Chalcone derivatives and their use to treat diseases
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Abstract
The invention relates to compounds, pharmaceutical compositions and methods of using compounds of the general formula
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Citations
40 Claims
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1. A compound of Formula I
- View Dependent Claims (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, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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2. The compound of claim 1 or its pharmaceutically acceptable salt or ester, wherein:
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R2α
, R3α
R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2 R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R1)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R2β
, R3β
, R4β
, R5β
or R62 , or one of R2α
, R3α
, R4α
, R5α
or R6α
must be a carbon-carbon linked heterocyclic or heteroaryl;
wherein when one of R2β
, R3β
, R4β
, R5β
or R6β
is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
wherein when one of R2α
, R3α
, R4α
, R5α
or R6α
is a carbon-carbon linked heterocyclic or heteroaryl, only one of R2β
, R3β
, R4β
, R5β
or R6β
can be —
OCH3;
with the proviso that R2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together, or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —
NR7R8, and halo;
orR2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R1)2;
provided that R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
cannot be —
OC(R1)2C(O)OH; and
at least one of R2α
R3α
, R4α
, or one of R2β
, R3β
, R4β
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2—
SO2NHC(O)NR7R8, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2 SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2.
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3. The compound of claim 1 or its pharmaceutically acceptable salt or ester, wherein:
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R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R2β
, R3β
, R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that R2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together, or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —
NR7R8, and halo;
orR2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
provided that R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
cannot be —
OC(R1)2C(O)OH; and
with the proviso that at least one of R2α
, R3α
, R4α
, R5α
, or R6α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl,-cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R2)2.
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4. The compound of claim 3 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R1)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that R2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together, or R2β
and R3β
taken together or R3β and
R4β
taken together or R4β
and R5β
taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —
NR7R8, and halo;
orR2α
and R3α
taken together of R3α
and R4α
taken together or R4α
and R5α
taken together or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
provided that R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R6β
and R6β
cannot be —
OC(R1)2C(O)OH; and
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R2)2.
-
-
5. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2 SO2R2, —
NHC(O)NHR7, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R1)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH—
SCF2C(O)OH—
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
6. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R1)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
7. The compound of claim 6 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R1)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, and —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
(O)N(R2)2.
-
-
8. The compound of claim 7 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
N(R2)C(O)R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R1)2, —
SO2NHC(O)NR7R8, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, and —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, oxo, cyano, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
9. The compound of claim 8 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, alkyl, lower alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, heterocyclicamino lower alkyl, hydroxyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, dialkylamino, N(R2)2, —
NR7R8, tetrazol-5-yl, carboxy, —
C(O)OR, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(CH3)2C(O)OH, and —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 8-membered monocyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6;
wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
10. The compound of claim 9 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, lower alkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, heteroaryl lower alkoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, carboxy, —
C(O)OR2, —
C(O)N(R2)2, and —
C(O)NR7R8, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, hydroxy, hydroxyalkyl, heterocyclic, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, and lower alkyl, wherein all may be substituted by one or more selected from the group consisting of halo, lower alkyl, —
NR7R8, alkoxy, —
C(O)NR7R8, and —
C(O)N(R1)2;
R7 and R8 are independently alkyl, and linked together forming a 5- to 7-membered monocyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from carboxy or —
C(O)OR2;
wherein all R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, lower alkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
11. The compound of claim 10 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, heteroaryl lower alkoxy, heterocyclic lower alkoxy, and carboxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
12. The compound of claim 11 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, and R6α
are independently selected from the group consisting of hydrogen and carboxy;
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
13. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, and R6α
are independently selected from the group consisting of hydrogen and carboxy;
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, heteroaryl, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heteroaryl;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
14. The compound of claim 13 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, and R6α
are independently selected from the group consisting of hydrogen and carboxy;
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH3O(CH2)2O(CH2)2—
,and wherein one of R4β
, R5β
or R6β
must be selected from the group consisting of thiophen-2-yl, thiophen-3-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, indol-2-yl, indol-3-yl, pyrrol-2-yl, pyrrol-3-yl, 1-methyl-indol-2-yl, 1-methyl-indol-3-yl, N-Boc-indol-2-yl, N-Boc-indol-3-yl, N-Boc-pyrrol-2-yl, and N-Boc-pyrrol-3-yl;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
15. The compound of claim 14 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5, and R6α
are independently selected from the group consisting of hydrogen and carboxy;
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, methoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, and CH3O(CH2)2O(CH2)2;
wherein one of R4β
, R5β
or R6β
must be selected from the group consisting of thiophen-2-yl, benzo[b]thiophen-2-yl, indol-2-yl, 1-methyl-indol-2-yl, N-Boc-indol-2-yl, N-Boc-pyrrol-2′
yl, and N-Boc-pyrrol-3-yl;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
16. The compound of claim 15 selected from the group consisting of:
-
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid;
4-[3E-(3,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt;
4-[3E-(4-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid, sodium salt;
4-[3-{4-(thien-2-yl)-phenyl}-3-oxo-E-propenyl]-benzoic acid;
4-[3-(2-Methoxy-4-thiophen-2-yl-phenyl)-3-oxo-E-propenyl]-benzoic acid;
4-[3E-(4-Pyrrolidin-1-yl-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-{4-Fluoro-3-(thiophen-2-yl)-phenyl}-acryloyl]-benzoic acid;
4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid;
4-[3E-(2-Fluoro-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-pyrimidin-5-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[5-(3,5-Dimethyl-isoxazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-[3E-(4-Methoxy-2-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-indole-1-carboxylic acid tert-butyl ester;
4-[3E-(2,6-Dimethoxy-4-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-[3E-(2,4-Dimethoxy-6-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[2,4-Dimethoxy-5-(5-methyl-thiophen-2-yl)-phenyl]-acryloyl}-benzoic acid;
4-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(3-Thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
3-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(3-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2-Methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-pyrazin-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[4-(1-Carboxy-1-methyl-ethoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
2-[3E-(4-Methoxy-3-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid;
4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid methyl ester;
5-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-thiophene-2-carboxylic acid;
4-[3E-(4-Ethoxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Hydroxy-2-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-thiazol-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid, sodium salt;
2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-phenyl}-pyrrole-1-carboxylic acid tert-butyl ester;
4-[3E-(2-Hydroxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[2-(1-Carboxy-1-methyl-ethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-S-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;
2 4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-{3E-[2-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
4-[3E-(2-Pyrrolidin-1-yl-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
4-{3E-[2-(3-Morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;
4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride;
4-[3E-(2-Dimethylcarbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-[3E-(4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acryloyl}-benzoic acid;
4-{3E-[5-(1H-Benzoimidazol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-[3E-(2-Carbamoylmethoxy-4-methoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid;
4-(3E-{4-Methoxy-2-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic acid, hydrochloride;
4-{3E-[2,4-Dimethoxy-5-(1H-pyrazol-4-yl)-phenyl]-acryloyl}-benzoic acid;
4-{3E-[2,4-Dimethoxy-5-(2H-tetrazol-5-yl)-phenyl]-acryloyl}-benzoic acid;
4-{3E-[5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
2-{4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-2-methyl-propionic acid;
4-{3E-[5-(2-Cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid, hydrochloride;
4-{3E-[5-(4-Isobutyl-4H-[1,2,4]triazol-3-yl)-2,4-dimethoxy-phenyl]-acryloyl}-benzoic acid;
4-{3E-[2,4-Dimethoxy-5-(1-methyl-1H-indol-2-yl)-phenyl]-acryloyl}-benzoic acid; and
4-[3E-(5-Benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid ethyl ester, or its pharmaceutically acceptable salt or ester.
-
-
17. The compound of claim 16 selected from the group consisting of:
-
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid;
4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid;
4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid; and
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride, or its pharmaceutically acceptable salt or ester.
-
-
18. The compound of claim 17 wherein the compound is 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid or its pharmaceutically acceptable salt or ester.
-
19. The compound of claim 17 wherein the compound is 4-[3E-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid, or its pharmaceutically acceptable salt or ester.
-
20. The compound of claim 17 wherein the compound is 4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thiophen-2-yl-phenyl}-acryloyl)-benzoic Acid;
- and, or its pharmaceutically acceptable salt or ester.
-
21. The compound of claim 17 wherein the compound is 4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thiophen-2-yl-phenyl]-acryloyl}-benzoic acid, hydrochloride, or its pharmaceutically acceptable salt or ester.
-
22. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, and R6α
are independently selected from the group consisting of hydrogen and carboxy;
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, heteroaryl, heterocyclic, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, heteroaryl lower alkoxy, and heterocyclic lower alkoxy, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, hydroxyalkyl, —
NR7R8, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is lower alkyl;
R7 and R8 are independently alkyl, and linked together forming a 6-membered monocyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
23. The compound of claim 22 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, and R6α
are independently selected from the group consisting of hydrogen and carboxy;
R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, ethoxy, propoxy, 3-(1-morpholino) propoxy, 2-(1-morpholino) ethoxy, CH3O(CH2)2O(CH2)2—
,and wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked tetrahydrofuran-2-yl or dihydrofuran-2-yl;
with the proviso that at least one of R2α
, R3α
, or R4α
must be carboxy.
-
-
24. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
25. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R1)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R2)2.
-
-
26. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2) 2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R1)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2;
wherein all R1, R2 R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R2)2.
-
-
27. The compound of claim 5 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2 R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R1)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
28. The compound of claim 3 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2, R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R1)2, —
C(O)NR7R8, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that R2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together, or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a heterocyclic or heteroaryl optionally substituted by one or more alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl or aminoalkyl and optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, —
NR7R8, and halo; and
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2)2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R2)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R2)2C(O)OH, —
NHC(R1)2C(O)OR2, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2;
wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2.
-
-
29. The compound of claim 3 or its pharmaceutically acceptable salt or ester, wherein:
-
R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
are independently selected from the group consisting of hydrogen, halogen, nitro, alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl lower alkyl, heterocyclic, heterocyclic lower alkyl, alkylthioalkyl, cycloalkylthioalkyl, arylthio lower alkyl, aralkyl lower thioalkyl, heteroarylthio lower alkyl, heteroaralkyl lower thioalkyl, heterocyclicthio lower alkyl, heterocyclicalkyl lower thioalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, —
C(O)R2 R2C(O)alkyl, aminoalkyl, cycloalkylaminoalkyl, arylamino lower alkyl, heteroarylamino lower alkyl, heterocyclicamino lower alkyl, hydroxyl, hydroxyalkyl, alditol, carbohydrate, polyol alkyl, alkoxy, lower alkoxy, —
(O(CH2)2)1-3—
O-lower alkyl, polyoxyalkylene, cycloalkyloxy, cycloalkylalkoxy, haloalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, heteroaryl lower alkoxy, heterocyclicoxy, heterocyclicalkoxy, heterocyclic lower alkoxy, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R1)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, alkylamino, acylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclicamino, heterocyclicalkylamino, —
NHR2, N(R2)2, —
NR7R8, —
NHC(R1)2C(O)OH, —
NHC(R2)2C(O)OR, —
NHC(O)R2)2, —
N(R1)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, —
NHC(O)N(R2)2, thiol, alkylthio, cycloalkylthio, cycloalkylalkylthio, haloalkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, heterocyclicthio, heterocyclicalkylthio, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R2)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R2)2, —
SO2NHC(O)NR7R8, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR78R2, —
C(O)NHC(O)R2, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2R2, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, —
PO2H2, —
PO3H2, —
P(R2)O2H, and phosphate, all of which can be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, and heterocyclicalkyl, wherein all may be substituted by one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
R7 and R8 are independently selected from the group consisting of alkyl, alkenyl and aryl and linked together forming a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
wherein one of R4β
, R5β
or R6β
must be a carbon-carbon linked heterocyclic or heteroaryl, and only one of R2α
, R3α
, R4α
, R5α
or R6α
can be —
OCH3;
with the proviso that R2α
and R3α
taken together or R3α
and R4α
taken together or R4α
and R5α
taken together or R2β
and R3β
taken together or R3β
and R4β
taken together or R4β
and R5β
taken together form a 5- or 6-membered ring containing one nitrogen, which may optionally be substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and —
C(O)N(R2)2;
provided that R2α
, R3α
, R4α
, R5α
, R6α
, R2β
, R3β
, R4β
, R5β
and R6β
cannot be —
OC(R1)2C(O)OH; and
with the proviso that at least one of R2α
, R3α
, or R4α
must be selected from the group consisting of cyano, tetrazol-5-yl, carboxy, —
C(O)OR2, —
C(O)NH2, —
C(O)NHR2, —
C(O)N(R2)2, —
C(O)NR7R8, —
C(O)NHC(O)NHR2, —
C(O)NHC(O)N(R2)2, —
C(O)NHC(O)NR7R8, —
C(O)NHSO2NHR2, —
C(O)NHSO2N(R2), —
C(O)NHSO2NR7R8, —
C(O)NHC(O)R2, —
C(O)NHSO2R2, —
C(CH3)2C(O)OH, —
(CH2)yC(O)OH, wherein y is 1, 2, 3, 4, 5, or 6, thiol, —
SC(R1)2C(O)OH, —
SC(R1)2C(O)OR2, —
SCH2C(O)OH, —
SCF2C(O)OH, —
SO2NH2, —
SO2NHR2, —
SO2N(R1)2, SO2NR7R8, —
SO2NHC(O)R2, —
SR2, —
SO2NHC(O)NHR2, —
SO2NHC(O)N(R1)2, —
SO2NHC(O)NR7R8, —
OC(R1)2C(O)OH, —
OC(R1)2C(O)OR2, —
OC(R1)2C(O)NH2, —
OC(R2)2C(O)NHR2, —
OC(R1)2C(O)N(R2)2, —
OC(R1)2C(O)NR7R8, amino, —
NHR2, N(R2)2, NR7R8, —
NHC(R2)2C(O)OH, —
NHC(R1)2C(O)OR, —
NHC(O)R2, —
N(R2)C(O)R2, —
NHC(O)OR2, —
NHC(O)SR2, —
NHSO2NHR2, —
NHSO2R2, —
NHSO2NR7R8, —
N(C(O)NHR2)2, —
NR2SO2R2, —
NHC(O)NHR2, —
NHC(O)NR7R8, and —
NHC(O)N(R2)2, wherein all R1, R2, R7 and R8 substituents can be optionally substituted with one or more selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, amino, aminoalkyl, —
NR7R8, alkoxy, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —
C(O)NR7R8, and C(O)N(R1)2.
-
-
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with one or more pharmaceutically acceptable carrier.
-
31. A method for the treatment or prophylaxis of an inflammatory disorder, comprising administering an effective amount of a compound of claim 1.
-
32. The method of claim 31, wherein the disorder is arthritis.
-
33. The method of claim 31, wherein the disorder is rheumatoid arthritis.
-
34. The method of claim 31, wherein the disorder is asthma.
-
35. The method of claim 31, wherein the treatment is disease modifying for the treatment of rheumatoid arthritis.
-
36. The method of claim 31, wherein the disorder is allergic rhinitis.
-
37. The method of claim 31, wherein the disorder is chronic obstructive pulmonary disease.
-
38. The method of claim 31, wherein the disorder is atherosclerosis.
-
39. The method of claim 31, wherein the disorder is restinosis.
-
40. A method for inhibiting the expression of VCAM-1, comprising administering an effective amount of a compound of claim 1.
-
2. The compound of claim 1 or its pharmaceutically acceptable salt or ester, wherein:
Specification
- Resources
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Current AssigneeCharles Q. Meng, James A. Sikorski, Kimberly J. Worsencroft, Liming Ni, Weingarten M. David
-
Original AssigneeCharles Q. Meng, James A. Sikorski, Kimberly J. Worsencroft, Liming Ni, Weingarten M. David
-
InventorsWeingarten, M. David, Meng, Charles Q., Sikorski, James A., Ni, Liming, Worsencroft, Kimberly J.
-
Application NumberUS11/337,207Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/25CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 11/16 Central respiratory analepticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 27/02 Ophthalmic agentsA61P 27/16 OtologicalsA61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 37/02 ImmunomodulatorsA61P 37/08 Antiallergic agents antiast...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/08 Vasodilators for multiple i...A61P 9/10 for treating ischaemic or a...C07C 45/63 by introduction of halogen;...C07C 47/575 : containing ether groups, g...C07D 207/333 : Radicals substituted by oxy...C07D 209/12 : Radicals substituted by oxy...C07D 213/50 : Ketonic radicalsC07D 231/12 : with only hydrogen atoms, h...C07D 233/64 : with substituted hydrocarbo...C07D 235/18 : with aryl radicals directly...C07D 239/26 : with only hydrogen atoms, h...C07D 239/52 : Two oxygen atomsC07D 241/12 : with only hydrogen atoms, h...C07D 249/08 : 1,2,4-Triazoles; Hydrogenat...C07D 257/04 : Five-membered ringsC07D 261/08 : with only hydrogen atoms, h...C07D 277/24 : Radicals substituted by oxy...C07D 307/28 : with only hydrogen atoms, h...C07D 307/46 : Doubly bound oxygen atoms, ...C07D 307/80 : Radicals substituted by oxy...C07D 333/22 : Radicals substituted by dou...C07D 333/38 : Carbon atoms having three b...C07D 333/56 : Radicals substituted by oxy...C07D 409/10 : linked by a carbon chain co...C07D 409/12 : linked by a chain containin...C07D 413/12 : linked by a chain containin...C07D 471/04 : Ortho-condensed systemsC07H 15/203 : Monocyclic carbocyclic ring...