CA2470931A1 - Chalcone derivatives and their use to treat diseases - Google Patents

Chalcone derivatives and their use to treat diseases Download PDF

Info

Publication number
CA2470931A1
CA2470931A1 CA002470931A CA2470931A CA2470931A1 CA 2470931 A1 CA2470931 A1 CA 2470931A1 CA 002470931 A CA002470931 A CA 002470931A CA 2470931 A CA2470931 A CA 2470931A CA 2470931 A1 CA2470931 A1 CA 2470931A1
Authority
CA
Canada
Prior art keywords
alpha
lower alkyl
nhc
beta
nr7r8
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002470931A
Other languages
French (fr)
Inventor
Liming Ni
Kimberly J. Worsencroft
M. David Weingarten
Charles Q. Meng
James A. Sikorski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Atherogenics Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2470931A1 publication Critical patent/CA2470931A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Abstract

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

Description

CHALCONE DERIVATIVES AND THEIR USE TO TREAT DISEASES
This patent application claims priority to U.S. Provisional Patent Application Serial No.
60/342,034 filed December 19, 2001 and U.S. Provisional Patent Application Serial No.
60/386,482 filed June 5, 2002.
The present invention is in the field of novel chalcone derivatives, pharmaceutical compositions and methods for treating a variety of diseases and disorders, including inflammation and cardiovascular disease.
BACKGROUND OF THE INVENTION
Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are 1 S recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis (including rheumatoid arthritis), asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.

Coronary heart disease (CHD), primarily as a result of atherosclerosis, remains the leading cause of death in industrialized countries. Atherosclerosis is a disease characterized by vascular inflammation, deposition of lipids in the arterial vessel wall and smooth muscle cell proliferation resulting in a narrowing of the vessel passages. In advanced stages of the disease atherosclerotic lesions can become unstable resulting in plaque rupture, thrombosis, myocardial infarction and ischemic heart disease. It is now well accepted that the initiating events in atherosclerosis are local injury to the arterial endothelium that results in the induction of VCAM-1 and recruitment of mononuclear leukocytes that express the integrin counterreceptor, VLA-4, (O'Brien, et al., J. Clin. Invest., 92: 945-951, 1993). Subsequent conversion of leukocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help propagate formation of the mature atheromatous plaque by further inducing endothelial activation, leukocyte recruitment, smooth muscle cell proliferation, and extracellular matrix deposition.
Pharmacological inhibition of VCAM-1 expression has been shown to inhibit atherosclerosis in several animal models (Sundell et al., Circulation, 100: 42, 1999). A monoclonal antibody against VCAM-1 has also been shown to inhibit neointimal formation in a mouse model of arterial wall injury (Oguchi, S., et al., Arterioscler. Thromb. Yasc. 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 hyper eactivity. 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; Hacker, 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-I 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-I 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 con-elates 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 1 S VCAM-1 has also been demonstrated in kidneys of lupus-prone MRL/lpr mice compared to nonautoimmune strains and its expression increased with disease severity (McHale, J. F., et al., J. Immunol. 163: 3993-4000, 1999). VCAM-1 expression on mesangial cells in vitro can be stimulated by IL-1, TNF-a, and INFy exposure as well as by anti-endothelial cell IgG fraction and anti-DNA autoantibodies from SLE patients (Wuthrich, Kidney Int. 42: 903-914, 1992;
Papa, N. D., et al., Lupus, 8: 423-429, 1999; Lai, K. N., et al., Clin Immunol Immunopathol, 81: 229-238, 1996). Furthermore, soluble VCAM-1 is higher in SLE patients than in normal subjects (Mrowka, C., et al., Clin. Nephrol. 43: 288-296, 1995; Baraczka, K., et al., Acta.
' Neurol. Scand 99: 95-99, 1999; Kaplanski, G., et al., Arthritis Rheumol. 43:
55-64, 2000;
Ikeda, Y., Lupus, 7: 347-354, 1998) and correlates with disease activity (Scudla, V., Ynitr. Lek, 43: 307-311, 1997).
Increased VCAM-I 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-I 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 1 S tissue VCAM-I 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 were detected in cultures of human cerebral endothelial cells induced by TNFa, but not in peripheral blood mononuclear cells (Kallmann et al., Brain, 123:687-697, 2000). Clinical data also show that adhesion molecules in blood and cerebrospinal fluid are up-regulated throughout the clinical spectrum of multiple sclerosis (Baraczka, K., et al., Acta.
Neurol. Scand. 99: 95-99, 1999; Reickmann, P., et al., Mult. Scler., 4: 178-182, 1998; Frigerio, S., et al., J.
Neuroimmunol., 87: 88-93, 1998) supporting the notion that therapies which interfere with cell adhesion molecules such as VCAM-1 may be beneficial in modifying this disease (Elovaara et al., Arch. Neurol. 57:546-551, 2000).
Diabetes mellitus is a metabolic disease in which carbohydrate utilization is reduced and that of lipid and protein is enhanced. Evidence has accumulated that increased levels of adhesion molecules may play a functional pathophysiological role in diabetes (Wagner and Jilma, Hormone and Metabolic Research, 29: 627-630, 1997; Kado, S., Diabetes Res. Clin.
Pract., 46: 143-8, 1999). It is caused by an absolute or relative deficiency of insulin and is characterized by chronic hyperglycemia, glycosuria, water and electrolyte loss, ketoacidosis, and coma. Elevated circulating adhesion molecules including VCAM-1 have been detected in patients with diabetes and in experimental models of diabetes in animals (Lorini et al., Hormone Research, 48: 153, 1997; Otsuki et al., Diabetologia, 40: A440, 1997;
Hart et al., FASEB J. 11:A340, 1997; Albertini et al., Diabetologia, 39: A240, 1996; Wagner et al., Diabetologia, 39: A205, 1996; Enghofer et al., Diabetologia, 39: A97, 1996;
Koga M., Diabet.
Med , 15: 661-667, 1998). In addition, complications of diabetes often include peripheral vasculopathies such as diabetic retinopathy and diabetic nephropathy. It is believed that adhesion of leukocytes to the peripheral vasculature plays a central role in the vasculopathies often associated with diabetes.
Crohn's disease, also known as regional enteritis, is a subacute chronic inflammatory condition of unknown cause, involving the internal ileum and less frequently other parts of the gastrointestinal tract. It is characterized by patchy deep ulcers that may cause fistulas, and narrowing and thickening of the bowel by fibrosis and lymphocytic infiltration. Ulcerative colitis is a chronic disease of unknown cause characterized by ulceration of the colon and rectum, with rectal bleeding, mucosal crypt abscesses, inflammatory pseudopolyps, abdominal pain, and diarrhea. It has been reported that serum VCAM-1 reflects the grade of intestinal inflammation in patients with Crohn's disease or ulcerative colitis (Jones, et al., Gut, 36: 724-30, 1995; Goggins et al., Gastroenterology, 108: A825, 1995; Goeke and Manns, Gastroenterology, 106: A689, 1994; Goeke et al., J. Gasterokenterol. 32:480-486, 1997; Loftus et al., Gastroenterology, 108: A684, 1995; Tahami et al., Gastroenterolo~, 118: A344, 2000).
Antibodies to VCAM-1 have been shown to ameliorate experimentally-induced colitis in mice (Soriano, A., Lab. Invest. 80: 1541-1551, 2000).
Psoriasis is a chronic skin disease characterized by erythematous scaling plaques as a result of keratinocyte hyperplasia, influx of immune cells and endothelial activation (Nickoloff, B. J., et al., J. Invest. Dermatol., 127: 871-884, 1991). VCAM-1 is upregulated in psoriatic skin as compared to normal skin (Groves, R. W., J. Am. Acad. Dermatol., 29: 67-72, 1993;
Uyemura, K., et al., J. Invest. Dermatol. 101: 701-705, 1993) and levels of circulating VCAM-1 correlate with disease activity (Schopf, R. E., Br. J. Dermatol., 128: 34-7, 1993).
U.S. Patent Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231, and 5,773,209 to Medford, et al., as well as the corresponding WO 95/30415 to Emory University indicate that polyunsaturated fatty acids ("PUFAs") and their hydroperoxides ("ox-PUFAs"), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses. As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E-selectin.
WO 98/51662, filed by AtheroGenics, Inc. and listing as inventors Russell M.
Medford, Patricia K. Somers, Lee K. Hoong, and Charles ~Q. Meng, claims priority to provisional application U.S.S.N. 60/047,020, filed on May 14, 1997. This application discloses the use of a broad group of compounds as cardiovascular protectants that exhibit at least one, and sometimes a composite profile, of reducing cholesterol, lowering LDL, and inhibiting the expression of VCAM-1.
U.S. Patent No. 5,155,250 to Parker, et al. discloses that 2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same compounds are disclosed as serum cholesterol lowering agents in PCT Publication No. WO 95/15760, published on June 15, 1995. U.S.
Patent No.
5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower plasma cholesterol, and inhibit the expression of VCAM-1, and thus are useful in the treatment of atherosclerosis.
9, which claims priority to provisional application U.S.S.N.
60/047,020, filed on May 14, 1997 by Emory University listing Patty Somers as sole inventor, discloses the use of a group of compounds as cardiovascular protectants and antiinflammatory agents which exhibit at least one, and sometimes a composite profile, of reducing cholesterol, lowering LDL, and inhibiting the expression of VCAM-1 and thus can be used as antiinflammatory and cardivascular treating agents.
U.S. Patent Nos. 5,380,747; 5,792,787; 5,783,596; 5,750,351; 5,821,260;
5,807,884;
5,811,449; 5,846,959; 5,877,203; and 5,773,209 to Medford, et al., teach the use of dithiocarbamates of the general formula A-SC(S)-B for the treatment of cardiovascular and other inflammatory diseases. Examples include sodium pyrrolidine-N-carbodithioate, tri-sodium N,N-di(carboxymethyl)-N-carbodithioate, and sodium N,N-diethyl-N-carbodithioate.
The patents teach that the compounds inhibit the expression of VCAM-1.
WO 98/23581 discloses the use of benzamidoaldehydes and their use as cysteine protease inhibitors.
WO 97/12613 of Cornicelli et al. discloses compounds for the inhibition of 15-lipogenase to treat and prevent inflammation or atherosclerosis. Compounds disclosed include benzopyranoindole, benzimidazole, catacholes, benzoxadiazines, benzo[a]phenothiazine, or related compounds thereof.
Japanese Patent No. 06092950 to Masahiko et al. discloses preparation of epoxy compounds wherein electron deficient olefins such as acylstyrene derivatives, styrene derivatives, and cyclohexenone derivatives are efficiently oxidized by a hydrogen peroxide derivative in the presence of a primary or secondary amine in an organic solvent to give said epoxides which are useful intermediates for pharmaceutical and flavoring materials.
U.S. Patent No. 5,217,999 to Levitzki et al. discloses substituted styrene compound as a method of inhibiting cell proliferation.

Chalcone (1, 3-bis-aromatic-prop-2-en-1-ones) compounds are natural products related to flavonoids. WO 99/00114 (PCT/DK98/00283) discloses the use of certain chalcones, 1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and 1,3-bisaromatic-prop-2-yn-1-ones for the preparation of pharmaceutical compositions for the treatment of prophylaxis of a number of serious diseases including i) conditions relating to harmful effects of inflammatory cytokines, ii) conditions involving infection by Helicobacter species, iii) conditions involving infections by viruses, iv) neoplastic disorders, and v) conditions caused by microorganisms or parasites.
WO 00/47554 filed by Cor Therapeutics describes a broad class of substituted unsaturated compounds for use as antithrombotic agents.
WO 96/20936 (PCT/KR95/00183) discloses thiazolidin-4-one derivatives of the formula:
R~ R3 Ra O
/ \ Rs n T-N
R ~ ~R
H~ R~
Q
which act as PAF antagonists or 5-lipoxygenase inhibitors. The compounds are used in the prevention and treatment of inflammatory and allergic disorders mediated by platelet-activating factor and /or leukotrienes.
U.S. Patent No. 4,085,135 discloses 2'-(carboxymethoxy)-chalcones with antigastric and antiduodenal ulcer activities.
U.S. Patent No. 5,744,614 to Merkle et al. discloses a process for preparing 3,5-diarylpyrazoles and various derivatives thereof by reacting hydrazine hydrate with 1,3-diarylpropenone in the presence of sulfuric acid and an iodine compound.
U.S. Patent No. 5,951,541 to Wehlage et al. discloses the use of salts of aromatic hydroxy compounds, such as (hydroxyaryl)alkenone salts, as brighteners in aqueous acidic electroplating baths. In addition the invention discloses that such compounds have a lower vapor pressure than the known brighteners, as a single substance and in the electroplating baths,in order to avoid losses of substance. They also have high water solubility properties.
Japanese Patent No. 07330814 to Shigeki et al. discloses benzylacetophenone compounds as photoinitiator compounds.
Japanese Patent No. 04217621 to Tomomi discloses siloxane chalcone derivatives in sunscreens.
U.S. Patent No. 4,085,135 to Kyogoku et al. discloses a process for preparation of 2'-(carboxymethoxy)-chalcones having antigastric and anti duodenal activities with low toxicity and high absorptive ratio in the body. This patent suggests that the high absorptive ratio in the body is due to the 2'-carboxymethoxy group attached to the chalcone derivative.
U.S. Patent No. 4,855,438 discloses the process for preparation of optically active 2-hydroxyethylazole derivatives which have fungicidal and plant growth-regulating action by reacting an a-(3-unsaturated ketone which could include a chalcone or a chalcone derivative with an enantiomerically pure oxathiolane in the presence of a strongly basic organometallic compound and at temperatures ranging from -80 to 120 °C.
European Patent No 307762 assigned to Hofmann-La Roche discloses substituted phenyl chalcones.
E. Bakhite et al. in J. Chem. Tech. Biotech. 1992, 55, 157-161, have disclosed a process for the preparation of some phenyloxazole derivatives of chalcone by condensing 5-(p-acetylphenyl)-2-phenyloxazole with aromatic aldehydes.
Herencia, et al., in Synthesis and Anti-inflammatory Activity of Chalcone Derivatives, Bioorganic & Medicinal Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone derivatives with anti-inflammatory activity.
Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J. Pharm.
Pharmacol. 2000, 52; 163-171 describes that certain chalcones have potent antiinflammatory activity.
Zwaagstra, et al., Synthesis and Structure-Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT, (LT4) Receptor Antagonists; J. Med. Chem., 1997, 40, 1075-1089 discloses that in a series of 2-, 3-, and 4-(2-quinolinylmethoxy)-and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2', 3', 4', or 5' carboxylated chalcones, certain compounds are CysLT, receptor antagonists.
JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the S following formula (wherein R~ and R2 are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can be used in treating allergies.
Rz JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloses chalcones of the following structure as 5-lipoxygenase inhibitors, wherein R is acyl and R'-RS
are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R'-RS are hydrogen.
R~

Ra I R= Ac II R-RS=H
U.S. Patent No. 6,046,212 to Kowa Co. Ltd. discloses heterocyclic ring-containing chalcones of the following formula as antiallergic agents, wherein A
represents a substituted or 1 S unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a group x !

in which X represents a hydrogen or halogen atom or a hydroxyl, lower alkyl or lower alkoxyl group and B represents -CH=CH-,-N(R6)-, R6 is a lower alkyl group or a lower alkoxyalkyl group, -O- or -S-; W represents -CH=CH- or -CHZO-, and R,_5 is the same or different and each independently represent a hydrogen or halogen atom, a hydroxyl, a lower alkyl, lower alkoxyl, carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, a group -CONHR~ in which R~
represents a hydrogen atom or a lower alkyl group, or a group -O(CH2)" R8 in which R8 represents a carboxyl, alkyloxycarbonyl or tetrazolyl group and n is from 1 to 4, with the proviso that at least one of the groups R~_5 represents a carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, the group --CONHR~ or the group --O(CHZ)nRB; or a salt or solvate thereof.
Reported bioactivies of chalcones have been reviewed by Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6, 1125-1149;
Liu et al., Antimalarial Alkoxylated and Hydroxylated Chalones: Structure-Activity Relationship Analysis, J.Med. Chem. 2001, 44, 4443-4452; Herencia et al, Novel Anit-inflammatory Chalcone Derivatives Inhibit the Induction of Nitric Oxide Synthase and Cyclooxygenase-2 in Mouse Peritoneal Macrophages, FEBS Letters, 1999, 453, 129-134; and Hsieh et al., Synthesis and Anti-inflammatory Effect of Chalcones and Related Compounds, Pharmaceutical Research, 1998, Vo1.15, No. I, 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-l, 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.
I S 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
S It has been discovered that particular chalcone derivatives inhibit the expression of VCAM-I, and thus can be used to treat a patient with a disorder mediated by VCAM-1.
Examples of inflammatory disorders that are mediated by VCAM-I include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
The compounds disclosed herein can also be used in the treatment of inflammatory skin diseases that are mediated by VCAM-I, as well as human endothelial disorders that are mediated by VCAM-I, 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 2a ~ H R2(3 R3a R3a A H I B
R4a ~ R6a R6t~ ~ R4a Sa R5~
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 1 st embodiment, the invention is represented by Formula I
2a O H R2f~
R3a ~ R3R
\ \
A H I B
R4a ~ R6a R6P ~ R4a sa RS(3 (I) or its pharmaceutically acceptable salt or ester, wherein:
RZ«~ R3«~ Ra«~ Rs«~ R6«~ RZp~ R3a, Rap, Rsp and R6p 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, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R~)2C(O)OH, -OC(R~)2C(O)OR2, -OC(Rl)ZC(O)NH2, -OC(R~)zC(O)NHR2, -OC(R~)zC(O)N(R2)2, -OC(R~)2C(O)NR'R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR~RB, -NHC(R~)ZC(O)OH, -NHC(R~)zC(O)OR2, -NHC(O)R2, -N(Rz)C(O)R2, -NHC(O)ORz, -NHC(O)SRZ, -NHS02NHR2, -NHS02R2, -NHS02NR~R8, -N(C(O)NHR2)2, -NRZSOZR2, -NHC(O)NHR2, -NHC(O)NR~RB , NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCH2C(O)OH, SCFzC(O)OH, -SOzNHz, -SOzNHRz, -SO2N(Rz)z, S02NR'R8, -SOzNHC(O)Rz, -SRz, -S02NHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR'R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'R8, -C(O)NHSOzRz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR'R8, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)OZH, 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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of Rza, R3p, R4a, RSa or R6p, or one of Rz«, R3«, R4«, Rs« or R6«
must be a carbon-carbon linked heterocyclic or heteroaryl; and/or wherein when one of RzR, R3p, R4p, RSR or R6p is a carbon-carbon linked heterocyclic or heteroaryl, only one of Rz«, R3«, R4«, Rs« or R6« can be -0CH3; and/or wherein when one of Rz«, R3«, R4«, Rs« or R6« is a carbon-carbon linked heterocyclic or heteroaryl, only one of Rzp, R3~, R4~, Rsa or R6p can be -0CH3; and/or Rz« and R3« taken together or R3« and R4« taken together or R4« and RS« taken together, or Rz~ and R3~ taken together or R3~ and R4p taken together or R4p and R5~ 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, -NR~RB, and halo; and/or Rz« and R3« taken together or R3« and R4« taken together or R4« and RS« taken together or Rzp and R3R taken together or R3p and R4p taken together or R4p and Rsp 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, I S hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and ~(O)N(Rz)z; provided that Rz«, R3a~ Ra«~
RS«, Rte', Rzp, R3p, R4a, RSp and R6~ cannot be -0C(R')zC(O)OH; and/or at least one of Rz«, R3«, Ray', R5«, R6°' or one of Rzp, R3~, R4p, RS~, R6a must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)NHRz, C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHS02NHRz, -C(O)NHSOzN(Rz), -C(O)NHSOZNR~RB, -C(O)NHC(O)Rz, =C(O)NHSO2Rz, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCH2C(O)OH, -SCF2C(O)OH, -SOZNHz, -SOZNHRz, -SOZN(Rz)z, SOzNR~RB, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR~Rg, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, -NHRz, N(Rz)z, NR~RB, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)OR2, -NHC(O)SRz, -NHSO2NHRz, -NHSOZRz, -NHSOZNR~RB, -N(C(O)NHRz)z, -NRZSOZRz, -NHC(O)NHRz, -NHC(O)NR~RB , and NHC(O)N(Rz)z;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and ~(O)N(Rz)z.
In a 2°d embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ Rsp~ Rap Rsp ~d R6a are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(Rl)zC(O)NI-Iz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(RI)zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~RB, NHC(R')2C(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(RZ)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOZNHRz, -NHSOZRz, -NHSOZNR~Rg, -N(C(O)NHRz)z, -NRZSOzRz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCH2C(O)OH, -SCFZC(O)OH, -S02NH2, -SO2NHR2, -S02N(RZ)2, SOZNR'R8, -S02NHC(O)R2, -SR2, -S02NHC(O)NHRz, -S02NHC(O)N(RZ) 2, -S02NHC(O)NR'Rg, 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(RZ)2, -C(O)NR'Rg, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)z, -C(O)NHC(O)NR'R8, -C(O)NHS02R2, -C(O)NHS02NHR2, -C(O)NHS02N(Rz), -C(O)NHSOzNR'Rg, -C(CH3)ZC(O)OH, -(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02H2, -P03H2, -P(R2)OzH, 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)z;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(RZ)2;
. .. n R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R2a, R3R, R4~, Rsa or Rbp, or one of RZ«, R3«, R4«, Rs« or R6«
must be a carbon-carbon linked heterocyclic or heteroaryl; and/or wherein when one of RZa, R3~, R4a, Rsp or R6~ is a carbon-carbon linked heterocyclic or heteroaryl, only one of Rz«, R3a, Ra«~ Rs« or R6« can be -0CH3; and/or wherein when one of R2", R3", Ra«, Rs" or R6" is a carbon-carbon linked heterocyclic or heteroaryl, only one of RZp, R3a, Rap, R5~ or R6p can be -0CH3; and/or R2« and R3« taken together or R3« and Ra« taken together or Ra" and Rs« taken together, or R2a and R3p taken together or R3p and Rah taken together or Rah and Rsa 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, -NR'Rg, and halo; and/or RZ« and R3« taken together or R3« and Ra« taken together or Ra« and Rs« taken together or R2~ and R3R taken together or R3~ and RaR taken together or Rap and RsR taken together form a S-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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)Z; provided that RZ«, R3«~ Ra«~ Rs«~ R6«~ RZR~ R3a, Rap, Rsa and R6~ cannot be -0C(R')ZC(O)OH;
and/or at least one of RZ«, R3«, R''°', or one of RZR, R3a, RaR must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NH2, -C(O)NHRz, C(O)N(RZ)2, -C(O)NR'Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, C(O)NHC(O)NR'Rg, -C(O)NHSOzNHR2, -C(O)NHSOZN(RZ), -C(O)NHS02NR'R8, -C(O)NHC(O)R2, -C(O)NHS02R2, -C(CH3)2C(O)OH, -(CHZ)YC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')2C(O)OH, -SC(R')2C(O)OR2, -SCH2C(O)OH, -SCFZC(O)OH, -SO2NH2;
-SOZNHR2, -SOZN(RZ)z, SOzNR'R8, -S02NHC(O)Rz, -SR2, SOZNHC(O)NHR2, -S02NHC(O)N(R2)2, -SOZNHC(O)NR'R8, -OC(R')ZC(O)OH, OC(R')ZC(O)OR2, -OC(R')ZC(O)NH2, -OC(R')ZC(O)NHRz, -OC(R')ZC(O)N(RZ)2, OC(R')ZC(O)NR'R8, amino, -NHR2, N(R2)z, NR'R8, -NHC(R')ZC(O)OH, -NHC(R')2C(O)ORZ, -NHC(O)RZ, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSOzNHRz, -NHSOZR2, -NHSOZNR'R8, -N(C(O)NHRZ)2, NR2SOzR2, -NHC(O)NHR2, NHC(O)NR'R8 , and -NHC(O)N(R2)z;

wherein all R', RZ, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)2.
In a 3~d embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
R2«~ Rs«~ Ra«~ Rs«~ R6«~ R2p~ R3p~ Rap Rsp ~d Rba 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, RzC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)2),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')ZC(O)OH, -OC(R')ZC(O)OR2, -OC(R')2C(O)NHz, -OC(R')ZC(O)NHRZ, -OC(R')ZC(O)N(R2)2, -OC(R')ZC(O)NR'R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRZ, N(RZ)2, -NR'R8, -NHC(R')zC(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)RZ, -N(RZ)C(O)R2, -NHC(O)OR2, NHC(O)SR2, -NHSOZNHR2, -NHS02R2, -NHS02NR'R8, -N(C(O)NHR2)z, -NRZSOZR2, -NHC(O)NHR2, -NHC(O)NR'R8 , NHC(O)N(RZ)Z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')2C(O)OH, -SC(R')2C(O)OR2, -SCHzC(O)OH, -SCF2C(O)OH, -SOzNH2, -SO2NHR2, -SOZN(RZ)2, SOzNR'Rg, -S02NHC(O)R2, -SRz, -SOZNHC(O)NHR2, -SOZNHC(O)N(Rz) 2, -S02NHC(O)NR'Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, C(O)NHC(O)NR~RB, -C(O)NHSOZRz, -C(O)NHSOZNHRz, -C(O)NHS02N(Rz), -C(O)NHSOzNR~Rg, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -POZHz, -P03Hz, -P(Rz)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)2;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of Rz~, R3~, R4a, Rsp or R6R must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz", R3", R4«, Rs« or R6" can be -0CH3; and/or Rz°' and R3°' taken together or R3°' and R4" taken together or R4" and Rs°' taken together, or Rzp and R3R taken together or R3p and R4p taken together or R4p and Rsp 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, -NR'R8, and halo; and/or Rz« and R3« taken together or R3" and R4" taken together or R4« and Rs« taken together or Rzp and R3p taken together or R3p and R4a taken together or R4p and Rsp 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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z; provided that Rz«, R3«, Ra«~
Rs«, R6°', Rzp, R3R, R4~, Rsp and R6~ cannot be -0C(R')zC(O)OH;
and/or at least one of Rz«, R3«, R4°', Rs«, or R6" must be selected from the group consisting of cyano, tetrazol-S-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHSOZNHRz, -C(O)NHS02N(Rz), -C(O)NHSOzNR'R8, -C(O)NHC(O)Rz, -C(O)NHSOzRz, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH, -SCF2C(O)OH, -SOZNHz, -SOzNHRz, -SOZN(Rz)z, SOZNR'R8, -SOzNHC(O)Rz, -SRz, -S02NHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'R8, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR'R8, amino, -NHRz, N(Rz)z, NR'R8, -NHC(R')zC(O)OH, NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHSOZRz, -NHSOzNR'Rg, -N(C(O)NHRz)z, -NRZSOzRz, -NHC(O)NHRz, -NHC(O)NR'R8 , and NHC(O)N(Rz)z;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z.
In a 4th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3"~ Ra«~ Rs"~ R6«~ Rzp~ R3a~ Rap Rsa ~d Rbp 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)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')ZC(O)ORZ, -OC(R')ZC(O)NHZ, -OC(R')ZC(O)NHR2, -OC(R')2C(O)N(Rz)2, -OC(R')2C(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)Z, -NR~Rg, -NHC(Rl)2C(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)R2, -N(RZ)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHS02NHR2, -NHSOZR2, -NHSOZNR~Rg, -N(C(O)NHR2)z, -NR2SOZR2, -NHC(O)NHRZ, -NHC(O)NR~Rg, NHC(O)N(R2)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')ZC(O)OH, -SC(R')ZC(O)OR2, -SCH2C(O)OH, -SCFZC(O)OH, -SOZNH2, -SO2NHR2, -S02N(R2)z, SOZNR'R8, -S02NHC(O)RZ, -SR2, -S02NHC(O)NHR2, -SOZNHC(O)N(R2) 2, -S02NHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NH2, -C(O)NHRz, -C(O)N(R2)2, -C(O)NR~RB, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)z, -C(O)NHC(O)NR'R8, -C(O)NHSOzR2, -C(O)NHSOZNHR2, -C(O)NHS02N(R2), -C(O)NHS02NR~R8, -C(CH3)2C(O)OH, -(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -POZH2, -P03H2, -P(R2)OZH, 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;

R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(R2)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused I S ring;
wherein one of R4p, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZ", R3", R4", RS" or R6" can be -0CH3; and/or RZa and R3°' taken together or R3°' and R4°' taken together or R4°' and RS" taken together, or RZR and R3~ taken together or R3~ and R4p taken together or R4a and Rsp 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, -NR~Rg, and halo; and/or R2°' and R3°' taken together or R3" and R4°' taken together or R4°' and RS°' taken together or RZp and R3ataken together or R3p and R4ptaken together or R4p and Rs~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, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(RZ)2; provided that Rz«, R3«, Ra«~
Rs«, R6°', R2p, R3p, R4p, Rsp and R6p cannot be -0C(R')2C(O)OH;
and/or at least one of Rz«, R3«, or R4« must be selected from the group consisting of cyano, tetrazol-S-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(RZ)2, -C(O)NR'Rg, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR'Rg, -C(O)NHS02NHR2, -C(O)NHS02N(RZ), -C(O)NHS02NR'Rg, -C(O)NHC(O)R2, -C(O)NHSOzR2, -C(CH3)2C(O)OH, -(CHZ)YC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')ZC(O)OH, -SC(R')ZC(O)ORz, -SCHzC(O)OH, -SCFZC(O)OH, -S02NH2, -SOZNHR2, -S02N(RZ)Z, SOZNR'Rg, -S02NHC(O)R2, -SR2, -SOZNHC(O)NHR2, -S02NHC(O)N(Rz)2, -SOZNHC(O)NR'R8, -OC(R')2C(O)OH, -OC(R')zC(O)ORZ, -OC(R')ZC(O)NH2, -OC(R')zC(O)NHR2, -OC(R')2C(O)N(R2)2, -OC(R')ZC(O)NR'R8, amino, -NHRz, N(RZ)2, NR'Rg, -NHC(R')2C(O)OH, -NHC(R')2C(O)OR2, -NHC(O)R2, -N(RZ)C(O)R2, -NHC(O)OR2, -NHC(O)SRz, -NHSOZNHRz, -NHSOZR2, -NHSOZNR'R8,-N(C(O)NHRZ)Z, -NRZSOzR2, -NHC(O)NHR2, -NHC(O)NR'Rg , and NHC(O)N(R2)2;
wherein all R', R2, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)2.
In a 5th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZ«~ Rs«~ Ra«~ Rs«~ R6«~ RZa~ R3a, Rap, Rsp and R6p 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, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)2),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R~)2C(O)OH, -OC(Rl)ZC(O)ORZ, -OC(R~)2C(O)NH2, -OC(R~)2C(O)NHRZ, -OC(R~)2C(O)N(Rz)2, -OC(R~)2C(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(RZ)2, -NR~RB, NHC(R~)ZC(O)OH, -NHC(R~)ZC(O)ORz, -NHC(O)R2, -N(Rz)C(O)R2, -NHC(O)OR2, -NHC(O)SRZ, -NHSOZNHR2, -NHS02Rz, -NHS02NR~R8, -N(C(O)NHRZ)2, -NRZSOZRZ, -NHC(O)NHR2, -NHC(O)NR~Rg , NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)ZC(O)OH, -SC(Rl)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SOZNHRZ, -SOzN(RZ)z, SOzNR'R8, -SOZNHC(O)R2, -SR2, -SOzNHC(O)NHR2, -S02NHC(O)N(RZ) 2, -SOZNHC(O)NR~Rg, 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)z, -C(O)NR~Rg, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR~RB, -C(O)NHS02Rz, -C(O)NHS02NHR2, -C(O)NHSOZN(RZ), -C(O)NHSOZNR~RB, -C(CH3)2C(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -POZH2, -P03H2, -P(RZ)OzH, 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, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(R2)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)Z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4p, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«, Rs« or R6« can be -0CH3;
with the proviso that at least one of RZ«, R3°', or R4°' must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NHZ, -C(O)NHR2, C(O)N(R2)z, -C(O)NR'R8, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)z, -C(O)NHC(O)NR'R8, -1 S C(O)NHSOZNHR2, -C(O)NHSOZN(RZ), -C(O)NHSOZNR'R8, -C(O)NHC(O)RZ, -C(O)NHS02Rz, -C(CH3)ZC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')2C(O)OH, -SC(R')ZC(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SOZNH2, -S02NHRz, -SOZN(R2)2, SOZNR'R8, -S02NHC(O)Rz, -SR2, SOZNHC(O)NHR2, -S02NHC(O)N(RZ) 2, -SOZNHC(O)NR'R8, -OC(R')2C(O)OH, OC(R')ZC(O)OR2, -OC(R')ZC(O)NH2, -OC(R')ZC(O)NHR2, -OC(R')2C(O)N(RZ)2, OC(R')2C(O)NR'R8, amino, NHRZ, N(RZ)2, NR'Rg, NHC(R'~C(O)OH, -NHC(R')2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)ORz, -NHC(O)SRz, -NHSOZNHR2, -NHS02R2, -NHS02NR'Rg, -N(C(O)NHRz)2, -NRZSOzRz, -NHC(O)NHR2, NHC(O)NR'Rg , and -NHC(O)N(RZ)2;
wherein all R', R2, R' and R$ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)2.

In a 6th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ Rs«~ Ra«~ Rs«~ Rs«~ Rzp~ R3p~ Rap Rsp and R6p 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~Rg, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHS02NHRz, -NHSOzRz, -NHS02NR~R8, -N(C(O)NHRz)z, -NRZSOzRz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCH2C(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOZN(Rz)z, S02NR~Rg, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOZNHC(O)N(Rz) z, -SOZNHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOZRz, -C(O)NHS02NHRz, -C(O)NHSOZN(Rz), -C(O)NHS02NR~R8, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -P02H2, -P03Hz, -P(RZ)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -0(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4~, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2«, R3a~ Ra«~ Rs« or R6« can be -0CH3;
with the proviso 'that at least one of RZ°', R3a, or R4°' must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)zC(O)OH, (CH2)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2.

In a 7th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ R2a~ R3p, Rap, Rsp and R6p 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~RB, NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, NHC(O)SRz, -NHSOZNHRz, -NHSOZRz, -NHSOZNR~Rg, -N(C(O)NHRz)z, -NRzS02Rz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOZN(Rz)z, S02NR~R8, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR~Rg, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHS02N(Rz), -C(O)NHS02NR~Rg, -C(CH3~C(O)OH, and -(CHz)yC(O)OH, wherein y is l, 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)2;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(RZ)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4~, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZ°, R3°', R4a, Rs« or R6" can be -0CH3;
with the proviso that at least one of Rz°', R3", or R4°' must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)ZC(O)OH, (CHZ)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all Rl, R2, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)2.

In an 8th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
R2a~ R3«~ Ra«~ Rs«~ R6«~ Rza~ Rsp~ Rap Rsp ~d R6R 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, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)2),_3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R~)ZC(O)N(RZ)2, -OC(R')ZC(O)NR'R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR'R8, -N(Rz)C(O)Rz, -NHS02NR~R8, -N(C(O)NHRZ)2, -NHC(O)NR'Rg , NHC(O)N(R2)2, -S02NH2, -S02NHR2, I S -SOZN(R2)2, S02NR'R8, -SOZNHC(O)R2, -SR2, -S02NHC(O)NHR2, -S02NHC(O)N(RZ) 2, -SOZNHC(O)NR'R8, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(Rz)2, -C(O)NR'Rg, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR'Rg, -C(O)NHS02R2, -C(O)NHSOZNHRZ, -C(O)NHSOZN(R2), -C(O)NHSOZNR'Rg, -C(CH3)ZC(O)OH, and -(CHZ)yC(O)OH, wherein y is I, 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, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(Rz)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, oxo, cyano, -C(O)NR'Rg, and -C(O)N(RZ)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4R, Rsp or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«, Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(CH3)zC(O)OH, (CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 9t" embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsp ~d R6a 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(CHz)z),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(Rz)z, -NR'R8, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)N(Rz)z, -C(O)NR'R8, -C(CH3)zC(O)OH, and -(CHz)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, -NR'R8, -C(O)NR'Rg, and -C(O)N(Rz)z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4R, RsR or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rza, R3", R4°', Rsa or R6" can be -0CH3;
with the proviso that at least one of Rz«, R3a, or R4« must be selected from the group consisting of tetrazol-5-yl, carboxy, -C(O)ORz, -C(CH3)zC(O)OH, (CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 10th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rza~ R3p~ Rap Rsp ~d R6p are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy, -(O(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy, -C(O)ORz, -C(O)N(Rz)z, and -C(O)NR'R8, 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, -NR'R8, -C(O)NR'Rg, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR'Rg, alkoxy, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic or benzofused ring;

wherein one of R4a, Rsp or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2«, R3«, Ra«, Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from carboxy or -C(O)ORz;
wherein all Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, -NR'R8, -C(O)NR'R8, and C(O)N(Rz)z.
In an 11 th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«, R3«, Ra«~ Rs«~ R6«~ Rzp~ Rsp~ Rap Rsp and R6p are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z),_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, -NR'Rg, -C(O)NR'Rg, and -C(O)N(Rz)2;
I S Rz is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4p, Rs~ or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3a~ Ra«~ Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«; :or'Ra« must be carboxy.
In a 12th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ Rs«~ Ra«~ Rs«~ and R6« are independently selected from the group consisting of hydrogen and carboxy;
Rz~, R3R, R4R, Rs~ and R6p are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z)~_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, -NR~RB, -C(O)NR~RB, and ~(O)N(Rz)2;
RZ is lower alkyl;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4a, RSa or R6a must be a carbon-carbon linked heterocyclic or heteroaryl;
with the proviso that at least one of Rz«, R3«, or R4« must be carboxy.
In a 13th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ and R6« are independently selected from the group consisting of hydrogen and carboxy;
R2R, R3p, R4R, R5~ and R6R are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy, -(O(CHZ)2),_3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR~Rg, -C(O)NR~RB, and -C(O)N(RZ)2;
R2 is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring; ' wherein one of R4p, R5~ or R6p must be a carbon-carbon linked heteroaryl;
with the proviso that at least one of R2«, R3a, or R4« must be carboxy.
In a 14th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

Rz«~ R3«~ Ra«~ Rs«~ and R6« are independently selected from the group consisting of hydrogen and carboxy;
Rzp, R3a, RaR, Rsp and R6a are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH30(CHz)z0(CHz)z-, O ~ O
-CCH2C- N O -C(CHz)2C-N O
and ;
wherein one of RaR, Rsa or R6p 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 Rz«, R3«, or Ra« must be carboxy.
In a 15th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ and R6« are independently selected from the group consisting of hydrogen and carboxy;
Rzp, R3a, RaR, RsR and R6a are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, andCH30(CHz)z0(CH2)z;
wherein one of Rap, Rsa or R6R must be selected from the group consisting of thiophen-s-yl, benzo[b]thiophen-2-yl, indol-2-yl, 1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol-2'yl, and N-Boc-pyrrol-3-yl;
with the proviso that at least one of Rz«, R3«, or Ra« must be carboxy.
In a 16'~ embodiment, the invention is selected from a compound A compound selected from the group consisting of 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid;
4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt;
4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid, sodium salt;
4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid;
4-[3-(2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoic acid;
4-[3E-(4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-{4-Fluoro-3-(thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid;
4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid;
4-[3E-(2-Fluoro-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-[3E-(4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-{ 5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl }-indole-1-carboxylic acid tert-butyl ester;
4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-[3E-(2,4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic acid;
4-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
3-[3E-(2,4-Dimethoxy-S-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-I -methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl }-benzoic acid;
2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-(3E- { 2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thi ophen-2-yl-phenyl } -acryloyl)-benzoic acid;
4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
5-{S-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester;
S-{ 5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl }-thiophene-carboxylic acid;
4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
I S 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-I-carboxylic acid tert-butyl ester;
4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4- { 3 E-[2-( I -Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl } -benzo is 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-S-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-[S-(3H Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
2-{4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-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 17a' embodiment, the invention is a compound selected from the group consisting of 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid; and 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-S-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride,or its pharmaceutically acceptable salt or ester.
In an 18th embodiment, the invention is 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid or its pharmaceutically acceptable salt or ester.
In a 19'" embodiment, the invention is 4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid, or its pharmaceutically acceptable salt or ester.
In a 20'" embodiment, the invention is 4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid; and,or its pharmaceutically acceptable salt or ester.
In a 21 st embodiment, the invention is 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-S-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride,or its pharmaceutically acceptable salt or ester.
In a 22°d embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
R2«~ R3a~ Ra«~ Rs«~ and R6« are independently selected from the group consisting of hydrogen and carboxy;
R2a, R3~, R4~, Rsp and R6~ are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHZ)z)i-3-~-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, -NR~RB, -C(O)NR~RB, and -C(O)N(RZ)2;
R2 is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4p, Rsa or R6~ must be a carbon-carbon linked heterocyclic;
with the proviso that at least one of R2«, R3«, or Ra« must be carboxy.

In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3a~ Ra«~ Rsa~ and R6« are independently selected from the group consisting of hydrogen and carboxy;
RzR, R3~, R4a, Rsp and R6R are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)2),-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR'Rg, -C(O)NR'R8, and -C(O)N(Rz)z;
Rz is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4p, Rs~ or R6p must be a carbon-carbon linked tetrahydrofurn-2-yl or dihydrofuran-2-yl;
1 S with the proviso that at least one of Rz«, R3«, or R4« must be carboxy.
In a 24th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsa ~d R6P 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~Rg, NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, NHC(O)SRz, -NHSOzNHRz, -NHS02Rz, -NHSOzNR~RB, -N(C(O)NHRz)z, -NRZSOZRz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHzC(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOZN(Rz)z, SOZNR~Rg, -SOZNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -S02NHC(O)N(Rz) z, -SOzNHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHS02Rz, -C(O)NHS02NHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~Rg, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -POZHz, -P03Hz, -P(Rz)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(Rz)z; .
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4R, Rs~ or Rbp must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, R4«, Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHS02NR~Rg, -C(O)NHC(O)Rz, -C(O)NHSOZRz;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 25th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsp ~d R6P 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RzC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')ZC(O)OH, -OC(R')2C(O)ORz, -OC(R')ZC(O)NH2, -OC(R')ZC(O)NHR2, -OC(R')2C(O)N(RZ)2, -OC(R')ZC(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino-NHRz, N(RZ)Z, -NR~RB, -NHC(R')zC(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSOZNHR2, -NHSOZR2, -NHSOZNR~RB, -N(C(O)NHRZ)2, -NR2SOZR2, -NHC(O)NHR2, -NHC(O)NR~RB , NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')2C(O)OH, -SC(R')2C(O)OR2, -SCHZC(O)OH, -SCF2C(O)OH, -S02NH2, -SOzNHR2, -SOzN(R2)2, SOZNR~RB, -S02NHC(O)R2, -SRZ, -SOZNHC(O)NHR2, -S02NHC(O)N(RZ) 2, -SOZNHC(O)NR~RB, cyano, tetrazol-5-yl, carboxy, -C(O)ORZ, -C(O)NH2, -C(O)NHR2, -C(O)N(Rz)2, -C(O)NR~RB, -C(O)NHC(O)R2, -C(O)NHC(O)NHRZ, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR~RB, -C(O)NHSOZR2, -C(O)NHS02NHR2, -C(O)NHSOZN(RZ), -C(O)NHS02NR~R8, 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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)2;

Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R$ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4R, Rsp or R6~ must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3°', R4«, Rs° or R6a can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'Rg, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'R8, -C(O)NHSOzNHRz, -C(O)NHS02N(Rz), -C(O)NHSOZNR'R8, -C(O)NHC(O)Rz, and -C(O)NHSOZRz;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(Rz)z.
In a 26th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3a~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsp ~d R6P 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)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')ZC(O)N(Rz)2, -OC(R')2C(O)NR~RB, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRZ, N(R2)2, -NR~RB, -N(RZ)C(O)Rz, -NHSOZNR~RB, -N(C(O)NHRZ)z, -NHC(O)NR~RB, NHC(O)N(RZ)z, -SOZNHZ, -S02NHR2, -SO2N(R2)2, S02NR~Rg, -S02NHC(O)RZ, -SOzNHC(O)NHR2, -S02NHC(O)N(RZ) 2, -SOZNHC(O)NR~RB, cyano, tetrazol-5-yl, -C(O)OR2, -C(O)NHz, -C(O)NHRZ, -C(O)N(R2)2, -C(O)NR~RB, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR'R8, -C(O)NHSOZR2, -C(O)NHS02NHR2, -C(O)NHSOZN(RZ), -C(O)NHSOZNR~Rg, and -C(CH3)ZC(O)OH, -(CHZ)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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -0(O)N(Rz)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR~RB, and -C(O)N(RZ)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(R2)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4R, Rsa or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2«, R3a~ Ra«~ Rs« or R6« can be -0CH3;

with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR'Rg, -C(O)NHC(O)Rz, and -C(O)NHSOZRz;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 27th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3~t~ Rap Rs~ and R6~ 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(CHz)z)I-s-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(Rz)z, -NR~RB, -N(Rz)C(O)Rz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, and -C(CH3)zC(O)OH, -(CHz)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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarboriyl, -C(O)NR'Rg, and -C(O)N(Rz)z;
R~ is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, -C(O)NR'R8, and -C(O)N(Rz)z~
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' and R$ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4p, Rsa or R6~ must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, and -C(O)NHSOZRz;
wherein all R', Rz, R' and R$ substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, -C(O)NR~Rg, and -C(O)N(Rz)z.
In a 28'h embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3a~ Ra«~ Rs«~ R6«~ Rzp~ R3a~ Rap Rsp ~d R6~ are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -C(O)NHz, and -C(O)NHRz, 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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, and lower alkyl which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, -NR~RB, alkoxy, -C(O)NR~Rg, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, heteroaryl, and heterocyclic, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR'R8, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic ring;
wherein one of R4p, R5~ or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«~ Ra«~ Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)NHC(O)Rz, and -C(O)NHSOZRz;
wherein all Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, heterocyclic, amino, aminoalkyl, and -NR'R8.
In a 29th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Raa~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsa and Rbp are independently selected from the group 1 S consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)z),-s-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -C(O)NHz, and -C(O)NHRz, 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is hydrogeri;~ '~
Rz is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic ring;
wherein one of R4R, R5~ or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, R4«, Rs« or R6« can be -0CH3;

with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -C(O)NHz, =C(O)NHRz, -C(O)NHC(O)Rz, and -C(O)NHSOZRz;
wherein all Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of heterocyclic, amino, aminoalkyl, and -NR~RB.
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 I S 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-N
isobutyryl-benzamide.
In a 31St embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3a~ Ra«~ Rs«~ R6a~ Rzp~ Rsp~ Rap Rsp ~d R6p 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RzC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~RB, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~RB, NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, NHC(O)SRz, -NHSOzNHRz, -NHSOZRz, -NHSOzNR~RB, -N(C(O)NHRz)z, -NRZS02R2, -NHC(O)NHRz, -NHC(O)NR'R8 , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCH2C(O)OH, -SCFZC(O)OH, -SOZNHz, -SOzNHRz, -SOzN(Rz)z, SOzNR'Rg, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOZNHC(O)N(Rz) z, -S02NHC(O)NR~RB, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -1 S C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~Rg, -C(O)NHSOZRz, -C(O)NHSOZNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~RB, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)OZH, 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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and-C(O)N(Rz)z;
RI is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4R, Rsp or R6~ must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3a, or R4« must be selected from the group consisting of thiol, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHzC(O)OH, SCFzC(O)OH, -SOzNHz, -S02NHRz, -S02N(Rz)z, SOzNR~Rg, -SOZNHC(O)Rz, -SRz, -SOZNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR~RB;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(Rz)z.
1n a 32nd embodiment, the invention is represented by Formula 1 or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsa ~d R6a are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, . ~. cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')ZC(O)ORz, -OC(R')2C(O)NH2, -OC(R')2C(O)NHRZ, OC(R')2C(O)N(RZ)Z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)z, -NR~RB, -NHC(R')ZC(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)RZ, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SRZ, -NHSOZNHR2, -NHSO2R2, -NHSOzNR~RB, -N(C(O)NHRz)2, -NRZSO2R2, -NHC(O)NHRz, -NHC(O)NR'Rg , -NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')ZC(O)OH, -SC(R')2C(O)OR2, -SCHZC(O)OH, -SCFZC(O)OH, -S02NH2, -SOzNHR2, -SOZN(Rz)2, S02NR'Rg, -S02NHC(O)R2, -SR2, -S02NHC(O)NHR2, -SOZNHC(O)N(RZ) 2, -SOZNHC(O)NR~Rg, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NHZ, -C(O)NHRz, -C(O)N(RZ)2, -C(O)NR~RB, -C(O)NHC(O)RZ, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)Z, -C(O)NHC(O)NR~RB, -C(O)NHSOZR2, -C(O)NHSOZNHR2, -C(O)NHSOZN(R2), -C(O)NHS02NR~R8, -C(CH3)ZC(O)OH, and -(CH2)yC(O)OH, wherein y is l, 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, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4~, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZ", R3a, Ra«~ Rs« or R6" can be -0CH3;
with the proviso that at least one of RZ", R3a, or R4 must be selected from the group consisting of thiol, -SC(R')2C(O)OH, -SC(R')zC(O)OR2, -SCH2C(O)OH, SCFzC(O)OH, -S02NH2, -SOZNHR2, -SOZN(RZ)2, SOZNR~RB, -SOZNHC(O)Rz, -SR2, -SOZNHC(O)NHR2, -S02NHC(O)N(R2) 2, -S02NHC(O)NR~RB;
wherein all R', R2, R' and R$ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)z.
In a 33'd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZ«~ R3«~ Ra«~ Rs«~ R6«~ Raa~ R3p~ Rap Rsp ~d R6D 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, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)2)i_3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(RI)zC(O)N(Rz)z, -OC(R~)zC(O)NR'R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR'R8, -N(Rz)C(O)Rz, -NHSOzNR'R8, -N(C(O)NHRz)z, -NRZSOZRz, -NHC(O)NHRz, -NHC(O)NR'Rg , -NHC(O)N(Rz)z, -SC(Rl)zC(O)OH, -SC(R~)zC(O)ORz, -SCHZC(O)OH -SOzNHz, -SOZNHRz, -SOzN(Rz)z, SOzNR'Rg, -SOZNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'Rg, cyano, tetrazol-5-yl, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'Rg, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHSOZRz, -C(O)NHS02NHRz, -C(O)NHSOZN(Rz), -C(O)NHS02NR'R8, -C(CH3)zC(O)OH, and -(CHz)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, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylarylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(RZ)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(RZ)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4~, Rsp or R6~ must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz", R3", R4", RS" or R6" can be -0CH3;

with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCHZC(O)OH, SOZNHz, -SOzNHRz, -SOZN(Rz)z, S02NR'R8, -SOzNHC(O)Rz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'R8;
wherein all R', Rz, R' and R$ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(Rz)z.
In a 34th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3a~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsp and R6p 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(CHz)z),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(Rz)z, -NR'R8, -N(Rz)C(O)Rz, -SCHzC(O)OH -S02NHz, -SOZNHRz, -S02N(Rz)z, SOzNR'Rg, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR'Rg, -C(O)N(Rz)z, -C(O)NR'Rg, and -C(O)NHSOzRz, 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, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, -C(O)NR'Rg, and -C(O)N(Rz)z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R$ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4a, RsR or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, R4«, Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -SC(R')zC(O)ORz, -SCHzC(O)OH, -SOzNHz, -S02NHRz, -SO2N(Rz)z, SOzNR'R8, -SOzNHC(O)Rz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'Rg;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, -C(O)NR'Rg, and -C(O)N(Rz)z.
In a 35th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Raa~ Rs«~ R6«~ Rzp~ R3p~ Raa~ Rsa ~d R6a 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(CHz)z)i-s-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -SCH2C(O)OH -SOzNHz, -S02NHRz, -SOZN(Rz)z, SOzNR'R8, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR'Rg, and -C(O)NHSOZRz, 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, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z;

R' is independently selected from the group consisting of hydrogen and lower alkyl, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, -NR~RB, alkoxy, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl and lower alkyl, which may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR~Rg, alkoxy, -C(O)NR~Rg, and -C(O)N(Rz)2;
R' and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic ring;
wherein one of R4p, Rs~ or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, I 0 and only one of Rz«, R3«, Raa~ Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -SC(R')zC(O)ORz, -SCHZC(O)OH, -SOZNHz, -SOzNHRz, -SOZN(Rz)z, SOzNR~RB, and -SOZNHC(O)Rz ;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more 1 S selected from the group consisting of halo, NR~Rg, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 36'" embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsp ~d R6t~ are independently selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, carbocycle, heteroaryl, heterocyclic, 20 hydroxyl, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -SOZNHz, -SOzNHRz, SOzNHC(O)Rz, -SRz, SOzNHC(O)NHRz, -SOzNHC(O)N(Rz)z, -SOZNHC(O)NR~RB, and -C(O)NHSOzRz, all of which can be optionally substituted by one or more selected from the group consisting of alkenyl, acyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, -25 C(O)NR~Rg, and -C(O)N(Rz)z;
R' is hydrogen;
Rz is lower;

R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic ring;
wherein one of R4a, Rsp or R6~ must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz°', R3a, R4a, Rsa or R6a can be -0CH3;
with the proviso that at least one of RZa, R3°', or R4°' must be selected from the group consisting of -SC(R')ZC(O)OR2, -S02NH2, - S02NR'Rg, and -SOZNHC(O)R2 .
In a 37th embodiment, the invention is represented by the following compound:
4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzenesulfonamide;
4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide;
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide;
2-{5-Methoxy-2-[3-oxo-3-(4-sulfamoyl-phenyl)-E-propenyl]-4-thiophen-2-yl-phenoxy}-2-methyl-propionic acid;
2-{2,4-Dimethoxy-S-[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-yl-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-(lHtetrazol-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-1 H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;
4-{3E-[5-(3H Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide;
4-{3E-[2-(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:
R2«~ R3«~ Ra«~ Rs«~ Rs«~ R2p~ Rsp~ Rap RsR and R6~ are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)RZ, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)2)~_3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')2C(O)OR2, -OC(R~)ZC(O)NHz, -OC(R')ZC(O)NHR2, OC(R~)2C(O)N(RZ)2, -OC(R~)2C(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, NHR2, N(R2)2, -NR~RB, -NHC(R')2C(O)OH, -NHC(R~)ZC(O)OR2, -NHC(O)R2, N(RZ)C(O)RZ, -NHC(O)OR2, -NHC(O)SR2, -NHSOZNHR2, -NHSOZR2, -NHSOZNR~Rg, -N(C(O)NHR2)2, -NRzSO2R2, -NHC(O)NHR2, -NHC(O)NR~RB , NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')2C(O)OH, -SC(R~)ZC(O)OR2, -SCH2C(O)OH, SCF2C(O)OH, -SOZNH2, -SOZNHR2, -S02N(R2)Z, SOZNR~RB, -SOZNHC(O)R2, -SR2, -SOzNHC(O)NHR2, -SOZNHC(O)N(R2) 2, -SOZNHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NH2, -C(O)NHR2, -C(O)N(RZ)2, -C(O)NR'R8, -C(O)NHC(O)RZ, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(Rz)2, -C(O)NHC(O)NR~RB, -C(O)NHSOZRz, -C(O)NHS02NHR2, -C(O)NHSOZN(Rz), -C(O)NHS02NR~Rg, -C(CH3)2C(O)OH, -(CH2)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -POZH2, -P03H2, -P(RZ)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, "" ~ ' ~ heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)2;

R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4a, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3;
with the proviso that at least one of Rz«, R3a, or R4« must be selected from the group consisting of amino, -NHRz, N(Rz)z, NR~RB, -NHC(R')zC(O)OH, -NHC(R~)zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHS02NHRz, -NHSOZRz, -NHSOZNR~RB, -N(C(O)NHRz)z, -NRZSOZRz, -NHC(O)NHRz, -NHC(O)NR~RB , and -NHC(O)N(Rz)z;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 39'" embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3a~ Ra«~ Rs«~ R6«~ R2p~ R3a, Rap, Rsp and R6~ are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z)~-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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;
Rz is lower alkyl optionally substituted by alkoxycarbonyl.
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic ring;
wherein one of R4~, R5~ or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3;

with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of amino, -N(C(O)NHRz)z, NR2SOzRz and -NRzSO2Rz;
wherein all Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 40th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3a~ Rap Rsp ~d R6~ are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~Rg, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)R2, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHSOZRz, NHSOZNR~RB, -N(C(O)NHRz)z, -NRZSOZRz, -NHC(O)NHR2, -NHC(O)NR~Rg , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCHZC(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOzN(Rz)z, SOzNR'R8, -S02NHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'R8, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHSOzN(Rz), -C(O)NHS02NR'R8, -C(CH3)zC(O)OH, -(CHz)YC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy,l oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4R, Rsa or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3;

with the proviso that at least one of Rz«, R3«, or R4« must be selected from the group consisting of -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~RB;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and ~(O)N(Rz)z.
In a 41 st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz«, Rs«~ Ra«~ Rs«~ R6a~ Rzp~ R3p~ Rap Rsp and R6~ are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z),_3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, I S hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and ~(O)N(Rz)z;
R' is hydrogen or lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic ring;
wherein one of R4~, RsR or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3;

with the proviso that at least one of Rz«, R3«, or R4« must be selected from -OC(R')zC(O)OH;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z.
In a 42"a embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rza~ R3«~ Ra«~ Rs«~ R6«~ Rzp~ R3p~ Rap Rsp ~d R6a are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, ~ -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(Rz)z, -NR~RB, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, NHC(O)SRz, -NHSOzNHRz, -NHSOZRz, -NHSOZNR~RB, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')2C(O)OR2, -SCH2C(O)OH, -SCFZC(O)OH, -S02NH2, -SOzNHR2, -SOZN(R2)Z, S02NR~R8, -SOzNHC(O)R2, -SRz, -S02NHC(O)NHRZ, -S02NHC(O)N(RZ) 2, -S02NHC(O)NR~RB, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHRZ, -C(O)N(RZ)z, -C(O)NR~Rg, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)Z, -C(O)NHC(O)NR~RB, -C(O)NHS02R2, -C(O)NHSOZNHRZ, -C(O)NHSO2N(R2), -C(O)NHS02NR~R8, -C(CH3)ZC(O)OH, -(CH2)YC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -POZH2, -P03H2, -P(RZ)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg;'and -C(O)N(Rz)2;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4p, Rsp or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZ«, R3«, R4«, Rs« or R6« can be -0CH3; and/or RZ« and R3« taken together or R3« and R4« taken together or R4« and Rs« taken together, or RZp and R3~ taken together or R3p and R4p taken together or R4~ and Rsp 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 S from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, -NR'R8, and halo; and/or At least one of Rz«, R3«, or R4« must be selected from the group consisting of cyano, tetrazol-S-yl, carboxy, -C(O)OR2, -C(O)NHz, -C(O)NHR2, -C(O)N(RZ)Z, -C(O)NR'Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)z, C(O)NHC(O)NR'Rg, -C(O)NHS02NHR2, -C(O)NHSOZN(RZ), -C(O)NHSOZNR'R8, -C(O)NHC(O)R2, -C(O)NHS02RZ, -C(CH3)ZC(O)OH, --(CHZ)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(Rl)ZC(O)OH, -SC(R~)2C(O)OR2, -SCHzC(O)OH, -SCFZC(O)OH, -SOzNH2, -S02NHR2, -SOzN(RZ)2, SOZNR'Rg, -SOZNHC(O)R2, -SR2, -S02NHC(O)NHR2, -S02NHC(O)N(RZ) z, -SOZNHC(O)NR'R8, -OC(Rl)ZC(O)OH, OC(R~)ZC(O)OR2, -OC(R~)2C(O)NH2, -OC(R~)ZC(O)NHR2, -OC(R~)ZC(O)N(RZ)2, OC(Rl)ZC(O)NR'Rg, amino, -NHRZ, N(RZ)2, NR'Rg, -NHC(R~)2C(O)OH, -NHC(R~)ZC(O)ORZ, -NHC(O)Rz, -N(Rz)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSOZNHR2, -NHSO2R2, NHSOZNR'Rg, -N(C(O)NHRZ)2, -NR2SOZR2, -NHC(O)NHR2, NHC(O)NR'R8, and NHC(O)N(R2)2;
wherein all R~, RZ, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, ~. .
carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)2.
In a 43"d embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZ«~ R3«~ Ra«~ Rs«~ R6«~ RZp~ Rsp~ Rap Rsp ~d R6P are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O(CHZ)2),_3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)2;
Rz is independently alkyl or lower alkyl;
R' and Rg are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring;
wherein one of R4p, Rsp or R6~ must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2°, R3a, Raa, Rsa or R6a can be -0CH3; and/or R3« and R4« taken together or R4« and RS« taken together, or R3p and R4p taken together or R4~ and R5~ taken together form a heterocyclic ring optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.
In a 44'" embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZ«~ R3a~ Ra«~ Rs«~ R6a~ R2p~ R3a, Raa, Rsp and R6a are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)2),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')2C(O)OR2, -OC(R')ZC(O)NH2, -OC(R')ZC(O)NHR2, -OC(R')ZC(O)N(Rz)Z, -OC(R')2C(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR'R8, -NHC(R~)zC(O)OH, -NHC(R1)ZC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOZNHRz, -NHSOZRz, -NHS02NR'R8, N(C(O)NHRz)z, -NRZS02Rz, -NHC(O)NHRz, -NHC(O)NR'R8, NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCHZC(O)OH, -SCFZC(O)OH, -SOzNHz, -S02NHRz, -SOZN(Rz)z, SOZNR'Rg, -SOzNHC(O)Rz, -SRz, -SOZNHC(O)NHRz, -SOZNHC(O)N(Rz) z, -SOZNHC(O)NR'R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOZNR'R8, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -POZHz, -P03Hz, -P(Rz)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl,.
alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;

R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4p, Rs~ or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZ«, R3«, Ra«~ Rs« or R6« can be -0CH3; and/or R2« and R3« taken together or R3« and R4« taken together or R4« and Rs« taken together or R2p and R3~ taken together or R3a and R4p taken together or R4p and Rs~ 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)2; provided that RZ«, R3«, Ra«~
Rs«, R6°', RZa, R3R, R4p, Rsp and R6p cannot be -0C(R')2C(O)OH;
and/or at least one of R2«, R3«, or R4« must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2,t -C(O)NH2, -C(O)NHR2, -C(O)N(RZ)z, -C(O)NR'Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)z, -C(O)NHC(O)NR'Rg, -C(O)NHSOzNHR2, -C(O)NHS02N(R2), -C(O)NHSOZNR'R8, -C(O)NHC(O)Rz, -C(O)NHS02R2, -C(CH3)2C(O)OH, -(CH2)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, thiol, -SC(R')2C(O)OH, -SC(R')zC(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SOzNH2, -SOZNHRz, -S02N(RZ)2, SOzNR'Rg, -S02NHC(O)R2, -SR2, -S02NHC(O)NHR2, -SOzNHC(O)N(Rz) 2, -S02NHC(O)NR'Rg, -OC(R')2C(O)OH, -- OC(R')2C(O)OR2, -OC(R')2C(O)NHZ, -OC(R')ZC(O)NHR2, -OC(R')2C(O)N(R2)z, -.~~'j~.'-: _OC(R')2C(O)NR'Rg, amino, -NHRz, N(R2)2, NR'R8, -NHC(R')zC(O)OH, =NHC(R')2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSOZNHRz, -NHSOzR2, -NHSOZNR'Rg, -N(C(O)NHRZ)2, -NRZSOZR2, -NHC(O)NHR2, -NHC(O)NR'Rg, and -NHC(O)N(Rz)2, wherein all R', R2, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(RZ)2.

In a 45't' embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rza~ R3«~ Ra«~ Rsa~ R6«~ Rzp~ R3~~ Raa~ Rsp and R6~ are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O(CHz)z),_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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;
Rz is independently alkyl or lower alkyl;
R' and Rg are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring;
wherein one of R4p, Rsp or R6p must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz«, R3«, Ra«~ Rs« or R6« can be -0CH3; and/or R3« and R4« taken together or R4« and Rs« taken together or R3~ and R4~ taken together or R4~ and Rsp 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 Rz«~ R3a~ Ra«~ Rs«~ Rs«~ Rzp~ R3a~ RaR~ Rsp ~d R6a cannot be -0C(R')zCOOH.
In a 46th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz p, R3p, Rap, RsR, R6p, Rz«, R3a, Ra«~ Rs« and R~ 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)~_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')2C(O)ORz, -OC(R')ZC(O)NH2, -OC(R')zC(O)NHR2, -OC(R')ZC(O)N(R2)2, -OC(R')ZC(O)NR~RB, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR'Rg, -NHC(R')2C(O)OH, -NHC(R')2C(O)OR2, -NHC(O)RZ, -N(RZ)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHS02NHR2, -NHS02R2, -NHS02NR~Rg, -N(C(O)NHRZ)2, -NRZSOZR2, -NHC(O)NHR2, -NHC(O)NR~RB , NHC(O)N(Rz)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')2C(O)OH, -SC(R')ZC(O)OR2, -SCHZC(O)OH, -SCFZC(O)OH, -SOZNH2, -S02NHR2, -SOZN(R2)2, SOZNR'Rg, -S02NHC(O)R2, -SRz, -S02NHC(O)NHR2, -SOZNHC(O)N(RZ) z, -SOZNHC(O)NR~RB, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NHz, -C(O)NHRZ, -C(O)N(R2)2, -C(O)NR'Rg, -C(O)NHC(O)R2, -C(O)NHC(O)NHRZ, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR~Rg, -C(O)NHSOZR2, -C(O)NHS02NHR2, -C(O)NHSOZN(RZ), -C(O)NHSOZNR~RB, -C(CH3)2C(O)OH, -(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02H2, -P03H2, -P(RZ)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(R2)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)2;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(RZ)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R2", R3«, Ra«~ Rs« or R6", or one of RZp, R3p, R4R, Rsp or R6~
must be a carbon-carbon linked heterocyclic or heteroaryl; and/or wherein when one of RZ", R3", R4", Rs" or R6" is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2~, R3p, R4p, Rsp or Rbp can be -OCH3; and/or wherein when one of RZp, R3p, R4~, Rsp or R6a is a carbon-carbon linked heterocyclic or heteroaryl, only one of RZ", R3«, Ra«~ Rs« or R6" can be -0CH3; and/or R2R and R3p taken together or R3p and R4p taken together or R4p and Rsp taken together, or Rz" and R3" taken together or R3" and R4" taken together or R4" and Rs" 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, -NR'R8, and halo; and/or Rzp and R3p taken together or R3p and R4p taken together or R4~ and Rsp taken together or R2" and R3" taken together or R3" and R4" taken together or R4" and Rs" 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z; provided that Rzp, Rs~, Rap, RsR, R6p, Rz«, Rs«~ Ra«~ Rs« and R6" cannot be -0C(R~)zC(O)OH;
and/or at least one of Rzp, R3a, R4~, or one of Rz", R3", R4" must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, C(O)NHC(O)NR'Rg, -C(O)NHSOZNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR'Rg, -C(O)NHC(O)Rz, -C(O)NHS02Rz, -C(CH3)zC(O)OH, -(CHz)YC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')zC(O)OH, -SC(R~)zC(O)ORz, -SCH2C(O)OH, -SCFzC(O)OH, -SOZNHz, -SOZNHRz, -SOZN(Rz)z, SOzNR'Rg, -S02NHC(O)Rz, -SRz, -S02NHC(O)NHRz, -SOZNHC(O)N(Rz) z, -SOZNHC(O)NR'Rg, -OC(R~)zC(O)OH, OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(RZ)z, OC(R~)zC(O)NR'R8, amino, -NHRz, N(Rz)z, NR'R8, -NHC(Rl)zC(O)OH, -NHC(R~)zC(O)ORz, -NHC(O)R2, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOZNHRz, -NHS02Rz, -NHSOZNR'R8, -N(C(O)NHR2)z, -NRzSO2Rz, -NHC(O)NHR2, NHC(O)NR'R8, and-NHC(O)N(Rz)z;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(Rz)z.
In a 47th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rza, R3p, R4a, Rsp, R6p, Rz"; .R3"; .R4«, Rs« and R6" are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RzC(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)i_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')ZC(O)ORZ, -S OC(R')ZC(O)NHZ, -OC(R')2C(O)NHR2, -OC(R')2C(O)N(RZ)2, -OC(R')ZC(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(Rz)2, -NR'Rg, -NHC(R')2C(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)RZ, -N(RZ)C(O)R2, -NHC(O)ORZ, NHC(O)SR2, -NHSOZNHR2, -NHSOZR2, -NHSOZNR~RB, -N(C(O)NHRZ)2, -NRZS02R2, -NHC(O)NHR2, -NHC(O)NR7R8, NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')ZC(O)OH, -SC(R')ZC(O)OR2, -SCHZC(O)OH, -SCFZC(O)OH, -SOzNHz, -S02NHR2, -S02N(RZ)2, S02NR~Rg, -SOZNHC(O)RZ, -SR2, -SOZNHC(O)NHR2, -SOzNHC(O)N(RZ) Z, -SOZNHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORZ, -C(O)NH2, -C(O)NHR2, -C(O)N(RZ)2, -C(O)NR~RB, -C(O)NHC(O)RZ, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR~Rg, -C(O)NHS02R2, -C(O)NHSOZNHR2, -C(O)NHS02N(RZ), -C(O)NHSOzNR~RB, -C(CH3)2C(O)OH, -(CHZ)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -POZHZ, -P03H2, -P(RZ)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and ~(O)N(RZ)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)2;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R2«, R3«, Ra«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZR, R3a, R4p, Rsp or R6~ can be -0CH3;
with the proviso that R2~ and R3p taken together or R3~ and R4p taken together or R4p and Rsp taken together, or R2« and R3« taken together or R3" and R4« taken together or R4« and RS«
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, -NR'R8, and halo; or R2~ and R3p taken together or R3a and R4a taken together or R4p and RSR taken together or R2« and R3« taken together or R3« and R4« taken together or R4« and RS« 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, -NR'R8, alkoxy, oxo, cyano, carboxy, I ~ .. .
carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)2; provided that R2~, R3~, R4a, RS~, R6p~ Rz«~ R3«~ Ra«~ Rs« and R6° cannot be -0C(R~)2C(O)OH; and with the proviso that at least one of R2p, R3p, R4a, RS~, or R6a 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(RZ)2, -C(O)NR'Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR'Rg, -C(O)NHS02NHRz, -C(O)NHSOzN(R2), -C(O)NHS02NR'Rg, -C(O)NHC(O)R2, -C(O)NHS02R2, -C(CH3)ZC(O)OH, -(CH2)YC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHzC(O)OH, -SCF2C(O)OH, -SOzNHz, -SOZNHRz, -SOzN(Rz)z, S02NR~R8, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR~RB, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~RB, amino, -NHRz, N(Rz)z, NR~RB, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOZNHRz, -NHSOzRz, -NHSOzNR~Rg, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, -NHC(O)NR~RB , and NHC(O)N(Rz)z;
wherein all R', Rz, R' and R$ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z.
In a 48th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rza, R3R, Raa, Rsp, R6p, Rz«, R3«, Ra«~ Rs« ~d R6« ~.e 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~RB, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~RB, NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, NHC(O)SRz, -NHSOZNHRz, -NHSO2Rz, -NHS02NR~R8, -N(C(O)NHRz)z, -NRZSOzRz, -NHC(O)NHRz, -NHC(O)NR~Rg, NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCHZC(O)OH, -SCF2C(O)OH, -SOzNHz, -SOzNHRz, -SOZN(Rz)z, SOzNR~Rg, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR~RB, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOZRz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~RB, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl; and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)2;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R4", Rs" or R6" must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2p, R3p, R4p, RsR or R6R can be -0CH3;
with the proviso that R2~ and R3p taken together or R3p and R4ptaken together or R4a and RsR taken together, or R2" and R3« taken together or R3" and R4" taken together or R4« and Rs«
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, -NR'Rg, and halo; or Rz~ and R3~ taken together or R3~ and R4a taken together or R4R and Rsp taken together or RZ« and R3" taken together or R3" and R4" taken together or R4" and Rs" 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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(RZ)z; provided that RZp, R3~, R4a, Rs~, l 5 R6a, RZ«, R3«, R4«, Rs« and R6" cannot be -0C ' (R )2C(O)OH; and with the proviso that at least one of R2~, R3a, or R4a must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(RZ)2, -C(O)NR'R8, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR'Rg, -C(O)NHSOZNHR2, -C(O)NHS02N(R2), -C(O)NHS02NR'Rg, -C(O)NHC(O)R2, -C(O)NHSOZRZ, -C(CH3)2C(O)OH, -(CHZ)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')zC(O)OH, -SC(R')ZC(O)OR2, -SCHZC(O)OH, -SCFZC(O)OH, -SOzNH2, -SOZNHR2, -SO2N(RZ)Z, SOzNR'Rg, -S02NHC(O)R2, -SRz, -SOzNHG(O)NHR2, -SOzNHC(O)N(R2) 2, -S02NHC(O)NR'Rg, -OC(R')zC(O)OH, -OC(R')ZC(O)OR2, -OC(R')2C(O)NH2, -OC(R')zC(O)NHR2, -OC(R')ZC(O)N(RZ)2, -OC(R')ZC(O)NR'R8, amino, -NHRz, N(Rz)2, NR'R8, -NHC(R')ZC(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SRz, -NHS02NHR2, -NHSOZR2, -NHSOZNR'R8,-N(C(O)NHR2)2, -NRZSOZRz, -NHC(O)NHR2, -NHC(O)NR'R$ , and NHC(O)N(RZ)2;
wherein all R', R2, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 49th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, Rs~, R6p, Rz«, R3«, Ra«, Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(Rl)zC(O)ORz, -OC(R~)zC(O)NHz, -OC(R~)zC(O)NHRz, -OC(R~)zC(O)N(R2)z, -OC(R~)zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylainino, -NHRz, N(Rz)z, -NR~Rg, NHC(R~)zC(O)OH, -NHC(R~)zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOZNHRz, -NHSOZRz, -NHS02NR~Rg, -N(C(O)NHRz)z, =NR2S02Rz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCHzC(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOZN(Rz)z, SOZNR~RB, -SOzNHC(O)Rz, -SRz, -S02NHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR~RB, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOzRz, -C(O)NHSOZNHRz, -C(O)NHS02N(Rz), -C(O)NHSOZNR~Rg, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)OZH, 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, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4«, RS« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RzR, R3R, R4p, RSp or R6a can be -0CH3;
with the proviso that at least one of RzR, R3p, or R4R must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~RB, -C(O)NHC(O)Rz, -C(O)NHS02Rz, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, thiol, -SC(Rl)zC(O)OH, -SC(R~)zC(O)ORz, -SCHzC(O)OH, -SCFzC(O)OH, -SOzNHz, -SOzNHRz, -SOzN(Rz)z, SOzNR~RB, -SO2NHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz)z, -SOZNHC(O)NR~Rg, -OC(R')zC(O)OH, OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, OC(R')zC(O)NR~RB, amino, NHRz, N(Rz)z, NR~RB, NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHS02Rz, -NHS02NR~R8, -N(C(O)NHRz)z, -NRZS02Rz, -NHC(O)NHRz, NHC(O)NR~RB , and -NHC(O)N(Rz)z;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(Rz)z.
In a 50th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rah, Rsp, R6p, Rz«, R3«, Ra«~ Rs« ~d R6« are independently selected from the I 5 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~Rg, -NHC(R')zC(O)OH, -NHC(Rl)zC(O)ORz, -NHC(O)R2, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHSOzRz, -NHSOZNR'Rg, -N(C(O)NHRz)z, -NRZS02Rz, -NHC(O)NHRz, -NHC(O)NR'R8 , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)zC(O)ORz, -SCH2C(O)OH, -SCFzC(O)OH, -SOZNHz, -SOzNHRz, -SOzN(Rz)z, SOZNR'R8, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHS02Rz, -C(O)NHS02NHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR'Rg, -C(CH3)zC(O)OH, -(CHz)YC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)OZH, 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R4n, Rs« or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2~, R3a, R4~, Rsp or R6a can be -0CH3;
with the proviso that at least one of R2~, R3~, or R4p must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)ZC(O)OH, (CHZ)yC(O)OH, wherein y is 1, 2, 3, 4, S, or 6;
wherein all R', R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2.
In a S 1 st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3~, Rap, Rsa, R6p, R2a, R3a, Raa, Rsa and R6" are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate; polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')2C(O)OR2, -OC(R')ZC(O)NH2, -OC(R')zC(O)NHR2, -OC(R')2C(O)N(Rz)2, -OC(R')2C(O)NR'R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(Rz)Z, -NR~Rg, NHC(R')2C(O)OH, -NHC(Rl)ZC(O)OR2, -NHC(O)R2, -N(RZ)C(O)Rz, -NHC(O)OR2, -NHC(O)SRz, -NHSOZNHR2, -NHSOZR2, -NHS02NR~R8, -N(C(O)NHRZ)2, -NRZS02Rz, -NHC(O)NHRz, -NHC(O)NR~R$ , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)zC(O)OH, -SC(R~)2C(O)ORz, -SCH2C(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOzN(Rz)z, SOZNR~RB, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR~RB, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHS02Rz, -C(O)NHS02NHRz, -C(O)NHS02N(Rz), -C(O)NHSOzNR~RB, -C(CH3)zC(O)OH, and -(CHz)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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(R2)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all maybe substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4°', Rsa or R6° must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RzR, R3~, R4a, Rsa or R6a can be -0CH3;

with the proviso that at least one of Rza, R3p, or R4~ must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(CH3)zC(O)OH, (CHz)yC(O)OH, wherein y is I, 2, 3, 4, 5, or 6;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z.
In an 52"a embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rza, R3~, R4p, RsR, R6p, Rz«, R3«, R4«, Rs« and R6« 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)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, 1 S hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R~)zC(O)N(Rz)z, -OC(R')zC(O)NR'Rg, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR'Rg, -N(Rz)C(O)Rz, -NHSOzNR'Rg, -N(C(O)NHRz)z, -NHC(O)NR'Rg , NHC(O)N(Rz)z, -SOzNHz, -SOzNHRz, -SOzN(Rz)z, SOzNR'R8, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -S02NHC(O)N(Rz) zi -SOzNHC(O)NR'R8, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR'Rg, -C(CH3)zC(O)OH, and -(CHz)yC(O)OH, wherein y is I, 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, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(Rz)z;

R~ is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, oxo, cyano, -C(O)NR'R8, and -C(O)N(RZ)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(RZ)2;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to I2-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZp, R3p, R4R, Rs~ or R6p can be -0CH3;
with the proviso that at least one of RZp, R3a, or R4p must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)ZC(O)OH, (CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R~, R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(RZ)2.
In a 53'd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
R2a, R3p, R4p, Rsa, R6p, R2«, R3«, Ra«, Rs« and R6« 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)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(Rz)z, -NR~RB, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)N(Rz)z, -C(O)NR~RB, -C(CH3)zC(O)OH, and -(CHz)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, -NR~RB, -C(O)NR~Rg, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, -C(O)NR~RB, and -C(O)N(Rz)z;
R' and R$ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3~, R4p, RsR or R6p can be -0CH3;
with the proviso that at least one of RzR, R3a, or R4p must be selected from the group consisting of tetrazol-5-yl, carboxy, -C(O)ORz, -C(CH3)zC(O)OH, (CHz)YC(O)OH, wherein y is l, 2, 3, 4, S, or 6;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 54th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, R4p, Rsa, R6p, Rz«, R3«, Ra«, Rs« and R6°' are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-s-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy, -C(O)ORz, -C(O)N(Rz)z, and -C(O)NR~RB, 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, -NR'R8, -C(O)NR'R8, and -C(O)N(RZ)2;
R2 is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR'Rg, alkoxy, -C(O)NR'R8, and ~(O)N(RZ)2;
R' and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic or benzofused ring;
wherein one of R4°, Rs« or R6" must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZR, R3~, R4~, Rsp or R6a can be -0CH3;
with the proviso that at least one of RZa, R3p, or R4~ must be selected from carboxy or -C(O)OR2;
wherein all R', R2, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, -NR'Rg, -C(O)NR'R8, and -C(O)N(RZ)2.
In a 55th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
R2p, R3p, R4p, Rsp, Rbp, R2a, R3a, Ra«~ Rs« and R6°' are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHZ)2),-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, and carboxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR'Rg, -C(O)NR'R8, and -C(O)N(RZ)2;
R2 is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4", Rs" or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZR, R3R, R4~, Rs~ or R6~ can be -0CH3;
with the proviso that at least one of Rz~, R3a, or R4p must be carboxy.

In a 56th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rza, R3R, R4~, Rsp, and Rbp are independently selected from the group consisting of hydrogen and carboxy;
Rz«~ Rs«~ Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z)i-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, -NR'R8, -C(O)NR'Rg, and -C(O)N(Rz)z;
Rz is lower alkyl;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl;
with the proviso that at least one of Rzp, R3R, or R4~ must be carboxy.
In a 57th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3~, R4~, Rsp, and R6p are independently selected from the group consisting of hydrogen and carboxy;
Rz«~ R3«~ Ra«~ Rs« ~d R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy, -(O(CHz)z),-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, -NR'Rg, -C(O)NR'R8, and -C(O)N(Rz)z;
Rz is lower alkyl;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heteroaryl;

with the proviso that at least one of Rz~, R3R, or R4p must be carboxy.
In a 58th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3~, R4a, Rsp, and R6p are independently selected from the group consisting of hydrogen and carboxy;
Rz«~ R3«~ Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(l-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH30(CHz)z0(CHz)z-, O ~ O
-CCH2C- N O -C(CH2)2C-N O
and ;
wherein one of R4«, Rs« or R6« 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 Rzp, R3a, or R4p must be carboxy.
In a 59th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RzR, R3R, R4p, Rs~, and R6~ are independently selected from the group consisting of hydrogen and carboxy;
Rz«~ R3«~ Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, andCH30(CHz)z0(CHz)z;
wherein one of R4«, Rs« or R6« 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 Rzp, R3p, or R4~ must be carboxy.

In a 60th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3~, R4~, Rs~, and R6p are independently selected from the group consisting of hydrogen and carboxy;
Rz«~ Rs«~ Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z)~_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, liydroxyalkyl, -NR~Rg, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic;
with the proviso that at least one of Rz~, R3R, or R4a must be carboxy.
In a 23rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RzR, R3a, R4p, Rs~, and Rba are independently selected from the group consisting of hydrogen and carboxy;
Rz«~ R3«~ Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z)i-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, -NR~Rg, -C(O)NR~RB, and ~(O)N(Rz)z;
Rz is lower alkyl;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;

wherein one of R4«, Rs« or R6« must be a carbon-carbon linked tetrahydrofurn-2-yl or dihydrofuran-2-yl;
with the proviso that at least one of Rzp, R3~, or R4~ 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:
Rzp, R3p, Rap, Rsa, R6a, Rz«, R3«, Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, ~ -OC(R')zC(O)N(Rz)z, -OC(R')ZC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR7R8, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHS02NHRz, -NHSOZRz, -NHSOZNR~RB, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, -NHC(O)NR~Rg , NHC(O)N(Rz)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHzC(O)OH, -SCFZC(O)OH, -S02NH2, -SOZNHR2, -SOZN(R2)2, S02NR'Rg, -S02NHC(O)R2, -SR2, -SOZNHC(O)NHR2, -S02NHC(O)N(RZ) z, -SOZNHC(O)NR'Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHRZ, -C(O)N(R2)2, -C(O)NR'R8, -C(O)NHC(O)RZ, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR'R8, -C(O)NHS02Rz, -C(O)NHSOzNHR2, -C(O)NHS02N(Rz), -C(O)NHS02NR'Rg, -C(CH3)2C(O)OH, -(CHZ)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -POZH2, -P03H2, -P(RZ)OZH, 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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(Rz)2;
Rl is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and --C(O)N(Rz)2;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4°, Rs°' or R6°' must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2p, R3R, R4~, Rsp or R6p can be -0CH3;
with the proviso that at least one of R2R, R3~, or R4~ must be selected from the group consisting of -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR'R8, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHS02NR~Rg, -C(O)NHC(O)Rz, -C(O)NHSOZRz;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 62nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, Rsa, R6p, R2«, R3«, Ra«, Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino-NHRz, N(Rz)z, -NR~RB, -NHC(R')zC(O)OH, -NHC(R~)zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHS02Rz, -NHS02NR~R8, -N(C(O)NHRz)z, -NR2S02Rz, -NHC(O)NHRz, -NHC(O)NR~Rg , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH, -SCF2C(O)OH, -SOzNHz, -SOzNHRz, -SOzN(Rz)z, SOzNR~RB, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR~RB, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~RB, and -C(CH3)zC(O)OH, -(CHz)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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl , ~ .
and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4a, Rsa or R6° must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz~, R3~, R4p, Rsa or R6p can be -0CH3;
with the proviso that at least one of Rzp, R3~, or R4~ must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR'R8, -C(O)NHSOZNHRz, -C(O)NHSOZN(R2), -C(O)NHSOzNR'Rg, -C(O)NHC(O)R2, and -C(O)NHSOZR2;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)2.
In a 63'd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZp, R3p, R4p, Rsp, R6p, RZ", R3", R4«, Rs« and R6" 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, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)2),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)N(Rz)Z, -OC(R')ZC(O)NR'R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(RZ)2, -NR'Rg, N(RZ)C(O)R2, -NHS02NR'R8, -N(C(O)NHRZ)2, NHC(O)NR'Rg, NHC(O)N(RZ)Z, -SOZNH2, -SOZNHR2, -S02N(RZ)z, SOzNR'Rg, -S02NHC(O)R2, -SOZNHC(O)NHR2, -SOZNHC(O)N(RZ) 2, -S02NHC(O)NR'Rg, cyano, tetrazol-5-yl, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2;.
-C(O)NR'R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)z, C(O)NHC(O)NR'R8, -C(O)NHSOzR2, -C(O)NHS02NHRz, -C(O)NHSOZN(RZ), -C(O)NHSOZNR'R8, and -C(CH3)ZC(O)OH, -(CHZ)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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)2;

R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, -C(O)NR~RB, and -C(O)N(RZ)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2R, R3a, R4p, Rsp or R6~ can be -0CH3;
with the proviso that at least one of RZR, R3p, or R4R must be selected from the group consisting of -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR~Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR~Rg, -C(O)NHS02NHRz, -C(O)NHS02N(Rz), -C(O)NHS02NR~R8, -C(O)NHC(O)R2, and -C(O)NHSOZRZ;
wherein all R', R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl,' acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, -C(O)NR~Rg, and -C(O)N(R2)z.
In a 64th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZp, R3p, R4p, Rs~, R6a, R2«, R3°, Ra«, Rs« and R6« 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(CHz)z)~_3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(Rz)z, -NR'R8, -N(Rz)C(O)Rz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'Rg, and -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, S, 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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' is.independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, -C(O)NR'R8, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4a, RS°' or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3p, R4a, Rsp or R6~ can be -0CH3;
with the proviso that at least one of Rza, R3~, or R4p must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'R8, -C(O)NHC(O)Rz, and -C(O)NHSOzRz;

wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, -C(O)NR~RB, and -C(O)N(Rz)z.
In a 65~' embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3R, Rah, Rsp, R6p, RZ«, R3«, Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy, -(O(CHz)z),.3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -C(O)NHz, and -C(O)NHRz, 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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, and lower alkyl which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, -NR'Rg, alkoxy, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, heteroaryl, and heterocyclic, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR~Rg, alkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R8 are independently alkyl, and linked together forming a S- to 7-membered monocyclic ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3a, R4p, Rsp or R6p can be -0CH3;
with the proviso that at least one of Rzp, R3a, or R4p must be selected from the group consisting of -C(O)NHz, -C(O)NHRz, -C(O)NHC(O)Rz, and -C(O)NHSOZRz;

wherein all R2, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, heterocyclic, amino, aminoalkyl, and -NR'Rg.
In a 66th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rz~, R3p, Rap, RsR, Rbp, R2«, Rs«, Ra«, Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHZ)2)i_3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -N(RZ)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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(RZ)2;
R' is hydrogen;
Rz is lower alkyl;
R' and R8 are independently alkyl, and linked together forming a 6-membered monocyclic rmg;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2~, R3~, R4~, Rsp or R6p can be -0CH3;
with the proviso that at least one of R2~, R3p, or R4~ must be selected from the group consisting of -C(O)NHz, -C(O)NHRZ, -C(O)NHC(O)R2, and -C(O)NHS02R2;
wherein all R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of heterocyclic, amino, aminoalkyl, and -NR'Rg.
In a 67th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
R2a, R3~, R4p, Rsp, R6~, R2«, R3«, Ra«, Rs« and R~ 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~RB, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~Rg, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, NHC(O)SRz, -NHSOzNHRz, -NHSOZRz, -NHSOZNR~RB, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, -NHC(O)NR~Rg, NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH, -SCFZC(O)OH, -SOzNHz, -SOzNHRz, -SOzN(Rz)z, SOzNR~RB, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~Rg, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~Rg, -C(O)NHSOzRz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~Rg, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -P02Hz, -P03Hz, -P(Rz)OZH, 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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;

R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(RZ)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused I S ring;
wherein one of R4°', Rsa or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RzR, R3p, R4R, R5~ or R6p can be -0CH3;
with the proviso that at least one of R2~, R3R, or R4~ must be selected from the group consisting ofthiol, -SC(R')2C(O)OH, -SC(R')ZC(O)OR2, -SCHZC(O)OH, SCF2C(O)OH, -SOZNH2, -SOZNHR2, -S02N(R2)Z, SOzNR~Rg, -S02NHC(O)R2, -SR2, -SOZNHC(O)NHR2, -SOZNHC(O)N(R2) Z, -SOzNHC(O)NR'R8;
wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~Rg, and -C(O)N(R2)2.
In a 68th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

R2p, R3p, Rap, Rsp, R6p, R2«, R3«~ Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)Z-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(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')2C(O)OH, -OC(R')2C(O)OR2, -OC(R')2C(O)NHz, -OC(R')ZC(O)NHR2, OC(R')ZC(O)N(RZ)2, -OC(R')ZC(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(RZ)2, -NR~Rg, -NHC(R')zC(O)OH, -NHC(R')2C(O)ORz, NHC(O)R2, -N(RZ)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSOZNHR2, -NHS02R2, -NHSOZNR~RB, -N(C(O)NHRZ)2, -NR2SOZR2, -NHC(O)NHRz, -NHC(O)NR~RB , -NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')ZC(O)OH, -SC(R')ZC(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -S02NH2, -SOZNHR2, -SOZN(Rz)2, SOZNR~RB, -SOZNHC(O)R2, -SR2, -S02NHC(O)NHRz, -SOZNHC(O)N(R2) 2, -S02NHC(O)NR~RB, cyano, tetrazol-S-yl, carboxy, -C(O)OR2, -C(O)NHZ, -C(O)NHR2, -C(O)N(RZ)2, -C(O)NR~RB, -C(O)NHC(O)R2, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR~RB, -C(O)NHS02Rz, -C(O)NHSOzNHR2, -C(O)NHS02N(RZ), -C(O)NHS02NR~Rg, -C(CH3)ZC(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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)2;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4°', Rsa or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RZp, R3p, R4p, RS~ or R6~ can be -0CH3;
with the proviso that at least one of RZp, R3R, or R4p must be selected from the group consisting of thiol, -SC(R')zC(O)OH, -SC(R')2C(O)OR2, -SCHzC(O)OH, SCF2C(O)OH, -SOzNH2, -S~O2NHR2, -S02N(R2)2, S02NR'Rg, -SOZNHC(O)R2, -SRz, -SOZNHC(O)NHRz, -SOZNHC(O)N(Rz) 2, -S02NHC(O)NR'Rg;
wherein all R', RZ, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(R2)2.

In a 69th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, Rsp, R6p, Rz«, R3«, Ra«, Rs« and R6« 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)Rz, RzC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z),-s-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR'R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR'Rg, -N(Rz)C(O)Rz, -NHS02NR'R8, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, -NHC(O)NR'Rg, -NHC(O)N(Rz)z, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH -SOzNHz, -S02NHRz, -SO2N(Rz)z, SOzNR'Rg, -S02NHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOzNHC(O)NR'R8, cyano, tetrazol-5-yl, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR'Rg, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR'Rg, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHS02N(Rz), -C(O)NHSOzNR'Rg, -C(CH3)zC(O)OH, and -(CHz)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, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'Rg, and ~(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylarylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'R8, and ~(O)N(Rz}z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, -C(O)NR~Rg, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4", Rs" or R6" must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3p, R4p, Rsp or R6p can be -0CH3;
with the proviso that at least one of Rzp, R3p, or R4p must be selected from the group consisting of-SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH, -SOzNHz, -SOZNHRz, -SOZN(Rz)z, SOzNR'R8, -SOZNHC(O)Rz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR~Rg;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 70th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, Rsp, R6p, Rz«, Rs«~ Ra«~ Rs« and R6" 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(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(Rz)z, -NR~Rg, -N(Rz)C(O)Rz, -SCHzC(O)OH -S02NHz, -SOzNHRz, -S02N(Rz)z, SOZNR~Rg, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR'Rg, -C(O)N(Rz)z, -C(O)NR'Rg, and -C(O)NHSOZRz, 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, -NR'Rs, alkoxy, oxo, cyano, -C(O)NR'Rg, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, -C(O)NR'Rg, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, -C(O)NR'R8, and ~(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4°', Rsa or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of RzR, R3~, R4~, Rsa or R6a can be -0CH3;
with the proviso that at least one of Rz~, R3R, or R4p must be selected from the group consisting of -SC(R')zC(O)ORz, -SCHZC(O)OH, -SOzNHz, -SOZNHRz, -S02N(Rz)z, SOzNR'R8, -SOzNHC(O)Rz, -SOzNHC(O)NHRz, -SOZNHC(O)N(Rz) z, -SOzNHC(O)NR'R8;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 71 st embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

Rzp, R3p, Rah, Rs~, R6p, Rz«, R3«~ Ra"~ Rs" and R~" 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(CHz)z),-3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -SCH2C(O)OH -SOZNHz, -SOzNHRz, -SOZN(Rz)z, S02NR'Rg, -SOzNHC(O)Rz, -SRz, -S02NHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR'Rg, and -C(O)NHSOZRz, 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, -NR'R8, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen and lower alkyl, which may be optionally substituted by one or more selected from the group consisting of halo, lower alkyl, -NR'R8, alkoxy, -C(O)NR'R8, and -C(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl and lower alkyl, which may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR'Rg, alkoxy, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic ring;
wherein one of Ra", Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3a, Rah, Rsp or R6a can be -OCH3;
with the proviso that at least one of Rzp, R3p, or Rah must be selected from the group consisting of -SC(Rl)zC(O)ORz, -SCHZC(O)OH, -SOzNHz, -SOzNHRz, -S02N(Rz)z, SOzNR'Rg, and -SOzNHC(O)Rz ;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, NR'Rg, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 72nd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:

Rzp~ R3p~ Rap Rsp~ Rsp~ Rza~ R3a~ Raa~ Rs« ~d R6« are independently selected from the group consisting of hydrogen, halogen, alkenyl, alkynyl, carbocycle, heteroaryl, heterocyclic, hydroxyl, lower alkoxy, -(O(CHz)z)~-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -N(Rz)C(O)Rz, -SOzNHz, -SOZNHRz, S02NHC(O)Rz, -SRz, -SOZNHC(O)NHRz, -SOZNHC(O)N(Rz) z, -SOZNHC(O)NR'R8, and -C(O)NHSOZRz, all of which can be optionally substituted by one or more selected from the group consisting of alkenyl, acyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, -C(O)NR'R8, and -C(O)N(Rz)z;
R' is hydrogen;
Rz is lower;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic nng;
wherein one of Ra°, Rs" or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3p, Rap, Rsp or R6p can be -0CH3;
with the proviso that at least one of Rzp, R3p, or Rap must be selected from the group consisting of -SC(Rl)zC(O)ORz, -SOZNHz, - SOzNR'R8, and -SOzNHC(O)Rz .
In a 73rd embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, Rsp, R6p, Rz", R3", Ra°', Rsa and R6Q are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, ~heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl; cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RzC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)i-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR~RB, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, NHRz, N(Rz)z, -NR~RB, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHS02NHRz, -NHSOZRz, -NHSOZNR'Rg, -N(C(O)NHRz)z, -NRzSOZRz, -NHC(O)NHRz, -NHC(O)NR~Rg , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHZC(O)OH, SCFzC(O)OH, -S02NHz, -SOzNHRz, -S02N(Rz)z, SOZNR~RB, -SOzNHC(O)Rz, -SRz, I 5 -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -S02NHC(O)NR'R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~RB, -C(O)NHSOzRz, -C(O)NHSOZNHRz, -C(O)NHS02N(Rz), -C(O)NHSOZNR'Rg, -C(CH3~C(O)OH, -(CHz)yC(O)OH, wherein y is I, 2, 3, 4, 5, or 6, -POzHz, -P03Hz, -P(Rz)OZH, 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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;
R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
I O wherein one of R4«, RS« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz~, R3R, R4a, Rsa or R6a can be -0CH3;
with the proviso that at least one of Rz~, R3p, or R4p must be selected from the group consisting of amino, -NHRz, N(Rz)z, NR'Rg, -NHC(R1)zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHSOZRz, -NHSOzNR'R8, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, -NHC(O)NR'R8 , and -NHC(O)N(Rz)z;
wherein all R', Rz, R' and Rg substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(Rz)z.
In a 74''' embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein: ' ' RZa, R3p, R4p, Rsp, R6p, Rz«, R3«, Ra«~ Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHz)z)~_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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z;

Rz is lower alkyl optionally substituted by alkoxycarbonyl.
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rz~, R3p, R4~, Rs~ or R6R can be -0CH3;
with the proviso that at least one of Rz~, R3a, or R4~ must be selected from the group consisting of amino, -N(C(O)NHRz)z, NR2SOZRz and -NRZS02Rz;
wherein all Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(Rz)z.
In a 75th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, Rsp, R6p, R2a, R3«, Ra«~ Rs« and R6« are independently selected from the 1 S 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)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHz)z)i.3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')zC(O)OH, -OC(R')zC(O)ORz, -OC(R')zC(O)NHz, -OC(R')zC(O)NHRz, OC(R')zC(O)N(Rz)z, -OC(R')zC(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR'Rg, -NHC(Rl)zC(O)OH, -NHC(Rl)ZC(O)ORZ, NHC(O)R2, -N(RZ)C(O)R2, -NHC(O)ORz, -NHC(O)SR2, -NHS02NHR2, -NHSOZR2, NHSOZNR'R8, -N(C(O)NHRZ)2, -NR2SOzR2, NHC(O)NHR2, -NHC(O)NR'Rg , NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R~)2C(O)OH, -SC(Rl)2C(O)ORz, -SCH2C(O)OH, -SCFzC(O)OH, -S02NH2, -S02NHR2, -S02N(RZ)2, S02NR'R8, -S02NHC(O)R2, -SRZ, -SOzNHC(O)NHRz, -SOZNHC(O)N(RZ) 2, -S02NHC(O)NR'R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORZ, -C(O)NH2, -C(O)NHRz, -C(O)N(RZ)Z, -C(O)NR'R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR'Rg, -C(O)NHSOZR2, -C(O)NHSOZNHR2, -C(O)NHS02N(R2), -C(O)NHS02NR'Rg, C(CH3)ZC(O)OH, -(CH2)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -POZH2, -P03H2, -P(R2)02H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)2;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl~; -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(RZ)2;
RZ is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(RZ)2;

R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to I2-membered monocyclic, bicylic, tricyclic or benzofused rmg;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2a, R3p, R4a, Rsa or R6p can be -OCH3;
with the proviso that at least one of R2p, R3p, or R4~ must be selected from the group consisting of -OC(R')ZC(O)OH, -OC(R')ZC(O)ORZ, -OC(R')ZC(O)NH2, OC(R')2C(O)NHR2, -OC(R')ZC(O)N(R2)2, -OC(R')ZC(O)NR~RB;
wherein all R', R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and -C(O)N(RZ)Z.
In a 76th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZR, R3p, R4~, Rs~, R6p, R2«, R3«, Ra«, Rs« and R6« are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CHZ)2),-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, -OC(R')ZC(O)OH, -OC(R')ZC(O)N(R2)Z, -OC(R')2C(O)NR~RB, 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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
R' is hydrogen or lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(RZ)2;
Rz is lower alkyl optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)z;
R' and Rg are independently alkyl, and linked together forming a 6-membered monocyclic rmg;
wherein one of R4a, Rsa or R6°' must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2p, R3p, R4a, Rsa or R6p can be -0CH3;
with the proviso that at least one of RZp, R3~, or R4p must be selected from -OC(R')2C(O)OH;
wherein all R', R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)2.
1n a 77th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
RZp, R3R, R4p, Rs~, R6~, RZa, R3a, Ra°, Rsa and R6a are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, RZC(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2),_ 3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')ZC(O)OH, -OC(R')2C(O)OR2, -OC(R')2C(O)NH2, -OC(R')ZC(O)NHR2, -OC(R')ZC(O)N(Rz)2, -OC(R')zC(O)NR'R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHRz, N(Rz)z, -NR~Rg, -NHC(R')zC(O)OH, -NHC(R')zC(O)ORz, -NHC(O)Rz, -N(Rz)C(O)Rz, -NHC(O)ORz, -NHC(O)SRz, -NHSOzNHRz, -NHS02Rz, -NHSOzNR~RB, -N(C(O)NHRz)z, -NR2SOzRz, -NHC(O)NHRz, -NHC(O)NR~RB , NHC(O)N(Rz)z, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')zC(O)OH, -SC(R')zC(O)ORz, -SCHzC(O)OH, -SCFZC(O)OH, -SOzNHz, -SOZNHRz, -S02N(Rz)z, SOZNR~RB, -SOzNHC(O)Rz, -SRz, -SOzNHC(O)NHRz, -SOzNHC(O)N(Rz) z, -SOZNHC(O)NR~RB, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORz, -C(O)NHz, -C(O)NHRz, -C(O)N(Rz)z, -C(O)NR~RB, -C(O)NHC(O)Rz, -C(O)NHC(O)NHRz, -C(O)NHC(O)N(Rz)z, -C(O)NHC(O)NR~Rg, -C(O)NHS02Rz, -C(O)NHSOzNHRz, -C(O)NHSOZN(Rz), -C(O)NHSOzNR~Rg, -C(CH3)zC(O)OH, -(CHz)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -I 5 POzHz, -P03Hz, -P(Rz)OZH, 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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(Rz)z;
R' is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl; w . . .
alkoxycarbonyl, -C(O)NR~Rg, and ~(O)N(Rz)z;
Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;

R' and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4°, Rs« or R6a must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3~, R4p, Rs~ or R6p can be -0CH3; and/or RZp and R3a taken together or R3p and R4Rtaken together or R4a and Rs~taken together, or R2°' and R3°' taken together or R3°' and R4° taken together or R4" and Rsa 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, -NR'R8, and halo; and/or at least one of Rzp, R3~, or R4a must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(RZ)2, -C(O)NR'Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR'Rg, -C(O)NHSOZNHR2, -C(O)NHSOZN(RZ), -C(O)NHSOZNR'Rg, ---(CHZ)yC(O)OH, wherein y C(O)NHC(O)RZ, -C(O)NHSOZR2, -C(CH3)ZC(O)OH, is 1, 2, 3, 4, 5, or 6, thiol, -SC(R')ZC(O)OH, -SC(R')ZC(O)ORZ, -SCH2C(O)OH, -SCF2C(O)OH, -S02NH2, -SOZNHR2, -S02N(RZ)2, S02NR'R8, -SOzNHC(O)RZ, -SR2, -SOZNHC(O)NHR2, -S02NHC(O)N(R2) 2, -SOZNHC(O)NR'R8, -OC(R')zC(O)OH, -OC(R')ZC(O)ORZ, -OC(R')ZC(O)NH2, -OC(R')ZC(O)NHR2, -OC(R')2C(O)N(RZ)2, -OC(R')2C(O)NR'Rg, amino, -NHR2, N(RZ)2, NR'Rg, -NHC(R')ZC(O)OH, -NHC(R')ZC(O)ORZ, -NHC(O)R2, -N(RZ)C(O)Rz, -NHC(O)OR2, -NHC(O)SR2, -NHSOZNHR2, -NHSOZR2, NHSOzNR'R8, -N(C(O)NHR2)2, -NRZSOzR2, NHC(O)NHRz, -NHC(O)NR'R8 , and NHC(O)N(Rz)2;
wherein all R', R2, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(RZ)z.

In a 78th embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, Rap, RsR, R6a, Rz«, Rs«, Ra«, Rs« and R6" are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O(CHz)z),-3-4-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, -NR~RB, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(Rz)z;
Rz is independently alkyl or lower alkyl;
R' and R8 are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring;
wherein one of R4", Rs" or R6" must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rza, R3p, R4R, Rs~ or R6~ can be -0CH3; and/or R3p and R4a taken together or R4R and Rsp taken together, or R3" and R4" taken together or R4" and Rs" taken together form a heterocyclic ring optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, or hydroxyalkyl groups.
In a 79'h embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
20. Rza, R3a, R4~, Rsa, R6~, Rz", R3", Ra«, Rs« and R6" are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)z-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)Rz, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CHZ)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R')ZC(O)OH, -OC(R')ZC(O)OR2, -OC(R')2C(O)NH2, -OC(R')ZC(O)NHR2, -OC(R')zC(O)N(RZ)Z, -OC(R')ZC(O)NR'Rg, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(RZ)2, -NR~RB, NHC(R')ZC(O)OH, -NHC(R')ZC(O)OR2, -NHC(O)RZ, -N(RZ)C(O)Rz, -NHC(O)OR2, NHC(O)SR2, -NHSOzNHR2, -NHSOZR2, -NHS02NR~R8, -N(C(O)NHRZ)2, -NRZSOZR2, -NHC(O)NHRZ, -NHC(O)NR~RB , NHC(O)N(RZ)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R')2C(O)OH, -SC(R')2C(O)ORZ, -SCHZC(O)OH, -SCFZC(O)OH, -SOZNH2, -SOZNHR2, -S02N(RZ)Z, S02NR~Rg, -S02NHC(O)R2, -SR2, -SOZNHC(O)NHR2, -SOZNHC(O)N(Rz) 2, -SOZNHC(O)NR~Rg, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)ORZ, -C(O)NHZ, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR'Rg, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR~Rg, -C(O)NHSOzR2, -C(O)NHSOZNHR2, -C(O)NHS02N(Rz), -C(O)NHS02NR~R8, -C(CH3)zC(O)OH, -(CH2)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, -POZH2, -P03Hz, -P(R2)OZH, 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, -NR~Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and ~(O)N(RZ)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR~RB, and -C(O)N(R2)z;

Rz is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'Rg, and ~(O)N(RZ)z;
R' and Rg are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4«, Rs« or R6« must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2~, R3a, R4a, Rsp or R6p can be -OCH3; and/or RZp and R3~ taken together or R3~ and R4R taken together or R4p and RsR taken together or R2« and R3« taken together or R3« and R4« taken together or R4« and Rs« taken together form a S-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, -NR'Rg, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and ~(O)N(RZ)z; provided that RZp, R3~, R4a, Rsa, R6p, R2«, Rs«~ Ra«~ Rs« and R6« cannot be -0C(R~)ZC(O)OH; and/or at least one of RZa, R3p, or R4p must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHRZ, -C(O)N(RZ)2, -C(O)NR'Rg, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(RZ)2, -C(O)NHC(O)NR'R8, -C(O)NHSOZNHR2, -C(O)NHSOZN(Rz), -C(O)NHSOZNR'Rg, -C(O)NHC(O)R2, -C(O)NHS02R2, -C(CH3)zC(O)OH, -(CHZ)yC(O)OH, wherein y is l, 2, 3, 4, 5, or 6, thiol, -SC(R~)ZC(O)OH, -SC(Rl)2C(O)OR2, -SCH2C(O)OH, -SCFZC(O)OH, -SOZNH2, -SOZNHR2, -SOzN(RZ)z, SOZNR'R8, -SOZNHC(O)R2, -SR2, -SOZNHC(O)NHR2, -SOZNHC(O)N(R2)z, -SOZNHC(O)NR'Rg, -OC(R~)2C(O)OH, -OC(R')2C(O)OR2, -OC(R~)2C(O)NH2, -OC(R')2C(O)NHR2, -OC(R~)2C(O)N(RZ)2, -OC(R~)2C(O)NR'R8, amino, -NHRZ, N(R2)2, NR'R8, -NHC(R~~C(O)OH, -NHC(R~)ZC(O)OR2, -NHC(O)RZ, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHS02NHR2, -NHSOZR2, -NHS02NR'R8, -N(C(O)NHRz)z, -NR2SOZRz, -NHC(O)NHRz, NHC(O)NR'Rg , and -NHC(O)N(Rz)z, wherein all R', Rz, R' and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(Rz)z.
In a 80'E' embodiment, the invention is represented by Formula I or its pharmaceutically acceptable salt or ester, wherein:
Rzp, R3p, R4p, Rsp, R6p, Rza, R3", Ra«, Rs« and R6a are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, (O(CHz)z),_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, -NR'R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR'R8, and -C(O)N(R2)z;
Rz is independently alkyl or lower alkyl;
R' and R8 are independently selected from the group consisting of alkyl, linked together forming a 6-membered monocyclic ring;
wherein one of R4a, Rsa or Rba must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of Rzp, R3R, R4R, Rsp or R6p can be -0CH3; and/or R3a and R4p taken together or R4a and Rs~ taken together or R3°' and R4° taken together or R4° and Rs" taken together form a 5-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of alkyl, lower alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxycarbonyl;
provided that Rz~, R3~, R4~, Rsp, R6~, Rza, R3°, R4°', Rs« and R6" cannot be -0C(R~)zCOOH.
As an 81 S' embodiment, the invention is a pharmaceutical composition coprising any of the above 80 embodiments or any of the specific Examples below together with one or more pharmaceutically acceptable Garners.

An 82"a embodiment includes embodiments 1-80 above or any of the Examples as a means to treat or prophylactically treat an inflammatory disorder including arthritis, rheumatoid arthritis, asthma, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, multiple sclerosis, allergic rhinitis, chronic obstructive pulmonary disease, systemic lupus erthematosus, atherosclerosis, and restinosis.
A further embodiment includes the intermediates used to make the final compounds of the invention. Said intermediates are useful as starting materials for making the compounds of the invention as well as having pharmaceutical activity alone.
Another embodiment of the invention includes the process for making both the intermediates as well as the final compounds.
Definitions A wavy line used as a bond" ~n~w ", denotes a bond which can be either the E-or Z-geometric isomer.
When not used as a bond, the wavy line indicates the point of attachment of the particular substituent.
The terms "alkyl" or "alk", alone or in combination, unless otherwise specified, refers to a saturated straight or branched primary, secondary, or tertiary hydrocarbon from 1 to 10 carbon atoms, including, but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, and sec-butyl,. The term "lower alkyl" alone or in combination refers to an alkyl having from 1 to 4 carbon atoms. The alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al., Protective Groups in Organic Synthesis, John Wiley &
Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CHZCF3.

The term "alkenyl", alone or in combination, means a non-cyclic alkyl of 2 to 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, S 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 Or ang- is Synthesis, John Wiley & Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CH2CF3.
The term "alkynyl", alone or in combination, means a non-cyclic alkyl of 2 to 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 Or. and is Synthesis, John Wiley & Sons, Second . .
Edition, 1991, hereby incorporated by reference. Specifically included are CF3 and CHZCF3.
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 -0H.
The term "sulfonyl", alone or in combination means the radical -S(O)2-.
The term "oxo" refers to an oxygen attached by a double bond (=O).
The term "carbocycle", alone or in combination, means any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
The term "cycloalkyl", alone or in combination, means a saturated or partially unsaturated cyclic alkyl, having from 1 to 10 carbon atoms, including but not limited to mono-or bi-cyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl, and cyclohexyl.
The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The "aryl" group can be optionally substituted with one or more of the moieties selected from the group consisting of alkyl, alkenyl, alkynyl, heteroaryl, heterocyclic, carbocycle, alkoxy, oxo, aryloxy, arylalkoxy, cycloalkyl, tetrazolyl, heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halogen, haloalkylthi, haloalkoxy, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, aminoalkyl, 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 pteridiriyl. .
wherein said heteroaryl or heterocyclic group can be optionally substituted with one or more substituent selected from the same substituents as set out above for aryl groups. Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired.
Suitable protecting groups can include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

The term "thienyl", alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds.
The term "benzothienyl", alone or in combination, refers to a five member cyclic group wherein the ring contains one sulfur atom and two double bonds fused to a phenyl ring.
The term "aryloxy", alone or in combination, refers to an aryl group bound to the molecule through an oxygen atom.
The term "heteroaryloxy", alone or in combination, refers to a heteroaryl group bound to the molecule through an oxygen atom.
The term "aralkoxy", alone or in combination, refers to an aryl group attached to an alkyl group which is attached to the molecule through an oxygen atom.
The term "heterocyclearalkoxy" refers to a heterocyclic group attached to an aryl group attached to an alkyl-O- group. The heterocyclic, aryl and alkyl groups can be optionally substituted as described above.
The terms "halo" and "halogen", alone or in combination, refer to chloro, bromo, iodo and fluoro.
The terms "alkoxy" or "alkylthio", alone or in combination, refers to an alkyl group as defined above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.
The terms "lower alkoxy" or "lower alkylthio", alone or in combination, refers to a lower alkyl group as defined above bonded through an oxygen linkage (-O-) or a sulfur linkage (-S-), respectively.
The term "acyl", alone or in combination, refers to a group of the formula C(O)R', wherein R' is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.
The term "acetyl", alone or in combination, refers to the radical ~(O)CH3.
The term "amino", alone or in combination, denotes the radical NH2 or NH-.
The term "nitro", alone or in combination, denotes the radical NOZ.

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, vitro, 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 S~rnthesis, 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''' Edition (Whey lnterscience, New York, I 992) 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 IS carboxylic acid (e.g. formic acid, glacial acetic acid, propionic acid), or in aprotic organic solvents such as ethers (e.g. tetrahydrofuran, dioxane, diethyl ether), liquid amides (e.g.
dimethylformamide, hexamethylphosphordiamide), dimethylsulfoxide, or hydrocarbons (e.g.
toluene, benzene), or mixtures of such solvents. When carrying out the reaction under basic conditions, the base may be selected from sodium, lithium, potassium, barium, calcium, magnesium, aluminum, ammonium, or quarternary ammonium hydroxides, lower alkoxides (e.g. methoxides, ethoxides, tert-butoxides), carbonates, borates, oxides, hydrides, or amides of lower secondary amines (e.g. diisopropyl amides, methylphenyl amides). Primary aromatic amines such as aniline, free secondary amines such as dimethyl amine, diethyl amine, piperidine, or pyrrolidine, tertiary amines such as pyridine, as well as basic ion exchange resins may also be used. Alternatively, a phase-transfer catalyst such as cetyl trimethyl ammonium chloride can also be used to facilitate the reaction, particularly when water is the solvent.
Alternatively, the aldol condensation reaction can also be carried out in an aprotic solvent such as tetrahydrofuran (THF) with an organic base. The preferred solvent is THF and the preferred base is lithium diisopropylamide (LDA). In this manner an aldol reaction may take place first and the subsequent dehydration reaction may take place during an aqueous workup.
Acid catalysts may be selected from hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, sulfonic acids (such as paratoluenesulfonic or methansulfonic acid), lower carboxylic acid (such as formic, acetic, or propionic acid), lower halogenated carboxylic acid (such as trifluoroacetic acid), Lewis acids (such as BF3, POC13, PCIs, 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 (~ and trans (E) geometric isomers or either pure trans (EJ isomers. If desired, either the mixtures or the pure trans isomers may be isomerized to the corresponding predominantly cis (~
iomers using methods well known in the literature.
In the above reactions, it may be preferred or necessary to protect various sensitive or reactive groups present in the starting materials so as to prevent said groups from interfering with the reactions. Such protection may be carried out in a well-known manner as taught by Theodora W. Green and Peter G. M. Wuts, in Protective Groups in Organic Chemistry Third Edition (Wiley, 1999) or using methods from references cited therein or of the like. The protecting group may be removed after the reaction in a manner known per se.
The following schemes will prove useful to those skilled in the art in manufacturing the compounds of the invention:
Legend for all schemes:
1. R, R', R", R"', and R"" can be any substitution including H;
2. R, R', R", R"', and R"" can be suitabaly functionalized;
3. R, R', R", R"', and R"" can represent multiple substitutions;
4. Two adjacent R, R', R", R"', or R"" can form a ring;
5. Dashed double bond can be at any location of a ring;

6. Y, Y', Y", and Y"' independently represent N(H), O, or S, 7. X and X' independently represent Cl, Br, or I;
8. Each R, R', R", R"', R"", Y, Y', Y", Y"', X or X' is independent in each scheme;
9. HetAr represents suitably substituted heterocyclic aryl;
10. Cy represents cyclohexyl.
Scheme 1 R~~\, ~ H, Me O
R HO- ~ H, Me R
R" ~O, S, NH Tf20 r)n base Heck cross coupling solvent Pd(0), solvent, heat O
O
H, Me X i I H, Me or Tf0 ~~
R
R HetAr-B(OH)2 HetAr-H or HetAr-BEt2 Suzuki cross coupling 1. Bul.i ~. pd[Ph3P]4, solvent 2. BEt3 Na2C03, H20, heat or HetAr-BEt2 2. Pd[t-Bu3P]2, solvent, KF, heat O
~ ~ ~H, Me HetAr R R'O OR' acetone H20 R ~B ~ I H, Me acid R~~~' heat R
HetAr-X
R'O OR' Pd(0), base ~H, Me solvent, H20 HetAr ~\ heat R
O (R"')2BH, Pd(OAc)2 Cy2P-biphenyl ~H, Me base, solvent, heat X ~~ , R O OR
R R'-OH
acid, solvent X ~ i H, Me R
Scheme 2 base solvent O O R
O
o ~ v R'o 0 O L4H R'O
HO reduction HO
O
O R,O X
HO ~R R'O X
OH O
Friedel-Crafts acylation R"C(O)CI, AIC
solvent R
Scheme 3 O O
F ~~H, Me R~ N ~ I H, Me \R R"' ~\R
R' base NH solvent R"
heat Scheme 4 O O
HS ~\ H' Me R~-S ~\ H, Me R R'-X, base R
solvent Scheme 5 O
CI-S / ~ H~ Me O
O ~'~
R R'~ _,O, / H, Me R~~NH R.. N
R" ~ base R
solvent Scheme 6 O O
~,.~H, Me ~~H, Me \ ~~ R'-X, base I R solvent, heat ~ R
NH ~ NR' Scheme 7 HO O O
HO
H. M
bromination X ~~ I H, Me or iodination R R
HO O HetAr-B(OH)2 I H, Me Suzuki cross HetAr ~\ coupling R O
Ar0 H, Me Ar-X HetAr ~\
R
R'-X' or R'-OMs base, solvent O
heat R'O
I H, Me HetAr ~\
O R
HO O O hydrolysis when I H, Me e. ., R
HetAr ~\ OEt R
Scheme 8 S (NH) R"-1~NH2 R R
EtOH R, base or no base S \ ~ I
heat N
R,. ~ . R
O 1. TiCl4 , R' CI
S \ ~\ H CI ~O~
R"~N R ~ 2. H20 /

Scheme 9 O~~ ~ + Y ~ N H2 (HO) H
R Y, ~ JY", Y
EtOH
AcOH
heat _ N
Y
~NH ~~
Y R
1. TiCl4 O C!
N / H CI~O~
Y" ~NH ~~~ 2. H20 Y"~Y", R
Scheme 10 O O
H, Me N-N ~ H, Me NC ~~ N-NH ~-'~
R R
1. NaN3, ZnBr H20, heat 2. acid Scheme 11 O O
H, Me O~~' I H, Me HO~~~ R'-N~'~-~~
R
acylation R ~NH
R' Scheme 12 O
O OH N ~ ~ ~H, Me HO HO O
HO~OH R
HO OH
acid OH OH
solvent heat O CI O
R'-SO HN / I H, Me ~ ~ ~H, Me~
H2N ~~ base R'-S02~\R
R solvent O O
R"-X
HO OH solvent, heat base 2. R"'R""NH, EtOH solvent O O O
", i~ ~ H, Me R ~N HN ~ O
R""
R R"v ~~ ~H, Me N ~
R'-SO2 ~\R
Scheme 13 1. hydrazine solvent, heat ,N
o~~ , N~,~-Me0 ~ 2. R -N=C=S N
R solvent, heat R, R
3. Base, solvent heat 4. Raney Ni 1. TiCl4 EtOH, heat CI
O CI~O~
N.N / H 2. H20 ~\R
R' Scheme 14 O
O
AcCI, AICI3 solvent ~~~\
R' R R' R
Scheme 15 O O
R' ~ I \ + R"' ~ I ~ H
R R"
1. NaOH, DMF, H20 or 2. LiOMe, MeOH, DMF or 3. Surfactant, base, Hz0 O
R ~ I v~ I \~ R"' R R"
Scheme 16 O
HS ~~ v/ ~~ R"' R R"
R'_X
solvent O
R~-S ~~ v~ ~~ R", R R"
Scheme 17 O
O / /
R'-S-N ~\ ~~ R"' O R"" R R"
R""-X, base, solvent O
H / /
R~-S_N ~\R ~~ R,"
O R., and/or O
O.~
R'~~~N ~ I / I = R"' R'-S
O ~'O R R"
R'-S(O)2-CI
base, solvent O
H2N ~~ ~~ R"' R R"
R'-N=C=O
solvent, heat O
-N ~.~ / I ~ R
R-NH R R"/
and/or O O
R,\H~N ~ I / I = R
R N O R R"
Scheme 18 O
O /
R"' H2 ~~~\
R R
R'C(O)OC(O)R
or R'C(O)CI
base, solvent O
O /
R"' R' N~~'\
R R
O and/or O
R' ~ / I ~ I ~ R"' .\
R R"
O ~O
R' Scheme 19 O H
R' I I R"' /
R R"
o~~~
light solvent R"
R' Examples The following examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. All intermediates and final products have been completely characterized by conventional proton NMR, mass spectral analyses and standard analytical methods known to those skilled in the art.

1-(2,2-Bis-hydroxymethyl-benzo[1,3]dioxol-5-yl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-propenone Ex-lA: Catechol (2.2 g, 20 mmol) was dissolved in acetone. Diethyl dibromomalonate (7.0 g, 22 mmol) and potassium carbonate (2.76 g) were added, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and water was added to the residue. The residue was extracted with dichloromethane, and the organic phase was washed with brine, dried over magnesium sulfate and evaporated. Chromatography (hexanes/ethyl acetate, 4:1) gave 3.9 g of benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester.
'H-NMR (CDC13) 8 6.90-6.97 (m, 4H), 4.37(q, J = 7 Hz, 4H), 1.32(t, J = 7 Hz, 6H).
Ex-1B: [Bis(ethoxycarbonyl)methyldenedioxy]benzene obtained from Ex-lA (3.9 g, 14.7 mmol) was dissolved in THF (100 mL) and cooled with ice-water. Lithium aluminum hydride (1 M solution in THF, 44 mL) was added dropwise, and the mixture was stirred overnight. The reaction was carefully quenched with saturated sodium sulfate until there was no further bubbling. The mixture was stirred overnight, then filtered, and the filtrate was dried over magnesium sulfate. Chromatography (dichloromethane/methanol, 10: I ) gave 0.5 g of the desired (2-hydroxymethyl-benzo[1,3]dioxol-2-yl)-methanol.'H-NMR (CDC13) 8 6.82 (s, 4H), 3.94 (d, J = 7 Hz, 4H), 1.98 (t, J = 7 Hz, 2H).

Ex-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.
~ H-NMR (CDCl3) b 7.56 (d, J = 7 Hz, 1 H), 7.43 (s, 1 H), 6.85 (d, J = 7 Hz, 1 H), 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 I 5 solution of saturated sodium bicarbonate (75 mL), and extracted with dichloromethane (2 x 100 mL). The organic layer was dried over sodium sulfate and concentrated to a brown solid. The crude material was purified by silica gel chromatography (1:1 ethyl acetate/hexanes) to give 9.42 g (90%) of the desired 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde product.
'H-NMR (300 MHz, CDC13) b 9.94 (s, 1 H), 7.79 (d, 1 H), 7.57 (dd, 1 H), 7.41 (d, 1 H), 7.36 (d, 1 H), 7.13 (dd, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H).
5-Acetyl-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester obtained from Ex-1C (0.28 g, 1.11 mmol) and 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde obtained from Ex-1D
(0.275 g, I .11 mmol) were dissolved in ethanol, and 50% sodium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure, and water was added to the remainder. The resulting product was extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated. Chromatography gave 0.19 g (38%) of the title compound as a yellow solid, m.p.
74-80 °C. 'H-NMR (300 MHz, CDC13) 8 7.74 (d, I H), 7.63 (dd, 1 H), 7.49-7.55 (m, 3 H), 7.38 (d, 1 H), 7.37 (d, 1 H), 7.12 (dd, 1 H), 7.07 (d, 1 H), 6.88 (d, 1 H), 3.99 (s, 4 H), 3.98 (s, 3 H), 3.88 (s, 3 H). Anal. Calculated for C24HZZO~S: C, 63.42; H, 4.88; S, 7.06;
found: C, 63.46;
H,5.11;5,6.55.
S
C
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. 'H-NMR (CDC13) 8 10.00 (s, 1H), 7.88 (d, J = 9 Hz, 2H), 7.77 (d, J = 9 Hz, 2H), 7.46 (d, J = 4 Hz, 1H), 7.39-7.41 (m, 1H), 7.12-7.15 (m, 1H).
The title compound was obtained when 5-acetyl-benzo[1,3]dioxole-2,2-dicarboxylic acid diethyl ester from Ex-1C was condensed with 4-(Thien-2-yl)benzaldehyde from Ex-2A in a similar manner as described in Ex-1. Yellow solid, mp 166-168°C, 23.6%
yield. 'H-NMR
(CDC13) 8 7.77 (d, J = 1 SHz, 1 H), 7.60-7.65 (m, SH), 7.51 (d, J = 2 Hz, 1 H), 7.45 (d, J = 15 Hz, 1 H), 7.37-7.3 8 (m, 1 H), 7.32(d, J = 5 Hz, 1 H), 7.09 (dd, J= 4, S Hz, 1 H), 6.88 (d, J = 8 Hz, 1 H), 3.96 (d, J = 7 Hz, 4H). MS m/z = 394 ([M]+, 50%), 363 (100%). HRMS (EI) Calcd.
for C22H1gO5S: 394.0875. Found: 394.0869.

4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid Ex-3A: A sample of 5-bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL).
Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min.
Benzo[b]thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonate solution (2 M, 20 mL) were added. The mixture was stirred at reflux under nitrogen for 24 hours.
Upon cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) of the desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde. 'H NMR (CDC13) b 10.36 (s, lI~, 8.20 (s, 1H), 7.83-7.78 (m, 2H), 7.68 (s, 1H), 7.36-7.27 (m, 2H), 6.54 (s, 1H), 4.06 (s, 3H), 4.00 (s, 3H).
An alternative procedure: 5-bromo-2,4-dimethoxybenzaldehyde (20 g), benzo[b]thiophene-2-boronic acid (16 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter.
Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10 g), and Pd(tBu3P)Z (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 (0.551RRT). These impurities are removed during crystallization.) Upon completion, as determined by HPLC, the reaction was diluted with H20 (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H20 (200 mL).
The layers :..
were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g). The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was batch concentrated and solvent switched to 33 wt% 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde in THF in preparation for crystallization.
(Note: The internal temperature during batch concentration should be kept above 45 °C to prevent premature crystallization.) The resulting THF solution of 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde was then charged with heptane (20 mL) and slowly cooled to ambient temperature. Crystallization was then completed with the slow addition of heptane (175 mL) and cooling to 4 °C. After aging for 1 h, the batch was filtered and then dried on the filter funnel under a stream of Nz. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40 °C, 20 inHg) affording 23.74 g (97% yield) of desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde as a light orange crystalline solid, m.p. 134-136 °C. HPLC assay of this solid indicated > 99.9 LCAP. 'H-NMR
identical as above.
To a solution of 4-acetylbenzoic acid (1.50 g, 9.1 mmol) and S-(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%). 'H NMR (300 MHz, DMSO-d6) S
8.36 (s, 1 H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H), 7.82 (d, 1 H), 7.32 (m, 2H), 6.86 (s, 1 H), 4.08 (s, 3H), 4.00 (s, 3H). Anal. Calculated for Cz6HzoOsS'1/6H20: C, 69.78;
H, 4.58; S, 7.17;
found: C, 69.95; H, 4.69; S, 7.15. HPLC purity: 97.9% (area percentage).
An alternative procedure: 5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from, Ex-3A
(42.3 g), 4-acetylbenzoic acid (22.1 g), MeOH (250 mL) and DMF (600 mL) were sequentially charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter.
After complete dissolution, LiOMe (10.5 g) was added in one portion and the resulting solution was aged at 40 °C for 2 h. Upon completion, as determined by HPLC, the reaction mixture was transferred to a separatory funnel containing cold H20 (800 mL, precooled to 10 deg C). An additional 400 mL cold H20 was used to rinse the reaction vessel and this rinse was also added to the seperatory funnel. The combined aqueous was washed with iPrOAc (500 mL) and then acidified to a pH of 3 with 6 N 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 Nz affording desired acid 5 as a crude yellow solid. The crude dry product and THF (260 mL) were charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter. Heptane (30 mL) was slowly added to the resulting solution over 30 min and then aged resulting in crystallization.
Additional heptane (270 mL) was added over 1 h, aged for an additional 1 h and then filtered. The reaction vessel was then rinsed with 70% EtOH (100 mL) and this rinse was added to the filter cake. The wet cake was then transferred to a clean reaction vessel containing 70% EtOH (750 mL) and the resulting heterogeneous mixture was stirred overnight. The product was then filtered, rinsed with fresh 70% EtOH ( 100 mL) and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40 °C, 20 inHg) affording 52.05 g (87% yield) of desired 4-[3-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-E-acryloyl]-benzoic acid 5 as a yellow crystalline solid, m.p. 231-232 °C (dec.). HPLC assay of this solid indicated > 99.9 LCAP. 'H-NMR
identical as above.

HC
N
J
N
4-[3E-(4-Pyrimidin-5-yl-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.'H-NMR (CDC13) 8 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 4-acetylbenzoic acid. Yellow solid, mp >260°C, 45% yield. 'H-NMR (DMSO-d6) 8 9.21 (s, 2H), 9.19 (s, 1H), 8.24 (d, J = 9 Hz, 2H), 8.01-8.09 (m, SH), 7.9 (d, J = 6 Hz, 2H), 7.81(d, J = lSHz, H), MS m/z = 330 ([M]+, 100%). HRMS (EI) Calcd. for C2pH~qN2O3: 330.1004. Found: 330.1000.
4-[3E-(4-Thiazol-2-yl-phenyl}-acryloyl]-benzoic acid Ex-SA: 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.'H-NMR
(CDC13) 8 10.07 (s, 1 H), 8.15 (d, J = 8 Hz, 2H), 7.95-7.98 (m, 3H), 7.45 (d, J = 3 Hz, 1 H).
HMRS (EI) calcd. for C~oH~NOS: 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-SA) and 4-acetylbenzoic acid. Yellow solid, mp 232-235°C, 20% yield. ~H-NMR (CDCl3) 8 8.24 (d, J = 9 Hz, 2H), 8.11 (d, J = 9 Hz, 2H), 8.05 (d, J = 9 Hz, 2H), 7.93 (d, J = 3 Hz, 1H), 7.86 (d, J = 15 Hz, 1H), 7.74(d, J = 9Hz, 2H), 7.57 (d, J = 15 Hz, 1H), 7.41 (d, J
= 3 Hz, 1H), MS m/z = 335 ([M]+, 100%). HRMS (EI) Calcd. for C,9H,3NO3S:
335.0616.
Found: 335.0618.

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

Ex-6A: 5-bromo-2,4-dimethoxybenzaldehyde (20.3 g), thiophene-2-boronic acid (11.6 g) and THF (200 mL) were sequentially charged into a clean reaction vessel fitted with a reflux condenser, mechanical stirrer and nitrogen inlet adapter. Nitrogen was bubbled into the resulting solution for 20 min followed by the sequential addition of KF (10.1 g), and Pd('Bu3P)2 (0.424 g). The solution was immediately heated to 60 °C and aged for 1.5 h. The reaction was diluted with HZO (200 mL) and transferred to a separatory funnel containing EtOAc (200 mL) and H20 (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (100 mL). The combined organic cuts were filtered through a pre-washed pad of solka floc (5 g).
The pad of solka floc and spent catalyst were washed with fresh EtOAc (200 mL) and this wash combined with the batch. The resultant filtrate was concentrated to dryness.
The crude product was dissolved in THF (38 mL) and crystallized upon heptane (152 mL) addition.
The product was filtered and then dried to a constant weight in the vacuum oven (38 °C, 20 inHg) affording 19.32 g (94% yield) of desired 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde as a light off white solid, m.p. 125-126°C. 'H-NMR (300 MHz, CDC13): 10.34 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J= 3.5 and 1.5 Hz), 7.31 (dd, 1 H, J= 5.2 and 1.5 Hz), 7.07 (dd, 1 H, J= 5.2 and 3.5 Hz), 6.51 (s, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H).
2,4-Dimethoxy-S-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 Hz0 (200 mL) and transferred to a separatory funnel containing iPrOAc (100 mL). The layers were cut and the aqueous layer was acidified to a pH of 1 with 3 N HCI. The resulting precipitate was filtered and then dried on the filter funnel under a stream of N2. The crude product was then dissolved in THF (60 mL) and crystallized with the addition of heptane (60 mL). The product was filtered and then dried to a constant weight in the vacuum oven affording 8.9 g (75% yield) of the title compound as a yellow solid, m.p. 213-216°C. 'H-NMR (300 MHz, CDC13): 8.20 (d, 2 H, J = 8.5 Hz), 8.09 (d, 1 H, J = 16.1 Hz), 8.06 (d, 2 H, J = 8. S Hz), 7.85 (s, 1 H), 7.52 (d, 1 H, J = 16.1 Hz), 7.40 (m, 1 H), 7.30 (dd, 1 H, J = 5.2 and 1.7 Hz), 7.08 (dd, 1 H, J = 5.2 and 3.6 Hz), 6.53 (s, 1 H), 3.98 (s, 3 H), 3.97 (s, 3 H); EIMS m/z = 394 (M+).
Anal. calc. for Cz2H1805S: C, 66.99; H, 4.60; S, 8.13; found: C, 66.71; H, 4.59; S, 8.10.

2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid S
The title compound was obtained starting from 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A and 2-acetylbenzoinc acid in a similar manner as described in Ex-3. Yellow solid, mp 220-223 °C (dec.). ~H-NMR (DMSO-d6) 8 8.01 (s, 1H), 7.88 (d, J = 7.3 Hz, 1 H), 7.80-7.75 (m, 2H), 7.45-7.24 (m, 7H), 7.11 (d, J =
16.2 Hz, 1 H), 6.79 (s, 1 H), 4.00 (s, 3H), 3.88 (s, 3H). MS m/z = 445 (MF, 100%).
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.'H-NMR (DMSO-d6) 8 8.23 (d, 2H), 8.08 (d, 2H), 7.96 (d, 1H), 7.90 (m, 1H), 7.77 (m, 2H), 7.59 (d, 1H), 7.54 (m, 1H), 7.13 (dd, J= 4, 4 Hz, 1H). MS mlz = 395 ([M+H]+, 100%).

2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt To a solution of 2-acetyl-benzoic acid (0.75g, 4.6 mmol) and 5-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde (Ex-3A, 1.64g, 5.5 mmol) in N,N dimethylformamide (38 mL) was added sodium hydroxide (SM, 3.7 mL, 18.5 mmol). The reaction mixture was allowed to stir for 2 hours at ambient temperature and was diluted with water (50 mL) and sodium carbonate (2M, 20 mL). The aqueous solution was extracted with dichloromethane. A yellow precipitate formed in dichloromethane and was collected by filtration, washed with dichloromethane, dried in vacuo to give the title compound as a yellow solid (1.53g, 67 %), mp 214-217 °C (dec). 'H-NMR (DMSO-d6) S 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, 1 H), 6.78 (s, 1 H), 3.99 (s, 3H), 3.88 (s, 3H). MS m/z = 467([M +
Na]+, 75%), 445 ([M + H]+, 100%). Anal. (Cz6H,905SNa~1.3H20) Calc. C 63.55, H
4.35, S
6.52, found C 63.74, H, 4.44, S 6.55.
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. 'H-NMR (DMSO-d6) 8 8.01-8.08 (m, 4H), 7.72 (d, J = 8 Hz, 2H), 7.68 (s, 2H), 7.61 (d, J = 8 Hz, 2H), 7.41 (d, J = 4 Hz, 1 H), 7.35 (d, J = 4 Hz, 1 H), 7.04 (dd, J = 4, 8 Hz, 1 H). MS

m/z = 334([M + Na]+, 100%). Anal. (C22H,4O3S) Calc. C 71.84, H 4.22, S 9.59, found C 71.44, H 4.32, S 9.43.

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
H2S04 to a pH of 7. The mixture was extracted with dichloromethane (2 x 75 mL). The organic layer was washed with aqueous NaHC03 (2 x 25 mL), brine, dried over sodium sulfate, and concentrated to a yellow foam. The crude material was purified by silica gel chromatography (1:1 ethyl acetate and hexanes) to give 720.0 mg (27%) of the title compound as a yellow solid, mp. 67-71 °C. 1H-NMR (300 MHz, CDC13) 8 7.94 (d, 2 H), 7.75 (d, 1 H), 7.54 (s, 1 H), 7.53 (s, 1 H), 7.46 (d, 1 H), 7.39 (d, 1 H), 7.13 (d, I H), 7.11 (m, 1 H), 6.72 (d, 2H), 4.16 (s, 2H), 3.97 (s, 3H), 3.87 (s, 3H). Anal. calculated for C2~H,9N03S~1/5 HZO: C, 68.60, H, 5.28, S, 8.72; found C: 68.51, H: 5.40, S: 8.69. MS (Pos. lon ES): calcd for CZ~HZON03S: mlz =
366 [M+H]+, found: m/z = 366 [M+H]+.

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-S aminoacetophenone in a similar manner as described in Ex-11. Yellow solid, 45% yield, mp 185-187°C.'H-NMR (CDCl3) ~ 7.95 (d, 2 H), 7.79 (d, 1H), 7.65 (m, 4H), 7.55 (d, 1H), 7.39 (d, 1H), 7.33 (dd,J=5, 5 Hz, 1H), 7.11 (dd, J= 5, 5 Hz, 1H), 6.71 (d, 2H), 4.16 (s, 2H). MS m/z =
305 ([M]+, 100%). Anal. calculated for C~9H,SNOS: C, 74.72, H, 4.95, S, 10.50;
found C:
74.60, H: 5.05, S: 10.42.
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. 'H-NMR (CDCl3) b 8.10 (d, 1 H), 7.95 (m, 3H), 7.82 (m, 2H), 7.67 (s, 1 H), 7.60 (d, 1 H), 7.32 (dd, J = 8.8 Hz, 2H), 6.71 (d, 2H), 6.57 (s, 1 H), 4.11 (br s, 2H), 4.02 (s, 3H), 3.99 (s, 3H). MS m/z = 415 ([M]+, 39%), 384 (100%). Anal. calculated for Cz5H2~N03S~1/3 H20: C, 71.24, H, 5.18, S, 7.61; found C: 71.63, H: 5.18, S:
7.55.

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 ~L, 2.86 mmol) was stirred in 20 mL of anhydrous dichloromethane. The mixture was treated with mesyl chloride (100 pL, 1.3 mmol). The reaction mixture was stirred for 16 hours and heated gently for another 4 hours. The crude material was purified by silica gel chromatography (1:3 ethyl acetate/hexane) to give 337.0 mg (quantitative) of 1-[4-bis-(methanesulfonyl)aminophenyl]-3E-[(3,4-dimethoxy-5-(thien-2-yl)phenyl]-propenone.'H-NMR (300 MHz, CDCl3) b 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 I-[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/CHZC12 with 1% acetic acid) to give 269.2 mg (83%) of the title compound as a solid, 83% yield, mp. 71 - 75 °C. 'H-NMR (300 MHz, CDC13) 8 8.04 (d, 2H), 7.76 (d, 1 H), 7.52 (m, 2H), 7.40 (d, 1 H), 7.37 (m, I H), 7.29 (d, 2H), 7.10 (m, 1 H), 7.08 (m, 1 H), 3.95 (s, 3H), 3.86 (s, 3H), 3.12 (s, 1 H), 3.09 (s, 3H). MS (Pos.
Ion ES): calcd for C22HzzNOsS2: mlz = 444 [M+H]+, found: mlz = 444 [M+H]+.
HRMS m/z:
calc. 444.0939, found 444.0953.

O
\ ~j ~ \
~ / / g IOI H H
(3-{4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-phenyl}-ureido)-acetic acid ethyl ester A solution of 1-(4-amino-phenyl)-3-(4-thiophen-2-yl-phenyl)-propenone (Ex-12, 250 mg, 0.80 mmol) and isocyanato-acetic acid ethyl ester (105.7 mg, 0.80 mmol) in toluene (15 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and the crude product precipitated out of solution. The material was suctioned filtered and dried on hi-vac to give 280.2 mg (79%) of the title compound as a yellow solid, mp 209-212°C. 'H-NMR
(DMSO-d6) ~ 9.29 (br s, 1 H), 8.08 (d, 2H), 7.90 (m, 3H), 7.71 (d, 3H), 7.60 (m, 4H), 7.14 (t, 1H), 6.61 (t, 1H), 4.09 (q, 2H), 3.86 (dd, J= 2,6 Hz, 2H), 1.17 (t, 3H). MS
m/z = 435 ([M+H]+, 100%). HRMS m/z: calc. 435.1378, found 435.1375.
1 S (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 S hours. Due to no reaction, the reaction mixture was concentrated , diluted with toluene (20 mL), treated with ethyl isocyanatoacetate (177 mg, 1.37 mmol), and refluxed for 14 hours. The reaction was concentrated, diluted with methylene chloride (50 mL), and washed with water (3 x 50 mL). The organic portion was collected, dried over sodium sulfate, and concentrated over silica gel. The crude material was purified by silica gel chromatography (50-75% ethyl acetate/hexanes) to give 178.0 mg (21%) ofthe title compound as a yellow solid, mp 83-86°C.'H-NMR (CDC13) 8 8.09 (d, 2 H), 7.76 (d, 1H), 7.55 (m, 2H), 7.65 (d, 2H), 7.40 (m, 2H), 7.30 (m, 2H), 7.11 (m, 2H), 4.17 (q, 4H), 4.01 (d, 4H), 3.97 (s, 3H), 3.88 (s, 3H). MS m/z = 646 ([M+Na]+, 100%). Anal.
calculated for C3~H33N3O9S: C, 59.70, H, 5.33, S, 5.14; found C: 60.18, H: 5.38, S: 5.17.
4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid, sodium salt Ex-17A: 4'-Bromoacetophenone (3.98 g, 20 mmol) was dissolved in ethylene glycol dimethyl ether and then the solution was degassed with nitrogen for 15 minutes.
Tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2 mmol) was added, and the solution was further degassed for 10 minutes. Thiophene-2-boronic acid (3.07 g, 24 mmol) was added followed by the addition of sodium carbonate solution (2 M, 45 mL). The mixture was stirred at reflux under nitrogen overnight. Most of the solvent was removed, and water was added to the remainder. The solid was filtered out and recrystallized from ethanol and water to give 3.85 g of the desired 4'-(thien-2-yl)acetophenone as a solid, 95% yield. 'H-NMR
(CDC13) b.7.97 (d, J
= 9 Hz, 2H), 7.70 (d, J = 9 Hz, 2H), 7.44 (d, J = 4 Hz, 1 H), 7.3 8 (d, J = 5 Hz, 1 H), 7.11-7.14 (m, 1H), 2.62 (s, 3H). HMRS (EI) calcd. for Ci2HloOS: 202.0452; found:
202.0454.
4'-(Thien-2-yl)acetophenone obtained from Ex-17A (0.81 g, 4 mmol) and 4-carboxybenzaldehyde (0.6 g, 4 mmol) were dissolved in dimethylformamide (20 mL). Sodium hydroxide solution (5 M, 3.2 mL) was added over 30 minutes at room temperature, and the mixture was stirred for another 30 minutes at room temperature. The precipitate was filtered off and recrystallized from hot water to give the title compound as a yellow solid, 29% yield, m.p.

>260 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.17 (d, 2H), 7.89 (d, 1H), 7.87 (d, 2H), 7.81 (d, 2H), 7.76 (d, 2H), 7.72 (d, 1 H), 7.69 (d, 1 H), 7.64 (d, 1 H), 7.17 (dd, 1 H). Anal. calculated for CZOH~ 303NaS~ 1 /2H20: C, 65.74; H, 3.86; S, 8.78, found: C, 65.66; H, 4.04;
S, 9.04.

O
\ \% ~ \
\ / / OH
S O
4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl)-benzoic acid The title compound was prepared by acidifying its sodium salt from Ex-17.
Yellow solid, mp 260-265°C, 67% yield. ~H-NMR (DMSO-db) 8 8.18 (d, J = BHz, 2H), 8.00 (d, J = 15 Hz, 1 H), 7.91-7.94 (m, 4H), 7.82 (d, J = 8 Hz, 2H), 7.77-7.79 (m, 1 H), 7.71 (d, J =
3Hz, 1 H), 7.66 (d, J
=5 Hz, 1H), 7.16-7.19 (m, 1H), MS m/z = 334 ([M]+, 100%). HRMS (EI) Calcd. for CZpH~qO3S: 334.0664. Found: 334.0669.

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-methoxyacetophenone in a similar manner as described in Ex-17A. 'H-NMR (CDC13) 8 7.53 (d, J = 7 Hz, 1H), 7.37 (dd, J = 2, 5 Hz, 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. 'H-NMR (CDC13) ~
7.70 (d, J = 8Hz, 2H), 7.38 (d, J = 8 Hz, 1H), 7.07-7.16 (m, 4H), 6.75-6.80 (m, 4H), 6.42 (d, J
= 16 Hz, 1H), 3.67 (s, 3H), MS m/z = 364 ([M]+, 100%). Anal. Calculated for Cz,H~6O4S: C, 69.21;
H, 4.43; S, 8.80; found: C, 69.02; H, 4.56; S, 8.75.
4-[3E-(4-Pyrrolidin-1-yl-3-thiophen 2-yl-phenyl)-acryloyl]-benzoic acid Ex-20A: A solution of 3-bromo-4-flouro-benzaldehyde (5.0 g, 24.6 mmol) and thiophene-2-boronic acid (4.7 g, 37.0 mmol) in ethylene glycol dimethyl ether (100 mL) was stirred at room temperature under nitrogen for 15 min. Then tetrakis(triphenylphosphine)-palladium(0) (2.8 g, 2.42 mmol) and a sodium carbonate solution (2 M, 33 mL) were added, and the resulting mixture was refluxed under nitrogen overnight. Upon cooling to room temperature the reaction was poured into water (100 mL) and extracted with ethyl acetate (2 X 100 mL).
The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure.
Silica gel chromatography (hexane/ethyl acetate, 1:1) gave 4.8 g (95%) of the desired 4-fluoro-3-(thiophen-2-yl)-benzaldehyde product as a yellow oil. 1H-NMR (300 MHz, CDC13) 8 10.0 (s, 1 H), 8.18 (dd, 1 H, J = 7.3 and 2.4 Hz), 7.80 (m, 1 H), 7.56 (dd, 1 H, J= 3.7 and 1.7 Hz), 7.44 (d, t . 20 1 H, J = S. l Hz), 7.36 (m, 1 H), 7.16 (dd, 1 H, 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 KZC03 (1.7 g, 12.3 mmol), and the resulting mixture was stirred at reflux for 1 week.
Upon cooling to room temperature, the reaction was poured into water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 2:1) gave 400 mg (29%) of the desired 4-pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde product as a yellow oil.'H-NMR (300 MHz, CDC13) 8 9.75 (s, 1H), 7.71-7.74 (m, 2H), 7.30 (dd, 1 H, J = 5. I and 1.6 Hz), 7.02 (dd, 1 H, J = 5.1 and 3.7 Hz), 6.96 (m, 1 H), 6.81 (d, 1 H, J =
10.1 Hz), 3.15 (m, 4H), I .84 (m, 4H).
4-Pyrrolidin-I-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.
HC1 and extracted with ethyl acetate (2 X 100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Silica gel chromatography (100% ethyl acetate) followed by recrystallization from ethanol provided 80 mg (13%) of the title compound as a solid, m.p. 212-214°C with decomposition. 'H-NMR (300 MHz, CDC13) 8 8.21 (d, 2H, J= 8.4 Hz), 7.06 (d, 2H, J= 8.4 Hz), 7.80 (d, 1 H, J= 15.3 Hz), 7.58 (d, 1H, J= 1.9 Hz), 7.52 (dd, 1 H, J = 8.5 and 1.9 Hz), 7.3 3 (m, 1 H), 7.32 (d, 1 H, I 5.3 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.

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 X 100 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from ethanol provided 0.90 g (53%) of the title compound as a solid, m.p. 242-244 °C. 1H-NMR (300 MHz, d6-DMSO) 8 13.31 (bs, 1H), 8.32 (dd, 1 H, 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, 1 H, J =
16.1 Hz), 7.92 (m, 1 H), 7.80 (d, 1 H, J = 16.1 Hz), 7.69-7.73 (m, 2H), 7.41 (dd, 1 H, 10.8 and 9.2 Hz), 7.20 (m, IH). MS m/z = 352 ([M]+, 50%), 343 (100%). HRMS (EI) Calcd.
for CzoH,3F03S: 352.0569. Found: 352.0571.

\ ~ ~ \
H
1-(4-Mercapto-phenyl)-3E-(4-thiophen-2-yl-phenyl)-propenone To a solution of 4-mercaptoacetophenone (prepared according to European Patent Application 0271307) (0.57 g, 3.74 mmol) and 4-(thien-2-yl)-benzaldehyde (0.70 g, 3.74 mmol, Ex. 2A) in N,N dimethylformamide (20 mL) was added a solution of sodium hydroxide (5 M, 3 mL). The solution was allowed to stir at room temperature for 3 h. The reaction mixture was then acidified with hydrochloric acid (0.5 M) to pH 3. The precipitate was collected by filtration, washed with water, and stirred in ethanol overnight. The resulting yellow solid was collected by filtration, washed with ethanol, and dried in vacuo to afford 0.68 g (56%) of the title compound as a solid, m.p. > 110 °C (dec). MS (direct probe) mlz = 322 (M'~. 'H-NMR
(CDC13) 8 7.98-8.01 (d, 1H), 7.90-7.93 (d, 1H), 7.79-7.84 (d, 2H), 7.61-7.66 (m, 3H), 7.33-7.53 (m, 4H), 7.10-7.25 (m, 2H).

{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 (SM, 20 mL) was added benzenethiol (1.0 mL, 9.7 mmol). The reaction mixture was allowed to stir overnight at ambient temperature. The cloudy solution was then acidified to pH 3. The resulting solid was filtered, washed with water and dried in vacuo to obtain phenylthioacetic acid (0.55g). The aqueous filtrate was extracted with dichloromethane. The solution of dichloromethane was washed with brine, dried over sodium sulfate and concentrated to obtain additional phenylthioacetic acid (1.49g).'H NMR (CDC13) b 743-7.40 (m, 2H), 7.34-7.23 (m, 3H), 3.67 (s, 2H).
Ex-23B: To a mixture of alumina chloride (5.5g, 41.0 mmol) in carbon disulfide (100mL) was added acetyl chloride (1.17 mL, 16.5 mmol) followed by addition of phenylthioacetic acid (Ex-23A, 1.38g, 8.2 mmol) and nitromethane (15 mL). The reaction mixture was allowed to stir overnight at ambient temperature and then was poured into ice containing sulfuric acid (6M).
The insoluble solid was filtered, washed with water. After dried in vacuo, the solid was washed with toluene (2 x 60 mL), filtered and dried under reduced pressure to obtain (4-acetylphenylthio)acetic acid (1.28 g, 74%), m.p. 151-153 °C (Lit. 156-158 °C).'H NMR
(DMSO-d6) 8 12.80 (bs, 1 H), 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.). ~H-NMR (DMSO-d6) 8 8.35 (s, 1H), 8.08 (d, J
= 7.4 Hz, 2H), 8.03 (d, J = 16.3 Hz, I H), 7.93-7.87 (m, 3H), 7.82 (d, J = 7.0 Hz, I H), 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%).
1-(4-Methylthiophenyl)-3E-(4-thiophen-2-yl-phenyl)-propenone To a mixture of 1-(4-mercapto-phenyl)-3E-(4-thien-2-yl-phenyl)-proenone (Ex-22, 0.33g, 1.02 mmol) and potassium carbonate (0.54g, 3.9 mmol) in N,N-dimethylformamide (15 mL) was added iodomethane (0.32 mL, 5.1 mmol). The reaction mixture was allowed to stir at ambient temperature for 2 hours. The insoluble material was filtered. The solution was diluted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (0.5 M), sodium carbonate (2M) and brine, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave the title compound (20 mg, 6%) as a yellow solid, mp 138-140 °C. 'H-NMR
(CCD13) 8 7.98 (d, J
= 7.8 Hz, 2H), 7.89-7.86 (m, 1H), 7.83 (d, J = 15.3 Hz, 1H), 7.76 (s, 3H), 7.53 (d, J = 15.1 Hz, IH), 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%). " , . , . , ..

_ F F
Na+O S I ~ I / S
O
Dilluoro-{4-[3E-(4-thiophen-2-yl-phenyl)-acryloyl]-phenylthio}-acetic acid, sodium salt Ex-25A: To a solution of 4-mercaptoacetophenone (prepared according to published procedure, European Patent Application 0271307) (1.16g, 7.6 mmol) and ethyl bromodifluoroacetate (1.2 mL, 9.15 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.2g, 22.9 mmol). The reaction mixture was allowed to stir overnight at ambient temperature and then was diluted with ethyl acetate. The combined solution of ethyl acetate was subsequently washed with water, hydrochloric acid (O.SM), 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 (1.388, 66%).
'H NMR (CDC13) 8 7.97 (d, J = 8 Hz, 2H), 7.90 (d, J = 8 Hz, 2H), 4.29 (q, J =
7 Hz, 2H), 2.62 (s, 3H), 1.29 (t, J = 7 Hz, 3H).
The title compound was prepared by condensing (4-acetyl-phenylthio)-difluoro-acetic acid ethyl ester (Ex-25A) and 4-(thien-2-yl)benzaldehyde (Ex-2A) in a similar manner as described in Ex-22. Yellow solid, 3% yield, mp 118-220 °C. 1H-NMR (CCD13) 8 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, 1 H). MS m/z = 415 ([M - Na]+, 50%), 321 (100%).

\ ~% \
H2N~ ~ / ~ / S
O~~O
4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzenesulfonamide Ex-26A: To a solution of 4-acetyl-benzenesulfonyl chloride (Hoffinan, R.V.
Org. Syn. VII, 508; 4.18g, 19.1 mmol) in acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 min. The precipitate was filtered and the residue was washed with water and dried in vacuo to afford 4-acetyl-benzenesulfonamide as a white solid (3.54g, 93%). 'H NMR (DMSO-d6) 8 8.10 (d, J = 9 Hz, 2H), 8.03 (d, J = 9 Hz, 2H), 4.86 (bs, 2H), 2.65 (s, 3H).

To a solution of 4-acetyl-benzsulfonamide (Ex-26A, 0.44g, 2.2 mmol) and 4-thiophen-2-yl-benaldehde (Ex-2A, O.SOg, 2.7 mmol) in DMF (18 mL) was added a solution ofNaOH
(5 M, 1.77 mL, 8.8 mmol) dropwise. The reaction mixture was allowed to stir at ambient temperature. The reaction was quenched after 2 hours with water. The precipitate was filtered, washed with water, dried in vacuo and purified by stirring in aqueous ethanol overnight. The title compound was collected as a yellow solid (0.45g, 55%), mp >245 °C. 1H-NMR (DMSO-d6) 8 8.22 (d, J = 8.6 Hz, 2H), 7.96-7.89 (m, 6H), 7.77-7.72 (m, SH), 7.64 (d, J = 4.0 Hz, I H), 7.60 (d, J = 4.6, 1 H), 7.1 S (m, 1 H), 6.65 (bs, 1 H). MS m/z = 369 ([M +
H]+, 100%).

3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl~l-(1H 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 I / 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) 8 8.43 (s, 1H), 7.99 (d, 1H), 7.12-7.83 (m, lOH), 6.73 (s, 1H), 3.99 (s, 3H), 3.88 (s, 3H).

3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl~l-(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; 0.45g, 2.8 mmol) were added iodomethane (3 mL) and cesium carbonate (2.3g, 7.1 mmol). The reaction mixture was allowed to stir at 55 °C for 1.5 day during which additional iodomethane (11 mL) was added. The reaction was quenched with water. The aqueous solution was extracted with ether. The solution of ether was washed with saturated solution sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave 1-(1-methyl-1H indol-5-yl)-ethanone (0.25g, 51%).'H NMR (CDC13) 8 8.30 (s, 1 H), 7.91 (dd, J = 1.2, 8.1 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.12 (d, J =
3.2 Hz, I H), 6.61 (d, J
= 3.0, I H), 3.82 (s, 3H), 2.66 (s, 3H).
The title compound was prepared by condensing 1-(1-methyl-1H 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. 'H-NMR (CDC13) 8 8.41 (s, 1H), 8.00 (dd, J
= 1 Hz, 7 Hz, 1 H), 7.80 (d, J = 15 Hz, 1 H), 7.63 (d, J = I 5.0 Hz, 1 H), 7.58-7.55 (m, 2H?, 7.43-7.40 (m, 2H), 7.15-7.12 (m, 3H), 6.66 (d, J = 3 Hz, I H), 3.99 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H).
Anal. (C24HZ,NOS~0.25H20) 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.

4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid Ex-29A: 2-Hydroxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 °C using an ice-water bath.
Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added dropwise to the cooled solution and stirred for 2 h at 0 °C. The mixture was warmed to room temperature and stirred for an additional 1 h and the resulting yellow precipitate was collected. Recrystallization (ethyl acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-methoxybenzaldehyde as white needles, m.p. 63-64 °C. 'H-NMR (300 MHz, CDC13) 8 11.43 (s, 1 H), 9.69 (s, 1 H), 7.68 (s, 1 H), 6.48 (s, 1 H), 3.95 (s, 3 H). Anal. Calcd. for CBH~Br03: 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 (1 S
mL). Nitrogen was bubbled into the solution for 10 min followed by the sequential addition of potassium fluoride (0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)palladium (0) (0.033 g, 0.065 mmol). The solution was immediately heated to 60 °C and aged for 1.5 h. Upon completion, as determined by HPLC, the reaction was diluted with water (25 mL)~and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown solid. Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g (97%) of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde as a yellow solid, m.p.
118-119 °C.'H-NMR (300 MHz, CDC13) b 11.48 (s, 1 H), 9.79 (s, 1 H), 7.72 (s, 1 H), 7.37 (dd, 1 H), 7.31 (dd, 1 H), 7.08 (dd, 1 H), 6.54 (s, 1 H), 3.98 (s, 3 H). Anal.
Calcd. for C8H~03S: 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 nunol) 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 x 15 mL). The combined organic layers was sequentially washed with a saturated ammonium chloride solution (1 x 15 mL), water (1 x 15 mL), and brine (1 x 15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 4:1) afforded 0.13 g (87%) of 4-methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde as a pale yellow oil. 'H-NMR (300 MHz, CDC13) b 10.38 (s, I H), 8.12 (s, 1 H), 7.44 (dd, 1 H), 7.30 (dd, 1 H), 7.07 (dd, 1 H), 6.57 (s, 1 H), 4.33 (t, 2 H), 4.00 (s, 3 H), 3.94 (t, 2 H), 3.74m, 2 H), 3.59 (m, 2 H), 3.40 (s, 3 H).
HRMS (EI) Calcd. for C,~HZOOSS: 336.1031. Found: 336.1027.
4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-benzaldehyde obtained from Ex-29C (0.13 g, 0.37 mmol) and 4-acetylbenzoic acid (0.061 g, 0.37 mmol) were dissolved in a tetrahydrofuran-methanol solution (2 mL, 7:3). After complete dissolution, lithium methoxide (0.057 g, 1.5 mmol) was added and the resulting bright orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water ( 10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 x 1 S mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (3 mL) and warmed to 60 °C
to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected and dried in vacuo to yield 0.14 g (85%) of the title compound as a yellow solid, m.p. 145-146 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.22 (m, 3 H), 8.09 (d, 2 H), 8.01 (d, 2 H), 7.66 (dd, 1 H), 7.52 (d, 1 H), 7.13 (dd, 1 H), 6.88 (s, 1 H), 4.36 (t, 2 H), 4.00 (s, 3 H), 3.88 (t, 2 H), 3.65 (m, 2 H), 3.46 (m, 2 H), 3.22 (s, 3 H). Anal. Calcd.
for Cz6H26NO~S: C, 64.71; H, 5.43; S, 6.64. Found: C, 64.64; H, 5.44; S, 6.61.

O F
~ a HO / / S
O
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). 'H-NMR (300 MHz, d6-DMSO): 10.13 (s, 1 H), 7.81 (d, 1 H, J= 8.0 Hz), 7.76 (m, 1 H), 7.67 (m, 2 H), 7.59 (dd, 1 H J = 8.0 and 2.1 Hz), 7.17 (dd, 1 H J = 5.2 and 3.7 Hz).
The title compound was prepared by condensing 2-fluoro-4-thiophen-2-yl-benzaldehyde (Ex-30A) and 4-acetylbezoic acid in a similar manner as described in Ex-3. Yellow solid, 71%
yield, m.p. >260°C. 'H-NMR (300 MHz, d6-DMSO): 8.19 (d, 2 H, J= 8.4 Hz), 8.12 (d, 1 H, J
= 8 Hz), 8.06 (d, 2 H, J= 8 Hz), 7.95 (d, 1 H, J= 16 Hz), 7.80 (d, 1 H, J= 16 Hz), 7.71 (d, 1 H, J= 3.5 Hz), 7.62 (m, 2 H), 7.56 (d, 1 H, J= 8 Hz), 7.15 (m, 1 H). MS mlz = 352 ([M]+, 100%).
HRMS (EI) Calcd. for C2oH,3NO3S: 352.0569. Found: 352.0560.
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.'H-NMR (CDC13) 8 10.37 (s, 1H), 9.15 (s, 1H), 8.87 (s, 2H) 7.86(s, 1H), 6.57 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H).

The title compound was prepared by condensing 2,4-dimethoxy-5-pyrimidin-5-yl-benzaldehyde (Ex-31A) and 4-acetylbezoic acid in a similar manner as described in Ex-3.
Yellow solid, mp >260°C, 26% yield.'H-NMR (DMSO-d6) 8 9.11 (s, 1H), 8.96 (s, 2H), 8.13-8.16 (m, 3H), 8.01-8.09 (m, 3H), 7.90 (d, J = 15 Hz, 1H), 6.85(s, 1H), 3.99 (s, 3H), 3.91(s, 3H), MS m/z = 391 ([M+H]+, 100%). HRMS (ES+) Calcd. for CZZH~gN205: 391.1294.
Found:
391.1295.
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.'H-NMR (CDC13) I 0.41 (s, 1 H), 8.24 (s, 1 H), 7.43 (d, 1 H), 7.29 (d, 1 H), 7.06 (t, I H), 6.45 (s, 1 H), 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.'H-NMR (DMSO-d6) 8 8.22 (d, 2H), 8.19 (s, 1 H), 7.01 (m, 4H), 7.62 (d, 1 H), 7.47 (d, 1 H), 7.09 (t, 1 H), 6.76 (s, 1 H), 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 CZSH2zOsS. HRMS m/z: calc. 435.1266, found 435.1266.

4-{3E-[5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid Ex-33A: 5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 3,5-dimethyl-isoxazole-4-boronic acid in a similar manner as described in Ex-3A, 75% yield.'H-NMR (CDC13) 8 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 S-(3,5-dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-33A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp >260°C, 7% yield.'H-NMR (DMSO-d6) 8 8.15 (d, J = 8 Hz, 2H), 8.04 (d, J = 16 Hz, 1 H), 8.02 (d, J = 8 Hz, 2H), 7.89 (s, 1 H), 7.81 (d, J =
16 Hz, 1 H), 6.79(s, 1H), 4.00 (s, 3H), 3.97(s, 3H), 2.23 (s, 3H) 2.05 (s, 3H) MS m1z = 407 ([M]+, 60%), 376 (100%). HMRS (EI) calcd. for C23HZ1NO6: 407.1369; found: 407.1375.
. ..~,,. ., 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).
A$er diluting further with 1 N HCl (100 mL) the solution was extracted with dichloromethane (2 X
100 mL). The organic phase was washed with sat NaHC03 (100 mL) and dried over magnesium sulfate. The solvent was then removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, l :l) gave 1.65 g (18%) of the desired trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester. 'H-NMR (300 MHz, CDC13):
10.12 (s, 1 H), 7.94 (dd, 1 H, J= 8.7 Hz), 7.03 (dd, 1 H, J= 8.7 and 2.4 Hz), 6.87 (d, 1 H, J= 2.4 Hz), 3.92 (s, 3 H).
Ex-34B: A solution of trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (Ex-34A, 1.6 g, 5.63 mmol) in 1,4-dioxane (IS mL) was stirred at room temperature under nitrogen for 5 min. Thiophene-2-boronic acid (1.08 g, 8.44 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.65 g, 0.56 mmol) and a potassium phosphate (2.2 g, 10.36 mmol) were then added and the resulting mixture was heated to 95 °C under nitrogen overnight. Upon cooling to room temperature the reaction was diluted with EtOAc (25 mL) and water (25 mL) and the layers were cut. The organic phase was concentrated under reduced pressure.
Silica gel chromatography (hexane/ethyl acetate, 4:1 ) gave 1.1 g (90%) of the desired 4-methoxy-2-thiophen-2-yl-benzaldehyde product. 'H-NMR (300 MHz, CDC13): 10.06 (s, IH), 8.03 (m, 1 H), 7.45 (m, 1 H), 7.14 (m, 1 H), 7.09 (m, 1 H), 7.00 (m, 2 H), 3.91 (s, 3 H).
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.'H-NMR (300 MHz, d6-DMSO): 8.14 (m, 3 H), 8.04 (d, 2 H, J=
9.2 Hz), 7.89 (d, I H, J = 15.5 Hz), 7.76 (d, 1 H, J = 15.5 Hz), 7.70 (d, 1 H, J = 5.0 Hz), 7.18 (dd, 1 H, J = 5.6 and 3.6 Hz), 7.11 (d, 1 H, J = 2.1 Hz), 7.05 (dd, 1 H, J =
8.8 and 1.8 Hz), 6.98 (d, I H, J= 1.8 Hz), 3.83 (s, 3 H). MS m/z = 364 ([M]+, 100%). HRMS (EI) Calcd. for C21H,6O4S: 364.0769. Found: 364.0761.

2-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid The title compound was prepared by condensing 2,4-dimethoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-6A) and 2-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, 47 %yield, mp 196-198°C.'H-NMR (DMSO-d6) 8 8.00 (s, 1H), 7.84 (d, 1H), 7.61 (m, 3H), 7.45 (m, 3H), 7.21 (d, 1H), 7.08 (t, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H).
MS m/z = 394 ([M]+, 100%). Anal. calculated for C22H18OSS: C, 66.99, H, 4.60, S, 8.13;
found C: 67.08, H: 4.17, S: 7.97.
2-{5-[3-(4-Carboxy-phenyl)-3-oXO-E-propenyl]-2,4-dimethoxy-phenyl}-indole-1-carboxylic acid tent-butyl ester Ex-36A: 2-(5-Formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester was prepared from S-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as described in Ex-3A. Yellow oil, 79% yield. 'H-NMR (CDC13) 8 10.36 (s, 1H), 8.15 (d, J = 8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J = 8 Hz, 3H), 7.27-7.35 (m, 1H), 7.19-7.27 (m, 1 H), 6.52 (s, 1 H), 6.47 (s, 1 H), 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 tent-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. 'H-NMR (CDC13) 8 8.21 (d, J = 8 Hz, 2H), 8.19 (d, J = 13 Hz, 1 H), 8.16 (d, J = 7 Hz, 1 H), 8.07 (d, J = 8 Hz, 2H), 7.69 (s, 1 H), 7.54 (d, J = 7 Hz, 1 H), 7.52 (d, J = 13 Hz, I H), 7.29-7.35 (m, 1 H), 7.23 (d, J = 7 Hz, 1 H), 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 C3~Hz9NOyH20: C, 68.25; H, 5.73; N, 2.56; found: C, 68.63; H, 5.62; N, 2.45.
4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-37A: 2,6-Dimethoxy-4-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-34A and Ex-34B. 75% yield, m.p. 168-170°C. 'H-NMR (300 MHz, CDC13):
10.48 (s, 1 H), 7.43 (dd, 1 H, J= 3.6 and 1.3 Hz), 7.41 (d, 1 H, J= 5.3 Hz), 7.13 (dd, 1 H, J=
5.3 and 3.6 Hz), 6.79 (s, 2 H), 3.96 (s, 6 H).
The title compound was prepared by condensing 2,6-dimethoxy-4-thiophen-2-yl-benzaldehyde (Ex-37A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, 79% yield, m.p. 256-258°C. °'H-NMR (300 MHz, d6-DMSO): 8.11 (d, 1 H, J= 15.9 Hz), 8.10 (m, 4 H), 8.05 (d, 1 H, J = 15.9 Hz), 7.73 (d, 1 H, J = 3.6 Hz), 7.61 (d, 1 H, J = 5.3 Hz), 7. I 6 (dd, 1 H, J= 5.3 and 3.6 Hz), 6.95 (s, 2 H), 3.98 (s, 6 H). MS mlz = 394 ([M]+, 100%). HRMS
(EI) Calcd. for CzzH,gOSS: 394.0875. Found: 394.0877.

4-{3E-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid Ex-38A: 5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and 2,4-Dimethoxy-pyrimidin-5-boronic acid in a similar manner as described in Ex-3A, 75% yield. 'H-NMR (CDC13) 8 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. 'H-NMR (DMSO-d6) 8 8.11-9.15 (m, 3H), 7.99-8.06 (m, 3H), 7.88 (s, I H), 7.76 (d, J = 17 Hz, 1 H), 6.76(s, 1 H), 3.96(s, 3H), 3.90(s, 3H), 3.83 (s, 3H) 3.81 (s, 3H). MS m/z = 451 ([M+H]~. HRMS (ES+) Calcd. for C24H22N207~
451.1505. Found: 451.1524.
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. ~H-NMR (CDC13) S 10.02 (s, 1 H), 7.40 (d, IH), 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.). ~H-NMR (DMSO-d6) 8 8.02 (d, 2 H), 7.93 (d, 2H), 7.73 (m, 3H), 7.15 (t, 1 H), 7.07 (d, 1 H), 6.72 (d, 1 H), 6.62 (d, 1 H). MS m/z = 394 ([M]+, 6%), 245 ( 100%).
HRMS m/z: calc. 395.0953, found 395.0949.
4-{3E-[2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic acid Ex-40A: 2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and S-methyl-thiophene-2-boronic acid in a similar manner as described in Ex-3A, 100% yield. 1H-NMR (CDC13) 8 10.33 (s, 1H), 8.05 (s, 1H), 7.22 (d, J =
4 Hz, 1 H), 6.72 (d, J = 4 Hz, 1 H), 6.49 (s, 1 H), 4.00 (s, 3H), 3.97 (s, 3H), 2.50 (s, 3H). HN1RS
(EI) calcd. for C~4H~4O3S: 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) 8 8.18 (d, J =
7 Hz, 2H), 8.17 (s, 1H), 8.00-8.06 (m, 3H), 7.85 (d, J = lSHz, 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 C23HZOO5S:
408.1031; found: 408.1023.

4-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-41A: 4-Methoxy-3-(thiophen-2-yl)-benzaldehyde was prepared from 3-bromo-4-methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. Orange oil, 96% yield.'H-NMR (CDCl3) b 9.94 (s, 1H), 8.16 (d, J = 1.8 Hz, IH), 7.80 (dd, J = 2.4, 8.4 Hz, 1 H), 7.57 (dd, J = I .8, 3.6 Hz, 1 H), 7.3 8 (d, J = 5.1 Hz, I H), 7.12 (dd, J= 3.6, 5.1 Hz, IH), 7.09 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H). HRMS m/z: calc. 218.0402, found 218.0406.
The title compound was prepared by condensing 4-methoxy-3-(thiophen-2-yl)-benzaldehyde (Ex-41A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, mp 219-220°C, 71 % yield. ' H-NMR (DMSO-D6) S 13.36 (br s, 1 H), 8.25-8.31 (m, 3H), 8.11 (d, J
I S = 8 Hz, 2H), 7.85-7.98 (m, 3H), 7.78-7.80 (m, I H), 7.61 (d, J= 5 Hz, 1 H), 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.
H
4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-42A: 3-(Thiophen-2-yl)-benzaldehyde was prepared from 3-bromobenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. Orange oil, 93% yield.
'H-NMR (CDCl3) b 10.06 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1 H), 7.55 (dd, J = 7.2, 8.4 Hz, 1 H), 7.40 (dd, J= 1.5, 3.6 Hz, 1 H), 7.34 (dd, J = 1.5, 5.3 Hz, 1H), 7.11 (dd, J = 3.6, 5.3 Hz, 1H). HRMS m/z: calc. 188.0296, found 188.0293.
The title compound was prepared by condensing 3-(thiophen-2-yl)-benzaldehyde (Ex-42A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238°C (dec), 71 % yield. 'H-NMR (DMSO-D6) 8 13.40 (bs, 1 H), 8.29 (d, J = 8 Hz, 2H), 8.22 (s, 1 H), 8.13 (d, J = 8 Hz, 2H), 8.04 (s, 1 H), 7.87 (s, 1 H), 7.83 (d, J = 8 Hz, 1 H), 7.73 (d, J = 9 Hz, 1 H), 7.69 (d, J = 4 Hz, 1H), 7.63 (d, J = 5 Hz, 1H), 7.52 (t, J = 8 Hz, lI-n, 7,20 (dd, J =
4, 5 Hz, 1H). HRMS
m/z = calc. 335.0742, found 335.0749.
3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid 1 S The title compound was prepared by condensing 2,4-dimethoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-6A) and 3-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, 65% yield, mp 179-182 °C.'H-NMR (DMSO-d6) 8 8.54 (s, 1 H), 8.39 (d, 1H), 8.25 (s, 1 H), 8.15 (d, 1 H), 8.04 (d, 1 H), 7.90 (d, 1 H), 7.67 (m, 2H), 7.48 (d, 1 H), 7.09(t, 1 H), 6.81 (s, 1H), 3.98 (s, 3H), 3.97 (s,3H). MS m/z = 394 ([M]+, 72%), 363 (100%).
Anal.
calculated for C22H18OSS: C, 66.99, H, 4.60, S, 8.13; found C: 66.80, H: 4.60, S: 8.07.

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 (CDC13) ~ 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 NH4C1 to water and extracted with EtOAc (2x15 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to provide 58.5 mg of 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde as an orange, oily residue which was used without further purification, 97%
yield. ~H-NMR
(CDC13) 8 10.31 (s, 1H), 7.92 (d, J =9 Hz, 1H), 7.81-7.88 (m, ZH), 7.56 (d, 1H), 7.33-7.39 (m, 2H), 6.88 (d, J = 9 Hz, 1H), 3.91 (s, 3H), 3.64 (s, 3H).
The title compound was prepared by condensing 3-benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde (Ex-44B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, mp 237°C (dec.), 64% yield.'H-NMR (DMSO-d6) 8 13.37 (bs, 1H), 8.20-8.25 (m, 3H), 8.11 (d, J = 8 Hz, 2H), 8.02 (d, J = 8 Hz, I H), 7.96 (d, J = 9 Hz, 2H), 7.88-7.91 (m, 1 H), 7.65 (s, 1 H), 7.35-7.43 (m, 2H), 7.14 (d, J = 9 Hz, 1 H), 3.90 (s, 3H), 3.53 (s, 3H). HRMS
mlz = calc. 445.11 I 0, found 445.1112.

4-(3E-(2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-45A: 2-Methoxy-5-(thiophen-2-yl)-benzaldehyde was prepared from 5-bromo-2-methoxybenzaldehyde and thiophene-2-boronic acid in a similar manner as described in Ex-3A. ~ H NMR (CDC13) 8 10.49 (s, 1 H), 8.07 (d, J = 3 Hz, 1 H), 7.79 (dd, J =
3, 9.0 Hz, 1 H), 7.28-7.26 (m, 2H), 7.09-7.06 (m, 1H), 7.02 (d, J = 9 Hz, 1H), 3.97 (s, 3H).
The title compound was prepared by condensing 2-methoxy-5-(thiophen-2-yl)-benzaldehyde (Ex-45A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, mp 195-196 °C. 'H-NMR (DMSO-d6) 8 8.23-8.20 (m, 3H), 8.08-7.96 (m, 4H), 7.67 (dd, J = 2. l, 6.8 Hz, 1 H), 7.55 (d, J = 3.8 Hz, 1 H), 7.49 (d, J = 5.1 Hz, 1 H), 7.16-7.11 (m, 2H), 3.90 (s, 3H).
MS m/z = 364 (M~, 100%).
4-[3E-(2,4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid Ex-46A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.92 g, 20.1 mmol) was dissolved in benzene (41 mL). Ethylene glycol (3 mL, 54 mmol) and p-toluenesulfonic acid (25 mg, 0.13 mmol) were added and the solution was refluxed with a Dean-Stark trap attached.
After 6 h, the reaction was cooled and washed with water (1x20 mL), saturated, aqueous NaHC03 (1x20 mL), and water (1x20 mL). The organic phase was dried over sodium sulfate, filtered, concentrated, and dried to provide 5.32 g of 2-(5-bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane as a faint yellow oil which solidified upon standing (92% yield).
~ H-NMR (CDC13) 8 7.67 (s, 1 H), 6.47 (s, 1 H), 6.06 (s, 1 H), 4.11-4.13 (m, 2H), 3.98-4.03 (m, S 2H), 3.91 (s, 3H), 3.87 (s, 3H). HRMS (ES+) Calcd. for C~,Hi3Br04: 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 (1x100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to a dark oil.
The oil was purified via silica gel chromatography (1:1 EtOAc/hexanes after a column pre-wash of 5% Et3N in l:l 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 (CDC13) 8 7.85 (s, 1H), 6.39 (s, 1H), 6.07 (s, 1 H), 4.13-4.18 (m, 2H), 3.98-4.02 (m, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 1.33 (s, 9H).
Ex-46C: 2-(5-[ 1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Ex-46B, 2.22 g, 6.60 mmol, containing borolane impurity) was dissolved in DME (60 mL) and 2-iodopyrazine (0.59 mL, 6.0 mmol) was added. 2M aqueous Na2C03 ( 17.8 mL, 35.6 mmol) was added and the mixture was purged with nitrogen for 20 min.
Tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.60 mmol) was added and the mixture was heated at reflux for 2.5 h. After cooling, water (50 mL) was added and the mixture was extracted with CHZCl2 (2x30 mL). The organic phase was washed with brine (1x20 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the resulting yellow-orange solids via silica chromatography (50-80% EtOAc/hexanes) provided 1.02 g of 2-(5-[1,3]dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine as a yellow solid (59%
yield).'H-NMR

(CDC13) 8 9.10 (d, J = 2 Hz, 1H), 8.61 (m, 1H), 8.39 (d, J = 3 Hz, 1H), 8.07 (s, 1H), 6.57 (s, 1 H), 6.14 (s, l I~, 4.13-4.18 (m, 2H), 4.01-4.05 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H).
Ex-46D: 2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine (1.02 g, 3.54 mmol) was dissolved in acetone and p-toluenesulfonic acid (100 mg, 0.53 mmol) and water (5 mL) were added. The solution was stirred for 3 h at room temperature, then concentrated on the rotavap.
The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3x100 mL).
The organic phase was washed with 25% saturated aqueous NaHC03, dried over sodium sulfate, filtered, and concentrated. Drying gave 0.30 g of 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde as a yellow solid (18% yield).'H-NMR (CDC13) 8 10.35 (s, 1H), 9.06 (d, J = 2 Hz, 1H), 8.63-8.65 (m, 1H), 8.45 (d, J = 2 Hz, 1H), 8.39 (s, 1H), 6.56 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). HRMS m/z: calc. 244.0848, found 244.0853.
The title compound was prepared by condensing 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde (Ex-46D) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, mp 238°C (dec.), 4% yield.'H-NMR (DMSO-D6) 8 9.04 (d, J = 2 Hz, 1H), 8.75-8.76 (m, 1H), 8.56 (d, J = 2 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J = 9 Hz, 2H), 8.05-8.11 (m, 3H), 7.83 (d, J = 16 Hz, 1H), 6.90 (s, 1H), 4.05 (s, 3H), 4.00 (s,. 3H). HRMS m/z = calc. 391.1294, found 391.1313.

H
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. 'H-NMR (300 MHz, DMSO-d6) 8 11.58 (s, 1H), 10.07 (s, 1H), 7.75 (s, 1 H), 6.69 (s, 1 H), 3.87 (s, 3H). MS (EI) m/z = 230 ([M]+, 100%). Anal.
Calcd. for CBH~Br03~'/4Hz0: C, 40.79; H, 3.21. Found: C, 40.66; H, 3.01.
Ex-47B: 4-Hydroxy-2-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in an analogous fashion as described in Ex-29B. Silica gel chromatography (ethyl acetate/hexanes, 2:1) gave the expected product as a solid (85%), mp 200 °C (dec.). 'H-NMR (300 MHz, CDC13) 8 10.31 (s, 1 H), 7.89 (s, 1 H), 7.42 (dd, 1 H, J = 4.8, 1.2 Hz), 7.14-7.19 (m, 2H), 6.59 (s, I H), 6.14 (brs, 1H), 3.94 (s, 3H). MS (EI) m/z: 234 ([M]+, 100%). Anal. Calcd. for C,ZH,o03S~H20: 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 bromoisobutyrate. Silica gel chromatography (ethyl acetate/hexanes, 1:1) gave the expected product as a solid (82%), mp 111-113 °C.'H-NMR (300 MHz, CDCI3) 8 10.32 (s, 1H), 8.14 (s, 1 H), 7.45 (dd, 1 H, J = 3.7, 1.3 Hz), 7.30 (dd, 1 H, J = 5.2, 1.3 Hz), 7.07 (dd, 1 H, J = 5.2, 3.7 Hz), 6.35 (s, 1 H), 4.25 (q, 2H, J= 7.2 Hz), 3.85 (s, 3H), I .76 (s, 6 H), 1.23 (t, 3H, J= 7.2 Hz).
MS (EI) m/z = 348 ([M]+, 100%). Anal. Calcd. for C~gH2oO5S: C, 62.05; H, 5.79;
S, 9.20.
Found: C, 61.81;H,5.81;5,9.12.
Ex-47D: To a solution of 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid ethyl ester (0.29 g, 0.83 mmol) in a mixture of tetrahydrofuran, water and methanol (9 mL, 4:1:1) was added lithium hydroxide (0.10 g, 2.49 mmol) and the resulting yellow slurry was stirred at rt for 5 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (1 x 5 mL). The aqueous layer was acidified with a 1 N HCl solution and extracted with ethyl acetate (3 x 1 S mL). The combined organic layers was dried over sodium sulfate and concentrated to afford 0.13 g (87%) of 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid as a pale green solid, mp 183-184 °C.
'H-NMR (300 MHz, CDC13) 8 10.32 (s, 1 H), 8.12 (s, 1 H), 7.40 (d, 1 H, J = 3.6 Hz), 7.32 (d, 1 H, J = 4.8 Hz), 7.08 (dd, 1H, J= 4.8, 3.6 Hz), 6.47 (s, 1H), 3.86 (s, 3H), 1.78 (s, 6 H). MS (EI) mlz = 320 ([M]+, 100%). Anal. Calcd. for C,6H~605S: C, 59.99; H, 5.03; S, 10.01. Found: C, 60.04; H, 5.26; S, 9.70.
2-(4-Formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-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 x 25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in a tetrahydrofuran-heptane solution (5 mL, 10:1) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield I S 0.30 g (90%) of the title compound as a dark yellow solid, mp 135-137 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.32 (s, 1H), 8.23 (d, 2H, J= 8.4 Hz), 8.10 (d, 2H, J= 8.4 Hz), 7.99 (d, 2H, J = I 5.6 Hz), 7.7 I (d, 1 H, J = 3.0 Hz), 7.54 (d, 1 H, J= 5.1 Hz), 7.14 (dd, 1 H, J = S.1, 3.0 Hz), 6.49 (s, 1 H), 3.85 (s, 3H), 1.69 (s, 6H). MS (ESI) m/z = 467 ([M+H]+, 100%).
Anal. Calcd. for C25H2808S~EtOH: C, 63.27; H, 5.51; S, 6.26. Found: C, 63.40; H, 5.19; S, 6.38.
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. ~H-NMR (DMSO-D6) b 8.07 (d, J = 2 Hz, 1H), 7.91 (d, J =

8 Hz, 1 H), 7.73 (dd, J = 2, 4 Hz, 1 H), 7.67-7.70 (m, 2H), 7.63 (dd, J = 2, 7 Hz, 1 H), 7.57 (dd, J
= 2, 5 Hz, I H), 7.50 (d, J= 8 Hz, 1 H), 7.22 (d, J = 2 Hz, 2H), 7.19 (d, J =
8 Hz, 1 H), 7.12 (dd, J
= 4, 5 Hz, 1H), 3.96 (s, 3H). HRMS m/z = calc. 365.0848, found 365.0853.

H
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: I ) 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. 'H-NMR
(300 MHz, CDCl3) 8 10.34 (s, I H), 8.13 (s, 1 H), 7.48 (d, 1 H, J = 3.6 Hz), 7.30 (t, 1 H, J = 5. I Hz), 7.06 (dd, 1 H, J = 5.1, 3.6 Hz), 6.56 (s, 1 H), 4.34 (t, 2H, J = S.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 C,~H2oOSS: 336.1031. Found: 336.1028.
The title compound was prepared by condensing 2-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-benzaldehyde (Ex-49A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 174-175 °C, 61% yield. 'H-NMR (300 MHz, DMSO-d6) 8 8.28 (s, 1H), 8.23 (d, 2H, J= 8.1 Hz), 8.05-8.11 (m, 3H), 7.91 (d, 1H, J= 15.3 Hz), 7.72 (d, 1 H, J = 2.7 Hz), 7.52 (d, 1 H, J = 4.2 Hz), 7.11-7.1 S (m, 1 H), 6.86 (s, 1 H), 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 Cz6H2sW S:
C, 64.71; H, 5.43; S, 6.64. Found: C, 64.43; H, 5.34; S, 6.54.
4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid Ex-SOA: To a solution of 3-(tent-butyl-dimethyl-silanyloxy)-2-(tent-butyl-dimethyl-silanyloxymethyl)-propan-1-of (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, I
11 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).
I S The layers were separated and the aqueous was extracted with ethyl acetate ( 1 x 150mL). The combined organic extracts were washed with a saturated sodium bicarbonate (1 x 200 mL), a 50% sodium chloride solution (2 x 200 mL), dried over sodium sulfate and concentrated to afford 29.5 g (97%) of the expected methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propyl ester as a yellow oil, 97%
yield. 'H-NMR (300 MHz, CDC13) 8 4.29 (d, 2H, J= 5.7 Hz), 3.61-3.68 (m, 4H), 2.99 (s, 3H), 2.04-2.11 (rri, :LH), 0.88 (s, 18H), 0.049 (s, 12H). HRMS (ESI) Calcd. for C,~H4oO5SSiz: 413.2213.
Found:
413.2226.
Ex-SOB: 4-[3-(tert-Butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in an analogous fashion as described in EX-29C using methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-SOA). Silica gel chromatography (ethyl acetate/hexanes, I :6) gave the expected product as a pale green solid, 90%
yield.'H-NMR (300 MHz, CDC13) 8 10.34 (s, 1 H), 8.13 (s, 1 H), 7.4 I (dd, 1 H, J = 3.6, 1.2 Hz), 7.28 (dd, 1 H, 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, IH, J= 5.7 Hz), 0.88 (s, 18H), 0.012 (s, 12H). MS (ESI) m/z = 551 ([M+H]+, 100%). HRMS (EI) Calcd. for CZ8H4605SSiz: 550.2604. Found:
550.2593.
Ex-SOC: To a solution of 4-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-S-thiophen-2-yl-benzaldehyde (Ex-SOB, 0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 3.0 mL, 2.9 mmol) and the mixture was stirred at rt for 30 min. The reaction was diluted with ethyl acetate (50 mL) and washed with a 50% ammonium chloride solution (1 x 30 mL), water (2 x 30 mL), brine (1 x 30 mL), dried over sodium sulfate and concentrated to a crude yellow solid. Silica gel chromatography afforded 0.37 g (99%) of the expected 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde as a pale yellow solid, 90% yield, mp 144-145 °C..'H-NMR (300 MHz, CDC13) 8 10.33 (s, 1H), 8.10 (s, 1H), 7. 3 8 (dd, I H, J = 3 .6, I . S Hz), 7. 3 0 (dd, 1 H, J = 5 .1, 1. 5 Hz), 7.07 (dd, 1 H, J = 5 .1, 3 . 6 Hz), 6.59 (s, 1H), 4.35 (d, 2H, J= 6.0 Hz), 4.02 (t, 4H, J= 4.8 Hz), 3.96 (s, 3H), 2.33 (pentet, 1H, J
= 6.0 Hz), 1.89 (t, 2H, J= 4.8 Hz). MS (ESI) mlz = 323 ([M+H]+, 100%). Anal.
Calcd. for C~6H,805S: C, 59.61; H, 5.63; S, 9.95. Found: C, 59.34; H, 5.75; S, 9.82.
The title compound was prepared by condensing 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-SOC) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 199-201 °C, 60% yield. 'H-NMR
(300 MHz, DMSO-d6) 8 8.31 (s, 1H), 8.23 (d, 2H, J= 8.7 Hz), 8.06-8.11 (m, 3H), 7.93 (d, IH, 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) mlz = 469 ([M+H]+, 100%). Anal. Calcd. for C25HZqO~S''/4H2O: C, 63.48; H, 5.22; S, 6.78.
Found: C, 63.45; H, 5.29; S, 6.61.

H
5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester Ex-S1A: 5-(5-Formyl-2,4-dimethoxy-phenyl)-thiophene-2-carboxylic acid methyl ester was prepared starting from 5-bromo-thiophene-2-carboxylic acid methyl ester in a similar manner as described in Ex-46A through -46D. Yellow solid, 18% yield. 'H-NMR (CDC13) 8 10.32 (s, 1 H), 8.16 (s, 1 H), 7.74 (d, J = 4.4 Hz, 1 H), 7.42 (d, J = 4.4 Hz, 1 H), 6.51 (s, 1 H), 4.05 (s, 3H), 3.98 (s, 3H), 3.90 (s, 3H). HRMS (ES+) Calcd. for C~SH~qOSS: 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-S1A, 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 (3x20 mL); the organic phase was washed with brine (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated. The resulting orange residue was purified via silica gel chromatography (0-10% MeOH/CHZCIz) to provide 89 mg of yellow solid which still contained DMF. The solid was slurried in EtOH for several hours, filtered, and dried to provide 31 mg of final product as a yellow solid (47% yield). 'H-NMR (DMSO-d6) b 8.47 (s, 1 H), 8.23 (d, J = 9 Hz, 2H), 8.01-8.11 (m, 4H), 7.89 (d, J = 4 Hz, 1 H), 7.82 (d, J = 4 Hz, 1 H), 6.90 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 3.84 (s, 3H). HRMS (ES+) Calcd. for CZqH2007S:
453.1008. Found: 453.1020.

H
5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid The title compound was prepared through routine hydrolysis of 5-{ 5-[3-(4-Carboxy-phenyl)-3-oxo-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester (Ex-51).
Orange solid, mp >260°C, 43% yield. 'H-NMR (DMSO-db) 8 8.43 (s, 1H), 8.26 (d, J = 8 Hz, 2H), 8.01-8.12 (m, 4H), 7.82 (d, J = 4 Hz, 1 H), 7.71 (d, J = 4 Hz, 1 H), 6.89 (s, 1 H), 4.08 (s, 3H), 4.03 (s, 3H).

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-S-hydroxymethyl-[1,3]dioxolan-4-ylmethoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde, was not obtained. Instead, 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde was formed via cleavage of the cyclic ethyl orthoformate group under the reaction conditions. Silica gel chromatography (ethyl acetate/hexanes, 1:2) gave 0.16 g (90%) of 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde, mp 101-103 °C. 'H-NMR (300 MHz, CDCl3) 8 10.33 (s, 1H), 8.15 (s, 1H), 7.48 (d, IH, J= 3.6 Hz), 7.29 (d, 1H, J= 5.2 Hz), 7.07 (dd, 1H, J= 5.2, 3.6 Hz), 6.50 (s, 1H), 4.25 (q, 2H, J= 7.2 Hz), 3.97 (s, 3H), 1.59 (t, 3H, J
= 7.2 Hz). MS (EI) m/z = 262 ([M]+, 100%). HMRS (E1) Calcd. for C14H,4O3S:
262.0664.
S Found:262.0667.
The title compound was prepared by condensing 4-ethoxy-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-53A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, mp 210-212 °C, 76% yield.'H-NMR (300 MHz, DMSO-d6) 8 8.31 (s, 1H), 8.23 (d, 2H, J= 9.0 Hz), 8.06-8.11 (m, 3H), 7.92 (d, 1H, J= 16.2 Hz), 7.71 (d, 1H, J= 3.9 Hz), 7.52 (d, 1 H, J = 5.1 Hz), 7.13 (dd, 1 H, J = 5.1, 3.9 Hz), 6.82 (s, 1 H), 4.33 (q, 2H, J = 6.1 Hz), 3.99 (s, 3H), 1.48 (t, 3H, J= 6.1 Hz). MS (ESI) mlz = 409 ([M+H]+, 100%). Anal.
Calcd. for C23H20~SS'~/ZH2O: C, 66.17; H, 5.07; S, 7.68. Found: C, 65.88; H, 5.24; S, 7.36.

H
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 x 25 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was subjected to silica gel chromatography (CH2C12:MeOH, 20:1) to yield an orange solid containing residual amounts of starting acid. The solid was taken up in ethyl alcohol (5 mL) to remove acid impurity and the resulting precipitate was collected on filter paper and dried in vacuo to yield 0.010 g (5%) of the title compound as an orange solid, mp 243 °C (dec). 'H-NMR (300 MHz, DMSO-d6) 8 8.18-8.23 (m, 3H), 8.06-8.09 (m, 2H), 8.02 (s, 1H), 7.85 (d, IH, J= 15.6 Hz), 7.68 (d, 1H, J=
3.6 Hz), 7.47 (d, 1 H, J = 5.1 Hz), 7.11 (dd, 1 H, J = 5 .1, 3.6 Hz), 6.67 (s, 1 H), 4.13 (s, 1 H), 3. 89 (s, 3H). MS (ESI) m/z = 381 ((M+H]+, 100%). HRMS (ESI) Calcd. for C2,Hi6O5S:
381.0796.
Found: 381.0800.
4-[3E-(2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid Ex-SSA: 2,4-Dimethoxy-5-thiazol-2-yl-benzaldehyde was prepared from 2-bromothiazole in a similar manner as described in Ex-46A through -46D. Off white solid, 83%
yield. 'H-NMR
(CDCl3) S 10.34 (s, 1 H), 8.86 (s, 1 H), 7.89 (d, J = 3.6 Hz, 1 H), 7.36 (d, J
= 3.6 Hz, 1 H), 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-SSA) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, mp >260°C, 65% yield. ~H-NMR (DMSO-d6), 8;:1,3.33, (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, 1 H), 7.82 (d, J = 16 Hz, 1 H), 7.76 (d, J = 3 Hz, 1 H), 6.94 (s, 1H), 4.14 (s, 3H), 4.05 (s, 1H). HRMS m/z=calc. 396.0906, found 396.0903.

Na+
4-(3E-(5-Benzo[bJthiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt To a solution of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid (5.77g, 13.0 mmol) in tetrahydrofuran (50 mL) was added sodium methoxide (0.70g, 12.3 mmol). The reaction mixture was allowed to stir for 2 hours at ambient temperature. The precipitate was then filtered, washed with tetrahydrofuran and dried in vacuo to give the title compound (5.13g, 85%) as a yellow solid, mp > 235 °C. 'H-NMR (DMSO-d6) 8 8.35 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.00-7.89 (m, 4H), 7.82 (d, J = 7.6 Hz, 1H), 7.35-7.29 (m, 4H), 6.85 (s, 1 H), 4.02 (s, 3H), 3.99 (s, 3H). MS m/z = 443 (M~, 100%).
2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1-carboxylic acid tert-butyl ester Ex-57A: 2-(5-Formyl-2,4-dimethoxy-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester was prepared from pyrrole-I-carboxylic acid tert-butyl ester-2-boronic acid in a similar manner as described in Ex-3A, 81% yield.'H-NMR (CDC13) b 10.32 (s, 1H), 7.76 (s, 1H), 7.31-7.33 (m, 1H), 6.43 (s, 1H), 6.22-6.24 (m, 1H), 6.14-6.16 (m, 1H), 3.98(s, 3H), 3.85 (s, 3H), 1.40 (s, 9H).
HRMS (EI) Calcd. for C,$Hz,N05: 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) S 8.19 (d, J =
5 Hz, 2H), 8.00-8.10 (m, 3H), 7.87 (s, IH), 7.80 (d, J = 16 Hz, 1 H), 7.27-7.28(m, 1 H), 6.71 (s, IH), 6.22-6.23 (m, 1H), 6.14-6.16 (m, IH), 3.96 (s, 3H), 3.79(s, 3H), 1.29 (s, 9H). MS m/z =
476 ([M-HJ+). HMRS (EI) calcd. for C2~HZ~NO~: 477.1788; found: 477.1793.
H
4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloylJ-benzoic acid I S 2-Hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-29B, 0.10 g, 0.43 mmol) and 4-acetylbenzoic acid (0.070 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2.8 mL, 7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting red slurry was stirred in the dark at room temperature for 18 h. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature.
Note: the compound appears to decompose with heating. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.025 g (15%) of the title compound as a dark yellow solid, mp 125 °C (dec). 1H-NMR (300 MHz, DMSO-d6) 8 10.73 (s, 1 H), 8.18-8.22 (m, 3 H), 8.09 (d, 2 H, J= 8.1 Hz), 8.05 (s, I H), 7.87 (d, 1 H, J= 14.7 Hz), 7.60 (d, 1 H, J=
3.0 Hz), 7.49 (d, 1H, J= 4.2 Hz), 7.11 (dd, 1 H, J= 4.2, 3.0 Hz), 6.67 (s, 1 H), 3.90 (s, 3 H).

MS (ESI) m/z = 381 ([M+H]+, 100%). Anal. Calcd. for CZ~H~605S~EtOH: C, 64.77;
H, 5.20; S, 7.52. Found: C, 64.68; H, 5.00; S, 7.77.
H
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 bromoisobutyrate. Silica gel chromatography (ethyl acetate/hexanes, 1:2) gave the expected product as a dark yellow solid (97%), mp 87-88 °C. 'H-NMR (300 MHz, CDC13) b 10.37 (s, I H), 8.14 (s, 1 H), 7.45 (dd, I H, J = 3.6, 1.2 Hz), 7.30 (d, 1 H, J = 5.4 Hz), 7.07 (dd, 1 H, J = 5.1, 3.6 Hz), 6.42 (s, IH), 4.25 (q, 2H, J= 6.9 Hz), 3.90 (s, 3H), 1.72 (s, 6H), I
.26 (t, 3H, J= 6.9 Hz). MS (ESI) m/z = 349 ([M+H]+, 100%). Anal. Calcd. for C,BHZOOSS: 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. 'H-NMR (300 MHz, CDC13) b 9.33 (s, 1H), 7.99 (s, 1H), 7.47 (dd, IH, J= 3.6, 1.5 Hz), 7.37 (d, 1H, J= 4.8 Hz), 7. I 1 (dd, 1 H, J= 4.8, 3.6 Hz), 6.67 (s, I H), 4.00 (s, 3H), 1.75 (s, 6H).
MS (ESI) mlz = 321 ([M+H]+, 100%). Anal. Calcd. for C16H,6OSS: 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 x 15 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.15 g (85%) of the title compound as a dark yellow solid, mp 223-225 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.31 (s, 1H), 8.23 (d, 2H, J= 8.1 Hz), 8.10 (d, 2H, J= 8.1 Hz), 8.06 (s, 1H), 7.95 (d, 1H, J= 16.2 Hz), 7.69 (d, 1 H, J = 3.0 Hz), 7.5 5 ( d, 1 H, J = 5 .1 Hz), 7.14 (dd, 1 H, J = 5 .1, 3.0 Hz), 6.5 8 (s, 1 H), 3.88 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z = 467 ([M+H]+, 100%). Anal. Calcd.
for C25HZZO7S'~I3H2O: C, 63.55; H, 4.84; S, 6.79. Found: C, 63.39; H, 5.02; S, 6.53.

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 oil white solid (81%). 'H-NMR (300 MHz, CDCl3) 8 10.36 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J = 3.6, 1.5 Hz), 7.30 (dd, 1 H, J =
5.1, 1.5 Hz), 7.07 (dd, 1H, J= 5.1, 3.6 Hz), 6.53 (s, 1H), 4.27 (t, 2H, J= 6.3 Hz), 4.00 (s, 3H), 3.72-3.76 (m, 4H), 2.89 (t, 2H, J= 6.3 Hz), 2.60-2.63 (m, 4H). MS (ESI) mlz = 348 ([M+H]+, 100%). HRMS
(EI) Calcd. for C~BHz,N04S: 347.1191. Found: 347.1188.
4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-S-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 acetateaetrahydrofuran mixture (1:1, 6 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude solid was slurried in ethyl alcohol (5 mL) to remove residual impurities and the resulting solid was collected on filter paper and dried in vacuo to yield 0.21 g (98%) of the title compound as a dark yellow solid, mp: 255 °C
(dec).'H-NMR (300 MHz, DMSO-d6) 8 8.34 (s, 1H), 8.26 (d, 2H, J= 8.7 Hz), 8.11 (d, 2H, J=
8.7 Hz), 8.08 (s, I H), 7.95 (d, 1 H, J = 15 .9 Hz), 7.71 (d, 1 H, J = 3.3 Hz), 7.5 5 (d, 1 H, 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 CZ~H28C1NO6S: 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.
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.Og, 5.2 mmol) was dissolved in 100 ml of THF, and Bu4NF (6.86g, 26 mmol) was added. The reaction mixture was stirred at room temperature overnight. No reaction occured at this condition. Then, Bu4NF (6.86g, 26 mmol) was added to the mixture, and the mixture was stirred at reflux for 4 days. The reaction was about 50 % completion (HPLC).
The reaction mixture was poured into CHZC12, and washed with water and brine. The organic phase was dried over MgS04, and concentrated. The residue was purified by column chromatography (EtOAc: Hex, 2:1 ) to give 0.45 g (30 %) of5-( 1 H indol-2-yl)-2,4-dimethoxy-benzaldehyde. ~ H-NMR (CDCl3) 8 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 C1~H15N03: 281.1052; found: 281.1049.
The title compound was prepared by condensing 5-(1H indol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-61A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 210-212°C, 66% yield. 'H-NMR (Aceton-d6) 8 10.53 (br, s, 1H), 8.32 (s, 1H), 8.14-8.21 (m, SH), 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, 1 H), 4.07 (s, 3H), 4.02(s, 3H), MS m/z = 427 ([M]+).
HMRS (EI) calcd.
for C26HZ,N05: 427.1420; found: 427.1435.
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. 'H-NMR (CDC13) 8 10.26 (s, 1 H), 8.14 (s, 1 H), 7.45 (d, J = 6 Hz, 1 H), 7.32 (d, J = 5 Hz, 1 H), 7.07-710 (m, 1 H), 6.58 (s, 1 H), 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,S-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. 'H-NMR (CDCl3) 8 8.20 (d, J = 9 Hz, 2H), 7.88-8.03 (m, 4H), 7.58 (d, J = 16 Hz, 1 H), 7.44 (d, J = 4 Hz, 1 H), 7.34(d, J = S Hz, 1 H), S 7.12(dd, J = 4, 5 Hz, 1H), 6.63 (s, 1H), 4.97(s, 2H), 4.01 (s, 3H), 2.46(s, 3H), 2.34 (s, 3H). MS
m/z = 490 ([M+H]+). HRMS (ES+) Calcd. for C2~HZZN06S: 490.1324. Found:
490.1321.
4-[3E-(2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-63A: A solution of 2-fluoro-5-thiophen-2-yl-benzaldehyde (1.42g, 6.89 mmol) in pyrrolidine was refluxed (10 mL). After 4.5 days the reaction mixture was cooled and diluted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (O.SM) 1 S 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 (O.Sg, 32%). ~H NMR (CDC13) 8 10.14 (s, 1H), 7.94 (d, J = 2 Hz, 1H), 7.62 (dd, J = 2.7, 9 Hz, 1 H), 7.22-7.20 (m, 2H), 7.07-7.04 (m, 1 H), 6.86 (d, J = 9 Hz, 1 H), 3.41 (m, 4H), 2.01 (m, 4H).
The title compound was prepared by condensing 2-pyrrolidin-1-yl-5-thiophen-2-yl-benzaldehyde (Ex-63A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Red solid, mp 208-209 °C. 'H-NMR (DMSO-d6) 8 12.50 (bs, 1H), 8.22 ( d, J =
8.5 Hz, 2H), 8.09 7.99 (m, 4H), 7.73 (d, J = 1 S.5 Hz, 1 H), 7.52-7.41 (m, 3H), 7.10-7.07 ( m, 1 H), 6.93 (d, J = 9.0 Hz, 1 H), 3.28 (m, 4H), 1.87 (m, 4H).

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-SOA, 19.5 g, 46.9 mmol) was added dropwise and the reaction was stirred for an additional 24 h at 80 °C and cooled to room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers was sequentially washed with a saturated sodium bicarbonate solution (1 x 150 mL), water (1 x 150 mL), and brine (1 x 150 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography ( 100% ethyl acetate to I 0% ethyl acetate/hexanes) gave 19.0 g (81 %) of 2-[3-(tent-butyl-dimethyl-silanyloxy)-2-(tent-butyl-dimethyl-silanyloxymethyl)-propoxy]-4-methoxy-5-thiophen-2-yl-benzaldehyde as an off white solid, mp 91-92 °C. ~H-NMR (300 MHz, CDC13) 8 10.37 (s, 1 H), 8.12 (s, 1 H), 7.44 (dd, 1 H, J = 3.6, I .2 Hz), 7.29 (d, 1 H, J = 5.1 Hz), 7.07 (dd, 1 H, J = 5.1, 3.6 Hz), 6.54 (s, 1 H), 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) mlz = 550 ([M]+, 100%). Anal. Calcd. for CzgH46O5SS1z: 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-SOC. Silica gel chromatography (ethyl acetate/hexanes, 1:9) gave the expected product as an off white solid.'H-NMR
(300 MHz, CDCl3) 8 10.17 (s, 1 H), 8.03 (s, 1 H), 7.43 (dd, 1 H, J = 3.6, I .2 Hz), 7.3 I (d, 1 H, J = 5. I 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= S.1 Hz), 2.33 (pentet, 1H, J= 5.4 Hz). MS (EI) mlz = 322 ([M]+, 100%).
HRMS (EI) Calcd. for C,6H,gO5S: 322.0875. Found: 322.0873.
The title compound was prepared by condensing 2-(3-hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-64B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Light orange solid, mp 219-220 °C, 61 % yield. 'H-NMR (300 MHz, DMSO-d6) 8 8.36 (s, 1H), 8.20 (d, 2H, J= 7.5 Hz), 8.05-8.11 (m, 3H), 7.93 (d, IH, J= 16.2 Hz), 7.67 (d, 1 H, J = 3.0 Hz), 7.52 ( d, 1 H, J = 5.1 Hz), 7. I 3 (dd, 1 H, 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, 1 H). MS (ESI) m/z = 469 ([M+H]+, 100%). Anal. Calcd. for CZSH240~S~H20: C, 61.72; H, 5.39;
S, 6.59. Found: C, 61.93; H, 5.30; S, 7.06.
O O HCI ~O
\ ~ \
Ho I ~ I ~
O
S
4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-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. 'H=NMR (DMSO-D6) 8 10.36 (s, 1 H), 7.90 (dd, J = 3, S Hz, 1 H), 7.82 (d, 1 H), 7.48 (d, 1 H), 7.44 (d, I H), 7.25 (d, 1 H) , 7.09 (t, 1 H), 4.18 (t, 2H), 3.53 (m, 4H), 3.28 (br s, 2H), 2.43 (m, 4H), 1.89 (q, 2H).
The title compound was prepared by condensing 2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-65A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, 67% yield, mp 234-236 °C.'H-NMR (DMSO-d6) 8 13.32 (br s, I H), 11.10 (br s, IH), 8.21 (m, 3H), 8.02 (m, 3H), 7.67 (dd, J= 2,2 Hz, 1H), 7.56 (d, IH), 7.50 (d, IH), 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 Cz~H28C1NO5S~3/2 HZO: C, 59.94, H, 5.78, S, 5.93; found C: 60.20, H:
5.65, S: 5.94 4-{3E-(4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride Ex-66A: 4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-60A, 78% yield. 'H-NMR (DMSO-D6) 8 10.21 (s, 1 H), 7.88 (s, 1 H), 7.46 (m, 2H), 7.06 (t, 1 H), 6.82 (s, 1 H), 4.24 (t, 2H), 4.00 (s, 3H), 3.53 (m, 4H), 3.28 (m, 2H), 2.34 (m, 4H), 1.93 (q, 2H).
The title compound was prepared by condensing 4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 72% yield, mp 188-191°C (dec). 'H-NMR
(DMSO-d6) 8 12.63 (br s, 1 H), 11.08 (br s, 1 H), 8.33 (s, 1 H), 8.22 (d, 2H), 8.05 (m, 3H), 7.89 (d, 1 H), 7.65 (d, 1 H), 7.49 (d, 1 H), 7.10 (t, 1 H), 6.84 (s, 1 H), 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 C28H3zC1NO~S~
H20: C, 59.83, H, 5.74, S, 5.70; found C: 59.69, H: 5.80, S: 5.55.

y a 4-[3E-(2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid Ex-67A: 2-(2-Formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl-acetamide was prepared in an analogous fashion as described in Ex-29C using 2-chloro-N,N
dimethylacetamide. Methylene chloride was used in place of ethyl acetate for the work up procedure. The crude solid was slurried in ethyl acetate (25 mL) to remove residual impurities.
The resulting solid was collected on filter paper and dried in vacuo to give the expected product as a pale yellow solid (85%), mp 197-198 °C. 'H-NMR (300 MHz, CDC13) 8 10.38 (s, 1H), 8.13 (s, I H), 7.44 (d, 1 H, J = 3 .6 Hz), 7.3 0 (dd, 1 H, J = 5. I , 1. 8 Hz), 7.07 (dd, 1 H, J = 5 .1, 3.6 Hz), 6.73 (s, IH), 4.89 (s, 2H), 3.99 (s, 3H), 3.15 (s, 3H), 2.99 (s, 3H). MS
(EI) m/z = 319 ([M]+, 100%). Anal. Calcd. for C~6H»N04S~'/SH20: C, 59.50; H, 5.43; N, 4.34;
S, 9.93.
Found: C, 59.65; H, 5.42; N, 4.40; S, 9.69.
The title compound was prepared by condensing 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-N,N-dimethyl-acetamide (Ex-67A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 228-229 °C, 75% yield. 1H-NMR (300 MHz, DMSO-d6) 8 8.31 (d, 2H, J= 9.3 Hz), 8.22 (d, 2H, J= 13.3 Hz), 8.08 (d, 2H, J= 9.3 Hz), 7.95 (s, 1H), 7.65 (d, I H, J = 2.7 Hz), 7. S 2 (d, 1 H, J = 5 .1 Hz), 7.13 (dd, 1 H, J = 5 .1, 2. 7 Hz), 6. 8 5 (s, 1 H), 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 C25Hz3N06S: 465.1246. Found: 465.1246.

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%). 'H-NMR (300 MHz, CDCI3) 8 4.37-4.40 (m, 2H), 3.76-3.78 (m, 2H), 3.61-3.70 (m, 6H), 3.53-3.57 (d, 2H), 3.38 (s, 3H), 3.08 (s, 3H). MS
(ESI) m/z = 243 ([M+H]+, 100%). HRMS (ESI) Calcd. for CgH,g06S: 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%).'H-NMR (300 MHz, CDC13) 8 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (d, 1H, J=
3.6 Hz), 7.30 (d, 1H, J= 5.4 Hz), 7.07 (dd, 1 H, 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 CgH1806S:
243.0902.
Found: 243.0914.
The title compound was prepared by condensing 4-methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-S-thiophen-2-yl-benzaldehyde (Ex-68B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 137-138 °C, 82% yield.'H-NMR (300 MHz, DMSO-d6) b 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= S.1 Hz), 7.13 (dd, 1H, J= 5.1, 3.6 Hz), 6.88 (s, 1H), 4.37 (t, 2H, J= 3.6 Hz), 4.01 (s, 3H), 3.89 (t, 2H, J= 3.6 Hz), 3.64-3.67 (m, 2H), 3.53-3.56 (m, 2H), 3.47-3.50 (m, 2H), 3.36-3.95 (m, 2H), 3.19 (s, 3H). MS (ESI) m/z = 527 ([M+H]+, 100%). Anal.
Calcd. for C2gH3oOgS: C, 63.86; H, 5.74; S, 6.09. Found: C, 64.08; H, 5.77; S, 6.09.

4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoic acid Ex-69A: A solution of 2-bromo-1-(3,4-dimethoxy-phenyl)-ethanone (0.62g, 2.39 mmol) and thioacetamide (0.18g, 2.39 mmol) in ethanol (30 mL) was refluxed for 2 hours and the solvent was removed under reduced pressure. The product, 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole (0.56g, 100%) was obtained as a white solid and used without further purification. To a suspension of 4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole obtained above (0.70g, 2.97 mmol) in dichloromethane (60 mL) at 0 °C was added dichloromethyl methyl ether (0.40 mL, 4.46 mmol) followed by addition of titanium tetrachloride (1.0 M solution in dichloromethane, 8.9 mL, 8.9 mmol) dropwise. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. The aqueous solution was extracted with dichloromethane. The solution of dichloromethane was washed with hydrochloric acid (O.SM), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated.
,, The product, 2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde, was obtained as a white solid.'H NMR (CDC13) 8 10.33 (s, 1H), 8.67 (s, 1H), 7.56 (s, IH), 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.). 'H-NMR (DMSO-d6) b 8.47 (s, IH), 8.14-7.97 (m, SH), 7.76 (s, 1 H), 7.65 (d, J = 15.8 Hz, 1 H), 6.81 (s, I H), 4.00 (s, 3H), 3.98 (s, 3H), 2.69 (s, 3H).
MS m/z = 409 (M+, 70%), 378 ((M - OCH3]+, I 00%).
4-{3E-[5-(1H Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl)-acryloyl}-benzoic acid Ex-70A: A solution of benzene-1,2-diamine (2.60g, 24.1 mmol) and 2,4-dimethoxy-benzaldehyde (4.Og, 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 (0.76g, 12%). The crude product was used without further purification. To a solution of 2-(2,4-dimethoxy-phenyl)-IH benzoimidazole obtained above (0.76g, 2.99 mmol) in dichloromethane (20 mL) was added dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by addition of titanium tetrachloride (1.OM in dichloromethane, 9.0 mL, 9.0 mmol) at 0 °C. The reaction mixture was allowed to stir overnight at ambient temperature and then poured into ice. A
solution of sodium hydroxide (SM) 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 (0.40g, 47%), was obtain and used without further purification. lH NMR (CDC13) 8 10.32 (s, 1H), I 0.27 (bs, 1 H), 9.03 (s, 1 H), 7. 83 (d, J = 9 Hz, 1 H), 7.48-7.45 (m, 1 H), 7.3 I -7.22 (m, I H), 6. 5 8 (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.). 'H-NMR (DMSO-d6) 8 8.72 ( s, IH), 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, 1 H), 4.10 (s, 3H), 4.03 (s, 3H). MS m/z = 429 ([M + H]+, 100%).
~H
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, CDC13) 8 10.05 (s, 1H), 7.99 (s, IH), 7.67 (brs, 1H), 7.44 (d, 1H, J= 3.6 Hz), 7.34 (d, 1 H, J= 5.4 Hz), 7.10 (dd, I H, J= 5.4, 3.6 Hz), 6.48 (s, 1 H), 5.67 (brs, 1H), 4.64 (s, 2H), 4.02 (s, 3H). MS (EI) m/z = 291 ([M]+, 100%). Anal. Calcd.
for C,4H,3NO4S: 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.). 'H-NMR (300 MHz, DMSO-d6) S 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, I H), 6.77 (s, 1 H), 4.75 (s, 2H), 3.97 (s, 3H). MS
(EI) m/z = 437 ([M]+, 100%). HRMS (EI) Calcd. for C23H~gNO6S: 437.0933. Found: 437.0924.

H
~o NJ
O O
/ ~ O
O ( / ~ /
'O
O
~S
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.'H-NMR (300 MHz, CDC13) 8 10.33 (s, 1H), I 0 8. I 2 (s, 1 H), 7.44 (d, 1 H, J = 3 .6 Hz), 7.31 (d, 1 H, J = 5 .1 Hz), 7.08 (dd, 1 H, 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 C,gHI9NOSS: C, 59.82; H, 5.30; N, 3.88; S, 8.87. Found: C, 59.88; H, 5.36; N, 3.90; S, 8.75.
The title compound was prepared by condensing 4-methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-72A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Orange solid, mp 231-233 °C, 70% yield. ~H-NMR
(300 MHz, DMSO-d6) S 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='S:1'Hz), 7.13 (dd, IH, J= 5.1, 3.3 Hz), 6.87 (s, 1H), 5.13 (s, 2H), 4.00 (s, 3H), 3:65 (brm, 4H), 3.54-3.55 (m, 4H). MS (EI) m/z = 507 ([M]+, 100%). Anal. Calcd. for CZ~H25NO~S~%zEtOH: 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.

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-SOA using (S~-(-)-1-methyl-2-pynolidinemethanol. The crude orange oil was dried in vacuo to give the expected product and was used without any further purification (40%). 'H-NMR (300 MHz, CDC13) 8 4.99-5.04 (m, 1 H), 4.41-4.51 (m, 1 H), 4. I 9-4.29 (m, 1 H), 3.88-3.94 (m, 1 H), 3.49 (s, 3H), 3.17-3.29 (m, 1 H), 2.95-3.05 (m, 1 H), 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 C,8H,9NOSS: 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. 'H-NMR (300 MHz, CDC13, major isomer) 8 10.35 (s, 1 H), 8.09 (s, 1 H), 7.42-7.44 (m, I H), 7.30 (d, 1 H, J = 5.1 Hz), 7.06-7.09 (m, 1 H), .6.49 (s, 1 H), 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 C~gH,9NO5S:
345.1399. Found:
345.1401.
The title compound was prepared by condensing 4-methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-benzaldehyde (Ex-73B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Dark Yellow solid, 52%, mp 206-208 °C.. 'H-NMR
(300 MHz, DMSO-d6, major isomer) b 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, 1 H, J = 3 .3 Hz), 7. 52 (d, 1 H, J = 5 .1 Hz), 7.14 (dd, 1 H, J = 5.1, 3.3 Hz), 6.86 (s, 1 H), 5.05 (m, 1 H), 4.34 (m, 1 H), 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 C28H3aC1NO5S~'/ZH20: 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.
HN-N
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 (0.33g, 1.70 mmol) and di-tert-butyl dicarbonate (0.51g, 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 (0.28g, 1.13 mmol), 4-(4,4,5,5-~r 20'' '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 (0.24g, 4.08 mmol) was added degassed tetrahydrofuran (15 mL). The reaction mixture was heated at 60 °C for one day. Additional potassium fluoride (0.24g, 4.08 mmol) and water (20 p,L) 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 tent-butyl ester (O.lSg, 40%) as white solid. 'H NMR (CDC13) 8 10.35 (s, 1 H), 8.43 (s, 1 H), 8.09 (s, 1 H), 8.02 (s, 1 H), 6.52 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 1.68 (s, 9H). MS m/z = 333 ([M + H]+, 100%).
The title compound was prepared by condensing 2,4-dimethoxy-5-(1H pyrazol-4-yl)-benzaldehyde (Ex-74B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3 including an acid work-up. Yellow solid, mp >250 °C. 'H-NMR (DMSO-d6) 8 12.42 (bs, 1H), 8.20-8.03 (m, 8H), 7.85 (d, J = 16.1 Hz), 6.74 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). MS m/z = 379 ([M + H]+, 100%).
H
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 x 75 mL).
The organic ws concentrated to a white solid. The solid was stirred in 0.25N NaOH (100 mL) for one hour.
The suspension was filtered and the filtrate was collected and acidified with 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%).'H-NMR (DMSO-d6) 8 10.09 (s, 1 H), 7.97 (s, 1H), 6.89 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). MS m/z = 234 ([M]+, 94%), 191 (100%).

The title compound was prepared by condensing 2,4-dimethoxy-5-(2H tetrazol-5-yl)-benzaldehyde (Ex-75A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3.
Yellow solid, 19% yield, mp 218 °C (dec). 'H-NMR (DMSO-d6) 8 8.58 (s, 1 H), 8.20 (d, 2H), 8.03 (m, 3H), 7.85 (d, 1H), 6.90 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H). MS m/z =

([M+CH3CN+H]+, 100%). HRMS m/z: calc. 381.1199, found 381.1184.
H
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 POC13 in a 50 ml of a round-bottom flask, 2,3-diaminopyridine (0.22 g, 2 mmol) was added. The mixture was heated to reflux for 4 hours and then cooled to room temperature. The reaction mixture was then concentrated to remove most of the POC13. The residue was carefully treated with 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%). 'H-NMR (DMSO-d6) 8 8.28-8.36 (m, 2H), 7.97 (d, J = 8 Hz, 1H), 7.21-7.25(m, 1H), 6.80 (s, 1H), 6.78 (d, J = 9 Hz, 1H), 4.05(s, 3H), 3.91 (s, 3H). HRMS (ES+) Calcd. for Cz4H,9N305:
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 CHZC12, l, 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 CHzCl2) was added dropwise. The mixture was stirred at 0 °C for 2 hrs, then room temperature for overnight. The reaction mixture was poured into ice-water and the precipitate was filtered to give 0.31 g (63%) of 5-(3H imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde as a white solid.'H-NMR (DMSO-d6) 8 10.22 (s, 1H), 8.67(s, IH), 8.56 (d, J = 5 Hz, 1H), 8.44 (d, J
= 8 Hz, 1H), 7.57-7.61(m, 1H), 6.97 (s, 1H), 4.19(s, 3H), 4.06 (s, 3H). HMRS
(EI) calcd. for C,SH,3N3O3: 283.0957; found: 283.0952.
The title compound was prepared by condensing 5-(3H imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-76B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 222-224°C, 60% yield. 'H-NMR (DMSO-d6) 8 8.75 (s, 1H), 8.38-8.40 (m, 1H), 8.18 (d, J = 9Hz, 2H), 7.99-8.08(m, 4H), 7.83(d, J= 15 Hz, 1H), 7.28-7.33(m, 1 H), 6.91 (s, 1 H), 4.11 (s, 3H), 4.04 (s, 3H). MS m/z = 430 ([M+H]~.
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 (2.8g, 20.8 mmol) in carbon disulfide (50 mL) was added acetyl chloride (0.74 mL, 10.4 mmol) followed by addition of 2-methyl-2-phenyl propionic acid ethyl ester ( l .Og, 5.2 mmol). The reaction mixture was refluxed for 2 hours and then poured into ice containing sulfuric acid (6M). The mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The solution of ethyl acetate was washed with hydrochloric acid (O.SM), saturated solution of sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography.
Elution with ethyl acetate (33%, v/v, in hexane) gave 2-(4-acetyl-phenyl)-2-methyl-propionic acid ethyl ester (0.57g, 47%). 'H NMR (CDCl3) 8 7.92 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H).

The title compound was prepared by condensing 2-(4-acetyl-phenyl)-2-methyl-propionic acid (Ex-77A) and 2,4-dimethoxy-S-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manner as described in Ex-3. White foam. 'H-NMR (CCD13) 8 8.11-7.86 (m, SH), 7.62-7.46 (m, 3H), 7.42 (d, J = 3.2 Hz, 1 H), 7.31 (d, J = 5.3, I H), 7.10-7.08 (m, 1 H), 6.54 (s, 1 H), 3.99 (s, 3H), 3.97 (s, 3H), I .67 (s, 3H), 1.65 (s, 3H). MS m/z = 436 (M+, 55%), 405 ([M-OCH3]+, 100%).
H
3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl~l-(4-(2H tetrazol-5-yl)-phenyl]-propenone Ex-78A: A suspension of 4-acetylbenznitrile (2.9g, 20.0 mmol), sodium azide (1.43g, 22.0 mmol) and zinc bromide (4.Sg, 20.0 mmol) in water (50 mL) was refluxed for one day.
Additional water (40 mL), HCl (3M, 30 mL) and EtOAc (200 mL) were added subsequently.
The mixture was stirred until no solid in the aqueous layer. The mixture was then portioned.
The aqueous solution was further extracted with EtOAc (3 x 60 mL). The combined EtOAc was concentrated. The residue was treated with NaOH (0.25 M, 200 mL). After stirred for 50 min, insoluble material was filtered, washed with NaOH (1M). The filtrate was then acidified with HCl (cone) to pH 3. The resulting white precipitate was filtered, washed with water and dried in vacuo to obtain 1-[4-(2H tetrazol-5-yl)-phenyl]-ethanone as white solid.'H NMR
(DMSO-d6) 8 8.17-8.10 (m, 4H), 2.61 (s,,3H). MS m/z = 188 (M~.
The title compound was prepared by condensing 1-[4-(2H tetrazol-5-yl)-phenyl]-ethanone (Ex-78A) and 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (Ex-6A) in a similar manner as described in Ex-3. Yellow solid, mp 235 °C (dec.). 'H-NMR (DMSO-d6) S
8.33 (d, J = 8.4 Hz, 2H), 8.26 (s, 1 H), 8.20 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 16.0 Hz, I H), 7.93 (d, J = 15.0 Hz, 1 H), 7.66-7.64 (m, 1 H), 7.50-?.48 (m, 1 H), 7.12-7.09 (m, 1 H), 6.81 (s, I H), 3.983 (s, 3H), 3.976 (s, 3H). MS m/z = 418 (M+, 100%).

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

HZI
4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide To a solution of 4-acetyl-benzsulfonamide (Ex-26A, 0.20g, 1.0 mmol) and 5-benzo[b]thiophene-2-yl-2,4-dimethoxyphenylbenzaldehyde (Ex-3A, 0.31g, 1.05 mmol) in DMF (S mL) and methanol (2 mL) was added lithium methoxide (O.lSg, 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 (NaZS04) and concentrated. The solid residue was stirred in ethanol (10 mL) for 1.5 hours, filtered, washed with aqueous ethanol (50%) and dried in vacuo.
The title compound was obtained as a yellow solid (0.3g, 63%), mp 204-205 °C
(dec.). 'H-NMR
(DMSO-d6) 8 8.35 (s, 1H), 8.27 (d, J = 7.7 Hz, 2H), 8.06 (d, J = 16.0 Hz, 1H), 7.97-7.92 (m, 4H), 7.88 (d, J = 6.6 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.53 (s, 2H), 7.37-7.27 (m, 2H), 6.85 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H).

~o NJ
O O~
\ ~ \
O
O
H~N~
HO ~ S
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 x 25 mL). The combined organic extracts were dried over sodium sulfate and . ..
evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.13 g (82%) of the title compound as a yellow solid, mp 186-188 °C. ~H-NMR (300 MHz, DMSO-d6) 8 8.23-8.28 (m, 3H), 7.93-8.09 (m, 4H), 7. 66 (d, 1 H, J = 3 .0 Hz), 7. 5 6 (brs, 1 H), 7. 52 (d, 1 H, J = 5 .1 Hz), 7.13 (dd, 1 H, J =
5.1, 3.0 Hz), 6.89 (s, 1H), 4.34 (t, 2H, J= 6 Hz), 4.01 (s, 3H), 3.54-3.58 (m, 4H), 2.83 (t, 2H, J
= 6 Hz), 2.51-2.53 (m, 4I-~. MS (ESI) m/z = 529 ([M+H]+, 100%). Anal. Calcd.
for C26HzgNz06S2: 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.

H
,N
H
2-{5-Methoxy-2-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-4-thiophen-2-yl-phenoxy}-2-methyl-propionic acid The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2-(2-formyl-5-methoxy-4-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-59B) in a similar manner as described in Ex-22. Yellow solid, mp 164-165 °C, 85% yield.
~H-NMR (300 MHz, DMSO-d6) 8 8.21-8.28 (m, 3H), 7.96-8.12 (m, 4H), 7.67 (d, 1H, J= 3.0 Hz), 7.56 (brs, 3.OH), 7.14 (dd, 1H, J= 5.7, 3.0 Hz), 6.57 (s, 1H), 3.88 (s, 3H), 1.66 (s, 6H). MS
(ESI) mlz = 502 ([M+H]+, 100%). Anal. Calcd. for C24H23NO~S2: 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.
2-{2,4-Dimethoxy-5-[3-oxo-3-(4-aminosulfonyl-phenyl)-E-propenyl]-phenyl}-indole-1-carboxylic acid tent-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 tent-butyl ester (Ex-36A) in a similar manner as described in Ex-22. Yellow solid, 40% yield, mp 120 -122°C.'H-NMR
(CDC13) 8 8.01-8.19 (m, 6H), 7.68 (s, 1H), 7.56 (d, J = 8 Hz, 1H), 7.46(d, J =
16 Hz, 1H), 7.21-7.35(m, 2H), 6.53 (d, J = 14 Hz, 2H), 5.01(s, 2H), 4.00 (s, 3H), 3.85(s, 3H), 1.42 (s, 9H). MS
m/z = 563 ([M+H]+). HRMS (ES+) Calcd. for C3oH3oNzO~S: 563.1852. Found:
563.1862.

H~N
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.'H-NMR (DMSO-d6) 8 11.15 (br, s, 1H), 8.33(s, 1H), 8.24 (d, J = 8 Hz, 2H), 8.07 (d, J = 15 Hz, 1 H), 7.98 (d, J = 8 Hz, 2H), 7.80(d, J = 15 Hz, 1H), 7.41-7.55(m, 4H), 7.03-7.08 (m, 1H), 6.93-6.99 (m, 2H), 6.83 (s, 1H), 4.04(s, 3H), 3.99(s, 3H). MS m/z = 463 ([M+H]~. HRMS (ES+) Calcd. for CZSH22N2OSS ~ 463.1327.
Found:
463. I 316.
0 0~
o O~ I ~ ~ I ~
O
N
I
O
S
4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-22. Yellow solid, 48% yield, mp 193-196°C. 'H-NMR (DMSO-d6) 8 8.24 (m, 3 H), 8.06 (s, 1 H), 7.96 (d, 2H), 7.89 (d, I H), 7.63 (d, 1 H), 7.51 (m, 1 H), 7.10 (dd, J
= 3, 4 Hz, 1H), 6.81 (s, IH), 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 Cz~H3oNz06S2~3/5Hz0: C, 58.59, H, 5.68, S, 11.59; found C: 58.59, H: 5.55, S:
11.40.
H
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 x 200 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (150 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 7.0 g (60%) of the title compound as a light orange solid, mp 123-124 °C. IH-NMR (300 MHz, DMSO-d6) 8 8.25-8.29 (m, 3H), 7.90-8.11 (m, 4H), 7.66 (d, 1H, J=
3.0 Hz), 7.56 (brs, 1 H), 7.52 (d, 1 H, J= 5.1 Hz), 7.13 (dd, 1 H, J= 5.1, 3.0 Hz), 6.88 (s, I H), 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, 1 H). MS

(ESI) m/z = 504 ([M+H]+, 100%). Anal. Calcd. Cz4H2sNO~Sz~H20: 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.

O 0~
N~s i i of o° ~o o ~ s 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl] N isobutyryl-benzenesulfonamide A solution of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzenesulfonamide (Ex-80, 0.1 Sg, 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 (O.15g, 87%), mp > 240 °C (dec.). 'H-NMR (CDC13) 8 8.21 ( d, J= 8.6 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 8.09 (s, 1H), 8.02 (bs, 1H), 7.94 (s, 1H), 7.85-7.78 (m, 2H), 7.68 (s, 1H), 7.55 (d, J =
16.9 Hz, 1H), 7.38-7.30 (m, 2H), 6.58 (s, IH), 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%).

NJ
H-CI
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). 'H-NMR (300 MHz, DMSO-d6): 8 8.31-8.34 (m, 3H), 8.13 (d, 1 H, J= 1 S.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, SH), 3.72-3.79 (m, 4H), 3.56-3.60 (m, 4H). MS (ESI) m/z = 529 ([M+H]+, 100%). Anal.
Calcd. for C26HZ9C1N2O6Sz: 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.
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 slurned 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. 'H-NMR (300 MHz, CDC13) S 10.29 (s, 1H), 8.17 (s, 1H), 7.48 (d, 1H, J= 3.6 Hz), 7.3 S (d, 1 H, J = 5.1 Hz), 7.10 (dd, I H, J = 5.1, 3.6 Hz), 6.64 (s, I H), 4.96 (s, 2H), 4.06 (s, 3H).
MS (EI) m/z = 273 ([M]+, 99%), 233 (100%). Anal. Calcd. for C~4H»N03S: 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 reflex and vigorously stirred for 24 h.
Additional solvent (1 mL, 1:1 water:isopropanol) was added after 10 h at reflex due to evaporation. The reaction was diluted with an ethyl acetateaetrahydrofuran mixture (25 mL, 2:1) and a 3 N HCl solution (10 mL) and vigorously stirred until a homogenous solution was obtained (1 h).
The layers were separated and the aqueous was extracted with ethyl acetate (3 x SO 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-(IH-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-benzaldehyde as a pale green solid. 'H-NMR (300 MHz, DMSO-d6) b 10.33 (s, 1H), 7.97 (s, 1H), 7.52-7.56 (m, 2H), 7.10-7.12 (m, 2H), 5.81 (s, 2H), 4.05 (s, 3H). MS (ESI) m/z = 317 ([M+H]+, 100%). HRMS
(ESI) Calcd. for CZ~HZSNO~S: 317.0708. Found: 317.0712.
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4-methoxy-2-(IH-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. 'H-NMR (300 MHz, DMSO-d6) 8 8.31-8.34 (m, 3H), 7.92-8.15 (m, 4H), 7.70 (d, IH, J= 4.0 Hz), 7.54 (m, 3H), 7.15-7.17 (m, 1H), 6.92 (s, IH), 4.64 (brs, 2H), 4.03 (s, SH). MS (ESI) m/z = 498 ([M+H]+, 100%). Anal. Calcd. for C22H,9NSOSS2~1'/2H20: 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.

H
~N~N
O
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-yl-ethylamine (0.18 mL) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2 mmol) and the mixture was stirred at room temperature for four hours. It was poured into brine (100 mL) and extracted with dichloromethane (2 x 50 mL). The organic phase was dried and evaporated. Chromatography (dichloromethane/methanol 50:1 ) gave the title compound as a yellow solid (0.43 g, 77%). 1H-NMR (300 MHz, CDC13) 8 8.12 (d, J = 16 Hz, 1H), 8.09 (d, J =
8 Hz, 2H), 7.95 (s, 1 H), 7.90 (d, J = 8 Hz, 2H), 7..77-7.85 (m, 2H), 7.68 (s, 1 H), 7.56 (d, J = 16 I S Hz, 1 H), 7.29-7.40 (m, 2H), 6.80-6.85 (br s, I H), 6.5 8 (s, 1 H), 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 C32H32N2~SS~H2O: C, 67.94; H, 5.88; N, 4.95; found: C, 68.12; H, 5.92; N, 4.96.
F' 4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloylJ-N-(2,2,2-trifluoro-ethyl)-benzamide The title compound was prepared in a similar manner as described in Ex-90.
Yellow solid, 53%
yield, mp 215-217°C. 'H-NMR (Aceton-d6) 8 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 CZBHZZF3N04S: 526.1300.
Found:
526.1324.

HZN
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzamide Ex-92A: To a solution of 4-acetyl-benzoic acid (0.5g, 3.05 mmol) in tetrahydrofuran (10 mL) was added carbonyldiimidazole (0.74g, 4.75 mmol). The solution was allowed to stir at ambient temperature for one hour and cooled to 0 °C followed by addition of ammonia (28% in water, 3 mL, 21 mmol). The solution was continued to stir at 0 °C for another one hour. The solvent was removed under reduced pressure. The residue was treated with water, filtered, washed with water, dried in vacuo to give 4-acetyl-benzamide (0.25g, 50%) as a white solid. 'H
NMR (DMSO-d6) 8 8.11 (bs, IH), 8.00 (d, J = 9 Hz, 2H), 7.95 (d, J = 9 Hz, 2H), 7.53 (bs, 1H), 2.59 (s, 3H).
To a solution of 4-acetyl-benzamide (Ex-92A, 0.25g, I .53 mmol) and 2-(2-morpholin-4-yl-ethoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-60A, 0.53g, I .53 mmol) in DMF (7 mL) and methanol (3 mL) was added lithium methoxide. The solution was allowed to stir at ambient temperature. The reaction was quenched with water after 2 hours. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NaHC03, NHaCI, brine, dried (Na2SOa) and concentrated. The residue was stirred in ethanol overnight to afford the title compound as a yellow solid (0.43g, 57%), mp 183-184 °C. 'H-NMR (CDC13) 8 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, 1 H), 7.32 (d, 4.4 Hz, 1 H), 7.11-7.08 (m, 1 H), 6.55 (s, 1 H), 6.25 (bs, 1 H), 5.75 (bs, 1 H), 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%).
4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide To a solution of 4-acetyl-benzamide (0.3g, 1.84 mmol) and 5-(benzo[b]them-2y1)-2,4-dimethoxybenzaldehyde (O.SSg, 1.84 mmol) in a mixture of N,N dimethylformamide (7 mL) and methanol (3 mL) was added lithium methoxide (0.14g, 3.68 mmol). The reaction mixture was allowed to stir at ambient temperature for 9 hours. The resulting precipitate was collected by filtration, washed with methanol, dried in vacuo to obtain the title compound as a yellow solid (5.56g, 68%). Alternatively, to mixture of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid (Ex-3, 3.0 g, 6.75 mmol), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.81 g, 9.45 mmol), 1-hydroxybenzotriazole hydrate (1.09g, 8.10 mmol) and ammonium chloride (1.81g, 33.7 mmol) in N,N dimethylformamide (60 mL) was added triethylamine (2.4 mL, 16.9 mmol).
The reaction mixture was allowed to stir overnight at ambient temperature. Any insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate to 180 mL. The solution of ethyl acetate was washed with a saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give the title compound as a yellow solid (2.82g, 94%), mp 240-241 °C. 'H-NMR (DMSO-d6) 8 8.37 (s, 1H), 8.19 (d, J = 7.8 Hz, 2H), 8.12 (d, J = 15.3 Hz, 1H), 8.04- 7.91 (m, 6H), 7.83 (d, J = 7.5 Hz, 1H), 7.55 (s, 1H), 7.36-7.30 (m, 2H), 6.87 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). MS m/z = 444 ([M+H]+, 100%).
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 methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-92. Orange solid, mp 81-83°C.'H-NMR (CDCl3) 8 8.08 (m, 3 H), 7.94 (d, 2H), 7.86 (s, 1 H), 7.56 (d, I H), 7.41 (d, 1 H), 7.32 (d, I H), 7.10 (m, 1 H), 6.55 (s, 1 H), 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 C2gH3oN205S~2/5H20: C, 65.45, H, 6.04, S, 6.24; found C: 65.30, H: 6.16, S: 6.17.

H
\ /N
~O
N Acetyl-4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide A suspension of 4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide (Ex-93, 0.5g, 1.13 mmol) in THF (15 mL) was cooled to -78 °C followed by addition of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.3 mL, 2.3 mmol). The mixture was stirred at this temperature for 1 hour and warmed up to 0 °C. Acetic anhydride (0.48 mL, 6.8 mmol) was then added dropwise. After the addition was complete the reaction mixture was warmed up to ambient temperature and stirred for 2 hours. The reaction was quenched with water. The aqueous solution was extracted with ethyl acetate. The combined extract was washed with NH4C1, brine, dried and concentrated. The residue was purified by flash chromatography.
Elution with 50% EtOAc/hexane gave the title compound as yellow solid (0.16g, 29%), mp 228-229 °C. 'H-NMR (CCDl3) 8 8.52 (s, 1H), 8.15-8.10 (m, 3H), 7.96 (d, J = 7.6 Hz, 2H), 7.85-7.77 (m, 2H), 7.67 (s, 1H), 7.55 (d, J = 16.7 Hz, 1H), 7.34-7.29 (m, 3H), 6.58 (s, l I-~, 4.05 (s, 3H), 4.01 (s, 3H), 2.65 (s, 3H). MS m/z = 485 (M~, 100%).
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 (CCD13) S 8.14 (s, 1H), 8.15-8.10 (m, 3H), 7.96 (d, J = 7.2 Hz, 2H), 7.85-7.77 (m, 2H), 7.67 (s, 1H), 7.56 (d, J = 16.2 Hz, 1H), 7.38-7.29 (m, 3H), 6.59 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.68-3.59 (m, 1H), 1.28 (d, J = 6.2 Hz, 6H). .
MS m/z = 513 (M+, 93%), 425 (100%).

HO~ N~N ~ / ~ / S
II H H
O
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: H20 (2:1:1, 6 mL) was treated with lithium monohydrate (73.2 mg, 1.74 mmol) and stirred for 4 hours. The reaction mixture was titrated with SN HCl to a pH2. The mixture was extracted with ethyl acetate (30 mL). The organic phase was collected, dried over NazS04, and concentrated to a pure yellow solid (131.7 mg, 93%), mp 222-225°C.'H-NMR (DMSO-d6) b 9.27 (br s, 1 H), 8.14 (d, 2H), 7.87 (m, 3H), 7.71 (d, 3H), 7.56 (m, 4H), 7.14 (t, 1H), 6.54 (t, 1H), 3.78 (d, 2H). MS m/z =
407 ([M+H]+, 88%), 306 (100%). Anal. calculated for C22H~gN204S~1/2H20: C, 63.60, H, 4.61, S, 7.72;
found C: 63.23, H: 4.70, S: 7.66.
N {4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-N methyl-methanesulfonamide A solution ofN {4-[3E-(3,4-dimethoxy-S-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-methanesulfonamide (Ex-14, 90 mg, 0.20 mmol) in anhydrous DMF was treated with potassium carbonate (56.1 mg, 0.41). Methyl iodide (126.32 uL, 2.03 mmol) was added to the reaction mixture which was then refluxed for 1.5 hours under inert conditions.
The reaction.
was diluted with water (25 mL) and extracted with diethyl ether (2 x 50 mL).
The organic portion was dried over sodium sulfate, filtered, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (30-SO% ethyl acetate/hexanes) to give 42 mg (45%) of the title compound as a yellow solid. 'H-NMR (CDCl3) 8 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%).

OH
O
HO~S~ I ~
HO OH N
H ~ S
3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-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 209-210°C (dec). 'H-NMR (DMSO-D6) 8 7.71 (d, J = 8 Hz, 2H), 7.06 (d, J =
8 Hz, 1H), 6.69 (d, J = 8 Hz, 2H), 4.98 (d, J = 4 Hz, 1H), 4.89 (d, J = 7 Hz, 2H), 4.38-4.45 (m, 2H), 3.55-3.64 (m, 1H), 3.30-3.46 (m, 1H), 3.00-3.30 (m, 4H), 2.38 (s, 3H). MS
m/z = 297 ([M]+, 15%), 148 (100%).
4-(D-Glucopyranosylamino)acetophenone (Ex-99A, 326 mg, 0.6 mmol) and (benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A, 150 mg, 0.5 mmol) were mixed in DMF (10 ml) and methanol (5 ml). Lithium methoxide (120 mg) was added, and the mixture was stirred at room temperature for 18 hours. Lithium methoxide ( 120 mg) was added again and the mixture was stirred overnight. Saturated sodium chloride solution (50 ml) was added and the mixture was extracted with dichloromethane. Chromatography (dichloromethane/methanol 10:1) gave an oily yellow residue as the title compound (20 mg, 6%). 'H-NMR (DMSO-D6) 8 8.29 (s, 1 H), 7.78-8.02 (m, 7H), 7.25-7.38 (m, 2H), 7.15 (d, 1 H), 6.84 (s, 1 H), 6.77 (d, 2H), 4.99 (d, 1 H), 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%).

~/S~N
O
H
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 (S.Og, 37.0 mmol) and pyridine (3.0 mL) in anhydrous dichloromethane (300 mL) was treated with mesyl chloride (2.86 mL, 37.0 mmol).
The reaction was stirred for 84 hours at room temperature under nitrogen, and then quenched with saturated NH4CI solution (100 mL). The organic phase was collected, washed with water ( 100 mL) and brine, dried over sodium sulfate, and concentrated over silica.
The material was purified by silica gel chromatography (50 % ethyl acetate/hexanes) to give 4.72 g (60%) of N
(4-acetyl-phenyl)-methanesulfonamide as a yellowish oil. 'H-NMR (DMSO-d6) 8 10.28 (s, 1 H), 7.90 (d, 1H), 7.24 (d, 1H), 3.06 (s, 3H), 2.48 (s,3H).
A solution of N (4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 279.6 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47D, 400 mg, 1.20 inmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide ( 182.2 mg, 4.8 mmol) and stirred for 5 hours at room temp. under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2 x 50 mL). The aqueous portion was collected and acidified to a pH' of 3 with 3N
HC1. The aqueous solution was then extracted with isopropyl acetate (2 x 50 mL). The organic was collected, dried over sodium sulfate, and concentrated to a green solid.
Attempted to recrystallize crude material from ethanol/hexanes; however, this mixture was concentrated and stirred with ethyl acetate (3 mL) to give 95.6 mg (14%) of the title compound as a yellow solid, mp 181-183°C.'H-NMR (DMSO-d6) 8 10.31 (br s, 1 H), 8.24 (s, 1H), 8.12 (d, 2H), 7.95 (d, 1 H), 7.87 (d, 1 H), 7.67 (d, 1 H), 7.50 (d, 1 H), 7.30 (d, 2H), 7.09 (t, 1 H), 6.45 (s, 1 H), 3.81 (s, 3H), 3.08 (s, 3H), 1.65 (s, 6H). MS m/z = 516 ([M+H]+, 100%). HRMS m/z: calc.
516.1150, found 516.1165.
2-(4-{3-[4-(Methanesulfonyl-methyl-amino)-phenyl]-3-oxo-E-propenyl}-5-methoxy-thiophen-2-yl-phenoxy)-2-methyl-propionic acid Ex-lOlA: A solution of N (4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 2.Og, 9.4 mmol) in anhydrous DMF (300 mL) was treated with potassium carbonate (2.59 g, 18.8 mmol), followed by the addition of methyl iodide (5.85 mL, 94 mmol). The reaction mixture refluxed for two hours and was then treated with more methyl iodide (5.85 mL, 94 mmol).
The reaction refluxed for another two hours, and reaction completeness was confirmed by HPLC analysis.
The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 x 100mL).
). The organic phase was collected, dried over sodium sulfate, and concentrated to a clear oil with residual DMF. Water (25 mL) was added to precipitate a white solid. The white solid was then filtered and dried by vacuum oven at 20 °C (-20 mm Hg) to give 1.37 g (64%) of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide. 'H-NMR (CDC13) 8 7.88 (d, 2 H), 7.48 (d, 2H), 3.38 (s, 3H), 2.86 (s, 3H), 2.60 (s, 3H). HRMS m/z: calc. 530.1307, found 530.1313.
A solution of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide (Ex-lOlA, 298 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-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 x 50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCI. The aqueous solution was then extracted with isopropyl acetate (2 x 50 mL).

The organic was collected, dried over sodium sulfate, and concentrated to a yellow foam. The crude material was purified by silica gel chromatography (50% ethyl acetate/hexanes;10%
MeOH/CH2CLz) to give 293 mg (42%) of the title compound as a yellow solid, mp 197-200°C.
'H-NMR (DMSO-d6) 8 8.20 (s, 1 H), 8.12 (d, 2H), 8.00 (d, 1H), 7.83 (d, 1H), 7.66 (dd, J= 2,2 Hz, 1 H), 7.53 (d, 2H), 7.44 (d, 1 H), 7.06 (dd, J= 2, 4 Hz, 1 H), 6.78 (s, 1 H), 3.82 (s, 3H), 3.28 (s, 3H), 2.98 (s, 3H), 1.56 (s, 3H). MS m/z = 530 ([M+H]+, 100%).

O / N I / I / O
H

S
3-Amino-4-{4-[3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-phenylamino}-cyclobut-3-ene-1,2-dione Ex-lOZA: To a solution of 2.7g (20 mmol) of 4'-aminoacetophenone in 90 mL of ethanol, 4.5 g (20 mmol) of 3,4-dibutoxy-3-cyclobutene-1,2-dione (Aldrich) was added. The mixture was then heated to reflex 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.
'H-NMR
(DMSO-d6) 8 9.99 (br, 1H), 7.90 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 2H), 4.31 (br, 2H), 2.48 (s, 3H). HMRS (EI) calcd. for C,2H,oN203: 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, 2mmo1) 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 pHl with 3N HCI, extracted with dichloromethane. The combined organic phase was then washed with brine and water, dried over MgS04, column chromatography (5 % MeOH in CHZC12) to give 57 mg (5.4 %) title compound as a yellow solid, mp > 260°C.'H-NMR (DMSO-db) 8 10.08 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 8 Hz, 2H), 8.03 (d, J = 15 Hz, 1H), 7.82-7.95 (m, 4H), 7.57 (d, J = 8 Hz, 2H), 7.27-7.37 (m, 2H), 6.85 (s, 1 H), 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 C29HZZNzOSS: 511.1327. Found: 511.1326.
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.Og, 13.1 mmol) and cetyltrimethylamonium chloride (25% in water, 17 mL, 13.1 mmol).
The suspension was stirred at ambient temperature for 10 min followed by the addition of a suspension of 3,4-dimethoxy-5-thiophen-2yl-benzaldehyde (Ex-6A, 3.9g, 15.8 mmol) in ethanol (10 mL). The reaction mixture was allowed to stir at ambient temperature overnight and was acidified with concentrated HCI to pH 3, saturated with NaCI, extracted with CHZCl2.
The combined solution of CH2C12 was washed with brine, dried (Na2S04) and concentrated under reduced pressure. The crude product was purified by flash chromatography. Elution with 50% EtOAc/hexane gave 1-(3,4-dihydroxy-phenyl)-3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-propenone as a yellow oil.'H NMR (DMSO-d6) 8 7.88 (s, IH), 7.83-7.81 (m, 2H), 7.76 (d, J = 2.4 Hz, 1 H), 7.68-7.74 (m, 2H), 7.61-7.57 (m, 1 H), 7.51 (s, 1 H), 7.50 (d, J = 5.2 Hz, 1 H), 7.13 (t, J = 4.5 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 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. 'H-NMR (DMSO-d6) 8 7.76 (d, J = 15 Hz, 1 H), 7.73 (dd, J
= 2, 7 Hz, 1 H), 7.64 (d, J = 2 Hz, I H), 7.54 (d, J = 1 Hz, 1 H), 7.53 (d, J = 2 Hz, I H), 7.39 (d, J = 5 Hz, 1 H), 7.3 8 (d, J = 15 Hz, 1 H), 7.11 (dd, J = 2, 5 Hz, 1 H), 7.08 (d, J = 1 Hz, I
I~, 7.05 (d, J = 7 Hz, 1 H), 3.97 (s, 3H), 3.87 (s, 3H), 4.41 (quad, J = 7 Hz, 4H), 1.30 (t, J = 7 Hz, 6H).
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 S-bromo-2,4-dimethoxybenzaldehyde, 68% yield. 'H-NMR (CDCl3) b 10.33 (s, 1H), 8.71 (d, J = lHz, IH), 8.51-8.53(m, IH), 7.81 (s, 1H), 7.74-7.78 (m, 1H), 7.27-7.31 (m, 1H), 6.52 (s, 1H), 3.99 (s, 3H), 3.91 (s, 3H). HMRS (EI) calcd. for C,4H~3NO3: 243.0895; found: 243.0888.
The title compound was prepared by condensing 2,4-dimethoxy-5-pyridin-3-yl-benzaldehyde (Ex-104A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 51% yield, mp 253-255°C. 'H-NMR (DMSO-d6) 8 8.69 (d, J = lHz, 1H), 8.50 (d, J = 4 Hz, 1 H), 8.25 (d, J = 9 Hz, 2H), 8.08 (d, J = 1 SHz, 1 H), 8.02 (s, 1 H),7.84-7.94(m, 4H), 7.51 (s, 2H), 7.40-7.44 (m, 1H), 6.82(s, 1H), 3.98 (s, 3I-n, 3.88 (s, 3H). MS m/z =

424([M]+, 45%), 393 (100 %). HMRS (EI) calcd. for CZZH20N2~SS: 424.1093;
found:
424.1100.
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 (0.3g, 1.16 mmol), cyclopropanecarboxamidine (0.14g, 1.16 mmol) and sodium hydroxide (0.18g, 4.5 mmol) in ethanol was refluxed overnight. The solvent was removed under reduced pressure, the residue taken up to water. The aqueous solution was then extracted with dichloromethane which was subsequently washed with brine, dried over sodium bicarbonate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (50%, v/v, in hexane) then methanol ( 10%, v/v in dichloromethane) afforded 2-cyclopropyl-4-(2,4-dimethoxy-phenyl)-1H imidazole as white, solid (O.15g, 53%): 'HNMR (CDC13) 8 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 (O.S lg, 2.09 mmol) was added dichloromethyl methyl ether (0.28 mL, 3.13 mmol) followed by addition of titanium tetrachloride (1.OM in dichloromethane, 8.4 mL, 8.4 mmol) dropwise at 0 °C. The solution was allowed to warm up to ambient temperature and stir for 4.5 hours.
The reaction mixture was then poured into ice. The aqueous layer was adjusted to pH 12 and extracted with dichloromethane. The combined solution of dichloromethane was washed with saturated solution of sodium bicarbonate, brine, dried over sodium sulfate and concentrated to afford 5-(2-cyclopropyl-1H imidazol-4-yl)-2,4-dimethoxy-benzaldehyde which was used without further purification. 'H NMR (DMSO-d6) 8 13.95 (bs, 1H), 10.22 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1 H), 6.88 (s, 1 H), 4.04 (s, 3H), 4.00 (s, 3H), 2.25 (m, I H), 1.20 (m, 4H).
MS m/z = 245 ([M +
H]+, 100%).
The title compound was prepared by condensing 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-lOSB) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, m.p. > 240 °C. 'H NMR (DMSO-d6) 8 13.31 (bs, 1H), 8.29 (d, J = 8.9 Hz, 2H), 8.06-8.01 (m, 3H), 7.91 (s, 1 H), 7.67 (s, 1 H), 6.83 (s, 1 H), 4.02 (s, 3H), 3.98 (s, 3H), 1.29-1.22 (m, 4H). MS m/z = 419 ([M + H]+, 100%).
H
4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-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-SOC) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 72% yield, mp 191-192 °C.'H-NMR
(300 MHz, DMSO-d6) S 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, 1 H, J = 16.0 Hz), 7.70 (d, 1 H, J = 3.3 Hz), 7.53-7.56 (m, 3H), 7.14 (dd, 1 H, 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 C24H25NO~S2~'hH20: 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.

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. 'H-NMR (CDCl3) 8 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, 1 H), 7.46-7.60(m, 4H), 7.26-7.37(m, 2H), 6.56(s, 1 H), 4.03 (s, 3H), 3.99 (s, 3H). MS m/z = 540 ([M]+, 100%). HRMS (EI) Calcd. for C~3H24OSS2: 540.1605.
Found:
540.1074.

1-(4-Acetyl-phenyl)-3E-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-propenone The title compound was prepared by condensing 1-(4-acetyl-phenyl)-ethanone with 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A) in a similar manner as described in Ex-3. The product was purified using column chromatography. Yellow solid, 2%
yield, mp 165-167°C.'H-NMR (CDCl3) 8 8.06-8.12 (m, 5H), 7.92 (s, 1H), 7.75-7.82 (m, 2H), 7.65 (s, 1H), 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 CZ~H2204S: 442.1239; found: 442.1229.

o w ~ w H2N, I ~ I ~
~O
O~ ~O
N
S N
4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzenesulfonamide Ex-109A: A solution of 2,4-dimethoxy-benzoic acid methyl ester (4.24g, 21.6 mmol) and hydrazine (3.4 mL, 108. I 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 (3.31g, 78%) as a white solid: 'H NMR (CDC13) 8 8.77 (bs, 1 H), 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.Og, 5.1 mmol) and isobutyl-isothiocyanate (0.70g, 6.1 mmol) in ethanol (30 mL) was refluxed for 8 hours. The precipitate was filtered, washed with ethanol, dried in vacuo to afford 1-(2,4-dimethoxy-benzoyl)amino-3-isobutyl-thiourea (1.43g). Additional product (O.lg, 96%
overall) was obtained by concentrating the mother liquid. 'H NMR (CDCI3) 8 10.71 (bs, 1H), 9.23 (bs, IH), 8.03 (d, J = 8.6 Hz, 1 H), 6.98 (bs, 1 H), 6.59 (dd, J = 8.6, 2.6 Hz, I H), 6.51 (d, J = 2.6 Hz, 1 H), 4.02 (s, 3H), 3.86 (s, 3H), 3.41 (dd, J = 6.4, 6.6 H~ 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, O.Sg, 1.61 mmol) and sodium hydroxide (0.999M, 4.8 mL, 4.8 mmol) in ethanol (30 mL) was refluxed for one day. The solvent was removed under reduced pressure and the residue re-dissolved in ethyl acetate. The solution of ethyl acetate was washed with water and brine, dried over sodium sulfate, and concentrated to give 5-(2,4-dimethoxy-phenyl)-4-isobutyl-4H
[1,2,4]triazole-3-thiol (O.lg). Additional product (0.36g, 98% overall) was obtained by extracting the water wash with dichloromethane and a mixture of isopropyl alcohol (33%, v/v, in dichloromethane). ~H NMR (CDC13) 8 10.82 (bs, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.56 (dd, J
= 8.1, 2.4 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H), 3.72 (d, J = 6.7 Hz, 2H), 2.17-2.08 (m, 1H), 0.70 (d, J = 6.7 Hz, 6H).
Ex-109D: To a solution of 5-(2,4-dimethoxy-phenyl)-4-isobutyl-4X
[1,2,4]triazole-3-thiol (Ex-109C, 0.1 g, 0.34 mmol) in ethanol ( 10 mL) was added wet Raney Ni (0.27g, 4.6 mmol). The suspension of ethanol was refluxed overnight and then passed through a bed of Hyflo Super Gel and diatomaceous earth. The filtrate was concentrated to afford 3-(2,4-dimethoxy-phenyl)-4-isobutyl-4H [1,2,4]triazole (0.09g, 100%) as a white solid: 'H NMR (CDCl3) 8 8.15 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.57 (dd, J = 7.8, 2.3 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.62 (d, J = 7.5 Hz, 2H), 1.89-1.80 (m, 1H), 0.76 (d, J = 6.6 Hz, 6H).
Ex-109E: To a solution of 3-(2,4-dimethoxy-phenyl)-4-isobutyl-4H
[1,2,4]triazole (Ex-109D, 0.78g, 2.98 mmol) was added dichloromethyl methyl ether (0.4 mL, 4.48 mmol) followed.by addition of titanium tetrachloride (1.OM in dichloromethane, 9.0 mL, 9.0 mmol) over 10 min at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 min and ambient temperature overnight. The reaction mixture was poured into ice. The aqueous solution was extracted with dichloromethane and isopropyl alcohol (33%, v/v, in dichloromethane). The combined dichloromethane and isopropyl alcohol were washed with brine, dried over sodium sulfate and concentrated. The aqueous solution was treated with sodium hydroxide to pH 12 and extracted again with isopropyl alcohol (33%, v/v, in dichloromethane) to give additional product. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) afford 5-(4-isobutyl-4H [1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (0.24g, 28%): 'H NMR (CDC13) b 10.30 (s, I H), 8.17 (s, 1 H), 7.90 (s, I H), 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, 1 H), 0.77 (d, J = 6.5 Hz, 6H).

To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12g, 0.62 mmol) and 5-(4-isobutyl-4H [1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.18g, 0.62 mmol) in N,N-dimethylformamide (9 mL) was added lithium methoxide (1.OM in methanol, 2.4 mL, 2.4 mmol). The solution was allowed to stir overnight. The reaction was quenched with water.
The aqueous solution was washed ethyl acetate, acidified to pH S, 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 (SO%, v/v, in acetone) to give the title compound as a light yellow solid: m.p. > 240 °C. 'H NMR (DMSO-d6) 8 8.60 (s, 1H), 8.26 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 15.3 Hz, 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%).
H
4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid To a solution of 4-acetyl-benzoic acid (0.12g, 0.75 mmol) and 5-(4-isobutyl-4H
[1,2,4]triazol-3-yl)-2,4-dimethoxy-benzaldehyde (Ex-109E, 0.24g, 0.83 mmol) in N,N-dimethylformamide (6 mL) was added lithium methoxide (1.OM in methanol, 3.0 mL, 3.0 mmol). The solution was allowed to stir overnight and additional lithium methoxide (0.11 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.).
~H NMR (DMSO-d6) 8 8.59 (s, 1H), 8.18 (d, J = 7.9 Hz, 2H), 8.07 (s, 1H), 8.04-8.01 (m, 3H), 7.85 (d, J = 15.7 Hz, 1 H), 6.84 (s, 1 H), 4.06 (s, 3H), 3.92 (s, 31-n, 3.66 (d, J = 7.2 Hz, 2H), 1.87-1.74 (m, 1 H), 0.72 (d, J = 6.7 Hz, 6H). MS m/z = 436 ([M + H]+, 100%).

4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl)-acryloyl}-benzenesulfonamide To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12g, 0.59 mmol) and 5-(2-cyclopropyl-1H imidazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-105B, 0.16g, 0.59 mmol) in N,N-dimethylformamide (16 mL) was added lithium methoxide (1.OM in methanol, 2.4 mL, 2.4 mmol). The reaction mixture was allowed to stir for I 8 hours at ambient temperature. The reaction was quenched with water. The aqueous solution was extracted with dichloromethane.
The combined dichloromethane was concentrated. The crude product was purified by flash chromatography. Elution with methanol ( 10%, v/v, in dichloromethane) gave the title compound as red solid: m.p. 156-160 °C. 'H NMR (DMSO-d6) 8 11.65 (bs, 1H), 8.32 (s, 1H), 8. I 9 (d, J = 9.0 Hz, 2H), 8.00 (d, J = 15.7 Hz, 1 H), 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%).
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. 'H-NMR (DMSO-d6) 8 S 8.73 (s, 1 H), 8.31 (dd, J = 1, 4 Hz, 1 H), 8.26 (d, J = 8 Hz, 2H), 8.05(d, J = 16 Hz, 1 H), 7.89-7.97 (m, 3H), 7.82(d, J = 16 Hz, 1 H), 7.17-7.21 (m, 1 H), 6.89(s, 1 H), 4.09 (s, 3H), 4.03 (s, 3H).
MS m/z = 465([M+H]+, 65%), 256 (100 %). HRMS (ES+) Calcd. for C23HZON4OSS:
465.1232.
Found: 465.1240.

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).'H-NMR (300 MHz, DMSO-d6) 0 10.44 (s, 1H), 8.00 (s,1H), 7.79-7.84 (m, 2H), 7.49-7.57 (m, 4H), 7.16 (s, 1H), 7.12 (dd, 1H, J= 5.4, 3.6 Hz), 5.91 (s, 2H), 4.07 (s, 3H). MS (ESI) m/z = 365 ([M+H]+, 100%). Anal. Calcd. for CZpH~7C1N2O3S''~3H2O: C, 59.04; H, 4.38; N, 6.88; S, 7.88. Found: C, 59.07; H, 4.25; N, 6.85; S, 7.77.
The title compound was prepared by condensing 2-(1H benzoimidazol-2-ylmethoxy)-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-113A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Light orange solid, 56% yield, mp 235-237 °C
(dec). 'H-NMR (300 MHz, DMSO-d6) 8 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, ZH, 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. I S (m, 2H), 5.59 (s, 2H), 4.01 (s, 3H). MS
(ESI) m/z = 546 ([M+H]+, 100%). Anal. Calcd. for C28H23N3OSS2: 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.
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.. 'H-NMR
(300 MHz, CDCl3) 8 10.49 (s, 1H), 8.62 (d, IH, J= S.l Hz), 8.13 (s, 1H), 7.77 (dt, 1H, J= 7.5, 1.5 Hz), 7. 5 8 (d, 1 H, J = 7.5 Hz), 7.44 (dd, 1 H, J = 3 .6, 1.5 Hz), 7.28-7.31 (m, 2H), 7.07 (dd, 1H, J= 5.4, 3.6 Hz), 6.64 (s, IH), 5.39 (s, 2H), 3.94 (s, 3H). MS (ESI) mlz =
326 ([M+H]+, 100%). Anal. Calcd. for C18H~SN03S: C, 66.44; H, 4.65; N, 4.30; S, 9.85.
Found: C, 66.43; H, 4.72; N, 4.37; S, 9.81.
The title compound was prepared by condensing 4-methoxy-2-(pyridin-2-ylmethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-114A) and 4-acetyl-benzenesulfonamide (Ex-26A) in a similar manner as described in Ex-22. Yellow solid, 90% yield, mp 188-189 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.66 (d, 1 H, J = 3.6 Hz), 8.28 (s, 1 H), 8.21 (d, 2H, J = 7.8 Hz), 8.11 (d, 1 H, J= 15.4 Hz), 7.89-7.99 (m, 4H), 7.57-?.68 (m, 4H), 7.53 (dd, 1H, J= 5.4, 1.5 Hz), 7.41-7.45 (m, IH), 7.13 (dd, 1H, J= 5.4, 3.6 Hz), 7.02 (s, 1H), 5.45 (s, 2H), 3.99 (s, 3H). MS (ESI) mlz =
507 ([M+H]+, 100%). Anal. Calcd. for C26HZZN205S2~'/2Hz0: 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.

0 o~N
i \ / \ N_N
HN ~ I / ( / O
a o s 4-{3E-[2-(Benzotriazol-1-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzenesulfonamide Ex-115A: 2-(Benzotriazol-I-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..'H-NMR (300 MHz, CDC13) 8 10.30 (s, IH), 8.10 (d, 1H, J= 8.1 Hz), 8.06 (s, 1H), 7.75 (d, IH, J= 8.1 Hz), 7.57-7.62 (m, 1H), 7.40-7.48 (m, 2H), 7.30 (d, 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) mlz =
366 ([M+H]+, 100%). Anal. Calcd. for C~9H,SN3O3S: 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). 'H-NMR (300 MHz, DMSO-d6) 8 8.21 (s, 1 H), 8.09 (d, 3H, J= 9.4 Hz), 8.01 (d, I H, 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, IH), 7.38 (s, lI~, 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. CZ~H2zN405S2: C, 59.33; H, 4.06; N, 10.25; S, I 1.73.
Found: C, 59.45; H, 4.27; N, 9.92; S, 1 I .27.

4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H indol-2-yl)-phenyl]-acryloyl}-benzoic acid Ex-116A: To a solution ofN-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)Z (0.35 g, 0.5 mmol) and 5-bromo-2,4-dimethoxybenzaldehyde (3.7g, 15 mmol) were added, and the mixture was heated to about 60 °C for 30 minutes. The reaction mixture was poured into 50 ml 10% NaOH and treated with 30 % H202 and then stirred for 10 minutes. The mixture was extracted with EtOAc and combined organic phase was washed with HZO and brine, dried over MgS04, and absorbed to small amount of silica gel. Column chromatography ( EtOAc: Hexane, 1:2) gave 0.72 g (25%) 2,4-dimethoxy-5-(1-methyl-1H indol-2-yl)-benzaldehyde.'H-NMR (CDCl3) 8 10.33 (s, 1 H), 7.84 (s, 1 H), 7.60 (d, J = 8 Hz, 1 H), 7.31 (d, J = 8 Hz, 1 H), 7.18-7.24 (m, 1 H), 7.07-7.12(m, 1H), 6.53 (s, 1H), 6.46(s, 1H), 4.00 (s, 3H), 3.89 (s, 3H), 3.53 (s, 3H). HRMS (EI) Calcd. for C,gH,~N03: 295.1208. Found: 295.1202.
The title compound was prepared by condensing 4-acetylbenzoic acid and 2,4-dimethoxy-5-(1-methyl-1 H indol-2-yl)-benzaldehyde (Ex-116A) in a similar manner as described in Ex-3.
Yellow solid, 87% yield, mp 157-160 °C.'H-NMR (DMSO-d6) 8 8.17 (d, J =
8 Hz, 2H), 8.08 (d, J = 15 Hz, 1 H), 7.99-9.02 (m 3H), 7.83 (d, J = 15 Hz, 1 H), 7.52 (d, J =
8 Hz, 1 H), 7.42 (d, J
= 8 Hz, 1 H), 7.10-7.15 (m, I I-~, 6.99-7.04(m, 1 H), 6.85 (s, 1 H), 6.42(s, 1 H), 4.01 (s, 3H), 3.88 (s, 3H), 3.50 (s, 3H). MS m/z = 442 ([M+H]+, 100%). HRMS (ES+) Calcd. for CZ~H23NO5:
442.1654. Found: 442.1633.

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
(CDC13) 8 8.17 (d, J = 16 Hz, 1H), 8.09 (d, J = 9 Hz, 2H), 8.01 (d, J = 9 Hz, 2H),7.68 (s, l I~, 7.64 (d, J = 8 Hz, I I-n, 7.47 I 0 (d, J = 16 Hz, 1 H), 7.35 (d, J = 8 Hz, I H), 7.22-7.26 (m, 1 H), 7.11-7.
I 6(m, 1 H), 6.5 8 (s, 1 H), 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 C26H24NOSS: 477.1484. Found: 477.1487.

4-[3E-(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-I51°C.'H-NMR (300 MHz, CDC13):
8.17 (d, 2 H, J
= 6.7 Hz), 8.10 (d, I H, J= 15.8 Hz), 8.05 (d, 2 H, J= 6.7 Hz), 7.95 (s, 1 H), 7.82 (m, 2 H), 7.67 (s, 1 H), 7.57 (d, 1 H, J= 15.8 Hz), 7.33 (m, 2 H), 6.58 (s, 1 H), 4.04 (s, 3 H), 4.00 (s, 3 H), 3.97 (s, 3 H). MS m/z = 458 ([M]+, 100%). HRMS (EI) Calcd. for CZ~H2205S:
458.1188.
Found: 458.1196.

H O
N-S
H O
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-butylphospMne)palladium(0) (0.014 g, 0.027 mmol). The solution was immediately heated to 45 °C and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated to a brown oil.
Silica gel chromatography (ethyl acetate/hexanes, 1:9) gave 0.18 g (40%) of 3-(2,3-dihydro-furan-2-yl)-benzaldehyde as a clear, colorless oil. 'H-NMR (300 MHz, CDCl3) 8 10.03 (s, 1H), 7.88 (s, I H), 7.82 (d, 1 H, J = 7.2 Hz), 7.62-7.64 (m, 1 H), 7.53 (t, 1 H, J = 7.2 Hz), 6.48 (q, 1 H, J = Hz), 5.60 (dd, 1 H, J = 8.1, 10. 8 Hz), 4.98 (q, 1 H, J = 3 .3 Hz), 3 .15 (ddt, 1 H, J = 15.0, 8.1, 2. 5 Hz), 2.59 (ddt, 1H, J= 15.0, 8.1, 2.5 Hz). MS (EI) mlz = 174 ([M]+, 100%). HRMS
(EI) Calcd. for C~lH,o02: 174.0681. Found: 174.0677.
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 3-(2,3-dihydro-furan-2-yl)-benzaldehyde (Ex-119A) in a similar manner as described in Ex-3.
Tan solid, 40% yield, mp 152-153 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.31 (d, 2H, J= 7.5 Hz), 7.99 (d, 2H, J= 7.5 Hz), 7.95 (d, 1H, J= 15.8 Hz), 7.85 (brs, 3H), 7.78 (d, 1H, J= 15.8 Hz), 7.57 (brs, 1 H), 7.44-7.52 (m, 2H), 6.62 (q, 1 H, J= 2.4 Hz), 5.58 (dd, 1H, J= 8.7, 10.8 Hz), 5 .5 9 (q, 1 H, J = 2.4 Hz), 3.10 (ddt, 1 H, J = I S .0, 8.1, 2.5 Hz), 2.54 (ddt, 1 H, J = 15.0, 8.1, 2.5 Hz). MS (ESI) m/z = 356 ([M+H]+, 100%). Anal. Calcd. for C,9H,~N04S~'/SH20: 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.

CHZNHCf OH
HO
OH
OH
CHzOH
4-(3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid, N
methyl-D-glucamine salt 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid of Ex.
3 was then made into a meglumine salt by suspending the 4-[3E-(5-benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid (4.45 g, 10 mmol) and N methyl-D-glucamine (1.95 g, 10 mmol) in THF (100 mL). The mixture was stirred at room temperature for 5 minutes. Then, ethanol (100 mL) was added. This mixture was stirred at room temperature for 30 minutes.
THF (20 mL) and ethanol (20 mL) were added and the mixture was heated slightly until it became a solution. This solution was stirred for 30 minutes and evaporated to a yellow foam.
Crystallization from methanol gave the desired 4-[3E-(5-benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid N methyl-D-glucamine salt as a yellow solid (4 g, 63%), mp 75-80 °C (changing forms). 1H NMR (300 MHz, DMSO-d6) 8 8.39 (s, 1H), 8.14 (d, 2H), 8.02-8.10 (m, 3H), 7.94-7.98 (m, 3H), 7.86 (d, 1H), 7.36 (m, 2H), 6.89 (s, 1H), 4.06 (s, 3H), 4.04 (s, 3H), 3.94 (m, IH), 3.71 (d, IH), 3.61 (m, 1H), 3.39-3.55 (m, 3H), 3.04 (m, 1 H), 2.95 (m, 1H), 2.54 (s, 3H). Anal. Calculated for C33H3~NOloS~1.3H20: C, 59.77; H, 6.02; N, 2.11;
S, 4.84; found:
C, 59.84; H, 5.75; N, 2.05; S, 4.70; Parent EIMS m/z = 443 (M+).

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

H O
ii N-S
H O
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 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 1 S 24 h and 48 h to drive the reaction to completion. Upon completion, as determined by HPLC, the reaction was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an orange oil.
Silica gel chromatography (ethyl acetate/hexanes, 1:2) afforded 0.32 g (50%) of 5-(2,5-dihydro-fuian-2-yl)-2,4-dimethoxy-benzaldehyde as a pale yellow solid, mp 84-85 °C. ~H-NMR (300 MHz, CDCl3) 8 10.29 (s, 1H), 7.79 (s, 1H), 6.42 (s, 1H), 5.99-6.06 (m, 2H), 5.89-5.92 (m, 1H), 4.80-4.87 (m, 1H), 4.71-4.77 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS (EI) m/z =
234 ([M]+, 100%). Anal. Calcd. C~3H,4O4: 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 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vaczro to yield 0.13 g (70%) of the title compound as a yellow solid, mp 194-195 °C. 'H-NMR (300 MHz, DMSO-d6) 8 8.23 (d, 2H, J= 8.2 Hz), 8.03 (d, 1H, J= 15.3 Hz), 7.97 (d, 2H, J= 8.2 Hz), 7.69 (s, 1H), 7.65 (d, 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), 4.63-4.68 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z =
416 ([M+H]+, 100%). Anal. Calcd. C21H2~N06S: 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.

H
N
i H
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), 5~
molecular sieves (0.36 g), cesium carbonate (0.94 g, 2.9 mmol), and copper(I) triflate-benzene complex (0.020 g, 0.036 mmol). The phenoxide crashed out of solution upon addition of cesium carbonate and additional toluene (1 mL) was added to facilitate stirring. The heterogeneous solution was immediately heated to 110 °C and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with a 5% sodium hydroxide solution (10 mL) and ethyl acetate (10 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (5 x 20 mL). The combined organic extracts were washed with a 50% brine solution (1 x 25 mL), brine (1 x 25 mL), dried over sodium sulfate and concentrated to an dark brown semi-solid. Silica gel chromatography (ethyl acetate/hexanes, 1:4) afforded 0.30 g (65%) of 4-methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehydeas a light orange solid, mp 140-141 °C.'H-NMR (300 MHz, CDC13) 8 10.21 (s, 1H), 8.23 (s, 1H), 7.64 (dd, 1H, J= 7.8, 7.2 Hz), 7.52 (d, 1H, J= 3.3 Hz), 7.35 (d, 1H, J= 5.1 Hz), 7.10 (dd, 1H, J= 5.1, 3.3 Hz), 6.94 (d, 1 H, J = 7.2 Hz), 6.78 (d, 1 H, J = 7.8 Hz), 6.75 (s, 1 H), 3.92 (s, 3H), 2.44 (s, 3H).
HRMS (EI) Calcd. for C~gH15N03S: 325.0773. Found: 325.0775. Anal. Calcd.
C1gH15N03S: 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 1 S dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60 °C to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.25 g (82%) of the title compound as a yellow solid, mp 164-165 °C. 'H-NMR (300 MHz, DMSO-d6) b 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, 1 H, J = 5.1, 3 .6 Hz), 7.04 (d, 1 H, J = 7.5 Hz), 6.99 (s, 1 H), 6.91 (d, 1 H, J = 8.4 Hz), 3.90 (s, 3H), 2.33 (s, 3H). Anal. Calcd. Cz6HzzN20sS2: 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.

5-Iodo-2,4-dimethoxy-benzaldehyde To a solution of 2,4-dimethoxy-benzaldehyde (20.Og, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.52g, 144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution was allowed to stir at ambient temperature for 3 hours and then poured into a solution of hydrochloric acid (0.5 M, 600 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (I:1, v/v) to give the tiltle compound as a white solid (30.62g, 87.5%), m.p. 170-172 °C. 'H NMR
(CDCl3) 8 10.19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H).
5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-benzaldehyde Ex-123A: Potassium fluoride (0.42g, 7.2 mmol), 5-iodo-2,4-dimethoxy-benzaldehyde (Ex-123, I.Og, 3.42 mmol), 2-benzo[b]thiophene boronic acid (0.67g, 3.77 mmol), degased tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (l9mg, 0.02 mmol), and tri-tert-butylphosphine (I OOmg, 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, I-[(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-S-yl)-3-{(heteroaryl or heterocyclic)-phenyl}-propen-2-ones, I-[(heteroaryl or heterocyclic)phenyl]-3-phenyl-2-propen-I-ones, and substituted 3-[(heteroaryl or heterocyclic)phenyl]-1-phenyl-2-propen-1-ones can be prepared by one skilled in the art using similar methods, as shown in Example Tables 1 through 33.
Example Table 1. Substituted 4-[3-{2-Isopropoxy-4-methoxy-(5-heteroaryl or 5-heterocyclic)phenyl}-acryloyl]-benzoic Acids.
O OCH(CH3)z O H OCH(CH3)z ~/~ H ~/~
HOZC / Y _OCH3 HOZC / ~OCr RI sP Rsa A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
200A 201 A s ~ 202A
200B ~ ~ 201B ~ ~ 202B
203A \ ~ 204A , ~ 205A _ 203B o 204B ' ~ s~ 205B "~
206A \ ~ 207A ~ 208A s 206B o 207B s 208B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
209A N ~ ~ 21 OA ,"~ ~. 211 A
2098 '~ 2108 I 2118 N
212A o ~ 213A ~ 214A
2128 ~~ 2138 "N \ 2148 215A o ~ 216A 217A
2158 ~ ~ 2168 " ~ ~ 2178 N ~N
218A ~~ 219A , ~ 220A
w 2188 ~ 2198 ~ ~ ~ 2208 H
221 A ~ 222A N ~ 223A HN
2218 C~ 2228 ~ 2238 O N
224A 225A ~ 226A
2248 p ~ 2258 I \ 2268 NJ
227A o ~ 228A ~ 229A
2278 ~ 228B ( \ 2298 N
230A N\'~.; 231A ~ 232A 'z,i 2308 ~ ~ 231 B ~ , ~ . \ 2328 H-N
'N~
233A ~.,;~ 234A N\ ~ 235A ~N\'~
2338 p~ 2348 C 2358 N
N
236A ~.,;~ 237A N~N\~.,' 238A ~N~~
2368 o~~OH 237B I , 238B N~ IN
239A , N 240A ~ N\'~ 241 A ~ ''~.,~
2398 N / 5 2408 ( , ~ 2418 N N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
242A N o 243A , ~ N 244A H
242B ~- / ~ 243B ~ I ~ N 244B
245A N-N~ 246A I w N~~- 247A
245B ~N 246B aN 247B
H H
H
248A N ~ z 249A I w N 250A N-O
248B N~N 5 249B ~ ~~ 250B
H N
251 A N-o 252A \ N 253A
251 B ~ / 252B II i~ ~~ 253B
254A / N-N 255A N ~ N 256A
254B ~~N~~ 255B ~~N~~ 256B w N H
257A N-o 258A / w 259A
257B ,~ ,~ I / 258B ~ I ~ N 259B
260A ~ N~ 261 A '~,~ 262A
260B ~ ~ ~ ~ 261B ~ ~ \ 262B
W
Example Table 12. Substituted 4-[3-{2-Cyclopropylmethoxy-4-methoxy-(5-heteroaryl or 5-heterocyclic)phenyl-acryloyl]-benzoic Acids.
HOZC
R''' A B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
263A 264A s ~ 265A
263B ~ ~ 264B ~ ~ 265B
266A \ ~ 267A ~ 268A _ 266B o 267B s~ 268B "~
269A \ ~ 270A ~ 271 A s 269B o 270B s 271B
\ / \ /
272A N x'7.,7 273A N ~ 274A
272B '~ 273B I 274B
N

275A o ~ 276A ~ 277A s 275B ~~ 276B " \ 277B
278A o ~ 279A 280A ,"r 278B ~ ~ 279B " ~ ~ 280B
N ~N
281 A ~~ 282A / ~ 283A
281B ~ 282B N ~ ~ 283B
H
284A ~ 285A N ~ 286A HN
284B C~ 285B ~ ~ 286B
O N
287A 288A ~ 289A
287B p Z 288B I \ 289B
NJ
290A o ~ 291 A ~ 292A
290B ~ 291 B I \ 292B
N

Ex. R5~ Ex. No. R5~ Ex. No. R5~
No.

293A N\'~,~ 294A ~ 295A
293B ~ ~ 294B ( \ 295B

H-N
N

296A '~.,7 297A N '-~,7 298A N ''~
296B ~ 297B C 298B

p N

299A ~ 300A N~N\'~.~ 301A ~N~~
299B ~~OH 300B I 301 B

p , N ~ N

302A N,N Z 303A \ N\ ~ 304A \'~
I ~
~

302B / s 303B , 304B

N N

305A N O 306A , ~ N 307A
I' / ~ I

305B 306B ~ 307B
~ N

308A N-N z 309A \ N 310A H
~ I N
~ ~~

308B N 309B i N 310B ~
c H H
N

H

311A N ~ ~ 312A I \ N 313A -O
N a ~~

311B ~N 312B 313B

H N

314A N-O 315A \ N 316A N-N z I / I i ~~

317A ~ N~N 318A N \ N 319A N \
317B ~~N~~ 318B '~ 319B \ ~ i ~~

N
N

H

320A N-O 321 A / \ 322A , N~
320B I / 321 B \ I ~ N 322B

~, ,~

323A ~ N~ 324A '~,~ 325A N
i I ~
\

323B ~ r 324B ~ 325B
~

r \ iN

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

326A \ z 327A H3COZC~ 328A Br \
s I\
326B H3C o 327B N,N S 328B H3c s H

329A CHs 330A I \ a 331 A I \ z 329B I \ s 330B H3c(o)C s 5 331 B N 5 332A '~ 333A w \ 334A
332B r~oH 333B I ~ s ~ 334B

HN

Example Table 3. Substituted 4-[3-{2,4-dimethoxy-(6-Heteroaryl or 6-heterocyclic)phenyl}-acryloyl]-benzoic Acids.

\ ~ \ \
~~~ H ~/~
HOZC / R6p~OCH3 H02C / R6p v _OCH3 A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
335A 336A s ~ 337A
335B \ ~ 336B \ ~ 337B
338A \ ~ 339A ~ 340A
338B o\~ 339B s\~ 340B HN , ,iJ i 341A \ ~ 342A ~ 343A s 341B o 342B s 343B
344A N ~'~ 345A N ~ 346A
344B ~~ 345B I 346B
N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
347A o ~ 348A ~ 349A
3478 ~~ 3488 " \ 3498 350A o ~ 351A 352A
3508 ~ ~ 3518 " I ~ ~ 3528 353A ~~ 354A ~ ~ 355A ,"~
3538 ~ 354B N ~ ~ 3558 H
356A ~ 357A N ~ 358A HN
3568 C\ J 3578 ~ ~ 3588 359A 360A ~ 361 A
3598 O z 3608 I \ 3618 C\ J
NJ
362A o ~ 363A ~ 364A
3628 ~ 3638 I \ 3648 N NH
365A N\ ~ 366A ~ 367A '7,' 3658 ~ ~ 3668 ~ \ 3678 H-N
N
368A ~.,;~ 369A N '~,7 370A N
3688 0~ 3698 C 3708 N
371A ~ 372A N,N\'~; 373A ~N~~
3718 or~OH 372B I ~ 3738 N ~ N
374A N,N ~ 375A ~ N\'7.~ 376A ~'z.~
3748 I / s 3758 ~ , ~ 3768 N N
377A N O 378A , w N 379A ,N
377B I' / ~ 3788 ~ I ~ N 3798 Ex. R5~ Ex. No. R5~ Ex. No. RS[i No.

380A N-N Z 381A ~N ; 382A H
~ I N
~ ~~

3808 H 3818 i 3828 C

H N

H

383A N ~ z 384A I \ N 385A N.O
N ~ ~~' 3838 'N 3848 3858 H N

386A N~o 387A ~N 388A N,N
_ ~ L
~ ~ I i ~~

389A / N~N 390A N \ N 391A N \
3898 ~~N~~ 3908 ~~N~~ 3918 \ ~ i N H

392A N-o 393A ~ w 394A ~ N
3928 I ~ 3938 \ I ~ N 3948 ~, ,~

395A ~ N~ 396A '~y 397A
i I ~
\

3958 ~ 396B ~ 3978 ~ r r \ ~N

Example Table 4. Substituted 1-(2,2-Bis-hydroxymethyl-benzo[1,3]dioxol-S-yl)-3-[2,4-dimethoxy-(S-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.
CHZOH
A B
Ex. No. R5~ Ex. No. R5~ Ex. No.

O OCH, Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
398A 399A s ~ 400A
398B ~ ~ 399B ~ ~ 400B
401A \ ~ 402A ~ 403A _ 401B o 402B s~ 403B "~
r 404A \ ~ 405A ~ 406A s 404B o 405B s 406B
407A N ~'z,;~ 408A N ~ 409A
407B ~~ 408B ~ 409B
N
41 OA o ~ 411 A ~ 412A s 410B ~~ 411B " \ 412B
413A o ~ 414A 415A
413B ~ ~ 414B " ~ ~ 415B
N ~N
416A ~~ 417A / ~ 418A "
N
416B ~ 417B N ~ ~ 418B
H
419A ~ 420A N ~ 421A HN
419B C~ 420B ~ 421B
O N
422A 423A ~ 424A
422B p z 423B ( \ 424B C\ J
NJ
425A o ~ 426A ~ 427A
425B ~ 426B ~ \ 427B
N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
428A N\'t,i 429A ~ 430A
428B ~ ~ 4298 ~ \ 4308 H_N
N
431A ~ 432A N\'z,:~ 433A ~N\'~;, 4318 p~ 4328 C 4338 N
N
434A ~ 435A N,N\~ 436A ~N~'~.,;t 4348 pr~OH 4358 ~ , 4368 N ~ N
437A ~N 438A \ N\ ~ 439A \
4378 N / s 4388 ~ , ~ 4398 N N~N
440A N O 441 A / ~ N 442A H
_ ,N
4408 I/ / ~ 441 B \ I ~ N 4428 443A N~N~ 444A I \ N~~- 445A
4438 ~H 4448 i H 4458 N
H
446A N ~ z 447A I \ N 448A N-O
4468 N'N S 4478 a ~~ 4488 H N
449A N-O 450A \ N 451 A N-N
4498 ~ / 4508 I ~ ~~ 451 B
452A / N~N 453A N \ N 454A N \
4528 ~~N~~ 4538 ~~N~~ 4548 \ I
N N H
455A N-O 456A / \ 457A , N~
4558 ~. ~, I / 4568 \ I ~ N 4578 458A ~ N~ 459A '~,~ 460A ~ N\ '~~
4588 ~ I ~ r 4598 ~ ~ \ 4608 r \ /N

Ex. R5~ Ex. R5~ Ex. No. RS[i No. No.

461A \ z 462A HsCO2C 2 463A B~ \ a \
461B H3c I o 462B ~ 463B H3c I
s N s H

464A cHs 465A ~ \ a 466A

464B ~ \ s 465B H3c(o)c s 5 466B N s O CHg 467A '~ 468A w \ 469A
467B r~OH 468B I i S ~ 469B

gN

Example Table 5. Substituted 1-(3-Aminophenyl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-I-ones.
HzN H2N
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
470A 471 A ~ 472A "
N
470B \ ~ 471B \ ~ 472B
473A \ ~ 474A ~ 475A _ 473B o 474B s~ 475B "~~
476A \ ~ 477A ~ 478A s 476B o 477B s 478B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
479A N ~'t,z 480A N ~. 481 A
4798 ~~ 4808 ~ 4818 N
482A o ~ 483A ~ 484A
4828 ~~ 4838 " \ 4848 485A o ~ 486A 487A
4858 ~ ~ 486B H ~ ~ 4878 N ~N
488A ~~ 489A , ~ 490A
4888 ~ 4898 N ~ ~ 4908 H
491A ~ 492A N ~ 493A HN
4918 C~ 4928 ~ ~ 4938 O N
494A 495A ~ 496A
4948 p ~ 4968 I \ 4968 J N
N H
497A o ~ 498A ~ 499A
4978 ~ 4988 I \ 4998 N
SOOA N\'~.; SOIA ~ 502A
SOOB ~ ~ 501 B ~ \ 5028 H-N
N /
503A 't.5 504A N\'i,~ SOSA ~N\''~
5038 p~ 5048 C SOSB N
N
506A '~,~ 507A N,N\'~.~ 508A ~N~~
5068 or~OH 5078 ~ , 5088 NON
509A ,N S10A ~ N\~ S11A
5098 N / s S10B ~ , ~ S11B
N N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

512A N ~ 513A , ~ N 514A H
_ ~ N,N
I' ~ ~ I

512B S 13B \ 514B I /
~ N

S I N~N~ 516A ( \ N~~- 517A
SA ~-=
~

S15B H 516B ~ 517B

H N

H

518A N ~ z 519A I \ N 520A -O
N a ~~

518B 'N 519B 520B

H N

521A N-o 522A ~N 523A
.N
I ~ \ _ N
I \ z ~~

521B 522B i 523B

524A / N~N 525A N \ N 526A
524B ~~N~~ 525B ~~N~~' S26B \ ~

N H

527A N-o 528A , \ 529A , N
527B ~, n I 528B \ I ~ N 529B
~

530A ~ N~ 531 ''y 532A
530B ~ I ~ ~ A ~ ~ \ 532B

r \ /N

Example Table 6. Substituted 1-(4-Aminophenyl)-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.

A B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
533A 534A s ~ 535A
533B ~ ~ 534B ~ ~ 535B
536A ~ 537A ~ 538A _ 536B o~ 537B s~~ 538B "~~
539A \ ~ 540A ~ 541 A s 539B o 540B s 541B
542A N ~'~,7 543A N ~. 544A
542B ~~ 543B I 544B
N
545A o ~ 546A ~ 547A s 545B ~~ 546B "" \ 547B
H
548A o ~ 549A H - 550A N
548B ~ ~ 549B I ~ ~ 550B
551A \ ~ 552A , ~ 553A
551B ~ 552B N ~ ~ 553B
H
554A ~ 555A ,"J ~ 556A HN
554B C\ J 555B ~ ~ 556B

557A 558A ~ 559A
557B p 2 558B I \ 559B
NJ H
560A o ~ 561 A ~ 562A
560B ~ 561B I \ 562B
N

Ex. R5~ Ex. No. R5~ Ex. No. RS~i No.

S63A N\'~ S64A ~ S6SA
S63B ~ ~ S64B ~ \ S6SB

H-N
N

S66A '~ S67A N ~ S68A N
S66B ~ S67B C S68B

o N

S69A ~ S70A N~N\ ~.,7 S71A ~N~~
S69B r~OH S70B I S71B I

O , N ~
N

S72A ,N S73A \ N\ ~.,~ $74A \ ~.,,~
N ~
s ~

S72B / S73B , S74B

N N

S7SA N o S76A ~ w N S77A
I' / ~ I
N

S7SB S76B \ S77B
~

S78A N_N~ $79A \ N S80A
~ I
~~

S78B N S79B i N S80B
~
~

H H N

H

S81A N ~ r S82A I \ N S83A -O
N a ~~-$81B 'N S82B S83B

H N

S84A N_o S8SA \ N S86A N.N z I / I i ~~

S84B S8SB $86B

S87A ~ N_N S88A N \ N S89A N \
S87B ~~N~~- S88B ~~ S89B \
~~-N
N H

S90A N_o S91A ~ \ S92A ~ N~
S90B I / S91B \ I ~ N S92B

M ~, \

S93A ~ N~ S94A '~,~ $9SA N
S93B ~ I ~ r S94B ~ ~ \ S9SB

w r \ /N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

596A I \ z 597A H3COzC \ z 598A Br \
596B H3C~ 597B ni~ S 598B H3c I s N

H

599A CH3 600A I \ s 601A \ 2 599B \ 600B H
c(o)c s 601 B

~ 3 s 602A '7,~ 603A ~ \ 604A
602B r~~H 603B I i s ~ 604B

HN

Example Table 7. Substituted 1-(4-(Pyrrolidin-1-yl)phenyl}-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.

GN
RSP
A B, Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
605A 606A s ~ 607A
605B \ ~ 606B \ ~ 607B
608A \ ~ 609A ~ 610A _ 608B o~ 609B s~ 610B "~~
611A \ ~ 612A ~ 613A s 611B o 612B s 613B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
614A N ~'~,z 615A N ~ 616A
614B ~~ 615B I 616B
N
617A o ~ 618A ~ 619A
617B ~~ 618B " \ 619B
620A o ~ 621 A 622A
620B ~ ~ 621B " ~ ~ 622B
N ~N
623A ~~ 624A / ~ 625A "
N
623B ~ 624B / ~ ~ 625B
H
626A ~ 627A N ~ 628A HN
626B C~ 627B ~ ~ 628B
O N
629A 630A ~ 631 A
629B O ~ 630B I \ 631B
NJ
632A o ~ 633A ~ 634A
632B ~ 633B I \ 634B
N
635A N\'t,:~ 636A ~ 637A ~.,,~
635B ~ ~ 636B ~ \ 637B H-N
N
638A ~ 639A N\'~.,;t 640A ~N\~
638B p~ 639B C 640B N
N
641A ~ 642A N~N\~,;~ 643A ~N~'~,?
641B or~OH 642B I , 643B N ~ N
644A N,N ~ 645A ~ N\'~ 646A
644B I / s 645B ~ , ~ 646B
N N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~

647A N o 648A r ~ N 649A H
_ ,N
~' / ~ I N

647B 648B \ 649B /
~ N

650A N-N~ 651A I \ N~~- 652A
~

650B N 651B i H N

H

653A N ~ z 654A I \ N 655A N,O
N a ~~
S

653B 'N 654B 655B

H N

656A N-o 657A ~ N 658A N-N
~ / I
~~

656B 657B i 658B

659A / N-N 660A N \ N 661A N \
659B ~~N~~ 660B ~~ 661B \ ~
~~

N
N H

662A N-o 663A / \ 664A , N
662B ~ / 663B \ I ~ N 664B

,~ ,~

665A ~ N~ 666A '~,~ 667A ~ N\ y 665B ~ I ~ 666B ~ ~ \ 667B
r r \ iN

Example Table 8. Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[2,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.
H
N
I
S~_~___, A B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
668A 669A s ~ 670A
668B ~ ~ 669B ~ ~ 670B
671A \ ~ 672A ~ 673A _ 671B o~ 672B s~~ 673B "''~
674A \ ~ 675A ~ 676A s 674B o 675B s 676B
N
677A N ~'~.,7 678A N ~ 679A
677B ~~ 678B I 679B
N ' 680A o ~ 681 A ~ 682A s 680B ~~ 681B "N \ 682B
H
683A o ~ 684A " - 685A N
683B ~ ~ 684B I ~ ~ 685B
686A ~~ 687A , ~ 688A "
N
686B ~ 687B ~ ~ ~ 688B
H
689A ~ 690A N ~ 691 A HN. '\ Z
689B C~ 690B ~ ~ 691B
O/ N
692A 693A ~ 694A
692B p 2 693B I \ 694B
NJ
695A o ~ 696A ~ 697A
695B ~ 696B I \ 697B
N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
698A N\'~,;, 699A ~ 700A ~.,;~
698B ~ ~ 699B ~ \ 700B H-N
N
701 A '~ 702A N\'~ 703A ~ N\ ~
701B p~ 702B C 703B N
N
704A 'z,z 705A , N\'~,; 706A ~ N~'~;
704B pr~OH 705B N , 706B NON
707A N, N t 708A \ N~'~; 709A \' 707B t / s 708B ~ , ~ 709B
N N
710A N O 711A / ~N 712A H
_ ,N
71 OB I' / ~ 711 B \ I ~ N 712B
713A N~N z 714A \ N 715A H
713B ~N~ 714B I i N~~- 715B N
H H cN~
H
716A N ~ z 717A I \ N 718A N,O
716B N'N s 717B ~ ~~- 718B
H N
719A N-O 720A \ N 721A N-N z 719B I / 720B I i ~~ 721B
722A i N~N 723A N \ N 724A N \
722B ~~N~~ 723B ~~N~~ 724B \
N N H
725A N-O 726A r \ 727A , N~
725B M ,~ I / 726B \ I ~ N 727B \ ~ /
728A ~ N~ 729A ~,~ 730A ~ N\ '~~
728B ~ I ~ ~ 729B ~ ~ \ 730B
r \ ~N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

731A \ z 732A H3C~2C~ 733A
731B H3c I o 732B N,N s 733B H3c I s s H

734A cH3 735A I \ 5 736A \ z 734B \ 735B c(o)c s 736B ~ N s H

~ 3 CH3 s O

737A '~ 738A ~ \ 739A '' 737B r~OH 738B I i s ~ 739B

gN

Example Table 9. Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[3,4-dimethoxy-(5-heteroaryl or 5-heterocylic)phenyl]-2-propen-1-ones.
H
CH3S02 3 ~N
St S A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
740A 741 A ~ \ 742A "
_ N
740B ~ 741B I i s ~ 742B
743A \ ~ 744A . ~ 745A
743B o~ 744B s~ 745B "~
746A \ ~ 747A ~ 748A s 746B o 747B s 748B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
749A N ~ '~.,~ 750A ~ ~ 751 A
749B ~~ 750B I 751B
N
752A o ~ 753A ~ 754A
752B ~~ 753B " \ 754B
755A o ~ 756A 757A
755B ~ ~ 756B H I ~ ~ 757B
758A ~~ 759A , ~ 760A
N
758B ~ 759B N ~ ~ 760B
H
761A ~ 762A N ~ 763A HN
761B C~ 762B ~ 763B
O N
764A 765A ~ 766A
764B p z 765B I \ 766B
NJ
767A o ~ 768A ~ 769A
767B ~ 768B I \ 769B
N NH
770A N\'~ 771A ~ 772A
770B ~ ~ 771 B ~ \ 772B H-N
N
773A ~ 774A N '~ 775A N
773B p~~ 774B C 775B
N
776A 'zz 777A N,N\'~,,~ 778A ~N~'~,;7 776B or~pH 777B ~ , 778B N ~ 'N
a 779A ,N 780A ~ N\~.,;~ 781A
779B N / s 780B ~ , ~ 781B
N N

Ex. No. R5~ Ex. R5~ Ex. R5~
No. No.

782A N o 783A ~ ~ N 784A H
_ .N
I' / ~ I

7828 7838 \ 7848 ~ N

785A N~N~ 786A \ N 787A
~- I
~ ~~

7858 N 7868 i N 7878 ~
~

H H
N

H

788A N ~ z 789A I \ N 790A -O
N ~~- ~

7888 'H 7898 i 7908 N

791A N~o 792A ~N 793A N~N z ~ / I ~ ~~

794A ~ N~N 795A N \ N 796A N \
7948 ~~N~~_ 7958 ~~N~~- 7968 \ I

N H

797A N~o 798A ~ \ 799A ~ N
7978 I / 7988 \ I ~ N 7998 ,~ ,~

800A ~ N~ 801A '~~ 802A
I ~
\

800B ~ 8018 ~ 8028 ~ r r \ iN

Example Table 10. Substituted 1-{4-(Amino)phenyl-3-[3,4-dimethoxy-(5-heteroaryl~br 5-heterocylic)phenyl]-2-propen-1-ones.

R'N
A

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
803A 804A w ~ 805A
8038 8048 I i S ~ 8058 806A \ ~ 807A ~ 808A _ 8068 0~ 8078 s~~ 8088 "'~
809A \ ~ 81 OA ~ 811 A s 8098 0 810B s 8118 \ / \ /
812A N ~'-r.~ 813A N ~ 814A
8128 ~~ 8138 I 8148 N ' 815A o ~ 816A ~ 817A s 8158 ~~ 8168 " \ 8178 v 818A o ~ 819A 820A ,"r H
8188 ~ ~ 8198 I \ ~ 8208 821A ~~ 822A / ~ 823A
8218 ~ 8228 N ~ ~ 8238 H
824A ~ 825A N ~ 826A HN
8248 C~ 8258 ~ 8268 O N
827A 828A ~ 829A
827B p 2 8288 I \ 8298 C\ J
NJ
830A o ~ 831 A ~ 832A
8308 ~ 8318 I \ 8328 N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
833A N\ ~,.; 834A ~ 835A
833B ~ ~ 834B ~ \ 835B H_N
N
836A '~.~ 837A N\'~,z 838A ~ N\ ~
836B p~ 837B C 838B N
N
839A 'z,,~ 840A N, N\ ~'~,; 841 A ~ N~~
839B pr~oH 840B ~ / 841B N~IN
842A N,N r 843A \ N\'7,7 844A \
842B t / s 843B ~ / ~ 844B
N N
845A N o 846A / ~ N 847A H
_ ,N
845B I' / ~ 846B \ I ~ N 847B
848A N~N~ 849A \ N 850A N ~,,~
848B ~N 849B I / N~~ 850B
cN~
H H
H
851A N ~ z 852A I \ N 853A N-O
851B N'N s 852B a ~~ 853B
H N
854A N~o 855A \ N 856A N~N
854B I / 855B I / ~~ 856B
857A / N~N 858A N \ N 859A, N \
857B ~~N~~ 8588 ~~N~~ 859B \ ~ /
N N H
860A N-o 861 A / \ 862A / N\

860B ~, ~, ~ / 861 B \ I ~ N 862B ~ ~ /
863A i N~ 864A '~,~ 865A ~ N\ '~' 863B ~ I ~ r 864B / ~ - \ 865B
W ~N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

866A I \ s 867A H3C~2C I \ 2 868A Br I \
8668 H3c o 8678 N~N s 8688 t H3c s H

869A CH3 870A ~ \ 5 871 A I \ z 8698 ~ ~ s 8708 H3~(o)c s 871 B N s 872A \~ 873A H3c ~ \ 874A
8728 ~H 8738 ~ ~ 8748 ~

Example Table 11. Substituted 1-{4-(Amino)phenyl}-3-[2,6-dimethoxy-(4-heteroaryl or 4-heterocylic)-phenyl]-2-propen-1-ones.

H
HzN / H3CO~R4a HZN ~ H3CO~R4a A B
Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
875A 876A s ~ 877A
8758 \ ~ 8768 \ ~ 8778 878A \ ~ 879A ~ 880A _ 8788 0~ 8798 s~ 8808 " \~
r 881A \ ~ 882A ~ 883A s 881B o 8828 s 883B
_ ~i ~i 884A \~ 885A N ~ 886A
8848 ~ ~ 8858 ' I 8868 N

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
887A o ~ 888A ~ 889A
887B ~~ 888B " \ 889B
890A o ~ 891A 892A
890B ~ ~ 891B " ~ ~ 892B
N ~N
893A ~~ 894A , ~ 895A
893B ~ 894B N ~ ~ 895B
H
896A ~ 897A N ~ 898A HN
896B C~ 897B ~ ~ 898B
O N
899A 900A ~ 901 A
899B O Z 900B I \ 901B
NJ
902A o ~ 903A ~ 904A
902B ~ 903B I \ 904B
N
905A N\ ~ 906A ~ 907A
905B ~ ~ 906B ~ \ 907B H-N
N
908A ~ 909A N\ ~,, 91 OA ~ N\ '~
908B p~ 909B C 910B N
N
911A '7.,~ 912A N,N\'~; 913A ~N~~
911 B Or~OH 912B I , 913B N ~ N
914A N,N Z 915A ~ N\ ~ 916A ~''~.~
914B I / s 915B ~ , ~ 916B
N N

Ex. R4~ Ex. R4~ Ex. No. R4~
No. No.

917A N o 918A r ~ N 919A H
_ ~N
~' / ~ I

9178 9188 \ 9198 ~ N

920A N-N~ 921A \ N 922A
~ I
~~

9208 N 9218 ~ N 9228 ~
c H H N

H

923A N ~ i 924A I \ N 925A N-O
N a ~~

9238 'N 9248 9258 H N

926A N-o 927A ~N 928A N-N
I / I
~~

9268 9278 i 9288 929A / N~N 930A N \ N 931A N \
9298 ~~N~~ 930B ~~ 9318 \ ~ i ~~

N
N

H

932A N-o 933A / \ 934A , N~
9328 I / 9338 \ I ~ N 9348 ,~ ~

935A ~ N~ 936A '~,~ 937A

9358 ~ I ~ r 9368 ~ ~ \ 9378 r \ ,N

Example Table 12. Substituted 1-{4-(Methanesulfonylamino)phenyl}-3-[2,6-dimethoxy-(4-heteroaryl or 4-heterocylic)phenyl]-2-propen-1-ones.
n H ~ /~
H3CSOZNH ~ H3CO~R4~
A B

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
938A 939A s ~ 940A
938B ~ ~ 939B ~ ~ 940B
941A \ ~ 942A ~ 943A
941 B o~~ 942B s\~ 943B "N~
944A \ ~ 945A ~ 946A s 944B o 945B s 946B
\ / \ /
947A N ~'~.,7 948A N ~ 949A
947B ~~ 948B I 949B
N
950A o ~ 951A ~ 952A s 950B ~~ 951B " \ 952B
H
953A o ~ 954A " - 955A N
953B ~ ~ 954B I ~ ~ 955B
956A ~~ 957A , ~ 958A
N
956B ~ 957B N ~ ~ 958B.
H
959A ~ 960A ,"~ ~ 961 A HN
959B C~ 960B ~ ~ 961B
O N
962A 963A ~ 964A
962B p z 963B I \ 964B
NJ
965A o ~ 966A ~ 967A
965B ~ 966B I \ 967B
/ N NH

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
968A N\ ~ 969A ~ 970A
9688 ~ ~ 9698 ~ \ 9708 H-N
N
971A '~,7 972A N '~,7 973A N ~
9718 or~ 9728 C 9738 N
974A '~.,~ 975A N, N\ '~ 976A ~ N~'z, 9748 ~r~OH 9758 ~ , 9768 N ~ N
977A N-N Z 978A \ N\'~.,~ 979A
9778 t / s 9788 ~ , ~ 9798 N N
980A N o 981 A ~ ~ N 982A H
_ -N
9808 ~- / ~ 981 B \ I ~ N 9828 983A N-N~ 984A \ N 985A
9838 ~N 9848 I i N~~ 9858 H H cN~
H
986A N ~ r 987A I \ N 988A .O
9868 N'N s 9878 a ~~- 9888 H N
989A N-o 990A ~N 991A N-N
9898 ~ / 9908 I i 992A / N-N 993A N \ N 994A
9928 ~~N~~ 9938 ~~N~~ 9948 \ ~ i N H
995A N-o 996A ~ \ 997A ~ N
9958 ,~ ,~ ~ / 9968 \ ~ ~ N 9978 998A / N~ 999A ''y 1000A , N\ '~~
9988 ~ ~ i ~ 9998 ~ ~ \ 10008 r \ /N

Ex. R4~ Ex. R4~ Ex. No. R4~
No. No.

1001A I \ z 1002A HscozC \ z 1003A Br \ z 1001B H3C~ 1002B N~ s 1003B H3C I
N s H

1004A cHs 1005A I \ S 1006A
1 \ 1005B C(o)C S 1006B

00 ~ 3 s 1007A ''~ 1008A w \ 1009A
1007B r~OH 1008B I i S ~ 1009B

~

Example Table 13. Substituted 1-(1H Indol-5-yl)-3-{2,4-dimethoxy-5-(heteroaryl or heterocyclic)phenyl}-propen-2-ones.

\ / ~ \
N

H Rsp A B
Ex. No. R5~ Ex. No. R5~ Ex. No. RS(3 lOlOA 1O11A s ~ 1012A
loloB ~ ~ 1o11B ~ ~ 1o12B
1013A \ ~ 1014A ~ 1 O1 SA
I 013B o~~ 1014B s\~ 101 SB "~
,~J
1016A \ ~ lOl7A ~ 1018A s 1016B o 1017B s 1018B
\ / \ /

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1 O 19A N ~'z.~ 1020A N ~ I 021 A
1019B ~~ 1020B I 1021B
N
1022A o ~ 1023A ~ 1024A
1022B ~~ 1023B " \ 1024B
1025A o ~ 1026A 1027A
1025B ~ ~ 1026B " I ~ ~ 1027B
1028A \ ~ 1029A , ~ 1030A
1028B ~ 1029B N ~ ~ 1030B
H
1031 A ~ 1032A N ~ 1033A HN
1031B C~ 1032B ~ ~ 1033B
O N
1034A 1035A ~ 1036A
1034B O 2 1035B ( \ 1036B C\ J
NJ
1037A o ~ 1038A ~ 1039A
1037B ~ 1038B I \ 1039B
N NH
1040A N~'~; I 041 A ~ 1042A '~,7 1040B ~ ~ 1041B ~ \ 1042B H-N
N
1043A ~ 1044A N '~ 1045A N
1043B p~ 1044B C 1045B
N
1046A '7,7 1047A N,N\~.,;~ 1048A ~N~~
1046B Or~OH 1047B ~ , 1048B N ~ N
1049A ,N IOSOA \ N\'7,' 1OSIA
1049B N / 5 1O50B ~ , ~ 1O51B
N N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1052A N ~ 1053A , ~ N 1054A N H
_ ,N
1052B I/ / ~ 1053B ~ I ~ N 1054B t /
H
1055A N~N~ 1056A w N 1057A N
1055B ~N 1056B I i N~~ 1057B
cN~
H H
H
1058A N ~ r 1059A I ~ N 1060A N-O
1058B N~N 5 1059B ~ ~~ 1060B
H N
1061A N-o 1062A ~N 1063A N-N
1061B I / 1062B I ~ ~~1 1063B
1064A / N~N 1065A N w N 1066A
1064B ~~N~~ 1065B ~~N~~ 1066B w I
N H
1067A N-o 1068A , w 1069A , N~
1067B ,~ ,~ I / 1068B ~ I ~ N 1069B
1070A ~ I N~ 1071 A I w ~ ~- 1072A
1070B ~ ~ r 1071 B ~.~~ 1072B w r Example Table 14. Substituted 1-(1H Indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or heterocyclic)phenyl}-propen-2-ones.
A B

H R'N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1073A 1074A H3~ I ~ ~ ~- 1075A
1073B ~ ~ 1074B \~~V~ 1075B
1076A \ ~ 1077A ~ 1078A _ 1076B o 1077B s~ 1078B "~~~
1079A \ ~ 1080A ~ 1081 A s 1079B o 1080B s 1081B
\ / \ /
1082A N ~ ~ 1083A N ~. 1084A
1082B ~~ 1083B ~ 1084B
N
1085A o ~ 1086A ~ 1087A s 1085B ~~ 1086B " \ 1087B
1088A o ~ 1089A 1090A ,"J
H
1088B ~ ~ 1089B I ~ ~ 1090B
1091 A ~~ 1092A , ~ 1093A
1091B ~ 1092B N ~ ~ 1093B
H
1094A ~ 1095A , .. N ~ 1096A HN
1094B C~ 1095B ~ ~ ~ 1096B
O N
1097A 1098A ~ 1099A
1097B p z 1098B I \ 1099B
N H
11 OOA o ~ 11 O 1 A ~ 1102A
11 OOB ~ 1 I O 1 B I \ 1102B
N

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1103A N\'~,; 1104A ~ 1105A
1103B ~ ~ 1104B ~ \ 1105B H.Nr N
1106A '~,~ 1107A N '~,7 1108A N
1106B p~ 1107B C 1108B
N
1109A ~.,,r 1110A N,N\~ 1111A ~N~'~
1109B pr~OH 111 OB ~ , 1111 B N ~ IN
I 112A ,N 1113A \ N\ ~ 1114A \'~
1112B N / s 1113B ~ , ~ 1114B
N N
1115A N O 1116A , ~ N 1117A H
_ ,N
1115B ~' / ~ 1116B \ I ~ N 1117B
1118A N-N z 1119A \ N 1120A H
1118B ~H~ 1119B II i H~~ 1120B CN
N
H
1121A N ~ z 1122A I \ N 1123A N,O
1121B N'N 5 1122B a ~~ 1123B
H N
1124A N-O 1125A \ N 1126A N-N
1124B ~ / 1125B I ~ ~~ 1126B
1127A / N~N 1128A N \ N 1129A N \
1127B ~~N~~ 1128B ' ~~N~~ 1129B \ ~ i N N H
1130A N-O 1131A r \ 1132A , N~
I 130B ~, ,~ I / 1131B \ I ~ N 1132B \ ~ /
1133A ~ N~ 1134A '~~ 1135A N y i 1133B ~ I ~ r 1134B ~ ~ \ 1135B w r \ /N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

1136A I \ s 1137A HscozC I \ z 1138A B' ~ \
1136B H3C o 1137B N,N s 1138B s H3c s H

1139A cH3 1140A I \ 5 1141A

1139B ~ \ s 1140B H3c(o)c s 1141B

1142A '~,7 1143A w \ 1144A
1142B r~OH 1143B I i g ~ 1144B

HN

Example Table 15. Substituted 1-(IH I-Methyl-indol-S-yl)-3-{2,4-dimethoxy-5-(heteroaryl or heterocyclic)phenyl}-propen-2-ones.

N'~ ~OCH3 HOC R5~ H
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1145A 1146A s ~ 1147A
1145B ~ ~ 1146B ~ ~ 1147B
1148A \ ~ 1149A ~ I150A
1148B o~ 1149B s~ 1150B ""\~
1 I 51 A \ ~ 1152A ~ I 153A s I151B o I152B s 1153B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1154A N ~'t,,r 1155A N ~. 1156A
1154B ~~ 1155B I 1156B
N ~ ~ ' 1157A o ~ 1158A ~ 1159A
1157B ~~ 1158B " \ 1159B
I 160A o ~ 1 I 61 A 1162A
1160B ~ ~ 1161B " I ~ ~ 1162B
1163A ~~ 1164A ~ ~ 1165A
1163B ~ 1164B N ~ ~ 1165B
H
1166A ~ 1167A N ~ 1168A HN
1166B C~ 1167B ~ ~ 1168B
O N
1169A 1170A ~ 1171 A
1169B O ~ 1170B I \ 1171B
J
N
1172A o ~ 1173A ~ 1174A
1172B ~ 1173B I \ 1174B
N NH
1175A N\'t,; 1176A ~ 1177A . '7,,z 1175B ~ ~ 1176B ~ \ 1177B H-N
N
1178A '~.,,1 1179A N '~ 1180A N
1178B o~ 1179B C ~ 1180B
N
1181A ~ 1182A N,N\'~.~ 1183A ~N~'~.~
1181B Or~OH 1182B ~ , 1183B N ~ N
1184A ,N 1185A ~ N\'z.~ 1186A
1184B N / s 1185B ~ , ~ 1186B
N N

Ex. R5~ Ex. No. R5~ Ex. No. R5~
No.

1187A N o 1188A , w N 1189A H
~- / ~ I
N

1187B 1188B w 1189B
~

1190A N-N~ 1191A w N 1192A
H
~ I
~~

1190B N 1191B i N 1192B
~
c H H
N

H

1193A N ~ z 1194A I w N 1195A -O
ii s ~~~- N
N

1193B 'H 1194B i S 1195B

1196A N-o 1197A ~N 1198A
~ / I ~ ~~

1199A / N-N 1200A N ~ N 1201A
1199B ~~N~~ 1200B ~~ 1201B w ~~

N
N H

1202A N-o 1203A , w 1204A
1202B ~ / 1203B w I ~ N 1204B

~, ,~

1205A ~ I N~ 1206A I ~ ~ ~- 1207A
~~

1205B ~ ~ r 1206B 1207B

r Example Table 17. Substituted 1-(1H 1-Methyl-indol-5-yl)-3-{3,4-dimethoxy-5-(heteroaryl or heterocyclic)phenyl}-propen-2-ones.
O

H3C R5~ H
A B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1208A 1209A HsC ( ~ ~ ~- 1210A
12088 ~ 12098 \~~~~ 12108 1211 A ~ 1212A ~ 1213A _ 12118 0~~ 12128 s~~ 12138 "~~
1214A \ ~ 1215A ~ 1216A s 12148 0 12158 s 12168 \ / \ /
1217A N ~ ~ 1218A N ~ 1219A
12178 ~~ 12188 I 12198 N ~ ~ ' 1220A o ~ 1221 A ~ 1222A s 12208 ~~ 12218 " \ 12228 1223A o ~ 1224A 1225A
12238 ~ ~ 12248 H I ~ ~ 12258 1226A ~~ 1227A , ~ 1228A H
N
12268 ~ 12278 N ~ ~ 12288 H
1229A ~ , 1230A N ~ 1231A HN
12298 C~ 12308 ~ ~ 12318 O N
1232A 1233A ~ 1234A
12328 p z 12338 I \ 12348 NJ
1235A o ~ 1236A ~ 1237A
12358 ~ 12368 I \ 12378 N NH

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1238A N\'~,; 1239A ~ 1240A '~,;~
1238B ~ ~ 1239B ~ \ 1240B H-N
N
1241 A '~,~ 1242A N ~,,~ 1243A N
1241 B p~ 1242B C 1243B
N
1244A ~ 1245A ,N ~,;~ 1246A N
1244B pr~OH 1245B N , 1246B
1247A -N 1248A ~ N\'z.S 1249A
1247B N / s 1248B ~ , ~ 1249B
N N
1250A N O 1251A , w N 1252A -N
1250B I-/ ~ 1251B w I ~N 1252B
1253A N-N~ 1254A w N 1255A
1253B ~N 1254B I i N~~ 1255B
H H cN~
H
1256A N ~ Z 1257A I w N 1258A -O
ii S ~~~- N
1256B N'H 1257B i S 1258B
1259A N-O 1260A ~ N 1261A N-N Z
1259B I / 1260B I i ~~ 1261B
1262A / N-N 1263A N ~ N 1264A
1262B ~~N~~ 1263B ~~N~~ 1264B w ~ i N H
1265A N-O 1266A , w 1267A , N~
1265B ~, ,~ I / 1266B w I ~ N 1267B ~ ~ /
1268A ~ N~ 1269A '~,~ 1270A ~ N\ '~~
1268B ~ I ~ ~ 1269B ~ ~ \ 1270B w r ,N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

1271A I \ 5 1272A H3C~2C I \ z 1273A Br I \
1271B H3C o 1272B N,N S 1273B a H3c s H

1274A CH3 1275A I \ S 1276A

1274B ~ \ s 1275B H3C(o)C s 1276B

1277A '~ 1278A w \ 1279A \t 1277B r~OH 1278B I i s ~ 1279B

HN

Example Table 17. Substituted 4-[3-{2-(Pyrrolidin-I-yl)-(4-heteroaryl or 4-heterocyclic)-phenyl}-acryloylJ-benzoic Acids.
O ~ O H
\ ~ ~ \ \ / ~ \
~~~ H ~ /~
H02C / " R4R HOZC / ~R4p A B
Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
1280A 1281 A s ~ 1282A ,"~
1280B ~ ~ 1281B ~ ~ 1282B
1283A \ ~ 1284A ~ 1285A
1283B o 1284B s~~ 1285B ""~
,~J
1286A \ ~ 1287A ~ 1288A s 1286B o 1287B s 1288B

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
1289A N ~ ''~,i 1290A N ~ 1291 A
1289B ~~ 1290A ~ 1291B
N
1292A o ~ 1293A ~ 1294A
1292B ~~ 1293B " \ 1294B
1295A o ~ 1296A 1297A
H
1295B ~ ~ 1296B I ~ ~ 1297B
1298A ~~ 1299A / ~ 1300A ~", 1298B ~ 1299B N ~ ~ 1300B
H
1301A ~ 1302A N ~ 1303A HN
1301B C~ 1302B ~ ~ 1303B
O N
1304A 1305A ~ 1306A
1304B p ~ 1305B I \ 1306B
J N
N H
1307A o ~ 1308A ~ 1309A
1307B ~ 1308B I \ 1309B
N
13 I OA N\'~; 1311 A ~ 1312A ''~
131 OB ~ ~ 1311 B ~ \ 1312B H_N
N
1313A 'z,~ 1314A N\'7,:, 1315A ~N\ ~
1313B p~ 1314B C 1315B N
N
1316A '7,~ I 317A N, N\ ~ 1318A ~ N
1316B Or\~OH 1317B ( , 1318B N ~ N
1319A N! N Z 1320A - ~ N\ ~ 1321 A ~ '~.,;~
1319B I / s 1320B ~ , ~ 1321 B
N N

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
1322A N O 1323A , ~ N 1324A H
13228 I' / ~ 13238 ~ I ~ N 13248 1325A N-N z 1326A w N 1327A H \t 13258 ~N~ 13268 I ~ N~~ 13278 N
CND
H H
H
1328A N \ z 1329A I w N 1330A N-O
13288 N'N 5 13298 a ~~ 13308 H N
1331A N-O 1332A w N 1333A N-N z 13318 I / 13328 I ~ ~~ 13338 1334A / N~N 1335A N 1336A N
_ N ~ _ 13348 ~~N~~ 13358 ~~N~~ 13368 w I i N H
1337A N-O 1338A , ~ 1339A , N
13378 ,~ ,~ I / 13388 ~ I ~ N 13398 w ~ i 1340A ~ N~ 1341A '~~ 1342A
13408 ~ I ~ r 13418 ~ ~ \ 13428 w s ~ ~N
1343A I \ S 1344A H3CO2C I \ z 1345A Br I \ z 13438 H3c O 13448 N~N S 13458 H3c s H .
1346A CH3 1347A I \ 5 1348A \
13468 ~ \ s 13478 H3c(o)c s 134gg 1349A ''~,7 1350A w \ 1351A
13498 HNr~OH 13508 I i s ~ 13518 Example Table 18. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.
HOzC
R''' R''' A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1352A 1353A H3C ~ ~ 1354A
1352B ~ ~ 1353B I i S ~ 1354B
1355A \ ~ 1356A \ ~ 1357A
1355B o~ 1356B s~ 1357B ""~
1358A \ ~ 1359A \ ~ 1360A s 1358B o 1359B s 1360B
\ / \ /
1361A N ~'~; 1362A ~ ~ 1363A
1361B '~ 1362B I 1363B
1364A o ~ 1365A ~ 1366A s 1364B ~~ 1365B " \ 1366B
v 1367A o ~ 1368A 1369A
1367B ~ ~ 1368B " I ~ ~ 1369B
1370A ~~ 1371 A ~ ~ 1372A
w 1370B ~ 1371B N ~ ~ 1372B
H

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1373A ~ 1374A N ~ 1375A HN
1373B C\ J 1374B ~ ~ 1375B
O N
1376A 1377A ~ 1378A
1376B O Z 1377B I \ 1378B
N H
1379A o ~ 1380A ~ 1381A
1379B ~ 1380B I \ 1381B
/N NH
1382A N\ ~ 1383A ~ 1384A ~'.,7 1382B ~ ~ 1383B ~ \ 1384B H-N
N
1385A '~,7 1386A N '~,7 1387A N '~
1385B p~ 1386B C 1387B
N
1388A '~,;~ 1389A N~N\ ~,,; 1390A ~N~~
1388B or~OH 1389B I ~ 1390B N ~ N
1391A N,N ~ 1392A ~ N\'~.i 1393A
1391B I / s 1392B ~ , ~ 1393B
N N
1394A N O 1395A / ~ N 1396A
1394B I' / ~ 1395B ~ I ~ N 1396B
1397A N-N~ 1398A w N 1399A
1397B ~N 1398B I i N~~ 1399B
H H cN~
H
1400A N ~ z 1401 A I ~ N 1402A -O
1400B N'N s 1401B ~ ~~ 1402B
H N
1403A N-O 1404A ~ N 1405A N-N
1403B I / 1404B I ~ ~~ 1405B

Ex. R5~ Ex. No. R5~ Ex. No. R5~
No.

1406A / N-N 1407A N \ N 1408A N \
1406B ~~N~~ 1407B ~~ 1408B \ I i ~~

N
N H

1409A N-o 141 OA / \ 1411 , N~
1409B ~, ,~ ~ 141 OB \ I ~ N A
~ 14 I

1412A ~ N~ 1413A '~,~ 1414A
I ~
\

1412B ~ 1413B ~ 1414B
~ ~

r \ rN

Example Table 19. Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.
H
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1415A 1416Ai ~ 1417A
1415B ~ ~ 1416B ~ ~ 1417B
1418A \ ~ 1419A ~ 1420A \
1418B o\~ 1419B s\~ 1420B "~
1421 A \ ~ 1422A ~ 1423A s 1421B o 1422B s 1423B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1424A N ~'~.; 1425A ~ ~. 1426A
14248 ~~ 14258 I 14268 1427A o ~ 1428A ~ 1429A
14278 ~~ 14288 " \ 14298 1430A o ~ 1431A 1432A
14308 ~ ~ 14318 " ( ~ ~ 14328 1433A ~~ 1434A / ~ 1435A
14338 ~ 14348 N ~ ~ 14358 H
1436A ~ 1437A N ~ 1438A HN
14368 C~ 14378 ~ ~ 14388 O N
1439A 1440A ~ 1441 A
14398 p ~ 14408 I \ 14418 J
N
1442A o ~ 1443A ~ 1444A
14428 ~ 14438 I \ 14448 N
1445A N\'~,,~ 1446A ~ 1447A '~.~
14458 ~ ~ ~ ~446B ~ \ 14478 H-N
N
1448A ':.~ 1449A N '2,t 1450A N '~
1448B p~ 14498 C 14508 N
1451 A '7.,~ 1452A N, N\ ~ 1453A ~ N~~.,;
14518 or~OH 14528 ~ , 14538 N ~ N
1454A ~N 1455A ~ N\'z.~ 1456A
14548 N / s 14558 ( , ~ 14568 N N

Ex. R5~ Ex. No. R5~ Ex. No. R5~
No.

1457A N O 1458A , ~ N 1459A H
_ ,N
~/ / ~ I

14578 14588 \ 14598 ~ N

1460A N' N~ 1461 \ N ; 1462A
~ A I
~~

14608 N 1461 ~ N 14628 B D
C

H H N

H

1463A N ~ 2 1464A I \ N 1465A -O
ii s ~~~- N
N

14638 'H 14648 ~ g 14658 1466A N-O 1467A ~N 1468A N-N z ~ / I ~ ~~

1469A / N~ N 1470A N \ N 1471 N \
14698 ~~N~~ 14708 ~~ A \ ~
~~ 14718 N
N H

1473A N-O 1474A , \ 1475A , N~
14738 ~ / 14748 \ I ~ N 14758 \ ~ /

,~ ,~

1476A ~ N~ 1477A '~,~ 1478A

14768 ~ I ~ ~ 14778 ~ ~ \ 14788 s \ /N

1479A I ~ Z 1480A H3COzC ~ Z 1481 Br ~
14798 H3C~o 14808 N~ 5 A H3C I S
N 14818 s H

1482A CH3 1483A I ~ ~ 1484A

14828 ~ ~ s 14838 H3C(0)C S 5 1484B N S

1485A '~,~ 1486A \ ~ 1487A
14858 ~~OH 14868 I ~ S ~ 14878 gN

Example Table 20. Substituted 2-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.
R''' A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1488A 1489A s ~ 1490A
1488B ~ ~ 1489B ~ ~ 1490B
1491 A \ ~ I 492A ~ 1493A
1491 B o~ 1492B s~ 1493B "N~
1494A \ ~ 1495A ~ 1496A s 1494B o 1495B s 1496B
N
1497A N ~'~.; 1498A ,"r ~ 1499A
1497B ~~ 1498B ~ 1499B
1500A o ~ 1501A ~ 1502A s 1500B ~~ 1501B " \ 1502B
1503A o ~ 1504A 1505A
1503B ~ ~ 1504B H I ~ ~ 1505B
1506A ~~ 1507A ~ ~ 1508A
1506B ~ 1507B N ~ ~ 1508B
H

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1509A ~ 151 OA ,"~ ~ 1511 A HN
15098 C~ 15108 ~ ~ 15118 O N
1512A 1513A ~ 1514A
15128 O Z 15138 I \ 15148 C\ J
NJ
1515A o ~ 1516A ~ 1517A
15158 ~ 15168 I \ 15178 N NH
1518A N\ ''~ I 519A ~ 1520A '~
15188 ( ~ 15198 ~ \ 15208 H.N
N
1521 A ~ 1522A N '7.,~ 1523A N
1521 B p~ 15228 C 15238 N
1524A 'z,7 1525A N, N\ ~; I 526A ~ N~' 15248 or~OH 15258 I , 15268 N ~ IN
1527A N,N Z 1528A ~ N\''~,~ 1529A
15278 I / S 15288 ~ , ~ 15298 N N
1530A N O 1531 A ~ ~ N 1532A H
_ ,N
15308 I' / ~ 15318 ~ I ~ N 1532B
1533A N-N~ 1534A \ N ~ 1535A
15338 ~H 15348 'I ~ H~~ 15358 N
H
1536A N ~ z 1537A I w N 1538A .O
15368 N'N S 15378 ~ ~~ 15388 H N
1539A N-O 1540A ~ N 1541 A N-N 2 15398 I / 15408 I i ~~ 15418 Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1542A i N-N 1543A N ~ N 1544A
15428 ~~N~~ 1543B '~N~~ 15448 w N H
1545A N-o 1546A / w 1547A
15458 ,~ ,~ I ~ 15468 ~ I ~ N 15478 1548A , N~ 1549A '~y 1550A
15488 ~ I ~ ~ 15498 ~ ~ \ 15508 w Example Table 21. Substituted 2-[3- f (5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]-5-methanesulfonylamino-benzoic Acids.
H
\ ~ \

H -~ /J H

A B
Ex. No. R5~ Ex. No. R5~ Ex. No. RS[i 1551A 1552A s ~ 1553A
ISS1B ~ ~ 15528 ~ ~ 15538 ~ ~'~
1554A \ ~ 1555A ~ 1556A _ 15548 0 15558 s~ 15568 "''~
1557A \ ~ 1558A ~ 1559A s 15578 0 15588 s 15598 i Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1560A N ~~:, 1561A N ~. 1562A
1560B ~~ 1561B ~ 1562B
1563A o ~ 1564A ~ 1565A
1563B ~~ 1564B "N \ 1565B
1566A o ~ 1567A 1568A
1566B ~ ~ 1567B H I ~ ~ 1568B
1569A ~~ 1570A ~ ~ 1571 A
1569B ~ 1570B N ~ ~ 1571B
H
1572A ~ 1573A N ~ 1574A HN
1572B C~ 1573B ~ ~ 1574B ss O N
1575A 1576A ~ 1577A
1575B O z 1576B I \ 1577B C\ J
N H
1578A o ~ 1579A ~ 1580A
1578B ~ 1579B I \ 1580B
NH
N
1581A N\'~,, 1582A ~ 1583A
1581B. ~ ~ 1582B ~ \ 1583B, H-N
N
1584A ~ 1585A N '~.~ 1586A N
1584B p~ 1585B C 1586B
N
1587A '~.,~ 1588A N,N\'~ 1589A ~N~~
1587B or~OH 1588B ~ , 1589B N ~ IN
1590A N,N 2 1591A ~ N\'z,;~ 1592A
1590B t / s 1591B ~ , ~ 1592B
N N

Ex. No. R5~ Ex. No. R5~ Ex. R5~
No.

1593A N ~ 1594A , ~ N 1595A H
_ .N
~' / ~ I

15938 15948 ~ 15958 ~ N

1596A N~N~ 1597A \ N 1598A
~

H H N

H

1599A N \ 2 1600A I ~ N 1601 N-O
N ~ ~~ A
s 15998 'N 16008 16018 H N

1602A N-o 1603A ~N 1604A N-N
I / I
~~

16028 16038 i 16048 1605A / N~N 1606A N w N 1607A
16058 ~~N~~ 16068 ~~N~~ 16078 w I i N H

1608A N-o 1609A r w 1610A , N
16088 ~. ,~ 16098 ~ I ~ N 161 ~ ~ i ~ / OB

1611 ~ N~ 1612A '~,~ 1613A
A I ~
\

16118 ~ 16128 ~ 16138 ~ r ,N

1614A I \ ~ 1615A H3COzC \ ~ 1616A Br . \
16148 C~ 16158 N 16168 c I s H S H

3 ~ 3 N

H

1617A cH3 1618A I \ 5 1619A \

s 16178 ( ~ 5 16188 H3c(o)c s 16198 1620A '7,~ I 621 w \ 1622A
16208 r~OH A I i S ~ 16228 HN

Example Table 22. Substituted 5-Amino-2-[3-{(5-heteroaryl or 5-heterocyclic)-2,4-dimethoxy-phenyl}- acryloyl]- benzoic Acids.
H2N HzN
R''' A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1623A 1624A s ~ 1625A
1623B ~ ~ 1624B ~ ~ 1625B
1626A \ ~ 1627A ~ 1628A
1626B o~~ 1627B s~ 1628B ""~
1629A \ ~ 1630A ~ 1631A s 1629B o 1630B s 1631B
1632A N ~'~,; 1633A N ~. 1634A
I
1632B ~~ 1633B ~ 1634B
1635A o ~ 1636A ~ 1637A s 1635B ~~ ' 1636B " \ 1637B
1638A o ~ 1639A 1640A
1638B ~ ~ 1639B " I ~ ~ 1640B
1641 A ~~ 1642A , ~ 1643A
1641B ~ 1642B ~ ~ ~ 1643B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1644A ~ 1645A N ~ 1646A HN
1644B C~ 1645B ~ ~ 1646B
O N
1647A 1648A ~ 1649A
1647B p ~ 1648B I \ 1649B
NJ
1650A o ~ 165 I A ~ 1652A
1650B ~ 1651B I \ 1652B
N NH
1653A N\'~,7 1654A ~ 1655A
1653B ~ ~ 1654B ~ \ 1655B H-N
N
1656A ~ 1657A N '~.,~ 1658A N
1656B p~ 1657B C 1658B
N
1659A ~ 1660A N,N\~.,,; 1661A ~N~~
1659B or~OH 1660B ~ , 1661B N ~ N
1662A .N 1663A ~ N\ ~.,;~ 1664A
1662B N / s 1663B ~ , ~ 1664B
N N
1665A N O 1666A ~ ~ N 1667A H
_ ,N
1665B ~' / ~ 1666B ~ I ~ N 1667B
1668A N-N r 1669A ~ ~N 1670A H
1668B ~H~ 1669B ~ I i H~~ 1670B CN
N
H
1671 A N ~ Z 1672A ~ N 1673A N-O
1671B N'N 5 1672B I ~ ~~ 1673B
H N
1674A N-O 1675A ~ N 1676A N-N
1674B I / 1675B ~ ~ ~~ 1676B

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

1677A ~ N~N 1678A N \ N 1679A N \
16778 ~~N~~ 16788 ~~N~~ 16798 \

N H

1680A N-o 1681 / \ 1682A , N~
16808 ,~ ,~ ~ A \ I ~ N 16828 ~ 1681 B

1683A ~ N~ 1684A '~,~ 1685A
i 16838 ~ I ~ r 16848 ~ ~ \ 16858 w r \ rN

Example Table 23. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.
O H
/ ~ OCH3 / H I /
HOZC HOZC ~OCH3 RSP
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1686A 1687A ~ 1688A
N
16868 ~ ~ 16878 s\~ 16888 1689A ~ 1690A 1691 A _ 16898 0~ 1690A I \ ~ 1691 B "''~
s 1692A \ ~ 1693A \ ~ 1694A s 16928 0 16938 s 16948 Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1695A N ~'~.; 1696A N ~. 1697A
1695B ~~ 1696B ~ 1697B
1698A o ~ 1699A ~ 1700A
1698B ~~ 1699B " \ 1700B
v 1701A o ~ 1702A 1703A
H
1701B ~ ~ 1702B I ~ ~ 1703B
1704A ~~ 1705A , ~ 1706A
N
1704B ~ 1705B N ~ ~ 1706B
H
1707A ~ 1708A N ~ 1709A HN
1707B C~ 1708B ~ 1709B ss O N
171 OA 1711 A ~ 1712A
1710B O z 1711B I \ 1712B
NJ
1713A o ~ 1714A ~ 1715A
1713B ~ 1714B I \ 1715B
N
1716A N\'~,; 1717A ~ 1718A
1716B ~ ~ 1717B ~ \ 1718B H_N
N /
1719A '~,7 1720A N\'7.,~ 172 I A ~ N\ '~
1719B p~~ 1720B C 1721 B N
N
1722A ~ 1723A N, N\ '~ 1724A ~ N
1722B or\~OH 1723B ~ , 1724B N~IN
1725A N,N z 1726A ~ N\'~ 1727A ~'z.,~
1725B t / s 1726B ~ , ~ 1727B
N N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

1728A N O 1729A , ~ N 1730A H
_ .N
I/ / ~ I

1728B 1729B \ 1730B
~ N

1731A N-N 2 1732A \ N 1733A H
~ I N
~ ~~

1731B N 1732B ~ N 1733B D
C

H H
N

H

1734A N ~ z 1735A I \ N 1736A N-O
N ~ ~~
S

1734B 'N 1735B 1736B

H N

1737A N-O 1738A \ N 1739A N-N z I / I i ~~

1740A / N~N 1741A N \ N 1742A
1740B ~~N~~ 1741B ~~ 1742B \ ~ i ~~

N
N H

1743A N-O 1744A / \ 1745A , N
1743B I / 1744B \ I ~ N 1745B \

,~ ,~

1746A ~ N~ 1747A ''y 1748A
i I ~
\

1746B ~ 1747B ~ 1748B
~ r r \ /N

1749A \ z 1750A H3C~2C ~ 2 1751A Br ~
S I ~ S
1749B H3c o 1750B N~N s 1751B H3c s :H

1752A CH3 1753A I ~ s 1754A

1752B ~ ~ s 1753B H3c(o)c s 1754B

1755A '~,:t 1756A \ ~ 1757A
1755B ~~OH 1756B I ~ s ~ 1757B

HN

Example Table 24. Substituted 3-[3-{(5-Heteroaryl or 5-heterocyclic)-3,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.
HOZC HOzC
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1758A 1759A s ~ 1760A
1758B ~ ~ 17598 ~ ~ 17608 1761 A \ ~ 1762A ~ 1763A _ I 761 B o~~ 17628 s~ 17638 "~
1764A \ ~ 1765A \ ~ 1766A s 17648 0 17658 s 17668 1767A N ~'~,;, 1768A N ~. 1769A
17678 ~~ 17688 ~ 17698 1770A o ~ 1771 A ~ 1772A s 1770B ~~ 1771B "" 1772B
i 1773A o ~ 1774A 1775A
17738 ~ ~ 17748 " I ~ ~ 17758 1776A ~~ 1777A ~ ~ 1778A
17768 ~ 17778 N ~ ~ 17788 H

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1779A ~ 1780A N ~ 1781A HN
17798 C\ J 17808 ~ ~ 1781 B
O N
1782A 1783A ~ 1784A
17828 O z 17838 I \ 17848 C\ J
NJ
1785A o ~ 1786A ~ 1787A
17858 ~ 17868 I \ 17878 N
1788A N\'~,; 1789A ~ 1790A
17888 ~ ~ 17898 ~ \ 17908 H-N
N
1791 A ''~ 1792A N\'~,7 1793A ~ N\ '~.,~
17918 p~ 17928 C 17938 N
N
1794A '~.~ 1795A N~N\''z,,; 1796A ~N~~
17948 or~OH 17958 ~ , 17968 N ~ N
1797A N-N j 1798A ~ N\ ~; 1799A ~'~,;~
17978 t / 5 17988 ~ , ~ 17998 N N
I 800A N O 1801 A / ~ N I 802A H
_ -N
18008 ~- / ~ 1801 B ~ I ~ N 18028 H
1803A N-N~ 1804A I ~ N~~- 1805A ~ N
18038 ~ N I 8048 ~ N 18058 H H CN
H
1806A N ~ z 1807A I w N 1808A -O
18068 N~N 5 18078 a ~ 18088 H N
1809A N-O 1810A w N 1811A N-N
18098 ~ / 18108 ( / ~~ 18118 Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1812A / N~N 1813A N ~ N 1814A
1812B ~~N~~ 1813B ~~N~~ 1814B w ~
N H
1815A N-o 1816A , w 1817A , N
1815B ~, ,~ ~ ~ 1816B ~ I ~ N 1817B
1818A ~ N~ 1819A '~,~ 1820A N y 1818B ~ I ~ r 1819B ~ ~ \ 1820B w s' ~ , N
Example Table 25. Substituted 2-[3-f (S-Heteroaryl or S-heterocyclic)-3,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.

/ ~ OCH3 H ~ /
~OCH3 RsP
A B
Ex. No. R5~ Ex. No. ' R5~ Ex. No. R5~
1821 A 1822A s ~ 1823A n", 1821B ~ ~ 1822B ~ ~ 1823B
1824A \ ~ 1825A ~ 1826A _ 1824B o\~ 1825B s~~ 1826B ""~
1827A \ ~ 1828A ~ 1829A s 1827B o 1828B s 1829B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1830A N ~'~.; 1831A N ~ 1832A
18308 ~~ 18318 I 18328 1833A o ~ 1834A ~ 1835A
18338 ~~ 18348 " \ 1835B
1836A o ~ 1837A 1838A
18368 ~ ~ 18378 " ~ ~ 18388 N ~N
1839A ~ 1840A , ~ 1841 A
18398 ~ 18408 N ~ ~ 18418 H
1842A ~ 1843A N ~ 1844A HN
18428 C~ 18438 ~ ~ 18448 O N
1845A 1846A ~ 1847A
18458 p ~ 18468 I \ 18478 N H
1848A o ~ 1849A ~ 1850A
18488 ~ 18498 I \ 18508 / N NH
1851A N\'~ 1852A ~ 1853A ''~,7 1851 B ~ ~ 18528 ~ \ 18538 H.N
N
1854A ~ 1855A N ~ 1856A N
18548 p~ 18558 C 18568 N
1857A ''~ 1858A N,N\'~;~ 1859A ~N~~
18578 or~OH 18588 I , 18598 N ~ N
a 1860A N, N z I 861 A ~ N\ ~.,' 1862A
1860B I / s 18618 ~ , ~ 18628 N N

Ex. R5~ Ex. No. R5~ Ex. R5~
No. No.

1863A N o 1864A / ~ N 1865A H
N.N
I' ~ ~ I

1863B 1864B \ 1865B t ~ N

1866A N-N z 1867A ~N 1868A H
~ I N
~ ~~

H H N

H

1869A N ~ 2 1870A I \ N 1871 N.O
N a ~~ A

1869B ~N 1870B 1871B

H N

1872A N-o 1873A \ N 1874A N-N
I ~ I ~ ~~

1875A / N~N 1876A N \ N 1877A N \
1875B ~~N~~_ 1876B ~~N~~' 1877B \ I /

N H

1878A N-o 1879A / \ 1880A N
/
1878B I ~ 1879B \ I ~ N 188OB \ ~ /

,,~ ", 1881A ~ N~ 1882A '~~ 1883A
( /
\

1881B ~ 1882B ~ 1883B w ~ r r \ /N

1884A I \ 2 1885A H3CO2C ~ ~ 1886A Br \ r C~ s C I S s 3 , 3 H

1887A CH3 1888A I ~ S 1889A

1887B ~ ~ 5 1888B H3C(o)C S 1889B

1890A '~,~ 1891 \ ~ 1892A
1890B ~~OH A I / S ~ 1892B

gN

Example Table 26. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-4-fluorophenyl}-acryloyl]-benzoic Acids.
O
H02C / ~ F HOzC
RSP
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1893A 1894A ~ 1895A
18938 ~ ~ 18948 s~~ 18958 1896A ~ 1897A I w ~ ~- 1898A
18968 0\~ 18978 i S 18988 ""~
1899A \ ~ 1900A ~ I 901 A s 18998 0 19008 s 19018 1902A N ~'~,,; 1903A N ~ 1904A
19028 '~ 19038 I 19048 1905A o ~ 1906A ~ 1907A s 19058 ~~ 19068 " \ 19078 1908A o ~ 1909A 1910A
19088 ~ ~ 19098 " I ~ ~ 19108 1911A ~~ 1912A , ~ 1913A
19118 ~ 19128 ~ ~ ~ 19138 Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1914A ~ 1915A ~ ~ 1916A HN
1914B C\ J 1915B ~ ~ 1916B ss O N
1917A 1918A ~ 1919A
1917B p Z 1918B ( \ 1919B
NJ
1920A o ~ 1921 A ~ 1922A
1920B ~ 1921B I \ 1922B
N NH
1923A N\'~; 1924A ~ 1925A '~
1923B ~ ~ 1924B ~ \ 1925B H_Nr N
1926A '~ 1927A N ~ 1928A N
1926B p~ 1927B C 1928B
N
1929A '~.~ 1930A N, N\ ~ 193 I A ~ N~'~., 1929B or~OH 1930B ~ , 1931 B N ~ N
1932A N,N 2 1933A ~ N\ ~.y 1934A
1932B t / s 1933B ~ , ~ 1934B
N N
1935A N o 1936A / ~ N 1937A H
_ ,N
1935B I' / ~ 1936B ~ I ~ N 1937B
1938A N~N~ 1939A w N .1940A
1938B ~N 1939B I i N~~ 1940B
H H cN~
H
1941A N ~ ~ 1942A I ~ N 1943A N,O
1941B N'N s 1942B a ~~ 1943B
H N
1944A N-~ 1945A ~ N 1946A N-N
1944B I / 1945B I i ~~ 1946B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1947A / N~N 1948A N ~ N 1949A
1947B ~~N~~ 1948B ~~N~~ 1949B w I i N H
1950A N-o 1951 A / w 1952A , N
1950B ,~ ,~ ~ ~ 1951B ~ I ~ N 1952B
1953A r N~ 1954A '~y 1955A
i 1953B ~ I ~ N 1954B ~ f \ 1955B w r ~ ,N
Example Table 27. Substituted 4-[3-{(3-Heteroaryl or 3-heterocyclic)-4-(pyrrolidin-1-yl)-phenyl}acryloyl]-benzoic Acids.
O O H
\ ~ ~ \ \ ~ \
~ /~ H
HOZC ~ Y 'N HOzC / ~N
IRsP ~ Rsa A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1956A 1957A s ~ 1958A
1956B ~ ~ 1957B ~ ~ 1958B
1959A \ ~ 1960A \ ~ 1961A _ 1959B o 1960B s\~ 1961B "~~
1962A \ ~ 1963A ' ~ 1964A s 1962B o 1963B s 1964B
\ / \ /

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
1965A N ~ ~,; 1966A N ~ 1967A
1965B ~~ 1966B ~ 1967B
1968A o ~ 1969A ~ 1970A
1968B ~~ 1969B HN \ 1970B
1971A o ~ 1972A 1973A ,Hr 1971B ~ ~ 1972B H I ~ ~ 1973B
1974A ~~ 1975A , ~ 1976A
N
1974B ~ 1975B N ~ ~ 1976B
H
1977A ~ 1978A N ~ 1979A HN
1977B C~ 1978B ~ ~ 1979B
O N
1980A 1981A ~ 1982A
1980B O z 1981B I \ 1982B
NJ
1983A o ~ 1984A ~ 1985A
1983B ~ 1984B I \ 1985B
N NH
1986A N\'~,; 1987A ~ 1988A '~,7 1986B ~ ~ 1.987B ~ \ 1988B H-N
N
1989A ~ 1990A N\'z,~ 1991 A ~ N\ '~,7 1989B o~ 1990B C ~ 1991B N
N
1992A '7.,~ 1993A N,N\~ 1994A ~N~'~,~
1992B Or~OH 1993B ~ , 1994B N ~ IN
1995A N~N 2 1996A ~ N\'z,z 1997A
1995B t / s 1996B ~ , ~ 1997B
N N

Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

1998A N ~ 1999A , ~ N 2000A H
_ ,N
~' / ~ I

19988 19998 \ 20008 ~ N

2001A N-N z 2002A ~N 2003A H
I N~
~

20018 H 20028 ~ H 20038 C

N

H

2004A N ~ z 2005A I \ N 2006A N,O
N a ~~

20048 'N 20458 20068 H N

2007A N-O 2008A \ N 2009A N-N Z
~ / I i ~~

201 / N~N 2011 N \ N 2012A N \
OA ~~N~~ A ~~ 20128 \ I
20108 20118 ~~

N
N H

2013A N-O 2014A r \ 2015A , N~
20138 ,~ n I 20148 \ I ~ N 201 SB \ I
/

2016A ~ N~ 2017A '~,~ 2018A
i 20168 ~ I ~ ~ 20178 ~ I \ 20188 w r \ /N

2019A I ~ s 2020A H3C~2C I ~ j 2021 B~ I ~
2019B H3C o 20208 N~N s A z H

2022A cH3 2023A I ~ a 2024A I ~ z 20228 ~ ~ s 20238 H3c(o)c s 5 20248 N S

2025A '~.,~ 2026A \ ~ 2027A
20258 r~~H 20268 I i S ~ 20278 HN

Example Table 28. Substituted 4-[3-{(5-Heteroaryl or S-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]benzonitriles.
NC
A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
2028A 2029A ~ 2030A
20288 ~ ~ 20298 ~ ~ 20308 2031A \ ~ 2032A ~ 2033A _ 20318 0~ 20328 s~ 20338 "~
2034A \ ~ 2035A ~ 2036A s 20348 0 20358 s 20368 N
2037A N ~ ~,; 2038A N ~ 2039A
20378 ~~ 20388 ~ 20398 2040A o ~ 2041 A ~ 2042A s 20408 ~~ 20418 " \ 20428 2043A o ~ 2044A 2045A
20438 ~ ~ 20448 H I ~ ~ 20458 2046A ~~ 2047A , ~ 2048A
20468 ~ 20478 N ~ ~ 20488 H

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
2049A ~ 2050A N ~ 2051 A HN
2049B C\ J 2050B ~ ~ 2051B
O N
2052A 2053A ~ 2054A
2052B O ~ 2053B I \ 2054B
N H
2055A o ~ 2056A ~ 2057A
2055B ~ 2056B I \ 2057B
N NH
2058A N\'~.; 2059A ~ 2060A '7.,7 2058B ~ ~ 2059B ~ \ 2060B H-N
N
2061 A ''~ 2062A N '~,7 2063A N
2061 B p~ 2062B C ~ 2063B
N
2064A 'zy 2065A N~N\'~,; 2066A ~N~~
2064B Or~OH 2065B ~ , 2066B N ~ IN
2067A N,N Z 2068A ~ N\''~ 2069A
2067B t / s 2068B ~ , ~ 2069B
N N
2070A N O 2071 A / ~ N 2072A
2070B ~' / ~ 2071 B ~ I ~ N 2072B
2073A N-N~ 2074A ~N 2075A
2073B ~N 2074B

H
2076A N ~ z 2077A ( ~ N 2078A N-O
2076B N'N 5 2077B a ~~ 2078B
H N
2079A N-O 2080A ~ N 2081A N-N
2079B ~ / 2080B I i ~~ 2081B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
2082A / N~N 2083A N ~ N 2084A
2082B ~~N~~ 2083B ~~N~~ 2084B w I i N H
2085A N-o 2086A / ~ 2087A , N
2085B ~, ,~ ~ ~ 2086B ~ I ~ N 2087B
2088A ~ "~ 2089A '~h 2090A
2088B ~ I ~ ~ 2089B ~ ~ \ 2090B
,N
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.

/~ n N y - ~ ~~ri3 N
N-N-H RSP ~ ~ ~-.-A B
Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
2091A 2092A s ~ 2093A
2091B ~ ~ 2092B ~ ~ 2093B
2094A \ ~ 2095A \ ~ 2096A
2094B o~ 2095B s~ 2096B "~
2097A \ ~ 2098A \ ~ 2099A s 2097B o 2098B s 2099B

Ex. No. R5~ Ex. No. R5~ Ex. No. R5~
21 OOA N ~'~.; 21 O 1 A N ~. 2102A
I
2100B ~~ 2101B ~ 2102B
2103A o ~ 2104A ~ 2105A
2103B ~~ 2104B " \ 2105B
2106A o ~ 2107A 2108A
2106B ~ ~ 2107B H I ~ ~ 2108B
2109A ~~ 211 OA , ~ 2111 A
2109B ~ 2110B N ~ ~ 2111B
H
2112A ~ 2113A ,"r ~ 2114A HN
2112B C~ 2113B ~ ~ 2114B
O N
2115A 2116A ~ 2117A
2115B O ~ 2116B I \ 2117B
N H
2118A o ~ 2119A ~ 2120A
2118B ~ 2119B I \ 2120B
N NH
2121 A N\'t,~ 2122A ~ 2123A '~
2121B ~ ~ 2122B ~ \ 2123B H_N
N
2124A '~,~ 2125A N ~ 2126A N '7.~
2124B pr~ 2125B C 2126B
N
2127A '~.,z 2128A N, N\ ~ 2129A ~ N
2127B or~OH 2128B I , 2129B N ~ IN
2130A N,N Z 2131A ~ N\'~ 2132A
2130B I / 5 2131B ~ , ~ 2132B
N N

Ex. R5~ Ex. No. R5~ Ex. No. R5~
No.

2133A N o 2134A , ~ N 2135A H
I' / ~ I

2133B 2134B \ 2135B
~ N

2136A N-N z 2137A \ N 2138A H
~ I N
~ ~~

2136B N 2137B i N 2138B ~
~

H H N

H

2139A N \ 2 2140A \ N 2141A N-O
N I
5 ~~

2139B 'N 2140B i 2141B

H N

2142A N-~ 2143A \ N 2144A N-N Z
~ / I i ~~

2145A / N~N 2146A N \ N 2147A N \
2146B ~~N~~ 2146B ~~N~~ 2147B \ I

N H

2148A N-o 2149A / \ 2150A , N
2148B ~ / 2149B \ I ~ N 2150B

~, ,~

2151 ~ N~ 2152A '~,~ 2153A
A I ~
\

2151B ~ 2152B ~ 2153B w ~ ~

r \ rN

2154A I \ S 2155A H3COzC I \ 2 2156A Br I \
2154B H3C O 2155B N~N S 2156B i H3C s H

2157A CHs 2158A I \ z 2159A I \ z 2157B ( ~ s 2158B H3C(o)C s s 2159B

2160A ''~ 2161 \ \ 2162A \~
2160B r~~H A I i S ~ 2162B

HN

Example Table 30. Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)phenyl}-acryloyl]-benzoic Acids.
O O H
~/~ H ~~~
HOZC / v R4p HO2C / " R4R
A B
Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
2163A 2164A w ~ 2165A "
_ N
2163B ~ ~ 2164B I i S ~ 2165B
2166A ~ 2167A H3C I ~ ~ ~- 2168A
2166B o~ 2167B i S 2168B "~
2169A \ ~ 2170A ~ 2171 A s 2169B o 2170B s 2171B
\ / \ /
2172A N ~'7,,; 2173A N ~ 2174A
2172B ~~ 2173B I 2174B
2175A o ~ 2176A ~ 2177A
2175B ~~ 2176B " \ 2177B s 2178A o ~ 2179A 2180A
2178B ~ ~ 2179B " I ~ ~ 2180B
2181A ~~ 2182A , ~ 2183A "
N
2181B ~ 2182B ~ ~ ( 2183B

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
2184A ~ 2185A N ~ 2186A HN
2184B C\ J 2185B ~ ~ 2186B

2187A 2188A ~ 2189A
2187B O ~ 2188B I \ 2189B
NJ
2190A o ~ 2191 A ~ 2192A
2190B ~ 2191B I \ 2192B
N
2193A N ~'z,;l 2194A ~ 2195A
2193B ~~ 2194B ~ \ 2195B H-N

2196A '7,7 2197A N '~.~ 2198A N '~.,~
2196B p~ 2197B C 2198B
N
2199A '~,7 2200A N, N\ '~,,~ 2201 A ~ N~~
2199B pr~OH 2200B ~ , 2201 B N ~ IN
2202A ,N 2203A ~ N\'~,7 2204A
2202B N / s 2203B ~ , ~ 2204B
N N
2205A N O 2206A ~ ~ N 2207A H
_ ,N
2205B I / ~ 2206B ~ I ~ N 2207B
2208A N-N~ 2209A w N 2210A
2208B ~N 2209B I i N~~ 2210B
H H cN~
H
2211 A N ~ z 2212A I ~ N 2213A N-O
2211B N'N 5 2212B a ~~ 2213B
H N
2214A N-O 2215A ~ N 2216A N-N 2 2214B ~ / 2215B I i ~~ 2216B

Ex. R4~ Ex. R4~ Ex. No. R4~
No. No.

2217A / N~N 2218A N w N 3 2219A
22178 ~~N~~ 22188 ~~ 22198 w ~ i ~~

N
N

H

2220A N-o 2221 / ~ 2222A , N~
22208 ,~ ,~ I A ~ I ~ N 22228 ~ 2221 B

2223A ~ N~ 2224A '~,~ 2225A

22238 ~ I ~ r 2224B ~ ~ \ 22258 ,N

Example Table 31. Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)phenyl}-3-oxo-propenyl]-benzoic Acids.
O O H
~ /~ H ' /~
R4" ~ ~COZH R4a ~ ~C02H
A B
Ex. No. R4a Ex. No. R4a Ex. No. R4a 2226A 2227A s ~ 2228A n", 22268 ~ ~ 22278 _ ~ I 22288 2229A \ ~ 2230A ~ 2231 A _ 22298 0~ 22308 s\~ 22318 "''~
,~J
2232A \ ~ 2233A \ ~ 2234A s 22328 0 22338 s 22348 \ / \ /

Ex. No. R4a Ex. No. R4a Ex. No. R4a 2235A N ~'~,; 2236A ~ ~ 2237A
2235B ~~ 2236B I 2237B
2238A o ~ 2239A ~ 2240A
2238B ~~ 2239B " \ 2240B
2241 A o ~ 2242A 2243A
2241B ~ ~ 2242B " I ~ ~ 2243B
2244A ~~ 2245A / ~ 2246A
2244B ~ 2245B N ~ ~ 2246B
H
2247A ~ 2248A N ~ 2249A HN
2247B C~ 2248B ~ ~ 2249B
O N
2250A 2251A ~ 2252A
2250B O z 2251B I \ 2252B
N H
2253A o ~ 2254A ~ 2255A
2253B ~ 2254B I \ 2255B
N
2256A N\'~,~ 2257A ~ 2258A '~,;~
2256B ~ ~ 2257B ~ \ 2258B H_Nr N
2259A '~,~ 2260A N '~.,,~ 2261 A N 'z,7 2259B p~ 2260B C ~ 2261B
N
2262A 'z.,7 2263A N, N\ ~ 2264A ~ N~~
2262B or~OH 2263B I , 2264B N ~ N
2265A N,N r 2266A ~ N\ ~ 2267A
2265B I / s 2266B ~ , ~ 2267B
N N

Ex. R4a Ex. R4a Ex. No. R4a No. No.

2268A N o 2269A , ~ N 2270A H
I/ ~ ~ I Nr /

22688 22698 \ 22708 ~ N

2271A N-N z 2272A ~N 2273A H
~ I N
~ ~~

22718 H 22728 i 22738 C

H N

H

2274A N \ z 2275A I \ N 2276A -O
N a ~~

22748 'N 22758 22768 H N

2277A N-o 2278A ~N 2279A N-N z ~ ~ I i ~~

2280A / N~N 2281A N \ N 2282A N \
22808 ~~N~~ 22818 ~~ 22828 \
~~

N
N H

2283A N-o 2284A / \ 2285A , N
22838 I ~ 22848 \ I ~ N 22858 ,~ n 2286A ~ N~ 2287A '~,~ 2288A

2286B ~ I ~ ~ 22878 ~ ~ \ 22888 r \ /N

2289A I \ S 2290A HsC02C I \ z 2291 Br I \
22898 H3C o 22908 N~ N 5 A z 2291 H3C s B

' H

2292A CH3 2293A I \ z 2294A I \ z 22928 ~ \ s 22938 H3C(o)c s s 22948 N s 2295A '~,;~ 2296A \ \ 2297A
22958 r~~H 22968 I i S ~ 2297B

gN

Example Table 32. Substituted 4-[3-{(4-Heteroaryl or 4-heterocyclic)-2,6-dimethoxyphenyl}-acryloyl]-benzoic Acids.

I
~ /~ H
H3C0~~ 4R HO C / ~~ R4P

A B
Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
2298A 2299A s ~ 2300A
2298B ~ ~ 2299B ~ ~ 2300B
2301A \ ~ 2302A ~ 2303A
2301B o~ 2302B s\~ 2303B "~
2304A \ ~ 2305A ~ 2306A
2304B o 2305B s 2306B
\ ~ \
2307A N ~'~,; 2308A N ~ 2309A
I
2307B '~ 2308B ~ 2309B
231 OA o ~ 2311 A ~ 2312A s 2310B ~~ 2311B " \ 2312B
2313A o ~ 2314A 2315A ,"r 2313B ~ ~ 2314B " ~ ~ ~ 2315B
2316A ~~ 2317A , ~ 2318A
2316B ~ 2317B N ~ ~ 2318B
H

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
2319A ~ 2320A N ~ 2321A HN
2319B C~ 2320B ~ ~ 2321B
O N
2322A 2323A ~ 2324A
2322B O Z 2323B I \ 2324B
NJ
2325A o ~ 2326A ~ 2327A
2325B ~ 2326B I \ 2327B
N
2328A N\'~ 2329A ~ 2330A
2328B ~ ~ 2329B ~ \ 2330B H-N
N
2331A '~ 2332A N 'z.,~ 2333A N '~,~
2331B p~ 2332B C 2333B
N
2334A '7.,z 2335A N,N\'~ 2336A ~N~~
2334B or~OH 2335B ~ , 2336B N ~ IN
2337A N,N z 2338A ~ N\'~,7 2339A ~'~
2337B I / s 2338B ~ , ~ 2339B
N N
2340A N O 2341 A , ~ N 2342A H
_ ,N
2340B I' / ~ 2341B ~ I ~ N 2342B
H
2343A N~N~ 2344A I w N~~- 2345A N
2343B ~ H 2344B i H 2345B
N
H
2346A N ~ z 2347A I ~ N 2348A -O
2346B N'N 5 2347B a ~~ 2348B
H N
2349A N-O 2350A ~ N 2351A N-N 2 2349B I / 2350B I i ~~ 2351B

Ex. No. R4~ Ex. No. R4~ Ex. No. R4~
2352A / N-N 2353A N \ N 2354A N \
2352B ~~N~~ 2353B ~~ ~~ 2354B \
N H
2355A N-o 2356A , \ 2357A , N~
2355B ,~ n I ~ 23568 \ I ~ N 2357B
2358A ~ N~ 2359A '~,~ 2360A
2358B ~ I ~ ~ 2359B ~ ~ \ 2360B
r \ iN
Example Table 33. Substituted 4-[3-{(5-Heteroaryl or 5-heterocyclic)-2,4-dimethoxyphenyl}-acryloyl]-benzoic Acids.

H ~/~
HOZC H02C / ~OCH3 IRsa A B
Ex. R5~ Ex. R5~ Ex. No. R5~
No. No.

2361A \ Z 2362A H3C~2C . ~ Z 2363A Br ~
s I. ~ s o 5 6 2361B H3C 2362B N,N 23 H3c s H

2364A CH3 2365A I ~ 5 2366A

2364B ~ ~ 5 2365B H3C(o)c s 2366B

2367A '~ 2368A \ ~ 2369A
2367B r\~oH 2368B I i s ~ 2369B

gN

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 I S 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 chromato-g_raphy - 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 chromato:-~raphy - 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, a-ketoglutarate and a-glycerophosphate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts. Alternatively, the pharmaceutically acceptable salts may be made with sufficiently basic compounds such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) base addition salts formed with metal canons such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like. Also included in this definition are pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR+A-, wherein R is as defined above and A is a.counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
Particular FDA-approved salts can be conveniently divided between anions and cations (Approved Drug Products with Therapeutic Equivalence Evaluations (1994) U.S.
Department of Health and Human Services, Public Health Service, FDA, Center for Drug Evaluation and Research, Rockville, Md; L:D. Bighley, S.M. Berge and D.C. Monkhouse, Salt Forms of Drugs ~~ ~ s.
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, allow, 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 Or an~ynthesis, 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 Z\ R
N ~~ ~ n OH
Y
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 l, 2, 3, 4, or S.
Among these hydroxyl amines are a particular class characterized when n is 4. A
representative of this group is meglumine, represented when Y is hydrogen, Z is methyl and R is methoxy.
Meglumine is also known in the art as N-methylglucamine, N-MG, and 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.
1n another aspect the invention provides a method for treating a disease or disorder mediated by VCAM-1 comprising administering to a patient a VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
In another aspect the invention provides a method for treating cardiovascular and inflammatory disorders in a patient in need thereof comprising administering to said patient an VCAM-1 inhibiting effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

In another aspect the invention provides a method and composition for treating asthma or arthritis in a patient in need thereof comprising administering to said patient an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
The compounds of the present invention can be used to treat any disorder that is mediated by VCAM-1. VCAM-1 is upregulated in a wide variety of disease states, including but not limited to arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, atherosclerosis, coronary artery disease, angina, small artery disease, and conjunctivitis.
Nonlimiting examples of arthritis include rheumatoid (such as soft-tissue rheumatism and non-articular rheumatism, fibromyalgia, fibrositis, muscular rheumatism, myofascil pain, I S 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-I, and MCP-1 is a chemoattractant for monocytes. MCP-1 has been shown to play a role in leukocyte recruitment in a number of chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, and asthma. Its expression is upregulated in these diseases and as such inhibition of MCP-1 expression represents a desirable property of anti-inflammatory therapeutics. Furthermore, smooth muscle cell hyperplasia and resulting tissue remodeling and decreased organ function is yet another characteristic of many chronic inflammatory diseases including atherosclerosis, chronic transplant rejection and asthma. Inhibition of the hyperproliferation of smooth muscle cells is another desirable property for therapeutic compounds.
Combination and Alternation Therapy Any of the compounds disclosed herein can be administered in combination or alternation with a second biologically active agent to increase its effectiveness against the target disorder.
In combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy an effective dosage of each agent is administered serially. The dosages will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
The efficacy of a drug can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, agent that induces a different biological pathway from that caused by the principle drug.
Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the condition.
Any method of alternation can be used that provides treatment to the patient.
Nonlimiting examples of alternation patterns include 1-6 weeks of administration of an effective amount of one agent followed by 1-6 weeks of administration of an effective amount of a second agent. The alternation schedule can include periods of no treatment. Combination therapy generally includes the simultaneous administration of an effective ratio of dosages of two or more active agents.
Illustrative examples of specific agents that can be used in combination or alternation with the compounds of the present invention are described below in regard to asthma and arthritis. The agents set out below or others can alternatively be used to treat a host suffering from any of the other disorders listed above or that are mediated by VCAM-1 or MCP-1.
Illustrative second biologically active agents for the treatment of cardiovascular disease are also provided below.
Asthma In one embodiment, the compounds of the present invention are administered in combination or alternation with heparin, frusemide, ranitidine, an agent that effects respiratory function, such as DNAase, or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane inhibitors, leukotriene-D4-receptor antagonists such as Accolate (zafirlukast), Ziflo (zileuton), leukotriene C~ or CZ antagonists and inhibitors of leukotriene synthesis such as zileuton for the treatment of asthma, or an inducible nitric oxide synthase inhibitor.
In another embodiment, the active compound is administered in combination or alternation with one or more other prophylactic agent(s). Examples of prophylactic agents that can be used in alternation or combination therapy include but are not limited to sodium cromoglycate, Intal (cromolyn sodium, Nasalcrom, Opticrom, Crolom, Ophthalmic Crolom), Tilade (nedocromil, nedocromil sodium) and ketotifen.
In another embodiment, the active compound is administered in combination or alternation with one or more other (32-adrenergic agonist(s) ((3 agonists).
Examples of (3z-adrenergic agonists ((3 agonists) that can be used in alternation or combination therapy include but are not limited to albuterol (salbutamol, Proventil, Ventolin), terbutaline, Maxair (pirbuterol), Serevent (salmeterol), epinephrine, metaproterenol (Alupent, Metaprel), Brethine (Bricanyl, Brethaire, terbutaline sulfate), Tornalate (bitolterol), isoprenaline, ipratropium bromide, bambuterol hydrochloride, bitolterol meslyate, broxaterol, carbuterol hydrochloride, clenbuterol hydrochloride, clorprenaline hydrochloride, efirmoterol fumarate, ephedra (source of alkaloids), ephedrine (ephedrine hydrochloride, ephedrine sulfate), etafedrine hydrochloride, ethylnoradrenaline hydrochloride, fenoterol hydrochloride, hexoprenaline hydrochloride, isoetharine hydrochloride, isoprenaline, mabuterol, methoxyphenamine hydrochloride, methylephedrine hydrochloride, orciprenaline sulphate, phenylephrine acid tartrate, phenylpropanolamine (phenylpropanolamine polistirex, phenylpropanolamine sulphate), pirbuterol acetate, procaterol hydrochloride, protokylol hydrochloride, psuedoephedrine (psuedoephedrine polixtirex, psuedoephedrine tannate, psuedoephedrine hydrochloride, psuedoephedrine sulphate), reproterol hydrochloride, rimiterol hydrobromide, ritodrine hydrochloride, salmeterol xinafoate, terbutaline sulphate, tretoquinol hydrate and tulobuterol hydrochloride.
In another embodiment, the active compound is administered in combination or alternation with one or more other corticosteriod(s). Examples of corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium Phosphate), Dichlorisone Acetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Valerate), Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone .Hexanoate, Prednisolone Pivalate, Prednisolone Sodium Metasulphobenzoate, Prednisolotle Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide, Rimexolone, Suprarenal Cortex, Tixocortol Pivalate, Triamcinolone (Triamcinolone Acetonide, Triamcinolone Diacetate and Triamcinolone Hexacetonide).
In another embodiment, the active compound is administered in combination or alternation with one or more other antihistimine(s) (H, receptor antagonists).
Examples of antihistimines (H, receptor antagonists) that can be used in alternation or combination therapy include alkylamines, ethanolamines ethylenediamines, piperazines, piperidines or phenothiazines. Some non-limiting examples of antihistimes are Chlortrimeton (Teldrin, chlorpheniramine), Atrohist (brompheniramine, Bromarest, Bromfed, Dimetane), Actidil (triprolidine), Dexchlor (Poladex, Polaramine, dexchlorpheniramine), Benadryl (diphen-hydramine), Tavist (clemastine), Dimetabs (dimenhydrinate, Dramamine, Marmine), PBZ
(tripelennamine), pyrilamine, Marezine (cyclizine), Zyrtec (cetirizine), hydroxyzine, Antivert (meclizine, Bonine), Allegra (fexofenadine), Hismanal (astemizole), Claritin (loratadine), Seldane (terfenadine), Periactin (cyproheptadine), Nolamine (phenindamine, Nolahist), Phenameth (promethazine, Phenergan), Tacaryl (methdilazine) and Temaril (trimeprazine).
Alternatively, the compound of the present invention is administered in combination or alternation with (a) xanthines and methylxanthines, such as Theo-24 (theophylline, Slo-Phylline, Uniphyllin, Slobid, Theo-Dur), Choledyl (oxitriphylline), aminophylline;
(b) anticholinergic agents (antimuscarinic agents) such as belladonna alkaloids, Atrovent (ipratropium bromide), atropine, oxitropium bromide;
(c) phosphodiesterase inhibitors such as zardaverine;
(d) calcium antagonists such as nifedipine; or (e) potassium activators such as cromakalim for the treatment of asthma.
Arthritic disorders In one embodiment, the compound of the present invention can also be administered in combination or alternation with apazone, amitriptyline, chymopapain, collegenase, cyclobenzaprine, diazepam, fluoxetine, pyridoxine, ademetionine, diacerein, glucosamine, hylan (hyaluronate), misoprostol, paracetamol, superoxide dismutase mimics, TNFa receptor antagonists, TNFa antibodies, P38 Kinase inhibitors, tricyclic antidepressents, cJun kinase inhibitors or immunosuppressive agents, IV gamma globulin, troleandomycin, cyclosporin (Neoral), methotrexate, FK-506, gold compounds such as Myochrysine (gold sodium thiomalate), platelet activating factor (PAF) antagonists such as thromboxane inhibitors, and inducible nitric oxide sythase inhibitors.

In another embodiment, the active compound is administered in combination or alternation with one or more other corticosteriod(s). Examples of corticosteriods that can be used in alternation or combination therapy include but are not limited to glucocorticoids (GC), Aerobid (Aerobid-M, flunisolide), Azmacort (triamcinolone acetonide), Beclovet (Vanceril, beclomethasone dipropionate), Flovent (fluticasone), Pulmicort (budesonide), prednisolone, hydrocortisone, adrenaline, Alclometasone Dipropionate, Aldosterone, Amcinonide, Beclomethasone Dipropionate, Bendacort, Betamethasone (Betamethasone Acetate, Betamethasone Benzoate, Betamethasone Dipropionate, Betamethasone Sodium Phosphate, Betamethasone Valerate), Budesonide, Ciclomethasone, Ciprocinonide, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Pivalate, Cloprednol, Cortisone Acetate, Cortivazol, Deflazacort, Deoxycortone Acetate (Deoxycortone Pivalate), Deprodone, Desonide, Desoxymethasone, Dexamethasone (Dexamethasone Acetate, Dexamethasone Isonicotinate, Dexamethasone Phosphate, Dexamethasone Sodium Metasulphobenzoate, Dexamethasone Sodium Phosphate), Dichlorisone Acetate, Diflorasone Diacetate, Diflucortolone Valerate, Difluprednate, Domoprednate, Endrysone, Fluazacort, Fluclorolone Acetonide, Fludrocortisone Acetate, Flumethasone (Flumethasone Pivalate), Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone (Fluocortolone Hexanoate, Fluocortolone Pivalate), Fluorometholone (Fluorometholone Acetate), Fluprednidene Acetate, Fluprednisolone, Flurandrenolone, Fluticasone Propionate, Formocortal, Halcinonide, Halobetasol Propionate, Halometasone, Hydrocortamate Hydrochloride, Hydrocortisone (Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Cypionate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone . Valerate), Medrysone, Meprednisone, Methylprednisolone (Methylprednisolone Acetate, Methylprednisolone, Hemisuccinate, Methylprednisolone Sodium Succinate), Mometasone Furoate, Paramethasone Acetate, Prednicarbate, Prednisolamate Hydrochloride, Prednisolone (Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone Hexanoate, Prednisolone Pivalate, Prednisolone Sodium Metasulphobenzoate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Steaglate, Prednisolone Tebutate), Prednisone (Prednisone Acetate), Prednylidene, Procinonide, lRimexolone, 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 drugs) (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 S 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 I S (oxyphenbutazone), piroxicam (Feldene), Relafen (nabumetone), Myochrysine (gold sodium thiomalate), Ridaura (auranofin), Solganal (aurothioglucose), acetaminophen, colchicine, Zyloprim (allopurinol), Benemid (probenecid), Anturane (sufinpyrizone), Plaquenil (hydroxychloroquine), Aceclofenac, Acemetacin, Acetanilide, Actarit, Alclofenac, Alminoprofen, Aloxiprin, Aluminium Aspirin, Amfenac Sodium, Amidopyrine, Aminopropylone, Ammonium Salicylate, Ampiroxicam, Amyl Salicylate, Anirolac, Aspirin, Auranofin, Aurothioglucose, Aurotioprol, Azapropazone, Bendazac (Bendazac Lysine), Benorylate, Benoxaprofen, Benzpiperylone, Benzydamine, Hydrochloride, Bornyl Salicylate, Bromfenac Sodium, Bufexamac, Bumadizone Calcium, Butibufen Sodium; Capsaicin, Carbaspirin Calcium, Carprofen, Chlorthenoxazin, Choline Magnesium Trisalicylate, Choline Salicylate, Cinmetacin, Clofexamide, Clofezone, Clometacin, Clonixin, Cloracetadol, Cymene, Diacerein, Diclofenac (Diclofenac Diethylammonium Salt, Diclofenac Potassium, Diclofenac Sodium), Diethylamine Salicylate, Diethylsalicylamide, Difenpiramide, Diflunisal, Dipyrone, Droxicam, Epirizole, Etenzamide, Etersalate, Ethyl Salicylate, Etodolac, Etofenamate, Felbinac, Fenbufen, Fenclofenac, Fenoprofen Calcium, Fentiazac, Fepradinol, Feprazone, Floctafenine, Flufenamic, Flunoxaprofen, Flurbiprofen (Flurbiprofen Sodium), Fosfosal, Furprofen, Glafenine, Glucametacin, Glycol Salicylate, Gold Keratinate, Harpagophytum Procumbens, Ibufenac, Ibuprofen, Ibuproxam, lmidazole Salicylate, Indomethacin (Indomethacin Sodium), Indoprofen, Isamifazone, Isonixin, Isoxicam, Kebuzone, Ketoprofen, Ketorolac Trometamol, Lithium Salicylate, Lonazolac Calcium, Lornoxicam, Loxoprofen Sodium, Lysine Aspirin, Magnesium Salicylate, Meclofenamae Sodium, Mefenamic Acid, Meloxicam, Methyl Butetisalicylate, Methyl Gentisate, Methyl Salicylate, Metiazinic Acid, Metifenazone, Mofebutazone, Mofezolac, Morazone Hydrochloride, Morniflurnate, Morpholine Salicylate, Nabumetone, Naproxen (Naproxen Sodium), Nifenazone, Niflumic Acid, Nimesulide, Oxametacin, Oxaprozin, Oxindanac, Oxyphenbutazone, Parsalmide, Phenybutazone, Phenyramidol Hydrochloride, Picenadol Hydrochloride, Picolamine Salicylate, Piketoprofen, Pirazolac, Piroxicam, Pirprofen, Pranoprofen, Pranosal, Proglumetacin 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.
heal bile acid transporter (IBAT) inhibitors, for example, are useful in the present invention, and are disclosed in patent application no. PCT/LTS95/10863, herein incorporated by ' ~ reference. More IBAT inhibitors are described in PCT/LJS97/04076, herein incorporated by reference. Still further IBAT inhibitors useful in the present invention are described in U.S.
Application Serial No. 08/816,065, herein incorporated by reference. More IBAT
inhibitor compounds useful in the present invention are described in WO 98/40375, and WO
00/38725, herein incorporated by reference. Additional IBAT inhibitor compounds useful in the present invention are described in U.S. Application Serial No. 08/816,065, herein incorporated by reference.
In another aspect, the second biologically active agent is a statin. Statins lower cholesterol by inhibiting of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, a key enzyme in the cholesterol biosynthetic pathway. The statins decrease liver cholesterol biosynthesis, which increases the production of LDL receptors thereby decreasing plasma total and LDL cholesterol (Grundy, S. M. New Engl. J. Med. 319, 24 (1988); Endo, A.
J. Lipid Res.
33, 1569 (1992)). Depending on the agent and the dose used, statins may decrease plasma triglyceride levels and may increase HDLG. Currently the statins on the market are lovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and fluvastatin (Sandoz). A
fifth statin, atorvastatin (Parke-Davis/Pfizer), is the most recent entrant into the statin market.
Any of these statins or thers can be used in combination with the chalcones of the present invention.
MTP inhibitor compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the MTP inhibitor compounds of particular interest for use in the present invention are disclosed in WO 00/38725, the disclosure from which is incorporated by reference. Descriptions of these therapeutic compounds can be found in Science, 282, 23 October 1998, pp. 751-754, herein incorporated by reference.
Cholesterol absorption antagonist compounds useful in the combinations and methods of the present invention comprise a wide variety of structures and functionalities. Some of the cholesterol absorption antagonist compounds of particular interest for use in the present invention are described in U.S. Patent No. 5,767,115, herein incorporated by reference. Further cholesterol absorption antagonist compounds of particular interest for use in the present invention, and methods for making such cholesterol absorption antagonist compounds are described in U.S. Patent No. 5,631,365, herein incorporated by reference.
A number of phytosterols suitable for the combination therapies of the present invention are described by Ling and Jones in "Dietary Phytosterols: A Review of Metabolism, Benefits and Side Effects," Life Sciences, 57 (3), 195-206 (1995). Without limitation, some phytosterols of particular use in the combination of the present invention are Clofibrate, Fenofibrate, Ciprofibrate, Bezafibrate, Gemfibrozil. The structures of the foregoing compounds can be found in WO 00/38725.
Phytosterols are also referred to generally by Nes (Physiolo 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 HDLG elevating agent. In one aspect, the second HDLG elevating agent can be a CETP inhibitor. Individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/38725, the disclosure of which is herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 99/14174, EP818448, WO
99/15504, WO
99/14215, WO 98/04528, and WO 00/17166, the disclosures of which are herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 00/18724, WO 00/18723, and WO 00/18721, the disclosures of which are herein incorporated by reference. Other individual CETP inhibitor compounds useful in the present invention are separately described in WO 98/35937 as well as U.S. Patent Nos. 6,313,142, 6,310,075, 6,197,786, 6,147,090, 6,147,089, 6,140,343, and 6,140,343, the disclosures of which is herein incorporated by reference.
In another aspect, the second biologically active agent can be a fabric acid derivative.
Fabric 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 I S 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 bisulfate; 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 ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable Garners. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipids) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa. In addition to the other materials listed above for systemic administration, thickening agents, emollients and stabilizers can be used to prepare topical compositions.
Examples of thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
Any of the compounds described herein for combination or alternation therapy can be administered as any derivative that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound, or that exhibits activity itself.
Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts"), and a compound which has been alkylated or acylated at an appropriate position. The modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its anti-inflammatory activity according to known methods.

Biological Activity of Active Compounds The ability of a compound described herein to inhibit the expression of VCAM-1 or in the treatment of diseases in a host can be assessed using any known method, including that described in detail below.
In Vitro MCP-1 Activity Assay Cultured human endothelial cells were seeded in 96-well plates. On the following day cells were stimulated with TNF-a (lng/ml) in the presence or absence of compounds dissolved in DMSO. To establish a dose curve and an ICSO, multiple concentrations in 2-to 5-fold increments were used. Cells were exposed to TNF-a and compounds for approximately 16 hours. The next day the cells were visually examined via light microscopy to score for visual signs 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 ICSO values of > 10(the amount of compound (pM) required to achieve a 50% reduction compared to control (cells stimulated with TNF-a only)).
In Vitro VCAM-1 Assay Cell Culture and compound dosing: Cultured primary human aortic (HAEC) or pulmonary (HPAEC) endothelial cells were obtained from Clonetics, Inc., and were used below passage 9. Cells were seeded in 96 well plates such that they would reach 90-95% confluency .
by the following day. On the following day the cells were stimulated with TNF-a (lng/ml) in the presence or absence of compounds dissolved in DMSO such that the final concentration of DMSO is 0.25% or less. To establish a dose curve for each compound, four concentrations in 2- to 5-fold increments were used. Cells were exposed to TNF-a and compounds for approximately 16 hours. The next day the cells were examined under microscope to score for visual signs of toxicity or cell stress.

Following l6hr exposure to TNF-a and compound the media was discarded and the cells were washed once with Hanks Balanced Salt Solution (HBSS)/ Phosphate buffered saline (PBS) (1:1). Primary antibodies against VCAM-1 (0.25~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 450nm. The results are expressed as ICso values (the concentration (micromolar) of compound required to inhibit 50% of the maximal response of the control sample stimulated by TNF-a only). Compounds exhibiting ICSO's of less than 5 micromolar are tabulated in Biological Table 1.
Biological Table 1 Example VCAM-1 ExampleVCAM- Example VCAM-1 Example VCAM-Number IC50 Number 1 IC50 Number IC50 Number 1 IC50 (NM) (N~'1) (1~M) (N~

1 <1 31 >10 61 <1 91 <5 2 <5 32 <5 62 <5 92 <1 3 <1 33 <5 63 <10 93 <1 4 <10 34 >10 64 >10 94 <1 5 <1 35 >10 65 <1 95 <1 6 <1 36 <5 66 <1 96 <5 7 <1 37 >10 67 <10 97 NE

8 <1 38 <10 68 <5 98 <S

9 <5 39 >10 69 <5 99 >10 <5 40 <1 70 <S 100 >10 11 <5 41 <5 71 NE 101 >10 12 <5 42 <5 72 0 102 >10 13 <5 43 <5 73 0 103 >10 14 <1 44 <1 74 >10 104 NE

>10 45 <5 75 >10 105 NE

16 <5 46 <10 76 >10 106 <10 17 <5 47 >10 77 <5 107 NE

18 <5 48 <10 78 <10 108 <10 19 <1 49 <10 79 <1 109 NE

>10 50 >10 80 <5 110 >10 21 <S 51 <5 81 <1 111 >10 22 > 10 52 > 10 82 NE 112 NE

23 <1 53 <5 83 <1 113 <5 24 >10 54 <10 84 <5 114 <5 >10 55 <5 85 <1 115 <5 26 >10 56 <1 86 <5 116 27 <5 57 <5 87 <1 117 <S

28 <5 58 >10 88 118 <10 29 < 1 59 NE 89 NE 119 <1 60 <1 90 <1 120 <1 Rheumatoid Arthritis Protocol Male Lewis rats (150-175g) from Charles River Laboratories were anesthetized on day 0 with 3-5% isoflurane anesthesia while the tail base was shaved and adjuvant mixture was injected. Fifty pL 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 occun ed rapidly between d9-11 and daily measurements were performed every weekday between d9 and day 15. Compounds of the invention and vehicles were dosed either prophylactically (dl-14), or therapeutically (d9-14) after swelling was confirmed. Solutions were injected subcutaneously or given orally by gavage 1-2 times per day. From day 0, rats were weighed every 2-3 days and overall health was monitored. Plasma drug levels, if desired, were measured in tail-vein derived blood samples taken on day 14. On day 15, blood samples were obtained by cardiac puncture, rats were euthanized with COZ , selected organs removed and both hindpaws were amputated and placed in 10% buffered fonnalin for histopathological analysis. See Biological Table 2.
Biological Table 2 Compound Example % Inhibition 60 mg/Kg/day, Number sq, bid, dl-14 60 62*

* 75 mg/kg/day, sq,bid, dl-14 Asthma Protocol Balb/C mice (6-8 weeks old) are sensitized to ovalbumin (ova) (8 ug ova absorbed in 3.3 mg Alum inject) on days 0 and 5. On day 12, the mice were aerosol challenged with 0.5%
ovalbumin dissolved in sterile saline for 1 hr in the AM, and then again in the PM (at least 4 hr apart). On day 14, the mice were anesthetized with ketamine/xylazine/acepromazine cocktail, exsanguinated, and then euthanized. Following blood collection, bronchoaveolar lavage was performed on each animal. Total cell counts were conducted on the lavage fluid, which was subsequently diluted with cell media 1:1. Slides of the lavage fluid were made by spinning the samples with a cytospin centrifuge. Slides were airdried and stained with x.
Cell differentials of the lavage fluid were completed at the conclusion of the study. All compounds except Example 2 were well tolerated with no body weight loss throughout the course of the study.
Statistical analysis involved ANOVA and Tukey-Kramer post hoc tests. Compounds were administered except where noted by subcutaneous injection once daily from day 0-13. The formulations used contained various mixtures of the following excipients (pharmasolve, cremophor RH 40, tween 80, PEG 300). See Biological Table 3 Biological Table 3 Compound Example Number% Inhibition sc, daily dosing at 100 mg/kg from day 0-13 Effect of serum IgE levels in ovalbumin sensitized Balb/c mice Peripheral blood samples were collected from ovalbumin (Calbiochem) or vehicle (2%
CremophorBicarbonate) treated Balb/c mice (Charles River) with or without administration of test compound (100mg/kg/d, from day 0 to day 14). Serum was obtained by centrifugation and transferred into Microtainer serum tubes and frozen at -80°C. Mouse IgE
ELISA Quantitation Kit (Bethyl Laboratories, Inc. Montgomery, TX or PharMingen, San Diego, CA) was applied to measure the IgE levels of serum samples. Immuno-reactions were performed as Kit protocol with IgE standard and serum samples in duplicates. The results were read in a microplate reader (Bio-Rad Model 550) at 450nm and the amounts of IgE were calculated according to the standard curve. The limit of detection in our experiments was 7ng/ml. Compound administrated at 100mg/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%
CremophorBicarbonate) sensitized Balb/c mice (Charles River) with or without treatment of test compound (100mg/kg/d, from day 0 to day 14). Total RNA samples were isolated by the Trizol method (Life Technologies, Grand Island, NY) and quantitatively measured by UV
spectrophotometer, as well as qualitatively examined by ethidum bromide stained gel electrophoresis. First strand cDNA templates were generated with oligo (dT) by Reverse Transcription Kit (Invitrogen, Carlsbad, CA). The initial amounts of mRNA of each samples were quantitatively determined by running a SYBR Green (Qiagen, Valencia, CA) based real-time PCR (programmed as: initial denaturation at 95°C for 15 minutes, denaturation at 95°C for 15 seconds, annealing and elongation at 511 °C for 1 minute for total 40 cycles) with a specific pair of primers (IDT Corporation, Coralville, IA) and control primers for GAPDH in iCycler IQ Optical System (Hercules, CA). The data were statistically analyzed by ANOVA

and t-tests with multiple comparisons of means (n = 5 and P < 0.05 were considered significant). Compound 3 administrated at 100mg/kg/d, significantly inhibited ovalbumin induced levels of IL-13, IL-S 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 S treated mice.
List of Primers used in above experiments:
Primer Forward Sequence Reverse Sequence Annealing Name Temperature GAPDH CTA CCC CCA ATG TGT CC CTG CTT CAC CAC CTT CTT 52.2 IL-13 AAF AFF AGA GCA AAT GAA CTG TGT AAC CTT CCC AAC 51.3 AG A

IL-4 TGA ATG AGT CCA AGT CCA AGC ATG GTG GCT CAG TA 51.2 ILS AGC TCT GTT GAC AAG CAA CCC TGA AAG ATT TCT CCA 52.4 T ATG

IL-2 GTC GAC TTT CTG AGG AGA ATG TGT TGT AAG CAG GAG 53.2 TG GT

IFN-y TTC TGT CTC CTC AAC TAT CAA TCA CAG TCT TGG CTA 51.3 TTC T 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 houis. The cells were, then, stimulated by 5% serum in the presence or absence of compounds dissolved in DMSO. To establish a dose curve and ICso for each compound, multiple concentrations in the range of 20 to 0.05 p.M
were used.
Rapamycin (at 1 and 0.11tM) was used as a positive control for the assay.
After a 20 hour incubation with or without test compounds, 3H-thymidine (O.SpCi/ 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 CytoITox 96 assay kit (Promega, Madison, WI). Compound 3 had an ICso of 0.5 ~tM.

Effect of Test Compounds on LPS-Stimulated IL-l~
Human peripheral blood mononuclear cells were treated with or without Compound for 1 hour, then stimulated with LPS (1-2 wg/ml) for 3 hours. Condition media was collected and IL-1 (3 measured using an ELISA kit. Compound 3 demonstrated a dose dependent inhibition of LPS-stimulated IL-1(3 secretion. See Biological Table 4 Biological Table 4 Amount of Compound 3 Percent IL-1(3 Secreted (1~M) 1.25 >40 2.5 > 10 5 >5 >1 10 Reduction of Plasma TNF-a levels and lung VCAM-1 mRNA levels in LPS-Challenged Mice.
Balb/C mice (6-8 weeks) were injected with LPS (1 mg/kg; 5 mls/kg) and sacrificed 2hr later. Blood was collected for plasma TNF-a levels and lungs for measurement of VCAM-1 mRNA levels by quantitative RT-PCR: Compound 3 administered subcutaneously at a dose of 100 mg/kg/d, 2hr prior to LPS injection, inhibited TNF-a production by 80% and expression by 60% compared with vehicle controls.
Disease Modifying Anti-Rheumatic Drug (DMARD) activity in Rat Adjuvant Arthritis Compound 3 at twice daily subcutaneous doses of 60, 40 and 20 mg/kg/d was found to inhibit bone erosion in the ankle joint by histopathological analysis when administered prophylactically in the rat adjuvant arthritis model. The evaluation was carried out with hematoxylin and eosin stained ankle cross sections by a certified veterinary pathologist. When dosed prophylactically at doses of 100, 50 and 25 mg/kg/d, b.i.d., s.c., Compound 3 was also found to inhibit splenomegaly. Splenomegaly tracks with bone erosion in the adjuvant arthritis model and is thought to be a predictor of DMARDs activity.
Modifications and variations of the present invention relating to compounds and methods of treating diseases will be obvious to those skilled in the art from the foregoing detailed description of the invention. Such modifications and variations are intended to come within the scope of the appended claims.

Claims (50)

We Claim
1. A compound of Formula I

or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta., R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, -NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta., or one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. must be a carbon-carbon linked heterocyclic or heteroaryl;

wherein when one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta. is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;

wherein when one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta.
can be -OCH3;

with the proviso that R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha.
and R5.alpha. taken together, or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta.
and R5.beta. 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 R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha. and R5.alpha. taken together or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta. and R5.beta. taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2; provided that R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. cannot be -OC(R1)2C(O)OH;
or at least one of R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha. or one of R2.beta., R3.beta., R4.beta., R5.beta., R6.beta. 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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
2. The compound of Claim 1 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , -NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2) 2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and ~C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R2.beta., R3.beta., R4.beta., R5.beta., or R6.beta., or one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. must be a carbon-carbon linked heterocyclic or heteroaryl;
wherein when one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta. is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
wherein when one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta.
can be -OCH3;

with the proviso that R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha.
and R5.alpha. taken together, or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta.
and R5.beta. 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 R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha. and R5.alpha. taken together or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta. and R5.beta. taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and ~C(O)N(R2)2; provided that R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. cannot be ~OC(R1)2C(O)OH; and at least one of R2.alpha., R3.alpha., R4.alpha., or one of R2.beta., R3.beta., R4.beta. 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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , and NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and ~C(O)N(R2)2.
3. The compound of Claim 1 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta., R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R2.beta., R3.beta., R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha.
and R5.alpha. taken together, or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta.
and R5.beta. 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 R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha. and R5.alpha. taken together or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta. and R5.beta. taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2; provided that R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. cannot be -OC(R1)2C(O)OH;
and with the proviso that at least one of R2.alpha., R3.alpha., R4.alpha., R5.alpha., or R6.alpha. 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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
4. The compound of Claim 3 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta.,R5.beta. and R6.beta. 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, -NR~R8, -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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha.
and R5.alpha. taken together, or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta.
and R5.beta. 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 R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha. and R5.alpha. taken together or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta. and R5.beta. taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2; provided that R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta.
R5.beta. and R6.beta. cannot be -OC(R1)2C(O)OH;
and with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. 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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8,-N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
5. The compound of Claim 4 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. 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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
6. The compound of Claim 5 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be ~OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha., must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and ~C(O)N(R2)2.
7. The compound of Claim 6 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2) 2, -SO2NHC(O)NR7R8, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR78, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, and -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR78, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;

with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)2C(O)OH, (CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
8. The compound of Claim 7 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha. R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. 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),-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -N(R2)C(O)R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NHC(O)NR7R8, -NHC(O)N(R2)2, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2) 2, -SO2NHC(O)NR7R8, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, and -(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, -C(O)NR7R8, and -C(O)N(R2)2;

R1 is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, oxo, cyano, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR~RB, alkoxy, oxo, cyano, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)2C(O)OH, (CH2)y C(O)OH, wherein y is 1, 2, 3, 4, S, or 6;
wherein all R1, R2, R3 and R4 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, -C(O)NR7R8, and -C(O)N(R2)2.
9. The compound of Claim 8 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. 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(CHz)z)i-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)y 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, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, -C(O)NR7R8, and ~C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, -C(O)NR7R8, and ~C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be ~OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of tetrazol-5-yl, carboxy, -C(O)OR2, -C(CH3)2C(O)OH, (CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, -C(O)NR7R8, and ~C(O)N(R2)2.
10. The compound of Claim 9 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy, -C(O)OR2, -C(O)N(R2)2, and -C(O)NR7R8, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, -NR7R8, -C(O)NR7R8, and ~C(O)N(R2)2;

R2 is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, -NR7R8, alkoxy, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from carboxy or -C(O)OR2;
wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, -NR7R8, -C(O)NR7R8, and -C(O)N(R2)2.
11. The compound of Claim 10 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha. R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, and carboxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4.beta., R5.beta., or R6.beta., must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
12. The compound of Claim 11 or its pharmaceutically acceptable salt or ester, wherein:

R2.alpha., R3.alpha., R4.alpha., R5.alpha., and R6.alpha. are independently selected from the group consisting of hydrogen and carboxy;
R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
13. The compound of Claim 12 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., and R6.alpha. are independently selected from the group consisting of hydrogen and carboxy;
R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heteroaryl;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
14. The compound of Claim 13 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., and R6.alpha. are independently selected from the group consisting of hydrogen and carboxy;
R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH3O(CH2)2O(CH2)2-, wherein one of R4.beta., R5.beta. or R6.beta. must be selected from the group consisting of thiophen-2-yl, thiophen-3-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl, N-Boc-indol-3-yl, N-Boc-pyrrol-2-yl, and N-Boc-pyrrol-3-yl;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
15. The compound of Claim 14 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., and R6.alpha. are independently selected from the group consisting of hydrogen and carboxy;
R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. 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 R4.beta., R5.beta. or R6.beta. must be selected from the group consisting of thiophen-2-yl, benzo[b]thiophen-2-yl, indol-2-yl, 1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol-2'yl, and N-Boc-pyrrol-3-yl;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
16. The compound of Claim 15 selected from the group consisting of:
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;

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

4-{3E-[4-(1-Carboxy-1-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid;
4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester;
5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid;
4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt;
2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1 -carboxylic acid tert-butyl ester;
4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-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.
17. The compound of Claim 16 selected from the group consisting of:
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;
4-(3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid; and 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride,or its pharmaceutically acceptable salt or ester.
18. The compound of Claim 17 wherein the compound is 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid or its pharmaceutically acceptable salt or ester.
19. The compound of Claim 17 wherein the compound is 4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid, or its pharmaceutically acceptable salt or ester.
20. The compound of Claim 17 wherein the compound is 4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid; and,or its pharmaceutically acceptable salt or ester.
21. The compound of Claim 17 wherein the compound is 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride,or its pharmaceutically acceptable salt or ester.
22. The compound of Claim 5 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., and R6.alpha. are independently selected from the group consisting of hydrogen and carboxy;
R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, -NR7R8, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
23. The compound of Claim 22 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., and R6.alpha. are independently selected from the group consisting of hydrogen and carboxy;
R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH3O(CH2)2O(CH2)2-, wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked tetrahydrofuran-2-yl or dihydrofuran-2-yl;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be carboxy.
24. The compound of Claim 5 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(O)NHC(O)R2, -C(O)NHSO2R2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
25. The compound of Claim 5 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
26. The compound of Claim 5 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , and -NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
27. The compound of Claim 5 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and ~C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;

with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. must be selected from the group consisting of -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
28. The compound of Claim 3 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6p are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;
with the proviso that R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha.
and R5.alpha. taken together, or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta.
and R5.beta. taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, -NR7R8, and halo; and with the proviso that at least one of R2.alpha., R3.alpha., or R4.alpha. 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)y C(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, and NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
29. The compound of Claim 3 or its pharmaceutically acceptable salt or ester, wherein:
R2.alpha., R3.alpha., R4.alpha., R5.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, -C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, -(O(CH2)2)1-3-O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, -NHR2, N(R2)2, -NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8, NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, -SC(R1)2C(O)OH, -SC(R1)2C(O)OR2, -SCH2C(O)OH, -SCF2C(O)OH, -SO2NH2, -SO2NHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2)2, -SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, -C(O)OR2, -C(O)NH2, -C(O)NHR2, -C(O)N(R2)2, -C(O)NR7R8, -C(O)NHC(O)R2, -C(O)NHC(O)NHR2, -C(O)NHC(O)N(R2)2, -C(O)NHC(O)NR7R8, -C(O)NHSO2R2, -C(O)NHSO2NHR2, -C(O)NHSO2N(R2), -C(O)NHSO2NR7R8, -C(CH3)2C(O)OH, -(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, -PO2H2, -PO3H2, -P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2;

R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4.beta., R5.beta. or R6.beta. must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2.alpha., R3.alpha., R4.alpha., R5.alpha. or R6.alpha. can be -OCH3;

with the proviso that R2.alpha. and R3.alpha. taken together or R3.alpha. and R4.alpha. taken together or R4.alpha.
and R5.alpha. taken together or R2.beta. and R3.beta. taken together or R3.beta. and R4.beta. taken together or R4.beta.
and R5.beta. taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2; provided that R2.alpha., R3.alpha., R5.alpha., R6.alpha., R6.alpha., R2.beta., R3.beta., R4.beta., R5.beta. and R6.beta. cannot be -OC(R1)2C(O)OH; and with the proviso that at least one of R2.alpha., R3.alpha., or R.alpha., 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, -SONHR2, -SO2N(R2)2, SO2NR7R8, -SO2NHC(O)R2, -SR2, -SO2NHC(O)NHR2, -SO2NHC(O)N(R2) 2, -SO2NHC(O)NR7R8, -OC(R1)2C(O)OH, -OC(R1)2C(O)OR2, -OC(R1)2C(O)NH2, -OC(R1)2C(O)NHR2, -OC(R1)2C(O)N(R2)2, -OC(R1)2C(O)NR7R8, amino, -NHR2, N(R2)2, NR7R8, -NHC(R1)2C(O)OH, -NHC(R1)2C(O)OR2, -NHC(O)R2, -N(R2)C(O)R2, -NHC(O)OR2, -NHC(O)SR2, -NHSO2NHR2, -NHSO2R2, -NHSO2NR7R8, -N(C(O)NHR2)2, -NR2SO2R2, -NHC(O)NHR2, -NHC(O)NR7R8 , and NHC(O)N(R2)2, wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, -NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -C(O)NR7R8, and -C(O)N(R2)2.
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28 or 29, together with one or more pharmaceutically acceptable carrier.
31. A method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28 or 29.
32. The method of Claim 31, wherein the disorder is arthritis.
33. The method of Claim 31, wherein the disorder is rheumatoid arthritis.
34. The method of Claim 31, wherein the disorder is asthma.
35. The method of Claim 31, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.
36. The method of Claim 31, wherein the disorder is allergic rhinitis.
37. The method of Claim 31, wherein the disorder is chronic obstructive pulmonary disease.
38. The method of Claim 31, wherein the disorder is atherosclerosis.
39. The method of Claim 31, wherein the disorder is restinosis.
40. A method for inhibiting the expression of VCAM-1, comprising administering an effective amount of a compound of Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28 or 29.
41. A use of compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28 or 29 in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disorder.
42. The use of claim 41, wherein the disorder is arthritis.
43. The use of claim 41, wherein the disorder is rheumatoid arthritis.
44. The use of claim 41, wherein the disorder is asthma.
45. The use of claim 41, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.
46. The use of claim 41, wherein the disorder is allergic rhinitis.
47. The use of claim 41, wherein the disorder is chronic obstructive pulmonary disease.
48. The method of Claim 31, wherein the disorder is atherosclerosis.
49. The use of claim 41, wherein the disorder is restinosis.
50. A use of compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28 or 29 in the manufacture of a medicament for inhibiting the expression of VCAM-1.
CA002470931A 2001-12-19 2002-12-19 Chalcone derivatives and their use to treat diseases Abandoned CA2470931A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US34203401P 2001-12-19 2001-12-19
US60/342,034 2001-12-19
US38648202P 2002-06-05 2002-06-05
US60/386,482 2002-06-05
PCT/US2002/041336 WO2003053368A2 (en) 2001-12-19 2002-12-19 Chalcone derivatives and their use to treat diseases

Publications (1)

Publication Number Publication Date
CA2470931A1 true CA2470931A1 (en) 2003-07-03

Family

ID=26992787

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002470931A Abandoned CA2470931A1 (en) 2001-12-19 2002-12-19 Chalcone derivatives and their use to treat diseases

Country Status (13)

Country Link
US (2) US7094801B2 (en)
EP (1) EP1465854A4 (en)
JP (1) JP2005516941A (en)
CN (1) CN1596240A (en)
AU (1) AU2002360763A1 (en)
BR (1) BR0215240A (en)
CA (1) CA2470931A1 (en)
HU (1) HUP0500165A2 (en)
IL (1) IL162533A0 (en)
MX (1) MXPA04005864A (en)
RU (1) RU2004121898A (en)
TW (1) TW200303302A (en)
WO (1) WO2003053368A2 (en)

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1465854A4 (en) 2001-12-19 2005-06-08 Atherogenics Inc Chalcone derivatives and their use to treat diseases
CN101413143B (en) 2002-12-19 2013-09-18 斯克里普斯研究学院 Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding
WO2004056727A2 (en) * 2002-12-19 2004-07-08 Atherogenics, Inc. Process of making chalcone derivatives
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
US7279576B2 (en) 2002-12-31 2007-10-09 Deciphera Pharmaceuticals, Llc Anti-cancer medicaments
WO2004108094A2 (en) * 2003-06-06 2004-12-16 Atherogenics, Inc. Sulfonamide-substituted chalcone derivatives and their use to treat diseases
US7504401B2 (en) * 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
EP1755585A4 (en) * 2004-05-20 2009-04-01 Scripps Research Inst Transthyretin stabilization
US20060063828A1 (en) * 2004-06-28 2006-03-23 Weingarten M D 1,2-Bis-(substituted-phenyl)-2-propen-1-ones and pharmaceutical compositions thereof
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
KR20070083484A (en) 2004-07-14 2007-08-24 피티씨 테라퓨틱스, 인크. Methods for treating hepatitis c
EP1781289A1 (en) 2004-07-22 2007-05-09 PTC Therapeutics, Inc. Thienopyridines for treating hepatitis c
TWI444187B (en) 2005-01-25 2014-07-11 Synta Pharmaceuticals Corp Thiophene compounds for inflammation and immune-related uses
JP2006316027A (en) * 2005-05-16 2006-11-24 Mitsui Chemicals Inc 1, 3-dialkyl-2-imidazolidinone and method for purifying the same
CN100336797C (en) * 2005-08-19 2007-09-12 浙江大学 Tetra substituted chalcone derivative and preparing method and use
US20080280891A1 (en) * 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
DK2035369T3 (en) * 2006-07-05 2014-10-06 Fibrotech Therapeutics Pty Ltd THERAPEUTIC
WO2008034016A2 (en) * 2006-09-15 2008-03-20 Foldrx Pharmaceuticals, Inc. Assays for detecting native-state proteins and identifying compounds that modulate the stability of native-state proteins
JP5343267B2 (en) * 2006-10-17 2013-11-13 スティーフェル・ラボラトリーズ・インコーポレーテッド Talarozole metabolite
US8278345B2 (en) 2006-11-09 2012-10-02 Probiodrug Ag Inhibitors of glutaminyl cyclase
SI2091948T1 (en) 2006-11-30 2012-07-31 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
KR20090114427A (en) * 2007-01-31 2009-11-03 바이오액티브스, 인코포레이티드 Methods of reducing 15-F2t-IsoP levels in mammals
CA2679446C (en) 2007-03-01 2016-05-17 Probiodrug Ag New use of glutaminyl cyclase inhibitors
EP2865670B1 (en) 2007-04-18 2017-01-11 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
MX337320B (en) * 2007-12-21 2016-01-06 Fibrotech Therapeutics Pty Ltd Halogenated analogues of anti-fibrotic agents.
CN102438988B (en) * 2009-04-21 2015-06-24 内尔维阿诺医学科学有限公司 Resorcinol derivatives as hsp90 inhibitors
WO2011009826A2 (en) 2009-07-21 2011-01-27 ADAMED Sp.z o.o. Novel chalcone derivatives with cytotoxic activity
PL2475428T3 (en) 2009-09-11 2015-12-31 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
CN105153188B (en) 2009-10-22 2018-06-01 法博太科制药有限公司 The fused ring analogs of antifibrotic agents
US8889874B2 (en) 2010-01-12 2014-11-18 Council Of Scientific And Industrial Research Imidazolone-chalcone derivatives as potential anticancer agent and process for the preparation thereof
EP2542549B1 (en) 2010-03-03 2016-05-11 Probiodrug AG Inhibitors of glutaminyl cyclase
CA2789440C (en) 2010-03-10 2020-03-24 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
US8530670B2 (en) 2011-03-16 2013-09-10 Probiodrug Ag Inhibitors
US9229007B2 (en) 2011-08-03 2016-01-05 Portland State University Fluorescence detection of cysteine and homocysteine
CA2847293C (en) 2011-09-16 2017-03-28 Richard Frederic Labaudiniere Solid forms of a transthyretin dissociation inhibitor
WO2013102145A1 (en) 2011-12-28 2013-07-04 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
EP3141542B1 (en) 2011-12-28 2020-05-27 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US8461179B1 (en) 2012-06-07 2013-06-11 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
WO2014086697A1 (en) * 2012-12-06 2014-06-12 F. Hoffmann-La Roche Ag Substituted thiazole compounds
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
EP2968299B1 (en) 2013-03-15 2021-01-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
AP2015008721A0 (en) 2013-03-15 2015-09-30 Global Blood Therapeutics Inc Compounds and uses thereof for the modulation of hemoglobin
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US20140274961A1 (en) 2013-03-15 2014-09-18 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN105051044A (en) 2013-03-15 2015-11-11 全球血液疗法股份有限公司 Compounds and uses thereof for the modulation of hemoglobin
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
EA202092627A1 (en) 2013-11-18 2021-09-30 Глобал Блад Терапьютикс, Инк. COMPOUNDS AND THEIR APPLICATIONS FOR HEMOGLOBIN MODULATION
KR102588476B1 (en) 2014-02-07 2023-10-11 글로벌 블러드 테라퓨틱스, 인크. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
CN103755541B (en) * 2014-02-19 2015-09-02 厦门大学 One class chalcone derivative and its production and use
MA41841A (en) 2015-03-30 2018-02-06 Global Blood Therapeutics Inc ALDEHYDE COMPOUNDS FOR THE TREATMENT OF PULMONARY FIBROSIS, HYPOXIA, AND AUTOIMMUNE AND CONNECTIVE TISSUE DISEASES
MX2018006832A (en) 2015-12-04 2018-11-09 Global Blood Therapeutics Inc Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl) pyridin-3-yl)methoxy)benzaldehyde.
AR108435A1 (en) 2016-05-12 2018-08-22 Global Blood Therapeutics Inc PROCESS TO SYNTHETIZE 2-HYDROXI-6 - ((2- (1-ISOPROPIL-1H-PIRAZOL-5-IL) -PIRIDIN-3-IL) METOXI) BENZALDEHYDE
CN106279082B (en) * 2016-08-02 2019-02-01 浙江大学 Substituted furans chalcone derivative and preparation method thereof
TWI778983B (en) 2016-10-12 2022-10-01 美商全球血液治療公司 Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
JP7185631B2 (en) 2017-02-03 2022-12-07 サータ セラピューティクス プロプライエタリー リミテッド antifibrotic compound
PL232668B1 (en) * 2017-07-31 2019-07-31 Univ Przyrodniczy We Wroclawiu 2'-Amino-4-carboxychalcone and method for obtaining 2'-amino-4-carboxychalcone
PL232667B1 (en) * 2017-07-31 2019-07-31 Univ Przyrodniczy We Wroclawiu 3'-Amino-4-carboxychalcone and method for obtaining 3'-amino-4-carboxychalcone
PL3461819T3 (en) 2017-09-29 2020-11-30 Probiodrug Ag Inhibitors of glutaminyl cyclase
CN108440278B (en) * 2018-03-07 2021-01-12 中国计量大学 Dicarboxy chalcone compound and its application in preparing anti-inflammatory medicine
WO2020072377A1 (en) 2018-10-01 2020-04-09 Global Blood Therapeutics, Inc. Modulators of hemoglobin for the treatment of sickle cell disease
CN109651226B (en) * 2019-01-22 2022-06-07 中美（河南）荷美尔肿瘤研究院 Chalcone indole derivative, preparation method and application thereof
CN109705017B (en) * 2019-01-22 2022-09-20 中美（河南）荷美尔肿瘤研究院 Application of chalcone indole derivative in preparation of antitumor drugs
KR20220045189A (en) 2019-08-12 2022-04-12 데시페라 파마슈티칼스, 엘엘씨. How to treat gastrointestinal stromal tumors
WO2021030405A1 (en) 2019-08-12 2021-02-18 Deciphera Pharmaceuticals, Llc Ripretinib for treating gastrointestinal stromal tumors
EP4084778B1 (en) 2019-12-30 2023-11-01 Deciphera Pharmaceuticals, LLC Amorphous kinase inhibitor formulations and methods of use thereof
KR20220123058A (en) 2019-12-30 2022-09-05 데시페라 파마슈티칼스, 엘엘씨. 1-(4-Bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl ) -3-Phenylurea composition
CN114105753B (en) * 2021-09-17 2024-02-20 温州医科大学 Fisetin derivative and application thereof in preparation of anti-inflammatory drugs
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Family Cites Families (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE787838R (en) 1971-08-25 1973-02-22 Delalande Sa NEW DERIVATIVES OF CINNAMOYL-5 BENZOFURANNE, THEIR PROCESS FOR PREPARATION AND THEIR USE IN THERAPEUTICS
FR2175634A1 (en) 1972-03-16 1973-10-26 Delalande Sa Carboxymethoxybenzofurans derivs - analgesic antiinflammatory hypotensive activity etc
FR2217001B2 (en) 1973-02-12 1976-03-12 Delalande Sa
JPS5297950A (en) 1976-02-13 1977-08-17 Taisho Pharmaceut Co Ltd Chalconeether derivatives
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
DE3415033C2 (en) * 1983-04-20 1986-04-03 Hitachi Chemical Co., Ltd. 4'-Azidobenzal-2-methoxyacetophenone, process for its preparation and photosensitive composition containing it
JPS6310720A (en) 1986-07-01 1988-01-18 Nippon Kayaku Co Ltd 5-lipoxygenase inhibitor and anti-allergic agent
DE3627673A1 (en) 1986-08-14 1988-02-25 Bayer Ag METHOD FOR PRODUCING OPTICALLY ACTIVE 2-HYDROXYETHYL AZOL DERIVATIVES
US4794205A (en) 1986-12-10 1988-12-27 Hoechst Celanese Corporation Method for producing alkenylthiophenols and their esters
US4904697A (en) 1987-04-09 1990-02-27 Merrell Dow Pharmaceuticals Inc. Controlling the growth of certain tumor tissue with chalcone derivatives
EP0307762A1 (en) 1987-09-16 1989-03-22 F. Hoffmann-La Roche Ag Acrylic-acid amides and their use as fungicides
US5217999A (en) 1987-12-24 1993-06-08 Yissum Research Development Company Of The Hebrew University Of Jerusalem Styryl compounds which inhibit EGF receptor protein tyrosine kinase
KR0139296B1 (en) * 1988-11-21 1998-05-15 가와무라 시게꾸니 Chalcone derivatives and process for producing the same
FR2663633B1 (en) * 1990-06-22 1994-06-17 Adir NEW CHALCONES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US5155250A (en) 1990-07-05 1992-10-13 Merrell Dow Pharmaceuticals Inc. 2,6-di-alkyl-4-silyl-phenols as antiatheroscerotic agents
ZA917369B (en) 1990-09-20 1992-06-24 Merrell Dow Pharma Calcium uptake inhibitors
JPH04217621A (en) 1990-10-01 1992-08-07 Shiseido Co Ltd Cosmetic
US6159988A (en) 1992-01-16 2000-12-12 Hoeschst Aktiengesellschaft Arylcycloalkyl derivatives, their production and their use
JPH0692950A (en) 1992-09-16 1994-04-05 Kanegafuchi Chem Ind Co Ltd Production of epoxy compound
JPH06116206A (en) 1992-10-02 1994-04-26 Morinaga Milk Ind Co Ltd Chalcone derivative and its use
US5807884A (en) 1992-10-30 1998-09-15 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5821260A (en) 1992-10-30 1998-10-13 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5380747A (en) 1992-10-30 1995-01-10 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
US5631365A (en) 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
DE69434720T2 (en) 1993-12-10 2007-05-16 Aventis Inc. Use of 2,6-dialkyl-4-silyl-phenol derivatives for the treatment of xanthoma
FR2713635B1 (en) 1993-12-15 1996-01-05 Cird Galderma New bi-aromatic propynyl compounds, pharmaceutical and cosmetic compositions containing them and uses.
JPH07330814A (en) 1994-06-06 1995-12-19 Hitachi Chem Co Ltd Photoinitiator, photosensitive composition, photosensitive material and production of relief pattern
DK0781278T3 (en) 1994-09-13 2001-04-17 Monsanto Co New benzothiepines which have activity as inhibitors of ileal bile acid transport and taurocholate uptake
IT1271301B (en) 1994-12-20 1997-05-27 Indena Spa NATURAL AND SYNTHETIC CALCONES AND THEIR ESTERS WITH ANTI-PROLIFERATIVE ACTIVITY IN CANCER OF THE UTERUS, OVARIAN AND BREAST AND FORMULATIONS CONTAINING THEM
DE4446329A1 (en) 1994-12-23 1996-06-27 Basf Ag Salts of aromatic hydroxyl compounds and their use as brighteners
KR960022486A (en) 1994-12-29 1996-07-18 김준웅 New Thiazolidin-4-one Derivatives
DE19500838A1 (en) 1995-01-13 1996-07-18 Basf Ag Process for the preparation of 3,5-diarylpyrazoles
AU692090B2 (en) 1995-04-13 1998-05-28 Taiho Pharmaceutical Co., Ltd. Novel 4,6-diarylpyrimidine derivatives and salts thereof
US5792787A (en) 1995-06-07 1998-08-11 Emory University Treatment for atherosclerosis and other cardiovascular and inflammatory diseases
AU6966696A (en) 1995-10-05 1997-04-28 Warner-Lambert Company Method for treating and preventing inflammation and atherosclerosis
IL126038A0 (en) 1996-03-11 1999-05-09 Searle & Co Novel benzothiepines and derivatives thereof and pharmaceutical compositions comprising them
US5608095A (en) 1996-04-30 1997-03-04 Hoechst Marion Roussel, Inc. Alkyl-4-silyl-phenols and esters thereof as antiatherosclerotic agents
JP3895404B2 (en) 1996-05-17 2007-03-22 興和株式会社 Chalcone derivative and pharmaceutical containing the same
HRP970330B1 (en) 1996-07-08 2004-06-30 Bayer Ag Cycloalkano pyridines
AR008789A1 (en) 1996-07-31 2000-02-23 Bayer Corp PIRIDINES AND SUBSTITUTED BIPHENYLS
DE19648793A1 (en) 1996-11-26 1998-05-28 Basf Ag New benzamides and their application
JP2894445B2 (en) 1997-02-12 1999-05-24 日本たばこ産業株式会社 Compounds effective as CETP activity inhibitors
WO1998040375A2 (en) 1997-03-11 1998-09-17 G.D. Searle & Co. COMBINATION OF ILEAL BILE ACID TRANSPORT INHIBITING BENZOTHIEPINES AND HMG Co-A REDUCTASE INHIBITORS
EA200800375A1 (en) 1997-05-14 2008-06-30 Атеродженикс, Инк. COMPOUNDS AND METHODS OF INHIBITING VCAM-1 EXPRESSION
US6423740B1 (en) 1997-06-19 2002-07-23 Indena S.P.A. Chalcones having antiproliferative activity
WO1999000114A2 (en) 1997-06-26 1999-01-07 Statens Serum Institut Biologically active 1,3-bis-aromatic-prop-2-en-1-ones, 1,3-bis-aromatic-propan-1-ones, and 1,3-bis-aromatic-prop-2-yn-1-ones
DE19741051A1 (en) 1997-09-18 1999-03-25 Bayer Ag New tetrahydroquinoline derivatives useful in treatment of raised lipid levels and arteriosclerosis
MA24643A1 (en) 1997-09-18 1999-04-01 Bayer Ag SUBSTITUTED TETRAHYDRO-NAPHTHALENES AND SIMILAR COMPOUNDS
DE19741399A1 (en) 1997-09-19 1999-03-25 Bayer Ag New tetrahydroquinoline derivatives useful in treatment of elevated lipid levels and arteriosclerosis
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
US6147089A (en) 1998-09-17 2000-11-14 Pfizer Inc. Annulated 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
US6147090A (en) 1998-09-17 2000-11-14 Pfizer Inc. 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
GT199900147A (en) 1998-09-17 1999-09-06 1, 2, 3, 4- TETRAHIDROQUINOLINAS 2-SUBSTITUTED 4-AMINO SUBSTITUTED.
WO2000018723A1 (en) 1998-09-25 2000-04-06 Monsanto Company Substituted n-aliphatic-n-aromatic tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
WO2000018721A1 (en) 1998-09-25 2000-04-06 Monsanto Company Substituted polycyclic aryl and heteroaryl tertiary-heteroalkylamines useful for inhibiting cholesteryl ester transfer protein activity
PT1140187E (en) 1998-12-23 2004-01-30 Searle Llc COMBINATIONS OF AN INHIBITOR OF IBAT AND AN INHIBITOR OF MTP FOR CARDIOVASCULAR INDICATIONS
CA2362375A1 (en) 1999-02-11 2000-08-17 Younghong Song Alkenyl and alkynyl compounds as inhibitors of factor xa
US6677350B1 (en) * 1999-09-22 2004-01-13 Advanced Life Sciences, Inc. Beta-fluoroethyl thiourea compounds and use
HN2000000203A (en) 1999-11-30 2001-06-13 Pfizer Prod Inc PROCEDURE FOR OBTAINING 1,2,3,4-TETRAHYDROQUINOLINS 4-CARBOXYAMIN-2-SUBSTITUTED.
US6462075B1 (en) 1999-12-23 2002-10-08 The University Of Georgia Research Foundation, Inc. Chalcone and its analogs as agents for the inhibition of angiogensis and related disease states
GB0007401D0 (en) * 2000-03-27 2000-05-17 Cancer Res Campaign Tech Substituted chalcones as therapeeutic compounds
CN1447804A (en) 2000-06-20 2003-10-08 阿特罗吉尼克斯公司 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders
BR0115474A (en) 2000-11-17 2006-01-31 Idenix Cayman Ltd Composition and method for inhibiting hiv transmission using topically applied 6-benzyl-4-oxopyrimidines
CA2467237C (en) * 2001-11-15 2011-09-20 Herman Jan Tijmen Coelingh Bennink Method of preventing or treating benign gynaecological disorders
EP1465854A4 (en) 2001-12-19 2005-06-08 Atherogenics Inc Chalcone derivatives and their use to treat diseases
WO2003053359A2 (en) 2001-12-19 2003-07-03 Atherogenics, Inc. 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
WO2004056727A2 (en) 2002-12-19 2004-07-08 Atherogenics, Inc. Process of making chalcone derivatives

Also Published As

Publication number Publication date
WO2003053368A2 (en) 2003-07-03
MXPA04005864A (en) 2004-10-29
CN1596240A (en) 2005-03-16
BR0215240A (en) 2004-10-26
IL162533A0 (en) 2005-11-20
TW200303302A (en) 2003-09-01
RU2004121898A (en) 2006-01-20
JP2005516941A (en) 2005-06-09
EP1465854A2 (en) 2004-10-13
HUP0500165A2 (en) 2006-09-28
US7094801B2 (en) 2006-08-22
WO2003053368A3 (en) 2003-09-18
AU2002360763A1 (en) 2003-07-09
EP1465854A4 (en) 2005-06-08
US20040048858A1 (en) 2004-03-11
US20060189549A1 (en) 2006-08-24

Similar Documents

Publication Publication Date Title
CA2470931A1 (en) Chalcone derivatives and their use to treat diseases
US20040181075A1 (en) Process of making chalcone derivatives
US7329675B2 (en) Substituted azabicyclic compounds
US8487009B2 (en) 1,2-diphenylethene derivatives for treatment of immune diseases
US20110070297A1 (en) Glucokinase activators
US20060205941A1 (en) Histone deacetylase inhibitors
US20070149495A1 (en) Histone deacetylase inhibitors
NZ523443A (en) 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders
US20030236298A1 (en) 1,3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders
WO2009109999A1 (en) Novel protein tyrosine phosphatase - ib inhibitors
WO2003053359A2 (en) 1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
WO1999000373A1 (en) Benzimidazole derivatives
US7329679B2 (en) 1,2 Diarylbenzimidazoles and their pharmaceutical use
AU2002226225A1 (en) Novel 1,2-diphenylethene derivatives for treatment of immune diseases
JPH10182550A (en) Hydroxybenzoic acid derivative and medicine containing the same as active ingredient
CN110885318B (en) Benzoxazole derivative and preparation method and application thereof
JPH10147568A (en) Naphthalene derivative and medicine containing the same as active ingredient
EP2842937A1 (en) Amine compound and use thereof for medical purposes
EP0633248A1 (en) Butenoic acid derivatives
WO2010025558A1 (en) Triazolium and imidazolium salts and uses thereof as antimalarials
WO2018159650A1 (en) Guanidine derivative and medicinal use thereof
JP2003534245A (en) Fused ring imidazoles as histamine H3 receptor ligands

Legal Events

Date Code Title Description
EEER Examination request
FZDE Discontinued