Chalcone derivatives and their use to treat diseases

Abstract

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula or its pharmaceutically acceptable salt or ester, wherein the substituents are defined in the application.

Description

This patent application claims priority to U.S. Provisional Patent Application Ser. No. 60/342,034 filed Dec. 19, 2001 and U.S. Provisional Patent Application Ser. No. 60/386,482 filed Jun. 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, autoimmnune 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-α, and INFγ 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; 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 TNFα, 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. Pat. 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. Ser. No. 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. Pat. 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 Jun. 15, 1995. U.S. Pat. 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. Ser. No. 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. Pat. 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 Comicelli et al. discloses compounds for the inhibition of 15-lipogenase to treat and prevent inflammation or atherosclerosis. Compounds disclosed include benzopyranoindole, benzimidazdle, 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. Pat. 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-1-ones (dihydrochalcones), and 1,3-bisaromatic-prop2-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. Pat. No. 4,085,135 discloses 2′-(carboxymethoxy)-chalcones with antigastric and antiduodenal ulcer activities.

U.S. Pat. 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. Pat. 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. Pat. 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. Pat. 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 α-β-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 CysLT₁ (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 CysLT₁ receptor antagonists.

JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the following formula (wherein R¹ 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 R¹-R⁵ are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R¹-R⁵ are hydrogen.

U.S. Pat. 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, —O— or —S—; W represents —CH═CH— or —CH₂O—, and R_1-5 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 R_1-5 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-1, 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-1, 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:

R^2α, R^3α, R^4α, R^{5α, R6α}, R^2β, R^3α, R^4β, R^{5β and R6β} 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-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(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(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, —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, —PO₃H₂, —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;

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)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 R^2β, R^3β, R^4β, R^5β or R^6β, or one of R^2α, R^3α, R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl; and/or

wherein when one of R^2β, R^3β, R^4β, R^5β or R^6β is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2α, R^3α, R^4α, R^05α or R^6α can be —OCH₃; and/or

wherein when one of R^2α, R^3α, R^4α, R^5α or R^6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃; and/or

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together, or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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 R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2α, R^3α, R^4α, R^5α, R^6α or one of R^2β, R^3β, R^4β, R^5β, R^6β 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, —(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, —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(R¹)₂C(O)NR⁷RR, 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, —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, and —NHC(O)N(R²)₂;

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 2^nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(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), —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, —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)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)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;

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)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 R^2β, R^3β, R^4β, R^5β or R^6β, or one of R^2α, R^3α, R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl; and/or

wherein when one of R^2β, R^3β, R^4β, R^5β or R^6β is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

wherein when one of R^2α, R^3α, R^4α, R^5α or R^6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃; and/or

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together, or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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 R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2α, R^3α, R^4α, or one of R^2β, R^3β, R^4β 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(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, —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(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 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 3^rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —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)NR²)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, —PO₃H₂, —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;

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)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 R^2β, R^3β, R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together, or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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 R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3βB, R^4β, R^5β and R^6β cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2α, R^3α, R^4α, R^5α, or R^6α 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(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R², SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(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(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 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 4th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)₂C(O)OH, —OC(R¹)C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(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, —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)NR₂, —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), —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, —PO₃H₂, —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;

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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together, or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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 R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2α, R^3α, or R^4α 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(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, —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(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 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 5th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —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), —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, —PO₃H₂, —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;

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)NR⁷R⁸, and —C(O)N(R¹²);

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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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(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, —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(R¹)₂C(O)NR⁷R⁸, amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)C(O)OH, —NHC(R¹)C(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 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:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(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, —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)NH₂, —C(O)NHC(O)NR⁷R⁸, —C(O)NHSO₂R², —C(O)NHSO₂NHR², —C(O)NHSO₂N(R²), —C(O)NHSO₂NR⁷RS, —C(CH₃)₂C(O)OH, —(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —PO₂H₂, —PO₃H₂, —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;

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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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 7th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)NHR², —C(O)N(R²), —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(CH₁₃C(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;

• R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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 —(O)N(R²)₂.

In an 8th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R⁶β 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(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(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, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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 9^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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 10th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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—O-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, —NR⁷R⁵, 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be carboxy.

In a 12th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, and R^6α are independently selected from the group consisting of hydrogen and carboxy;

R^2β, R^3β, R^4β, R^5β and R^6β 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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl;

with the proviso that at least one of R^2α, R^3α, or R^4α must be carboxy.

In a 13th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, and R^6α are independently selected from the group consisting of hydrogen and carboxy;

R^2β, R^3β, R^4β, R^5β and R^6β 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);

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;

wherein one of R^4β, R^5β or R^6β must be a carbon-carbon linked heteroaryl;

with the proviso that at least one of R^2α, R^3α, or R^4α must be carboxy.

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

R^2α, R^3α, R^4α, R^5α, and R^6α are independently selected from the group consisting of hydrogen and carboxy;

R^2β, R^3β, R^4β, R^5β and R^6β are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-1-morpholino)ethoxy, CH₃O(CH₂)₂O(CH₂)₂—,

wherein one of R^4β, R^5β or R^6β 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 R^2α, R^3α, or R^4α must be carboxy.

In a 15th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, and R^6α are independently selected from the group consisting of hydrogen and carboxy;

R^2β, R^3β, R^4β, R^5β and R^6β are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino)propoxy, 2-(1-morpholino)ethoxy, and CH₃O(CH₂)₂O(CH₂)₂;

wherein one of R^4β, R^5β or R^6β 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 R^2α, R^3α, or R^4α must be carboxy.

In a 16^th 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;
• 4-[3E-(4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;
• 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-yl)-phenyl}-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;
• 4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
• 4-{3E-[5-(3,5-Dimethyl-isoxazol 4-y)-2,4dimethoxy-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-phenyl}-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;
• 3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
• 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;
• 4-{3E-[4-(1-Carboxy-1-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-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid;
• 4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
• 5-{5-[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]-benzoic acid;
• 4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic 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;
• 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]-benzoic acid;
• 4-{3E-[2-1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
• 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;
• 2 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
• 4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-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-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
• 4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;
• 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)-acryloyl]-benzoic acid;
• 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl)}-benzoic acid;
• 4-(3E-{4-Methoxy-2-[2-1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid, hydrochloride;
• 4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid;
• 4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid;
• 4-{3E-[5-(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-methyl-propionic acid;
• 4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride;
• 4-{3E-[5-(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]-acryloyl}-benzoic acid; and
• 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)acryloyl]-benzoic acid ethyl ester, or its pharmaceutically acceptable salt or ester.

In a 17^th 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-y-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^th 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^th 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 22^nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, and R^6α are independently selected from the group consisting of hydrogen and carboxy;

R^2β, R^3β, R^4β, R^5β and R^6β 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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic;

with the proviso that at least one of R^2α, R^3α, or R^4α must be carboxy.

In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, and R^6α are independently selected from the group consisting of hydrogen and carboxy;

R^2β, R^3β, R^4β, R^5β and R^6β 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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked tetrahydrofurn-2-yl or dihydrofuran-2-yl;

with the proviso that at least one of R^2α, R^3α, or R^4α must be carboxy.

In a 24th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —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)₂, —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)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 —(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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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 25th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —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(R²)₂;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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 26th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R²)₂, SO₂NR⁷R⁸, —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)C(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;

R¹ 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 —(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 —(O)N(R²);

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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 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:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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 R¹, 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 28^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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—O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, 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;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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;

R¹ is hydrogen;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a 6-membered monocyclic ring;

wherein one of R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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]-acryloyl}-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 31^st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(O)NHR², —OC(R¹)₂C(O)N(R¹)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)C(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, —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)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)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;

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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from the group consisting of 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, —SO₂NHC(O)NR⁷R⁸;

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 32nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —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;

R¹ 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 R⁹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R⁴ must be selected from the group consisting of 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, —SO₂NHC(O)NR⁷R⁸;

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 33^rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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), —NR²SO₂R², —NHC(O)NHR², —NHC(O)NR⁷R⁸, —NHC(O)N(R²)₂, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH—SO₂NH₂, SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —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, —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;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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(R²) 2, —SO₂NHC(O)NR⁷R⁸;

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 34th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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, SO₂N(R²)₂, —SO₂NHC(O)R², —SR₂, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²) 2, —SO₂NHC(O)NR⁷R⁸, —C(O)N(R²)₂, —C(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;

R¹ 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(R¹)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from the group consisting of —SC(R¹)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 R¹, 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:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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 —N(R²)C(O)R², —SCH₂C(O)OH —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(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;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from the group consisting of —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, and —SO₂NHC(O)R²;

wherein all R¹, 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 36^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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, SO₂NHC(O)R², —SR₂, SO₂NHC(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;

R¹ is hydrogen;

R² is lower;

R⁷ and R⁸ are independently alkyl, and linked together forming a 6-membered monocyclic ring;

wherein one of R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from the group consisting of —SC(R¹)₂C(O)OR², —SO₂NH₂, —SO₂NR⁷R⁸, and —SO₂NHC(O)R².

In a 37^th 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-2,4dimethoxy-phenyl)-acryloyl]-benzenesulfonamide;
• 4-{3E-[4Methoxy-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;
• 2-{2,4-Dimethoxy-5-[3-oxo-3-(4-sulfamoyl-phenyl)-E-propenyl]-phenyl}-indole-1-carboxylic acid tert-butyl ester;
• 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;
• 4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-y-phenyl]-acryloyl}-benzenesulfonamide;
• 4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-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-phenyl]-acryloyl}-benzenesulfonamide;
• 4-[3E-(2,4-Dimethoxy-5-pyridin-3-yl-phenyl)-acryloyl]-benzenesulfonamide;
• 4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;
• 4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;
• 4-{3E-[5-(2-Cyclopropyl-1H-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-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;
• 4-{3E-[4-Methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-phenyl]-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]-acryloyl}-benzenesulfonamide.

In a 38th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)₂C(O)OH, —OC(R¹)₂(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(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, —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)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)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;

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)NR⁷R³, and —C(O)N(R²);

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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from the group consisting of amino, —NHR², N(R²)₂, NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)C(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 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 39^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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, cycloakyl, 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 alkoxycarbonyl.

R⁷ and R⁸ are independently alkyl, and linked together forming a 6-membered monocyclic ring;

wherein one of R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α 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:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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-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(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(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, —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, —PO₃H₂, —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;

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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from the group consisting of —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;

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 41st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)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;

R¹ 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃;

with the proviso that at least one of R^2α, R^3α, or R^4α must be selected from —OC(R¹)₂C(O)OH;

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 42^nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)₂C(O)NH₂, —OC(R¹)C(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, —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)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)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;

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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together, or R^2β and R^3β taken together or R^3β and R^4β taken together or R⁴ and R^5β 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 R^2α, R^3α, or R^4α 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(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, —SO₂NHC(O)NR⁷R⁸, —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)C(O)NH₂, —OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R², —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 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 43^nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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, 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^3α and R^4α taken together or R^4α and R^5α taken together, or R^3β and R^4β taken together or R^4β and R^5β taken together form a heterocyclic ring optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.

In a 44^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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(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(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, —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)N—HSO₂NHR², —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)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;

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)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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α taken together or R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β 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 R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2α, R^3α, or R^4α 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(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, S(2NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(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(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)N⁷R⁸, 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 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 45^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β 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, 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 R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^3α and R^4α taken together or R^4α and R^5α taken together or R^3β and R^4β taken together or R^4β and R^5β 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 R^2α, R^3α, R^4α, R^5α, R^6α, R^2β, R^3β, R^4β, R^5β and R^6β cannot be —OC(R¹)₂COOH.

In a 46th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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)C(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(R²k, 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)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)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;

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)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 R^2α, R^3α, R^4α, R^5α or R^6α, or one of R^2β, R^3β, R^4β, R^5β or R^6β must be a carbon-carbon linked heterocyclic or heteroaryl; and/or

wherein when one of R^2α, R^3α, R^4α, R^5α or R^6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃; and/or

wherein when one of R^2β, R^3β, R^4β, R^5β or R^6β is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2α, R^3α, R^4α, R^5α or R^6α can be —OCH₃; and/or

R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together, or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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

R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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 R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2β, R^3β, R^4β, or one of R^2α, R^3α, R^4α 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(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, —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)C(O)N(R¹)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 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 47th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α are inden 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(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(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, —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)₂, —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)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;

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)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 R^2α, R^3α, R^4α, R⁵α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together, or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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

R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together or R^2α and R^3α taken together or R^3α′ and R^4α taken together or R^4α and R^5α 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 R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α cannot be —OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^2β, R^3β, R^4β, R^5β, or R^6β 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(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²), SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(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(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 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 48th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(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, —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), —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, —PO₃H₂, —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;

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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together, or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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

R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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 R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α cannot be —OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^2β, R^3β, or R^4β 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(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, —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(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 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 49th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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)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, —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)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)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;

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)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 R^4α, R^5α or must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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(CH₃₂C(O)OH, 4CH₂)_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, —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(R¹)C(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 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 50th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(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, —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), —C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)N)C(O)N(R²), —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, —PO₃H₂, —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;

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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 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 51st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(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, —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;

R¹ 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 —(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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 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 an 52^nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R⁷R⁸, —SR₂, —SO₂NHC(O)NR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl, carboxy, —C(O)OR², —C(O)NH₂, —C(O)N², —C(O)N(R²)₂, —C(O)NR⁷R⁸, —C(O)NHC(O)R², —C(O)NHC(O)NHR², —C(O)NHC(O)N(R²), —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, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 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 53^rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(R²k, —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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 R¹, 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:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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—O-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(R²)₂;

R⁷ and R⁸ are independently alkyl, and linked together forming a 5- to 7-membered monocyclic or benzofused ring;

wherein one of R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from carboxy or —C(O)OR²;

wherein all R¹, 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 a 55th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be carboxy.

In a 56th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, and R^6β are independently selected from the group consisting of hydrogen and carboxy;

R^2α, R^3α, R^4α, R^5α and R^6α 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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl;

with the proviso that at least one of R^2β, R^3β, or R^4β must be carboxy.

In a 57th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, and R^6β are independently selected from the group consisting of hydrogen and carboxy;

R^2α, R^3α, R^4α, R^5α and R^6α 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heteroaryl;

with the proviso that at least one of R^2β, R^3β, or R^4β must be carboxy.

In a 58th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, and R^6β are independently selected from the group consisting of hydrogen and carboxy;

R^2α, R^3α, R^4α, R^5α and R^6α are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH₃O(CH₂)₂O(CH₂)₂—,
and

wherein one of R^4α, R^5α or R^6α 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 R^2β, R^3β, or R^4β must be carboxy.

In a 59th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β and R^6β are independently selected from the group consisting of hydrogen and carboxy;

R^2α, R^3α, R^4α, R^5α and R^6α are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino)propoxy, 2-(1-morpholino)ethoxy, and CH₃O(CH₂)₂O(CH₂)₂;

wherein one of R^4α, R^5α or R^6α 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 R^2β, R^3β, or R^4β must be carboxy.

In a 60th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, and R^6β are independently selected from the group consisting of hydrogen and carboxy;

R^2α, R^3α, R^4α, R^5α and R^6α 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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic;

with the proviso that at least one of R^2β, R^3β, or R^4β must be carboxy.

In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, and R^6β are independently selected from the group consisting of hydrogen and carboxy;

R^2α, R^3α, R^4α, R^5α and R^6α 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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked tetrahydrofurn-2-yl or dihydrofuran-2-yl;

with the proviso that at least one of R^2β, R^3β, or R^4β 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:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(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, —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, —PO₃H₂, —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 —(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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 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 —(O)N(R²)₂.

In a 62nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(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, —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(R²)₂;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 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 63^rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R³, 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;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 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 64th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 R¹, 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 65^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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—O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, 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;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(R²2;

R¹ is hydrogen;

R² is lower alkyl;

R⁷ and R⁸ are independently alkyl, and linked together forming a 6-membered monocyclic ring;

wherein one of R^4α, R^5α, or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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 67th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(R¹)C(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)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)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;

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)NR⁷ R⁸, 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of 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, —SO₂NHC(O)NR⁷R⁸;

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

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, SO₂NHC(O)R², —SR₂, —SO₂NHC(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;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of 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, —SO₂NHC(O)NR⁷R⁸;

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 69th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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)C(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, —NHC(O)N(R²)₂, —SC(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OH —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —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, —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;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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(R²)₂, —SO₂NHC(O)NR⁷R⁸;

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 70th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, —SO₂NHC(O)NHR², —SO₂NHC(O)N(R²)₂, —SO₂NHC(O)NR⁷R⁸, —C(O)N(R²)₂, —C(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;

R¹ 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of —SC(R¹)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 R¹, 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:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, SO₂NHC(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;

R¹ 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 R^4α, R^5α or R^6α l must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of —SC(R¹)₂C(O)OR², —SCH₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²)₂, SO₂NR⁷R⁸, and —SO₂NHC(O)R²;

wherein all R¹, 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:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, —NR²)C(O)R², —SO₂NH₂, —SO₂NHR₂, SO₂NHC(O)R², —SR₂, SO₂NHC(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;

R¹ is hydrogen;

R² is lower;

R⁷ and R⁸ are independently alkyl, and linked together forming a 6-membered monocyclic ring;

wherein one of R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of —SC(R¹)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:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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)C(O)NR⁷R⁸,

amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroaryl amino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, NHR², N(R²)₂, —NR⁷R⁸, —NHC(R¹)₂C(O)OH, —NHC(R¹)C(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), 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)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)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,

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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of 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 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 74^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, aminoalkyl, —NR⁷R⁸, 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β 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^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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)NHR²k, —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, —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)NR₂, —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, —PO₃H₂, —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;

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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from the group consisting of —OC(R¹)₂C(O)OH, —OC(R¹)₂C(O)OR², —OC(R¹)C(O)NH₂, OC(R¹)₂C(O)NHR², —OC(R¹)₂C(O)N(R²)₂, —OC(R¹)₂C(O)NR⁷R⁸;

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 76th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3βR^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(R¹)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;

R¹ 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 R^4α, R^5α or must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃;

with the proviso that at least one of R^2β, R^3β, or R^4β must be selected from —OC(R¹)₂C(O)OH;

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 77th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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(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, —NHSO₂NR², —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, —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)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)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;

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);

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;

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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5α or R^6β can be —OCH₃; and/or

R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together, or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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 R^2β, R^3β, or R^4β 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(R¹)₂C(O)OH, —SC(R¹)C(O)OR², —SCH₂C(O)OH, —SCF₂C(O)OH, —SO₂NH₂, —SO₂NHR₂, —SO₂N(R²), SO₂NR⁷R⁸, —SO₂NHC(O)R², —SR₂, —SO₂NHC(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(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 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 78th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃; and/or

R^3β and R^4β taken together or R^4β and R^5β taken together, or R^3α and R^4α taken together or R^4α and R^5α taken together form a heterocyclic ring optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.

In a 79^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, aryl amino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl,

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —C(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)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(R¹)₂C(O)OH, —SC(R¹)₂C(O)OR², —SCH₂C(O)OR, —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)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)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;

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)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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be —OCH₃; and/or

R^2β and R^3β taken together or R^3β and R^4β taken together or R^4β and R^5β taken together or R^2α and R^3α taken together or R^3α and R^4α taken together or R^4α and R^5α 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 R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α cannot be —OC(R¹)₂C(O)OH; and/or

at least one of R^2β, R^3β, or R^4β 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(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, —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(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 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 80^th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α 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, 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 R^4α, R^5α or R^6α must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2β, R^3β, R^4β, R^5β or R^6β can be OCH₃; and/or

R^3β and R^4β taken together or R^4β and R^5β taken together or R^3α and R^4α taken together or R^4α and R^5α 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 R^2β, R^3β, R^4β, R^5β, R^6β, R^2α, R^3α, R^4α, R^5α and R^6α cannot be —OC(R¹)₂COOH.

As an 81^st 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 82^nd 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 “”, 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 1 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 —H.

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 26membered 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, aminoacyl, 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, 1-butyidimethylsilyl, and t-butyidiphenylsilyl, 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, 4^th 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, POCl₃, PCl₅, FeCl₃), 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.

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-1A: 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. ¹H-NMR (CDCl₃) δ 6.90-6.97 (m, 4H), 4.37(q, J=7 Hz, 4H), 1.32(t, J=7 Hz, 6H).

Ex-1B: [Bis(ethoxycarbonyl)methyldenedioxy]benzene obtained from Ex-1A (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. ¹H-NMR (CDCl₃) δ 6.82 (s, 4H), 3.94 (d, J=7 Hz, 4H), 1.98 (t, J=7 Hz, 2H).

Ex-1C: 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-1B (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. ¹H-NMR (CDCl₃) δ 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-1D: 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 (2×100 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. ¹H-NMR (300 MHz, CDCl₃) δ 9.94 (s, 1H), 7.79 (d, 1H), 7.57 (dd, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 7.13 (dd, 1H), 3.97 (s, 3H), 3.93 (s, 3H).

5-Acetyl-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester obtained from Ex-1C (0.28 g, 1.11 mmol) and 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde obtained from Ex-1D (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. ¹H-NMR (300 MHz, CDCl₃) δ 7.74 (d, 1H), 7.63 (dd, 1H), 7.49-7.55 (m, 3H), 7.38 (d, 1H), 7.37 (d, 1H), 7.12 (dd, 1H), 7.07 (d, 1H), 6.88 (d, 1H), 3.99 (s, 4H), 3.98 (s, 3H), 3.88 (s, 3H). Anal. Calculated for C₂₄H₂₂O₇S: 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-benzo[1,3]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-1D from 4-bromobenzaldehyde. ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (CDCl₃) δ 7.77 (d, J=15 Hz, 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 C₂₂H₁₈O₅S: 394.0875. Found: 394.0869.

Example 3

4-[3E-(5Benzo[b]thien-2-yl-2,4dimethoxyphenyl)-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. ¹H NMR (CDCl₃) δ 10.36 (s, 1H), 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(¹Bu₃P)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 H₂O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H₂O (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 floe (5 g). The pad of solka floe 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 1 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 in Hg) 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. ¹H-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) δ 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 C₂₆H₂₀O₅S.⅙H₂O: 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).

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 H₂O (800 mL, precooled to 10 deg C.). An additional 400 mL cold H₂O was used to rinse the reaction vessel and this rinse was also added to the separatory funnel. The combined aqueous was washed with iPrOAc (500 mL) and then acidified to a pH of 3 with 6 N HCl (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 in Hg) 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. ¹H-NM identical as above.

Example 4

4-[3E-(4-Pyrimidin-5yl-phenyl)-acryloyl]-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. ¹H-NMR (CDCl₃) δ 10.11 (s, 1H), 9.28 (s, 1H), 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 4acetylbenzoic acid. Yellow solid, mp>260° C., 45% yield. ¹H-NMR (DMSO-d₆) δ 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=15 Hz, H), MS m/z=330 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₀H₁₄N₂O₃: 330.1004. Found: 330.1000.

Example 5

4-[3E-(4-Thiazol-2-yl-phenyl)acryloyl]-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) δ 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. ¹H- NMR (CDCl₃) δ 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=9 Hz, 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 C₁₉H₁₃NO₃S: 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(¹Bu₃P)₂ (0.424 g). The solution was immediately heated to 60° C. and aged for 1.5 h. The reaction was diluted with H₂O (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H₂O (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 floe 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 in Hg) 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. ¹H-NMR (300 MHz, CDCl₃): 10.34 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.5 and 1.5 Hz), 7.31 (dd, 1H, J=5.2 and 1.5 Hz), 7.07 (dd, 1H, J=5.2 and 3.5 Hz), 6.51 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H).

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 HCl. 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. ¹H-NMR (300 MHz, CDCl₃): 8.20 (d, 2H, J=8.5 Hz), 8.09 (d, 1H, J=16.1 Hz), 8.06 (d, 2H, J=8.5 Hz), 7.85 (s, 1H), 7.52 (d, 1H, J=16.1 Hz), 7.40 (m, 1H), 7.30 (dd, 1H, J=5.2 and 1.7 Hz), 7.08 (dd, 1H. J=5.2 and 3.6 Hz), 6.53 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H); EIMS m/z=394 (M+). Anal. calc. for C₂₂H₁₈O₅S: 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.). ¹H-NMR (DMSO-d₆) δ 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-1D) and 4-acetylbenzoic acid. Yellow solid, mp 231° C. ¹H-NMR (DMSO-d₆) δ 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). MS m/z=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 (0.75 g, 4.6 mmol) and 5-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde (Ex-3A, 1.64 g, 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 (1.53 g, 67%), mp 214-217° C. (dec). ¹H-NMR (DMSO-d₆) δ 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 m/z=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)-acryloyl]-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. ¹H-NMR (DMSO-d₆) δ 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, 1H). MS m/z=334([M+Na]⁺, 100%). Anal. (C₂₂H₁₄O₃S) 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-1D 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 (2×75 mL). The organic layer was washed with aqueous NaHCO₃ (2×25 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. 67-710C. ¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d, 2H), 7.75 (d, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.46 (d, 1H), 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.⅕H₂O: 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: m/z=366 [M+H]⁺, found: m/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. ¹H-NMR (CDCl₃) δ 7.95 (d, 2H), 7.79 (d, 1H), 7.65 (m, 41), 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 C₁₉H₁₅NOS: 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. ¹H-NMR (CDCl₃) δ 8.10 (d, 1H), 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.⅓H₂O: 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)-acryloyl]-phenyl}-methanesulfonamide

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 μL, 2.86 mmol) was stirred in 20 mL of anhydrous dichloromethane. The mixture was treated with mesyl chloride (100 μL, 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. ¹H-NMR (300 MHz, CDCl₃) δ 8.06 (d, 2H), 7.76 (d, 1H), 7.53 (m, 2H), 7.49 (d, 2H), 7.38 (m, 1H), 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 1N 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/CH₂Cl₂ with 1% acetic acid) to give 269.2 mg (83%) of the title compound as a solid, 83% yield, mp. 71-75° C. ¹H-NMR (300 MHz, CDCl₃) δ 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, 1H), 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: m/z=444 [M+H]⁺, found: m/z=444 [M+H]⁺. HRMS m/z: calc. 444.0939, found 444.0953.

Example 15

{3-[4-13E-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. ¹H-NMR (DMSO-d6) δ 9.29 (br s, 1H), 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-[Ethoxycarbonylmethylaminocarbonyl]-3-{4-[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 (3×50 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 (210%) of the title compound as a yellow solid, mp 83-86° C. ¹H-NMR (CDCl₃) δ 8.09 (d, 2H), 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 C₃₁H₃₃N₃O₉S: 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. ¹H-NMR (CDCl₃) δ 7.97: (d, J=9 Hz, 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 C₁₂H₁₀OS: 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. ¹H-NMR (300 MHz, DMSO-4) δ 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 C₂₀H₁₃O₃NaS.½H₂O: 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. ¹H-NMR (DMSO-d₆) δ 8.18 (d, J=8 Hz, 2H), 8.00 (d, J=15 Hz, 1H), 7.91-7.94 (m, 4H), 7.82 (d, J=8 Hz, 2H), 7.77-7.79 (m, 1H), 7.71(d, J=3 Hz, 1H), 7.66 (d, J=5 Hz, 1H), 7.16-7.19 (m, 1H), MS m/z=334 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₀H₁₄O₃S: 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. ¹H-NMR (CDCl₃) δ 7.53 (d, J=7 Hz, 1H), 7.37 (dd, J=2, 5 Hz, 1H), 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. ¹H-NMR (CDCl₃) □ 7.70 (d, J=8 Hz, 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 C₂₁H₁₆O₄S: 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 (2×100 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. ¹H-NMR (300 MHz, CDCl₃) δ 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, 1H, 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 (2×100 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. ¹H-NMR (300 MHz, CDCl₃) δ 9.75 (s, 1H), 7.71-7.74 (m, 2H), 7.30 (dd, 1H, J=5.1 and 1.6 Hz), 7.02 (dd, 1H, J=5.1 and 3.7 Hz), 6.96 (m, 1H), 6.81 (d, 1H, 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. HCl and extracted with ethyl acetate (2×100 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. ¹H-NMR (300 MHz, CDCl₃) δ 8.21 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.80 (d, 1H, 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 C₂₄H₂₁NO₃S: 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. HCl and extracted with ethyl acetate (2×100 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. ¹H-NMR (300 MHz, d₆-DMSO) δ 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 C₂₀H₁₃FO₃S: 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) m/z=322 (M+). ¹H-NMR (CDCl₃) δ 7.98-8.01 (d, 1H), 7.90-7.93 (d, 1H), 7.797.84 (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 (0.55 g). 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 (1.49 g). ¹H NMR (CDCl₃) δ 743-7.40 (m, 2H), 7.34-7.23 (m, 3H), 3.67 (s, 2H).

Ex-23B: To a mixture of alumina chloride (5.5 g, 41.0 mmol) in carbon disulfide (100 mL) was added acetyl chloride (1.17 mL, 16.5 mmol) followed by addition of phenylthioacetic acid (Ex-23A, 1.38 g, 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 (2×60 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.). ¹H NMR (DMSO-d₆) δ 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.). ¹H-NMR (DMSO-d₆) δ 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, 0.33 g, 1.02 mmol) and potassium carbonate (0.54 g, 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. ¹H-NMR (CCDl₃) δ 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) (1.16 g, 7.6 mmol) and ethyl bromodifluoroacetate (1.2 mL, 9.15 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.2 g, 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 (1.38 g, 66%). ¹H NMR (CDCl₃) δ 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 118-2200C. ¹H-NMR (CCDl₃) δ 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 (Hoffman, R. V. Org. Syn. VII, 508; 4.18 g, 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 (3.54 g, 93%). ¹H NMR (DMSO-d₆) δ 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, 0.44 g, 2.2 mmol) and 4-thiophen-2-yl-benaldehde (Ex-2A, 0.50 g, 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 (0.45 g, 55%), mp>2450C. ¹H-NMR (DMSO-d₆) δ 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-H-indol-5-yl)propenone

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-1D) 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 (M+). ¹H-NMR (300 MHz, CDCl₃) δ 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-phenyl)-1-(1-methyl-1H-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; 0.45 g, 2.8 mmol) were added iodomethane (3 mL) and cesium carbonate (2.3 g, 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 (0.25 g, 51%). ¹H NMR (CDCl₃) δ 8.30 (s, 1H), 7.91 (dd, J=1.2, 8.1 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.12 (d, J=3.2 Hz, I), 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-1 H-indol-5-yl)-ethanone (Ex-28A) and 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde (Ex-1D) in a similar manner as described in Ex-27. Yellow solid, 43% yield, mp 70-71-C. ¹H-NMR (CDCl₃) δ 8.41(s, 1H), 8.00 (dd, J=1 Hz, 7 Hz, 1H), 7.80 (d, J=15 Hz, 1H), 7.63 (d, J=15.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.43-7.40 (m, 2H), 7.15-7212 (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. 63-640C. ¹H- NMR (300 MHz, CDCl₃) δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H), 3.95 (s, 3H). 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 completions as determined by HPLC, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (3×30 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. ¹H-NMR (300 MHz, CDCl₃) δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H), 7.37 (dd, 1H), 7.31 (dd, 1H), 7.08 (dd, 1H), 6.54 (s, 1H), 3.98 (s, 3H). Anal. Calcd. for C₈H₇O₃S: 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-dimethylformamide (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 (3×15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1×15 mL), water (1×15 mL), and brine (1×15 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. ¹H-NMR (300 MHz, CDCl₃) δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H), 7.30 (dd, 1H), 7.07 (dd, 1H), 6.57 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.94 (t, 2H), 3.74m, 2H), 3.59 (m, 2H), 3.40 (s, 3H). HRMS (EI) Calcd. for C₁₇H₂₀O₅S: 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 (3×15 mL). The combined organic extracts were dried over sodium sulfate and to dryness. The crude oil was taken up in ethyl alcohol (3 mL) a 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.22 (m, 3H), 8.09 (d, 2H), 8.01 (d, 2H), 7.66 (dd, 1H), 7.52 (d, 1H), 7.13 (dd, 1H), 6.88 (s, 1H), 4.36 (t, 2H), 4.00 (s, 3H), 3.88 (t, 2H), 3.65 (m, 2H), 3.46 (m, 2H), 3.22 (s, 3H). 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). ¹H-NMR (300 MHz, d₆-DMSO): 10.13 (s, 1H), 7.81 (d, 1H, J=8.0 Hz), 7.76 (m, 1H), 7.67 (m, 2H), 7.59 (dd, 1H J=8.0 and 2.1 Hz), 7.17 (dd, 1H 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. ¹H-NMR (300 MHz, d₆-DMSO): 8.19 (d, 2H, J=8.4 Hz), 8.12 (d, 1H, J=8 Hz), 8.06 (d, 2H, J=8 Hz), 7.95 (d, 1H, J=16 Hz), 7.80 (d, 1H, J=16 Hz), 7.71 (d, 1H, J=3.5 Hz), 7.62 (m, 2H), 7.56 (d, 1H, J=8 Hz), 7.15 (m, 1H). MS m/z=352 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₀H₁₃NO₃S: 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) δ 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 2,4dimethoxy-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) & 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 C₂₂H₁₈N₂O₅: 391.1294. Found: 391.1295.

Example 32

4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-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. ¹H-NMR (CDCl₃) & 10.41 (s, 1H), 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) & 8.22 (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 C₂₅H₂₂O₅S. HRMS m/z: calc. 435.1266, found 435.1266.

Example 33

4-{3E-[5-(3,5Dimethyl-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. ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-4) δ 8.15 (d, J=8 Hz, 2H), 8.04 (d, J=16 Hz, 1H), 8.02 (d, J=8 Hz, 2H), 7.89 (s, 114), 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 m/z=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 HCl (100 mL) the solution was extracted with dichloromethane (2×100 mL). The organic phase was washed with sat NaHCO₃ (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. ¹H-NMR (300 MHz, CDCl₃): 10.12 (s, 1H), 7.94 (dd, 1H, J=8.7 Hz), 7.03 (dd, 1H, J=8.7 and 2.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 3.92 (s, 3H).

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. ¹H-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, 2H), 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. ¹H-NMR (300 MHz, d₆-DMSO): 8.14 (m, 3H), 8.04 (d, 2H, J=9.2 Hz), 7.89 (d, 1H, J=15.5 Hz), 7.76 (d, 1H, J=15.5 Hz), 7.70 (d, 1H, J=5.0 Hz), 7.18 (dd, 1H, J=5.6 and 3.6 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.05 (dd, 1H, J=8.8 and 1.8 Hz), 6.98 (d, 1H, J=1.8 Hz), 3.83 (s, 3H). MS m/z=364 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₁H₁₆O₄S: 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. ¹H-NMR (DMSO-d₆) δ 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-dimethoxy-phenyl)indole-1-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as described in Ex-3A. Yellow oil, 79% yield. ¹H-NMR (CDCl₃) δ 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, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 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) δ 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 C₃₁H₂₉NO₇—H₂O: 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. ¹H-NMR (300 MHz, CDCl₃): 10.48 (s, 1H), 7.43 (dd, 1H, J=3.6 and 1.3 Hz), 7.41 (d, 1H, J=5.3 Hz), 7.13 (dd, 1H, J=5.3 and 3.6 Hz), 6.79 (s, 2H), 3.96 (s, 6H).

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. ¹H-NM, (300 MHz, d₆-DMSO): 8.11 (d, 1H, J=15.9 Hz), 8.10 (m, 4H), 8.05 (d, 1H, J=15.9 Hz), 7.73 (d, 1H, J=3.6 Hz), 7.61 (d, 1H, J=5.3 Hz), 7.16 (dd, 1H, J=5.3 and 3.6 Hz), 6.95 (s, 2H), 3.98 (s, 6H). MS m/z=394 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₂H₁₈O₅S: 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. ¹H-NMR (CDCl₃) δ 10.34 (s, 1H), 8.13 (s, 1H), 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. ¹H-NMR (DMSO-d₆) δ 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 C₂₄H₂₂N₂O₇: 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. ¹H-NMR (CDCl₃) δ 10.02 (s, 1H), 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.). ¹H-NMR (DMSO-d₆) δ 8.02 (d, 2H), 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-S-(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. ¹H-NMR (CDCl₃) δ 10.33 (s, 1H), 8.05 (s, 1H), 7.22 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 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. ¹H-NMR (DMSO-d₆) δ 8.18 (d, J=7 Hz, 2H), 8.17 (s, 1H), 8.00-8.06 (m, 3H), 7.85 (d, J=15 Hz, 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 m/z=408 ([M]⁺, 100%). HMRS (EI) calcd. for C₂₃H₂₀O₅S: 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. ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-D₆) δ 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 m/z=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. ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-D₆) δ 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. ¹H-NMR (DMSO-d₆) δ 8.54 (s, 1H), 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 m/z=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). ¹H-NMR (CDCl₃) δ 12.08 (s, 1H), 9.80 (s, 1H), 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 NH₄Cl to water and extracted with EtOAc (2×15 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. ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-d₆) δ 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. ¹H NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-d₆) δ 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 (M⁺, 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 (1×20 mL), saturated, aqueous NaHCO₃ (1×20 mL), and water (1×20 mL). The organic phase was dried over sodium sulfate, filtered, concentrated, and dried to provide 5.32 g of 2-5-bromo-2,4dimethoxy-phenyl)-[1,3]dioxolane as a faint yellow oil which solidified upon standing (92% yield). ¹H-NMR (CDCl₃) δ 7.67 (s, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 4.114.13 (m, 2H), 3.984.03 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H). HRMS (ES+) Calcd. for C₁₁H₁₃BrO₄: 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 NH₄Cl (60 mL) and water (20 mL) were added and the solution extracted with EtOAc (1×100 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. ¹H-NMR (CDCl₃) δ 7.85 (s, 1H), 6.39 (s, 1H), 6.07 (s, 1H), 4.134.18 (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 Na₂CO₃ (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 CH₂Cl₂(2×30 mL). The organic phase was washed with brine (1×20 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). ¹H-NMR (CDCl₃) δ9.10 (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), 4.134.18 (m, 2H), 4.01-4.05 (m, 2), 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 (3×100 mL). The organic phase was washed with 25% saturated aqueous NaHCO₃, 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). ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-D₆) δ 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-[4-(1-Carboxy-1-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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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 C₈H₇BrO₃.¼H₂O: 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.). ¹H-NMR (300 MHz, CDCl₃) δ 10.31 (s, 1H), 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-propionic 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. ¹H-NMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.14 (s, 1H), 7.45 (dd, 1H, 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, 6H), 1.23 (t, 3H, J=7.2 Hz). MS (EI) m/z=348 ([M]⁺, 100%). Anal. Calcd. for C₁₈H₂₀O₅S: 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, 0.83mmol) 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 (1×5 mL). The aqueous layer was acidified with a 1 N HCl solution and extracted with ethyl acetate (3×15 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. ¹H-NMR (300 MHz, CDCl₃) δ 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, 6H). MS (EI) m/z=320 ([M]⁺, 100%). Anal. Calcd. for C₁₆H₁₆O₅S: 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-propionic 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 (4×25 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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, 1H, J=3.0 Hz), 7.54 (d, 1H, 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 C₂₅H₂₈O₈S.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. ¹H-NMR (DMSO-D₆) δ 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, 1H),7.50 (d, J=8 Hz, 1H), 7.22 (d, J=2 Hz, 2H), 7.19 (d, J=8 Hz, 1H), 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)-ethoxy]-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, CDCl₃) δ 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, 1H, J=5.1, 3.6 Hz), 6.56 (s, 1H), 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 C₁₇H₂₀O₅S: 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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 C₂₆H₂₆O₇S: 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-yl-phenyl]-acryloyl}-benzoic acid

Ex-50A: To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl- silanyloxymethyl)-propan-1-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 (1×150 mL). The combined organic extracts were washed with a saturated sodium bicarbonate (1×200 mL), a 50% sodium chloride solution (2×200 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, CDCl₃), 4.29 (d, 2H, J=5.7 Hz), 3.61-3.68 (m, 4H), 2.99 (s, 3H), 2.04-2.11 (m, 1H), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for C₁₇H₄₀O₅SSi₂: 413.2213. Found: 413.2226.

Ex-50B: 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. ¹H-NMR (300 MHz, CDCl₃) δ 10.34 (s, 1H), 8.13 (s, 1H), 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 C₂₈H₄₆O₅SSi₂: 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-benzaldehyde (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 (1×30 mL), water (2×30 mL), brine (1×30 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-benzaldehyde as a pale yellow solid, 90% yield, mp 144-145° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.33 (s, 1H), 8.10 (s, 1H), 7.38 (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), 6.59 (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) m/z=323 ([M+H]⁺, 100%). Anal. Calcd. for C₁₆H₁₈O₅S: 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-50C) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 199-201° C., 60% yield. ¹H-NMR (300 MHz, DMSO- d₆) δ 8.31s, 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 C₂₅H₂₄O₇S”/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. ¹H-NMR (CDCl₃) δ 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, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 3.90 (s, 3H). HRMS (ES+) Calcd. for C₁₅H₁₄O₅S: 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 1N HCl (3 mL) and extracted with EtOAc (3×20 mL); the organic phase was washed with brine 1×10 mL), dried over sodium sulfate, filtered, and concentrated. The resulting orange residue was purified via silica gel chromatography (0-10% MeOH/CH₂Cl₂) 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). ¹H-NMR (DMSO-d₆) δ 8.47 (s, 1H), 8.23 (d, J=9 Hz, 2H), 8.01-8.11 (m, 4H), 7.89 (d, J=4 Hz, 1H), 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 C₂₄H₂₀O₇S: 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. ¹H-NMR (DMSO-d₆) δ 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]-benzoic 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 101-1030C. ¹H-NMR (300 MHz, CDCl₃) δ 10.33 (s, 1H), 8.15 (s, 1H), 7.48 (d, 1H, 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 C₁₄H₁₄O₃S: 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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) m/z=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]-benzoic 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 (4×25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was subjected to silica gel chromatography (CH₂Cl₂: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). ¹H-NMR (300 MHz, DMSO-d₆) δ 8.18-8.23 (m, 3H), 8.06-8.09 (m, 2H), 8.02 (s, 1H), 7.85 (d, 1H, 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 C₂₁H₁₆O₅S: 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. ¹H-NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-d₆) δ 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[b]thiophen-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 (5.77 g, 13.0 mmol) in tetrahydrofuran (50 mL) was added sodium methoxide (0.70 g, 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 (5.13 g, 85%) as a yellow solid, mp>235° C. ¹H-NMR (DMSO-d₆) δ 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, 1H), 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-1-carboxylic acid tert-butyl ester-2-boronic acid in a similar manner as described in Ex-3A, 81% yield. ¹H-NMR (CDCl₃) δ 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 C₁₈H₂₁NO₅: 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. ¹H-NMR (DMSO-d₆) δ 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 (EI) calcd. for C₂₇H₂₇NO₇: 477.1788; found: 477.1793.

Example 58

4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)acryloyl]-benzoic 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 (3×20 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) δ 10.73 (s, 1H), 8.18-8.22 (m, 3H), 8.09 (d, 2H, J=8.1 Hz), 8.05 (s, 1H), 7.87 (d, 1H, J=14.7 Hz), 7.60 (d, 1H, J=3.0 Hz), 7.49 (d, 1H, J=4.2 Hz), 7.11 (dd, 1H, J=4.2, 3.0 Hz), 6.67 (s, 1H), 3.90 (s, 3H). MS (ESI) m/z=381 ([M+H]⁺, 100%). Anal. Calcd. for C₂₁H₁₆O₅S.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-propionic 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. ¹H-NMR (300 MHz, CDCl₃) δ 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 C₁₈H₂₀O₅S: 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-propionic 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. ¹H-NMR (300 MHz, CDCl₃) δ 9.33 (s, 1H), 7.99 (s, 1H), 7.47 (dd, 1H, 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-propionic 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 (3×15 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 223-2250C. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.10 (d, 2K, 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 C₂₅H₂₂O₇S.⅓H₂O: 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-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride

Ex-60A: 4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzaldehyde 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) δ 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) m/z=348 ([M+H]⁺, 100%). HRMS (EI) Calcd. for C₁₈H₂₁NO₄S: 347.1191. Found: 347.1188.

4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-benzaldehyde (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, 6×20 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). ¹H-NMR (300 MHz, DMSO-d₆) δ 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-{3E-[5-(1H-Indol-2-yl)-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, 2.0 g, 5.2 mmol) was dissolved in 100 ml of THF, and Bu₄NF (6.86 g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No reaction occured at this condition. Then, Bu₄NF (6.86 g, 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 CH₂Cl₂, and washed with water and brine. The organic phase was dried over MgSO₄, and concentrated. The residue was purified by column chromatography (EtOAc: Hex, 2:1) to give 0.45 g (30%) of 5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde. ¹H-NMR (CDCl₃) δ 10.37 (s, 1H), 9.25 (br, 1H), 8.28 (s, 1H), 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 C₁₇H₁₅NO₃: 281.1052; found: 281.1049.

The title compound was prepared by condensing 5-(1H-indol-2-yl)-2,4dimethoxy-benzaldehyde (Ex-61A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 210-212° C., 66% yield. ¹H-NMR (Aceton-d₆) δ 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-phenyl]-acryloyl}-benzoic acid

Ex-62A: 2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-29C using 4-chloromethyl-3,5-dimethyl-isoxazole. ¹H-NMR (CDCl₃) δ 10.26 (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. ¹H-NMR (CDCl₃) δ 8.20 (d, J=9 Hz, 2H), 7.88-8.03 (m, 4H), 7.58 (d, J=16 Hz, 114), 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, 31), 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-[3E-2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid

Ex-43A: A solution of 2-fluoro-5-thiophen-2-yl-benzaldehyde (1.42 g, 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-1-yl-5-thiophen-2-yl-benzaldehyde (0.5 g, 32%). ¹H NMR (CDCl₃) δ 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. ¹H-NMR (DMSO-d,) δ 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-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-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 (3×150 mL). The combined organic layers was sequentially washed with a saturated sodium bicarbonate solution (1×150 mL), water (1×150 mL), and brine (1×150 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%) of 2-[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. ¹H-NMR (300 MHz, CDCl₃) δ 10.37 (s, 1H), 8.12 (s, 114), 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-yl-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. ¹H-NMR (300 MHz, CDCl₃)δ 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, 1H, J=5.4 Hz). MS (EI) m/z=322 ([M]⁺, 100%). HRMS (EI) Calcd. for C₁₆H₁₈O₅S: 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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, 1H, 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 C₂₅H₂₄O₇S.H₂O: 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-2yl-phenyl]-acryloyl}-benzoic 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. ¹H-NMR (DMSO-D6) δ 10.36 (s, 1H), 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. ¹H-NMR (DMSO-d6) δ 13.32 (br s, 1H), 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. 3/2H₂O: 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. ¹H-NMR (DMSO-D6) δ 10.21 (s, 1H), 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). ¹UH-NMR (DMSO-d₆) δ 12.63 (br s, 1H), 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 C₂₈H₃₂ClNO₇S.H₂O: 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. ¹H-NMR (300 MHz, CDCl₃) δ 10.38 (s, 1H), 8.13 (s, 1H), 7.44 (d, 1H, J=3.6 Hz), 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 C₁₆H₁₇NO₄S.⅕H₂O: 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-47A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 228-229° C., 75% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 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, 1H, 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 (EI) 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, CDCl₃) δ 4.374.40 (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 C₈H₁₈O₆S: 243.0902. Found: 243.0914.

Ex-68B: 4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-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, CDCl₃) δ 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 (EI) m/z=380 ([M]⁺, 100%): HRMS (ESI) Calcd. for C₈H₁₈O₆S: 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-48B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 137-138° C., 82% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 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), 3.363.95 (m, 2H), 3.19 (s, 3H). MS (ESI) m/z=527 ([M+H]⁺, 100%). Anal. Calcd. for C₂₈H₃₀O₈S: 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 (0.62 g, 2.39 mmol) and thioacetamide (0.18 g, 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 (0.56 g, 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 (0.70 g, 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 (0.5M), 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. ¹H NMR (CDCl₃) δ 10.33 (s, 1H), 8.67 (s, 1H), 7.56 (s, 1H), 6.52 (s, 1H), 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.). ¹H-NMR (DMSO-d₆) δ 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-(1H-Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid

Ex-70A: A solution of benzene-1,2-diamine (2.60 g, 24.1 mmol) and 2,4-dimethoxy-benzaldehyde (4.0 g, 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-dimethoxy-phenyl)-1H-benzoimidazole (0.76 g, 12%). The crude product was used without further purification. To a solution of 2-(2,4-dimethoxy-phenyl)-1H-benzoimidazole obtained above (0.76 g, 2.99 mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride (11.0M 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-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (0.40 g, 47%), was obtain and used without further purification. ¹H NMR (CDCl₃) δ 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-(1H-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.). ¹H-NMR (DMSO-d₆) 88.72 (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)-acryloyl]-benzoic acid

Ex-71A: 2-2-Formyl-5-methoxy-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. ¹H-NMR (300 MHz, CDCl₃) δ 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, 1H, 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 C₁₄H₁₃NO₄S: 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) δ 8.26-8.30 (m, 3H), 8.08-8.11 (m, 4H) 7.67 (d, 1H, 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]-acryloyl}-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. ¹H-NMR (300 MHz, CDCl₃) δ 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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]⁺, 1100%). 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-thiophen-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) δ 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 (EI) m/z.=207 ([M]⁺, 100%). HRMS (EI) Calcd. for C₁₈H₁₉NO₅S: 207.0929. Found: 207.0922.

Ex-73B: 4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-benzaldehyde 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. ¹H-NMR (300 MHz, CDCl₃, major isomer) δ 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. ¹H-NMR (300 MHz, DMSO-d₆, major isomer) δ 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, 1H, J=3.3 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.14 (dd, 1H, 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 C₂₈H₃₀ClNO₅S.½H₂O: 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-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid

Ex-74A: A solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.33 g, 1.70 mmol) and di-tert-butyl dicarbonate (0.51 g, 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 tert-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 (0.28 g, 1.13 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (Ex-76A, 0.61 g, 1.70 mmol), bis(tri-tert-butylphosphine)palladium (43 mg, 0.085 mmol) and potassium fluoride (0.24 g, 4.08 mmol) was added degassed tetrahydrofuran (15 mL). The reaction mixture was heated at 60° C. for one day. Additional potassium fluoride (0.24 g, 4.08 mmol) and water (20 μL) 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 (0.15 g, 40%) as white solid. ¹H NMR (CDCl₃) δ 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 2,4dimethoxy-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. ¹H-NMR (DMSO-d₆) δ 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 HCl (60 mL) and extracted with ethyl acetate (2×75 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 1N HCl 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) δ 10.09 (s, 1H), 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). ¹H-NMR (DMSO-d₆) 8.58 (s, 1H), 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 ml of POCl₃ 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 POCl₃. The residue was carefully treated with 1N HCl 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%). ¹H-NMR (DMSO-d₆) δ 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 CH₂Cl₂, 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 TiCl₄ (1.0 m in CH₂Cl₂) 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. ¹H-NMR (DMSO-d₆) δ 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 C₁₅H₃N₃O₃: 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. ¹H-NMR (DMSO-4) δ 8.75 (s, 1H), 8.38-8.40 (m, 1H), 8.18 (d, J=9 Hz, 2H), 7.99-8.08(m, 4H), 7.83(d, J=15 Hz, 1H), 7.28-7.33(m, 1H), 6.91 (s, 1H), 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-methyl-propionic acid

Ex-77A: To a mixture of aluminum chloride (2.8 g, 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 (1.0 g, 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 (0.57 g, 470 %). ¹H NMR (CDCl₃) δ 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. ¹H-NMR (CCDl₃) δ 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 (2.9 g, 20.0 mmol), sodium azide (1.43 g, 22.0 mmol) and zinc bromide (4.5 g, 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 (3×60 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 HCl (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. ¹H NMR (DMSO-d₆) δ 8.17-8.10 (m, 4H), 2.6-[(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 2350C (dec.). ¹H-NMR (DMSO-d₆) δ 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 (20×20 cm, RP-18 F₂₅₄, 1 mm) eluted with MEOH/ACN/H₂O (45:45:10) to give 22.2 mg of the title compound, which was 86% the cis isomer by NMR analysis. ¹H-NMR (DMSO-D₆, major isomer) δ 7.98 (s, 4H), 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, 0.20 g, 1.0 mmol) and 5-benzo[b]thiophene-2-yl-2,4-dimethoxyphenylbenzaldehyde (Ex-3A, 0.31 g, 1.05 mmol) in DMF (5 mL) and methanol (2 mL) was added lithium methoxide (0.15 g, 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 (Na₂SO₄) 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 (0.3 g, 63%), mp 204-205° C. (dec.). ¹H-NMR (DMSO-d₆) δ 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]-acryloyl}-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 (3×25 mL). The combined organic extracts were dried over sodium sulfate and 1-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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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), 3.543.58 (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 C₂₆H₂₈N₂O₆S₂: 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-{5Methoxy-2-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-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-propionic acid (Ex-59B) in a similar manner as described in Ex-22. Yellow solid, mp 164-165° C., 85% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 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) m/z=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. ¹H-NMR (CDCl₃) δ 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 C₃₀H₃₀N₂O₇S: 563.1852. Found: 563.1862.

Example 84

4-{3E-[5-(1H-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. ¹H-NMR (DMSO-0.4) δ 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), 6.936.99 (m, 2H), 6.83 (s, 1H), 4.04(s, 3H), 3.99(s, 3H). MS m/z=463 ([M+H]⁺). HRMS (ES+) Calcd. for C₂₅H₂₂N₂O₅S: 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-46A) in a similar manner as described in Ex-22. Yellow solid, 48% yield, mp 193-196° C. ¹H-NMR (DMSO-d6) δ 8.24 (m, 3H), 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 C₂₇H₃₀N₂O₆S₂.⅗H₂O: 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-yl-phenyl]-acryloyl}-benzenesulfonamide

2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-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 (6×200 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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. C₂₄H₂₅NO₇S₂H₂O: 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-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N-isobutryl-benzenesulfonamide

A solution of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide (Ex-80, 0:15 g, 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 (0.15 g, 87%), mp>240° C. (dec.). ¹H-NMR (CDCl₃) δ 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, 1H), 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 HCl (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). ¹H-NMR (300 MHz, DMSO-d₆): δ 8.31-8.34 (m, 3H), 8.13 (d, 1H, 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 C₂₆H₂₉ClN₂O₆S₂: 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-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-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. ¹H-NMR (300 MHz, CDCl₃) δ 10.29 (s, 1H), 8.17 (s, 1H), 7.48 (d, 1H, 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 C₁₄H₁₁NO₃S: 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 (3×50 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-(1H-tetrazol-5-ylmethoxy)₅-thiophen-2-yl-benzaldehyde as a pale green solid. ¹H-NMR (300 MHz, DMSO-d₆). 10.33 (s, 114), 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) m/z=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-benzaldehyde (Ex-89A) in a similar manner as described in Ex-22. Yellow solid, mp 163-164° C. (dec), 60% yield. ¹H-NMR (300 MHz, DMSO-d₆) δ 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 C₂₂H₁₉N₅O₅S₂-11/2H₂O: 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-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-ylethylamine (0.18 mL) in dichloromethane (20 mL) was added 13-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 (2×50 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%). ¹H-NMR (300 MHz, CDCl₃) δ 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 C₃₂H₃₂N₂O₅S.H₂O: 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. ¹H-NMR (Aceton-d₆) δ 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 (0.5 g, 3.05 mmol) in tetrahydrofuran (10 mL) was added carbonyldiimidazole (0.74 g, 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 (0.25 g, 50%) as a white solid. ¹H NMR (DMSO-d₆) δ 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, 0.25 g, 1.53 mmol) and 2-(2-morpholin-4-yl-ethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-60A, 0.53 g, 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 NaHCO₃, NH₄Cl, brine, dried (Na₂SO₄) and concentrated. The residue was stirred in ethanol overnight to afford the title compound as a yellow solid (0.43 g, 57%), mp 183-1840C. ¹H-NMR (CDCl₃) δ 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 m/z=493 ([M+H]⁺, 100%).

Example 93

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4dimethoxy-phenyl)-acryloyl]-benzamide

To a solution of 4-acetyl-benzamide (0.3 g, 1.84 mmol) and 5-(benzo[b]thein-2yl)-2,4-dimethoxybenzaldehyde (0.55 g, 1.84 mmol) in a mixture of N,N-dimethylformamide (7 mL) and methanol (3 mL) was added lithium methoxide (0.14 g, 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 (5.56 g, 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 (1.09 g, 8.10 mmol) and ammonium chloride (1.81 g, 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 (2.82 g, 94%), mp 240-241-C. ¹H-NMR (DMSO-d₆) δ 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. ¹H-NMR (CDCl₃) δ 8.08 (m, 3H), 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 C₂₉H₃₀N₂O₅S.⅖H₂O: 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, 0.5 g, 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 NH₄Cl, brine, dried and concentrated. The residue was purified by flash chromatography. Elution with 50% EtOAc/hexane gave the title compound as yellow solid (0.16 g, 29%), mp 228-229° C. ¹H-NMR (CCDl₃) δ 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, 1H), 7.34-7.29 (m, 3H), 6.58 (s, 1H), 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) δ 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 m/z=513 (M⁺, 93%), 425 (100%).

Example 97

4(3E-{4-[3-(4-Thiophen-2-yl-phenyl)acryloyl]-phenyl}-ureido)-acetic acid

A solution of (3-{4-[3-(4-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-ureido)-acetic acid ethyl ester (Ex-15, 151.3 mg, 0.35 mmol) in THF:MeOH:H₂O (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 HCl to a pH2. The mixture was extracted with ethyl acetate (30 mL). The organic phase was collected, dried over Na₂SO₄, and concentrated to a pure yellow solid (131.7 mg, 93%), mp 222-225° C. ¹H-NMR (DMSO-d₆) δ 9.27 (br s, 1H), 8.14 (d, 2H), 7.87 (m, 3H), 7.71 (d, 3H), 7.56 (m, 4H), 7.14 (t, 1H), 6.54 (t, 1H), 3.78 (d, 2H). MS m/z=407 ([M+H]⁺, 88%), 306 (100%). Anal. calculated for C₂₂H₁₈N₂O₄S.½H₂O: 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-methyl-methanesulfonamide

A solution of N-{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 (2×50 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. ¹H-NMR (CDCl₃) δ 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)-1-1-[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 209-210C (dec). ¹H-NMR (DMSO-D₆) δ 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), 4.384.45 (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%). ¹H-NMR (DMSO-D₆) δ 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, 1H), 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-100A: A solution of 4-aminoacetophenone (5.0 g, 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 NH₄Cl 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. ¹H-NMR (DMSO-d₆) δ 10.28 (s, 1H), 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-propionic 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 (2×50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCl. The aqueous solution was then extracted with isopropyl acetate (2×50 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. ¹H-NMR (DMSO-d₆) δ 10.31 (br s, ¹H), 8.24 (s, 1H), 8.12 (d, 2H), 7.95 (d, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.50 (d, 1H), 7.30 (d, 2H), 7.09 (t, 1H), 6.45 (s, 1H), 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-[4-(Methanesulfonyl-methyl-amino)-phenyl]-3-oxo-E-propenyl}-5 methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid

Ex-101A: A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 2.0 g, 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 (2×100 mL). 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. ¹H-NMR (CDCl₃) δ 7.88 (d, 2H), 7.48 (d, 2H), 3.38 (s, 3H), 2.86 (s, 3), 2.60 (s, 3H). HRMS m/z; calc. 530.1307, found 530.1313.

A solution of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide (Ex-101A, 298 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic 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 (2×50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCl. The aqueous solution was then extracted with isopropyl acetate (2×50 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. ¹H-NMR (DMSO-d₆) δ 8.20 (s, 1H), 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, 1H), 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 2.7 g (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. ¹H-NMR (DMSO-d₆) δ 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 C₁₂H₁₀N₂O₃: 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, 2 mmol) 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 pH1 with 3N HCl, extracted with dichloromethane. The combined organic phase was then washed with brine and water, dried over MgSO₄, column chromatography (5% MeOH in CH₂Cl₂) to give 57 mg (5.4%) title compound as a yellow solid, mp>260° C. ¹H-NMR (DMSO-d₆) δ 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 C₂₉H₂₂N₂O₅S: 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 (2.0 g, 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-4A, 3.9 g, 15.8 mmol) in ethanol (10 mL). The reaction mixture was allowed to stir at ambient temperature overnight and was acidified with concentrated HCl to pH 3, saturated with NaCl, extracted with CH₂Cl₂. The combined solution of CH₂Cl₂ was washed with brine, dried (Na₂SO₄) 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. ¹H NMR (DMSO-d₆) δ 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, 1H), 7.51 (s, 1H), 7.50 (d, J=5.2 Hz, 1H), 7.13 (t, J=4.5 Hz, 114), 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. ¹H-NMR (DMSO-d₆) δ 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, 1H), 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]-benzenesulfonamide

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-bromo-2,4-dimethoxybenzaldehyde, 68% yield. ¹H-NMR (CDCl₃) δ 10.33 (s, 1H), 8.71 (d, J=1 Hz, 1H), 8.51-8.53(m, 1H), 7.81 (s, 1H), 7.74-7.78 (m, 1H), 7.27-7.31 i (m, 1H), 6.52 (s, 1H), 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. ¹H-NMR (DMSO-d₆) δ 8.69 (d, J=1 Hz, 1H), 8.50 (d, J=4 Hz, 1H), 8.25 (d, J=9 Hz, 2H), 8.08 (d, J=15 Hz, 1H), 8.02 (s, 1H), 7.84-7.94(m, 41-1), 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 C₂₂H₂₀N₂O₅S: 424.1093; found: 424.1100.

Example 105

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride

Ex-105A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.3 g, 1.16 mmol), cyclopropanecarboxamidine (0.14 g, 1.16 mmol) and sodium hydroxide (0.18 g, 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)-1H-imidazole as white solid (0.15 g, 53%): ¹HNMR (CDCl₃) δ 9.50 (bs, 1H), 7.63 (s, 1H), 7.20 (s, 1H), 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 m/z=245 ([M+H]⁺, 100%).

Ex-105B: To a solution of 2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H-imidazole (0.51 g, 2.09 mmol) was added dichloromethyl methyl ether (0.28 mL, 3.13 mmol) followed by addition of titanium tetrachloride (11.0M 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. ¹H NMR (DMSO-d₆) δ 13.95 (bs, 1H), 10.22 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 6.88 (s, 1H), 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-1 H-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. ¹H NMR (DMSO-d₆) δ 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-hydroxy methyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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, 1H, 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 C₂₄H₂₅NO₇S₂.½H₂O: 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) δ 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 (EI) Calcd. for C₁₃H₂₄O₅S₂: 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. ¹H-NMR (CDCl₃) δ 8.06-8.12 (m, 5H), 7.92 (s, 1H), 7.75-7.82 (m, 2H), 7.65 (s, H), 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 C₂₇H₂₂O₄S: 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 (4.24 g, 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: ¹H NMR (CDCl₃) δ 8.77 (bs, 1H), 8.15 (d, J=8.8 Hz, 1H), 6.58 (dd, J=8.8, 2.2 Hz, 1H), 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, 1.0 g, 5.1 mmol) and isobutyl-isothiocyanate (0.70 g, 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 (1.43 g). Additional product (0.1 g, 96% overall) was obtained by concentrating the mother liquid. ¹H NMR (CDCl₃) δ 10.71 (bs, 1H), 9.23 (bs, 1H), 8.03 (d, J=8.6 Hz, 1H), 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, 0.5 g, 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) isobutyl-4H-[1,2,4]triazole-3-thiol (0.1 g). Additional product (0.36 g, 98% overall) was obtained by extracting the water wash with dichloromethane and a mixture of isopropyl alcohol (33%, v/v, in dichloromethane). ¹H NMR (CDCl₃) δ 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, 0.1 g, 0.34 mmol) in ethanol (10 mL) was added wet Raney Ni (0.27 g, 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 (0.09 g, 100%) as a white solid: ¹H NMR (CDCl₃) δ 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, 0.78 g, 2.98 mmol) was added dichloromethyl methyl ether (0.4 mL, 4.48 mmol) followed by addition of titanium tetrachloride (11.0M 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 (0.24 g, 28%): ¹HNMR (CDCl₃) δ 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, 0.12 g, 0.62 mmol) and 5-4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.18 g, 0.62 mmol) in N,N-dimethylformamide (9 mL) was added lithium methoxide (11.0M 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. ¹H NMR (DMSO-d₆) δ 8.60 (s, 1H), 8.26 (d, J=8.1 Hz, 2H), 8.06 (d, J=15.3 Hz, 1H), 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 (0.12 g, 0.75 mmol) and 5-(4-isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.24 g, 0.83 mmol) in N,N-dimethylformamide (6 mL) was added lithium methoxide (11.0M in methanol, 3.0mL, 3.0 mmol). The solution was allowed to stir overnight and additional lithium methoxide (0.11 g, 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.). ¹H NMR (DMSO-d₆) δ 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, 1H), 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-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide

To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12 g, 0.59 mmol) and 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-105B, 0.16 g, 0.59 mmol) in N,N-dimethylformamide (16 mL) was added lithium methoxide (11.0M 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. ¹H NMR (DMSO-d₆) δ 11.65 (bs, 1H), 8.32 (s, 1H), 8.19 (d, J=9.0 Hz, 2H), 8.00 (d, J=15.7 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.62-7.52 (m, 2H), 7.24 (bs, 1H), 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-b]pyridin-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. ¹H-NMR (DMSO-d₆) δ 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 m/z=465([M+H]⁺, 65%), 256 (100%). HRMS (ES+) Calcd. for C₂₃H₂₀N₄O₅S: 465.1232. Found: 465.1240.

Example 113

4-{3E-[2-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide

Ex-113A: 2-(1H-Benzoimidazol-2-ylmethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-29C. Off-white solid, 67% yield, mp 230° C. (dec). ¹H-NMR (300 MHz, DMSO-d₆) □ 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.⅓H₂O: C, 59.04; H, 4.38; N, 6.88; S, 7.88. Found: C, 59.07; H, 4.25; N,. 0.77.

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). ¹H-NMR (300 MHz, DMSO-d₆) δ 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-benzaldehyde was prepared in a similar manner as described in Ex-29C. Yellow solid, 93% yield, mp 93-94° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.49 (s, 1H), 8.62 (d, 1H, J=5.1 Hz), 8.13 (s, 1H), 7.77 (dt, 1H, J=7.5, 1.5 Hz), 7.58 (d, 1H, J=7.5 Hz), 7.44 (dd, 1H, 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) m/z=326 ([M+H]⁺, 100%). Anal. Calcd. for C₁₈H₁₅NO₃S: 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. ¹H-NMR (300 MHz, DMSO-d₆)δ 8.66 (d, 1H, J=3.6 Hz), 8.28(s, 1H), 8.21 (d, 2H, J=7.8 Hz), 8.11 (d, 1H, 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, 1H, 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}-benzenesulfonamide

Ex-115A: 2-Benzotriazol-1-ylmethoxy)₄-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-29C. Off-white solid, 92% yield, mp 137-138° C. ¹H-NMR (300 MHz, CDCl₃) δ 10.30 (s, 1H), 8.10 (d, 1H, J=8.1 Hz), 8.06 (s, 1H), 7.75 (d, 1H, J=8.1 Hz), 7.57-7.62 (m, 1H), 7.40-7.48 (m, 21), 7.30 (d, 1H, 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) m/z=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). 1H- NMR (300 MHz, DMSO-d₆) δ 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. C₂₇H₂₂N₄O₅S₂: 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-1H-indol-2-yl)-phenyl]-acryloyl}-benzoic 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, PdCl₂(PPh₃)₂ (0.35 g, 0.5 mmol) and 5-bromo-2,4-dimethoxybenzaldehyde (3.7 g, 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% H₂O₂ and then stirred for 10 minutes. The mixture was extracted with EtOAc and combined organic phase was washed with H₂O and brine, dried over MgSO₄, 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) δ 10.33 (s, 1H), 7.84 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.31 (d, J=8 Hz, 1H), 7.18-7.24 (m, 1H), 7.07-7.12(m, 1H), 6.53 (s, 1H), 6.46(s, 1H), 4.00 (s, 3}1), 3.89 (s, 3H), 3.53 (s, 3H). HRMS (EI) Calcd. for C₁₈H₁₇NO₃: 295.1208. Found: 295.1202.

The title compound was prepared by condensing 4-acetylbenzoic acid and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3. Yellow solid, 87% yield, mp 157-160° C. ¹H-NMR (DMSO-d₆) δ 8.17 (d, J=8 Hz, 2H), 8.08 (d, J=15 Hz, 1H), 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-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzenesulfonamide

The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2,4-dimethoxy-5-(1-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. ¹H-NMR (CDCl₃) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 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

4-13E-5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-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. ¹H-NMR (300 MHz, CDCl₃): 8.17 (d, 2H, J=6.7 Hz), 8.10 (d, 1H, J=15.8 Hz), 8.05 (d, 2H, J=6.7 Hz), 7.95 (s, 1H), 7.82 (m, 2H), 7.67 (s, 1H), 7.57 (d, 1H, J=15.8 Hz), 7.33 (m, 2H), 6.58 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H). MS m/z=458 ([M]⁺, 100%). HRMS (EI) Calcd. for C₂₇H₂₂O₅S: 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 (3×20 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. ¹H-NMR (300 MHz, CDCl₃) δ 10.03 (s, 1H), 7.88 (s, 1H), 7.82 (d, 1H, J=7.2 Hz), 7.62-7.64 (m, 1H), 7.53 (t, 1H, J=7.2 Hz), 6.48 (q, 1H, J=Hz), 5.60(dd, 1H, 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, 1H, J=15.0, 8.1, 2.5 Hz). MS (EI) m/z=174 ([M]⁺, 100%). HRMS (EI) Calcd. for C₁₁H₁₀O₂: 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. ¹H-NMR (300 MHz, DMSO-6)δ 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, 1H, J=2.4 Hz), 3.10 (ddt, 1H, J=15.0, 8.1, 2.5 Hz), 2.54 (ddt, 1H, J=15.0, 8.1, 2.5 Hz). MS (ESI) m/z=356 ([M+H]⁺, 100%). Anal. Calcd. for C₁₉H₁₇NO₄S.⅕H₂O: 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-dimethoxyphenyl)-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-dimethoxyphenyl)-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) δ 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, 1H), 3.61 (m, 1H), 3.39-3.55 (m, 3H), 3.04 (m, 1H), 2.95 (m, 1H), 2.54 (s, 3H). Anal. Calculated for C₃₃H₃₇NO₁₀S.1.3H₂O: 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 hydroxylamine salt and in particular the meglumine salt.

Example 121

4-{3E-[5-(2,5-Dihydro-furan-2-yl)-2,4-dimethoxy-phenyl]-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 (3×30 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. ¹H-NMR (300 MHz, CDCl₃) δ 10.29 (s, 1H), 7.79 (s, 1H), 6.42 (s, 1H), 5.99-6.06 (m, 2H), 5.89-5.92 (m, 1H), 4.804.87 (m, 1H), 4.71-4.77 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS (EI) m/z=234 ([M]⁺, 100%). Anal. Calcd. C₁₃H₁₄O₄: C, 66.66; H, 6.02. Found: C, 66.49; H, 6.08.

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 (3×20 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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, 1H, J=15.3 Hz), 7.55 (brs, 2H), 6.73 (s, 1H), 6.06-6.09 (m, 1H), 5.90-5.98 (m, 2H), 4.86-4.92 (m, 1H), 4.634.68 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z=416 ([M+H]⁺, 100%).-Anal. Calcd. C₂₁H₂₁NO₆S: 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 (5×20 mL). The combined organic extracts were washed with a 50% brine solution (1×25 mL), brine (1×25 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. ¹H-NMR (300 MHz, CDCl₃) δ 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, 1H, J=7.2 Hz), 6.78 (d, 1H, J=7.8 Hz), 6.75 (s, 1H), 3.92 (s, 3H), 2.44 (s, 3H). HRMS (EI) Calcd. for C₁₈H₁₅NO₃S: 325.0773. Found: 325.0775. Anal. Calcd. C₁₈H₁₅NO₃S: 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 (3×20 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. ¹H-NMR (300 MHz, DMSO-d₆) δ 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, 1H, J=5.1, 3.6 Hz), 7.04 (d, 1H, J=7.5 Hz), 6.99 (s, 1H), 6.91 (d, 1H, J=8.4 Hz), 3.90 (s, 3H), 2.33 (s, 3H). Anal. Calcd. C₂₆H₂₂N₂O₅S₂: 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 (20.0 g, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.52 g, 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 (30.62 g, 87.5%), m.p. 170-172° C. ¹H NMR (CDCl₃) δ 10.19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H).

Example 124

5Benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde

Ex-123A: Potassium fluoride (0.42 g, 7.2 mmol), 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, 11.0 g, 3.42 mmol), 2-benzo[b]thiophene boronic acid (0.67 g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol), and tri-tert-butylphosphine (100 mg, 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-1-ones, and substituted 3-[(heteroaryl or heterocyclic)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. R5β
200A 200B
201A 201B
202A 202B
203A 203B
204A 204B
205A 205B
206A 206B
207A 207B
208A 208B
209A 209B
210A 210B
211A 211B
212A 212B
213A 213B
214A 214B
215A 215B
216A 216B
217A 217B
218A 218B
219A 219B
220A 220B
221A 221B
222A 222B
223A 223B
224A 224B
225A 225B
226A 226B
227A 227B
228A 228B
229A 229B
230A 230B
231A 231B
232A 232B
233A 233B
234A 234B
235A 235B
236A 236B
237A 237B
238A 238B
239A 239B
240A 240B
241A 241B
242A 242B
243A 243B
244A 244B
245A 245B
246A 246B
247A 247B
248A 248B
249A 249B
250A 250B
251A 251B
252A 252B
253A 253B
254A 254B
255A 255B
256A 256B
257A 257B
258A 258B
259A 259B
260A 260B
261A 261B
262A 262B

EXAMPLE TABLE 12
Substituted4-[3-{2-Cyclopropylmethoxy-4-methoxy-(5-heteroaryl or 5-
heterocyclic)phenyl}-acryloyl]-benzoic Acids.
Ex. No. R5β
263A 263B
264A 264B
265A 265B
266A 266B
267A 267B
268A 268B
269A 269B
270A 270B
271A 271B
272A 272B
273A 273B
274A 274B
275A 275B
276A 276B
277A 277B
278A 278B
279A 279B
280A 280B
281A 281B
282A 282B
283A 283B
284A 284B
285A 285B
286A 286B
287A 287B
288A 288B
289A 289B
290A 290B
291A 291B
292A 292B
293A 293B
294A 294B
295A 295B
296A 296B
297A 297B
298A 298B
299A 299B
300A 300B
301A 301B
302A 302B
303A 303B
304A 304B
305A 305B
306A 306B
307A 307B
308A 308B
309A 309B
310A 310B
311A 311B
312A 312B
313A 313B
314A 314B
315A 315B
316A 316B
317A 317B
318A 318B
319A 319B
320A 320B
321A 321B
322A 322B
323A 323B
324A 324B
325A 325B
326A 326B
327A 327B
328A 328B
329A 329B
330A 330B
331A 331B
332A 332B
333A 333B
334A 334B

EXAMPLE TABLE 3
Substituted 4-[3-{2,4-dimethoxy-(6-Heteroaryl or 6-heterocyclic)phenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
335A 335B
336A 336B
337A 337B
338A 338B
339A 339B
340A 340B
341A 341B
342A 342B
343A 343B
344A 344B
345A 345B
346A 346B
347A 347B
348A 348B
349A 349B
350A 350B
351A 351B
352A 352B
353A 353B
354A 354B
355A 355B
356A 356B
357A 357B
358A 358B
359A 359B
360A 360B
361A 361B
362A 362B
363A 363B
364A 364B
365A 365B
366A 366B
367A 367B
368A 368B
369A 369B
370A 370B
371A 371B
372A 372B
373A 373B
374A 374B
375A 375B
376A 376B
377A 377B
378A 378B
379A 379B
380A 380B
381A 381B
382A 382B
383A 383B
384A 384B
385A 385B
386A 386B
387A 387B
388A 388B
389A 389B
390A 390B
391A 391B
392A 392B
393A 393B
394A 394B
395A 395B
396A 396B
397A 397B

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. R5β
398A 398B
399A 399B
400A 400B
401A 401B
402A 402B
403A 403B
404A 404B
405A 405B
406A 406B
407A 407B
408A 408B
409A 409B
410A 410B
411A 411B
412A 412B
413A 413B
414A 414B
415A 415B
416A 416B
417A 417B
418A 418B
419A 419B
420A 420B
421A 421B
422A 422B
423A 423B
424A 424B
425A 425B
426A 426B
427A 427B
428A 428B
429A 429B
430A 430B
431A 431B
432A 432B
433A 433B
434A 434B
435A 435B
436A 436B
437A 437B
438A 438B
439A 439B
440A 440B
441A 441B
442A 442B
443A 443B
444A 444B
445A 445B
446A 446B
447A 447B
448A 448B
449A 449B
450A 450B
451A 451B
452A 452B
453A 453B
454A 454B
455A 455B
456A 456B
457A 457B
458A 458B
459A 459B
460A 460B
461A 461B
462A 462B
463A 463B
464A 464B
465A 465B
466A 466B
467A 467B
468A 468B
469A 469B

EXAMPLE TABLE 5
Substituted 1-(3-Aminophenyl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-
heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R5β
470A 470B
471A 471B
472A 472B
473A 473B
474A 474B
475A 475B
476A 476B
477A 477B
478A 478B
479A 479B
480A 480B
481A 481B
482A 482B
483A 483B
484A 484B
485A 485B
486A 486B
487A 487B
488A 488B
489A 489B
490A 490B
491A 491B
492A 492B
493A 493B
494A 494B
495A 495B
496A 496B
497A 497B
498A 498B
499A 499B
500A 500B
501A 501B
502A 502B
503A 503B
504A 504B
505A 505B
506A 506B
507A 507B
508A 508B
509A 509B
510A 510B
511A 511B
512A 512B
513A 513B
514A 514B
515A 515B
516A 516B
517A 517B
518A 518B
519A 519B
520A 520B
521A 521B
522A 522B
523A 523B
524A 524B
525A 525B
526A 526B
527A 527B
528A 528B
529A 529B
530A 530B
531A 531B
532A 532B

EXAMPLE TABLE 6
Substituted 1-(4-Aminophenyl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-
heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R5β
533A 533B
534A 534B
535A 535B
536A 536B
537A 537B
538A 538B
539A 539B
540A 540B
541A 541B
542A 542B
543A 543B
544A 544B
545A 545B
546A 546B
547A 547B
548A 548B
549A 549B
550A 550B
551A 551B
552A 552B
553A 553B
554A 554B
555A 555B
556A 556B
557A 557B
558A 558B
559A 559B
560A 560B
561A 561B
562A 562B
563A 563B
564A 564B
565A 565B
566A 566B
567A 567B
568A 568B
569A 569B
570A 570B
571A 571B
572A 572B
573A 573B
574A 574B
575A 575B
576A 576B
577A 577B
578A 578B
579A 579B
580A 580B
581A 581B
582A 582B
583A 583B
584A 584B
585A 585B
586A 586B
587A 587B
588A 588B
589A 589B
590A 590B
591A 591B
592A 592B
593A 593B
594A 594B
595A 595B
596A 596B
597A 597B
598A 598B
599A 599B
600A 600B
601A 601B
602A 602B
603A 603B
604A 604B

EXAMPLE TABLE 7
Substituted 1-{4-(Pyrrolidin-1-yl)phenyl}-3-[2,4-dimethoxy-(5-heteroaryl
or 5-heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R5β
605A 605B
606A 606B
607A 607B
608A 608B
609A 609B
610A 610B
611A 611B
612A 612B
613A 613B
614A 614B
615A 615B
616A 616B
617A 617B
618A 618B
619A 619B
620A 620B
621A 621B
622A 622B
623A 623B
624A 624B
625A 625B
626A 626B
627A 627B
628A 628B
629A 629B
630A 630B
631A 631B
632A 632B
633A 633B
634A 634B
635A 635B
636A 636B
637A 637B
638A 638B
639A 639B
640A 640B
641A 641B
642A 642B
643A 643B
644A 644B
645A 645B
646A 646B
647A 647B
648A 648B
649A 649B
650A 650B
651A 651B
652A 652B
653A 653B
654A 654B
655A 655B
656A 656B
657A 657B
658A 658B
659A 659B
660A 660B
661A 661B
662A 662B
663A 663B
664A 664B
665A 665B
666A 666B
667A 667B

EXAMPLE TABLE 8
Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[2,4-dimethoxy-(5-
heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R5β
668A 668B
669A 669B
670A 670B
671A 671B
672A 672B
673A 673B
674A 674B
675A 675B
676A 676B
677A 677B
678A 678B
679A 679B
680A 680B
681A 681B
682A 682B
683A 683B
684A 684B
685A 685B
686A 686B
687A 687B
688A 688B
689A 689B
690A 690B
691A 691B
692A 692B
693A 693B
694A 694B
695A 695B
696A 696B
697A 697B
698A 698B
699A 699B
700A 700B
701A 701B
702A 702B
703A 703B
704A 704B
705A 705B
706A 706B
707A 707B
708A 708B
709A 709B
710A 710B
711A 711B
712A 712B
713A 713B
714A 714B
715A 715B
716A 716B
717A 717B
718A 718B
719A 719B
720A 720B
721A 721B
722A 722B
723A 723B
724A 724B
725A 725B
726A 726B
727A 727B
728A 728B
729A 729B
730A 730B
731A 731B
732A 732B
733A 733B
734A 734B
735A 735B
736A 736B
737A 737B
738A 738B
739A 739B

EXAMPLE TABLE 9
Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[3,4-dimethoxy-(5-
heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R5β
740A 740B
741A 741B
742A 742B
743A 743B
744A 744B
745A 745B
746A 746B
747A 747B
748A 748B
749A 749B
750A 750B
751A 751B
752A 752B
753A 753B
754A 754B
755A 755B
756A 756B
757A 757B
758A 758B
759A 759B
760A 760B
761A 761B
762A 762B
763A 763B
764A 764B
765A 765B
766A 766B
767A 767B
768A 768B
769A 769B
770A 770B
771A 771B
772A 772B
773A 773B
774A 774B
775A 775B
776A 776B
777A 777B
778A 778B
779A 779B
780A 780B
781A 781B
782A 782B
783A 783B
784A 784B
785A 785B
786A 786B
787A 787B
788A 788B
789A 789B
790A 790B
791A 791B
792A 792B
793A 793B
794A 794B
795A 795B
796A 796B
797A 797B
798A 798B
799A 799B
800A 800B
801A 801B
802A 802B

EXAMPLE TABLE 10
Substituted 1-{4-(Amino)phenyl}-3-[3,4-dimethoxy-(5-heteroaryl or 5-
heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R5β
803A 803B
804A 804B
805A 805B
806A 806B
807A 807B
808A 808B
809A 809B
810A 810B
811A 811B
812A 812B
813A 813B
814A 814B
815A 815B
816A 816B
817A 817B
818A 818B
819A 819B
820A 820B
821A 821B
822A 822B
823A 823B
824A 824B
825A 825B
826A 826B
827A 827B
828A 828B
829A 829B
830A 830B
831A 831B
832A 832B
833A 833B
834A 834B
835A 835B
836A 836B
837A 837B
838A 838B
839A 839B
840A 840B
841A 841B
842A 842B
843A 843B
844A 844B
845A 845B
846A 846B
847A 847B
848A 848B
849A 849B
850A 850B
851A 851B
852A 852B
853A 853B
854A 854B
855A 855B
856A 856B
857A 857B
858A 858B
859A 859B
860A 860B
861A 861B
862A 862B
863A 863B
864A 864B
865A 865B
866A 866B
867A 867B
868A 868B
869A 869B
870A 870B
871A 871B
872A 872B
873A 873B
874A 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. R4β
875A 875B
876A 876B
877A 877B
878A 878B
879A 879B
880A 880B
881A 881B
882A 882B
883A 883B
884A 884B
885A 885B
886A 886B
887A 887B
888A 888B
889A 889B
890A 890B
891A 891B
892A 892B
893A 893B
894A 894B
895A 895B
896A 896B
897A 897B
898A 898B
899A 899B
900A 900B
901A 901B
902A 902B
903A 903B
904A 904B
905A 905B
906A 906B
907A 907B
908A 908B
909A 909B
910A 910B
911A 911B
912A 912B
913A 913B
914A 914B
915A 915B
916A 916B
917A 917B
918A 918B
919A 919B
920A 920B
921A 921B
922A 922B
923A 923B
924A 924B
925A 925B
926A 926B
927A 927B
928A 928B
929A 929B
930A 930B
931A 931B
932A 932B
933A 933B
934A 934B
935A 935B
936A 936B
937A 937B

EXAMPLE TABLE 12
Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[2,6-dimethoxy-(4-
heteroaryl or 4-heterocylic)phenyl]-2-propen-1-ones.
Ex. No. R4β
938A 938B
939A 939B
940A 940B
941A 941B
942A 942B
943A 943B
944A 944B
945A 945B
946A 946B
947A 947B
948A 948B
949A 949B
950A 950B
951A 951B
952A 952B
953A 953B
954A 954B
955A 955B
956A 956B
957A 957B
958A 958B
959A 959B
960A 960B
961A 961B
962A 962B
963A 963B
964A 964B
965A 965B
966A 966B
967A 967B
968A 968B
969A 969B
970A 970B
971A 971B
972A 972B
973A 973B
974A 974B
975A 975B
976A 976B
977A 977B
978A 978B
979A 979B
980A 980B
981A 981B
982A 982B
983A 983B
984A 984B
985A 985B
986A 986B
987A 987B
988A 988B
989A 989B
990A 990B
991A 991B
992A 992B
993A 993B
994A 994B
995A 995B
996A 996B
997A 997B
998A 998B
999A 999B
1000A 1000B
1001A 1001B
1002A 1002B
1003A 1003B
1004A 1004B
1005A 1005B
1006A 1006B
1007A 1007B
1008A 1008B
1009A 1009B

EXAMPLE TABLE 13
Substituted 1-(1H-Indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or
heterocyclic)phenyl}-propen-2-ones.
Ex. No. R5β
1010A 1010B
1011A 1011B
1012A 1012B
1013A 1013B
1014A 1014B
1015A 1015B
1016A 1016B
1017A 1017B
1018A 1018B
1019A 1019B
1020A 1020B
1021A 1021B
1022A 1022B
1023A 1023B
1024A 1024B
1025A 1025B
1026A 1026B
1027A 1027B
1028A 1028B
1029A 1029B
1030A 1030B
1031A 1031B
1032A 1032B
1033A 1033B
1034A 1034B
1035A 1035B
1036A 1036B
1037A 1037B
1038A 1038B
1039A 1039B
1040A 1040B
1041A 1041B
1042A 1042B
1043A 1043B
1044A 1044B
1045A 1045B
1046A 1046B
1047A 1047B
1048A 1048B
1049A 1049B
1050A 1050B
1051A 1051B
1052A 1052B
1053A 1053B
1054A 1054B
1055A 1055B
1056A 1056B
1057A 1057B
1058A 1058B
1059A 1059B
1060A 1060B
1061A 1061B
1062A 1062B
1063A 1063B
1064A 1064B
1065A 1065B
1066A 1066B
1067A 1067B
1068A 1068B
1069A 1069B
1070A 1070B
1071A 1071B
1072A 1072B

EXAMPLE TABLE 14
Substituted 1-(1H-Indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or
heterocyclic)phenyl}-propen-2-ones.
Ex. No. R5β
1073A 1073B
1074A 1074B
1075A 1075B
1076A 1076B
1077A 1077B
1078A 1078B
1079A 1079B
1080A 1080B
1081A 1081B
1082A 1082B
1083A 1083B
1084A 1084B
1085A 1085B
1086A 1086B
1087A 1087B
1088A 1088B
1089A 1089B
1090A 1090B
1091A 1091B
1092A 1092B
1093A 1093B
1094A 1094B
1095A 1095B
1096A 1096B
1097A 1097B
1098A 1098B
1099A 1099B
1100A 1100B
1101A 1101B
1102A 1102B
1103A 1103B
1104A 1104B
1105A 1105B
1106A 1106B
1107A 1107B
1108A 1108B
1109A 1109B
1110A 1110B
1111A 1111B
1112A 1112B
1113A 1113B
1114A 1114B
1115A 1115B
1116A 1116B
1117A 1117B
1118A 1118B
1119A 1119B
1120A 1120B
1121A 1121B
1122A 1122B
1123A 1123B
1124A 1124B
1125A 1125B
1126A 1126B
1127A 1127B
1128A 1128B
1129A 1129B
1130A 1130B
1131A 1131B
1132A 1132B
1133A 1133B
1134A 1134B
1135A 1135B
1136A 1136B
1137A 1137B
1138A 1138B
1139A 1139B
1140A 1140B
1141A 1141B
1142A 1142B
1143A 1143B
1144A 1144B

EXAMPLE TABLE 15
Substituted 1-(1H-1-Methyl-indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or
heterocyclic)phenyl}-propen-2-ones.
Ex. No. R5β
1145A 1145B
1146A 1146B
1147A 1147B
1148A 1148B
1149A 1149B
1150A 1150B
1151A 1151B
1152A 1152B
1153A 1153B
1154A 1154B
1155A 1155B
1156A 1156B
1157A 1157B
1158A 1158B
1159A 1159B
1160A 1160B
1161A 1161B
1162A 1162B
1163A 1163B
1164A 1164B
1165A 1165B
1166A 1166B
1167A 1167B
1168A 1168B
1169A 1169B
1170A 1170B
1171A 1171B
1172A 1172B
1173A 1173B
1174A 1174B
1175A 1175B
1176A 1176B
1177A 1177B
1178A 1178B
1179A 1179B
1180A 1180B
1181A 1181B
1182A 1182B
1183A 1183B
1184A 1184B
1185A 1185B
1186A 1186B
1187A 1187B
1188A 1188B
1189A 1189B
1190A 1190B
1191A 1191B
1192A 1192B
1193A 1193B
1194A 1194B
1195A 1195B
1196A 1196B
1197A 1197B
1198A 1198B
1199A 1199B
1200A 1200B
1201A 1201B
1202A 1202B
1203A 1203B
1204A 1204B
1205A 1205B
1206A 1206B
1207A 1207B

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. R5β
1208A 1208B
1209A 1209B
1210A 1210B
1211A 1211B
1212A 1212B
1213A 1213B
1214A 1214B
1215A 1215B
1216A 1216B
1217A 1217B
1218A 1218B
1219A 1219B
1220A 1220B
1221A 1221B
1222A 1222B
1223A 1223B
1224A 1224B
1225A 1225B
1226A 1226B
1227A 1227B
1228A 1228B
1229A 1229B
1230A 1230B
1231A 1231B
1232A 1232B
1233A 1233B
1234A 1234B
1235A 1235B
1236A 1236B
1237A 1237B
1238A 1238B
1239A 1239B
1240A 1240B
1241A 1241B
1242A 1242B
1243A 1243B
1244A 1244B
1245A 1245B
1246A 1246B
1247A 1247B
1248A 1248B
1249A 1249B
1250A 1250B
1251A 1251B
1252A 1252B
1253A 1253B
1254A 1254B
1255A 1255B
1256A 1256B
1257A 1257B
1258A 1258B
1259A 1259B
1260A 1260B
1261A 1261B
1262A 1262B
1263A 1263B
1264A 1264B
1265A 1265B
1266A 1266B
1267A 1267B
1268A 1268B
1269A 1269B
1270A 1270B
1271A 1271B
1272A 1272B
1273A 1273B
1274A 1274B
1275A 1275B
1276A 1276B
1277A 1277B
1278A 1278B
1279A 1279B

EXAMPLE TABLE 17
Substituted 4-[3-{2-(Pyrrolidin-1-yl)-(4-heteroaryl or 4-heterocyclic)-
phenyl}-acryloyl]-benzoic Acids.
Ex. No. R4β
1280A 1280B
1281A 1281B
1282A 1282B
1283A 1283B
1284A 1284B
1285A 1285B
1286A 1286B
1287A 1287B
1288A 1288B
1289A 1289B
1290A 1290B
1291A 1291B
1292A 1292B
1293A 1293B
1294A 1294B
1295A 1295B
1296A 1296B
1297A 1297B
1298A 1298B
1299A 1299B
1300A 1300B
1301A 1301B
1302A 1302B
1303A 1303B
1304A 1304B
1305A 1305B
1306A 1306B
1307A 1307B
1308A 1308B
1309A 1309B
1310A 1310B
1311A 1311B
1312A 1312B
1313A 1313B
1314A 1314B
1315A 1315B
1316A 1316B
1317A 1317B
1318A 1318B
1319A 1319B
1320A 1320B
1321A 1321B
1322A 1322B
1323A 1323B
1324A 1324B
1325A 1325B
1326A 1326B
1327A 1327B
1328A 1328B
1329A 1329B
1330A 1330B
1331A 1331B
1332A 1332B
1333A 1333B
1334A 1334B
1335A 1335B
1336A 1336B
1337A 1337B
1338A 1338B
1339A 1339B
1340A 1340B
1341A 1341B
1342A 1342B
1343A 1343B
1344A 1344B
1345A 1345B
1346A 1346B
1347A 1347B
1348A 1348B
1349A 1349B
1350A 1350B
1351A 1351B

EXAMPLE TABLE 18
Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1352A 1352B
1353A 1353B
1354A 1354B
1355A 1355B
1356A 1356B
1357A 1357B
1358A 1358B
1359A 1359B
1360A 1360B
1361A 1361B
1362A 1362B
1363A 1363B
1364A 1364B
1365A 1365B
1366A 1366B
1367A 1367B
1368A 1368B
1369A 1369B
1370A 1370B
1371A 1371B
1372A 1372B
1373A 1373B
1374A 1374B
1375A 1375B
1376A 1376B
1377A 1377B
1378A 1378B
1379A 1379B
1380A 1380B
1381A 1381B
1382A 1382B
1383A 1383B
1384A 1384B
1385A 1385B
1386A 1386B
1387A 1387B
1388A 1388B
1389A 1389B
1390A 1390B
1391A 1391B
1392A 1392B
1393A 1393B
1394A 1394B
1395A 1395B
1396A 1396B
1397A 1397B
1398A 1398B
1399A 1399B
1360A 1360B
1401A 1401B
1402A 1402B
1403A 1403B
1404A 1404B
1405A 1405B
1406A 1406B
1407A 1407B
1408A 1408B
1409A 1409B
1410A 1410B
1411A 1411B
1412A 1412B
1413A 1413B
1414A 1414B

EXAMPLE TABLE 19
Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1415A 1415B
1416A 1416B
1417A 1417B
1418A 1418B
1419A 1419B
1420A 1420B
1421A 1421B
1422A 1422B
1423A 1423B
1424A 1424B
1425A 1425B
1426A 1426B
1427A 1427B
1428A 1428B
1429A 1429B
1430A 1430B
1431A 1431B
1432A 1432B
1433A 1433B
1434A 1434B
1435A 1435B
1436A 1436B
1437A 1437B
1438A 1438B
1439A 1439B
1440A 1440B
1441A 1441B
1442A 1442B
1443A 1443B
1444A 1444B
1445A 1445B
1446A 1446B
1447A 1447B
1448A 1448B
1449A 1449B
1450A 1450B
1451A 1451B
1452A 1452B
1453A 1453B
1454A 1454B
1455A 1455B
1456A 1456B
1457A 1457B
1458A 1458B
1459A 1459B
1460A 1460B
1461A 1461B
1462A 1462B
1463A 1463B
1464A 1464B
1465A 1465B
1466A 1466B
1467A 1467B
1468A 1468B
1469A 1469B
1470A 1470B
1471A 1471B
1473A 1473B
1474A 1474B
1475A 1475B
1476A 1476B
1477A 1477B
1478A 1478B
1479A 1479B
1480A 1480B
1481A 1481B
1482A 1482B
1483A 1483B
1484A 1484B
1485A 1485B
1486A 1486B
1487A 1487B

EXAMPLE TABLE 20
Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1488A 1488B
1489A 1489B
1490A 1490B
1491A 1491B
1492A 1492B
1493A 1493B
1494A 1494B
1495A 1495B
1496A 1496B
1497A 1497B
1498A 1498B
1499A 1499B
1500A 1500B
1501A 1501B
1502A 1502B
1503A 1503B
1504A 1504B
1505A 1505B
1506A 1506B
1507A 1507B
1508A 1508B
1509A 1509B
1510A 1510B
1511A 1511B
1512A 1512B
1513A 1513B
1514A 1514B
1515A 1515B
1516A 1516B
1517A 1517B
1518A 1518B
1519A 1519B
1520A 1520B
1521A 1521B
1522A 1522B
1523A 1523B
1524A 1524B
1525A 1525B
1526A 1526B
1527A 1527B
1528A 1528B
1529A 1529B
1530A 1530B
1531A 1531B
1532A 1532B
1533A 1533B
1534A 1534B
1535A 1535B
1536A 1536B
1537A 1537B
1538A 1538B
1539A 1539B
1540A 1540B
1541A 1541B
1542A 1542B
1543A 1543B
1544A 1544B
1545A 1545B
1546A 1546B
1547A 1547B
1548A 1548B
1549A 1549B
1550A 1550B

EXAMPLE TABLE 21
Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-
acryloyl]-5-methanesulfonylamino-benzoic Acids.
Ex. No. R5β
1551A 1551B
1552A 1552B
1553A 1553B
1554A 1554B
1555A 1555B
1556A 1556B
1557A 1557B
1558A 1558B
1559A 1559B
1560A 1560B
1561A 1561B
1562A 1562B
1563A 1563B
1564A 1564B
1565A 1565B
1566A 1566B
1567A 1567B
1568A 1568B
1569A 1569B
1570A 1570B
1571A 1571B
1572A 1572B
1573A 1573B
1574A 1574B
1575A 1575B
1576A 1576B
1577A 1577B
1578A 1578B
1579A 1579B
1580A 1580B
1581A 1581B
1582A 1582B
1583A 1583B
1584A 1584B
1585A 1585B
1586A 1586B
1587A 1587B
1588A 1588B
1589A 1589B
1590A 1590B
1591A 1591B
1592A 1592B
1593A 1593B
1594A 1594B
1595A 1595B
1596A 1596B
1597A 1597B
1598A 1598B
1599A 1599B
1600A 1600B
1601A 1601B
1602A 1602B
1603A 1603B
1604A 1604B
1605A 1605B
1606A 1606B
1607A 1607B
1608A 1608B
1609A 1609B
1610A 1610B
1611A 1611B
1612A 1612B
1613A 1613B
1614A 1614B
1615A 1615B
1616A 1616B
1617A 1617B
1618A 1618B
1619A 1619B
1620A 1620B
1621A 1621B
1622A 1622B

EXAMPLE TABLE 22
Substituted 5-Amino-2-[3-{(5-heteroaryl or 5-heterocyclic)-2,4-
dimethoxy-phenyl}-acryloyl]-benzoic Acids.
Ex. No. R5β
1623A 1623B
1624A 1624B
1625A 1625B
1626A 1626B
1627A 1627B
1628A 1628B
1629A 1629B
1630A 1630B
1631A 1631B
1632A 1632B
1633A 1633B
1634A 1634B
1635A 1635B
1636A 1636B
1637A 1637B
1638A 1638B
1639A 1639B
1640A 1640B
1641A 1641B
1642A 1642B
1643A 1643B
1644A 1644B
1645A 1645B
1646A 1646B
1647A 1647B
1648A 1648B
1649A 1649B
1650A 1650B
1651A 1651B
1652A 1652B
1653A 1653B
1654A 1654B
1655A 1655B
1656A 1656B
1657A 1657B
1658A 1658B
1659A 1659B
1660A 1660B
1661A 1661B
1662A 1662B
1663A 1663B
1664A 1664B
1665A 1665B
1666A 1666B
1667A 1667B
1668A 1668B
1669A 1669B
1670A 1670B
1671A 1671B
1672A 1672B
1673A 1673B
1674A 1674B
1675A 1675B
1676A 1676B
1677A 1677B
1678A 1678B
1679A 1679B
1680A 1680B
1681A 1681B
1682A 1682B
1683A 1683B
1684A 1684B
1685A 1685B

EXAMPLE TABLE 23
Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1686A 1686B
1687A 1687B
1688A 1688B
1689A 1689B
1690A 1690B
1691A 1691B
1692A 1692B
1693A 1693B
1694A 1694B
1695A 1695B
1696A 1696B
1697A 1697B
1698A 1698B
1699A 1699B
1700A 1700B
1701A 1701B
1702A 1702B
1703A 1703B
1704A 1704B
1705A 1705B
1706A 1706B
1707A 1707B
1708A 1708B
1709A 1709B
1710A 1710B
1711A 1711B
1712A 1712B
1713A 1713B
1714A 1714B
1715A 1715B
1716A 1716B
1717A 1717B
1718A 1718B
1719A 1719B
1720A 1720B
1721A 1721B
1722A 1722B
1723A 1723B
1724A 1724B
1725A 1725B
1726A 1726B
1727A 1727B
1728A 1728B
1729A 1729B
1730A 1730B
1731A 1731B
1732A 1732B
1733A 1733B
1734A 1734B
1735A 1735B
1736A 1736B
1737A 1737B
1738A 1738B
1739A 1739B
1740A 1740B
1741A 1741B
1742A 1742B
1743A 1743B
1744A 1744B
1745A 1745B
1746A 1746B
1747A 1747B
1748A 1748B
1749A 1749B
1750A 1750B
1751A 1751B
1752A 1752B
1753A 1753B
1754A 1754B
1755A 1755B
1756A 1756B
1757A 1757B

EXAMPLE TABLE 24
Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1758A 1758B
1759A 1759B
1760A 1760B
1761A 1761B
1762A 1762B
1763A 1763B
1764A 1764B
1765A 1765B
1766A 1766B
1767A 1767B
1768A 1768B
1769A 1769B
1770A 1770B
1771A 1771B
1772A 1772B
1773A 1773B
1774A 1774B
1775A 1775B
1776A 1776B
1777A 1777B
1778A 1778B
1779A 1779B
1780A 1780B
1781A 1781B
1782A 1782B
1783A 1783B
1784A 1784B
1785A 1785B
1786A 1786B
1787A 1787B
1788A 1788B
1789A 1789B
1790A 1790B
1791A 1791B
1792A 1792B
1793A 1793B
1794A 1794B
1795A 1795B
1796A 1796B
1797A 1797B
1798A 1798B
1799A 1799B
1800A 1800B
1801A 1801B
1802A 1802B
1803A 1803B
1804A 1804B
1805A 1805B
1806A 1806B
1807A 1807B
1808A 1808B
1809A 1809B
1810A 1810B
1811A 1811B
1812A 1812B
1813A 1813B
1814A 1814B
1815A 1815B
1816A 1816B
1817A 1817B
1818A 1818B
1819A 1819B
1820A 1820B

EXAMPLE TABLE 25
Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1821A 1821B
1822A 1822B
1823A 1823B
1824A 1824B
1825A 1825B
1826A 1826B
1827A 1827B
1828A 1828B
1829A 1829B
1830A 1830B
1831A 1831B
1832A 1832B
1833A 1833B
1834A 1834B
1835A 1835B
1836A 1836B
1837A 1837B
1838A 1838B
1839A 1839B
1840A 1840B
1841A 1841B
1842A 1842B
1843A 1843B
1844A 1844B
1845A 1845B
1846A 1846B
1847A 1847B
1848A 1848B
1849A 1849B
1850A 1850B
1851A 1851B
1852A 1852B
1853A 1853B
1854A 1854B
1855A 1855B
1856A 1856B
1857A 1857B
1858A 1858B
1859A 1859B
1860A 1860B
1861A 1861B
1862A 1862B
1863A 1863B
1864A 1864B
1865A 1865B
1866A 1866B
1867A 1867B
1868A 1868B
1869A 1869B
1870A 1870B
1871A 1871B
1872A 1872B
1873A 1873B
1874A 1874B
1875A 1875B
1876A 1876B
1877A 1877B
1878A 1878B
1879A 1879B
1880A 1880B
1881A 1881B
1882A 1882B
1883A 1883B
1884A 1884B
1885A 1885B
1886A 1886B
1887A 1887B
1888A 1888B
1889A 1889B
1890A 1890B
1891A 1891B
1892A 1892B

EXAMPLE TABLE 26
Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-4-fluorophenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
1893A 1893B
1894A 1894B
1895A 1895B
1896A 1896B
1897A 1897B
1898A 1898B
1899A 1899B
1900A 1900B
1901A 1901B
1902A 1902B
1903A 1903B
1904A 1904B
1905A 1905B
1906A 1906B
1907A 1907B
1908A 1908B
1909A 1909B
1910A 1910B
1911A 1911B
1912A 1912B
1913A 1913B
1914A 1914B
1915A 1915B
1916A 1916B
1917A 1917B
1918A 1918B
1919A 1919B
1920A 1920B
1921A 1921B
1922A 1922B
1923A 1923B
1924A 1924B
1925A 1925B
1926A 1926B
1927A 1927B
1928A 1928B
1929A 1929B
1930A 1930B
1931A 1931B
1932A 1932B
1933A 1933B
1934A 1934B
1935A 1935B
1936A 1936B
1937A 1937B
1938A 1938B
1939A 1939B
1940A 1940B
1941A 1941B
1942A 1942B
1943A 1943B
1944A 1944B
1945A 1945B
1946A 1946B
1947A 1947B
1948A 1948B
1949A 1949B
1950A 1950B
1951A 1951B
1952A 1952B
1953A 1953B
1954A 1954B
1955A 1955B

EXAMPLE TABLE 27
Substituted 4-[3-{(3-Heteroaryl or 3-heterocyclic)-4-(pyrrolidin-1-yl)-
phenyl}acryloyl]-benzoic Acids.
Ex. No. R5β
1956A 1956B
1957A 1957B
1958A 1958B
1959A 1959B
1960A 1960B
1961A 1961B
1962A 1962B
1963A 1963B
1964A 1964B
1965A 1965B
1966A 1966B
1967A 1967B
1968A 1968B
1969A 1969B
1970A 1970B
1971A 1971B
1972A 1972B
1973A 1973B
1974A 1974B
1975A 1975B
1976A 1976B
1977A 1977B
1978A 1978B
1979A 1979B
1980A 1980B
1981A 1981B
1982A 1982B
1983A 1983B
1984A 1984B
1985A 1985B
1986A 1986B
1987A 1987B
1988A 1988B
1989A 1989B
1990A 1990B
1991A 1991B
1992A 1992B
1993A 1993B
1994A 1994B
1995A 1995B
1996A 1996B
1997A 1997B
1998A 1998B
1999A 1999B
2000A 2000B
2001A 2001B
2002A 2002B
2003A 2003B
2004A 2004B
2005A 2005B
2006A 2006B
2007A 2007B
2008A 2008B
2009A 2009B
2010A 2010B
2011A 2011B
2012A 2012B
2013A 2013B
2014A 2014B
2015A 2015B
2016A 2016B
2017A 2017B
2018A 2018B
2019A 2019B
2020A 2020B
2021A 2021B
2022A 2022B
2023A 2023B
2024A 2024B
2025A 2025B
2026A 2026B
2027A 2027B

EXAMPLE TABLE 28
Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-
acryloyl]benzonitriles.
Ex. No. R5β
2028A 2028B
2029A 2029B
2030A 2030B
2031A 2031B
2032A 2032B
2033A 2033B
2034A 2034B
2035A 2035B
2036A 2036B
2037A 2037B
2038A 2038B
2039A 2039B
2040A 2040B
2041A 2041B
2042A 2042B
2043A 2043B
2044A 2044B
2045A 2045B
2046A 2046B
2047A 2047B
2048A 2048B
2049A 2049B
2050A 2050B
2051A 2051B
2052A 2052B
2053A 2053B
2054A 2054B
2055A 2055B
2056A 2056B
2057A 2057B
2058A 2058B
2059A 2059B
2060A 2060B
2061A 2061B
2062A 2062B
2063A 2063B
2064A 2064B
2065A 2065B
2066A 2066B
2067A 2067B
2068A 2068B
2069A 2069B
2070A 2070B
2071A 2071B
2072A 2072B
2073A 2073B
2074A 2074B
2075A 2075B
2076A 2076B
2077A 2077B
2078A 2078B
2079A 2079B
2080A 2080B
2081A 2081B
2082A 2082B
2083A 2083B
2084A 2084B
2085A 2085B
2086A 2086B
2087A 2087B
2088A 2088B
2089A 2089B
2090A 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. R5β
2091A 2091B
2092A 2092B
2093A 2093B
2094A 2094B
2095A 2095B
2096A 2096B
2097A 2097B
2098A 2098B
2099A 2099B
2100A 2100B
2101A 2101B
2102A 2102B
2103A 2103B
2104A 2104B
2105A 2105B
2106A 2106B
2107A 2107B
2108A 2108B
2109A 2109B
2110A 2110B
2111A 2111B
2112A 2112B
2113A 2113B
2114A 2114B
2115A 2115B
2116A 2116B
2117A 2117B
2118A 2118B
2119A 2119B
2120A 2120B
2121A 2121B
2122A 2122B
2123A 2123B
2124A 2124B
2125A 2125B
2126A 2126B
2127A 2127B
2128A 2128B
2129A 2129B
2130A 2130B
2131A 2131B
2132A 2132B
2133A 2133B
2134A 2134B
2135A 2135B
2136A 2136B
2137A 2137B
2138A 2138B
2139A 2139B
2140A 2140B
2141A 2141B
2142A 2142B
2143A 2143B
2144A 2144B
2145A 2145B
2146A 2146B
2147A 2147B
2148A 2148B
2149A 2149B
2150A 2150B
2151A 2151B
2152A 2152B
2153A 2153B
2154A 2154B
2155A 2155B
2156A 2156B
2157A 2157B
2158A 2158B
2159A 2159B
2160A 2160B
2161A 2161B
2162A 2162B

EXAMPLE TABLE 30
Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)phenyl}-acryloyl]-
benzoic Acids.
Ex. No. R4β
2163A 2163B
2164A 2164B
2165A 2165B
2166A 2166B
2167A 2167B
2168A 2168B
2169A 2169B
2170A 2170B
2171A 2171B
2172A 2172B
2173A 2173B
2174A 2174B
2175A 2175B
2176A 2176B
2177A 2177B
2178A 2178B
2179A 2179B
2180A 2180B
2181A 2181B
2182A 2182B
2183A 2183B
2184A 2184B
2185A 2185B
2186A 2186B
2187A 2187B
2188A 2188B
2189A 2189B
2190A 2190B
2191A 2191B
2192A 2192B
2193A 2193B
2194A 2194B
2195A 2195B
2196A 2196B
2197A 2197B
2198A 2198B
2199A 2199B
2200A 2200B
2201A 2201B
2202A 2202B
2203A 2203B
2204A 2204B
2205A 2205B
2206A 2206B
2207A 2207B
2208A 2208B
2209A 2209B
2210A 2210B
2211A 2211B
2212A 2212B
2213A 2213B
2214A 2214B
2215A 2215B
2216A 2216B
2217A 2217B
2218A 2218B
2219A 2219B
2220A 2220B
2221A 2221B
2222A 2222B
2223A 2223B
2224A 2224B
2225A 2225B

EXAMPLE TABLE 31
Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)phenyl}-3-oxo-
propenyl]-benzoic Acids.
Ex. No. R4α
2226A 2226B
2227A 2227B
2228A 2228B
2229A 2229B
2230A 2230B
2231A 2231B
2232A 2232B
2233A 2233B
2234A 2234B
2235A 2235B
2236A 2236B
2237A 2237B
2238A 2238B
2239A 2239B
2240A 2240B
2241A 2241B
2242A 2242B
2243A 2243B
2244A 2244B
2245A 2245B
2246A 2246B
2247A 2247B
2248A 2248B
2249A 2249B
2250A 2250B
2251A 2251B
2252A 2252B
2253A 2253B
2254A 2254B
2255A 2255B
2256A 2256B
2257A 2257B
2258A 2258B
2259A 2259B
2260A 2260B
2261A 2261B
2262A 2262B
2263A 2263B
2264A 2264B
2265A 2265B
2266A 2266B
2267A 2267B
2268A 2268B
2269A 2269B
2270A 2270B
2271A 2271B
2272A 2272B
2273A 2273B
2274A 2274B
2275A 2275B
2276A 2276B
2277A 2277B
2278A 2278B
2279A 2279B
2280A 2280B
2281A 2281B
2282A 2282B
2283A 2283B
2284A 2284B
2285A 2285B
2286A 2286B
2287A 2287B
2288A 2288B
2289A 2289B
2290A 2290B
2291A 2291B
2292A 2292B
2293A 2293B
2294A 2294B
2295A 2295B
2296A 2296B
2297A 2297B

EXAMPLE TABLE 32
Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)-2,6-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R4β
2298A 2298B
2299A 2299B
2300A 2300B
2301A 2301B
2302A 2302B
2303A 2303B
2304A 2304B
2305A 2305B
2306A 2306B
2307A 2307B
2308A 2308B
2309A 2309B
2310A 2310B
2311A 2311B
2312A 2312B
2313A 2313B
2314A 2314B
2315A 2315B
2316A 2316B
2317A 2317B
2318A 2318B
2319A 2319B
2320A 2320B
2321A 2321B
2322A 2322B
2323A 2323B
2324A 2324B
2325A 2325B
2326A 2326B
2327A 2327B
2328A 2328B
2329A 2329B
2330A 2330B
2331A 2331B
2332A 2332B
2333A 2333B
2334A 2334B
2335A 2335B
2336A 2336B
2337A 2337B
2338A 2338B
2339A 2339B
2340A 2340B
2341A 2341B
2342A 2342B
2343A 2343B
2344A 2344B
2345A 2345B
2346A 2346B
2347A 2347B
2348A 2348B
2349A 2349B
2350A 2350B
2351A 2351B
2352A 2352B
2353A 2353B
2354A 2354B
2355A 2355B
2356A 2356B
2357A 2357B
2358A 2358B
2359A 2359B
2360A 2360B

EXAMPLE TABLE 33
Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-
acryloyl]-benzoic Acids.
Ex. No. R5β
2361A 2361B
2362A 2362B
2363A 2363B
2364A 2364B
2365A 2365B
2366A 2366B
2367A 2367B
2368A 2368B
2369A 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 chromatopraphy—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 “pharmaceutically 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, α-ketoglutarate and α-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 ad 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, aspartate, 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 hydroxylamines 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 1-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 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-i (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-1, 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 C₁ 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 (nedocromiil, nedocromil sodium) and ketotifen.

In another embodiment, the active compound is administered in combination or alternation with one or more other O₂-adrenergic agonist(s) (p agonists). Examples of β₂-adrenergic agonists (β 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), Tomalate (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, terbutatine 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, Prednisb lone 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) (H₁ receptor antagonists). Examples of antihistimines (H₁ 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 (diphenhydramine), Tavist (clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ (tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine), bydroxyzine, Antivert (meclizine, Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin (loratadine), Seldane (terfenadine), Periactin (cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth (romethazine, 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, TNFα receptor antagonists, TNFα 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, Chloithenoxazin, 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, Lomoxicam, Loxoprofen Sodium, Lysine Aspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid, Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate, Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, Morazone Hydrochloride, Momiflurnate, 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 Maleate, 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 Ser. 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 Ser. 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 Oct. 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. Pat. 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. Pat. 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. Pat. 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 EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (TBS).

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 Pharmaceuticals, 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. Pat. 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-α (1 ng/ml) in the presence or absence of compounds dissolved in DMSO. To establish a dose curve an IC₅₀, multiple concentrations in 2- to 5-fold increments were used. Cells were exposed to TNF-α and compounds for approximately 16 hours. The next day the cells were visually examined via light microscopy to score for visual signs of toxicity. 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 IC₅₀ values of >10(the amount of compound (μM) required to achieve a 50% reduction compared to control (cells stimulated with TNF-α 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-α (1 ng/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-α 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 16 hr exposure to TNF-α 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 (0.251 g/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 450 nm. The results are expressed as IC₅₀ values (the concentration (micromolar) of compound required to inhibit 50% of the maximal response of the control sample stimulated by TNF-α only). Compounds exhibiting IC₅₀'s of less than 5 micromolar are tabulated in Biological Table 1.

Biological Table 1
        VCAM-1
Example IC50
Number  (μM)
1       <1
2       <5
3       <1
4       <10
5       <1
6       <1
7       <1
8       <1
9       <5
10      <5
11      <5
12      <5
13      <5
14      <1
15      >10
16      <5
17      <5
18      <5
19      <1
20      >10
21      <5
22      >10
23      <1
24      >10
25      >10
26      >10
27      <5
28      <5
29      <1
30      <1
31      >10
32      <5
33      <5
34      >10
35      >10
36      <5
37      >10
38      <10
39      >10
40      <1
41      <5
42      <5
43      <5
44      <1
45      <5
46      <10
47      >10
48      <10
49      <10
50      >10
51      <5
52      >10
53      <5
54      <10
55      <5
56      <1
57      <5
58      >10
59      NE
60      <1
61      <1
62      <5
63      <10
64      >10
65      <1
66      <1
67      <10
68      <5
69      <5
70      <5
71      NE
72      0
73      0
74      >10
75      >10
76      >10
77      <5
78      <10
79      <1
80      <5
81      <1
82      NE
83      <1
84      <5
85      <1
86      <5
87      <1
88
89      NE
90      <1
91      <5
92      <1
93      <1
94      <1
95      <1
96      <5
97      NE
98      <5
99      >10
100     >10
101     >10
102     >10
103     >10
104     NE
105     NE
106     <10
107     NE
108     <10
109     NE
110     >10
111     >10
112     NE
113     <5
114     <5
115     <5
116
117     <5
118     <10
119
120     <1

Rheumatoid Arthritis Protocol

Male Lewis rats (150-175 g) 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 μL 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 (d1-14), 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 CO₂, 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, d1-14
3                96
6                77
29               82
60               62*
*75 mg/kg/day, sq, bid, d1-14

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, cremdphor RH 40, tween 80, PEG 300). See Biological Table 3

Biological Table 3
                        % Inhibition sc, daily
                        dosing at 100 mg/kg
Compound Example Number 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 (100 mg/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, Tex. or PharMingen, San Diego, Calif.) 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 450 nm and the amounts of IgE were calculated according to the standard curve. The limit of detection in our experiments was 7 ng/ml. Compound 3 administrated at 100 mg/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, IL-4, 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 (100 mg/kg/d, from day 0 to day 14). Total RNA samples were isolated by the Trizol method: (Life Technologies, Grand Island, N.Y.) 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, Calif.). The initial amounts of mRNA of each samples were quantitatively determined by running a SYBR Green (Qiagen, Valencia, Calif.) 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, Iowa) and control primers for GAPDH in iCycler IQ Optical System (Hercules, Calif.). 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 100 mg/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			Annealing
Name	Forward Sequence	Reverse Sequence	Temperature
GAPDH	CTA CCC CCA ATG	CTG CTT CAC CAC	52.2
	TGT CC	CTT CTT
IL-13	AAF AFF AGA GCA	CTG TGT AAC CTT	51.3
	AAT GAA AG	CCC AAC A
IL-4	TGA ATG AGT CCA	AGC ATG GTG GCT	51.2
	AGT CCA	CAG TA
IL5	AGC TCT GTT GAC	CCC TGA AAG ATT	52.4
	AAG CAA T	TCT CCA ATG
IL-2	GTC GAC TTT CTG	ATG TGT TGT AAG	53.2
	AGG AGA TG	CAG GAG GT
IFN-γ	TTC TGT CTC CTC	CAA TCA CAG TCT	51.3
	AAC TAT TTC T	TGG CTA AT

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 IC₅₀ for each compound, multiple concentrations in the range of 20 to 0.05 μM were used. Rapamycin (at 1 and 0.1 μM) was used as a positive control for the assay. After a 20 hour incubation with or without test compounds, 3H-thymidine (0.5 μCi/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, Wis.). Compound 3 had an IC₅₀ of 0.5 μM.

Effect of Test Compounds on LPS-Stimulated IL-1β

Human peripheral blood mononuclear cells were treated with or without Compound 3 for 1 hour, then stimulated with LPS (1-2 μg/ml) for 3 hours. Condition media was collected and IL-1β measured using an ELISA kit. Compound 3 demonstrated a dose dependent inhibition of LPS-stimulated IL-1β secretion. See Biological Table 4

Biological Table 4
Amount of Compound 3
(μM) Percent IL-1β Secreted
1.25 >40
2.5  >10
5    >5
10   >1

Reduction of Plasma TNF-α 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 2 hr later. Blood was collected for plasma TNF-α 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, 2 hr prior to LPS injection, inhibited TNF-α 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.

Claims

1. A compound of Formula I or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(R1)2C(O)OH, —OC(R1)2C(O)OR2, —OC(R1)2C(O)NH2, —OC(R1)2C(O)NHR2, —OC(R1)2C(O)N(R1)2, —OC(R1)2C(O)NR7 R8, 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, —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)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)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;

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)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 R2β, R3β, R4β, R5β or R6β, or one of R2α, R3α, R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl;

wherein when one of R2β, R3β, R4β, R5β or R6β is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2α, R3α, R4α, R5α or R6α can be —OCH3;

wherein when one of R2α, R3α, R4α, R5α or R6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2β, R3β, R4β, R5β or R6β can be —OCH3;

with the proviso that R2α and R3α, taken together or R3α and R4α, taken together or R4α and R5α taken together, or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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

R2α and R3α taken together or R3α and R4α, taken together or R4α and R5α taken together or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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 R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β cannot be —OC(R1)2C(O)OH; or

at least one of R2α, R3α, R4α, R5α, R6α or one of R2β, R3β, R4β, R5β, R6β 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(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, —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(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 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 —(O)N(R2)2.

2. The compound of claim 1 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(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, —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, —PO3H2, —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;

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(R1)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 R2β, R3β, R4β, R5β or R62, or one of R2α, R3α, R4α, R5α or R6α must be a carbon-carbon linked heterocyclic or heteroaryl;

wherein when one of R2β, R3β, R4β, R5β or R6β is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2α, R3α, R4α, R5α or R6α can be —OCH3;

wherein when one of R2α, R3α, R4α, R5α or R6α is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2β, R3β, R4β, R5β or R6β can be —OCH3;

with the proviso that R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together, or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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

R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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(R1)2; provided that R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β cannot be —OC(R1)2C(O)OH; and

at least one of R2α R3α, R4α, or one of R2β, R3β, R4β 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(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—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(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, —NR2 SO2R2, —NHC(O)NHR2, —NHC(O)NR7R8, and —NHC(O)N(R2)2;

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.

3. The compound of claim 1 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(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, —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, —PO3H2, —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;

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)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 R2β, R3β, R4β, R5β or R6β 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 R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together, or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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

R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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 R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β cannot be —OC(R1)2C(O)OH; and

with the proviso that 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)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, —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(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 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.

4. The compound of claim 3 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(R1)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, —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)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)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;

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)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 R4β, R5β or R6β 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 R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together, or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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

R2α and R3α taken together of R3α and R4α taken together or R4α and R5α taken together or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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 R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R6β and R6β cannot be —OC(R1)2C(O)OH; and

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(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(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, —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(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 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.

5. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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, —NR2 SO2R2, —NHC(O)NHR7, —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, —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)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)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;

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(R1)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 R4β, R5β or R6β 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(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(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, —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(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 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.

6. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(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, —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(R1)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, —PO3H2, —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;

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)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 R4β, R5β or R6β 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 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.

7. The compound of claim 6 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(R1)2C(O)OH, —OC(R1)2C(O)OR2, —OC(R1)2C(O)NH2, —OC(R1)2C(O)NHR2, —OC(R1)2C(O)N(R1)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, —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;

R1 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 R4β, R5β or R6β 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 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 —(O)N(R2)2.

8. The compound of claim 7 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(R2)2, SO2NR7R8, —SO2NHC(O)R2, —SR2, —SO2NHC(O)NHR2, —SO2NHC(O)N(R1)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, —C(O)NR7R8, and —C(O)N(R2)2;

R1 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 R4β, R5β or R6β 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 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.

9. The compound of claim 8 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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)OR, —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 R4β, R5β or R6β 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 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 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.

10. The compound of claim 9 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α R2β, R3β, R4β, R5β and R6β 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—O-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(R1)2;

R7 and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic or benzofused ring;

wherein one of R4β, R5β or R6β 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 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.

11. The compound of claim 10 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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 R4β, R5β or R6β 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 carboxy.

12. The compound of claim 11 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;

R2β, R3β, R4β, R5β and R6β 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)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 R4β, R5β or R6β must be a carbon-carbon linked heterocyclic or heteroaryl;

with the proviso that at least one of R2α, R3α, or R4α must be carboxy.

13. The compound of claim 12 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;

R2β, R3β, R4β, R5β and R6β 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 R4β, R5β or R6β must be a carbon-carbon linked heteroaryl;

with the proviso that at least one of R2α, R3α, or R4α must be carboxy.

14. The compound of claim 13 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;

R2β, R3β, R4β, R5β and R6β are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH3O(CH2)2O(CH2)2—,

and

wherein one of R4β, R5β or R6β must be selected from the group consisting of thiophen-2-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 R2α, R3α, or R4α must be carboxy.

15. The compound of claim 14 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5, and R6α are independently selected from the group consisting of hydrogen and carboxy;

R2β, R3β, R4β, R5β and R6β are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, and CH3O(CH2)2O(CH2)2;

wherein one of R4β, R5β or R6β must be selected from the group consisting of thiophen-2-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 R4α must be carboxy.

16. The compound of claim 15 selected from the group consisting of:

4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;

4-[3E-(4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;

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-yl)-phenyl}-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;

4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-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-phenyl}-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;

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

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;

4-{3E-[4-(1-Carboxy-1-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-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid;

4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

5-{5-[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]-benzoic acid;

4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic 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;

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]-benzoic acid;

4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-S-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;

2 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-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-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;

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)-acryloyl]-benzoic acid;

4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;

4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid, hydrochloride;

4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid;

4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid;

4-{3E-[5-(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-methyl-propionic acid;

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride;

4-{3E-[5-(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]-acryloyl}-benzoic acid; and

4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid ethyl ester, or its pharmaceutically acceptable salt or ester.

17. The compound of claim 16 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.

18. The compound of claim 17 wherein the compound is 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid or its pharmaceutically acceptable salt or ester.

19. The compound of claim 17 wherein the compound is 4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid, or its pharmaceutically acceptable salt or ester.

20. The compound of claim 17 wherein the compound 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.

21. The compound of claim 17 wherein the compound 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.

22. The compound of claim 5 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;

R2β, R3β, R4β, R5β and R6β 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)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 R4β, R5β or R6β must be a carbon-carbon linked heterocyclic;

with the proviso that at least one of R2α, R3α, or R4α must be carboxy.

23. The compound of claim 22 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;

R2β, R3β, R4β, R5β and R6β are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH3O(CH2)2O(CH2)2—,

and

wherein one of R4β, R5β or R6β must be a carbon-carbon linked tetrahydrofuran-2-yl or dihydrofuran-2-yl;

with the proviso that at least one of R2α, R3α, or R4α must be carboxy.

24. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(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, —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, —PO3H2, —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;

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)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 R4β, R5β or R6β 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 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.

25. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(R1)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, —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)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)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;

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)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 R4β, R5β or R6β 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 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, —SO2NHC(O)NR7R8;

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.

26. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(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, —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, —PO3H2, —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;

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)NR7R8, and —C(O)N(R1)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 R4β, R5β or R6β 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 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 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.

27. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(R1)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, —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)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)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;

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)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 R4β, R5β or R6β 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(R1)2C(O)NHR2, —OC(R1)2C(O)N(R2)2, —OC(R1)2C(O)NR7R8;

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.

28. The compound of claim 3 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(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, —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(R1)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, —PO3H2, —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;

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)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 R4β, R5β or R6β 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 R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together, or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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

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(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(R1)2C(O)OH, —SC(R1)2C(O)OR2, —SCH2C(O)OH, —SCF2C(O)OH, —SO2NH2, —SO2NHR2, —SO2N(R2)2, SO2NR7R8, —SO2NHC(O)R2)2, —SR2, —SO2NHC(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(R2)2C(O)N(R2)2, —OC(R1)2C(O)NR7R8, amino, —NHR2, N(R2)2, NR7R8, —NHC(R2)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 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.

29. The compound of claim 3 or its pharmaceutically acceptable salt or ester, wherein:

R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β 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(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(R2)2C(O)OR, —NHC(O)R2)2, —N(R1)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, —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)NR78R2, —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, —PO3H2, —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;

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)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 R4β, R5β or R6β 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 R2α and R3α taken together or R3α and R4α taken together or R4α and R5α taken together or R2β and R3β taken together or R3β and R4β taken together or R4β and R5β 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 R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β cannot be —OC(R1)2C(O)OH; and

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(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(R1)2C(O)OH, —SC(R1)2C(O)OR2, —SCH2C(O)OH, —SCF2C(O)OH, —SO2NH2, —SO2NHR2, —SO2N(R1)2, SO2NR7R8, —SO2NHC(O)R2, —SR2, —SO2NHC(O)NHR2, —SO2NHC(O)N(R1)2, —SO2NHC(O)NR7R8, —OC(R1)2C(O)OH, —OC(R1)2C(O)OR2, —OC(R1)2C(O)NH2, —OC(R2)2C(O)NHR2, —OC(R1)2C(O)N(R2)2, —OC(R1)2C(O)NR7R8, amino, —NHR2, N(R2)2, NR7R8, —NHC(R2)2C(O)OH, —NHC(R1)2C(O)OR, —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 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(R1)2.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with one or more pharmaceutically acceptable carrier.

31. A method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of claim 1.

32. The method of claim 31, wherein the disorder is arthritis.

33. The method of claim 31, wherein the disorder is rheumatoid arthritis.

34. The method of claim 31, wherein the disorder is asthma.

35. The method of claim 31, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.

36. The method of claim 31, wherein the disorder is allergic rhinitis.

37. The method of claim 31, wherein the disorder is chronic obstructive pulmonary disease.

38. The method of claim 31, wherein the disorder is atherosclerosis.

39. The method of claim 31, wherein the disorder is restinosis.

40. A method for inhibiting the expression of VCAM-1, comprising administering an effective amount of a compound of claim 1.