59.69, H: 5.80, S: 5.55.

EXAMPLE 67

4- [3E- (2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl )-acryloyl]- benzoic acid Ex-67A: 2-(2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl- acetamide was prepared in an analogous fashion as described in Ex-29C using 2-chloro-N, N- dimethylacetamide. Methylene chloride was used in place of ethyl acetate for the work up procedure. The crude solid was slurried in ethyl acetate (25 mL) to remove residual impurities.

The resulting solid was collected on filter paper and dried in vacuo to give the expected product as a pale yellow solid (85%), mp 197-198 °C.'H-NMR (300 MHz, CDCl3) 8 10. 38 (s, 1H), 8.13 (s, lH), 7.44 (d, lH, J=3. 6Hz), 7. 30 (dd, 1H, J=5. 1,1. 8 Hz), 7.07 (dd, 1H, J=5. 1,3. 6 Hz), 6.73 (s, 1H), 4.89 (s, 2H), 3.99 (s, 3H), 3.15 (s, 3H), 2.99 (s, 3H), MS (EI) m/z= 319 ([M]+, 100%). Anal. Calcd. for C, 6HI7NO4S-'/sH2o : C, 59.50 ; H, 5.43 ; N, 4.34 ; S, 9.93.

Found: C, 59.65 ; H, 5.42 ; N, 4.40 ; S, 9.69.

The title compound was prepared by condensing 2-(2-formyl-5-methoxy-4-thiophen-2-yl- phenoxy) -N, N-dimethyl-acetamide (Ex-67A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 228-229 °C, 75% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.31 (d, 2H, J= 9.3 Hz), 8.22 (d, 2H, J= 13.3 Hz), 8.08 (d, 2H, J= 9.3 Hz), 7.95 (s, 1H), 7.65 (d, 1H, J= 2.7 Hz), 7. 52 (d, 1H, J= 5.1 Hz), 7.13 (dd, 1, J= 5.1, 2.7 Hz), 6. 85 (s, 1H), 5.11 (s, 2H), 3.99 (s, 3H), 3.06 (s, 3H), 2.93 (s, 3H). MS (EI) m/z = 465 ([M]+, 100%). HRMS (El) Calcd. for C25H23NO6S : 465.1246. Found: 465.1246.

EXAMPLE 68

4- [3E- (4-Methoxy-2- {2- [2- (2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)- acryloyl]-benzoic acid Ex-68A: Methanesulfonic acid 2- [2- (2-methoxy-ethoxy)-ethoxy]-ethyl ester was prepared in an analogous fashion as described in Ex-50A using di (ethylene glycol) methyl ether. The crude orange oil was dried in vacuo to give the expected product (oil) and was used without any further purification (99%). 1H-NMR (300 MHz, CDC13) 8 4.37-4. 40 (m, 2H), 3.76-3. 78 (m, 2H), 3.61-3. 70 (m, 6H), 3.53-3. 57 (d, 2H), 3.38 (s, 3H), 3.08 (s, 3H). MS (ESI) m/z = 243 ([M+H]+, 100%). HRMS (ESI) Calcd. for C8HI806S : 243.0902. Found: 243.0914.

Ex-68B: 4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiop hen-2-yl- benzaldehyde was prepared in an analogous fashion as as described in Ex-29C using methanesulfonic acid 2- [2- (2-methoxy-ethoxy)-ethoxy]-ethyl ester (Ex-68A). Silica gel chromatography (ethyl acetate/hexanes, 8: 1) gave the expected product as a pale yellow oil (70%). 1H-NMR (300 MHz, CDC13) 8 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (d, 1H, J= 3.6 Hz), 7. 30 (d, 1H, J= 5.4 Hz), 7.07 (dd, 1H, J= 5.4, 3.6 Hz), 6.57 (s, 1H), 4.31 (t, 2H, J= 4.8 Hz), 3.99 (s, 3H), 3.94 (t, 2H, J= 4. 8 Hz), 3.74-3. 78 (m, 2H), 3.62-3. 69 (m, 4H), 3.53-3. 56 (m, 2H), 3. 37 (s, 3H). MS (El) m/z =380 ( [M] , 100%). HRMS (ESI) Calcd. for C8HI806S : 243.0902.

Found: 243.0914.

The title compound was prepared by condensing 4-methoxy-2- {2- [2- (2-methoxy-ethoxy)- ethoxy]-ethoxy}-5-thiophen-2-yl-benzaldehyde (Ex-68B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 137-138 °C, 82% yield. IH-NMR (300 MHz, DMSO-d6) 6 8.20-8. 23 (m, 3H), 8.09 (d, 2H, J= 8. 3 Hz), 8.01 (m, 2H), 7.66 (d, 1H, J=3. 6 Hz), 7.52 (d, 1H, J=5. 1 Hz), 7.13 (dd, 1H, J=5. 1,3. 6 Hz), 6.88 (s, 1H), 4.37 (t, 2H, J= 3. 6

Hz), 4.01 (s, 3H), 3.89 (t, 2H, J= 3.6 Hz), 3.64-3. 67 (m, 2H), 3.53-3. 56 (m, 2H), 3.47-3. 50 (m, 2H), 3.36-3. 95 (m, 2H), 3. 19 (s, 3H). MS (ESI) m/z = 527 ([M+H] +, 100%). Anal. Calcd. for C28H3008S : C, 63.86 ; H, 5.74 ; S, 6.09. Found: C, 64.08 ; H, 5.77 ; S, 6.09.

EXAMPLE 69 4- {3E- [2, 4-Dimethoxy-5- (2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoic acid Ex-69A: A solution of 2-bromo-1- (3, 4-dimethoxy-phenyl) -ethanone (0.62g, 2. 39 mmol) and thioacetamide (0. 18g, 2.39 mmol) in ethanol (30 mL) was refluxed for 2 hours and the solvent was removed under reduced pressure. The product, 4- (3, 4-dimethoxy-phenyl) -2-methyl- thiazole (0.56g, 100%) was obtained as a white solid and used without further purification. To a suspension of 4-(3, 4-dimethoxy-phenyl) -2-methyl-thiazole obtained above (0.70g, 2.97 mmol) in dichloromethane (60 mL) at 0 °C was added dichloromethyl methyl ether (0.40 mL, 4.46 mmol) followed by addition of titanium tetrachloride (1.0 M solution in dichloromethane, 8.9 mL, 8.9 mmol) dropwise. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. The aqueous solution was extracted with dichloromethane. The solution of dichloromethane was washed with hydrochloric acid (0. SM), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated.

The product, 2, 4-dimethoxy-5- (2-methyl-thiazol-4-yl)-benzaldehyde, was obtained as a white solid NMR (CDCl3) 8 10. 33 (s, 1H), 8.67 (s, 1H), 7.56 (s, 1H), 6.52 (s, IH), 4.03 (s, 3H), 3.99 (s, 3H), 2.75 (s, 3H).

The title compound was prepared by condensing 2, 4-dimethoxy-5- (2-methyl-thiazol-4-yl)- benzaldehyde (Ex-69A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, mp 201-202 °C (dec.). IH-NMR (DMSO-d6) 6 8.47 (s, 1H), 8.14-7. 97 (m, 5H), 7.76 (s, 1H), 7.65 (d, J = 15.8 Hz, 1H), 6.81 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.69 (s, 3H).

MS m/z = 409 (M+, 70%), 378 ([M-OCH3] +, 100%).

EXAMPLE 70

4- {3E- [5- (lH-Benzoimidazol-2-yl)-2, 4-dimethoxy-phenyll-acryloyl}-benzoic acid Ex-70A: A solution of benzene-1,2-diamine (2.60g, 24.1 mmol) and 2,4-dimethoxy- benzaldehyde (4. 0g, 24.1 mmol) in ethanol (60 mL) containing catalytic amount of acetic acid was refluxed overnight. Solvent was then evaporated under reduced pressure. The residue oil was triturated in ethyl acetate to obtain 2-(2,4-diemthoxy-phenyl)-1H-benzoimidazole (0.76g, 12%). The crude product was used without further purification. To a solution of 2- (2, 4- dimethoxy-phenyl)-lH-benzoimidazole obtained above (0.76g, 2.99 mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1. OM in dichloromethane, 9.0 mL, 9.0 mmol) at 0 °C. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. A solution of sodium hydroxide (5M) was added dropwise until the pH of the solution was about 12. The basic solution was extracted with dichloromethane. The combined solution of dichloromethane was subsequently washed with brine, dried over sodium carbonate and concentrated. The product, 5- (lH-benzoimidazol-2-yl)-2, 4-dimethoxy-benzaldehyde (0.40g, 47%), was obtain and used without further purification. lH NMR (CDCI3) 6 10.32 (s, 1H), 10.27 (bs, 1H), 9.03 (s, 1H), 7.83 (d, J = 9 Hz, 1H), 7.48-7. 45 (m, 1H), 7.31-7. 22 (m, 1H), 6. 58 (s, 1H), 4.18 (s, 3H), 4.01 (s, 3H). MS m/z=282 (M+, 100%).

The title compound was prepared by condensing 5- (lH-benzoimidazol-2-yl)-2, 4-dimethoxy- benzaldehyde (Ex-70A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, mp > 240 °C (dec.). IH-NMR (DMSO-d6) 6 8.72 (s, 1H), 12.10 (s, 1H), 8.18 (d, J = 8. 4 Hz, 2H), 8.08-8. 02 (m, 3H), 7.80 (d, J = 15. 4 Hz, 1H), 7.59 (s, 2H), 7.17-7. 13 (m, 2H), 6.89 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H). MS m/z = 429 ( [M + H] +, 100%).

EXAMPLE 71

4- [3E- (2-Carbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acrylo yl]-benzoic acid Ex-71A: 2-(2-Formyl-5-emthoxy-4-thiophen-2-yl-phenoxy)-acetamide was prepared in an analogous fashion as described in Ex-29C using 2-bromoacetamide. Silica gel chromatography (ethyl acetate/hexanes, 8: 1) gave the expected product as a pale yellow solid (75%), mp: 178- 179 °C. IH-NMR (300 MHz, CDCl3) 8 10.05 (s, 1H), 7.99 (s, 1H), 7.67 (brs, 1H), 7.44 (d, 1H, J= 3.6 Hz), 7. 34 (d, 1H, J= 5.4 Hz), 7.10 (dd, 1 H, J= 5.4, 3.6 Hz), 6.48 (s, 1H), 5.67 (brs, 1H), 4.64 (s, 2H), 4.02 (s, 3H). MS (EI) m/z= 291 ([M]+, 100%). Anal. Calcd. for Cl4Hl3NO4S : C, 57.72 ; H, 4.50 ; N, 4.81 ; S, 11.01. Found: C, 57.63 ; H, 4.50 ; N, 4.87 ; S, 11.03.

The title compound was prepared by condensing 2- (2-formyl-5-methoxy-4-thiophen-2-yl- phenoxy) -acetamide (Ex-71A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 70% yield, mp 235 °C (dec.). 1H-NMR (300 MHz, DMSO-d6) 8 8.26-8. 30 (m, 3H), 8.08-8. 11 (m, 4H), 7.67 (d, lH, J= 2. 7 Hz), 7.65 (brs, 1H), 7.53 (d, 1H, J= 4. 0-Hz),' 7.49 (brs, 1H), 7.13 (m, 1H), 6.77 (s, 1H), 4.75 (s, 2H), 3.97 (s, 3H). MS (EI) m/z = 437 ([M]+, 100%). HRMS (EI) Calcd. for C23H19NO6S : 437.0933. Found: 437.0924.

EXAMPLE 72

4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acry loyl}- benzoic acid Ex-72A: 4-Methoxy-2- (2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-benzaldehyde was prepared in an analogous fashion as described in Ex-29C using 4- (2-chloroacetyl) morpholine.

Silica gel chromatography (80% ethyl acetate/hexanes to 100% ethyl acetate) gave the expected product as a pale yellow solid, mp 200-201 °C.'H-NMR (300 MHz, CDCl3) 8 10.33 (s, 1H), 8. 12 (s, 1H), 7.44 (d, 1H, J= 3. 6 Hz), 7.31 (d, 1H, J= 5. 1 Hz), 7.08 (dd, 1H, J=5. 1, 3. 6 Hz), 6.74 (s, 1H), 4.89 (s, 2H), 4.00 (s, 3H), 3.67 (brs, 8H). MS (ESI) m/z = 362 ([M+H]+, 100%).

Anal. Calcd. for C18H19NO5S : C, 59.82 ; H, 5.30 ; N, 3.88 ; S, 8.87. Found: C, 59.88 ; H, 5.36 ; N, 3.90 ; S, 8.75.

The title compound was prepared by condensing 4-methoxy-2- (2-morpholin-4-yl-2-oxo- ethoxy) -5-thiophen-2-yl-benzaldehyde (Ex-72A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Orange solid, mp 231-233 °C, 70% yield.'H-NMR (300 MHz, DMSO- d6) 6 8.28-8. 35 (m, 3H), 8.21 (s, 1H), 8.07-8. 11 (m, 3H), 7.66 (d, 1H, J= 3. 3 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J= 5.1, 3.3 Hz), 6. 87 (s, 1H), 5.13 (s, 2H), 4.00 (s, 3H), 3@ 65 (brm, 4H), 3.54-3. 55 (m, 4H). MS (EI) m/z = 507 ([M]+, 100%). Anal. Calcd. for C27H25NO7S#½EtOH : C, 63.55 ; H, 5.61 ; N, 2.60 ; S, 5.95. Found: C, 63.13 ; H, 5.55 ; N, 2.53 ; S, 5.84.

EXAMPLE 73

4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-t hiophen-2-yl-phenyl}- acryloyl)-benzoic acid, hydrochloride Ex-73A: Methanesulfonic acid 2- (1-methyl-pyrrolidin-2-yl)-ethyl ester was prepared in an analogous fashion as described in Ex-50A using (S)-(-)-1-methyl-2-pyrrolidinemethanol. The crude orange oil was dried in vacuo to give the expected product and was used without any further purification (40%). 1H-NMR (300 MHz, CDCl3) 8 4.99-5. 04 (m, 1H), 4. 41-4. 51 (m, 1H), 4. 19-4. 29 (m, 1H), 3.88-3. 94 (m, 1H), 3.49 (s, 3H), 3.17-3. 29 (m, 1H), 2.95-3. 05 (m, 1H), 2.74 (s, 3H), 2.41-2. 58 (m, 3H), 1.98-2. 08 (m, 2H). MS (El) m/z= 207 ([M] +, 100%). HRMS (EI) Calcd. for Cl8Hl9NOss : 207.0929. Found: 207.0922.

Ex-73B: 4-Methoxy-2- [2- ( 1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-benzaldehy de was prepared in an analogous fashion as described in Ex-29C using Methanesulfonic acid 2- (1- methyl-pyrrolidin-2-yl) -ethyl ester (Ex-73A). Silica gel chromatography (10% methanol/methylene chloride to 15% methanol/methylene chloride) gave 0.50 g (70 %) of the expected product as a pale yellow oil. 'H-NMR (300 MHz, CDC13, major isomer) 8 10.35 (s, 1H), 8.09 (s, 1H), 7.42-7. 44 (m, 1H), 7.30 (d, 1H, J= 5. 1 Hz), 7.06-7. 09 (m, 1H), 6.49 (s, 1H), 4.80 (m, 1H), 4. 20-4. 26 (m, 1H), 3.98 (s, 3H), 2.64-2. 84 (m, 2H), 2.47 (s, 3H), 1.80-2. 33 (m, 7H). MS (EI) m/z = 345 ([M]+, 100%). HRMS (EI) Calcd. for C18H19NO5S : 345.1399. Found: 345.1401.

The title compound was prepared by condensing 4-methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)- ethoxy] -5-thiophen-2-yl-benzaldehyde (Ex-73B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Dark Yellow solid, 52%, mp 206-208 °C..'H-NMR (300 MHz, DMSO-

d6, major isomer) 6 8.30 (s, 1H), 8.25 (d, 2H, J= 7. 8 Hz), 8.07-8. 12 (m, 3H), 7.94 (d, 1H, J= 15. 6 Hz), 7.68 (d, lH, J=3. 3Hz), 7.52 (d, lH, J=5. 1 Hz), 7.14 (dd, 1 H, J = 5. 1, 3. 3 Hz), 6.86 (s, 1H), 5.05 (m, 1H), 4.34 (m, 1H), 4.00 (s, 3H), 3.40-3. 46 (m, 2H), 2.81 (s, 3H), 2.40-2. 44 (m, 1H), 2.16-2. 27 (m, 2H), 1.81-2. 00 (m, 4H). MS (ESI) m/z= 492 ([M+H]+, 100%). Anal. Calcd. for C28H30ClNO5S½H2O : C, 60.59 ; H, 5.99 ; N, 2.52 ; S, 5.78. Found: C, 60.70 ; H, 5.85 ; N, 2.64 ; S, 6. 15.

EXAMPLE 74 4- 3E- [2, 4-Dimethoxy-5- (lH-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid Ex-74A: A solution of 4-(4, 4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl)-lH-pyrazole (0.33g, 1.70 mmol) and di-tert-butyl dicarbonate (0. 5 Ig, 2.34 mmol) in dichloromethane (10 mL) was allowed to stir overnight at ambient temperature. The solution was then washed with saturated solution of sodium bicarbonate and brine, dried over sodium sulfate, and concentrated. The crude product of 4-(4, 4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl)-pyrazole-1-carboxylic acid ter-butyl ester (0. 61 g) was used in next step without further purification.

Ex-74B: To a mixture of 2, 4-dimethoxy-5-bromo-benzaldehye (0.28g, 1.13 mmol), 4- (4, 4,5, 5- 'tetramethyl- [1, 3,2] dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (Ex-76A, 0. 61g, 1.70 mmol), bis (tri-tert-butylphosphine) palladium (43 mg, 0.085 mmol) and potassium fluoride (0.24g, 4.08 mmol) was added degassed tetrahydrofuran (15 mL). The reaction mixture was heated at 60 °C for one day. Additional potassium fluoride (0.24g, 4.08 mmol) and water (20 pL) were added. The reaction mixture continued to stir at 60 °C for another 8 hours. The reaction was then quenched by water. The aqueous solution was extracted with ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified

by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) afforded 4- (5- formyl-2, 4-dimethoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (0. 15g, 40%) as white solid.'H NMR (CDC13) 8 10. 35 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 6.52 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.68 (s, 9H). MS m/z = 333 ( [M + H] +, 100%).

The title compound was prepared by condensing 2, 4-dimethoxy-5-(1H-pyrazol-4-yl)- benzaldehyde (Ex-74B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3 including an acid work-up. Yellow solid, mp >250 °C.'H-NMR (DMSO-d6) 8 12.42 (bs, 1H), 8.20-8. 03 (m, 8H), 7.85 (d, J = 16.1 Hz), 6.74 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). MS m/z= 379 ([M+H]+, 100%).

EXAMPLE 75 4-{3E-[2, 4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid Ex-75A: A solution of 2- (5-bromo-2, 4-dimethoxy-phenyl)- [1, 3] dioxolane (Ex-46A, 1.16 g, 4.9 mmol), sodium azide (641.3 mg, 9.86), and zinc bromide (552.2 mg, 2.46 mmol) in water (14 mL) and isopropanol (17 mL) were mixed and refluxed for 18 hours. The reaction mixture was quenched with 3N HCI (60 mL) and extracted with ethyl acetate (2 x 75 mL). The organic ws concentrated to a white solid. The solid was stirred in 0.25N NaOH (100 mL) for one hour.

The suspension was filtered and the filtrate was collected and acidified with IN HCI to a pH of 2. The aqueous solution was extracted with ethyl acetate: THF (40%). The organics were collected and concentrated to a crude brown solid of 2,4-dimethoxy-5-(2H-tetrazol-5-yl)- benzaldehyde (77.8 mg, 7%). 1H-NMR (DMSO-d6) 8 10.09 (s, 1 H), 7.97 (s, 1H), 6.89 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). MS m/z = 234 ( [M] +, 94%), 191 (100%).

The title compound was prepared by condensing 2, 4-dimethoxy-5- (2H-tetrazol-5-yl)- benzaldehyde (Ex-75A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.

Yellow solid, 19% yield, mp 218 °C (dec).'H-NMR (DMSO-d6) 8 8.58 (s, 1 H), 8.20 (d, 2H), 8.03 (m, 3H), 7.85 (d, 1H), 6.90 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). MS m/z = 422 [(M+CH3CN+H]+, 100%). HRMS m/z: calc. 381.1199, found 381.1184.

EXAMPLE 76 4- {3E- [5- (3H Imidazo [4, 5-b] pyridin-2-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid Ex-76A: To a suspension of 2,4-dimethoxybenzoic acid (0.36 g, 2 mmol) and 8 MI of POC13 in a 50 ml of a round-bottom flask, 2,3-diaminopyridine (0.22 g, 2 mmol) was added. The mixture was heated to reflux for 4 hours and then cooled to room temperature. The reaction mixture was then concentrated to remove most of the POC13. The residue was carefully treated with IN HC1 at 0 °C using a water-ice bath, then neutralized with NaOH (50 %). The off-white solid was filtered to give 2- (2, 4-dimethoxy-phenyl)-3H-imidazo [4, 5-b] pyridine (0.44 g, 88%).'H- NMR (DMSO-d6) 8 8.28-8. 36 (m, 2H), 7.97 (d, J = 8 Hz, 1H), 7.21-7. 25 (m, 1H), 6.80 (s, 1H), 6.78 (d, J = 9 Hz, 1H), 4.05 (s, 3H), 3.91 (s, 3H). HRMS (ES+) Calcd. for C24H19N3O5 : 430.1403. Found: 430.1414.

Ex-76B: To a suspension of 2- (2, 4-dimethoxy-phenyl)-3H-imidazo [4, 5-b] pyridine (0.44 g, 1.7 mmol) in 20 ml of CH2CI2, 1, 1-dichlorodimethyl ether (0.55 g, 4.8 mmol) was added. The mixture was cooled to 0 °C with a water-ice bath, and 7 ml (7 mmol) of TiC4 (1.0 m in CH2CI2) was added dropwise. The mixture was stirred at 0 °C for 2 hrs, then room temperature for overnight. The reaction mixture was poured into ice-water and the precipitate was filtered to give 0.31 g (63%) of 5- (3H-imidazo [4,5-b] pyridin-2-yl) -2, 4-dimethoxy-benzaldehyde as a

white solid.'H-NMR (DMSO-d6) 5 10.22 (s, 1H), 8.67 (s, 1H), 8.56 (d, J = 5 Hz, 1H), 8.44 (d, J = 8 Hz, 1H), 7.57-7. 61 (m, 1H), 6.97 (s, 1H), 4.19 (s, 3H), 4.06 (s, 3H). HMRS (EI) calcd. for C, Hl 3N303 : 283.0957 ; found: 283.0952.

The title compound was prepared by condensing 5-(3H-imidazo [4,5-b] pyridin-2-yl) -2,4- dimethoxy-benzaldehyde (Ex-76B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 222-224°C, 60% yield.'H-NMR (DMSO-d6) 8 8.75 (s, 1H), 8.38- 8.40 (m, 1H), 8.18 (d, J = 9Hz, 2H), 7.99-8. 08 (m, 4H), 7.83 (d, J = 15 Hz, 1H), 7.28-7. 33 (m, 1H), 6.91 (s, IH), 4. 11 (s, 3H), 4.04 (s, 3H). MS m/z = 430 ([M+H] +).

EXAMPLE 77 2- {4- [3E- (2, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-meth yl-propionic acid Ex-77A: To a mixture of aluminum chloride (2.8g, 20.8 mmol) in carbon disulfide (50 mL) was added acetyl chloride (0.74 mL, 10.4 mmol) followed by addition of 2-methyl-2-phenyl- propionic acid ethyl ester (1. Og, 5.2 mmol). The reaction mixture was refluxed for 2 hours and then poured into ice containing sulfuric acid (6M). The mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0. 5M), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography.

Elution with ethyl acetate (33%, v/v, in hexane) gave 2- (4-acetyl-phenyl)-2-methyl-propionic acid ethyl ester (0.57g, 47%). 1H NMR (CDCI3) 8 7.92 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 4.13 (q, J = 7. 2 Hz, 2H), 2.59 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.18 (t, J = 7. 2 Hz, 3H).

The title compound was prepared by condensing 2- (4-acetyl-phenyl)-2-methyl-propionic acid (Ex-77A) and 2, 4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manner as described in Ex-3. White foam.'H-NMR (CCD13) 8 8.11-7. 86 (m, 5H), 7.62-7. 46 (m, 3H), 7.42 (d, J = 3. 2 Hz, 1H), 7.31 (d, J = 5.3, 1H), 7.10-7. 08 (m, 1H), 6.54 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H). MS m/z = 436 (M+, 55%), 405 ([M-OCH3] +, 100%).

EXAMPLE 78 3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-1-[4-(2H-tetrazol- 5-yl)-phenyl]-propenone Ex-78A: A suspension of 4-acetylbenznitrile (2.9g, 20.0 mmol), sodium azide (1. 43g, 22.0 mmol) and zinc bromide (4. 5g, 20.0 mmol) in water (50 mL) was refluxed for one day.

Additional water (40 mL), HCl (3M, 30 mL) and EtOAc (200 mL) were added subsequently.

The mixture was stirred until no solid in the aqueous layer. The mixture was then portioned.

The aqueous solution was further extracted with EtOAc (3 x 60 mL). The combined EtOAc was concentrated. The residue was treated with NaOH (0.25 M, 200 mL). After stirred for 50 min, insoluble material was filtered, washed with NaOH (1M). The filtrate was then acidified with HCI (conc.) to pH 3. The resulting white precipitate was filtered, washed with water and dried in vacuo to obtain 1-[4-(2H-tetrazol-5-yl)-phenyl]-ethanone as white solid.'H NMR (DMSO-d6) 8 8.17-8. 10 (m, 4H), 2.61 (s, 3H). MS m/z = 188 (M+) The title compound was prepared by condensing 1- [4- (2H-tetrazol-5-yl)-phenyl]-ethanone (Ex- 78A) and 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manner as described in Ex-3. Yellow solid, mp 235 °C (dec.).'H-NMR (DMSO-d6) S 8.33 (d, J = 8.4 Hz, 2H), 8.26 (s, 1H), 8.20 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 16.0 Hz, 1H), 7.93 (d, J = 15.0 Hz, 1H), 7.66-7. 64 (m, 1H), 7. 50-7. 48 (m, 1H), 7.12-7. 09 (m, 1H), 6.81 (s, 1H), 3.983 (s, 3H), 3.976 (s, 3H). MS m/z = 418 (M+, 100%).

EXAMPLE 79

4- [3Z-(5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid A solution of 4- [3E- (5-benzo [b] thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid (Ex-3, 101.4 mg, 0.23 mmol) in ethyl acetate (889 ml) was stirred in a well lighted-area at room temperature for 36 hours. The solution was concentrated to a yellow solid. The crude material was purified on reversed-phase preprative plates (20 x 20 cm, RP-18 F254, lmm) eluted with MEOH/ACN/H20 (45: 45: 10) to give 22.2 mg of the title compound, which was 86% the cis isomer by NMR analysis.'H-NMR (DMSO-D6, major isomer) 8 7.98 (s, 4 H), 7.86 (m, 2H), 7.76 (d, J = 9 Hz 1H), 7.56 (s, 1H), 7.28 (m, 2H), 7.17 (d, J = 12 Hz, 1H), 6.78 (d, J= 12 Hz, 2H), 6.71 (s, 1H), 3.94 (s, 3H), 3.77 (s, 3H).

EXAMPLE 80 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide To a solution of 4-acetyl-benzsulfonamide (Ex-26A, 0.20g, 1.0 mmol) and 5- benzo [b] thiophene-2-yl-2, 4-dimethoxyphenylbenzaldehyde (Ex-3A, 0. 31g, 1.05 mmol) in DMF (5 mL) and methanol (2 mL) was added lithium methoxide (0. 15g, 4.0 mmol). The reaction mixture was allowed to stir at ambient temperature. The reaction was quenched with

water (30 mL) after 2 hours. The aqueous solution was acidified to pH 4 with HCl (3 M) and extracted with ethyl acetate. The combined solution of ethyl acetate was subsequently washed with brine, dried (Na2S04) and concentrated. The solid residue was stirred in ethanol (10 mL) for 1.5 hours, filtered, washed with aqueous ethanol (50%) and dried in vacuo. The title compound was obtained as a yellow solid (0.3g, 63%), mp 204-205 °C (dec.). IH-NMR (DMSO-d6) 8 8.35 (s, 1H), 8.27 (d, J = 7.7 Hz, 2H), 8.06 (d, J = 16.0 Hz, 1H), 7.97-7. 92 (m, 4H), 7.88 (d, J = 6. 6 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.53 (s, 2H), 7.37-7. 27 (m, 2H), 6.85 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H).

EXAMPLE 81 4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acrytoyl}- benzenesulfonamide 4-Acetyl-benzenesulfonamide (Ex-26A) (0.10 g, 0.29 mmol) and 4-acetylbenzenesulfonamide (0.057 g, 0.29 mmol) were dissolved in a dimethylformamide-methanol solution (2.0 mL, 7: 3).

After complete dissolution, lithium methoxide (0.044 g, 1.2 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.13 g (82%) of the title compound as a yellow solid, mp 186-188 °C.'H-NMR (300 MHz, DMSO-d6) 8 8.23-8. 28 (m, 3H), 7.93-8. 09 (m, 4H), 7.66 (d, 1H, J= 3. 0 Hz), 7. 56 (brs, 1H), 7.52 (d, 1H, J = 5.1 Hz), 7.13 (dd, 1H, J= 5.1, 3.0 Hz), 6.89 (s, 1H), 4.34 (t, 2H, J= 6 Hz), 4.01 (s, 3H), 3.54-3. 58 (m, 4H), 2.83 (t, 2H, J = 6 Hz), 2.51-2. 53 (m, 4H). MS (ESI) m/z = 529 ([M+H] +, 100%). Anal. Calcd. for C26H28N206S2 : C, 59.07 ; H, 5.34 ; N, 5.30 ; S, 12.13. Found: C, 58.90 ; H, 5.38 ; N, 5.37 ; S, 12.01.

EXAMPLE 82

2- {5-Methoxy-2- [3-oxo-3- (4-aminosulfonyl-phenyl)-E-propenyl]-4-thiophen-2-yl- phenoxy}-2-methyl-propionic acid The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2- (2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid (Ex-59B) in a similar manner as described in Ex-22. Yellow solid, mp 164-165 °C, 85% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.21-8. 28 (m, 3H), 7.96-8. 12 (m, 4H), 7.67 (d, 1H, J= 3.0 Hz), 7.56 (brs, 3. 0H), 7.14 (dd, 1H, J= 5.7, 3.0 Hz), 6.57 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) mlz = 502 ([M+H] +, 100%). Anal. Calcd. for C24H23NO7S2 : C, 57.47 ; H, 4.62 ; N, 2.79 ; S, 12.79. Found: C, 57.70 ; H, 4.74 ; N, 2.85 ; S, 12. 51.

EXAMPLE 83 2- {2, 4-Dimethoxy-5- [3-oxo-3- (4-aminosulfonyl-phenyl)-E-propenyl]-phenyl}-indole-1- carboxylic acid tert-butyl ester The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2- (5-formyl-2, 4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex-36A) in a

similar manner as described in Ex-22. Yellow solid, 40% yield, mp 120-122°C.'H-NMR (CDC13) 8 8. 01-8. 19 (m, 6H), 7.68 (s, 1H), 7.56 (d, J = 8 Hz, 1H), 7.46 (d, J = 16 Hz, 1H), 7. 21- 7. 35 (m, 2H), 6.53 (d, J = 14 Hz, 2H), 5.01 (s, 2H), 4.00 (s, 3H), 3.85 (s, 3H), 1.42 (s, 9H). MS m/z = 563 ([M+H]+). HRMS (ES+) Calcd. for C3oH3oN207S : 563.1852. Found: 563.1862.

EXAMPLE 84 4- {3E- [5- (lH-Indol-2-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 5- (1H-indol-2-yl)-2, 4-dimethoxy-benzaldehyde (Ex-61A) in a similar manner as described in Ex- 22. Red solid, 70% yield, mp 185-187°C.'H-NMR (DMSO-d6) 8 11.15 (br, s, 1H), 8.33 (s, 1H), 8.24 (d, J = 8 Hz, 2H), 8.07 (d, J = 15 Hz, 1H), 7.98 (d, J = 8 Hz, 2H), 7.80 (d, J = 15 Hz, 1H), 7.41-7. 55 (m, 4H), 7.03-7. 08 (m, 1H), 6.93-6. 99 (m, 2H), 6.83 (s, 1H), 4.04 (s, 3H), 3.99 (s, 3H). MS m/z = 463 ([M+H]+). HRMS (ES+) Calcd. for C25H22N205S : 463.1327. Found: 463. 1316.

EXAMPLE 85 4- {3E- [4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl} - benzenesulfonamide

The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4- methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-22. Yellow solid, 48% yield, mp 193-196°C.'H-NMR (DMSO-d6) 8 8.24 (m, 3 H), 8.06 (s, 1H), 7.96 (d, 2H), 7.89 (d, 1H), 7.63 (d, 1H), 7.51 (m, 1H), 7.10 (dd, J = 3,4 Hz, 1H), 6.81 (s, 1H), 4.23 (t, 2H), 3.98 (s, 3H), 3.55 (t, 4H), 2.47 (m, 2H), 2.35 (t, 4H), 1.98 (q, 2H). MS m/z= 542 ([M] +, 38%), 100 (100%). Anal. calculated for C27H3oN206S23/5H2O : C, 58.59, H, 5.68, S, 11.59 ; found C: 58.59, H: 5.55, S: 11.40.

EXAMPLE 86 4- {3E- [2- (3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-y l-phenyl]-<BR> <BR> <BR> <BR> <BR> <BR> acryloyl}-benzenesulfonamide 2- (3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-y l-benzaldehyde (Ex-64B) (8.0 g, 24.8 mmol) and 4-acetylbenzenesulfonamide (4.9 g, 24.8 mmol) were dissolved in a dimethylformamide-methanol solution (170 mL, 7: 3). After complete dissolution, lithium methoxide (3.8 g, 99.2 mmol) was added and the resulting red-orange slurry was stirred in the dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (6 x 200 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (150 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 7.0 g (60%) of the title compound as a light orange solid, mp 123-124 °C. IH- NMR (300 MHz, DMSO-d6) 8 8.25-8. 29 (m, 3H), 7.90-8. 11 (m, 4H), 7.66 (d, 1H, J= 3.0 Hz), 7.56 (brs, 1H), 7.52 (d, 1H, J= 5.1 Hz), 7.13 (dd, 1H, J= 5.1, 3.0 Hz), 6.88 (s, 1H), 4.67 (t, 2H, J= 10. 8 Hz), 4.24 (d, 2H, J= 6.0 Hz), 4.00 (s, 3H), 3.54-3. 65 (m, 4H), 2.09-2. 13 (m, 1H). MS (ESI) m/z = 504 ([M+H]+, 100%). Anal. Calcd. C24H2sNO7S2H20 : C, 57.24 ; H, 5.00 ; N, 2.78 ; S, 12.73. Found: C, 56.72 ; H, 5.27 ; N, 2. 71 ; S, 12.11.

EXAMPLE 87

4-13E-(5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl-<BR> <BR> <BR> <BR> <BR> benzenesulfonamide A solution of 4- [3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]- benzenesulfonamide (Ex-80, 0.15g, 0.31 mmol) in tetrahydrofuran (3 mL) was cooled to-78 °C and a solution of lithium bis (trimethylsilyl) amide (1. 0 M in tetrahydrofuran, 0.63 mL, 0.63 mmol) was added dropwise. The solution was allowed to stir at this temperature for 1 hour and warm up to 0 °C. Isobutyric acid anhydride (0.31 mL, 1.88 mmol) was added at this temperature. The solution was allowed to stir at 0°C for 10 min and ambient temperature for 2 hours. The reaction then was quenched with water. The aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. The residual material was stirred in ethanol for 3 hours, filtered and dried in vacuo to give the title compound as a yellow solid (0.15g, 87%), mp > 240 °C (dec.).'H-NMR (CDC13) 8 8.21 (d, J= 8. 6 Hz, 2H), 8.13 (d, J = 8. 7 Hz, 2H), 8.09 (s, 1H), 8.02 (bs, 1H), 7.94 (s, 1H), 7.85-7. 78 (m, 2H), 7.68 (s, IH), 7.55 (d, J = 16.9 Hz, 1H), 7.38- 7.30 (m, 2H), 6. 58 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H), 2.47-2. 38 (m, 1H), 1.14 (d, J = 7.1 Hz, 6H). MS m/z = 549 (M+, 100%).

EXAMPLE 88

4- {3E- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzenesulfonamide, hydrochloride Th 4- {3- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzenesulfonamide (Ex-81,0. 065 g, 0. 12 mmol) was dissolved in tetrahydrofuran (5 mL) and 3 N HCI (1 mL) was added drop wise to the solution. The resulting yellow slurry was stirred in the dark at room temperature for 30 min. The precipitate was collected and dried in vacuo to yield 0.054 g (78%) of the title compound as a yellow solid, mp 235 °C (dec). 'H-NMR (300 MHz, DMSO-d6) : 8 8.31-8. 34 (m, 3H), 8.13 (d, 1 H, J= 15. 0 Hz), 7.92-8. 01 (m, 3H), 7.70 (d, 1H, J= 4.0 Hz), 7.54 (m, 3H), 7.15-7. 17 (m, 1H), 6.92 (s, 1H), 4.64 (brs, 2H), 4.03 (s, 5H), 3.72-3. 79 (m, 4H), 3.56-3. 60 (m, 4H). MS (ESI) m/z= 529 ([M+H]+, 100%). Anal. Calcd. for C26H29CIN206S2 : C, 55.26 ; H, 5.17 ; Cl, 6.27 ; N, 4.96 ; S, 11.35. Found: C, 55.31 ; H, 5.17 ; Cl, 6.32 ; N, 4.98 ; S, 11. 20.

EXAMPLE 89 4- {3E- [4-Methoxy-2- (lH-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyt}- benzenesulfonamide

Ex-89A: (2-Acetyl-5-methoxy-4-thiophen-2-yl-phenoxy) -acetonitrile was prepared in an analogous fashion as described in Ex-29C using iodoacetonitrile. The crude solid was slurried in ethyl acetate (50 mL) to remove residual impurities. The resulting solid was collected on filter paper and dried in vacuo to give the expected product as an orange solid (70%), mp 175- 176°C. IH-NMR (300MHz, CDCl3) 6 10.29 (s, lH), 8.17 (s, lH), 7.48 (d, lH, J= 3. 6 Hz), 7. 35 (d, 1H, J= 5.1 Hz), 7.10 (dd, 1H, J= 5. 1,3. 6 Hz), 6.64 (s, 1H), 4.96 (s, 2H), 4.06 (s, 3H).

MS (EI) m/z = 273 ([M]+, 99%), 233 (100%). Anal. Calcd. for Cl4HI, NO3S : C, 61.52 ; H, 4.06 ; N, 5.12 ; S, 11.73. Found: C, 61.65 ; H, 4.20 ; N, 5.16 ; S, 11.59.

Ex-89B: (2-Acetyl-5-methoxy-4-thiophen-2-yl-phenoxy)-acetonitrile (Ex-89A, 0.30 g, 1. 1 mmol) was slurried in a mixture of water : isopropanol (3 mL, 2: 1) to obtain a well-dispersed solution. Sodium azide (0.079 g, 1.2 mmol) followed by zinc bromide (0.25 g, 1.1 mmol) were added and the reaction was heated to reflux and vigorously stirred for 24 h. Additional solvent (1 mL, 1: 1 water: isopropanol) was added after 10 h at reflux due to evaporation. The reaction was diluted with an ethyl acetate: tetrahydrofuran mixture (25 mL, 2: 1) and a 3 N HCl solution (10 mL) and vigorously stirred until a homogenous solution was obtained (1 h). The layers were separated and the aqueous was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a dark green solid. Silica gel chromatography (15% methanol/methylene chloride containing 1% acetic acid) gave 0.22 g (65%) of 4-methoxy-2-(lH-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-benzal dehyde as a pale green solid.'H-NMR (300 MHz, DMSO-d6) S 10.33 (s, 1H), 7.97 (s, 1H), 7.52-7. 56 (m, 2H), 7.10-7. 12 (m, 2H), 5.81 (s, 2H), 4.05 (s, 3H). MS (ESI) milz = 317 ([M+H]+, 100%). HRMS (ESI) Calcd. for C27H25NO7S : 317.0708. Found: 317.0712.

The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4- methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-benzalde hyde (Ex-89A) in a similar manner as described in Ex-22. Yellow solid, mp 163-164 °C (dec), 60% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.31-8. 34 (m, 3H), 7.92-8. 15 (m, 4H), 7.70 (d, 1H, J= 4.0 Hz), 7.54 (m, 3H), 7.15-7. 17 (m, 1H), 6.92 (s, 1H), 4.64 (brs, 2H), 4.03 (s, 5H). MS (ESI) m/z = 498 ([M+H] +, 100%). Anal. Calcd. for C22Hl9N505S2'1 Y2H20 : C, 50.37 ; H, 4.23 ; N, 13. 35 ; S, 12.23. Found: C, 50.48 ; H, 4.24 ; N, 12.95 ; S, 12.35.

EXAMPLE 90

4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N- (2-morpholin-4-yl-<BR> <BR> <BR> <BR> ethyl)-benzamide To a solution of 4- [3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid (Ex-3,0. 44 mg, 1 mmol) and 2-morpholin-4-yl-ethylamine (0.18 mL) in dichloromethane (20 mL) was added 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2 mmol) and the mixture was stirred at room temperature for four hours. It was poured into brine (100 mL) and extracted with dichloromethane (2 x 50 mL). The organic phase was dried and evaporated. Chromatography (dichloromethane/methanol 50: 1) gave the title compound as a yellow solid (0.43 g, 77%).'H-NMR (300 MHz, CDC13) 8 8.12 (d, J = 16 Hz, 1H), 8.09 (d, J = 8 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J = 8 Hz, 2H), 7.. 77-7.85 (m, 2H), 7.68 (s, 1H), 7.56 (d, J = 16 Hz, 1H), 7.29-7. 40 (m, 2H), 6.80-6. 85 (br s, 1H), 6.58 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H), 3.75 (t, J =5 Hz, 4H), 3.59 (quad, J = 5 Hz, 2H), 2.64 (t, J = 5 Hz, 2H), 2.53 (t, J = 5 Hz, 4H). Anal. calc. for C32H32N2OsSH2O : C, 67.94 ; H, 5.88 ; N, 4.95 ; found: C, 68.12 ; H, 5.92 ; N, 4.96.

EXAMPLE 91 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N- (2, 2, 2-trifluoro-ethyl)- benzamide

The title compound was prepared in a similar manner as described in Ex-90. Yellow solid, 53% yield, mp 215-217°C.'H-NMR (Acetone) 5 8.46 (br, s, H), 8.12-8. 24 (m, 4H), 8.06 (d, J = 8 Hz, 2H), 7.78-7. 91 (m, 4H), 7.28-7. 36 (m, 2H), 6.92 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 2.79 (s, 2H). MS m/z = 526 ([M+H] +). HRMS (ES+) Calcd. for C28H22F3NO4S : 526.1300. Found: 526. 1324.

EXAMPLE 92 4- 3E- [4-Methoxy-2- (2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzamide Ex-92A: To a solution of 4-acetyl-benzoic acid (0. 5g, 3.05 mmol) in tetrahydrofuran (10 mL) was added carbonyldiimidazole (0.74g, 4.75 mmol). The solution was allowed to stir at ambient temperature for one hour and cooled to 0 °C followed by addition of ammonia (28% in water, 3 mL, 21 mmol). The solution was continued to stir at 0 °C for another one hour. The solvent was removed under reduced pressure. The residue was treated with water, filtered, washed with water, dried in vacuo to give 4-acetyl-benzamide (0.25g, 50%) as a white solid.'H NMR (DMSO-d6) 8 8.11 (bs, 1H), 8.00 (d, J = 9 Hz, 2H), 7.95 (d, J = 9 Hz, 2H), 7.53 (bs, 1H), 2.59 (s, 3H).

To a solution of 4-acetyl-benzamide (Ex-92A, 0.25g, 1.53 mmol) and 2- (2-morpholin-4-yl- ethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-60A, 0.53g, 1. 53 mmol) in DMF (7 mL) and methanol (3 mL) was added lithium methoxide. The solution was allowed to stir at ambient temperature. The reaction was quenched with water after 2 hours. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NaHC03,

NH4CI, brine, dried (Na2S04) and concentrated. The residue was stirred in ethanol overnight to afford the title compound as a yellow solid (0.43g, 57%), mp 183-184 °C. IH-NMR (CDCI3) õ 8.09-8. 04 (m, 3H), 7.93 (d, J = 8.3 Hz, 2H), 7.87 (s, 1H), 7.57 (d, J = 15.7 Hz, 1H), 7.42 (d, J = 3.9 Hz, 1H), 7.32 (d, 4.4 Hz, 1H), 7.11-7. 08 (m, 1H), 6.55 (s, 1H), 6.25 (bs, 1H), 5.75 (bs, 1H), 4.25 (t, J = 5.9 Hz, 2H), 3.98 (s, 3H), 3.71 (t, J = 4.2 Hz, 4H), 2.92 (t, J = 5.7 Hz, 2H), 2.59 (t, J = 4.6 Hz, 4H). MS nilz = 493 ( [M + H] +, 100%).

EXAMPLE 93 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyll-benzamide To a solution of 4-acetyl-benzamide (0.3g, 1.84 mmol) and 5- (benzo [b] thein-2yl)-2, 4- dimethoxybenzaldehyde (0. 55g, 1.84 mmol) in a mixture of N, N dimethylformamide (7 mL) and methanol (3 mL) was added lithium methoxide (0.14g, 3.68 mmol). The reaction mixture was allowed to stir at ambient temperature for 9 hours. The resulting precipitate was collected by filtration, washed with methanol, dried in vacuo to obtain the title compound as a yellow solid (5.56g, 68%). Alternatively, to mixture of 4- [3E- (5-benzo [b] thiophen-2-yl-2,4- dimethoxy-phenyl)-acryloyl]-benzoic acid (Ex-3,3. 0 g, 6.75 mmol), 1- (3- dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (1.81 g, 9.45 mmol), 1- hydroxybenzotriazole hydrate (1.09g, 8.10 mmol) and ammonium chloride (1. 81g, 33.7 mmol) in N, N-dimethylformamide (60 mL) was added triethylamine (2.4 mL, 16.9 mmol). The reaction mixture was allowed to stir overnight at ambient temperature. Any insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate to 180 mL. The solution of ethyl acetate was washed with a saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give the title compound as a yellow solid (2.82g, 94%), mp 240-241 OC.'H-NMR (DMSO-d6) 8 8. 37 (s, 1H), 8.19 (d, J = 7. 8 Hz, 2H), 8.12 (d, J = 15. 3 Hz, 1H), 8. 04- 7. 91 (m, 6H), 7.83 (d, J = 7.5 Hz, 1H), 7.55 (s, 1H), 7.36-7. 30 (m, 2H), 6.87 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). MS m/z = 444 ([M+H]+, 100%).

EXAMPLE 94

4- {3E- [4-Methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl} - benzamide The title compound was prepared by condensing 4-Acetyl-benzamide (Ex-92A) and 4- methoxy-2- (3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-92. Orange solid, mp 81-83°C.'H-NMR (CDCI3) 8 8.08 (m, 3 H), 7.94 (d, 2H), 7.86 (s, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.10 (m, 1H), 6.55 (s, 1H), 4.19 (t, 2H), 3.99 (s, 3H), 3.72 (t, 4H), 2.59 (t, 2H), 2.12 (t, 4H), 1.98 (quintet, 2H). MS m/z = 506 ([M]+, 34%), 100 (100%). 28 %. Anal. calculated for C28H3oN20sS'2/5H20 : C, 65.45, H, 6.04, S, 6.24 ; found C: 65.30, H: 6.16, S: 6.17.

EXAMPLE 95 N-Acetyl-4- [3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzamide A suspension of 4-[3E-(5-benzo[b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-benzamide (Ex-93, 0. 5g, 1.13 mmol) in THF (15 mL) was cooled to-78 °C followed by addition of lithium bis (trimethylsilyl) amide (1.0 M in THF, 2.3 mL, 2.3 mmol). The mixture was stirred at this

temperature for 1 hour and warmed up to 0 °C. Acetic anhydride (0.48 mL, 6.8 mmol) was then added dropwise. After the addition was complete the reaction mixture was warmed up to ambient temperature and stirred for 2 hours. The reaction was quenched with water. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NH4CI, brine, dried and concentrated. The residue was purified by flash chromatography.

Elution with 50% EtOAc/hexane gave the title compound as yellow solid (0.16g, 29%), mp 228-229 OC.'H-NMR (CCD13) 8 8.52 (s, 1H), 8.15-8. 10 (m, 3H), 7.96 (d, J = 7. 6 Hz, 2H), 7.85-7. 77 (m, 2H), 7.67 (s, 1H), 7.55 (d, J = 16.7 Hz, IH), 7. 34-7. 29 (m, 3H), 6.58 (s, IH), 4.05 (s, 3H), 4.01 (s, 3H), 2.65 (s, 3H). MS m/z = 485 (M+, 100%).

EXAMPLE 96 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]-N-isobutyryl-benzamide The title compound was prepared in a similar manner as described in Ex-95 from- [3E- (5- benzo [b] thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide (Ex-93) and isobutyric anhydride. Yellow solid, mp 208-209°C. 1H-NMR (CCDl3) # 8.14 (s, 1H), 8.15-8. 10 (m, 3H), 7.96 (d, J = 7.2 Hz, 2H), 7.85-7. 77 (m, 2H), 7.67 (s, 1H), 7.56 (d, J = 16. 2 Hz, 1H), 7.38-7. 29 (m, 3H), 6.59 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.68-3. 59 (m, 1H), 1.28 (d, J = 6.2 Hz, 6H).

MS two = 513 (M+, 93%), 425 (100%).

EXAMPLE 97 4 (3E-14- [3- (4-Thiophen-2-yl-phenyl)-acryloyll-phenyl)-ureido)-acetic acid

A solution of (3- {4- [3- (4-thiophen-2-yl-phenyl)-acryloyl]-phenyll-ureido)-acetic acid ethyl ester (Ex-15,151. 3 mg, 0.35 mmol) in THF: MeOH : H20 (2: 1: 1,6 mL) was treated with lithium monohydrate (73.2 mg, 1.74 mmol) and stirred for 4 hours. The reaction mixture was titrated with 5N HCI to a pH2. The mixture was extracted with ethyl acetate (30 mL). The organic phase was collected, dried over Na2S04, and concentrated to a pure yellow solid (131.7 mg, 93%), mp 222-225°C.'H-NMR (DMSO-d6) 8 9.27 (br s, 1 H), 8.14 (d, 2H), 7.87 (m, 3H), 7.71 (d, 3H), 7.56 (m, 4H), 7.14 (t, IH), 6.54 (t, 1H), 3.78 (d, 2H). MS m/z = 407 ( [M+H] +, 88%), 306 (100%). Anal. calculated for C22H18N2O4S#1/2H2O : C, 63.60, H, 4. 61, S, 7.72 ; found C: 63.23, H: 4.70, S: 7.66.

EXAMPLE 98 N-{4- [3E- (3, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-N-meth yl- methanesulfonamide A solution ofN-{4- [3E- (3, 4-dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}- methanesulfonamide (Ex-14,90 mg, 0.20 mmol) in anhydrous DMF was treated with potassium carbonate (56.1 mg, 0. 41). Methyl iodide (126.32 uL, 2.03 mmol) was added to the reaction mixture which was then refluxed for 1.5 hours under inert conditions. The reaction was diluted with water (25 mL) and extracted with diethyl ether (2 x 50 mL). The organic portion was dried over sodium sulfate, filtered, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (30-50% ethyl acetate/hexanes) to give 42 mg (45%) of the title compound as a yellow solid. lH-NMR (CDCI3) 6 8.06 (d, 2H), 7.59 (d, 1H), 7.54 (m, 4H), 7.42 (m, 2H), 7.12 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.40 (s, 3H), 2.89 (s, 3H). MS m/z = 457 ([M]+, 100%).

EXAMPLE 99

3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-l- [4- (D-glucopyranosylamino)- phenyl]-propenone Ex-99A: D-Glucose (1.8 g, 10 mmol) and 4-aminoacetophenone (1.35 g, 10 mmol) were mixed in ethanol (50 ml), acetic acid (5 drops) was added, and the mixture was stirred at reflux for 2 hours. Water (2 ml) was added and the mixture became a homogeneous solution and was then stirred at reflux for 4 hours. Upon cooling to room temperature the precipitate was filtered out, rinsed with ethanol, and dried to give 4- (D-glucopyranosylamino) acetophenone as a white solid (1.21 g, 41%), mp 209-210°C (dec). H-NMR (DMSO-D6) 8 7.71 (d, J = 8 Hz, 2H), 7.06 (d, J = 8 Hz, 1H), 6.69 (d, J = 8 Hz, 2H), 4.98 (d, J = 4 Hz, 1H), 4.89 (d, J = 7 Hz, 2H), 4. 38-4. 45 (m, 2H), 3.55-3. 64 (m, 1H), 3.30-3. 46 (m, 1H), 3.00-3. 30 (m, 4H), 2.38 (s, 3H). MS m/z = 297 ([M] +, 15%), 148 (100%).

4-(D-Glucopyranosylamino) acetophenone (Ex-99A, 326 mg, 0.6 mmol) and (benzo [b] thien-2- yl) -2,4-dimethoxybenzaldehyde (Ex-3A, 150 mg, 0.5 mmol) were mixed in DMF (10 ml) and methanol (5 ml). Lithium methoxide (120 mg) was added, and the mixture was stirred at room temperature for 18 hours. Lithium methoxide (120 mg) was added again and the mixture was stirred overnight. Saturated sodium chloride solution (50 ml) was added and the mixture was extracted with dichloromethane. Chromatography (dichloromethane/methanol 10: 1) gave an oily yellow residue as the title compound (20 mg, 6%).'H-NMR (DMSO-D6) 8 8.29 (s, 1H), 7.78-8. 02 (m, 7H), 7.25-7. 38 (m, 2H), 7.15 (d, 1H), 6.84 (s, 1H), 6.77 (d, 2H), 4.99 (d, IH), 4.86-4. 95 (m, 2H), 4.41-4. 49 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.00-3. 45 (m 6H). MS m/z = 578 ([M+H]+, 100%).

EXAMPLE 100

2- {4- [3- (4-Methanesulfonylamino-phenyl)-3-oxo-E-propenyl]-5-methoxy- 2-thiophen-2-yl- phenoxy}-2-methyl-propionic acid Ex-lOOA : A solution of 4-aminoacetophenone (5. 0g, 37.0 mmol) and pyridine (3.0 mL) in anhydrous dichloromethane (300 mL) was treated with mesyl chloride (2.86 mL, 37.0 mmol).

The reaction was stirred for 84 hours at room temperature under nitrogen, and then quenched with saturated NH4CI solution (100 mL). The organic phase was collected, washed with water (100 mL) and brine, dried over sodium sulfate, and concentrated over silica. The material was purified by silica gel chromatography (50 % ethyl acetate/hexanes) to give 4.72 g (60%) of N- (4-acetyl-phenyl)-methanesulfonamide as a yellowish oil.'H-NMR (DMSO-d6) 8 10.28 (s, 1 H), 7.90 (d, 1H), 7.24 (d, 1H), 3.06 (s, 3H), 2.48 (s, 3H).

A solution of N- (4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 279.6 mg, 1.31 mmol) and 2- (4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid (Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide (182.2 mg, 4.8 mmol) and stirred for 5 hours at room temp. under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2 x 50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCI. The aqueous solution was then extracted with isopropyl acetate (2 x 50 mL). The organic was collected, dried over sodium sulfate, and concentrated to a green solid. Attempted to recrystallize crude material from ethanol/hexanes ; however, this mixture was concentrated and stirred with ethyl acetate (3 mL) to give 95.6 mg (14%) of the title compound as a yellow solid, mp 181-183°C.'H-NMR (DMSO-d6) 8 10.31 (br s, 1 H), 8.24 (s, 1H), 8.12 (d, 2H), 7.95 (d, I H), 7.87 (d, 1H), 7.67 (d, I H), 7.50 (d, I H), 7.30 (d, 2H), 7.09 (t, 1H), 6.45 (s, I H), 3.81 (s, 3H), 3.08 (s, 3H), 1.65 (s, 6H). MS m/z = 516 ([M+H] +, 100%). HRMS m/z : calc. 516.1150, found 516.1165.

EXAMPLE 101

2-(4-{3-14-(Methanesulfonyl-methyl-amino)-phenyl]-3-oxo-E-pr openyl}-5-methoxy-2-<BR> <BR> <BR> <BR> thiophen-2-yl-phenoxy)-2-methyl-propionic acid Ex-lOlA : A solution of N- (4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 2. 0g, 9.4 mmol) in anhydrous DMF (300 mL) was treated with potassium carbonate (2.59 g, 18.8 mmol), followed by the addition of methyl iodide (5.85 mL, 94 mmol). The reaction mixture refluxed for two hours and was then treated with more methyl iodide (5.85 mL, 94 mmol). The reaction refluxed for another two hours, and reaction completeness was confirmed by HPLC analysis.

The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 x 100mL).

). The organic phase was collected, dried over sodium sulfate, and concentrated to a clear oil with residual DMF. Water (25 mL) was added to precipitate a white solid. The white solid was then filtered and dried by vacuum oven at 20 °C (-20 mm Hg) to give 1. 37 g (64%) of N- (4-acetyl-phenyl)-N-methyl-methanesulfonamide.'H-NMR (CDC13) 8 7.88 (d, 2 H), 7.48 (d, 2H), 3.38 (s, 3H), 2.86 (s, 3H), 2.60 (s, 3H). HRMS m/z: calc. 530. 1307, found 530.1313.

A solution of N- (4-acetyl-phenyl)-N-methyl-methanesulfonamide (Ex-lOlA, 298 mg, 1.31 mmol) and 2- (4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propio nic acid (Ex- 47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide (182 mg, 4.8 mmol) and stirred for 6 hours at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2 x 50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCI. The aqueous solution was then extracted with isopropyl acetate (2 x 50 mL).

The organic was collected, dried over sodium sulfate, and concentrated to a yellow foam. The crude material was purified by silica gel chromatography (50% ethyl acetate/hexanes; 10% MeOH/CH2CL2) to give 293 mg (42%) of the title compound as a yellow solid, mp 197-200°C.

'H-NMR (DMSO-d6) 8 8.20 (s, 1 H), 8.12 (d, 2H), 8.00 (d, 1H), 7.83 (d, 1H), 7.66 (dd, J= 2,2 Hz, 1H), 7.53 (d, 2H), 7.44 (d, IH), 7.06 (dd, J= 2, 4 Hz, 1H), 6.78 (s, 1H), 3.82 (s, 3H), 3.28 (s, 3H), 2.98 (s, 3H), 1.56 (s, 3H). MS m/z = 530 ([M+H] +, 100%).

EXAMPLE 102 3-Amino-4- {4- [3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyl]- phenylamino}-cyclobut-3-ene-1, 2-dione Ex-102A : To a solution of 2. 7g (20 mmol) of 4'-aminoacetophenone in 90 mL of ethanol, 4. 5 g (20 mmol) of 3, 4-dibutoxy-3-cyclobutene-1, 2-dione (Aldrich) was added. The mixture was then heated to reflux overnight. A light yellow precipitate formed. To the reaction mixture, 20 mL (40 mmol) of ammonia (2.0 M in ethanol) was added, and the resultant mixture was stirred at room temperature for 2 hr. The light yellow solid was filtered and washed with ethanol to give 2.4 g (52%) of 3-(4-acetyl-phenylamino)-4-amino-cyclobut-3-ene-1, 2-dione. lH-NMR (DMSO-d6) 8 9.99 (br, 1H), 7.90 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 2H), 4.31 (br, 2H), 2.48 (s, 3H). HMRS (EI) calcd. for Cl2HIoN203 : 230.0691 ; found: 230.0691.

3- (4-Acetyl-phenylamino)-4-amino-cyclobut-3-ene-1, 2-dione (Ex-102A, 0.46 g, 2 mmol), and 5-(benzo [b] thien-2-yl)-2, 4-dimethoxybenzaldehyde (Ex-3A, 0.596 g, 2mmol) were dissolved in DMF (10 mL) under nitrogen, and 4.0 ml (4 mmol) of LiOMe (1.0 M in MeOH) was added.

The mixture was stirred under nitrogen at room temperature over night. The reaction mixture was poured into ice-water, acidified to pHI with 3N HCI, extracted with dichloromethane. The

combined organic phase was then washed with brine and water, dried over MgSO4, column chromatography (5 % MeOH in CH2CI2) to give 57 mg (5.4 %) title compound as a yellow solid, mp > 260°C.'H-NMR (DMSO-d6) 8 10.08 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 8 Hz, 2H), 8.03 (d, J = 15 Hz, 1H), 7.82-7. 95 (m, 4H), 7.57 (d, J = 8 Hz, 2H), 7.27-7. 37 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.26 (s, 2H). MS m/z = 511 [M+H] +, (20%), 416 (100%).

HRMS (ES+) Calcd. for C29H22N205S : 511.1327. Found: 511.1326.

EXAMPLE 103 5- [3E- (3, 4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzo [1, 3] dioxole-2, 2- dicarboxylic acid, diethyl ester Ex-103A: To a solution of KOH (1.25 M, 200 mL) were added 3,4-dihydroxy-acetophenone (2. 0g, 13.1 mmol) and cetyltrimethylamonium chloride (25% in water, 17 mL, 13.1 mmol).

The suspension was stirred at ambient temperature for 10 min followed by the addition of a suspension of 3, 4-dimethoxy-5-thiophen-2yl-benzaldehyde (Ex-6A, 3.9g, 15.8 mmol) in ethanol (10 mL). The reaction mixture was allowed to stir at ambient temperature overnight and was acidified with concentrated HCI to pH 3, saturated with NaCI, extracted with CH2CI2.

The combined solution of CH2CI2 was washed with brine, dried (Na2S04) and concentrated under reduced pressure. The crude product was purified by flash chromatography. Elution with 50% EtOAc/hexane gave 1- (3, 4-dihydroxy-phenyl)-3E- (3, 4-dimethoxy-5-thiophen-2-yl- phenyl) -propenone as a yellow oil.'H NMR (DMSO-d6) 8 7. 88 (s, 1H), 7.83-7. 81 (m, 2H), 7.76 (d, J = 2.4 Hz, 1H), 7.68-7. 74 (m, 2H), 7.61-7. 57 (m, IH), 7.51 (s, IH), 7.50 (d, J = 5.2 Hz, 1H), 7.13 (t, J = 4.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.77 (s, 3H). MS m/z = 382 (M+, 100%).

1- (3, 4-Dihydroxy-phenyl)-3E- (3, 4-dimethoxy-5-thiophen-2-yl-phenyl) -propenone (106 mg), diethyl dibromomalonate (380 mg) and potassium carbonate (500 mg) was mixed in acetone (15 ml) and the mixture was stirred at room temperature over a weekend. It was poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was dried and evaporated. Chromatography (hexanes/ethyl acetate 4: 1) gave an oily residue. Crystallization from hexanes and dichloromethane gave the title compound as a slightly yellow solid (70 mg), mp 125-126°C. IH-NMR (DMSO-d6) 8 7.76 (d, J = 15 Hz, 1H), 7.73 (dd, J = 2,7 Hz, 1H), 7.64 (d, J = 2 Hz, 1H), 7.54 (d, J = 1 Hz, 1H), 7.53 (d, J = 2 Hz, 1H), 7.39 (d, J = 5 Hz, 1H), 7. 38 (d, J = 15 Hz, 1H), 7.11 (dd, J = 2,5 Hz, 1H), 7.08 (d, J = 1 Hz, IH), 7.05 (d, J = 7 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 4.41 (quad, J = 7 Hz, 4H), 1.30 (t, J = 7 Hz, 6H).

EXAMPLE 104 4- [3E- (2, 4-Dimethoxy-5-pyridin-3-yl-phenyl)-acryloyl]-benzenesulfonam ide Ex-104A: 2, 4-Dimethoxy-5-pyridin-3-yl-benzaldehyde was prepared in a similar manner as described in Ex-3A from pyridine-3-boronic acid and 5-brom-2, 4-dimethoxybenzaldehyde, 68% yield. 1H-NMR (CDCl3) 8 10. 33 (s, 1H), 8.71 (d, J = IHz, IH), 8.51-8. 53 (m, 1H), 7.81 (s, 1H), 7.74-7. 78 (m, 1H), 7.27-7. 31 (m, 1H), 6. 52 (s, IH), 3.99 (s, 3H), 3.91 (s, 3H). HMRS (EI) calcd. for C14H13NO3 : 243.0895 ; found: 243. 0888.

The title compound was prepared by condensing 2,4-dimethoxy-5-pyridin-3-yl-benzaldehyde (Ex-104A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex- 22. Yellow solid, 51% yield, mp 253-255°C.'H-NMR (DMSO-d6) 8 8.69 (d, J = 1Hz, 1H), 8.50 (d, J = 4 Hz, 1H), 8.25 (d, J = 9 Hz, 2H), 8.08 (d, J = 15Hz, IH), 8.02 (s, I H), 7.84-7. 94 (m, 4H), 7.51 (s, 2H), 7.40-7. 44 (m, 1H), 6.82 (s, 1H), 3.98 (s, 3H), 3.88 (s, 3H). MS m/z = 424 ([M] +, 45%), 393 (100 %). HMRS (EI) calcd. for C22H2oN205S : 424.1093 ; found: 424.1100.

EXAMPLE 105

4- 3E- [5- (2-Cyclopropyl-lH-imidazol-4-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride Ex-lOSA : A solution of 2-bromo-1- (3, 4-dimethoxy-phenyl)-ethanone (0.3g, 1. 16 mmol), cyclopropanecarboxamidine (0.14g, 1. 16 mmol) and sodium hydroxide (0. 18g, 4.5 mmol) in ethanol was refluxed overnight. The solvent was removed under reduced pressure, the residue taken up to water. The aqueous solution was then extracted with dichloromethane which was subsequently washed with brine, dried over sodium bicarbonate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) then methanol (10%, v/v in dichloromethane) afforded 2-cyclopropyl-4- (2, 4- dimethoxy-phenyl)-lH-imidazole as white solid (0.15g, 53%) :'HNMR (CDC13) 8 9.50 (bs, 1H), 7.63 (s, 1H), 7.20 (s, IH), 6.57-6. 53 (m, 2H), 3.93 (s, 3H), 3.03 (s, 3H), 1.97-1. 93 (m, 1H), 1.00-0. 94 (m, 4H). MS niz = 245 ( [M + H] +, 100%).

Ex-105B : To a solution of 2-cyclopropyl-4- (2, 4-dimethoxy-phenyl)-lH-imidazole (0. 5 zig, 2.09 mmol) was added dichloromethyl methyl ether (0.28 mL, 3.13 mmol) followed by addition of titanium tetrachloride (I. OM in dichloromethane, 8.4 mL, 8.4 mmol) dropwise at 0 °C. The solution was allowed to warm up to ambient temperature and stir for 4.5 hours. The reaction mixture was then poured into ice. The aqueous layer was adjusted to pH 12 and extracted with dichloromethane. The combined solution of dichloromethane was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to afford 5-

(2-cyclopropyl-1H-imidazol-4-yl)-2, 4-dimethoxy-benzaldehyde which was used without further purification.'H NMR (DMSO-d6) 8 13.95 (bs, IH), 10.22 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H, 6. 88 (s, IH), 4.04 (s, 3H), 4.00 (s, 3H), 2.25 (m, 1H), 1.20 (m, 4H). MS m/z = 245 ( [M + H] +, 100%).

The title compound was prepared by condensing 5-(2-cyclopropyl-1H-imidazol-4-yl)-2, 4- dimethoxy-benzaldehyde (Ex-105B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, m. p. > 240 °C.'H NMR (DMSO-d6) 8 13.31 (bs, 1H), 8.29 (d, J = 8.9 Hz, 2H), 8.06-8. 01 (m, 3H), 7.91 (s, 1H), 7.67 (s, 1H), 6.83 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H), 1.29-1. 22 (m, 4H). MS m/z = 419 ( [M + H] +, 100%).

EXAMPLE 106 4- {3E- [4- (3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-y l-phenyl]-<BR> <BR> <BR> <BR> <BR> acryloyl}-benzenesulfonamide The title compound was prepared by condensing 4- (3-hydroxy-2-hydroxymethyl-propoxy)-2- methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50C) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 72% yield, mp 191-192 °C.'H-NMR (300 MHz, DMSO-d6) 6 8.29-8. 32 (m, 3H), 8.09 (d, 1H, J= 16. 0 Hz), 7.99 (d, 2H, J= 8. 1 Hz), 7.92 (d, IH, J= 16. 0 Hz), 7.70 (d, 1H, J = 3.3 Hz), 7.53-7. 56 (m, 3H), 7.14 (dd, 1H, J = 5.4, 3.3 Hz), 6.87 (s, 1H), 4.61 (t, 2H, J= 5.1 Hz), 4.28 (d, 2H, J= 5.1 Hz), 4.00 (s, 3H), 3.60-3. 67 (m, 4H), 2.11-2. 15 (m, 1H). MS (ESI) m/z = 504 ([M+H]+, 100%). Anal. Calcd. for C24H25NO7S2'Y2H20 : C, 56.23 ; H, 5.11 ; N, 2.73 ; S, 12. 51. Found: C, 56.32 ; H, 5.06 ; N, 2.83 ; S, 12.55.

EXAMPLE 107

1- (4-Benzenesulfonyl-phenyl)-3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)- propenone The title compound was prepared by condensing 1- (4-benzenesulfonyl-phenyl)-ethanone with 5- (benzo [b] thien-2-yl) -2,4-dimethoxybenzaldehyde (Ex-3A) in a similar manner as described in Ex-3,5% yield. The product was purified using column chromatography. Yellow solid, mp 127-128°C. 1H-NMR (CDCl3) # 8.05-8. 11 (m, 5H), 7.97 (d, J = 7 Hz, 2H), 7.91 (s, 1H), 7.76- 7.84 (m, 2H), 7.66 (s, 1H), 7.46-7. 60 (m, 4H), 7.26-7. 37 (m, 2H), 6.56 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H). MS m/z = 540 ([M]+, 100%). HRMS (El) Calcd. for Cl3H24OsS2 : 540.1605. Found: 540.1074.

EXAMPLE 108 1- (4-Acetyl-phenyl)-3E- (5-benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-propenone The title compound was prepared by condensing 1- (4-acetyl-phenyl)-ethanone with 5- (benzo [b] thien-2-yl) -2,4-dimethoxybenzaldehyde (Ex-3A) in a similar manner as described in Ex-3. The product was purified using column chromatography. Yellow solid, 2% yield, mp 165-167°C.'H-NMR (CDC13) 8 8.06-8. 12 (m, 5H), 7.92 (s, IH), 7.75-7. 82 (m, 2H), 7.65 (s, IH), 7.55 (d, J = 15 Hz, 1H), 7.28-7. 33 (m, 2H), 6.56 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H). MS m/z = 442 ([M] +, 100%). HMRS (EI) calcd. for C27H2204S : 442.1239 ; found: 442.1229.

EXAMPLE 109

4- {3E- [5- (4-Isobutyl-4H- [1, 2,4] triazol-3-yl)-2, 4-dimethoxy-phenyl]-acryloyl}- benzenesulfonamide Ex-109A: A solution of 2, 4-dimethoxy-benzoic acid methyl ester (4.24g, 21.6 mmol) and hydrazine (3.4 mL, 108.1 mmol) in methanol (50 mL) was refluxed overnight. Solvent was removed under reduced pressure. The residue was re-dissolved in ethyl acetate. The solution of ethyl acetate was washed with saturated solution of sodium bicarbonate and brine, dried over sodium carbonate and concentrated to afford 2,4-dimethoxy-benzoic acid hydrazide (3. 31 g, 78%) as a white solid :'H NMR (CDC13) 8 8.77 (bs, IH), 8.15 (d, J = 8.8 Hz, 1H), 6. 58 (dd, J = 8.8, 2.2 Hz, IH), 6.46 (d, J = 2.2 Hz, 1H), 4.10 (bs, 2H), 3.91 (s, 3H), 3.83 (s, 3H).

Ex-109B: A solution of 2,4-dimethoxy-benzoic acid hydrazide (Ex-109A, 1. 0g, 5.1 mmol) and isobutyl-isothiocyanate (0.70g, 6.1 mmol) in ethanol (30 mL) was refluxed for 8 hours. The precipitate was filtered, washed with ethanol, dried in vacuo to afford 1- (2, 4-dimethoxy- benzoyl) amino-3-isobutyl-thiourea (1.43g). Additional product (0. lg, 96% overall) was obtained by concentrating the mother liquid.'H NMR (CDC13) 8 10.71 (bs, 1H), 9.23 (bs, 1H), 8.03 (d, J = 8.6 Hz, IH), 6.98 (bs, 1H), 6.59 (dd, J = 8.6, 2.6 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.41 (dd, J = 6.4, 6.6 Hz, 2H), 1.96-1. 87 (m, 1H), 0.91 (d, J = 6. 5 Hz, 6H).

Ex-109C: A solution of 1- (2, 4-dimethoxy-benzoyl) amino-3-isobutyl-thiourea (Ex-109B, 0. 5g, 1.61 mmol) and sodium hydroxide (0.999M, 4.8 mL, 4.8 mmol) in ethanol (30 mL) was

refluxed for one day. The solvent was removed under reduced pressure and the residue re- dissolved in ethyl acetate. The solution of ethyl acetate was washed with water and brine, dried over sodium sulfate, and concentrated to give 5-(2, 4-dimethoxy-phenyl)-4-isobutyl-4H- [1, 2, 4] triazole-3-thiol (0. lg). Additional product (0.36g, 98% overall) was obtained by extracting the water wash with dichloromethane and a mixture of isopropyl alcohol (33%, v/v, in dichloromethane).'H NMR (CDC13) 8 10. 82 (bs, 1H), 7.24 (d, J = 8. 1 Hz, 1H), 6.56 (dd, J = 8. 1,2. 4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.72 (d, J = 6.7 Hz, 2H), 2.17-2. 08 (m, 1H), 0.70 (d, J = 6.7 Hz, 6H).

Ex-109D: To a solution of 5-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1, 2,4] triazole-3-thiol (Ex- 109C, 0. 1g, 0.34 mmol) in ethanol (10 mL) was added wet Raney Ni (0.27g, 4.6 mmol). The suspension of ethanol was refluxed overnight and then passed through a bed of Hyflo Super Gel and diatomaceous earth. The filtrate was concentrated to afford 3- (2, 4-dimethoxy-phenyl) - 4-isobutyl-4H-[1, 2,4] triazole (0.09g, 100%) as a white solid :'H NMR (CDCI3) 8 8.15 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.57 (dd, J = 7.8, 2.3 Hz, 1H), 6.51 (d, J = 2. 3 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.62 (d, J = 7. 5 Hz, 2H), 1.89-1. 80 (m, 1H), 0.76 (d, J = 6.6 Hz, 6H).

Ex-109E: To a solution of 3-(2, 4-dimethoxy-phenyl)-4-isobutyl-4H-[1, 2,4] triazole (Ex-109D, 0.78g, 2.98 mmol) was added dichloromethyl methyl ether (0.4 mL, 4.48 mmol) followed by addition of titanium tetrachloride (I. OM in dichloromethane, 9.0 mL, 9.0 mmol) over 10 min at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 min and ambient temperature overnight. The reaction mixture was poured into ice. The aqueous solution was extracted with dichloromethane and isopropyl alcohol (33%, v/v, in dichloromethane). The combined dichloromethane and isopropyl alcohol were washed with brine, dried over sodium sulfate and concentrated. The aqueous solution was treated with sodium hydroxide to pH 12 and extracted again with isopropyl alcohol (33%, v/v, in dichloromethane) to give additional product. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) afford 5- (4-isobutyl-4H [1, 2,4] triazol-3-yl) -2,4-dimethoxy-benzaldehyde (0.24g, 28%) :'H NMR (CDCI3) 8 10.30 (s, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 6.51 (s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 3.58 (d, J = 7.2 Hz, 2H), 1.91-1. 80 (m, 1H), 0.77 (d, J = 6.5 Hz, 6H).

To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12g, 0.62 mmol) and 5- (4-isobutyl- 4H [1, 2,4] triazol-3-yl)-2, 4-dimethoxy-benzaldehyde (Ex-109E, 0. 18g, 0.62 mmol) in N, N- dimethylformamide (9 mL) was added lithium methoxide (I. OM in methanol, 2.4 mL, 2.4 mmol). The solution was allowed to stir overnight. The reaction was quenched with water.

The aqueous solution was washed ethyl acetate, acidified to pH 5, extracted with dichloromethane, isopropyl alcohol (33%, v/v, in dichloromethane). The combined dichloromethane and isopropyl alcohol was washed with brine, dried over sodium sulfate and concentrated. The crude product was then stirred in ethanol (50%, v/v, in acetone) to give the title compound as a light yellow solid: m. p. > 240 °C.'H NMR (DMSO-d6) 8 8.60 (s, 1H), 8.26 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 15.3 Hz, IH), 8.07 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 15. 3 Hz, 1H), 7.50 (s, 1H), 6.84 (s, 1H), 4.01 (s, 3H), 3.87 (s, 3H), 3.61 (d, J = 7. 3 Hz, 2H), 1.81-1. 74 (m, 1H), 0.67 (d, J = 16.7 Hz, 6H). MS m/z = 471 ( [M + H] +, 100%).

EXAMPLE 110 4- {3E- [5- (4-Isobutyl-4H- [1, 2,4] triazol-3-yl)-2, 4-dimethoxy-phenyl]-acryloyl}-benzoic acid To a solution of 4-acetyl-benzoic acid (0.12g, 0.75 mmol) and 5- (4-isobutyl-4H [1, 2,4] triazol- 3-yl) -2,4-dimethoxy-benzaldehyde (Ex-109E, 0.24g, 0.83 mmol) in N, N-dimethylformamide (6 mL) was added lithium methoxide (1. OM in methanol, 3.0 mL, 3.0 mmol). The solution was allowed to stir overnight and additional lithium methoxide (0. 1 Ig, 2.8 mmol). The reaction was quenched with water after 20 hours. The aqueous solution was washed ethyl acetate, acidified to pH 4. The precipitate was filtered, washed with ethanol and dried in vacuo to afford the title compound as a light yellow solid: m. p. >240 °C (dec.). IH NMR (DMSO-d6) 8 8.59 (s, 1H), 8.18 (d, J = 7.9 Hz, 2H), 8.07 (s, 1H), 8.04-8. 01 (m, 3H), 7.85 (d, J = 15.7 Hz, 1H), 6.84 (s, IH), 4.06 (s, 3H), 3.92 (s, 3H), 3.66 (d, J = 7. 2 Hz, 2H), 1.87-1. 74 (m, 1H), 0.72 (d, J = 6.7 Hz, 6H). MS m/z = 436 ( [M + H] +, 100%).

EXAMPLE 111

4-t3E-15-(2-Cyclopropyl-lH-imidazol-4-yl)-2, 4-dimethoxy-phenyl]-acryloyl}- benzenesulfonamide To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12g, 0.59 mmol) and 5- (2- cyclopropyl-1H-imidazol-4-yl)-2, 4-dimethoxy-benzaldehyde (Ex-lOSB, 0.16g, 0.59 mmol) in N, N-dimethylformamide (16 mL) was added lithium methoxide (I. OM in methanol, 2.4 mL, 2.4 mmol). The reaction mixture was allowed to stir for 18 hours at ambient temperature. The reaction was quenched with water. The aqueous solution was extracted with dichloromethane.

The combined dichloromethane was concentrated. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) gave the title compound as red solid: m. p. 156-160 °C.'H NMR (DMSO-d6) 8 11.65 (bs, 1H), 8.32 (s, 1H), 8. 19 (d, J = 9. 0 Hz, 2H), 8.00 (d, J = 15.7 Hz, IH), 7.95 (d, J = 9.0 Hz, 2H), 7.62-7. 52 (m, 2H), 7.24 (bs, IH), 6.73 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 1.98-1. 94 (m, 1H), 0.88-0. 85 (m, 4H).

MS m/z = 454 ( [M + H] +, 100%).

EXAMPLE 112 4- {3E- [5- (3H Imidazo [4, 5-blpyridin-2-yl)-2, 4-dimethoxy-phenyl]-acryloyl}- benzenesulfonamide

The title compound was prepared by condensing 5-(3H-imidazo [4,5-b] pyridin-2-yl) -2,4- dimethoxy-benzaldehyde (Ex-76A) with 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 26% yield, mp >260°C.'H-NMR (DMSO-d6) 8 8.73 (s, 1H), 8. 31 (dd, J = 1, 4 Hz, 1H), 8.26 (d, J = 8 Hz, 2H), 8.05 (d, J = 16 Hz, 1H), 7.89- 7.97 (m, 3H), 7.82 (d, J = 16 Hz, 1H), 7.17-7. 21 (m, 1H), 6.89 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H). MS nzlz = 465 ([M+H]+, 65%), 256 (100 %). HRMS (ES+) Calcd. for C23H2oN405S : 465.1232.

Found: 465.1240.

EXAMPLE 113 4-{3E-[2-(lH-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen -2-yl-phenyl]-acryloyl}- benzenesulfonamide Ex-113A: 2- ( H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benza ldehyde was prepared in a similar manner as described in Ex-29C. Off-white solid, 67% yield, mp 230 °C (dec).'H-NMR (300 MHz, DMSO-d6) 0 10.44 (s, 1H), 8.00 (s, 1H), 7.79-7. 84 (m, 2H), 7.49- 7. 57 (m, 4H), 7.16 (s, 1H), 7.12 (dd, 1H, J = 5.4, 3.6 Hz), 5.91 (s, 2H), 4.07 (s, 3H). MS (ESI) m/z = 365 ([M+H] +, 100%). Anal. Calcd. for C20H17ClN2O3S#1/3H2O : C, 59. 04 ; H, 4.38 ; N, 6.88 ; S, 7.88. Found: C, 59.07 ; H, 4.25 ; N, 6.85 ; S, 7. 77.

The title compound was prepared by condensing 2-(1H-benzoimidazol-2-ylmethoxy)-4- methoxy-5-thiophen-2-yl-benzaldehyde (Ex-113A) and 4-acetyl-benzenesulfonamide (Ex- 26A) in a similar manner as described in Ex-22. Light orange solid, 56% yield, mp 235-237 °C (dec).'H-NMR (300 MHz, DMSO-d6) 6 8.27 (s, 1H), 8.19 (d, 2H, J= 8.4 Hz), 8.11 (d, 1H, J= 15.4 Hz), 7.98 (d, 1H, J= 15.4 Hz), 7.89 (d, 2H, J= 8. 4 Hz), 7.66-7. 70 (m, 3H), 7.53-7. 55 (m, 3H), 7.22-7. 27 (m, 2H), 7.12-7. 15 (m, 2H), 5.59 (s, 2H), 4.01 (s, 3H). MS (ESI) m/z = 546 ([M+H]+, 100%). Anal. Calcd. for C28H23N3O5S2 : C, 61.64 ; H, 4.25 ; N, 7.70 ; S, 11.75. Found: C, 61.49 ; H, 4.47 ; N, 7.74 ; S, 11.58.

EXAMPLE 114

4- {3E- [4-Methoxy-2- (pyridin-2-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}- benzenesulfonamide Ex-114A: 4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-benzaldehy de was prepared in a similar manner as described in Ex-29C. Yellow solid, 93% yield, mp 93-94 °C.. IH-NMR (300 MHz, CDCI3) 6 10.49 (s, lH), 8.62 (d, IH, J= 5. 1 Hz), 8.13 (s, 1H), 7.77 (dt, 1H, J=7. 5, 1.5 Hz), 7. 58 (d, IH, J= 7. 5 Hz), 7.44 (dd, 1 H, J = 3.6, 1.5 Hz), 7.28-7. 31 (m, 2H), 7.07 (dd, 1H, J= 5.4, 3.6 Hz), 6.64 (s, 1H), 5.39 (s, 2H), 3.94 (s, 3H). MS (ESI) mlz = 326 ([M+H]+, 100%). Anal. Calcd. for C18Hl5NO3S : C, 66.44 ; H, 4.65 ; N, 4.30 ; S, 9.85. Found: C, 66.43 ; H, 4.72 ; N, 4. 37 ; S, 9. 81.

The title compound was prepared by condensing 4-methoxy-2- (pyridin-2-ylmethoxy)-5- thiophen-2-yl-benzaldehyde (Ex-114A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 90% yield, mp 188-189 °C.'H-NMR (300 MHz, DMSO-d6) 8 8. 66 (d, 1H, J = 3.6 Hz), 8.28 (s, 1H), 8.21 (d, 2H, J = 7.8 Hz), 8.11 (d, IH, J= 15.4 Hz), 7.89-7. 99 (m, 4H), 7. 57-7. 68 (m, 4H), 7.53 (dd, 1H, J= 5.4, 1.5 Hz), 7.41-7. 45 (m, 1H), 7.13 (dd, IH, J= 5.4, 3.6 Hz), 7.02 (s, 1H), 5.45 (s, 2H), 3.99 (s, 3H). MS (ESI) m/z = 507 ([M+H]+, 100%). Anal. Calcd. for C26H22N2O5S2#½H2O : C, 60.57 ; H, 4.50 ; N, 5.43 ; S, 12.44. Found: C, 60.92 ; H, 4.54 ; N, 5.48 ; S, 12.32.

EXAMPLE 115

4- {3E- [2- (Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl] -acryloyl}-<BR> <BR> <BR> <BR> <BR> benzenesulfonamide Ex-115A : 2-(Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benza ldehyde was prepared in a similar manner as described in Ex-29C. Off-white solid, 92% yield, mp 137-138 °C..'H-NMR (300 MHz, CDC13) 8 10.30 (s, IH), 8.10 (d, 1H, J = 8. 1 Hz), 8.06 (s, 1H), 7.75 (d, IH, J= 8. 1 Hz), 7.57-7. 62 (m, 1H), 7.40-7. 48 (m, 2H), 7.30 (d, IH, J= 5. 1 Hz), 7.08 (s, 1H), 7.05 (dd, 1H, J= 5.1, 3.6 Hz), 6.74 (s, 2H), 4.01 (s, 3H). MS (ESI) mlz = 366 ([M+H]+, 100%). Anal. Calcd. for C19H15N3O3S : C, 62.45 ; H, 4.14 ; N, 11.50 ; S, 8.78. Found: C, 62.69 ; H, 4. 30 ; N, 11. 52 ; S, 8.62.

The title compound was prepared by condensing 2-(benzotriazol-1-ylmethoxy)-4-methoxy-5- thiophen-2-yl-benzaldehyde (Ex-115A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Light yellow solid, 56% yield, mp 255 °C (dec). IH- NMR (300 MHz, DMSO-d6) 8 8.21 (s, 1H), 8.09 (d, 3H, J= 9.4 Hz), 8.01 (d, 1H), J= 7.8 Hz), 7.93 (d, 2H, J = 7. 8 Hz), 7.75 (d, 2H, J= 9.4 Hz), 7.56-7. 69 (m, 4H), 7.42-7. 47 (m, 1H), 7.38 (s, 1H), 7.13 (dd, 1H, J= 5.4, 3.6 Hz), 7.05 (s, 2H), 4.05 (s, 3H). MS (ESI) m/z = 547 ([M+H]+, 100%). Anal. Calcd. C27H22N405S2 : C, 59.33 ; H, 4.06 ; N, 10.25 ; S, 11. 73. Found: C, 59.45 ; H, 4.27 ; N, 9.92 ; S, 11.27.

EXAMPLE 116

4-{3E-[2, 4-Dimethoxy-5-(1-methyl-lH-indol-2-yl)-phenyl]-aclyloyl}-ben zoic acid Ex-116A: To a solution of N-methyl indole (1.3 g, 10 mmol) in 50 ml THF, t-BuLi (1.7m in THF, 7.1 ml, 12 mmol) was slowly added at 0°C under nitrogen. The mixture was stirred at room temperature for 1 hr, BEt3 (1. 0 M in THF, 12 ml, 12 mmol) was added, and the mixture stirred for another 1 hr at room temperature. Then, PdCI2 (PPh3) 2 (0.35 g, 0.5 mmol) and 5- bromo-2,4-dimethoxybenzaldehyde (3.7g, 15 mmol) were added, and the mixture was heated to about 60 °C for 30 minutes. The reaction mixture was poured into 50 ml 10% NaOH and treated with 30 % H202 and then stirred for 10 minutes. The mixture was extracted with EtOAc and combined organic phase was washed with H20 and brine, dried over MgS04, and absorbed to small amount of silica gel. Column chromatography (EtOAc: Hexane, 1 : 2) gave 0.72 g (25%) 2, 4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde. 1H-NMR (CDCl3) # 10.33 (s, 1H), 7.84 (s, IH), 7.60 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.18-7. 24 (m, IH), 7.07- 7.12 (m, 1H), 6.53 (s, 1H), 6.46 (s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.53 (s, 3H). HRMS (EI) Calcd. for Cl8Hs7NO3 : 295.1208. Found: 295.1202.

The title compound was prepared by condensing 4-acetylbenzoic acid and 2, 4-dimethoxy-5-(1- methyl-lH-indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3.

Yellow solid, 87% yield, mp 157-160 °C.'H-NMR (DMSO-d6) 8 8.17 (d, J = 8 Hz, 2H), 8.08 (d, J = 15 Hz, IH), 7.99-9. 02 (m 3H), 7.83 (d, J = 15 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.42 (d, J = 8 Hz, 1H), 7.10-7. 15 (m, 1H), 6.99-7. 04 (m, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 4.01 (s, 3H), 3.88 (s, 3H), 3.50 (s, 3H). MS m/z = 442 ([M+H]+, 100%). HRMS (ES+) Calcd. for C27H23NO5 : 442.1654. Found: 442.1633.

EXAMPLE 117

4- {3E- [2, 4-Dimethoxy-5- (l-methyl-lH-indol-2-yl)-phenyll-acryloyl}-benzenesulfonamid e The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2, 4-dimethoxy-5- (l-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3. Yellow solid, 90% yield, mp 148-150°C.'H-NMR (CDC13) 8 8.17 (d, J = 16 Hz, IH), 8.09 (d, J = 9 Hz, 2H), 8.01 (d, J = 9 Hz, 2H), 7.68 (s, IH), 7.64 (d, J = 8 Hz, 1H), 7.47 (d, J 16Hz, IH), 7. 35 (d, J = 8 Hz, 1H), 7.22-7. 26 (m, 1H), 7. 11-7. 16 (m, 1H), 6. 58 (s, 1H), 6.50 (s, 1H), 4.92 (br, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z = 477 ([M+H]+, 100%). HRMS (ES+) Calcd. for C26H24NO5S : 477.1484. Found: 477.1487.

EXAMPLE 118 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-phenyl)-acryloyll-benzoic acid methyl ester The title compound was prpared by esterification of 4- [3E- (5-Benzo [b] thiophen-2-yl-2, 4- dimethoxy-phenyl)-acryloyl]-benzoic acid (Ex-3) with methanol in the presence of EDCI and DMAP. Yellow solid, 34% yield, m. p. 149-151 °C. IH-NMR (300 MHz, CDC13) : 8.17 (d, 2 H, J = 6.7 Hz), 8. 10 (d, 1 H, J= 15.8 Hz), 8.05 (d, 2 H, J= 6.7 Hz), 7.95 (s, 1 H), 7.82 (m, 2 H),

7.67 (s, I H), 7.57 (d, 1 H, J= 15. 8 Hz), 7.33 (m, 2 H), 6.58 (s, I H), 4.04 (s, 3 H), 4.00 (s, 3 H), 3.97 (s, 3 H). MS m/z = 458 ([M]+, 100%). HRMS (EI) Calcd. for C27H2205S : 458.1188.

Found: 458.1196.

EXAMPLE 119 4- {3- [3E- (2, 3-Dihydro-furan-2-yl)-phenyl]-acryloyl}-benzenesulfonamide Ex-119A: 5-Bromobenzaldehyde (0.5 g, 2.7 mmol) and 2,3-dihydrofuran (0.56 g, 8.1 mmol) were dissolved in dioxane (5.0 mL). Nitrogen was bubbled into the solution for 15 min followed by the sequential addition of cesium carbonate (0.96 g, 2.9 mmol) and bis (tri-t- butylphosphine) palladium (0) (0.014 g, 0.027 mmol). The solution was immediately heated to 45 °C and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1 : 9) gave 0.18 g (40%) of 3- (2, 3-dihydro-furan-2-yl) - benzaldehyde as a clear, colorless oil.'H-NMR (300 MHz, CDCl3) 8 10.03 (s, 1H), 7.88 (s, IH), 7.82 (d, IH, J= 7.2 Hz), 7.62-7. 64 (m, 1H), 7.53 (t, IH, J= 7.2 Hz), 6.48 (q, 1H, J = Hz), 5.60 (dd, 1 H, J = 8.1, 10.8 Hz), 4.98 (q, 1H, J= 3.3 Hz), 3.15 (ddt, 1H, J= 15.0, 8.1, 2.5 Hz), 2. 59 (ddt, I H, J = 15.0, 8.1, 2.5 Hz). MS (El) mlz = 174 ( [M] +, 100%). HRMS (EI) Calcd. for CIlH, o02 : 174.0681. Found: 174.0677.

The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 3- (2,3-dihydro-furan-2-yl)-benzaldehyde (Ex-119A) in a similar manner as described in Ex-3.

Tan solid, 40% yield, mp 152-153 °C.'H-NMR (300 MHz, DMSO-d6) 8 8.31 (d, 2H, J= 7.5 Hz), 7.99 (d, 2H, J= 7.5 Hz), 7.95 (d, 1H, J = 15. 8 Hz), 7.85 (brs, 3H), 7.78 (d, 1H, J= 15.8 Hz), 7.57 (brs, 1H), 7.44-7. 52 (m, 2H), 6.62 (q, 1H, J = 2.4 Hz), 5. 58 (dd, 1H, J= 8.7, 10.8

Hz), 5. 59 (q, IH, J= 2. 4 Hz), 3.10 (ddt, IH, J= 15. 0,8. 1,2. 5 Hz), 2.54 (ddt, IH, J= 15.0, 8.1, 2.5 Hz). MS (ESI) M/z = 356 ([M+H]+, 100%). Anal. Calcd. for Cl9Hl7NO4S"/5H20 : C, 63.56 ; H, 4.89 ; N, 3.90 ; S, 8.93. Found: C, 63.64 ; H, 4.88 ; N, 4.00 ; S, 8.71.

EXAMPLE 120 4- 3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid, N-methyl-D- glucamine salt 4- [3E- (5-Benzo [b] thien-2-yl-2, 4-dimethoxyphenyl)-acryloyl]-benzoic acid of Ex. 3 was then made into a meglumine salt by suspending the 4- [3E- (5-benzo [b] thien-2-yl-2, 4-dimethoxy- phenyl) -acryloyl] -benzoic acid (4.45 g, 10 mmol) and N-methyl-D-glucamine (1.95 g, 10 mmol) in THF (100 mL). The mixture was stirred at room temperature for 5 minutes. Then, ethanol (100 mL) was added. This mixture was stirred at room temperature for 30 minutes.

THF (20 mL) and ethanol (20 mL) were added and the mixture was heated slightly until it became a solution. This solution was stirred for 30 minutes and evaporated to a yellow foam.

Crystallization from methanol gave the desired 4- [3E- (5-benzo [b] thien-2-yl-2,4-dimethoxy- phenyl)-acryloyl]-benzoic acid N-methyl-D-glucamine salt as a yellow solid (4 g, 63%), mp 75- 80 °C (changing forms). 1H NMR (300 MHz, DMSO-d6) 8 8.39 (s, 1H), 8.14 (d, 2H), 8.02-8. 10 (m, 3H), 7.94-7. 98 (m, 3H), 7.86 (d, 1H), 7.36 (m, 2H), 6.89 (s, 1H), 4.06 (s, 3H), 4.04 (s, 3H), 3.94 (m, 1H), 3.71 (d, IH), 3.61 (m, 1H), 3.39-3. 55 (m, 3H), 3.04 (m, 1 H), 2.95 (m, 1H), 2.54 (s, 3H). Anal. Calculated for C33H37NO) oS-1. 3H20 : C, 59.77 ; H, 6.02 ; N, 2. 11 ; S, 4.84 ; found: C, 59.84 ; H, 5.75 ; N, 2.05 ; S, 4.70 ; Parent EIMS m/z = 443 (M+).

Using the above procedure for producing the meglumine salt or procedures well known in the art, any of the compounds of the invention can be likewise made into a hydroxyl amine salt and in particular the meglumine salt.

EXAMPLE 121 4- {3E- [5- (2, 5-Dihydro-furan-2-yl)-2, 4-dimethoxy-phenyt]-acryloyl}-benzenesulfonamide Ex-121A: 5-Bromo-2, 4-dimethoxybenzaldehyde (1.0 g, 4.0 mmol) and 2,3-dihydrofuran (0.85 g, 12.2 mmol) were dissolved in dioxane (10.0 mL). Nitrogen was bubbled into the solution for 15 min followed by the sequential addition of cesium carbonate (1.4 g, 4.5 mmol) and bis (tri-t- butylphosphine) palladium (0) (0.021 g, 0.041 mmol). The solution was immediately heated to 45 °C and aged for 72 h. Additional equivalents of cesium carbonate (0.70 g, 2.1 mmol), 2,3- dihydrofuran (0.85 g, 12.2 mmol), and Pd catalyst (0.0021 g, 0.0041 mmol) were added after 24 h and 48 h to drive the reaction to completion. Upon completion, as determined by HPLC, the reaction was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an orange oil.

Silica gel chromatography (ethyl acetate/hexanes, 1 : 2) afforded 0.32 g (50%) of 5- (2, 5- dihydro-furan-2-yl)-2, 4-dimethoxy-benzaldehyde as a pale yellow solid, mp 84-85 °C. IH- NMR (300 MHz, Cd13) 8 10.29 (s, 1H), 7.79 (s, 1H), 6.42 (s, 1H), 5.99-6. 06 (m, 2H), 5.89- 5.92 (m, 1H), 4. 80-4. 87 (m, IH), 4.71-4. 77 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS (El) m/z = 234 ([M] +, 100%). Anal. Calcd. Cl3Hl404 : C, 66.66 ; H, 6.02. Found: C, 66.49 ; H, 6.08. <BR> <BR> <P>5- (2, 5-Dihydro-furan-2-yl) -2, 4-dimethoxy-benzaldehyde (Ex-121A, 0.10 g, 0.43 mmol) and 4- acetylbenzenesulfonamide (Ex-26A, 0.085 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2. 9 mL, 7: 3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting orange slurry was stirred in the

dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.13 g (70%) of the title compound as a yellow solid, mp 194-195 °C.'H-NMR (300 MHz, DMSO-d6) 8 8.23 (d, 2H, J= 8.2 Hz), 8.03 (d, 1H, J = 15.3 Hz), 7.97 (d, 2H, J = 8.2 Hz), 7.69 (s, 1H), 7.65 (d, IH, J= 15.3 Hz), 7. 55 (brs, 2H), 6.73 (s, IH), 6.06-6. 09 (m, 1H), 5.90- 5.98 (m, 2H), 4. 86-4. 92 (m, 1H), 4.63-4. 68 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z = 416 ([M+H] +, 100%). Anal. Calcd. C2lH2lNO6S : C, 60.71 ; H, 5.09 ; N, 3.37 ; S, 7.72. Found: C, 60.95 ; H, 5.24 ; N, 3.46 ; S, 7.72.

EXAMPLE 122 4- {3E- [4-Methoxy-2- (6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-phenyl]-acryloyl} - benzenesulfonamide Ex-122A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (0.68 g, 2.9 mmol) and 2-bromo-6-methylpyridine (0.25 g, 1.4 mmol) in toluene (1.0 mL) was added ethyl acetate (0.0063 g, 0.072 mmol, 1-naphthoic acid (0.50 g, 2.9 mmol), 5A molecular sieves (0.36 g), cesium carbonate (0.94 g, 2.9 mmol), and copper (I) triflate-benzene complex (0.020 g, 0.036 mmol). The phenoxide crashed out of solution upon addition of cesium carbonate and additional toluene (1 mL) was added to facilitate stirring. The heterogeneous solution was immediately heated to 110 °C and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with a 5% sodium hydroxide solution (10 mL) and ethyl acetate (10 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with

ethyl acetate (5 x 20 mL). The combined organic extracts were washed with a 50% brine solution (1 x 25 mL), brine (1 x 25 mL), dried over sodium sulfate and concentrated to an dark brown semi-solid. Silica gel chromatography (ethyl acetate/hexanes, 1 : 4) afforded 0.30 g (65%) of 4-methoxy-2- (6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehydeas a light orange solid, mp 140-141 °C.'H-NMR (300 MHz, CDC13) 8 10.21 (s, 1H), 8.23 (s, 1H), 7.64 (dd, 1H, J= 7. 8,7. 2 Hz), 7.52 (d, 1H, J = 3.3 Hz), 7.35 (d, 1H, J = 5. 1 Hz), 7.10 (dd, 1H, J = 5. 1,3. 3 Hz), 6.94 (d, 1 H, J = 7.2 Hz), 6.78 (d, 1 H, J = 7.8 Hz), 6.75 (s, 1H), 3.92 (s, 3H), 2.44 (s, 3H).

HRMS (EI) Calcd. for Cl8HlsNO3S : 325.0773. Found: 325.0775. Anal. Calcd. C18Hl5NO3S : C, 66.44 ; H, 4.65 ; N, 4.30 ; S, 9.85. Found: C, 60.00 ; H, 4.58 ; N, 4.05 ; S, 9.84.

4-Methoxy-2- (6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde (Ex-122A, 0.20 g, 0.62 mmol) and 4-acetylbenzenesulfonamide (Ex-26A, 0.12 g, 0.62 mmol) were dissolved in a dimethylformamide-methanol solution (4.2 mL, 7: 3). After complete dissolution, lithium methoxide (0.093 g, 2.5 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.25 g (82%) of the title compound as a yellow solid, mp 164-165 °C. IH-NMR (300 MHz, DMSO-d6) 8 8.47 (s, 1H), 8.24 (d, 2H, J= 8.1 Hz), 7.98 (d, 1H, J= 15.3 Hz), 7.96 (d, 2H, J= 8. 1 Hz), 7.78-7. 85 (m, 2H), 7.77 (d, 1H, J= 15.3 Hz), 7.62 (d, 1H, J = 5. 1 Hz), 7.57 (s, 2H), 7.19 (dd, IH, J=5. 1,3. 6 Hz), 7.04 (d, IH, J=7. 5Hz), 6.99 (s, 1H), 6.91 (d, IH, J=8. 4 Hz), 3.90 (s, 3H), 2.33 (s, 3H). Anal. Calcd. C26H22N205S2 : C, 61.64 ; H, 4.38 ; N, 5.53 ; S, 12.66. Found: C, 61.88 ; H, 4.47 ; N, 5.59 ; S, 12.62.

EXAMPLE 123

5-Iodo-2, 4-dimethoxy-benzaldehyde To a solution of 2, 4-dimethoxy-benzaldehyde (20. 0g, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.52g, 144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution was allowed to stir at ambient temperature for 3 hours and then poured into a solution of hydrochloric acid (0.5 M, 600 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1: 1, v/v) to give the tiltle compound as a white solid (30.62g, 87.5%), m. p. 170-172 °C.'H NMR (CDCI3) 5 10. 19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H).

EXAMPLE 124 5-Benzo [b] thiophen-2-yl-2, 4-dimethoxy-benzaldehyde Ex-123A: Potassium fluoride (0.42g, 7.2 mmol), 5-iodo-2, 4-dimethoxy-benzaldehyde (Ex-123, l. 0g, 3.42 mmol), 2-benzo [b] thiophene boronic acid (0.67g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris (dibenzylideneacetone) dipalladium (19mg, 0.02 mmol), and tri- tert-butylphosphine (100mg, 0.05 mmol) were sequentially charged into a flask equipped with a condenser and nitrogen inlet adapter. The reaction mixture was heated at 60 °C for one hour under nitrogen. HPLC analysis indicated of 100% conversion of 5-iodo-2, 4-dimethoxy- benzaldehyde (Ex-123) to the title compound prepared through another route (Ex-3A).

Using one or more of the preceding methods, additional substituted 1-[2, 2- bis (hydroxymethyl)-benzo [1, 3] dioxol-5-yl]-3-[(heteroaryl or heterocyclic) phenyl]-2-propen-1- ones, 4-[3-{(heteroaryl or heterocyclic) phenyl} acryloyl]-benzoic acids, 1-[(amino) phenyl]-3- [(heteroaryl or heterocyclic) phenyl]-2-propen-1-ones, 4- [3- { (heteroaryl or heterocyclic)- phenyl}-3-oxo-propenyl]-benzoic acids, 1-(1H-indol-5-yl)-3-{(heteroaryl or heterocyclic)- phenyl} -propen-2-ones, 1-[(heteroaryl or heterocyclic) phenyl]-3-phenyl-2-propen-I-ones, and substituted 3-[(heteroaryl or hetercyclic)phenyl]-1-phenyl-2-propen-1-ones can be prepared by one skilled in the art using similar methods, as shown in Example Tables 1 through 33.

Example Table 1. Substituted 4- [3- {2-Isopropoxy-4-methoxy- (5-heteroaryl or 5- heterocyclic) phenyl}-acryloyl]-benzoic Acids. Ex. No. R5ß Ex. No. R 5P Ex. No. | R5ß 200A 201A s N 200B 201B 202B 203A 204A 205A 203B 204B s 205B oa Ia 206A 207A 208A s 206B o 207B s 208B W W Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 209A N 21 OA N . 211 A 209B t, 210B v 211B t N 212A o 213A 214A 212B CN 213B HN 214B \\c N INT 215A 216A 217A H 215B 216B 217B zon N 218A 219A 220A N w 218B 219B 220B N 221 A 222A N 2 223A HN N 221 B/222B 6 W 223B s osa N 224A 225A 226A s rY 224B 0 225B 226B 9 Nv H 227A 0 228A 229A 227B 228B (\ 229B nu 230A N 231A 232A 230B 231 B . \ 232B H-N 'nez 233A < 234A N&KX 235A f NsVX 233B °J 234B ¢ 235B N 236A 237A N 238A N 236B oJ OH 237B W 238B N>N 239A N-N e 240A + NsyX 241A 1+ 239B N-N 240B 241B NON Ex. No. R 5P Ex. No. R 5P Ex. No. R 5P 242A N o j 243A, N 244A 242B 243B N 244B 245A N-N 246A N 247A H N 245B N 246B') : r- N 247B H H N H 248A N z 249A I w N 250A N-O 248B H 249B N N 251A N-o 252A ~ N 253A N-N t 251B 252B 254A/NN 255A N N 256A 254B 4., N N 255B N 256B N H 257A N 258A mN 259A C Nq 257B 258B N 259B 260A N 261A 262A WN 260B 261B 262B W Example Table 12. Substituted 4-[3-{2-Cyclopropylmethoxy-4-methoxy-(5-heteroaryl or 5- heterocyclic) phenyl}-acryloyl]-benzoic Acids.

Ex. No. R5ß Ex. No. R5ß Ex. No. R5p 263A 264A s N 263B 264B 265B 266A 267A 268A 266B 267B s 268B HI, oa _j 269A 270A 271A s 269B o 270B s 271B U W 272A 273A 274A 272B 273B 274B N 1 275A o 276A 277A 275B CN 276B Ht 277B CN '-N rk. ' 278A 0 279A 280A N 278B 279B 280B v nec 281A 282A 283A N 281B 283B 282B 284A. 285A N 4 286A HN 284B 285B < 31 286B osa N 287A 288A 289A s rr- 287B o 288B 289B 9 NrO H 290A o 4 291A 4 292A ~t S 290B 291B 292B y CL CN Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 293A N 294A 295A 293B 294B NC 295B H-NJ N 296A'., 7 297A N'-, 7 298A N'' 296B oJ 297B C 298B N 299A 300A N 301A N 299B ocf 300B W 301 B Nos N 302A H 303A N 304A 302B 303B 304B N N-N 305A N-O 306A < N 307A N ! t ') t'N"\ 305B 306B OY-N 307B I I li, I Y/ 308A N-N 309A N 310A H N 308B N 309B 310B H H N H H H 311A IA N-) 312A N 313A 311B IB H 313B N N 314A N-o 315A N ; 316A 314B 315B I i ; 316B o 317A CN-N 318A 317B 318B t'N 319B < H 320A N 321A 322A 320B 321B N 322B w w 323A N 324A 325A won " r \ iN Ex. No. R 5p Ex. No. R 5P Ex. No. R5ß 326A 327A H3CO2C 328A Br S I I 326B H3C 327B N-N 328B H3c s H 329A 1CH3 330A 331A 329B tÒ 330B H3C (O) C S 331 B N CH3 332A 333A 334A 332B OH 333B 334B Example Table 3. Substituted 4- [3- {2, 4-dimethoxy- (6-Heteroaryl or 6-heterocyclic)phenyl}- acryloyl]-benzoic Acids.

Ex. No. R5ß Ex. No. R 5P Ex. No. R5ß 335A 336A S 33337A N 335B 336B 337B 338A 339A 5 340A 338B oC 339B sC 340B HNa t 341A \ 34 A 3 343A 341B o 342B s 343B 344A 345A 346A 344B 345B I 346B N Ex. No. R 5D Ex. No. R5ß Ex. No. R5ß 347A o 4 348A N 349A s 4 347B X 348B H 4 349B X \CN \CN 350A 0 351A 352A N /S HNL \ < ?/S 350B (351B < 352B t N (-INT 353A 354A 355A H N 353B 354B 355B N- 356A 357A H N 358A 356B 357B 358B N : lu 359A 360A 361A s rT' 359B 360B 361B N L H 362A o 4 363A 4 364A 362B a 363B C 364B X /N NH 365A N 366A 367A 366B 367B N/ 368A/> 369A NsuoX 370A (NsSX 368B oJ 369B N' 370B N N 371A 372A N 373A N 371B rOH 372B , 373B 374A _N 375A ¢ Ns\ 376A HS 374B 375B 376B N11 "-N N 377A N o ; 378A, w N 379A, N l/l-N-N 377B 378B N 379B Ex. No. R 5p Ex. No. R 5P Ex. No. R5p 380A N-N 381A 382A H >-i-CN 380B HN 381B N 382B H H N H 383A N 384A N 383B N 384B H N 386A Nl-O) 387A N 388A L 386B 9 387B o 388B o o 389A/NN 390A N w N 391A N 391 A N C, N 390B 391B N N N 392A N-o 393A < 394A AN 392B ,, I 393B I N 394B 395A N 396A 397A WN 395B 396B 397B r Example Table 4. Substituted 1- (2, 2-Bis-hydroxymethyl-benzo [1, 3] dioxol-5-yl)-3- [2, 4- dimethoxy- (5-heteroaryl or 5-heterocylic) phenyl]-2-propen-1-ones.

Ex. No. R5ß Ex. No. R5ß Ex. No. Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 398A 399A s N , YS/'YS/'Y5 398B 399B 400B 401A 402A 403A 401B 402B s 403B r 404A 405A 406A s 404B o 405B s 406B U W 407A 408A H 409A 407B 408B 409B N 410A o t 41 IA N 412A s 1gt 410B 411B 412B N N 413A o 414A 415A 413B 414B H 415B II N 416A 417A 418A H N 416B 0 417B 418B N' 419A ~t 420A N 4 421 A HN N 419B Xo) 420B NW 421B osa N 422A 423A 424A fr rY"' 422B 423B 424B N 425A o 0 426A 4 427A /S fS rY" 425B 426B 427B CN Ex. No. R 5P Ex. No. R5ß Ex. No. R 5P 428A N 429A 430A 428B N 429B 430B H-NJ N 431A 432A N 433A ir N 431B oJ 432B 433B N N 434A 435A N 436A N 434B oJ\OH 435B W 436B Nof N 437A H 438A N 439A 437B 438B 439B N, N N-N 440A N o 441 A/ N 442A non 440B 441 B'N 442B liy 443A Nl_N\ 444A N 445A H L !) H' ! t 'f Y 443B H 444B N 445B H H N H 446A INl 447A > N 448A N-o 446B N_ H S 447B a 448B H N 449A N-0 450A N 451 A ! !/v ! ' ! !/ 449B 450B N-3 N 454A 452A/NN 453A N N 454A 452B 453B 453B N N 454B N H I 455A N-o 456A/w 457A, 455B 9 456B AN 457B HJ I d 458A N 459A 460A won r \/N Ex. No. R5ß Ex. No. R5ß Ex. No. R5P 461A \ z 462A H3C°ZC 2 463A 461B H3C O 462B H 463B H3C S H H 464A CH3 465A 466A 464B 0 465B H3C (O) C S 466B N in CH3 467A 468A 469A 467B HNJ OH 468B ws 469B 4, o Example Table 5. Substituted 1- (3-Aminophenyl)-3- [2, 4-dimethoxy- (5-heteroaryl or 5- heterocylic) phenyl]-2-propen-1-ones.

Ex. No. R ß Ex. No. R ß Ex. No. R5ß 470A 471A 472A H N 470B 471B 472B 473A R 474A R 475A 2 s 473B C 474B 475B 475B 476A 477A 478A s 476B o 477B s 478B Ex. No. R ß Ex. No. R ß Ex. No. R5ß 479A Nv 480A H 4 481 A X 479B 480B 481B N 482A o 4 483A s 484A s 482B 6oN 483B H t 484B CN '--N r' \L-N 485A 0 486A 487A H /'T'S HNL J. /'TS 485B 486B H S 487B II N N 488A 489A, 490A 488B 489B 490B H 491A 492A N 493A 491B 492B 493B osa N 494A 495A 496A S Y' 494B OX 496B I \ 496B 4/H Nua H 497A o 4 498A 4 499A v 497B 498B 499B y a CNH 500A 501A 502A IN, 500B 501B 502B H-NQJ N 503A 504A N 505A irN 503B oJ 504B C 505B N N 506A 507A N 506B oJ OH 507B W 508B N>N 509A H 510A N 51 IA 509B 510B WuN ; 511B N>NJ N N Ex. No. R 5p Ex. No. R 5P Ex. No. R5ß 512A N 513A, N 514A N, N 512B 513B 514B'ii -) ''vuy 515A N-nez 516A N 517A H N 515B N 516B N 517B H H N H 518A N 519A N 520A-0 518B N'N 5 519B ws 520B k N H N 521A N-o 522A N 523A viz o 523B 521B 522B 0 524A/NN 525A N w N 526A 524B +, N N 525B N N 526B H 527A Nl-O 528A 529 529A CNq 527B , n 528B I N 529B w < 530A N 531 A'y 532A 530B 531B 532B 'can Example Table 6. Substituted 1- (4-Aminophenyl)-3- [2, 4-dimethoxy- (5-heteroaryl or 5- heterocylic) phenyl]-2-propen-1-ones.

Ex. No. R5ß Ex. No. R5p Ex. No. R5ß 533A 534A S 535A s N 533B 534B 535B 536A 537A 538A 536B 537B 537B s 538B"^ osa 539A 540A 541A 5 539B o 540B s 541 B W W 542A 543A H 544A 542B 543B 544B N 545A o t 546A 4 547A s E N 545B CN 546B HNS 547B CN H 548A o 549A H-SSOA 548B < 549B 550B y N con 551A 552A 553A N 551B 552B 553B N 554A 555A H 556A 554B C\ J SSSB 556B 0 N 557A 558A 559A . s rY' 557B 0 558B 559B Na 560A o 561 A 562A Z S 560B C 561 B C 562B CS /N NH Ex. No. R ß Ex. No. R ß Ex. No. R5P 563A N 564A 565A 563B 564B 565B N 566A' 567A N , ; 568A 566B oc 567B C 568B N 569A 570A N 571A N 569B oJO"570B 57 ! B N 572A H 573A N 574A 572B N/S 573B , 574B 574B N 575A N o 576A r w N 577A _N 575B 576B N 577B I jr, I L/ 578A N-N 579A N 580A H (Njx 578B N 579B N 580B H H N H 581 A N r 582A I N\ 583A-O 581B N'N 5 582B aS -583B S 583B 584A N-0 585A N-N 584B 9 585B I i 586B 587A i NN 588A N w N 589A N w 587B N N 598B N N 589B H 590A N-0 591A 592A 590B 591B C'N 592B w < 593A 594A 595A aN 593B 594B 595B r Ex. No. R ß Ex. No. R 5P Ex. No. R 5p 596A I 597A H3CO2C 598A Br> 596B H3C ° 597B H 598B H3c s H H 599A CH3 600A \N 601A 599B tÒ 600B H3C (o) c s 601 B N o chu O CH3 602A 603A 604A 602B HNrH 603B I i S 604B Mi Example Table 7. Substituted 1-{4-(Pyrrolidin-1-yl) phenyl}-3-[2, 4-dimethoxy-(5-heteroaryl or 5-heterocyclic)phenyl]-2-propen-1-ones.

Ex. No. R 5P Ex. No. R 5P Ex. No. R5ß 605A 606A 607A H 4 N 605B 606B 607B 608A 609A 610A 608B 609B 61 OB oa S 611A 4 612A, 4 613A s 4 611B o 612B s 613B W W Ex. No. R 5p Ex. No. R ß T Ex. No. R5p 614A 615A H 616A 614B 615B 616B S\ 617A o E 618A N 619A s E 617B < H 619B '--N r.'-N 620A 0 621A 622A H /'YS HM j. /'T'S 620B 621 B 622B < N nec 623A 624A 625A N N 623B 624B 625B H 623B o.) 624B \-kJ S \. J 626A 2 627A H E 628A HNa 626B 627B 628B ( : lu 629A 630A 631 A S Y' 629B O\ R 630B I \ 631B \ N H 632A 0 633A 634A /"T f rT 632B 633B I \ 634B CN 635A N 636A 637A B 636B 637B 6 638A 639A N'., ; t 640A 638B 0 639B ¢ 640B (N' 641A 642A N 643A N 641B OH 642B C 643B N+N ocf,, N 644A H 645A 646A 644B 645B > N 646B N s NJ N N Ex. No. R ß Ex. No. R 5P Ex. No. R5ß 647A N-O 648A < N 649A , N 647B 648B N 649B N/ 650A N-N 651A N 652A H N 650B N 651B N 652B H H 652B H 653A N- 654A N 655A-0 653B 654B 655B H N 656A N-O 657A N 658A N-N 658A N 656B 657B I i 658B 659A N N 660A N N 659B ç 660B N 661 B N H 662A N-663A 664A 662B 663B 664B w w 665A N 666A 667A 665B 666B 667B r \ iN Example Table 8. Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[2,4-dimethoxy-(5- heteroaryl or 5-heterocylic) phenyl]-2-propen-1-ones.

Ex. No. R ß Ex. No. R ß Ex. No. R5ß 668A 669A s N 668B 669B 670B 671A 672A 673A 671B 672B s 673B H 674A 4 675A, 4 676A s t 674B o 675B s 676B 0 677A N '., 7 678A N 679A NY'/"'S/S 677B 678B 679B N 680A o t 681A N 682A s 4 680B I 681B H 682B \\Cy N N 683A o 684A H-685A 683B NX 684B < 685B CN N con 686A 687A 688A H N 686B 687B 688B H 689A 2 690A N t 691 A HNa 689B tC 690B < W 691B osa N 692A 693A 694A rr- 692B p 2 693B I \ 694B C\ J l N H CN-f H 695A 0 696A 697A /"Y r r< 695B 696B I \ 697B N Ex. No. R 5P Ex. No. R5p Ex. No. R 5P R R 698A N 699A 700A 698B 699B 700B N 701A. 702AN703A N., 701 B oJ 702B C 703B N 704A 705A N 706A N 704B OH 705B 706B N ocf 707A N, N t 708A N'. ; 709A 707B Li-N 709B N N 710A N o 711A/ N'712A Lo-N 71 OB 71 IB N 712B N H 713A NN z 714A w N 715A 713B'-N 714B'-N 715B ! H H N H 716A 717A N 718A 716B N'N S 717B S -718B H N 719A N-o 720A w N 721A N-N z 719B 9 720B o 721B o 3A N 724A N 722A N-N 72 Na >_, 722B NJuN 723B t NzJHN 724B + w 725A N-o 726A 727A 725B 726B 727B w w 728A N 729A 730A N 728B M,--729B N"'730B r \ rN Ex. No. R ß Ex. No. R ß Ex. No. R5ß 731A 732A H3CO2C 733A Br 731 B H3C O 732B H 733B H3cs H 734A CH3 735A 736A 734B 735B 3C 736B 0 CHg 737A 738A 739A 737B HNCF OH 738B S\ 739B CIO' Example Table 9. Substituted 1- {4- (Methanesulfonylamino) phenyl}-3- [3, 4-dimethoxy- (5- heteroaryl or 5-heterocylic) phenyl]-2-propen-1-ones.

Ex. No. | R5ß Ex. No. R5ß Ex. No. R 5p 740A 741A 742A H I N 740B 741B I S 742B 743A 744A 745A 743B 744B 745B oa 746A 747A 748A 746B o 747B s 748B W U Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 749A 750A 751A N 749B 750B 751B Zu 752A o 753A 754A s 752B 6N 753B H 4 754B CN 755A o 756A 757A 755B < 756B 757B N N 758A 759A 760A H N 758B 759B N 760B H 761A 762A 763A 761B 762B 763B cosy N 764A 765A 766A 764B 765B 766B U S N H 767A o 4 768A 4 769A /"Y" frr fY 767B 768B 769B a nu 770A irN 771A 772A 770B /N 771 B \ 772B N 773A 774A N' 7'75A 773B oJ 774B C 775B N D, N 776A 777A N 778A Nu% % 776B 777B 778B 779A N-N e 780A SNsyX 781A S 779B N/s 780B , 781B ans N Ex. No. R5ß Ex. No. R 5p Ex. No. R5ß 782A 1-0 783A H 784A 782B 783B N 784B Ir 785A N-N 786A N 787A H /'-r r 785B N 786B N 787B H H N H 788A N 789A N 790A N-o 788B N'H 5 789B i _ 790B N H N 791 A N-0 792A N 793A N-N H '- ;- ! t " 791B 792B I 793B 794A N-5 N 796A Njp 794B N 795B N N 796B H 797A N-0 798A 799A 797B 9 798B < 799B < 800A N 801A 802A aN 800B 801B 802B r \ iN Example Table 10. Substituted 1-{4-(Amino)phenyl}-3-[3,4-dimethoxy-(5-heteroaryl or 5- heterocylic) phenyl]-2-propen-1-ones.

Ex. No. R ß Ex. No. R ß. Ex. No. R5ß 803A 804A 805A 803B 804B ws 805B v 806A 807A 808A HN 806B 807B s 808B J' 809A 8] OA 81 IA s 809B o 810B s 811B b U 812A 813A H 814A 812B 813B 814B N 815A o E 816A N 817A s t 815B 816B H 817B N N 818A 0 819A 820A N H 818B < W 819B NY) 820B tY N 821A 822A 823A N 821B 822B 823B N 824A 825A N 4 826A HNa N 824B 825B 826B osa N 827A 828A 829A s rY' 828B 829B 4/N H N 830A o 4 831 A ~t 832A < S 830B \ 831B j 832B ! N Ex. No. R ß Ex. No. R 5P Ex. No. R5ß 833A N 834A 835A 833bon 834B NNOI 835B H-NsJ N 836A'. 837A N', z 838A 836B oJ 837B N : r 838B N N 839A 840A N 841 A N 839B oJ OH 840B C 841B 842A H 843A N 844A 842B 843B 844B N, N-.-" zon N 845A N o 846A/ N 847A , N 845B 846B 847B jr, /1 848A N-N 849A N 850A H T ! 'f 848B N 849B I i N-850B H H N H 851A N'i. 852A N 853A-0 851B N'N S 852B vsfs 853B tN H N 854A N-0 855A w ! 856A 854B SZ 855B wo 856B o m 857A i NN 858A N \ N 859A, 857B NAN 858B N 859B < 860A N 861A 862A 862A, 1 860B, 861 B uf 862B + < w 863A N 864A 865A 863B 864B 865B won Ex. No. R 5p Ex. No. R5p Ex. No. R ß 866A 867A H3CO2C 868A Br 866B H3C 867B N-N H3 H 869A CH3 870A 871 A 369B e 870B H3C (o) c s 871B N CL3 872A 873A H3 874A 872B OH 873B 874B Example Table 11. Substituted 1- {4- (Amino) phenyl}-3- [2, 6-dimethoxy- (4-heteroaryl or 4- heterocylic)-phenyl]-2-propen-1-ones.

Ex. No. R4ß Ex. No. R 4p Ex. No. R 4P 875A 876A s 4 877A N 4 N 875B 876B 877B 878A 879A 880A S 878B 879B 879B H14 880B" v W v 881A 882A 883A s 881B °Ct 882B ssa 883B 6 W 881B 882B 883B N 884A N 885A N 886A 884B 885B 886B N Ex. No. R ß Ex. No. R ß Ex. No. R4ß 887A o 888A 889A /TS/f/YS 887B 6N 888B"H 889B \CN \CN 890A 0 891A 892A N 890B (W 891 B Na 892B 6 ZON / 893A, 894A 895A N 893B 894B N 895B H 896A 897A N 4 898A HNa N 896B 897B 898B O N 899A 900A 901 A frT'rr- 899B p Z 900B I \ 901B C\ J N 902A o 4 903A 904A /"T f' rr 902B C 903B 904B ! /N 905A N 906A 907A 905B N H-N, Nu 908A 909A N\ ,, 91 OA N'' ; 908B oJ 909B ¢NJ 91OB N 911A oH 912A N, N', ; 913A 91 IB °9 912B W 913B 914A N-N 915A SNsY> 916A 4 914B 915B WuNJ 916B NsNJ N N Ex. No. R ß Ex. No. R 4p Ex. No. R4ß 917A N o 918A r N 919A ZON 917B 918B N 919B < w 920A N-NEZ 921A w N 922A N 920B HN 921B I N 922B H H N H H 923A N i 924A I w N 925A N-O 923B N 924B H N 926A Nl-Oß 927A N 928A 926B 9 927B wo 928B o 'vuv 929A NN 930A N w N 931A 929B Nv1N 930B N 931B w I i N H 932A N-o 933A/w 934A 932B 933B N 934B w w 935A N 936A 937A 936B 937B r Example Table 12. Substituted 1- {4- (Methanesulfonylamino) phenyl}-3- [2, 6-dimethoxy- (4- heteroaryl or 4-heterocylic) phenyl]-2-propen-1-ones.

Ex. No. R ß Ex. No. R ß Ex. No. R4ß 938A 939A 940A H s N 938B 939B 940B 941A \ 942A 943A 941 B o 942B s\ 943B"" osa 944A 945A 946A s 944B 945B 946B W W 947A N>X 948A H 4 949A < N"Y'/"TS/rs 947B 948B 949B N 950A o 4 951A N 952A s 4 950B IN 951B"\ 952B N N 953A o 954A H-955A /YS HM JL c*/'T'S 953B NW 954B < 955B 6N N CINT 956A 957A 958A H Y N 956B OY 957B \JL j) 958B \ N : a 959A 960A H 959B/960B < 31 961B O N 962A 963A 964A 962B °l) 963B (NJ 964B J 4B a 965A 966A 967A S 965B 966B 967B ANS Ex. No. R 4p Ex. No. R4ß Ex. No. R4ß 968A N \ ; 969A 970A m 968B C 969B NC 970B H-NJ zu 971A', 7 972A N', 7 973A 971 B oJ 972B ¢ 973B N 974A 0H 975A Nz N>KX 976A (NyX 974B rOH 975B , 976B 977A H 978A N 979A 978B 979B N N 980A N 0 981 A, N 982A N-N 980B 981 B < 982B 9 983A N-N 984A N 985A H N 983B N 984B N 985B H H N H 986A N 987A N 0 986B N'N 5 987B aS -988B N 989A N-o 990A \ N 991A N-N Il r 989B > 990B oo 991 B to s 992A 993A N N 994A N 993B 994B N H 995A N 996A 997A C (N, 995B, 996B CQ--N 997B w w 998A/N 999A'y 1000A, 998B 999B IOOOB r \/N Ex. No. R4p Ex. No. R4ß Ex. No. 4p R R 1001 A 9 1002A H3CO2C 1003A Br 1001B H3C'o 1002B N s 1003B H3c I s H H 1004A CH3 1005A 1006A 1004B s 1005B H3C (O) C S 1006B N CL3 1007A 1008A 1009A 1007B HNJ OH 1008B ~s 1009B O Example Table 13. Substituted 1-(1H-Indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or heterocyclic) phenyl}-propen-2-ones.

Ex. No. R5ß Ex. No. R5ß Ex. No. RS (3 1010A 1011A s 2 1012A N 4 N IOlOB . J 1011B , J 1012B J 1013A 1014A 1015A 1013B oC 1014B sC 1015B HlC J 1016A 1017A 1018A s 1016B o 1017B s 1018B W W Ex. No. R 5P Ex. No. R 5P Ex. No. R 5P 1019A 1020A H 1021A 1019B 1020B 1021B N 1022A o 4 1023A N 1024A s 0 1022B xc-17--1023B H 1024B N NY 1025A 0 1026A 1027 H 1025B 1026B 1027B N c NY 1028A 1029A 1030A H 1028B 1029B N 1030B N : là 1031 A ~t 1032A H E 1033A HNa N 1033A 1031B 1032B 6 W 1033B osa N 1034A 1035A 1036A 1034B 1035B 1036B N N 1037A 1038A 1039A S 1037B 1038B I \ 1039B ANS 1040A N 1041A 1042A ff frr rY 1040B N 1041B 1042B H-N N 1043A 1044A N' 1045A 1043B °J 1044B ¢NJ 1045B N 1048A 1046A 1047A N 1046B OH 1047B 1048B ocf,, N 1049A H 1050A N 1051A 1049B 1050B 1051B zon N Ex. No. R ß Ex. No. R 5P Ex. No. R5p 1052A N 1053A, N 1054A N H Z 1_ N-N 1052B 1053B N 1054B H 1055A N-N 1056A 5f N 1057A N X 1055B'-N 1056B -N 1057B ! H H N H H H 1058AN 1059A N 1060A N-0 1058B H 1059B 1060B N H N i 1061 A Nl-Oß 1062A wS 1063A 1061B B 9 1062B o 1063B o 1064A/NN 1065A N w N 1066A 1064B +, NN 1065B N-N 1066B A w 1067A Nl_Oß 1068A 1069A 1067B 1068B < 1069B wJ w w 1070A I N 1071A I w _ 1072A 1070B r 1071 B C. ; S 1072B w 1072B Example Table 14. Substituted 1-(1H-Indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or heterocyclic) phenyl}-propen-2-ones.

Ex. No. R ß Ex. No. R ß Ex. No. R5p 1073A 1074A H3 I _ 1075A 1073B 1074B \V 1075B 1076A 1077A 1078A 1076B oa 1077B/1078B HC 1079A 1080A 1081A s 1079B o 1080B s 108 B b U 1082A 1083A 1084A 1083B 1084B N 1085A o E 1086A N : 1087A s E 1085B y 1086B H 1087B '--N r. 1088A 0 1089A 1090A H H 1088B 1089B 1090B I N 1091A 1092A 1093A H 1091B 0 1092B 1093B N- 1094A 1095A.. N 1096A 1094B 1095B 1096B o N- 1097A 1098A 1099A 1097B OX 1098B v 1099B k) Na' 1100A o 4 1101A 4 1102A 4 /"Y fS rY 11 OOB 11 O 1 B I \ 1102B w Ex. No. R 5P Ex. No. R Ex. No. R 5p 1103A N 1104A 1105A ft 'rY 1103B 1104B \ 1105B H. Nr N 1103B N No"' H-N, r 1106B IN, 1107B C 1108B N 1109A \ ; 1110A N ; ll ! tA N. 1109B OH IIIOB IIIIB 11 12A H 11 13A N 11 14A 1112B 12B 11 13B I N N 11 15A 11 16A N 11 17A H , N 11 15B 11 16B N 11 17B 1118A N-N z 1119A \ N 1120A N 11 18B N 11 19B N 1120B H H N H H 1121A 1122A N 1121B H 1 : : : c 1123B N "N 1124A N-o 1125A N 1126A 1124B 9 1125B vo 1126B o 'wv 1127A/NN 1128A N \ N 1129A 1127B N N 1128B N N 1129B w 1130A N-o 1131A r w 1132A 1130B 1131B N I 132B w w 1133A 1134A 1135A N r nu Ex. No. R5ß Ex. No. R5p Ex. No. R5ß 1136A 1137A H3CO2C< 11 38A BrS 1136B H3C 1137B N-N 1138B H3cs H 1139A CH3 1140A 1141A 1139B tÒ 1140B 3C (O) CS 1141B O CH3 1142A 1143A 1144A 1142B OH 1143B 1144B Example Table 15. Substituted 1-(1H-1-Methyl-indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or heterocyclic) phenyl}-propen-2-ones.

A B Ex. No. R5p Ex. No. R5ß Ex. No. R5p 1145A 1146A s 4 1147A H 4 /3/YS/Y5 1145B 1146B 1147B 1148A 1149A H50A 1148B 1149B s 1150B H" 1151A 1152A 1153A s 1151B o 1152B s 1153B U W Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 1154A 1155A H 1156A NY/"TrS/S 1154B 1155B 1156B N. 11, 1157A 0 1158A 1159A s 1157B 1158B H 1159B y W 1160A 0 1161A 1162A H /YS H'< </'YS 1160B< 1161B 1162B / 1163A 1164A 1165A H 1163B 1164B 1165B H 1166A 2 1167A N 1168A 1166B a 1167B 6W 1168B cor N 1169A 1170A 4 1 171A ~4 s fY 1169B 1170B ! 1171B Con-f N 1172A 0 1173A 1174A 1172B 1173B 1174B a aNH 1175A N 1176A 1177A 1175B I 1176B 1177B \ 1178A 1179A N 1180A irN 1178B o 1179B C 1180B N 1181A 11 82A N 11 83A N 1181B °J 82B 1183B 1184A H 1185A N 1186A 1184B 1185B 1186B N r, zon N Ex. No. R 5p Ex. No. R 5p Ex. No. R5ß R 1187A-0 1188A 1189A H 1187B W 1188B w 1 8 B 1189B ) 1190A NI_ 1191A w N ; 1192A 1190B N 1191B N 1192B H N H 1193A N z 1194A I w N 1195A-O n s _ N . 1193B NH 1194B i S 1195B 1198A N- 1196A N-O 1197A N 1198A 1196B 1197B I 1198B 'wv 1199A 1 fs 1200A N N 1201A 1199B \NN 1200B N 1201B w I N H 1202A Nl_Oß 1203A 1204A 1202B 1203B N 1204B 1205A N 1206A 1207A WN 1206B 1207B r Example Table 17. Substituted 1-(1H-1-Methyl-indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or heterocyclic) phenyl}-propen-2-ones.

Ex. No. R ß Ex. No. R ß Ex. No. R5ß 1208A 1209A H3C\E 5 121 OA HN/t 1208B 1209B 12 1210B 121 IA 1212A 1213A 1211B oa 1212B sC 1213B t/ osa 1214A 1215A 1216A s 1214B 1215B s 1216B W W 1217A NX 1218A HN 4 1219A. 4 1217B 1218B 1219B N' 1220A o t 1221 A 4 1222A s E 1220B tN 1221 B Hq 1222B 6ÆN w 1223A 0 1224A 1225A H /"S HNL 1, /S 1223B 1224B H I 1225B zu 1226A 1227A 1228 H A N 1226B 1227B 1228B H 1229A 1230A H N 1231A HN-\ 1229B 1230B 1231B osa N 1232A 1233A 1234A s r' 1232B O~\ t 1233B 1t 1234B [ 9 Nv H 1235A 1236A 1237A S 1235B 1236B I \ 1237B /N NH Ex. No. R 5p Ex. No. R5p Ex. No. R5ß 1238A N 1239A 1240A 1238B 1239B 1240B N 1241 A ; : r H. NCF 1241 B oJ 1242B ¢NJ 1243B NJ N"" 1244A 1245A N 1246A N 1244B rOH 1245B N, 1246B 0 1247A H 1248A N 1249A 1247B N-N 1248B 1249B N N 1250A __o 1251A N 1252A H 1251B N 1252B 1250B Ut r- 1253A N-N 1254A w N 1255A N 1253B N 1254B N 1255B t H H N H 1256A N 1257A N 0 n S _ N . 1256B N'H 1257B i S 1258B H N 1259A N-o 1260A N-N 1261A N 1259B 1260B o 1261B o 1262A/N-N 1263A N N 1264A 1262B NJuN 1263B N N 1264B H 1265A Nl_Oß 1266A 1267A 1265B 1266B , f 1267B < 1268A N 1269A 1270A won r iN Ex. No. R Ex. No. R ß Ex. No. R5ß 1271A 1272A H3CO2C 1273A Br 1271 B H3C O 1272B H 1273B H3C s H 1274A CH3 1275A S 1276A ¢9 1274B 1275B 3C (O) c s 1276B CL3 1277A 1278A 1279A 1277B OH 1278B 1279B Example Table 17. Substituted 4- [3- {2- (Pyrrolidin-1-yl)- (4-heteroaryl or 4-heterocyclic)- phenyl}-acryloyl]-benzoic Acids.

A B Ex. No. R 4p Ex. No. R 4P Ex. No. R4p 1280A 1281A s N /"Y3/YS/"rS 1280B 1281B 1282B 1283A 1284A 1285A 1283B 1284B s 1285B oa 1286A, 4 1287A S 1288A s E 1286B o 1287B s 1288B U W Ex. No. R ß Ex. No. R ß Ex. No. R4ß 1289A N wS 1290A H 1291A N"Y/"S/rS 1289B 1290A 1291B N 1292A o 1293A 1294A 1292B CN 1293B H ($ 1294B CN \L-N r'.'-N 1295A 0 1296A 1297A H H 1295B 1296B 1297B zon 1298A 1299A 1300A H N 1298B 1299B 1300B N 1301A 1302A N t 1303A HNS N 1301B koJ 1302B 6W 1303B O N 1304A 1305A 1306A fr rY' 1304B p 1305B I \ 1306B 1 N N H 1307A 0 1308A 1309A 1307B _ 1308B I \ 1309B N 1310A N 131 IA 1312A 1310B [. N 1311B f j 13t2B H-. J zu 1313A'z, 1314A N'7, 7 1315A 1313B oj 1314B ¢NJ 1315B N N 1316A 1317A N 1318A 1316B r\OH 1317B (, 1318B 1319A N-N 1320A-SNsyX 1321A H 1319B 1320B 1321B N N Ex. No. R 4P Ex. No. R 4p Ex. No. R4ß 1322A N o 1323A, N 1324A 1322B I' 1323B I N 1324B 1325A N-N 1326A N 1327A H N 1325B H 1326B H 1327B H H H N H H 1328A N-) N 1329A N 1330A-0 1328B N'N 11329B as 133330B n N 1331A N-1332A-N w 1331B 1332B 1334A/NN 1335A N 1336A N 1335 1334B N B N N 1336B H-jr, 1337A Nl_OS 1338A, 1339A 1337B 1338B 1339B 'J 1340A rY' 1341A. 1342A. N 1340B 1341B 1342B CC, N (" 1343A 1344A H3CO2C 1345A Br 1343B H3C O 1344B N 1345B H3c s H 1346A CH3 1347A I 5 1348A 1346B 1347B 3C (O) C S 1348B CL3 1349A 1350A 1351A 1349B HNrH 1350B I S ; 1351B Example Table 18. Substituted 4- [3-1 (5-Heteroaryl or 5-heterocyclic)-2, 4-dimethoxyphenyl}- acryloyl]-benzoic Acids. Ex. No. R 5P Ex. No. R 5p Ex. No. R5ß 1352A 1353A H3C 1354A N 1352B U 1353B s 1354B 6 1355A 1356A 2 1357A 1355B oa 1356B s 1357B 1358A, 5 1359A 5 1360A s 4 1358B o 1359B s 1360B U U 1361A N ' ; 1362A 1363A 1361B 1362B 1363B N 1364A 0 1365A 1366A s 1364B 6N 1365B Ht 1366B CN N \c N 1367A 0 1368A 1369A H 1367B 1368B H I 1369B Vint 1370A 1371 A 1372A wry 1370B 1371B No 1372B g H Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 1373A 1374A N 4 1375A HN N 1373B 1374B 1375B 0 N 1376A 1377A 4 1378A 1376B °l9 1377B 1378B tl N H 1379A 0 1380A 1381A S 1379B 1380B I \ 1381B NU 1382A N 1383A 1384A 1382B 1383B 1384B N 1385A 1386A N 1387A ir N 1385B ( 1386B C 1387B N 1388A S 1389A N 1390A N 1388B OH 1389B 1390B N 1391A H 1392A N 1393A 1391B its 1392B uN 1393B aN N 1394A N o 1395A/ N 1396A 1394B 1395B 1396B 'uv 1397A N-N 1398A w N 1399A L \>-, L C N 1397B N 1398B 1399B ! ! H H N H 1400 1401A N 1400B N'N s 1401B ; 1402B H N 1403A N-o 1404A N 1405A 1403B 1404B '\nn Ex. No. R5ß Ex. No. R5P Ex. No. R 5P R R 1406A/N-N 1407A N N 1408A 1406B , N'J'N 1407B N1 ! 5 N 1408B 1409A Nl_Oß 1410A 141 IA 1409B 141 OB 1412A N 1413A 1414A 1413B 1414B C'CN (" Example Table 19. Substituted 3- [3- { (5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R 5P Ex. No. R ß Ex. No. R5ß 1415A 1416A 1417A H N 1415B 1416B Xb 1417B X 1418A 1419A 1420A 1418B 1419B s 1420B osa 1421 A 1422A 1423A s 1421B o 1422B s 1423B W W L Ex. No. R 5p Ex. No. R 5p Ex. No. R5p 1424A 1425A 1426A I 1424B 1425B I 1426B 1427A o 1428A 1429A 1427B y 1428B H 1429B \--N \\.'L-N 1430A 0 1431A 1432A H 1430B < 1431B 1432B / 1433A 1434A 1435A N 1433B 1434B 1435B N 1436A 1437A H N 1438A HN-\ 1436B a 1437B 6 W 1438B osa N 1439A 1440A 4 1441 A ~4 1439B p 1440B I \ 1441B NUA" N 1442A 0 1443A 1444A S 1442B 1443B 1444B CYNH N 1445A I446A 1447A 1445B j 446B 1447B N H-N 1448A 1449AjN1450A N., 1448B oJ 1449B N 1450B NS N 1451A 1452A N 1453A N 1451B orOH 1452B , 1453B 1454A H 1455A 1456A 1454B 456B N-N Ex. No. R 5p Ex. No. R 5p Ex. No. R5ß 1457A 1458A N 1459A H ;, N 1457B 1458B N 1459B 1460A N-N 1461A N 1462A H 1460B U 1461B W ~H 1462B U (nu H 1463A N 2 1464A I N 1465A-O n s _ N 1463B N'H 1464B g 1465B N-N S 1465B 1466A N-o 1467A N-N 1466B 1467B I 1468B 1469A N,-N 1470A N > 1469B NJ<N 1470B N N 1471B w 1473A N-O 1474A, w 1475A 1473B 1474B 1475B w w 1476 N 1477A 1478A 1476B 1477B 1478B W N 1479A 1480A H3CO2C N 1481 A Br 1479B H3C O 1480B N-N 1481B H3c s H H 1482A CH3 1483A 1484A 1482B ¢9 1483B H3C (°) C S 1484B NxcH3 CL3 1485A 1486A 1487A 1485B H 1486B 1487B m u Example Table 20. Substituted 2-[3-{(5-Heteoraryl or 5-heterocyclic)-2, 4-dimethoxyphenyl}- acryloyl]-benzoic Acids. Ex. No. R 5P Ex. No. R 5P Ex. No. R 5p 1488A 1489A s A N 1488B C} 1489B v 1490B X 1491 A 1492A 1493A 1491 B oa 1492B s/1493B J 1494A \ 1495A 1496A 1494B 1495B s 1496B N 1497A 1498A H 1499A 1497B 1498B 1499B zu 1500A 0 1501A 1502A s 1500B \C-INT 1501B H 1502B \C-NY C 1503A 0 1504A 1505A H 1503B 6 31 1504B < 1505B tN N nu 1506A 1507A 1508A H N 1506B I 1507B N I 1508B N-a Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 1509A 151 OA N 1511 A 1509B C\ J 1510B 1511B osa N 1512A 1513A 1514A s r' 1512B o 1513B 1514B N HN 1515A o 4 1516A 1517A e 1515B \ 15t6B I 1517B ! /N NH 1518A N 1519A 1520A 1518B UN 1519B NC 1520B H-N\p N 1521 A 1522A N'7., 1523A N ; 1521 B oJ 1522B ¢ NX 1523B N N 1524A 1525A N 1526A N 1524B orOH 1525B , 1526B 1527A H 1528A N 1529A 1527B 1528B B N N 1530A N o 153l A/ N 1532A -N 1530B 1531B N 1532B Ny 4r 1533A N-N, 1534A \ N 1535A /t') !' Y 1533B N 1534B C. N 1535B H H H 1536A N 1537A N 1538A 1536B H ( : : c 1538B N r) N 1539A N-o 1540A N 1541 A 1539B 1540B w Ex. No. R ß Ex. No. R ß. Ex. No. R5ß 1542A N N 154 A N C 1542B N'JIN 1543B N N 1544B N H 1545A N-O 1546A/w 1547A, 1545B 1546B 1547B 1548A N 1549A 1550A aN 1548B 1549B 1550B Example Table 21. Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-2, 4-dimethoxyphenyl}- acryloyl]-5-methanesulfonylamino-benzoic Acids.

Ex. No. R5ß Ex. No. R 5p Ex. No. | R5ß 1551A 1552A s N YS/"YS/"YS 1551B Ub 1552B v 1553B C 1 554A 1 555A 1 556A 1554B 1555B s 1556B 1557A 1558A c : 1559A s 1557B o 1558B s 1559B < W U Ex. No. R 5p Ex. No. R ß Ex. No. R5ß 1560A 1561A 1562A 1560B 1561B 1562B U 1563A o 1564A 1565A 1563B 6N 1564B HNC 1565B CN 1566A 0 1567A 1568A H 1566B 1567B H I 1568B N CINT 1569A 1570A 1571A H 1569B 1570B N 1571B H 1572A 1573A N 4 1574A HNL) 1572B to) 1573B 1574B osa N 1575A 1576A 1577A s fY"' 1575B 0 1576B 1577B a L I 1578A 0 1579A 1580A 1579B 1578B 1579B I \ 1580B nu 1581A N 1582A 1583A ft Y" rY 1581B N 1582B 1583B C', N 1584A 1585A N 1586A N 1584B 1585B 1586B N : 0 (nu 1587A'., 1588A N, N' 1589A 1587B ocf 1588B 1589B 1590A H 1591A N 1592A 1590B-1 1591B N N Ex. No. R 5p Ex. No. R 5P Ex. No. R5ß R R 1593A N 1594A, N 1595A . N 1593B '1594B k' 1595B'S '1 1596A N-N 1597A \ N 1598A [ !/r t !- f 1596B N 1598B f ! H H 1598B H 1599A N 1600A N 1601A N-O 1599B H 1600B 1601B N H N 1602A Nl-Oß 1603A N 1604A 1602B 1603B m 1605A/N-N 1606A N w N 1607A 1605B N N 1606B N N 1607B N H 1608A N-0 1609A 16 1 OA 1608B 1609B CQ-N 161 OB '- 1611 A N 1612A 1613A aN 1611B IB 1612B lN 1613B ion 1614A J 1615A H3CO2CX S 1616A Br 16 14B H3C ° 1615B NoN s 1616B H3C-s H H 1617A CH3 1618A 1619A s 1617B 1618B H3C (o) c s 1619B O CH3 1620A 1621 A 1622A 1620B H 1621B 1622B Example Table 22. Substituted 5-Amino-2-[3-{(5-heteroaryl or 5-heterocyclic)-2, 4- dimethoxy-phenyl}-acryloyl]-benzoic Acids. Ex. No. R5ß Ex. No. R 5P Ex. No. R 5P 1623A 1624A s 1625A H N 1623B 1624B 1625B 1626A 1627A 1628A 1626B 1627B s 1628B HNC : R oa 1629A \ 1630A 1631A 1629B o 1630B s 1631B W W 1632A N ', ; 1633A N . 1634A I 1632B 1633B 1634B U 1 635A o E 1 636A N 1 637A s E /'YS/r/YS 1635B NI'1636B"\ 1637B I 1638A 0 1639A 1640A N 1638B 1639B 1640B N 1641A 1642A 1643A H 1641B 1642B 1643B Ex. No. R ß Ex. No. R ß Ex. No. R ß 1644A 1645A H E 1646A HN> N 1644B 1645B 1646B L O N 1647A 1648A 1649A 1647B 1648B 1649B a 1650A o 0 1651A 1652A S 1650B a 1651B C 1652B C /N NH 1653A N 1654A 1655A N 1653B (e N 1654B 1655 ; B H-No N 1656A 1657A N 1658A ir N 1656B oJ 1657B ¢NJ 1658B N ; N 1659A 1660A N 1661A N 1659B 1660B 1661B 1662A H 1663A N 1664A 1662B NN. I ! N N 1665A N-O 1666A < N 1667A H , N 1665B 1666B N 1667B 14r Y/ 1668A N-N 1669A N 1670A H N 1668B HN s 1669B H 1670B t H H H N H 1671A 1672A N 167 1 B H 1672B I ; 1673B "N 1674A Nl-Oß 1675A N ; 1676A 1674B 9 1675B Wo 1676B to s w Ex. No. R 5P Ex. No. R 5p Ex. No. R 5p 1677A NN 1678A N w N 1679A N w 1677B N N 1678B N 1679B N H 1680A N-o 1681 A, 1682A 1 680B tH 1681 B A 1 682B W '' 1683A N 1684A 1685A won 1683B 1684B 1685B r \ rN Example Table 23. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R5ß Ex. No. R5ß Ex. No. R 5p 1686A 1687A, 4 1688A N g N 1686B 1687B 1688B 1689A 1690A 1691 A 1689B 1690A 1691B HO osa 1692A 1693A 1694A s 4 1692B o 1693B sa 1694B W < U Ex. No. R 5p Ex. No. R ß Ex. No. R 5P 1695A 169 A H 1697A 1695B 1696B 1697B 1698A o 1699A 1700A 1698B NI 1699B"\ 1700B v 1701A 0 1702A 1703A H H Z 1701B 1702B 1703B I N 1704A 1705A, 1706A N 1704B 1705B 1706B H 1707A 1708A H 1707B C\ J 1708B 1709B osa N 171 OA 1711 A 1712A 1710B p z 1711B I \ 1712B C\ J N 1713A 0 1714A 1715A 1713B C 1714B j 1715B) /N 1716A N 1717A 1718A 1716B N 1717B NC 1718B H-NJ N 1719A 7 1720A N'7., 1721 A 1719B 1720B (N 1721B N N 1722A S 1723A Nv Ns> 1724A (NsyX 1722B or\OH 1723B , 1724B 1725A H 1726A N 1727A 1725B 1726B ans N Ex. No. R 5p Ex. No. R 5p Ex. No. R5ß 1728A N o 1729A, N 1730A ;. N 1 728B 1 729B < 1 730B 9 H 1731A N-N 2 1732A w N 1733A 1731B N 1732B I N 1733B H H H H 1734A N 1735A N 1736A-0 1734B H 1735B 1736B N N 1737A Nl-Oß 1738A w N 1739A 1737B 1738B cc N 1742A N 1740A/NN 1741A N w N 1742A 1740, N N 1741B N N 1742B H 1743A N-0 1744A 1745A 1743B 1744B 1745B 1746A N 1747A 1748A aN 1746B 1747B 1748B r \/N 1749A 1750A H3CO2C 1751A Br S I I s 1749B H3C O 1750B N-N/1751B H3c s H 1752A CH3 1753A I S 1754A 1752B s 1753B H3c (o) c s 1754B 0 cl3 1755A', ; 1756A w ; 1757A H 1756B 1757B Example Table 24. Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}- acryloyl]-benzoic Acids. Ex. No. R5p Ex. No. R5ß Ex. No. R5ß 1758A 1759A s 1760A H N 1758B U 1759B 6 1760B C 1761 A 1762A 1763A 1761B 1762B sC 1763B oa I. a 1764A, 4 1765A 1766A s 4 1764B o 1765B s 1766B W U 1767A 1768A H 1769A 1767B 1768B 1769B 1770A o 1771 A 1772A 177B \\ NI 1771 B HN 1772B e N 1773A o 1774A 1775A 1773B 1774B H I 1775B N c INT 1776A 1777A 1778A H 1776B OY 1777B 1778B Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 1779A 1780A N 1781A 1779B 1780B 1781B L oa N : 1782A 1783A f 1784A 1782B p z 1783B I \ 1784B C\ J 9 Nv H 1785A o 1786A 1787A /"TS S Y 1785B 1786B I \ 1787B N 1788A N 1789A 1790A fr'r 1789B 1790B N 1791 A'' 1792A N'z, 7 1793A N'., 1791B p 1792B C 1793B N 1794A 1795A N 1796A N 1794B ocf 1795B 1796B 1797A H 1798A N 1799A 1797B /5 1798B , 1799B N N 1800A N o 1801 A/ N I 802A Li-N 1800B 1801B N 1802B ruz 1803A N-N 1804A I N_ 1805A 1803B N 1804B N 1805B H H H 1806A 1807A N 1808A 1806B NN 5 1807B a 1808B "N 1809A Nl-OS 1810A 1811AN-N 1809B 9 181 OB wo 1811 B to w Ex. No. R 5p Ex. No. R 5P Ex. No. R 5P 1812A/NN 1813A N N 1814A 1812B N N 1813B N 1814B N H 1815A N-o 1816A 1817 1815B ,, 1816B I N 1817B '' 1818A y' 1819A. 1820A . 1818B 1819B 1820B r Example Table 25. Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-3, 4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R 5P Ex. No. R 5P Ex. No. R5p 1821 A 1822A S 1823A 1821B 1822B 1823B 1824A 1825A 1826A 1824B 1825B s 1826B oa 1827A 1828A 1829A s 1827B o 1828B s 1829B U W Ex. No. R5ß Ex. No. R5P Ex. No. R5p 1830A 1831A H 1832A 1830B 1831B 1832B 1833A o 1834A 1835A 1833B 1834B H 1835B y NY \CN 1836A o 1837A 1838A 1836B < : 1837B 1838B NY ZON / 1839A 1840A 1841A N 1839B 1840B 1841B N : a 1842A 1843A H 1844A N 1842B 1843B 1844B O N 1845A 1846A 1847A frr fY' 1846B 1847B N H 1848A 0 1849A 1850A S 1848B C 1849B I \ 1850B /N NH 1851A N 1852A 1853A 1851B C N 1 852B NC 1853B H-N N 1854A 1855A N :, 1856A 1854B 0 1855B ¢NJ 1856B N N 1857A'' 1858A N, N' ;, 1859A 1857B J) 1858B W 1859B N>N 1860A Zu 1861A N 1862A 1860B 1862B NU N Ex. No. R5ß Ex. No. R5p Ex. No. R5p R R 1863A N 1864A, N 1865A ; N. N 1863B 1864B N 1865B 1866A N-N 1867A N 1868A H N 1866B NH 1867B C N 1868B H H N H 1869AN 1870A N 1869B N_ NH s 1870B Ws 1871 B t N H N 1872A Nl-O 1873A w N 1874A 1872B I 1873B I 1874B N 1877A N 1875A NN 1876A N \ N 1877A N w 1875B NAN 1876B N N 1877B H 1878A N-o 1879A, w 1880A 1878B 1879B CQ-N 1880B w w 1881A MN 1882A 1883A aN 1881B ( r 1882B \ 1883B w r \/N 1884A m 1885A H3CO2C, <> 1886A Br 1884B H3C O 1885B Ns HN 1886B H3C S H 1887A N H3 1888A 9 1889A ¢9 1887B 1888B 3C 1889B o CH3 1890A 1891 A 1892A 1890B HNa OH 1891B 1892B CIO' Example Table 26. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-4-fluorophenyl}- acryloyl]-benzoic Acids. Ex. No. R5ß Ex. No. R5ß Ex. No. R5ß 1893A 1894A 1895A H 1893B 1894B 1895B 1896A oa 1897A 1898A HN 1898B 1896B o\ 1897B i S 1898B"" 1899A 1900A 1901A s 1899B o 1900B s 1901B b U N 1902A 1903A H 1904A 5 1902B 1903B 1904B N 1905A o E 1906A N 1907A Y 1905B IN 1906B"\ 1907B N \\c N 1908A 0 1909A 1910A H 1908B ) 1909B Y" 10B f N c NY 191 IA 1912A 1913A H N 191 IB 1912B 1913B aq Ex. No. R5ß Ex. No. | R5ß Ex. No. R5ß 1914A 1915A m 1916A HN 1 914B G 1 9l 5B 6 W 1 91 6B cor N 1917A 1918A 1919A rrs r' 1917B o 1918B 1919B N 1920A 0 1921A 1922A /T" Y rT 1920B 1921B I \ 1922B CL 1923A N 1924A 1925A 1923B 1924B 1925B N 1926A 1927A N 1928A irN 1926B p 1927B C 1928B N 1929A 1930A N 1931A N 1929B orOH 1930B , 1931 B 1932A H 1933A N 1934A 1932B /s 1933B , 1934B N N 1935A N o 1936A/ N 1937A , N 1935B 1936B N 1937B jr, Y/ 1938A N-N 1939A N. 1940A H N 1938B N 1939B N 1940B H H N H 1941A N 1942A I N 1943A N, O 1941B N'N 5 1942B a 1943B H N 1944A N-1945A 1946A N 1944B 1945B w Ex. No. R 5P Ex. No. R 5p Ex. No. R5ß 1947A/NN 1948A N N 1949A 1947B WNJuN 1948B N N 1949B H 1 950A N-o 1951 A 1 952A, \<N) 1950B 1951B 1952B 1953A N 1954A 1955A WN i 1 953B r 1 954B SC 1 955B r iN Example Table 27. Substituted 4- [3- { (3-Heteroaryl or 3-heterocyclic)-4-(pyrrolidin-1-yl)- phenyl} acryloyl]-benzoic Acids.

Ex. No. R 5p Ex. No. R 5p Ex. No. R5p 1956A 1957A s 1958A H N 1956B 1957B 1958B 1959A 1960A 1961A 1959B 1960B S, 1961B oa a- 1962A 1963A 1964A s 1962B o 1963B s 1964B W U Ex. No. R5ß Ex. No. R5ß Ex. No. R ß 1965A 1966A H 1967A 1965B 1966B 1967B N 1968A o 1969A 1970A 1968B IN 1969B""\ 1970B 1971A 0 1972A 1973A H /"T'S HM L <*/'TS 1971B 6 W 1972B 1973B I zon 1974A 1975A 1976A H N 1974B 1975B N 1976B H 1977A 1978A H 1979A 1977B 1978B 1979B osa N 1980A 1981A 1982A 1980B 1981B 1982B N 1983A 0 1984A 1985A /s fS rY 1983B 1984B I \ 1985B /N NH 1986A N 1987A 1988A [f f fr) Ft 1986B 1987B 1988B H-N «) N 1989A. 1990Aj1991A N-, 1989B °J 1990B (N 1991B N N 1992A 1993A N 1994A N 1992B OH 1993B 1994B 1995A H 1996A N 1997A 1995B /S 1996B , 1997B N-N Ex. No. R 5P Ex. No. R 5p Ex. No. R5ß 1998A N 1999A, N 2000A , N 1 998B 1 999B v, f 2000B V A-N 2002A N 2003A H ' ! ' 2001B N 2002B C N 2003B H H N H 2004A INg 2005A >N 2006A N-o 2004B Ns H 5 2005B lS s-2006B t N H N 2007A N-Ob 2008A N 2009A N-N 2007B 2008B C N 2012A 201 OA/NN 2011 A N w N 2012A 2010B N N 201 IB N N 2012B H 2013A N-0 2014A 2015A 2013B 2014B 2015B 2016A N 2017A 2018A won 2016B 2017B 2018B 0'cl"' 2019A 2020A H3CO2C< 2021 A sr> 2019B H3C 2020B N-N 2021B H3c s H 2022A CH3 2023A 2024A 2022B ¢9 2023B H3C (O) C s 2024B t NCH3 CL3 2025A 2026A 2027A 2025B OH 2026B 2027B Example Table 28. Substituted 4- [3- { (5-Heteroaryl or 5-heterocyclic)-2, 4-dimethoxyphenyl}- acryloyl] benzonitriles. Ex. No. R ß Ex. No. R 5p Ex. No. R5ß 2028A 2029A 2030A H N 2028B 2029B 2030B 2031A 2032A 2033A 203 IB o/Y 2032B 2033B v W 8 2034A 2035A 2036A s 2034B o 2035B s 2036B N 2037A 2038A 2039A 2037B 2038B 2039B W 2040A ° 5 2041 A N 5 2042A s 5 2040B 2041B 2042B y INT \c N 2043A 0 2044A 2045A H /'Y'S HM JL /"YS 2043B 6 W 2044B w 2045B tY N NY 2046A 2047A 2048A 2046B 2047B 2048B \---N Ex. No. R ß Ex. No. R ß Ex. No. R ß 2049A 2050A Nv5 2051 A HNS 2049B 2050B 2051B O N 2052A 2053A 2054A rs rr 2052B 0 2053B 2054B a S Nt H 2055A o E 2056A ~E 2057A S / f fY 2055B bzw 2056B 1 2057B 4NH /N NH 2058A N 2059A 2060A 2060B 2058B 2059B \ 2060B H-N N 2061A 2062A N. h ; 2063A N 2061 B J 2062B C 2063B (nu 2064A 2065A N 2066A N 2064B ocf 2065B t 2066B 2067A H 2068A N 2069A 2067B 2068B 2069B N N 2070A N_O 2071 A eN 2072A N 2070B 2071B 2072B Ny 2073A N-N 2074A N 2075A H N 2073B N 2074B 2075B H H N H 2076A {NIX 2077A t fs~ 2078A N-O 2076B N'N 5 2077B Ws 2078B tN H N 2079A N-o 2080A N 2081A 2079B 9 2080B 2081B o 2081B Ex. No. R ß Ex. No. R 5P Ex. No. R5ß 2082A/NN 2083A N N 2084A 2082B N 2083B N 2084B w I i H 2085A N-o 2086A mN 2087A qNq 2085B-, v 2086B vf 2087B ? 2088A N 2089A 2090A aN 2088B 2089B 2090B Example Table 29. Substituted 3- [2, 4-Dimethoxy- (5-heteroaryl or 5-heterocyclic) phenyl] - 1-[4-(2H-tetrazol-5-yl)phenyl]-2-propen-1-ones.

Ex. No. R5ß Ex. No. R 5p Ex. No. R5ß 2091A 2092A s 2093A H N 2091B 2092B 2093B 2094A 2095A 2096A S 2094B 2095B s 2096B 2097A 2098A 2099A s 2097B 0 2098B s 2099B U U Ex. No. R5ß Ex. No. R5ß Ex. No. R5p 2100A 2101A H 2102A NEZ 2100B 2101B 2102B N 2103A 0 2104A 2105A s 2103B IN 2104B"\ 2105B \c N N 2106A o E 2107A 2108A 2106B 2107B 2108B / 2109A 21 IOA 211 IA H 2109B 21 IOB 211 IB N : a 2112A 2113A H 2114A 2112B 2113B 2114B osa N 2115A 2116A ~E 2117A wE S rY' 2115B 2116B 2117B N 2118A o 4 2119A 4 2120A 4 2118B 2119B I \ 2120B /N NH 2121A N 2122A 2123A 2121B ¢N 2122B NC 2123B H-NJ N 2124A', 2125A N 2126A N'7. 2124B pr 2125B C 2126B N 2127A z 2128A N, N\ 2129A 2127B OH 2128B 2129B 2129B 2130A N, N Z 2131A N' 2132A 2130B 2131B 2132B N, N N Ex. No. j. 5p Ex. No. R 5p Ex. No. R5ß 2133A N-o 2134A eN 2135A N 2133B I' 2134B I N 2135B w m 2136A N-N 2137A N 2138A H 2136B N 2137B N 2138B H H N H 2139A N 2140A t fs~ 2141A N-O 2139B NHN S 2140B 2141B N H N 2142A N-O 2143A XN 2144A N_N Z 2142B L 2143B 2145A/NN 2146A N N 2147A 21 46B WNJ<N 21 46B t NzJHN 21 47B w H 2148A N-o 2149A 2150A 2150A 2148B ,, 2149B I N 2150B 2151A N 2152A 2153A 2151B 2152B 2153B r \ ru 2154A 2155A H3CO2C< 2156A Br 2154B H3C 0 2155B N 2156B H3c s H 2157A CH3 2158A 2159A 2157B ( S 2158B H3c (o) c s S 2159B 0 C 2160A 2161A 2162A 2160B HNJ 2161B vs 2162B, o Example Table 30. Substituted 4-[3-{(4-Heteroaryl or 4-heterocylic)phenyl}-acryloyl]- benzoic Acids. Ex. No. R4ß Ex. No. R4ß Ex. No. R4ß 2163A 2164A 2165A N 2165B 2163B U 2164B Ws 2165B X 2166A 2167A H3C 2168A 2168B 2166B o 2167B i S 2168B" 2169A 2170A 2171A s 2169B o 2170B s 2171B < W W 2172A 2173A 2174A 2172B 2173B I 2174B W 2175A o 2176A 2177A 2175B INT 2176B H 2177B S, N y-L \j 2178A 0 2179A 2180A H /'YS HM i. /'YS 2178B 2179B 2180B / 2181A ' 2182A, 2183A Y N 2181B o 2182B 2183B Ex. No. R4ß Ex. No. R4ß Ex. No. T R4ß 2184A 2185A N 2186A 2184B a 2185B 6 W 21 86B oa N 2187A 2188A 2189A . s rY' 2187B 0 2188B 2189B a t/S N H 2190A o E 2191A 4 2192A S 2190B 2191B I \ 2192B N 2193A 2194A 2195A NY y rY 2193B 2194B \ 2195B H-N HIC N N/ 2196A'7, 7 2197A N'. 2198A N'., 2196B 2197B 2198B 2198B NJ 0 N-) 2199A 2200A N 2201 A N 2199B 2200B 2201B N N 2202A, N 2203A N', 7 2204A 2202B 2203B 2204B N an : N 2205A N-o 2206A v N 2207A N N 2205B 2206B N 2207B j Y/ 2208A Ntnsx 2209A N 2210A H N 2208B N 2209B C N 2210B H H N H 2211A N 2212A m fs$~ 2213A N-O 221 IB H 2213B N D N 2214A N-0 2215A N 2216A o 2216B 0 2214B Y 2215B WòfSs-2216B Ex. No. R4p Ex. No. R 4p Ex. No. | R4ß 2217A NN 2218A N N 2217B \NN 2218B N ; 2219B w I N H 2220A N-O 2221A 2222A 2220B, 9 2221 B W N 2222B AJ 2223A 2224A 2225A 2224B 2225B 2223B Example Table 31. Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic) phenyl}-3-oxo- propenyl] -benzoic Acids.

Ex. No. R4a Ex. No. R Ex. No. R4a K K K 2226A 2227A s 2228A H N 2226B U 2227B.,, v 2228B v 2229A 2230A 2231A 2229B 2230B S, 2231B H osa 2232A 2233A 2234A s 2232B °, 2233B s 2234B kd U Ex. No. R4a Ex. No. R4a Ex. No. R4a K JK K 2235A 2236A 2237A I 2235B 2236B 2237B 2238A 0 2239A 2240A s 2238B IN 2239B"\ 2240B '--N Y' \-N 2241A 0 2242A 2243A H 2241 B MX 2242B < 2243B X / 2244A 2245A 2246 H A N 2244B 2245B 2246B N 2247A 2248A N 2249A 2247B 2248B 2249B O N 2250A 2251A 2252A 2250B 0 2251B 2252B N H 2253A 0 2254A 2255A S 2253B CY 2254B t 2255B ! N 2256A ir N 2257A 2258A 2256B N ( : : r 2258B H-NJ N 2259A', 2260A N'.,, 2261 A N'z, 7 2259B oJ 2260B C 2261B N 2262A 2263A N 2264A N 2262B r 2263B 2264B 2264B 2265A N, N r 2266A N\ 2267A 2265B 2266B 2267B N, N N Ex. No. R4a Ex. No. R4a Ex. No. R4a K K K 2268A N 2269A, N 2270A 2268B 2269B'N 2270B Y/ ') 2271A AN-N 2272A N 2273A H 2271B N 2272B N 2273B H H N H 2274A 2275A N 2274B H 2275B c : 2276B N H N 2277A Nl-O 2278A N 2279A ! !/y !'' ! !/ 2277B 2278B I i 2279B -N N 2282A 2280A N 2281A N w N 2282A 2280B NN 2281B N 2282B N H 2283A Nl-O 2284A/ 2285A, 2283B 2284B 2285B r - 2286A N 2287A 2288A 2286B 2287B 2288B r \/N 2289A 2290A H3CO2C< 2291 A sr> 2289B H3C o 2290B N, N 5 2291 B H3c s H 2292A CH3 2293A J 2294A ¢9 2292B 2293B H3C (O) CS 2294B CL3 2295A 2296A 2297A 2295B OH 2296B 2297B Example Table 32. Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)-2,6-dimethoxyphenyl}- acryloyl]-benzoic Acids. Ex. No. R ß Ex. No. R 4p Ex. No. R 4p 2298A 2299A s N 2298B 2299B 2300B 2301A 2302A 2303A 2301 B oW 2302B sO 2303B < osa-a 2304A 2305A 2306A s 2304B o 2305B s 2306B U U 2307A 2308A H 2309A 2307B t NJ 2308B S 2309B u 2310A o E 231 IA 4 2312A sE 2310B X 23í IB Ht 2312B 1 2313A 0 2314A 2315A H 2313B 2314B 2315B ZON 2316A 2317A 2318A H 2316B 2317B 2318B H Ex. No. R4P Ex. No. R4p Ex. No. R4p R R 2319A 2320A N 2321A 2319B toJ 2320B 6 W 2321B osa N 2322A 2323A 2324A S rY' 2322B cr"\ 2323B ! 2324B N 2325A o E 2326A 2327A /s 's rY' 2325B 2326B 2327B y A CN 2328A N 2329A 2330A 2328B 2329B 2330B N 2331A 2332A N 2333A irN 233 IB °uJ 2332B tNJ 2333B N 2334A 2335A N 2336A f NyS 2334B o J OH 2335B 2336B 2336B 0 2337A H 2338A N 2339A 2337B 2338B N N 2340A Nt 2341A X I 2342A N-N . N 2340B I' 2341B I N 2342B 2340B-4r H. 2343A NtNsx 2345A N L !'T t -r V 2343B N 2344B N 2345B H H N H 2346A INI9 2347A m fs~ 2348A N-O 2346B H 2348B N H N 2349A Nl-Oß 2350A N 2351A 2349B S 2350B Wo 235 í B D Ex. No. R 4p Ex. No. R 4p Ex. No. R 4p 2352A/N-N 2353A N N 2354A 2352B N 2353B N N 2354B w H 2355A N-o 2356A 2357A C : pN 2355B 2356B 2357B 2358A N 2359A 2360A 2358B 4 S 2359B WN 2360B N Example Table 33. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2, 4-dimethoxyphenyl}- acryloyl]-benzoic Acids.

Ex. No. R5ß Ex. No. R ß Ex. No. R 5p 2361A I e 2362A H3CO2Cos 2363A BrS s I I s 2361B H3C O 2362B. 2363B H3c s H 2364A CH3 2365A 2366A 2364B 2365B 2366B o CH3 2367A 2368A 2369A 2367B H 2368B 2369B

Stereoisomerism and Polymorphism It is appreciated that compounds of the present invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, diastereomeric, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

Examples of methods to obtain optically active materials are known in the art, and include at least the following. i) physical separation of crystals-a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i. e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization-a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state ; iii) enzymatic resolutions-a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis-a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis-a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under

conditions that produce asymmetry (i. e. , chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations-a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first-and second-order asymmetric transformations-a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions-this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors-a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography-a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can

be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography-a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents-a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes-a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass through.

Pharmaceutically Acceptable Salt Formulations In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. The term"pharmoaceu, hcally acceptable salts"or"complexes"refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects.

Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a- ketoglutarate and a-glycerophosphate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts. Alternatively, the pharmaceutically acceptable

salts may be made with sufficiently basic compounds such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N, N-dibenzylethylenediamine, D- glucosamine, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e. g., a zinc tannate salt or the like. Also included in this definition are pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula-NR+A-, wherein R is as defined above and A is a counterion, including chloride, bromide, iodide,-O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

Particular FDA-approved salts can be conveniently divided between anions and cations (Approved Drug Products with Therapeutic Equivalence Evaluations (1994) U. S. Department of Health and Human Services, Public Health Service, FDA, Center for Drug Evaluation and Research, Rockville, Md; L : D. Bighley, S. M. Berge and D. C. Monkhouse, Salt Forms of Drugs and Absorption, Encyclopedia of Pharmaceutical Technology, Vol. 13, J. Swarbridk and J.

Boylan, eds., Marcel Dekker, NY (1996) ). Among the approved anions include aceglumate, acephyllinate, acetamidobenzoate, acetate, acetylasparaginate, acetylaspartate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartat, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, bromide, camphorate, camsylate, carbonate, chloride, chlorophenoxyacetate, citrate, closylate, cromesilate, cyclamate, dehydrocholate, dihydrochloride, dimalonate, edentate, edisylate, estolate, esylate, ethylbromide, ethylsulfate,

fendizoate, fosfatex, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycerophosphate, glysinate, glycollylarsinilate, glycyrrhizate, hippurate, hemisulfate, hexylresorcinate, hybenzate, hydrobromide, hydrochloride, hydroiodid, hydroxybenzenesulfonate, hydroxybenzoate, hydroxynaphthoate, hyclate, iodide, isethionate, lactate, lactobionate, lysine, malate, maleate, mesylate, methylbromide, methyliodide, methylnitrate, methylsulfate, monophosadenine, mucate, napadisylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, oxoglurate, pamoate, pantothenate, pectinate, phenylethylbarbiturate, phosphate, pacrate, plicrilix, polistirex, polygalacturonate, propionate, pyridoxylphosphate, saccharinate, salicylate, stearate, succinate, stearylsulfate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teprosilate, terephthalate, teoclate, thiocyante, tidiacicate, timonacicate, tosylate, triethiodide, triethiodide, undecanoate, and xinafoate. The approved cations include ammonium, benethamine, benzathine, betaine, calcium, carnitine, clemizole, chlorcyclizine, choline, dibenylamine, diethanolamine, diethylamine, diethylammonium diolamine, eglumine, erbumine, ethylenediamine, heptaminol, hydrabamine, hydroxyethylpyrrolidone, imadazole, meglumine, olamine, piperazine, 4- phenylcyclohexylamine, procaine, pyridoxine, triethanolamine, and tromethamine. Metallic cations include, aluminum, bismuth, calcium lithium, magnesium, neodymium, potassium, rubidium, sodium, strontium and zinc.

A particular class of salts can be classified as organic amine salts. The organic amines used to form these salts can be primary amines, secondary amines or tertiary amines, and the substituents on the amine can be straight, branched or cyclic groups, including ringed structures formed by attachment of two or more of the amine substituents. Of particular interest are organic amines that. are substituted by one or more hydroxyalkyl groups, including alditol or ; carbohydrate moieties. These hydroxy substituted organic amines can be cyclic or acyclic, both classes of which can be primary amines, secondary amines or tertiary amines. A common class of cyclic hydroxy substituted amines are the amino sugars.

Carbohydrate moieties that can comprise one or more substituents in the amine salt include those made from substituted and unsubstituted monosaccharides, disaccharides, oligosaccharides, and polysaccharides. The saccharide can be an aldose or ketose, and may comprise 3,4, 5,6, or 7 carbons. In one embodiment the carbohydrates are monosaccharides.

In another embodiment the carbohydrates are pyranose and furanose sugars. Non limiting examples of pyranose and furanose moieties that can be part of the organic amine salt include threose, ribulose, ketose, gentiobiose, aldose, aldotetrose, aldopentose, aldohexose, ketohexose, ketotetrose, ketopentose, erythrose, threose, ribose, deoxyribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, glactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose, cellulose, aldose, amylose, palatinose, trehalose, turanose, cellobiose, amylopectin, glucosamine, mannosamine, fucose, phamnose, glucuronate, gluconate, glucono-lactone, muramic acid, abequose, rhamnose, gluconic acid, glucuronic acid, and galactosamine. The carbohydrate moiety can optionally be deoxygenated at any corresponding C-position, and/or substituted with one or more moieties such as hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound. Exemplary substituents include amine and halo, particularly fluorine. The substituent or carbohydrate can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. In one embodiment the monosaccharide is a furanose such as (L or D)-ribose.

Of particular interest among the acyclic organic amines are a class represented by the formula wherein Y and Z are independently hydrogen or lower alkyl or, may be taken together to form a ring, R is hydrogen, alkyl or hydroxyloweralkyl, and n is 1, 2,3, 4, or 5. Among these hydroxyl amines are a particular class characterized when n is 4. A representative of this group

is meglumine, represented when Y is hydrogen, Z is methyl and R is methoxy. Meglumine is also known in the art as N-methylglucamine, N-MG, and l-deoxy-1-(methylamino)-D-glucitol.

The invention also includes pharmaceutically acceptable prodrugs of the compounds.

Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.

Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the compound. A number of prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the compound will increase the stability of the chalcone. Examples of substituent groups that can replace one or more hydrogens on the compound are alkyl, aryl, steroids, carbohydrates, including sugars, 1, 2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed compounds to achieve a desired effect.

The compounds can be used to treat inflammatory disorders that are mediated by VCAM-1 including, but not limited to arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ischemia-reperfusion injury, post- angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.

The compounds disclosed herein can be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1, and in particular, human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to, psoriasis, dermatitis, including

eczematous dermatitis, and Kaposi's sarcoma, as well as proliferative disorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.

In yet another embodiment, the compounds of the present invention can be selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but are not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. They are also indicated for the prevention or treatment of graft-versus-host disease, which sometimes occurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post- angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.

In another aspect the invention provides pharmaceutical compositions for the treatment of diseases or disorders mediated by VCAM-1 wherein such compositions comprise a VCAM- 1 inhibiting amount of a chalcone derivatives of the invention or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable carrier.

In another aspect the invention provides a method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

In another aspect the invention provides a method for treating cardiovascular and inflammatory disorders in a patient in need thereof comprising administering to said patient an VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

In another aspect the invention provides a method and composition for treating asthma or arthritis in a patient in need thereof comprising administering to said patient an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be used to treat any disorder that is mediated by VCAM-1. VCAM-1 is upregulated in a wide variety of disease states, including but not limited to arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, atherosclerosis, coronary artery disease, angina, small artery disease, and conjunctivitis.

Nonlimiting examples of arthritis include rheumatoid (such as soft-tissue rheumatism and non-articular rheumatism, fibromyalgia, fibrositis, muscular rheumatism, myofascil pain, humeral epicondylitis, frozen shoulder, Tietze's syndrome, fascitis, tendinitis, tenosynovitis, bursitis), juvenile chronic, spondyloarthropaties (ankylosing spondylitis), osteoarthritis, hyperuricemia and arthritis associated with acute gout, chronic gout and systemic lupus erythematosus.

Human endothelial disorders mediated by VCAM-1 include psoriasis, eczematous dermatitis, Kaposi's sarcoma, as well as proliferative disorders of smooth muscle cells.

In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.

In one embodiment, the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but are not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or corneal transplants. The compounds can also be used in the prevention or treatment of graft-versus- host disease, such as sometimes occurs following bone marrow transplantation.

In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post- angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.

In addition to inhibiting the expression of VCAM-1, some of the compounds of the invenion have the additional properties of inhibiting monocyte chemoattractant protein-1 (MCP-1) and/or smooth muscle proliferation. MCP-1 is a chemoattractant protein produced by endothelial cells, smooth muscle cells as well as macrophages. MCP-1 promotes integrin activation on endothelial cells thereby facilitating adhesion of leukocytes to VCAM-I, and MCP-1 is a chemoattractant for monocytes. MCP-1 has been shown to play a role in leukocyte recruitment in a number of chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, and asthma. Its expression is upregulated in these diseases and as such inhibition of MCP-1 expression represents a desirable property of anti-inflammatory therapeutics. Furthermore, smooth muscle cell hyperplasia and resulting tissue remodeling and decreased organ function is yet another characteristic of many chronic inflammatory diseases including atherosclerosis, chronic transplant rejection and asthma. Inhibition of the hyperproliferation of smooth muscle cells is another desirable property for therapeutic compounds.

Combination and Alternation Therapy Any of the compounds disclosed herein can be administered in combination or alternation with a second biologically active agent to increase its effectiveness against the target disorder.

In combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially. The dosages will depend on absorption, inactivation and excretion rates of the drug as

well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

The efficacy of a drug can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, agent that induces a different biological pathway from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the condition.

Any method of alternation can be used that provides treatment to the patient.

Nonlimiting examples of alternation patterns include 1-6 weeks of administration of an effective amount of one agent followed by 1-6 weeks of administration of an effective amount of a second agent. The alternation schedule can include periods of no treatment. Combination therapy generally includes the simultaneous administration of an effective ratio of dosages of two or more active agents.

Illustrative examples of specific agents that can be used in combination or alternation with the compounds of the present invention are described below in regard to asthma and arthritis. The agents set out below or others can alternatively be used to treat a host suffering from any of the other disorders listed above or that are mediated by VCAM-1 or MCP-1.

Illustrative second biologically active agents for the treatment of cardiovascular disease are also provided below.

Asthma In one embodiment, the compounds of the present invention are administered in combination or alternation with heparin, frusemide, ranitidine, an agent that effects respiratory function, such as DNAase, or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane

inhibitors, leukotriene-D4-receptor antagonists such as Accolate (zafirlukast), Ziflo (zileuton), leukotriene C or C2 antagonists and inhibitors of leukotriene synthesis such as zileuton for the treatment of asthma, or an inducible nitric oxide synthase inhibitor.

In another embodiment, the active compound is administered in combination or alternation with one or more other prophylactic agent (s). Examples of prophylactic agents that can be used in alternation or combination therapy include but are not limited to sodium cromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium) and ketotifen.

In another embodiment, the active compound is administered in combination or alternation with one or more other ß2-adrenergic agonist (s) (p agonists). Examples of (32- adrenergic agonists (ß agonists) that can be used in alternation or combination therapy include but are not limited to albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenamine hydrochloride, methylephedrine hydrochloride, orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolamine polistirex, phenylpropanolamine sulphate), pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterol hydrochloride, rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate, terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.

In another embodiment, the active compound is administered in combination or alternation with one or more other corticosteriod (s). Examples of corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril,

beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium Phosphate), Dichlorisone Acetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate, Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide, Triamcinolone Diacetate and Triamcinolone Hexacetonide).

In another embodiment, the active compound is administered in combination or alternation with one or more other antihistimine (s) (H, receptor antagonists). Examples of antihistimines (H, receptor antagonists) that can be used in alternation or combination therapy include alkylamines, ethanolamines ethylenediamines, piperazines, piperidines or

phenothiazines. Some non-limiting examples of antihistimes are Chlortrimeton (Teldrin, chlorpheniramine), Atrohist (brompheniramine, Bromarest, Bromfed, Dimetane), Actidil (triprolidine), Dexchlor (Poladex, Polaramine, dexchlorpheniramine), Benadryl (diphen- hydramine), Tavist (clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ (tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin (loratadine), Seldane (terfenadine), Periactin (cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth (promethazine, Phenergan), Tacaryl (methdilazine) and Temaril (trimeprazine).

Alternatively, the compound of the present invention is administered in combination or alternation with (a) xanthines and methylxanthines, such as Theo-24 (theophylline, Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl (oxitriphylline), aminophylline ; (b) anticholinergic agents (antimuscarinic agents) such as belladonna alkaloids, Atrovent (ipratropium bromide), atropine, oxitropium bromide; (c) phosphodiesterase inhibitors such as zardaverine; (d) calcium antagonists such as nifedipine; or (e) potassium activators such as cromakalim for the treatment of asthma.

Arthritic disorders In one embodiment, the compound of the present invention can also be administered in combination or alternation with apazone, amitriptyline, chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine, pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate), misoprostol, paracetamol, superoxide dismutase mimics, TNFa receptor antagonists, TNFa antibodies, P38 Kinase inhibitors, tricyclic antidepressents, cJun kinase inhibitors or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane inhibitors, and inducible nitric oxide sythase inhibitors.

In another embodiment, the active compound is administered in combination or alternation with one or more other corticosteriod (s). Examples of corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium Phosphate), Dichlorisone Acetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate, Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide, Triamcinolone Diacetate and Triamcinolone Hexacetonide).

In another embodiment, the active compound is administered in combination or alternation with one or more other non-steroidal anti-inflammatory drug (s) (NSAIDS).

Examples of NSAIDS that can be used in alternation or combination therapy are carboxylic acids, propionic acids, fenamates, acetic acids, pyrazolones, oxicans, alkanones, gold compounds and others that inhibit prostaglandin synthesis, preferably by selectively inhibiting cylcooxygenase-2 (COX-2). Some nonlimiting examples of COX-2 inhibitors are Celebrex (celecoxib), Bextra (valdecoxib), Dynastat (parecoxib sodium) and Vioxx (rofacoxib). Some non-limiting examples of NSAIDS are aspirin (acetylsalicylic acid), Dolobid (diflunisal), Disalcid (salsalate, salicylsalicylate), Trisilate (choline magnesium trisalicylate), sodium salicylate, Cuprimine (penicillamine), Tolectin (tolmetin), ibuprofen (Motrin, Advil, Nuprin Rufen), Naprosyn (naproxen, Anaprox, naproxen sodium), Nalfon (fenoprofen), Orudis (ketoprofen), Ansaid (flurbiprofen), Daypro (oxaprozin), meclofenamate (meclofanamic acid, Meclomen), mefenamic acid, Indocin (indomethacin), Clinoril (sulindac), tolmetin, Voltaren (diclofenac), Lodine (etodolac), ketorolac, Butazolidin (phenylbutazone), Tandearil (oxyphenbutazone), piroxicam (Feldene), Relafen (nabumetone), Myochrysine (gold sodium thiomalate), Ridaura (auranofin), Solganal (aurothioglucose), acetaminophen, colchicine, Zyloprim (allopurinol), Benemid (probenecid), Anturane (sufinpyrizone), Plaquenil (hydroxychloroquine), Aceclofenac, Acemetacin, Acetanilide, Actarit, Alclofenac, Alminoprofen, Aloxiprin, Aluminium Aspirin, Amfenac Sodium, Amidopyrine, Aminopropylone, Ammonium Salicylate, Ampiroxicam, Amyl Salicylate, Anirolac, Aspirin, Auranofin, Aurothioglucose, Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine), Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine, Hydrochloride, Bornyl Salicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium, Butibufen Sodium, Capsaicin, Carbaspirin Calcium, Carprofen, Chlorthenoxazin, Choline Magnesium Trisalicylate, Choline Salicylate, Cinmetacin, Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene, Diacerein, Diclofenac (Diclofenac Diethylammonium Salt, Diclofenac Potassium, Diclofenac Sodium), Diethylamine Salicylate, Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam, Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac, Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium, Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic, Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen, Glafenine, Glucametacin, Glycol Salicylate, Gold Keratinate, Harpagophytum

Procumbens, Ibufenac, Ibuprofen, Ibuproxam, Imidazole Salicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone, Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, Lithium Salicylate, Lonazolac Calcium, Lornoxicam, Loxoprofen Sodium, Lysine Aspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid, Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate, Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, Morazone Hydrochloride, Morniflurnate, Morpholine Salicylate, Nabumetone, Naproxen (Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide, Oxametacin, Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone, Phenyramidol Hydrochloride, Picenadol Hydrochloride, Picolamine Salicylate, Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen, Pranosal, Proglumetacin Maleat, Proquazone, Protizinic Acid, Ramifenazone, Salacetamide, Salamidacetic Acid, Salicylamide, Salix, Salol, Salsalate, Sodium Aurothiomalate, Sodium Gentisate, Sodium Salicylate, Sodium Thiosalicylate, Sulindac, Superoxide Dismutase (Orgotein, Pegorgotein, Sudismase), Suprofen, Suxibuzone, Tenidap Sodium, Tenoxicam, Tetrydamine, Thurfyl Salicylate, Tiaprofenic, Tiaramide Hydrochloride, Tinoridine Hydrochloride, Tolfenamic Acid, Tometin Sodium, Triethanolamine Salicylate, Ufenamate, Zaltoprofen, Zidometacin and Zomepirac Sodium.

Cardiovascular Disease Compounds useful for combining with the compounds of the present invention for the treatment of cardiovascular disease encompass a wide range of therapeutic compounds.

Ileal bile acid transporter (IBAT) inhibitors, for example, are useful in the present invention, and are disclosed in patent application no. PCT/US95/10863, herein incorporated by reference. More IBAT inhibitors are described in PCT/US97/04076, herein incorporated by reference. Still further IBAT inhibitors useful in the present invention are described in U. S.

Application Serial No. 08/816,065, herein incorporated by reference. More IBAT inhibitor compounds useful in the present invention are described in WO 98/40375, and WO 00/38725, herein incorporated by reference. Additional IBAT inhibitor compounds useful in the present invention are described in U. S. Application Serial No. 08/816,065, herein incorporated by reference.

In another aspect, the second biologically active agent is a statin. Statins lower cholesterol by inhibiting of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a

key enzyme in the cholesterol biosynthetic pathway. The statins decrease liver cholesterol biosynthesis, which increases the production of LDL receptors thereby decreasing plasma total and LDL cholesterol (Grundy, S. M. New Engl. J. Med. 319, 24 (1988); Endo, A. J Lipid Res.

33,1569 (1992) ). Depending on the agent and the dose used, statins may decrease plasma triglyceride levels and may increase HDLc. Currently the statins on the market are lovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and fluvastatin (Sandoz). A fifth statin, atorvastatin (Parke-Davis/Pfizer), is the most recent entrant into the statin market.

Any of these statins or thers can be used in combination with the chalcones of the present invention.

MTP inhibitor compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the MTP inhibitor compounds of particular interest for use in the present invention are disclosed in WO 00/38725, the disclosure from which is incorporated by reference. Descriptions of these therapeutic compounds can be found in Science, 282, 23 October 1998, pp. 751-754, herein incorporated by reference.

Cholesterol absorption antagonist compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the cholesterol absorption antagonist compounds of particular interest for use in the present invention are described in U. S. Patent No. 5,767, 115, herein incorporated by reference. Further cholesterol absorption antagonist compounds of particular interest for use in the present invention, and methods for making such cholesterol absorption antagonist compounds are described in U. S. Patent No. 5,631, 365, herein incorporated by reference.

A number of phytosterols suitable for the combination therapies of the present invention are described by Ling and Jones in"Dietary Phytosterols: A Review of Metabolism, Benefits and Side Effects,"Life Sciences, 57 (3), 195-206 (1995). Without limitation, some phytosterols of particular use in the combination of the present invention are Clofibrate, Fenofibrate, Ciprofibrate, Bezafibrate, Gemfibrozil. The structures of the foregoing compounds can be found in WO 00/38725.

Phytosterols are also referred to generally by Nes (Physiology and Biochemistry of Sterols, American Oil Chemists'Society, Champaign, Ill., 1991, Table 7-2). Especially

preferred among the phytosterols for use in the combinations of the present invention are saturated phytosterols or stanols. Additional stanols are also described by Nes (Id.) and are useful in the combination of the present invention. In the combination of the present invention, the phytosterol preferably comprises a stanol. In one preferred embodiment the stanol is campestanol. In another preferred embodiment the stanol is cholestanol. In another preferred embodiment the stanol is clionastanol. In another preferred embodiment the stanol is coprostanol. In another preferred embodiment the stanol is 22, 23-dihydrobrassicastanol. In another embodiment the stanol is epicholestanol. In another preferred embodiment the stanol is fucostanol. In another preferred embodiment the stanol is stigmastanol.

Another embodiment the present invention encompasses a therapeutic combination of a compound of the present invention and an HDLc elevating agent. In one aspect, the second HDLc elevating agent can be a CETP inhibitor. Individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/38725, the disclosure of which is herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 99/14174, EP818448, WO 99/15504, WO 99/14215, WO 98/04528, and WO 00/17166, the disclosures of which are herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/18724, WO 00/18723, and WO 00/18721, the disclosures of which are herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 98/35937 as well as U. S. Patent Nos. 6,313, 142,6, 310,075, 6,197, 786,6, 147,090, 6,147, 089,6, 140,343, and 6,140, 343, the disclosures of which is herein incorporated by reference.

In another aspect, the second biologically active agent can be a fibric acid derivative.

Fibric acid derivatives useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities which have been reported and published in the art.

In another embodiment the present invention encompasses a therapeutic combination of a compound of the present invention and an antihypertensive agent. Hypertension is defined as persistently high blood pressure. In another embodiment, the chalcone is administered in

combination with an ACE inhibitor, a beta andrenergic blocker, alpha andrenergic blocker, angiotensin II receptor antagonist, vasodilator and diuretic.

Pharmaceutical Compositions Any host organism, including a pateint, mammal, and specifically a human, suffering from any of the above-described conditions can be treated by the administration of a composition comprising an effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier or diluent.

The composition can be administered in any desired manner, including oral, topical, parenteral, intravenous, intradermal, intra-articular, intra-synovial, intrathecal, intra-arterial, intracardiac, intramuscular, subcutaneous, intraorbital, intracapsular, intraspinal, intrasternal, topical, transdermal patch, via rectal, vaginal or urethral suppository, peritoneal, percutaneous, nasal spray, surgical implant, internal surgical paint, infusion pump, or via catheter. In one embodiment, the agent and carrier are administered in a slow release formulation such as an implant, bolus, microparticle, microsphere, nanoparticle or nanosphere. For standard information on pharmaceutical formulations, see Ansel, et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Edition, Williams & Wilkins (1995).

An effective dose for any of the herein described conditions can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication. Typical systemic dosages for all of the herein described conditions are those ranging from 0.1 mg/kg to 500 mg/kg of body weight per day as a single daily dose or divided daily doses. Preferred dosages for the described conditions range from 5- 1500 mg per day. A more particularly preferred dosage for the desired conditions ranges from

25-750 mg per day. Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.

The compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.

The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects.

The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.

A preferred mode of administration of the active compound for systemic delivery is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed'into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an, excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes ; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

The compound or its salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The compound can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action. The compounds can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound can also be administered with corticosteriods.

Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiological saline, bacteriostatic water, Cremophor ELM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of

such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceutical, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U. S. Patent No. 4,522, 811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid (s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.

Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa. In addition to the other materials listed above for systemic administration, thickening agents, emollients and stabilizers can be used to prepare topical compositions.

Examples of thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.

Any of the compounds described herein for combination or alternation therapy can be administered as any derivative that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound, or that exhibits activity itself. Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as"physiologically acceptable salts"), and a compound which has been alkylated or acylated at an appropriate position. The modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its anti-inflammatory activity according to known methods.

Biological Activity of Active Compounds The ability of a compound described herein to inhibit the expression of VCAM-1 or in the treatment of diseases in a host can be assessed using any known method, including that described in detail below.

In Vitro MCP-1 Activity Assay Cultured human endothelial cells were seeded in 96-well plates. On the following day cells were stimulated with TNF-a (lng/ml) in the presence or absence of compounds dissolved in DMSO. To establish a dose curve and an ICso, multiple concentrations in 2-to 5-fold increments were used. Cells were exposed to TNF-a and compounds for approximately 16 hours. The next day the cells were visually examined via light microscopy to score for visual signs oftoxicity. Cell culture media, diluted 1: 10, was analyzed by an MCP-1 immunoassay kit (R & D Systems). This assay is a sandwich immunoassay using immobilized anti-MCP-1 antibody in 96-well plate to capture secreted MCP-1 in cell culture media. Captured MCP-1 was subsequently detected with a horse radish peroxidase-conjugated anti-MCP-1 antibody for color development. Compound 3 expressed an ICso values of > 10 (the amount of compound (u. M) required to achieve a 50% reduction compared to control (cells stimulated with TNF-a only)).

In Vitro VCAM-1 Assay Cell Culture and compound dosing: Cultured primary human aortic (HAEC) or pulmonary (HPAEC) endothelial cells were obtained from Clonetics, Inc. , and were used below passage 9. Cells were seeded in 96 well plates such that they would reach 90-95% confluency by the following day. On the following day the cells were stimulated with TNF-a (lng/ml) in the presence or absence of compounds dissolved in DMSO such that the final concentration of DMSO is 0.25% or less. To establish a dose curve for each compound, four concentrations in 2-to 5-fold increments were used. Cells were exposed to TNF-a and compounds for approximately 16 hours. The next day the cells were examined under microscope to score for visual signs of toxicity or cell stress.

Following 16hr exposure to TNF-a and compound the media was discarded and the cells were washed once with Hanks Balanced Salt Solution (HBSS) /Phosphate buffered saline (PBS) (1: 1). Primary antibodies against VCAM-1 (0. 2511g/ml in HBSS/PBS + 5% FBS) were added and incubated for 30-60 minutes at 37°C. Cells were washed with HBSS/PBS three times, and secondary antibody Horse Radish Peroxidase (HRP) -conjugated goat anti-mouse IgG (1: 500 in HBSS/PBS + 5% FBS) were added and incubated for 30 minutes at 37°C. Cells were washed with HBSS/PBS four time and TMB substrate were added and incubated at room temperature in the dark until there was adequate development of blue color. The length of time of incubation was typically 5-15 minutes. 2N sulfuric acid was added to stop the color development and the data was collected by reading the absorbance on a BioRad ELISA plate reader at OD 450nm. The results are expressed as ICso values (the concentration (micromolar) of compound required to inhibit 50% of the maximal response of the control sample stimulated by TNF-a only). Compounds exhibiting IC50's of less than 5 micromolar are tabulated in Biological Table 1.

Biological Table 1 Example VCAM-1 Example VCAM-Example VCAM-1 Example VCAM- Number IC50 Number 1 IC50 Number IC50 Number 1 IC50 (µM) (uM) (aM) (uM) 1 <1 31 >10 61 <1 91 <5 2 <5 32 <5 62 <5 92 <1 3 <1 33 <5 63 <10 93 <1 4 <10 34 >10 64 >10 94 <1 5 <1 35 >10 65 <1 95 <1 6 <1 36 <5 66<1 96 <5 7 <1 37 >10 67 <10 97 NE 8 <1 38 <10 68 <5 98 <5 9 <5 39 >10 69 <5 99 >10 10 <5 40 <1 70 <5 100 >10 11 <5 41 <5 71 NE 101 >10 12 <5 42 <5 72 0 102 >10 13 <5 43 <5 73 0 103 >103 14 <1 44 <1 74 >10 104 NE 15 >10 45 <5 75 >10 105 NE 16 <5 46 <10 76 >10 106 <10 17 <5 47 >10 77 <5 107 NE 18 <5 48 <10 78 <10 108 <10 19 <1 49 <10 79 <1 109 NE 20 >10 50 >10 80 <5 110 >10 21 <5 51 <5 81 <1 111 >10 22 >10 52 >10 82 NE 112 NE 23 <1 53 <5 83 <1 113 <5 24 >10 54 <10 84 <5 114 <5 25 >10 55 <5 85 <1 115 <5 26 >10 56 <1 86 <5 116 27 <5 57 <5 87 <1 117 <5 28 <5 58 >10 88 118 <10 29 <1 59 NE 89 NE 119 30 <1 60 <1 90 <1 120 <1

Rheumatoid Arthritis Protocol Male Lewis rats (150-175g) from Charles River Laboratories were anesthetized on day 0 with 3-5% isoflurane anesthesia while the tail base was shaved and adjuvant mixture was injected. Fifty uL of adjuvant (10 mg/ml M. butyricum in mineral oil) was injected subcutaneously into two sites at the tail base. Paw swelling was monitored using a plethysmometer (UGO Basile), after shaving each leg to the level of the Achilles tendon to mark the level of immersion. A baseline paw measurement for both hindpaws was taken between d2-d5 and a second measurement was taken on day 7-8. Onset of paw swelling occurred rapidly between d9-11 and daily measurements were performed every weekday between d9 and day 15. Compounds of the invention and vehicles were dosed either prophylactically (dl-14), or therapeutically (d9-14) after swelling was confirmed. Solutions were injected subcutaneously or given orally by gavage 1-2 times per day. From day 0, rats were weighed every 2-3 days and overall health was monitored. Plasma drug levels, if desired, were measured in tail-vein derived blood samples taken on day 14. On day 15, blood samples were obtained by cardiac puncture, rats were euthanized with C02, selected organs removed and both hindpaws were amputated and placed in 10% buffered formalin for histopathological analysis. See Biological Table 2.

Biological Table 2 Compound Example % Inhibition 60 mg/Kg/day, Number sq, bid, dl-14 3 96 6 77 29 82 60 62* * 75 mg/kg/day, sq, bid, dl-14

Asthma Protocol Balb/C mice (6-8 weeks old) are sensitized to ovalbumin (ova) (8 ug ova absorbed in 3.3 mg Alum inject) on days 0 and 5. On day 12, the mice were aerosol challenged with 0.5% ovalbumin dissolved in sterile saline for 1 hr in the AM, and then again in the PM (at least 4 hr apart). On day 14, the mice were anesthetized with ketamine/xylazine/acepromazine cocktail, exsanguinated, and then euthanized. Following blood collection, bronchoaveolar lavage was performed on each animal. Total cell counts were conducted on the lavage fluid, which was subsequently diluted with cell media 1: 1. Slides of the lavage fluid were made by spinning the samples with a cytospin centrifuge. Slides were airdried and stained with x. Cell differentials of the lavage fluid were completed at the conclusion of the study. All compounds except Example 2 were well tolerated with no body weight loss throughout the course of the study.

Statistical analysis involved ANOVA and Tukey-Kramer post hoc tests. Compounds were administered except where noted by subcutaneous injection once daily from day 0-13. The formulations used contained various mixtures of the following excipients (pharmasolve, cremophor RH 40, tween 80, PEG 300). See Biological Table 3 Biological Table 3 Compound Example Number % Inhibition sc, daily dosing at 100 mg/kg from day 0-13 3 79 6 81 86 48 36 71 60 36 29 24

Effect of serum IgE levels in ovalbumin sensitized Balb/c mice Peripheral blood samples were collected from ovalbumin (Calbiochem) or vehicle (2% Cremophor/Bicarbonate) treated Balb/c mice (Charles River) with or without administration of test compound (100mg/kg/d, from day 0 to day 14). Serum was obtained by centrifugation and transferred into Microtainer serum tubes and frozen at-80°C. Mouse IgE ELISA Quantitation Kit (Bethyl Laboratories, Inc. Montgomery, TX or PharMingen, San Diego, CA) was applied to measure the IgE levels of serum samples. Immuno-reactions were performed as Kit protocol with IgE standard and serum samples in duplicates. The results were read in a microplate reader (Bio-Rad Model 550) at 450nm and the amounts of IgE were calculated according to the standard curve. The limit of detection in our experiments was 7ng/ml. Compound 3 administrated at lOOmg/kg/d from day 0 to day 14, reduced serum IgE levels by 38% in ovalbumin sensitized Balb/c mice compared with vehicle treated mice.

Effect of levels of IL-13, IL-5, IL4, IFN-gamma and IL-2 mRNA in mouse lungs of Balb/c mice with ovalbumin sensitization and challenge Lung tissues were collected from ovalbumin (Calbiochem) or vehicle (2% Cremophor/Bicarbonate) sensitized Balb/c mice (Charles River) with or without treatment of test compound (lOOmg/kg/d, from day 0 to day 14). Total RNA samples were isolated by the Trizol method (Life Technologies, Grand Island, NY) and quantitatively measured by UV spectrophotometer, as well as qualitatively examined by ethidum bromide stained gel electrophoresis. First strand cDNA templates were generated with oligo (dT) by Reverse Transcription Kit (Invitrogen, Carlsbad, CA). The initial amounts of mRNA of each samples were quantitatively determined by running a SYBR Green (Qiagen, Valencia, CA) based real- time PCR (programmed as: initial denaturation at 95°C for 15 minutes, denaturation at 95°C for 15 seconds, annealing and elongation at 51+1 °C for 1 minute for total 40 cycles) with a specific pair of primers (IDT Corporation, Coralville, IA) and control primers for GAPDH in iCycler IQ Optical System (Hercules, CA). The data were statistically analyzed by ANOVA

and t-tests with multiple comparisons of means (n = 5 and P < 0.05 were considered significant). Compound 3 administrated at 100mg/kg/d, significantly inhibited ovalbumin induced levels of IL-13, IL-5 and IL-4 mRNA in the lung of Balb/c mice by 82%, 98% and 68% respectively; without significantly affecting IFN-gamma and IL-2 compared with vehicle treated mice.

List of Primers used in above experiments: Primer Forward Sequence Reverse Sequence Annealing Name Temperature GAPDH CTA CCC CCA ATG TGT CC CTG CTT CAC CAC CTT CTT 52. 2 IL-13 AAF AFF AGA GCA AAT GAA AG CTG TGT AAC CTT CCC AAC A 51. 3 IL-4 TGA ATG AGT CCA AGT CCA AGC ATG GTG GCT CAG TA 51. 2 IL5 AGC TCT GTT GAC AAG CAA T CCC TGA AAG ATT TCT CCA ATG 52. 4 IL-2 GTC GAC TTT CTG AGG AGA TG ATG TGT TGT AAG CAG GAG GT 53. 2 IFN-y TTC TGT CTC CTC AAC TAT TTC T CAA TCA CAG TCT TGG CTA AT 51. 3 Smooth Muscle Cell Proliferation Protocol Human Aortic Smooth Mucle Cells (HAoSMC) were obtained from Clonetics, Inc. and were used below passage 10. Cells were seeded in 24-well plates. When cells were 80% confluent, they were made quiescent by adding media containing 0.2% serum (as compared to 5% serum in normal culture media) for 48 hours. The cells were, then, stimulated by 5% serum in the presence or absence of compounds dissolved in DMSO. To establish a dose curve and ICso for each compound, multiple concentrations in the range of 20 to 0.05 uM were used.

Rapamycin (at 1 and 0. 1 uM) was used as a positive control for the assay. After a 20 hour incubation with or without test compounds, 3H-thymidine (0. 511Ci/well) was added to the cells for 4 hours of labeling. Washed cells were then lysed in NaOH and the amount of 3H- thymidine incorporation was determined. Cytotoxicity of the drug was measured by use of the CytolTox 96 assay kit (Promega, Madison, Wl). Compound 3 had an ICso of 0.5 uM.

Effect of Test Compounds on LPS-Stimulated IL-lp Human peripheral blood mononuclear cells were treated with or without Compound 3 for 1 hour, then stimulated with LPS (1-2 Rg/ml) for 3 hours. Condition media was collected and IL-lp measured using an ELISA kit. Compound 3 demonstrated a dose dependent inhibition of LPS-stimulated 1L-1 (3 secretion. See Biological Table 4 Biological Table 4 Amount of Compound 3 Percent IL-1 (3 Secreted (tM) 1. 25 >40 2. 5 >10 5 >5 10 >1 Reduction of Plasma TNF-a levels and lung VCAM-1 mRNA levels in LPS-Challenged Mice.

Balb/C mice (6-8 weeks) were injected with LPS (1 mg/kg ; 5 mls/kg) and sacrificed 2hr later. Blood was collected for plasma TNF-a levels and lungs for measurement of VCAM-1 mRNA levels by quantitative RT-PCR. Compound 3 administered subcutaneously at a dose of 100 mg/kg/d, 2hr prior to LPS injection, inhibited TNF-a production by 80% and VCAM-1 expression by 60% compared with vehicle controls.

Disease Modifying Anti-Rheumatic Drug (DMARD) activity in Rat Adjuvant Arthritis Compound 3 at twice daily subcutaneous doses of 60,40 and 20 mg/kg/d was found to inhibit bone erosion in the ankle joint by histopathological analysis when administered prophylactically in the rat adjuvant arthritis model. The evaluation was carried out with hematoxylin and eosin stained ankle cross sections by a certified veterinary pathologist. When dosed prophylactically at doses of 100,50 and 25 mg/kg/d, b. i. d. , s. c. , Compound 3 was also found to inhibit splenomegaly. Splenomegaly tracks with bone erosion in the adjuvant arthritis model and is thought to be a predictor of DMARDs activity.

Modifications and variations of the present invention relating to compounds and methods of treating diseases will be obvious to those skilled in the art from the foregoing detailed description of the invention. Such modifications and variations are intended to come within the scope of the appended claims.