Chalcone derivatives and their use to treat diseases

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:
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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 CysLT₁receptor antagonists.

JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the following formula (wherein R¹and R²are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can be used in treating allergies.
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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-R⁵are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R¹-R⁵are hydrogen.
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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:
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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)—, R⁶is a lower alkyl group or a lower alkoxyalkyl group, —O— or —S—; W represents —CH═CH— or —CH₂O—, and R_1-5is 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 —CONHR₇in which R₇represents a hydrogen atom or a lower alkyl group, or a group —O(CH₂)_nR₈in which R₈represents a carboxyl, alkyloxycarbonyl or tetrazolyl group and n is from 1 to 4, with the proviso that at least one of the groups R_1-5represents a carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, the group —CONHR₇or the group —O(CH₂)nR₈; or a salt or solvate thereof.
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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
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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
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or its pharmaceutically acceptable salt or ester, wherein:

R^2α, R^3α, R^4α, R^{5α, R}^6α, R^2β, R^3α, 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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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^ndembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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

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;

In a 3^rdembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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 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;

In a 4th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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

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;

In a 5th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

In a 6th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

In a 7th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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;

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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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;

In a 9^thembodiment, 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;

R²is 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R²is 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R²is lower alkyl;

R⁷and R⁸are 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;

R²is lower alkyl;

R⁷and R⁸are 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);

R²is lower alkyl;

R⁷and R⁸are 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—,
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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^thembodiment, 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^thembodiment, 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^thembodiment, 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^thembodiment, 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^ndembodiment, 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;

R²is lower alkyl;

R⁷and R⁸are 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;

R²is lower alkyl;

R⁷and R⁸are 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;

R⁷and R⁸are 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;

In a 25th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R¹is 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;

R⁷and R⁸are 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;

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;

R¹is 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;

R⁷and R⁸are 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;

In a 27th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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^thembodiment, 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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R¹is hydrogen;

R²is lower alkyl;

R⁷and R⁸are 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, R⁷and R⁸substituents 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^stembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

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

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;

R⁷and R⁹are 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 R⁴must 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;

In a 33^rdembodiment, 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;

R¹is 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;

R⁷and R⁸are 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;

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

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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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^thembodiment, 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;

R¹is hydrogen;

R²is lower;

R⁷and R⁸are 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^thembodiment, 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:

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

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;

R⁷and R⁸are 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;

In a 39^thembodiment, 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;

R²is lower alkyl optionally substituted by alkoxycarbonyl.

R⁷and R⁸are 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, NR²SO₂R²and —NR²SO₂R²;

wherein all R², R⁷and R⁸substituents 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:

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;

R⁷and R⁸are 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;

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;

R¹is 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;

R²is 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;

R⁷and R⁸are 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;

In a 42^ndembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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 R⁴and 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, R⁷and R⁸substituents 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^ndembodiment, 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;

R²is independently alkyl or lower alkyl;

R⁷and R⁸are 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^thembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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

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,

In a 45^thembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R²is independently alkyl or lower alkyl;

R⁷and R⁸are 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;

R⁷and R⁸are 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;

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;

R⁷and R⁸are 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;

In a 48th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

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;

In a 49th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

In a 50th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

In a 51st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R¹is 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;

R⁷and R⁸are 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;

In an 52^ndembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R⁷and R⁸are 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;

In a 53^rdembodiment, 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;

R⁷and R⁸are 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;

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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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,

R²is lower alkyl;

R⁷and R⁸are 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;

R²is lower alkyl;

R⁷and R⁸are 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;

R²is lower alkyl;

R⁷and R⁸are 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—,
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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;

R²is lower alkyl;

R⁷and R⁸are 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;

R²is lower alkyl;

R⁷and R⁸are 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:

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;

R⁷and R⁸are 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;

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

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;

R⁷and R⁸are 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;

In a 63^rdembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R¹is 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;

R⁷and R⁸are 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;

In a 64th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R⁷and R⁸are 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;

In a 65^thembodiment, 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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R¹is hydrogen;

R²is lower alkyl;

R⁷and R⁸are 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, R⁷and R⁸substituents 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:

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;

R⁷and R⁸are 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;

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

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;

R⁷and R⁸are 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;

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

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;

R⁷and R⁸are 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;

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;

R⁷and R⁸are 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;

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;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R¹is hydrogen;

R²is lower;

R⁷and R⁸are 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:

hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl,

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,

R⁷and R⁸are 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;

In a 74^thembodiment, 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;

R²is lower alkyl optionally substituted by alkoxycarbonyl.

R⁷and R⁸are 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, NR²SO₂R²and —NR²SO₂R²;

In a 75th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

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;

R¹is 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, —NR⁷R⁸alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —C(O)NR⁷R⁸, and —C(O)N(R²)₂;

R⁷and R⁸are 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, R⁷and R⁸substituents 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;

R⁷and R⁸are 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;

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

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;

R⁷and R⁸are 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

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;

In a 78th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R²is independently alkyl or lower alkyl;

R⁷and R⁸are 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^thembodiment, 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;

R⁷and R⁸are 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

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,

In a 80^thembodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R²is independently alkyl or lower alkyl;

R⁷and R⁸are 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^stembodiment, 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^ndembodiment 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 “ custom character ”, 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 CF₃and 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 CF₃and 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 CF₃and 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 —NH₂or —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^thEdition (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.
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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

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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

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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

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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 N₂affording 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

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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

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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

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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

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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

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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

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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

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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

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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 H₂SO₄to 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

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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

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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

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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/CH₂Cl₂with 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

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{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

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(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

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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

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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

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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

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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

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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

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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

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{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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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 POCl₃in 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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=^7.2Hz, 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

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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

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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

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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

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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

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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

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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

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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 CH₂Cl₂was 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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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% H₂O₂and 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

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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

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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

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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

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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

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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

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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

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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

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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 1Substituted 4-[3-{2-Isopropoxy-4-methoxy-(5-heteroaryl or 5-heterocyclic)phenyl}-acryloyl]-benzoic Acids. embedded image

Ex. No.R^5β200A 200B embedded image

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.

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Ex. No.
R^5β

263A 263B

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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.

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Ex. No.
R^5β

335A 335B

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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.

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Ex. No.
R^5β

398A 398B

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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.

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Ex. No.
R^5β

470A 470B

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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.

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Ex. No.
R^5β

533A 533B

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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.

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Ex. No.
R^5β

605A 605B

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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.

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Ex. No.
R^5β

668A 668B

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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.

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Ex. No.
R^5β

740A 740B

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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.

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Ex. No.
R^5β

803A 803B

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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.

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Ex. No.
R^4β

875A 875B

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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.

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Ex. No.
R^4β

938A 938B

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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

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1001A 1001B

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1002A 1002B

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1003A 1003B

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1004A 1004B

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1005A 1005B

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1006A 1006B

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1007A 1007B

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1008A 1008B

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1009A 1009B

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EXAMPLE TABLE 13

Substituted 1-(1H-Indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or

heterocyclic)phenyl}-propen-2-ones.

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Ex. No.
R^5β

1010A 1010B

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1011A 1011B

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1012A 1012B

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1013A 1013B

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1014A 1014B

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1015A 1015B

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1016A 1016B

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1017A 1017B

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1018A 1018B

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1019A 1019B

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1020A 1020B

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1021A 1021B

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1022A 1022B

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1023A 1023B

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1024A 1024B

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1025A 1025B

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1026A 1026B

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1027A 1027B

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1028A 1028B

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1029A 1029B

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1030A 1030B

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1031A 1031B

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1032A 1032B

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1033A 1033B

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1034A 1034B

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1035A 1035B

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1036A 1036B

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1037A 1037B

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1038A 1038B

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1039A 1039B

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1040A 1040B

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1041A 1041B

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1042A 1042B

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1043A 1043B

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1044A 1044B

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1045A 1045B

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1046A 1046B

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1047A 1047B

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1048A 1048B

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1049A 1049B

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1050A 1050B

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1051A 1051B

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1052A 1052B

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1053A 1053B

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1054A 1054B

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1055A 1055B

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1056A 1056B

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1057A 1057B

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1058A 1058B

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1059A 1059B

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1060A 1060B

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1061A 1061B

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1062A 1062B

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1063A 1063B

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1064A 1064B

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1065A 1065B

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1066A 1066B

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1067A 1067B

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1068A 1068B

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1069A 1069B

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1070A 1070B

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1071A 1071B

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1072A 1072B

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EXAMPLE TABLE 14

Substituted 1-(1H-Indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or

heterocyclic)phenyl}-propen-2-ones.

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Ex. No.
R^5β

1073A 1073B

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1074A 1074B

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1075A 1075B

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1076A 1076B

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1077A 1077B

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1078A 1078B

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1079A 1079B

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1080A 1080B

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1081A 1081B

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1082A 1082B

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1083A 1083B

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1084A 1084B

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1085A 1085B

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1086A 1086B

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1087A 1087B

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1088A 1088B

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1089A 1089B

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1090A 1090B

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1091A 1091B

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1092A 1092B

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1093A 1093B

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1094A 1094B

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1095A 1095B

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1096A 1096B

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1097A 1097B

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1098A 1098B

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1099A 1099B

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1100A 1100B

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1101A 1101B

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1102A 1102B

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1103A 1103B

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1104A 1104B

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1105A 1105B

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1106A 1106B

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1107A 1107B

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1108A 1108B

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1109A 1109B

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1110A 1110B

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1111A 1111B

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1112A 1112B

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1113A 1113B

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1114A 1114B

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1115A 1115B

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1116A 1116B

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1117A 1117B

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1118A 1118B

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1119A 1119B

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1120A 1120B

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1121A 1121B

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1122A 1122B

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1123A 1123B

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1124A 1124B

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1125A 1125B

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1126A 1126B

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1127A 1127B

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1128A 1128B

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1129A 1129B

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1130A 1130B

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1131A 1131B

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1132A 1132B

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1133A 1133B

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1134A 1134B

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1135A 1135B

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1136A 1136B

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1137A 1137B

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1138A 1138B

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1139A 1139B

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1140A 1140B

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1141A 1141B

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1142A 1142B

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1143A 1143B

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1144A 1144B

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EXAMPLE TABLE 15

Substituted 1-(1H-1-Methyl-indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or

heterocyclic)phenyl}-propen-2-ones.

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Ex. No.
R^5β

1145A 1145B

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1146A 1146B

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1147A 1147B

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1148A 1148B

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1149A 1149B

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1150A 1150B

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1151A 1151B

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1152A 1152B

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1153A 1153B

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1154A 1154B

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1155A 1155B

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1156A 1156B

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1157A 1157B

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1158A 1158B

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1159A 1159B

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1160A 1160B

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1161A 1161B

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1162A 1162B

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1163A 1163B

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1164A 1164B

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1165A 1165B

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1166A 1166B

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1167A 1167B

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1168A 1168B

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1169A 1169B

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1170A 1170B

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1171A 1171B

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1172A 1172B

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1173A 1173B

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1174A 1174B

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1175A 1175B

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1176A 1176B

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1177A 1177B

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1178A 1178B

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1179A 1179B

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1180A 1180B

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1181A 1181B

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1182A 1182B

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1183A 1183B

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1184A 1184B

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1185A 1185B

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1186A 1186B

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1187A 1187B

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1188A 1188B

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1189A 1189B

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1190A 1190B

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1191A 1191B

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1192A 1192B

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1193A 1193B

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1194A 1194B

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1195A 1195B

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1196A 1196B

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1197A 1197B

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1198A 1198B

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1199A 1199B

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1200A 1200B

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1201A 1201B

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1202A 1202B

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1203A 1203B

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1204A 1204B

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1205A 1205B

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1206A 1206B

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1207A 1207B

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EXAMPLE TABLE 17

Substituted 1-(1H-1-Methyl-indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or

heterocyclic)phenyl}-propen-2-ones.

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Ex. No.
R^5β

1208A 1208B

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1209A 1209B

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1210A 1210B

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1211A 1211B

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1212A 1212B

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1213A 1213B

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1214A 1214B

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1215A 1215B

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1216A 1216B

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1217A 1217B

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1218A 1218B

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1219A 1219B

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1220A 1220B

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1221A 1221B

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1222A 1222B

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1223A 1223B

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1224A 1224B

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1225A 1225B

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1226A 1226B

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1227A 1227B

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1228A 1228B

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1229A 1229B

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1230A 1230B

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1231A 1231B

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1232A 1232B

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1233A 1233B

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1234A 1234B

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1235A 1235B

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1236A 1236B

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1237A 1237B

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1238A 1238B

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1239A 1239B

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1240A 1240B

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1241A 1241B

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1242A 1242B

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1243A 1243B

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1244A 1244B

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1245A 1245B

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1246A 1246B

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1247A 1247B

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1248A 1248B

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1249A 1249B

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1250A 1250B

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1251A 1251B

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1252A 1252B

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1253A 1253B

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1254A 1254B

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1255A 1255B

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1256A 1256B

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1257A 1257B

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1258A 1258B

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1259A 1259B

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1260A 1260B

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1261A 1261B

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1262A 1262B

embedded image

1263A 1263B

embedded image

1264A 1264B

embedded image

1265A 1265B

embedded image

1266A 1266B

embedded image

1267A 1267B

embedded image

1268A 1268B

embedded image

1269A 1269B

embedded image

1270A 1270B

embedded image

1271A 1271B

embedded image

1272A 1272B

embedded image

1273A 1273B

embedded image

1274A 1274B

embedded image

1275A 1275B

embedded image

1276A 1276B

embedded image

1277A 1277B

embedded image

1278A 1278B

embedded image

1279A 1279B

embedded image

EXAMPLE TABLE 17

Substituted 4-[3-{2-(Pyrrolidin-1-yl)-(4-heteroaryl or 4-heterocyclic)-

phenyl}-acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^4β

1280A 1280B

embedded image

1281A 1281B

embedded image

1282A 1282B

embedded image

1283A 1283B

embedded image

1284A 1284B

embedded image

1285A 1285B

embedded image

1286A 1286B

embedded image

1287A 1287B

embedded image

1288A 1288B

embedded image

1289A 1289B

embedded image

1290A 1290B

embedded image

1291A 1291B

embedded image

1292A 1292B

embedded image

1293A 1293B

embedded image

1294A 1294B

embedded image

1295A 1295B

embedded image

1296A 1296B

embedded image

1297A 1297B

embedded image

1298A 1298B

embedded image

1299A 1299B

embedded image

1300A 1300B

embedded image

1301A 1301B

embedded image

1302A 1302B

embedded image

1303A 1303B

embedded image

1304A 1304B

embedded image

1305A 1305B

embedded image

1306A 1306B

embedded image

1307A 1307B

embedded image

1308A 1308B

embedded image

1309A 1309B

embedded image

1310A 1310B

embedded image

1311A 1311B

embedded image

1312A 1312B

embedded image

1313A 1313B

embedded image

1314A 1314B

embedded image

1315A 1315B

embedded image

1316A 1316B

embedded image

1317A 1317B

embedded image

1318A 1318B

embedded image

1319A 1319B

embedded image

1320A 1320B

embedded image

1321A 1321B

embedded image

1322A 1322B

embedded image

1323A 1323B

embedded image

1324A 1324B

embedded image

1325A 1325B

embedded image

1326A 1326B

embedded image

1327A 1327B

embedded image

1328A 1328B

embedded image

1329A 1329B

embedded image

1330A 1330B

embedded image

1331A 1331B

embedded image

1332A 1332B

embedded image

1333A 1333B

embedded image

1334A 1334B

embedded image

1335A 1335B

embedded image

1336A 1336B

embedded image

1337A 1337B

embedded image

1338A 1338B

embedded image

1339A 1339B

embedded image

1340A 1340B

embedded image

1341A 1341B

embedded image

1342A 1342B

embedded image

1343A 1343B

embedded image

1344A 1344B

embedded image

1345A 1345B

embedded image

1346A 1346B

embedded image

1347A 1347B

embedded image

1348A 1348B

embedded image

1349A 1349B

embedded image

1350A 1350B

embedded image

1351A 1351B

embedded image

EXAMPLE TABLE 18

Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1352A 1352B

embedded image

1353A 1353B

embedded image

1354A 1354B

embedded image

1355A 1355B

embedded image

1356A 1356B

embedded image

1357A 1357B

embedded image

1358A 1358B

embedded image

1359A 1359B

embedded image

1360A 1360B

embedded image

1361A 1361B

embedded image

1362A 1362B

embedded image

1363A 1363B

embedded image

1364A 1364B

embedded image

1365A 1365B

embedded image

1366A 1366B

embedded image

1367A 1367B

embedded image

1368A 1368B

embedded image

1369A 1369B

embedded image

1370A 1370B

embedded image

1371A 1371B

embedded image

1372A 1372B

embedded image

1373A 1373B

embedded image

1374A 1374B

embedded image

1375A 1375B

embedded image

1376A 1376B

embedded image

1377A 1377B

embedded image

1378A 1378B

embedded image

1379A 1379B

embedded image

1380A 1380B

embedded image

1381A 1381B

embedded image

1382A 1382B

embedded image

1383A 1383B

embedded image

1384A 1384B

embedded image

1385A 1385B

embedded image

1386A 1386B

embedded image

1387A 1387B

embedded image

1388A 1388B

embedded image

1389A 1389B

embedded image

1390A 1390B

embedded image

1391A 1391B

embedded image

1392A 1392B

embedded image

1393A 1393B

embedded image

1394A 1394B

embedded image

1395A 1395B

embedded image

1396A 1396B

embedded image

1397A 1397B

embedded image

1398A 1398B

embedded image

1399A 1399B

embedded image

1360A 1360B

embedded image

1401A 1401B

embedded image

1402A 1402B

embedded image

1403A 1403B

embedded image

1404A 1404B

embedded image

1405A 1405B

embedded image

1406A 1406B

embedded image

1407A 1407B

embedded image

1408A 1408B

embedded image

1409A 1409B

embedded image

1410A 1410B

embedded image

1411A 1411B

embedded image

1412A 1412B

embedded image

1413A 1413B

embedded image

1414A 1414B

embedded image

EXAMPLE TABLE 19

Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1415A 1415B

embedded image

1416A 1416B

embedded image

1417A 1417B

embedded image

1418A 1418B

embedded image

1419A 1419B

embedded image

1420A 1420B

embedded image

1421A 1421B

embedded image

1422A 1422B

embedded image

1423A 1423B

embedded image

1424A 1424B

embedded image

1425A 1425B

embedded image

1426A 1426B

embedded image

1427A 1427B

embedded image

1428A 1428B

embedded image

1429A 1429B

embedded image

1430A 1430B

embedded image

1431A 1431B

embedded image

1432A 1432B

embedded image

1433A 1433B

embedded image

1434A 1434B

embedded image

1435A 1435B

embedded image

1436A 1436B

embedded image

1437A 1437B

embedded image

1438A 1438B

embedded image

1439A 1439B

embedded image

1440A 1440B

embedded image

1441A 1441B

embedded image

1442A 1442B

embedded image

1443A 1443B

embedded image

1444A 1444B

embedded image

1445A 1445B

embedded image

1446A 1446B

embedded image

1447A 1447B

embedded image

1448A 1448B

embedded image

1449A 1449B

embedded image

1450A 1450B

embedded image

1451A 1451B

embedded image

1452A 1452B

embedded image

1453A 1453B

embedded image

1454A 1454B

embedded image

1455A 1455B

embedded image

1456A 1456B

embedded image

1457A 1457B

embedded image

1458A 1458B

embedded image

1459A 1459B

embedded image

1460A 1460B

embedded image

1461A 1461B

embedded image

1462A 1462B

embedded image

1463A 1463B

embedded image

1464A 1464B

embedded image

1465A 1465B

embedded image

1466A 1466B

embedded image

1467A 1467B

embedded image

1468A 1468B

embedded image

1469A 1469B

embedded image

1470A 1470B

embedded image

1471A 1471B

embedded image

1473A 1473B

embedded image

1474A 1474B

embedded image

1475A 1475B

embedded image

1476A 1476B

embedded image

1477A 1477B

embedded image

1478A 1478B

embedded image

1479A 1479B

embedded image

1480A 1480B

embedded image

1481A 1481B

embedded image

1482A 1482B

embedded image

1483A 1483B

embedded image

1484A 1484B

embedded image

1485A 1485B

embedded image

1486A 1486B

embedded image

1487A 1487B

embedded image

EXAMPLE TABLE 20

Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1488A 1488B

embedded image

1489A 1489B

embedded image

1490A 1490B

embedded image

1491A 1491B

embedded image

1492A 1492B

embedded image

1493A 1493B

embedded image

1494A 1494B

embedded image

1495A 1495B

embedded image

1496A 1496B

embedded image

1497A 1497B

embedded image

1498A 1498B

embedded image

1499A 1499B

embedded image

1500A 1500B

embedded image

1501A 1501B

embedded image

1502A 1502B

embedded image

1503A 1503B

embedded image

1504A 1504B

embedded image

1505A 1505B

embedded image

1506A 1506B

embedded image

1507A 1507B

embedded image

1508A 1508B

embedded image

1509A 1509B

embedded image

1510A 1510B

embedded image

1511A 1511B

embedded image

1512A 1512B

embedded image

1513A 1513B

embedded image

1514A 1514B

embedded image

1515A 1515B

embedded image

1516A 1516B

embedded image

1517A 1517B

embedded image

1518A 1518B

embedded image

1519A 1519B

embedded image

1520A 1520B

embedded image

1521A 1521B

embedded image

1522A 1522B

embedded image

1523A 1523B

embedded image

1524A 1524B

embedded image

1525A 1525B

embedded image

1526A 1526B

embedded image

1527A 1527B

embedded image

1528A 1528B

embedded image

1529A 1529B

embedded image

1530A 1530B

embedded image

1531A 1531B

embedded image

1532A 1532B

embedded image

1533A 1533B

embedded image

1534A 1534B

embedded image

1535A 1535B

embedded image

1536A 1536B

embedded image

1537A 1537B

embedded image

1538A 1538B

embedded image

1539A 1539B

embedded image

1540A 1540B

embedded image

1541A 1541B

embedded image

1542A 1542B

embedded image

1543A 1543B

embedded image

1544A 1544B

embedded image

1545A 1545B

embedded image

1546A 1546B

embedded image

1547A 1547B

embedded image

1548A 1548B

embedded image

1549A 1549B

embedded image

1550A 1550B

embedded image

EXAMPLE TABLE 21

Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-

acryloyl]-5-methanesulfonylamino-benzoic Acids.

embedded image

Ex. No.
R^5β

1551A 1551B

embedded image

1552A 1552B

embedded image

1553A 1553B

embedded image

1554A 1554B

embedded image

1555A 1555B

embedded image

1556A 1556B

embedded image

1557A 1557B

embedded image

1558A 1558B

embedded image

1559A 1559B

embedded image

1560A 1560B

embedded image

1561A 1561B

embedded image

1562A 1562B

embedded image

1563A 1563B

embedded image

1564A 1564B

embedded image

1565A 1565B

embedded image

1566A 1566B

embedded image

1567A 1567B

embedded image

1568A 1568B

embedded image

1569A 1569B

embedded image

1570A 1570B

embedded image

1571A 1571B

embedded image

1572A 1572B

embedded image

1573A 1573B

embedded image

1574A 1574B

embedded image

1575A 1575B

embedded image

1576A 1576B

embedded image

1577A 1577B

embedded image

1578A 1578B

embedded image

1579A 1579B

embedded image

1580A 1580B

embedded image

1581A 1581B

embedded image

1582A 1582B

embedded image

1583A 1583B

embedded image

1584A 1584B

embedded image

1585A 1585B

embedded image

1586A 1586B

embedded image

1587A 1587B

embedded image

1588A 1588B

embedded image

1589A 1589B

embedded image

1590A 1590B

embedded image

1591A 1591B

embedded image

1592A 1592B

embedded image

1593A 1593B

embedded image

1594A 1594B

embedded image

1595A 1595B

embedded image

1596A 1596B

embedded image

1597A 1597B

embedded image

1598A 1598B

embedded image

1599A 1599B

embedded image

1600A 1600B

embedded image

1601A 1601B

embedded image

1602A 1602B

embedded image

1603A 1603B

embedded image

1604A 1604B

embedded image

1605A 1605B

embedded image

1606A 1606B

embedded image

1607A 1607B

embedded image

1608A 1608B

embedded image

1609A 1609B

embedded image

1610A 1610B

embedded image

1611A 1611B

embedded image

1612A 1612B

embedded image

1613A 1613B

embedded image

1614A 1614B

embedded image

1615A 1615B

embedded image

1616A 1616B

embedded image

1617A 1617B

embedded image

1618A 1618B

embedded image

1619A 1619B

embedded image

1620A 1620B

embedded image

1621A 1621B

embedded image

1622A 1622B

embedded image

EXAMPLE TABLE 22

Substituted 5-Amino-2-[3-{(5-heteroaryl or 5-heterocyclic)-2,4-

dimethoxy-phenyl}-acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1623A 1623B

embedded image

1624A 1624B

embedded image

1625A 1625B

embedded image

1626A 1626B

embedded image

1627A 1627B

embedded image

1628A 1628B

embedded image

1629A 1629B

embedded image

1630A 1630B

embedded image

1631A 1631B

embedded image

1632A 1632B

embedded image

1633A 1633B

embedded image

1634A 1634B

embedded image

1635A 1635B

embedded image

1636A 1636B

embedded image

1637A 1637B

embedded image

1638A 1638B

embedded image

1639A 1639B

embedded image

1640A 1640B

embedded image

1641A 1641B

embedded image

1642A 1642B

embedded image

1643A 1643B

embedded image

1644A 1644B

embedded image

1645A 1645B

embedded image

1646A 1646B

embedded image

1647A 1647B

embedded image

1648A 1648B

embedded image

1649A 1649B

embedded image

1650A 1650B

embedded image

1651A 1651B

embedded image

1652A 1652B

embedded image

1653A 1653B

embedded image

1654A 1654B

embedded image

1655A 1655B

embedded image

1656A 1656B

embedded image

1657A 1657B

embedded image

1658A 1658B

embedded image

1659A 1659B

embedded image

1660A 1660B

embedded image

1661A 1661B

embedded image

1662A 1662B

embedded image

1663A 1663B

embedded image

1664A 1664B

embedded image

1665A 1665B

embedded image

1666A 1666B

embedded image

1667A 1667B

embedded image

1668A 1668B

embedded image

1669A 1669B

embedded image

1670A 1670B

embedded image

1671A 1671B

embedded image

1672A 1672B

embedded image

1673A 1673B

embedded image

1674A 1674B

embedded image

1675A 1675B

embedded image

1676A 1676B

embedded image

1677A 1677B

embedded image

1678A 1678B

embedded image

1679A 1679B

embedded image

1680A 1680B

embedded image

1681A 1681B

embedded image

1682A 1682B

embedded image

1683A 1683B

embedded image

1684A 1684B

embedded image

1685A 1685B

embedded image

EXAMPLE TABLE 23

Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1686A 1686B

embedded image

1687A 1687B

embedded image

1688A 1688B

embedded image

1689A 1689B

embedded image

1690A 1690B

embedded image

1691A 1691B

embedded image

1692A 1692B

embedded image

1693A 1693B

embedded image

1694A 1694B

embedded image

1695A 1695B

embedded image

1696A 1696B

embedded image

1697A 1697B

embedded image

1698A 1698B

embedded image

1699A 1699B

embedded image

1700A 1700B

embedded image

1701A 1701B

embedded image

1702A 1702B

embedded image

1703A 1703B

embedded image

1704A 1704B

embedded image

1705A 1705B

embedded image

1706A 1706B

embedded image

1707A 1707B

embedded image

1708A 1708B

embedded image

1709A 1709B

embedded image

1710A 1710B

embedded image

1711A 1711B

embedded image

1712A 1712B

embedded image

1713A 1713B

embedded image

1714A 1714B

embedded image

1715A 1715B

embedded image

1716A 1716B

embedded image

1717A 1717B

embedded image

1718A 1718B

embedded image

1719A 1719B

embedded image

1720A 1720B

embedded image

1721A 1721B

embedded image

1722A 1722B

embedded image

1723A 1723B

embedded image

1724A 1724B

embedded image

1725A 1725B

embedded image

1726A 1726B

embedded image

1727A 1727B

embedded image

1728A 1728B

embedded image

1729A 1729B

embedded image

1730A 1730B

embedded image

1731A 1731B

embedded image

1732A 1732B

embedded image

1733A 1733B

embedded image

1734A 1734B

embedded image

1735A 1735B

embedded image

1736A 1736B

embedded image

1737A 1737B

embedded image

1738A 1738B

embedded image

1739A 1739B

embedded image

1740A 1740B

embedded image

1741A 1741B

embedded image

1742A 1742B

embedded image

1743A 1743B

embedded image

1744A 1744B

embedded image

1745A 1745B

embedded image

1746A 1746B

embedded image

1747A 1747B

embedded image

1748A 1748B

embedded image

1749A 1749B

embedded image

1750A 1750B

embedded image

1751A 1751B

embedded image

1752A 1752B

embedded image

1753A 1753B

embedded image

1754A 1754B

embedded image

1755A 1755B

embedded image

1756A 1756B

embedded image

1757A 1757B

embedded image

EXAMPLE TABLE 24

Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1758A 1758B

embedded image

1759A 1759B

embedded image

1760A 1760B

embedded image

1761A 1761B

embedded image

1762A 1762B

embedded image

1763A 1763B

embedded image

1764A 1764B

embedded image

1765A 1765B

embedded image

1766A 1766B

embedded image

1767A 1767B

embedded image

1768A 1768B

embedded image

1769A 1769B

embedded image

1770A 1770B

embedded image

1771A 1771B

embedded image

1772A 1772B

embedded image

1773A 1773B

embedded image

1774A 1774B

embedded image

1775A 1775B

embedded image

1776A 1776B

embedded image

1777A 1777B

embedded image

1778A 1778B

embedded image

1779A 1779B

embedded image

1780A 1780B

embedded image

1781A 1781B

embedded image

1782A 1782B

embedded image

1783A 1783B

embedded image

1784A 1784B

embedded image

1785A 1785B

embedded image

1786A 1786B

embedded image

1787A 1787B

embedded image

1788A 1788B

embedded image

1789A 1789B

embedded image

1790A 1790B

embedded image

1791A 1791B

embedded image

1792A 1792B

embedded image

1793A 1793B

embedded image

1794A 1794B

embedded image

1795A 1795B

embedded image

1796A 1796B

embedded image

1797A 1797B

embedded image

1798A 1798B

embedded image

1799A 1799B

embedded image

1800A 1800B

embedded image

1801A 1801B

embedded image

1802A 1802B

embedded image

1803A 1803B

embedded image

1804A 1804B

embedded image

1805A 1805B

embedded image

1806A 1806B

embedded image

1807A 1807B

embedded image

1808A 1808B

embedded image

1809A 1809B

embedded image

1810A 1810B

embedded image

1811A 1811B

embedded image

1812A 1812B

embedded image

1813A 1813B

embedded image

1814A 1814B

embedded image

1815A 1815B

embedded image

1816A 1816B

embedded image

1817A 1817B

embedded image

1818A 1818B

embedded image

1819A 1819B

embedded image

1820A 1820B

embedded image

EXAMPLE TABLE 25

Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

embedded image

Ex. No.
R^5β

1821A 1821B

embedded image

1822A 1822B

embedded image

1823A 1823B

embedded image

1824A 1824B

embedded image

1825A 1825B

embedded image

1826A 1826B

embedded image

1827A 1827B

embedded image

1828A 1828B

embedded image

1829A 1829B

embedded image

1830A 1830B

embedded image

1831A 1831B

embedded image

1832A 1832B

embedded image

1833A 1833B

embedded image

1834A 1834B

embedded image

1835A 1835B

embedded image

1836A 1836B

embedded image

1837A 1837B

embedded image

1838A 1838B

embedded image

1839A 1839B

embedded image

1840A 1840B

embedded image

1841A 1841B

embedded image

1842A 1842B

embedded image

1843A 1843B

embedded image

1844A 1844B

embedded image

1845A 1845B

embedded image

1846A 1846B

embedded image

1847A 1847B

embedded image

1848A 1848B

embedded image

1849A 1849B

embedded image

1850A 1850B

embedded image

1851A 1851B

embedded image

1852A 1852B

embedded image

1853A 1853B

embedded image

1854A 1854B

embedded image

1855A 1855B

embedded image

1856A 1856B

embedded image

1857A 1857B

embedded image

1858A 1858B

embedded image

1859A 1859B

embedded image

1860A 1860B

embedded image

1861A 1861B

embedded image

1862A 1862B

embedded image

1863A 1863B

embedded image

1864A 1864B

embedded image

1865A 1865B

embedded image

1866A 1866B

embedded image

1867A 1867B

embedded image

1868A 1868B

embedded image

1869A 1869B

embedded image

1870A 1870B

embedded image

1871A 1871B

embedded image

1872A 1872B

embedded image

1873A 1873B

embedded image

1874A 1874B

embedded image

1875A 1875B

embedded image

1876A 1876B

embedded image

1877A 1877B

embedded image

1878A 1878B

embedded image

1879A 1879B

embedded image

1880A 1880B

embedded image

1881A 1881B

embedded image

1882A 1882B

embedded image

1883A 1883B

embedded image

1884A 1884B

embedded image

1885A 1885B

embedded image

1886A 1886B

embedded image

1887A 1887B

embedded image

1888A 1888B

embedded image

1889A 1889B

embedded image

1890A 1890B

embedded image

1891A 1891B

embedded image

1892A 1892B

embedded image

EXAMPLE TABLE 26

Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-4-fluorophenyl}-

acryloyl]-benzoic Acids.

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Ex. No.
R^5β

1893A 1893B

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1894A 1894B

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1895A 1895B

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1896A 1896B

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1897A 1897B

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1898A 1898B

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1899A 1899B

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1900A 1900B

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1901A 1901B

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1902A 1902B

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1903A 1903B

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1904A 1904B

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1905A 1905B

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1906A 1906B

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1907A 1907B

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1908A 1908B

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1909A 1909B

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1910A 1910B

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1911A 1911B

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1912A 1912B

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1913A 1913B

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1914A 1914B

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1915A 1915B

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1916A 1916B

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1917A 1917B

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1918A 1918B

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1919A 1919B

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1920A 1920B

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1921A 1921B

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1922A 1922B

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1923A 1923B

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1924A 1924B

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1925A 1925B

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1926A 1926B

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1927A 1927B

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1928A 1928B

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1929A 1929B

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1930A 1930B

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1931A 1931B

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1932A 1932B

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1933A 1933B

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1934A 1934B

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1935A 1935B

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1936A 1936B

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1937A 1937B

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1938A 1938B

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1939A 1939B

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1940A 1940B

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1941A 1941B

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1942A 1942B

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1943A 1943B

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1944A 1944B

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1945A 1945B

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1946A 1946B

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1947A 1947B

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1948A 1948B

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1949A 1949B

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1950A 1950B

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1951A 1951B

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1952A 1952B

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1953A 1953B

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1954A 1954B

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1955A 1955B

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EXAMPLE TABLE 27

Substituted 4-[3-{(3-Heteroaryl or 3-heterocyclic)-4-(pyrrolidin-1-yl)-

phenyl}acryloyl]-benzoic Acids.

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Ex. No.
R^5β

1956A 1956B

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1957A 1957B

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1958A 1958B

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1959A 1959B

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1960A 1960B

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1961A 1961B

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1962A 1962B

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1963A 1963B

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1964A 1964B

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1965A 1965B

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1966A 1966B

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1967A 1967B

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1968A 1968B

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1969A 1969B

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1970A 1970B

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1971A 1971B

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1972A 1972B

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1973A 1973B

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1974A 1974B

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1975A 1975B

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1976A 1976B

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1977A 1977B

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1978A 1978B

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1979A 1979B

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1980A 1980B

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1981A 1981B

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1982A 1982B

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1983A 1983B

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1984A 1984B

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1985A 1985B

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1986A 1986B

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1987A 1987B

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1988A 1988B

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1989A 1989B

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1990A 1990B

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1991A 1991B

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1992A 1992B

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1993A 1993B

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1994A 1994B

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1995A 1995B

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1996A 1996B

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1997A 1997B

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1998A 1998B

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1999A 1999B

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2000A 2000B

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2001A 2001B

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2002A 2002B

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2003A 2003B

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2004A 2004B

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2005A 2005B

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2006A 2006B

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2007A 2007B

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2008A 2008B

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2009A 2009B

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2010A 2010B

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2011A 2011B

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2012A 2012B

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2013A 2013B

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2014A 2014B

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2015A 2015B

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2016A 2016B

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2017A 2017B

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2018A 2018B

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2019A 2019B

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2020A 2020B

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2021A 2021B

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2022A 2022B

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2023A 2023B

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2024A 2024B

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2025A 2025B

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2026A 2026B

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2027A 2027B

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EXAMPLE TABLE 28

Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-

acryloyl]benzonitriles.

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Ex. No.
R^5β

2028A 2028B

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2029A 2029B

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2030A 2030B

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2031A 2031B

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2032A 2032B

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2033A 2033B

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2034A 2034B

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2035A 2035B

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2036A 2036B

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2037A 2037B

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2038A 2038B

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2039A 2039B

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2040A 2040B

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2041A 2041B

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2042A 2042B

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2043A 2043B

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2044A 2044B

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2045A 2045B

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2046A 2046B

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2047A 2047B

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2048A 2048B

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2049A 2049B

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2050A 2050B

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2051A 2051B

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2052A 2052B

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2053A 2053B

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2054A 2054B

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2055A 2055B

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2056A 2056B

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2057A 2057B

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2058A 2058B

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2059A 2059B

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2060A 2060B

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2061A 2061B

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2062A 2062B

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2063A 2063B

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2064A 2064B

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2065A 2065B

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2066A 2066B

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2067A 2067B

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2068A 2068B

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2069A 2069B

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2070A 2070B

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2071A 2071B

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2072A 2072B

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2073A 2073B

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2074A 2074B

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2075A 2075B

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2076A 2076B

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2077A 2077B

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2078A 2078B

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2079A 2079B

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2080A 2080B

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2081A 2081B

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2082A 2082B

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2083A 2083B

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2084A 2084B

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2085A 2085B

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2086A 2086B

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2087A 2087B

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2088A 2088B

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2089A 2089B

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2090A 2090B

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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.

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Ex. No.
R^5β

2091A 2091B

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2092A 2092B

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2093A 2093B

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2094A 2094B

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2095A 2095B

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2096A 2096B

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2097A 2097B

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2098A 2098B

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2099A 2099B

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2100A 2100B

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2101A 2101B

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2102A 2102B

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2103A 2103B

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2104A 2104B

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2105A 2105B

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2106A 2106B

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2107A 2107B

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2108A 2108B

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2109A 2109B

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2110A 2110B

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2111A 2111B

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2112A 2112B

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2113A 2113B

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2114A 2114B

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2115A 2115B

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2116A 2116B

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2117A 2117B

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2118A 2118B

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2119A 2119B

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2120A 2120B

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2121A 2121B

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2122A 2122B

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2123A 2123B

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2124A 2124B

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2125A 2125B

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2126A 2126B

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2127A 2127B

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2128A 2128B

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2129A 2129B

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2130A 2130B

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2131A 2131B

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2132A 2132B

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2133A 2133B

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2134A 2134B

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2135A 2135B

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2136A 2136B

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2137A 2137B

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2138A 2138B

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2139A 2139B

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2140A 2140B

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2141A 2141B

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2142A 2142B

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2143A 2143B

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2144A 2144B

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2145A 2145B

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2146A 2146B

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2147A 2147B

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2148A 2148B

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2149A 2149B

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2150A 2150B

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2151A 2151B

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2152A 2152B

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2153A 2153B

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2154A 2154B

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2155A 2155B

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2156A 2156B

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2157A 2157B

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2158A 2158B

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2159A 2159B

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2160A 2160B

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2161A 2161B

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2162A 2162B

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EXAMPLE TABLE 30

Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)phenyl}-acryloyl]-

benzoic Acids.

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Ex. No.
R^4β

2163A 2163B

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2164A 2164B

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2165A 2165B

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2166A 2166B

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2167A 2167B

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2168A 2168B

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2169A 2169B

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2170A 2170B

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2171A 2171B

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2172A 2172B

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2173A 2173B

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2174A 2174B

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2175A 2175B

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2176A 2176B

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2177A 2177B

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2178A 2178B

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2179A 2179B

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2180A 2180B

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2181A 2181B

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2182A 2182B

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2183A 2183B

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2184A 2184B

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2185A 2185B

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2186A 2186B

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2187A 2187B

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2188A 2188B

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2189A 2189B

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2190A 2190B

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2191A 2191B

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2192A 2192B

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2193A 2193B

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2194A 2194B

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2195A 2195B

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2196A 2196B

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2197A 2197B

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2198A 2198B

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2199A 2199B

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2200A 2200B

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2201A 2201B

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2202A 2202B

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2203A 2203B

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2204A 2204B

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2205A 2205B

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2206A 2206B

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2207A 2207B

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2208A 2208B

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2209A 2209B

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2210A 2210B

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2211A 2211B

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2212A 2212B

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2213A 2213B

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2214A 2214B

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2215A 2215B

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2216A 2216B

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2217A 2217B

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2218A 2218B

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2219A 2219B

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2220A 2220B

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2221A 2221B

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2222A 2222B

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2223A 2223B

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2224A 2224B

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2225A 2225B

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EXAMPLE TABLE 31

Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)phenyl}-3-oxo-

propenyl]-benzoic Acids.

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Ex. No.
R^4α

2226A 2226B

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2227A 2227B

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2228A 2228B

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2229A 2229B

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2230A 2230B

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2231A 2231B

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2232A 2232B

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2233A 2233B

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2234A 2234B

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2235A 2235B

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2236A 2236B

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2237A 2237B

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2238A 2238B

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2239A 2239B

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2240A 2240B

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2241A 2241B

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2242A 2242B

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2243A 2243B

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2244A 2244B

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2245A 2245B

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2246A 2246B

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2247A 2247B

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2248A 2248B

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2249A 2249B

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2250A 2250B

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2251A 2251B

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2252A 2252B

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2253A 2253B

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2254A 2254B

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2255A 2255B

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2256A 2256B

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2257A 2257B

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2258A 2258B

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2259A 2259B

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2260A 2260B

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2261A 2261B

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2262A 2262B

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2263A 2263B

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2264A 2264B

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2265A 2265B

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2266A 2266B

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2267A 2267B

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2268A 2268B

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2269A 2269B

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2270A 2270B

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2271A 2271B

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2272A 2272B

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2273A 2273B

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2274A 2274B

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2275A 2275B

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2276A 2276B

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2277A 2277B

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2278A 2278B

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2279A 2279B

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2280A 2280B

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2281A 2281B

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2282A 2282B

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2283A 2283B

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2284A 2284B

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2285A 2285B

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2286A 2286B

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2287A 2287B

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2288A 2288B

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2289A 2289B

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2290A 2290B

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2291A 2291B

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2292A 2292B

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2293A 2293B

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2294A 2294B

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2295A 2295B

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2296A 2296B

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2297A 2297B

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EXAMPLE TABLE 32

Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)-2,6-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

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Ex. No.
R^4β

2298A 2298B

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2299A 2299B

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2300A 2300B

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2301A 2301B

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2302A 2302B

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2303A 2303B

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2304A 2304B

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2305A 2305B

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2306A 2306B

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2307A 2307B

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2308A 2308B

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2309A 2309B

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2310A 2310B

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2311A 2311B

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2312A 2312B

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2313A 2313B

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2314A 2314B

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2315A 2315B

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2316A 2316B

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2317A 2317B

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2318A 2318B

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2319A 2319B

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2320A 2320B

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2321A 2321B

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2322A 2322B

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2323A 2323B

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2324A 2324B

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2325A 2325B

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2326A 2326B

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2327A 2327B

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2328A 2328B

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2329A 2329B

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2330A 2330B

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2331A 2331B

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2332A 2332B

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2333A 2333B

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2334A 2334B

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2335A 2335B

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2336A 2336B

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2337A 2337B

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2338A 2338B

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2339A 2339B

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2340A 2340B

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2341A 2341B

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2342A 2342B

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2343A 2343B

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2344A 2344B

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2345A 2345B

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2346A 2346B

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2347A 2347B

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2348A 2348B

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2349A 2349B

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2350A 2350B

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2351A 2351B

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2352A 2352B

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2353A 2353B

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2354A 2354B

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2355A 2355B

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2356A 2356B

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2357A 2357B

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2358A 2358B

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2359A 2359B

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2360A 2360B

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EXAMPLE TABLE 33

Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-

acryloyl]-benzoic Acids.

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Ex. No.
R^5β

2361A 2361B

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2362A 2362B

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2363A 2363B

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2364A 2364B

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2365A 2365B

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2366A 2366B

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2367A 2367B

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2368A 2368B

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2369A 2369B

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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
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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 C₁or C₂antagonists 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) (H₁receptor antagonists). Examples of antihistimines (H₁receptor 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 IC₅₀values 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 IC₅₀values (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 1VCAM-1ExampleIC50Number(μM)1<12<53<14<105<16<17<18<19<510<511<512<513<514<115>1016<517<518<519<120>1021<522>1023<124>1025>1026>1027<528<529<130<131>1032<533<534>1035>1036<537>1038<1039>1040<141<542<543<544<145<546<1047>1048<1049<1050>1051<552>1053<554<1055<556<157<558>1059NE60<161<162<563<1064>1065<166<167<1068<569<570<571NE72073074>1075>1076>1077<578<1079<180<581<182NE83<184<585<186<587<18889NE90<191<592<193<194<195<196<597NE98<599>10100>10101>10102>10103>10104NE105NE106<10107NE108<10109NE110>10111>10112NE113<5114<5115<5116117<5118<10119120<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 2Compound Example% Inhibition 60 mg/Kg/day,Numbersq, bid, d1-14396677298260 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, dailydosing at 100 mg/kgCompound Example Numberfrom day 0-133796818648367160362924

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:

PrimerAnnealingNameForward SequenceReverse SequenceTemperatureGAPDHCTA CCC CCA ATGCTG CTT CAC CAC52.2TGT CCCTT CTTIL-13AAF AFF AGA GCACTG TGT AAC CTT51.3AAT GAA AGCCC AAC AIL-4TGA ATG AGT CCAAGC ATG GTG GCT51.2AGT CCACAG TAIL5AGC TCT GTT GACCCC TGA AAG ATT52.4AAG CAA TTCT CCA ATGIL-2GTC GAC TTT CTGATG TGT TGT AAG53.2AGG AGA TGCAG GAG GTIFN-γTTC TGT CTC CTCCAA TCA CAG TCT51.3AAC TAT TTC TTGG 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 IC₅₀for 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 IC₅₀of 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 4Amount of Compound 3(μM)Percent IL-1β Secreted1.25>402.5>105>510>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.

	Number	Date	Country
	60342034	Dec 2001	US
	60386482	Jun 2002	US

	Number	Date	Country
Parent	10324987	Dec 2002	US
Child	11337207	Jan 2006	US

Chalcone derivatives and their use to treat diseases

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