Chalcone derivatives and their use to treat diseases

• US 20040048858A1
• Filed: 12/19/2002
• Published: 03/11/2004
• Est. Priority Date: 12/19/2001
• Status: Active Grant

• Current Assignee: Salutria Pharmaceuticals, LLC
• Original Assignee: Charles Q. Meng, James A. Sikorski, Kimberly J. Worsencroft, Liming Ni, Weingarten M. David
• Inventors: Weingarten, M. David, Meng, Charles Q., Sikorski, James A., Ni, Liming, Worsencroft, Kimberly J.
• Granted Patent: US 7,094,801 B2
• Time in Patent Office: Days
• US Class Current: 514/233.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 45/63 by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• CPC Class Codes: C07C 47/575 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 207/333 : Radicals substituted by oxygen or sulfur atoms
• CPC Class Codes: C07D 209/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 213/50 : Ketonic radicals
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 235/18 : with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/52 : Two oxygen atoms
• CPC Class Codes: C07D 241/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 261/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/24 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/28 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/46 : Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
• CPC Class Codes: C07D 307/80 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 333/22 : Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/56 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 409/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07H 15/203 : Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems

Abstract

The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula

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

Claims

1. A compound of Formula I

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the 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 R^2β

, R^3β

, R^4β

, R^5β

or R^6β

, or one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

must be a carbon-carbon linked heterocyclic or heteroaryl;

wherein when one of R^2β

, R^3β

, R^4β

, R^5β

or R^6β

is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

wherein when one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

is a carbon-carbon linked heterocyclic or heteroaryl, only one of R^2β

, R^3β

, R^4β

, R^5β

or R^6β

can be —

OCH₃;

with the proviso that R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together, or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —

NR⁷R⁸, and halo;

or

R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

provided that R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

cannot be —

OC(R¹)₂C(O)OH; and

at least one of R^2α

, R^3α

, R^4α

, or one of R^2β

, R^3β

, R^4β

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, and —

NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^2β

, R^3β

, R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together, or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —

NR⁷R⁸, and halo;

or

R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

provided that R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

cannot be —

OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^2α

, R^3α

, R^4α

, R^5α

, or R^6α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, and —

NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

P(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together, or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —

NR⁷R⁸, and halo;

or

R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

provided that R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

cannot be —

OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)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:

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

P(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, and —

NHC(O)N(R²)₂;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

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, beteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroaxyakyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, and —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consistiing of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

N(R²)C(O)R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, and —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, oxo, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(R²)₂, —

NR⁷R⁸, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(CH₃)₂C(O)OH, and —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzoftlsed ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of tetrazol-5-yl, carboxy, —

C(O)OR², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;

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

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selectef 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(²)₂;

R² is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, —

NR⁷R⁸, alkoxy, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

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

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from carboxy or —

C(O)OR²;

wherein all R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, —

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, and carboxy, all of which can be optionally substituted;

by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is lower alkyl;

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

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

, or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy.

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

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and carboxy;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is lower alkyl;

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

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy.

13. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and carboxy;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is lower alkyl;

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

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heteroaryl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy.

14. The compound of claim 13 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and carboxy;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

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

,

wherein one of R^4β

, R^5β

or R^6β

must be selected from the group consisting of thiophen-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 R^2α

, R^3α

, or R^4α

must be carboxy.

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

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and carboxy;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

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

wherein one of R^4β

, R^5β

or R^6β

must be selected from the group consisting of thiophen-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 R^2α

, R^3α

, or R^4α

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:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and carboxy;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —

NR⁷R⁸, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is lower alkyl;

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

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy.

23. The compound of claim 22 or its pharmaceutically acceptable salt or ester, wherein:

R^2α

, R^3α

, R^4α

, R^5α

, and R^6α

are independently selected from the group consisting of hydrogen and carboxy;

R^2β

, R^3β

, R^4β

, R^5β

and R^6β

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

,

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked tetrahydrofuran-2-yl or dihydrofuran-2-yl;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be carboxy.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

P(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

(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:

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

P(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NH(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-mernbered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)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:

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

P(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸;

wherein all R¹, R², R⁷ and R⁸ substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂.

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

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl loweralkyl, 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 R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together, or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —

NR⁷R⁸, and halo; and

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂NHR₂, —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)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:

R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)₂-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —

C(O)R², R²C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —

(O(CH₂)₂)_1-3—

O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —

NHR², N(R²)₂, —

NR⁷R⁸, —

NHC(R¹)₂C(O)OH, —

NHC(R¹)₂C(O)OR², —

NHC(O)R², —

N(R²)C(O)R², —

NHC(O)OR², —

NHC(O)SR², —

NHSO₂NHR², —

NHSO₂R², —

NHSO₂NR⁷R⁸, —

N(C(O)NHR²)₂, —

NR²SO₂R², —

NHC(O)NHR², —

NHC(O)NR⁷R⁸, —

NHC(O)N(R²)₂, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂R², —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —

PO₂H₂, —

PO₃H₂, —

P(R²)O₂H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R¹ is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R² is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

R⁷ and R⁸ are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

wherein one of R^4β

, R^5β

or R^6β

must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R^2α

, R^3α

, R^4α

, R^5α

or R^6α

can be —

OCH₃;

with the proviso that R^2α

and R^3α

taken together or R^3α

and R^4α

taken together or R^4α

and R^5α

taken together or R^2β

and R^3β

taken together or R^3β

and R^4β

taken together or R^4β

and R^5β

taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —

NR⁷R⁸, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —

C(O)NR⁷R⁸, and —

C(O)N(R²)₂;

provided that R^2α

, R^3α

, R^4α

, R^5α

, R^6α

, R^2β

, R^3β

, R^4β

, R^5β

and R^6β

cannot be —

OC(R¹)₂C(O)OH; and

with the proviso that at least one of R^2α

, R^3α

, or R^4α

must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —

C(O)OR², —

C(O)NH₂, —

C(O)NHR², —

C(O)N(R²)₂, —

C(O)NR⁷R⁸, —

C(O)NHC(O)NHR², —

C(O)NHC(O)N(R²)₂, —

C(O)NHC(O)NR⁷R⁸, —

C(O)NHSO₂NHR², —

C(O)NHSO₂N(R²), —

C(O)NHSO₂NR⁷R⁸, —

C(O)NHC(O)R², —

C(O)NHSO₂R², —

C(CH₃)₂C(O)OH, —

(CH₂)_yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —

SC(R¹)₂C(O)OH, —

SC(R¹)₂C(O)OR², —

SCH₂C(O)OH, —

SCF₂C(O)OH, —

SO₂NH₂, —

SO₂NHR₂, —

SO₂N(R²)₂, SO₂NR⁷R⁸, —

SO₂NHC(O)R², —

SR₂, —

SO₂NHC(O)NHR², —

SO₂NHC(O)N(R²)₂, —

SO₂NHC(O)NR⁷R⁸, —

OC(R¹)₂C(O)OH, —

OC(R¹)₂C(O)OR², —

OC(R¹)₂C(O)NH₂, —

OC(R¹)₂C(O)NHR², —

OC(R¹)₂C(O)N(R²)₂, —

OC(R¹)₂C(O)NR⁷R⁸, amino, —

NHR², N(R²)₂, NR⁷R⁸, —

NHC(R¹)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.