1,3-bis-(substituted-phenyl)-2-propyn-1-ones and their use to treat disorders
View Patent ↗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.
1. A compound of Formula I:
or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 5α , R 6α , R 6α , R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, alkyl, lower alkyl, alkenyl, alkynyl, hydroxyl, carboxy, carbocycle, aryl, heteroaryl, heterocycle, cycloalkyl, cyano, tetrazol-5-yl, alkoxy, lower alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl, haloalkyl, acylamino, amino, dialkylamino, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl, halogen, thiol, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, phosphate, alditol, carbohydrate, OC(R 1 ) 2 COOH, SC(R 1 ) 2 COOH, NHC(R 1 ) 2 COOH, C(O)R 2 , COOR 1 , polyoxyalkylene, polyol alkyl, alkylcarbonylalkyl, lower alkyl S(O) lower alkyl, lower alkyl-S(O) 2 -lower alkyl; hydroxyalkyl, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, arylamino, heterocycleamino, heteroarylamino, cycloalkylamino, cycloalkylalkyl, heterocyclealkoxy, cycloalkylalkoxy, cycloalkyloxy, alkylthioalkyl, cycloalkylthioalkyl, cycloalkylaminoalkyl, —C(O)NH 2 , —C(O)NHR 2 , —C(O)N(R 2 ) 2 , —NHC(O)R 2 , —N(R 2 )C(O)R 2 , —NHC(O)OR 2 , —NHC(O)SR 2 , —NHSO 2 NHR 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , —PO 2 H 2 , —PO 3 H 2 , P(R 2 )O 2 H, —SCF 2 CO 2 H, —NHSO 2 R 2 , —N(C(O)NHR 2 ) 2 , —NR 2 SO 2 R 2 , —NHC(O)NHR 2 , and —NHC(O)N(R 2 ) 2 , all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, alkenyl, carboxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, amino, cyano, alkoxy, acyl, alkoxycarbonyl, oxo, and halo;
R 1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl and heterocyclealkyl, wherein all may be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
R 2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, and heterocyclealkyl, wherein all may be substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
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 heterocycle or heteroaryl;
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 heterocycle or heteroaryl substituted by one or more 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, 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 hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo, 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(R 1 ) 2 COOH; or
at least one of R 2α , R 3α , R 4α , R 5α , R 6α or one of R 2β , R 3β , R 4β , R 5β , R 6β must be selected from the group consisting of carboxy, carboxyalkoxy, cyano, tetrazol-5-yl, —C(O)OR 2 , —C(O)NHR 2 , —C(O)NH 2 , —C(O)N(R 2 ) 2 , —C(CH 3 ) 2 C(O)OH, —CH 2 C(O)OH, —NHR 2 , NH 2 , —NHSO 2 R 2 , N(R 2 ) 2 , —NR 2 SO 2 R 2 , —NHSO 2 NHR 2 , —NHC(O)R 2 , —NHC(O)OR 2 , —SCH 2 CO 2 H, —SCF 2 CO 2 H, —SH, —SR 2 , —NR 2 C(O)R 2 , —NHC(O)SR 2 , NHC(O)NHR 2 , —NHC(O)N(R 2 ) 2 , SC(R 1 ) 2 COOH, —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , and NR 7 R 7 wherein R 7 and R 7 are linked together forming a 4- to 7-membered ring that is either unsaturated, saturated, fully saturated or aryl optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo.
2. A compound of the Formula I:
or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 4α , R 5α , R 6α , R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, alkyl, lower alkyl, alkenyl, alkynyl, hydroxyl, carboxy, carbocycle, aryl, heteroaryl, heterocycle, cycloalkyl, cyano, tetrazol-5-yl, alkoxy, lower alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl, haloalkyl, acylamino, amino, dialkylamino, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl, halogen, thiol, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, phosphate, alditol, carbohydrate, —OC(R 1 ) 2 COOH, —SC(R 1 ) 2 COOH, —NHC(R 1 ) 2 COOH, —C(O)R 2 , —COOR 1 , polyoxyalkylene, polyol alkyl, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O) 2 -lower alkyl; hydroxyalkyl, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, arylamino, heterocycleamino, heteroarylamino, cycloalkylamino, cycloalkylalkyl, heterocyclealkoxy, cycloalkylalkoxy, cycloalkyloxy, alkylthioalkyl, cycloalkylthioalkyl, cycloalkylaminoalkyl, —C(O)NH 2 , —C(O)NHR 2 , —C(O)N(R 2 ) 2 , —NHC(O)R 2 , —N(R 2 )C(O)R 2 , —NHC(O)OR 2 , —NHC(O)SR 2 , —NHSO 2 NHR 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , —PO 2 H 2 , —PO 3 H 2 , P(R 2 )O 2 H, —SCF 2 CO 2 H, —NHSO 2 R 2 , —N(C(O)NHR 2 ) 2 , —NR 2 SO 2 R 2 , —NHC(O)NHR 2 , and —NHC(O)N(R 2 ) 2 , all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, alkenyl, carboxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, amino, cyano, alkoxy, acyl, alkoxycarbonyl, oxo, and halo;
R 1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl and heterocyclealkyl, wherein all may be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
R 2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, and heterocyclealkyl, wherein all may be substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle or heteroaryl;
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 form a heterocycle or heteroaryl substituted by one or more 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, 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 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 hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo, 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(R 1 ) 2 COOH; or
at least one of R 2α , R 3α R 4α or one of R 2β , R 3β R 4β must be selected from the group consisting of carboxy, carboxyalkoxy, cyano, tetrazol-5-yl, —C(O)OR 2 , —C(O)NHR 2 , —C(O)NH 2 , —C(O)N(R 2 ) 2 , —C(CH 3 ) 2 C(O)OH, —CH 2 C(O)OH, —NHR 2 , NH 2 , —NHSO 2 R 2 , N(R 2 ) 2 , —NR 2 SO 2 R 2 , —NHSO 2 NHR 2 , —NHC(O)R 2 , —NHC(O)OR 2 , —SCH 2 CO 2 H, —SCF 2 CO 2 H, —SH, —SR 2 , —NR 2 C(O)R 2 , —NHC(O)SR 2 , NHC(O)NHR 2 , —NHC(O)N(R 2 ) 2 , SC(R 1 ) 2 COOH, —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , and NR 7 R 7 wherein R 7 and R 7 are linked together forming a 4- to 7-membered ring that is either unsaturated, saturated, fully saturated or aryl optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo.
3. A compound of the Formula I:
or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 4α , R 5α , R 6α , R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, alkyl, lower alkyl, alkenyl, alkynyl, hydroxyl, carboxy, carbocycle, aryl, heteroaryl, heterocycle, cycloalkyl, cyano, tetrazol-5-yl, alkoxy, lower alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl, haloalkyl, acylamino, amino, dialkylamino, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl, halogen, thiol, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, phosphate, alditol, carbohydrate, —OC(R 1 ) 2 COOH, —SC(R 1 ) 2 COOH, —NHC(R 1 ) 2 COOH, —C(O)R 2 , —COOR 1 , polyoxyalkylene, polyol alkyl, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O) 2 -lower alkyl; hydroxyalkyl, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, arylamino, heterocycleamino, heteroarylamino, cycloalkylamino, cycloalkylalkyl, heterocyclealkoxy, cycloalkylalkoxy, cycloalkyloxy, alkylthioalkyl, cycloalkylthioalkyl, cycloalkylaminoalkyl, —C(O)NH 2 , —C(O)NHR 2 , —C(O)N(R 2 ) 2 , —NHC(O)R 2 , —N(R 2 )C(O)R 2 , —NHC(O)OR 2 , —NHC(O)SR 2 , —NHSO 2 NHR 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , —PO 2 H 2 , —PO 3 H 2 , P(R 2 )O 2 H, —SCF 2 CO 2 H, —NHSO 2 R 2 , —N(C(O)NHR 2 ) 2 , —NR 2 SO 2 R 2 , —NHC(O)NHR 2 , and —NHC(O)N(R 2 ) 2 , all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, alkenyl, carboxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, amino, cyano, alkoxy, acyl, alkoxycarbonyl, oxo, and halo;
R 1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl and heterocyclealkyl, wherein all may be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
R 2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, and heterocyclealkyl, wherein all may be substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle or heteroaryl;
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 form a heterocycle or heteroaryl substituted by one or more 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, 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 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 hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo, 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(R 1 ) 2 COOH; or
at least one of R 2α , R 3α , or R 4α must be selected from the group consisting of carboxy, carboxyalkoxy, cyano, tetrazol-5-yl, —C(O)OR 2 , —C(O)NHR 2 , —C(O)NH 2 , —C(O)N(R 2 ) 2 , —C(CH 3 ) 2 C(O)OH, —CH 2 C(O)OH, —NHR 2 , NH 2 , —NHSO 2 R 2 , N(R 2 ) 2 , —NR 2 SO 2 R 2 , —NHSO 2 NHR 2 , —NHC(O)R 2 , —NHC(O)OR 2 , —SCH 2 CO 2 H, —SCF 2 CO 2 H, —SH, —SR 2 —NR 2 C(O)R 2 , —NHC(O)SR 2 , NHC(O)NHR 2 , —NHC(O)N(R 2 ) 2 , SC(R 1 ) 2 COOH, —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , and NR 7 R 7 wherein R 7 and R 7 are linked together forming a 4- to 7-membered ring that is either unsaturated, saturated, fully saturated or aryl optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo.
4. A compound of the Formula I:
or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 4α , R 5α , R 6α , R 2β , R 3β , R 4α , R 5β and R 6β are independently selected from the group consisting of hydrogen, alkyl, lower alkyl, alkenyl, alkynyl, hydroxyl, carboxy, carbocycle, aryl, heteroaryl, heterocycle, cycloalkyl, cyano, tetrazol-5-yl, alkoxy, lower alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl, haloalkyl, acylamino, amino, dialkylamino, haloalkoxy, alkylsulfonyl, haloalkylsulfonyl, halogen, thiol, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, phosphate, alditol, carbohydrate, —OC(R 1 ) 2 COOH, —SC(R 1 ) 2 COOH, —NHC(R 1 ) 2 COOH, —C(O)R 2 , —COOR 1 , polyoxyalkylene, polyol alkyl, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O) 2 -lower alkyl; hydroxyalkyl, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, arylamino, heterocycleamino, heteroarylamino, cycloalkylamino, cycloalkylalkyl, heterocyclealkoxy, cycloalkylalkoxy, cycloalkyloxy, alkylthioalkyl, cycloalkylthioalkyl, cycloalkylaminoalkyl, —C(O)NH 2 , —C(O)NHR 2 , —C(O)N(R 2 ) 2 , —NHC(O)R 2 , —N(R 2 )C(O)R 2 , —NHC(O)OR 2 , —NHC(O)SR 2 , —NHSO 2 NHR 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , —PO 2 H 2 , —PO 3 H 2 , P(R 2 )O 2 H, —SCF 2 CO 2 H, —NHSO 2 R 2 , —N(C(O)NHR 2 ) 2 , —NR 2 SO 2 R 2 , —NHC(O)NHR 2 , and —NHC(O)N(R 2 ) 2 , all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, alkenyl, carboxy, hydroxyalkyl, carboxyalkyl, aminoalkyl, amino, cyano, alkoxy, acyl, alkoxycarbonyl, oxo, and halo;
R 1 is independently selected from the group consisting of hydrogen, lower alkyl, carbocycle, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl and heterocyclealkyl, wherein all may be optionally substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
R 2 is independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, and heterocyclealkyl, wherein all may be substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle or heteroaryl;
with the proviso that at least one of R 2β , R 3α , or R 4α must be selected from the group consisting of carboxy, carboxyalkoxy, cyano, tetrazol-5-yl, —C(O)OR 2 , —C(O)NHR 2 , —C(O)NH 2 , —C(O)N(R 2 ) 2 , —C(CH 3 ) 2 C(O)OH, —CH 2 C(O)OH, —NHR 2 , NH 2 , —NHSO 2 R 2 , N(R 2 ) 2 , —NR 2 SO 2 R 2 , —NHSO 2 NHR 2 , —NHC(O)R 2 , —NHC(O)OR 2 , SC(R 1 ) 2 COOH, —SCH 2 CO 2 H, —SCF 2 CO 2 H, —SH, —SR 2 , —NR 2 C(O)R 2 , —NHC(O)SR 2 , NHC(O)NHR 2 , —NHC(O)N(R 2 ) 2 , —SO 2 NH 2 , —SO 2 NHR 2 , —SO 2 N(R 2 ) 2 , and NR 7 R 7 wherein R 7 and R 7 are linked together forming a 4- to 7-membered ring that is either unsaturated, saturated, fully saturated or aryl optionally substituted with one or more selected from the group consisting of hydroxy, alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo.
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, lower alkyl, carboxy, carboxyalkoxy, heteroaryl, heterocycle, alkoxy, lower alkoxy, alkylamino, amino, dialkylamino, halogen, and —NHSO 2 R 2 , all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkyl, hydroxyalkyl, aminoalkyl, amino, and halo;
R 1 is selected from the group consisting of lower alkyl, and aryl, wherein all may be substituted by one or more selected from the group consisting of hydroxy, alkyl, lower alkyl, carboxy, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, cyano, alkoxy, alkoxycarbonyl, acyl, oxo, and halo;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle or heteroaryl;
with the proviso that at least one of R 2α , R 3α , or R 4α must be selected from the group consisting of carboxy, and carboxymethoxy.
6. The compound of claim 4 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, lower alkyl, carboxy, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkyl, hydroxyalkyl, aminoalkyl, amino, acyl, carboxyalkoxy, alkoxycarbonyl, and halo;
R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, lower alkyl, carboxy, heteroaryl, heterocycle, lower alkoxy, dialkylamino, acyl, alkoxycarbonyl, carboxyalkoxy, and halogen, all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkyl, hydroxyalkyl, aminoalkyl, amino, and halo;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle or heteroaryl;
with the proviso that at least one of R 2α , R 3α , or R 4α must be carboxy or carboxymethoxy.
7. The compound of claim 4 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, lower alkyl, carboxy, lower alkoxy, carboxyalkoxy, and halogen;
R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen all of which can be optionally substituted by one or more selected from the group consisting of hydroxy, methyl, hydroxymethyl, aminomethyl, amino, acyl, alkoxycarbonyl, and halo;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle or heteroaryl;
with the proviso that at least one of R 2α , R 3α , or R 4α must be carboxy or carboxymethoxy.
8. The compound of claim 4 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, lower alkyl, carboxy, lower alkoxy, carboxyalkoxy, and halogen;
R 2β , R 3β , R 4β2 , R 5β and R 6β are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl;
with the proviso that at least one of R 2α , R 3α , or R 4α must be carboxy or carboxymethoxy.
9. The compound of claim 4 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, lower alkyl, carboxy, lower alkoxy, carboxyalkoxy, and halogen;
R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, lower alkyl, heteroaryl, heterocycle, lower alkoxy, dialkylamino, and halogen;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heterocycle selected from the group consisting of pyrrolidinyl, pyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, and piperazinyl;
with the proviso that at least one of R 2α , R 3α , or R 4α must be carboxy or carboxymethoxy.
10. The compound of claim 4 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, methyl, carboxy, carboxyalkoxy, methoxy, chloro and fluoro;
R 2β , R 3β , R 4β , R 5β and R 6β are independently selected from the group consisting of hydrogen, methyl, furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, isoquinolinyl, methoxy, dimethylamino, chloro and fluoro;
wherein one of R 4β , R 5β or R 6β must be a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl;
with the proviso that at least one of R 2α , R 3α , R 4α , R 5α or R 6α must be carboxy or carboxymethoxy.
11. The compound of claim 4 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, methyl, carboxy, carboxyalkoxy, methoxy, chloro and fluoro;
R 2β , R 3β , R 4β , and R 6β are independently selected from the group consisting of hydrogen, methyl, methoxy, dimethylamino, chloro and fluoro;
R 5β is a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl;
with the proviso that at least one of R 2β , R 3β , or R 4α must be carboxy or carboxymethoxy.
12. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 5α , R 6α R 3β , and R 6β are hydrogen;
R 4α is carboxy;
R 2β and R 4β are methoxy; and
R 5β is a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl.
13. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 5α , R 6α , R 3β , and R 6β are hydrogen;
R 4α is carboxy;
R 2β and R 4β are methoxy; and
R 5β is 5-(benzothien-2-yl).
14. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 5α , R 6α , R 3β , and R 6β are hydrogen;
R 4α is carboxy;
R 2β and R 4β are methoxy; and
R 5β is thienyl.
15. The compound of claim 12 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 3α , R 5α , R 6α , R 3β , and R 6β are hydrogen;
R 4α is carboxy;
R 2β and R 4β are methoxy; and
R 5β is indolyl.
16. The compound of claim 4 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 6α , R 3β and R 6β are hydrogen;
R 4α is carboxymethoxy;
R 3α , R 5α , R 2β and R 4β are methoxy; and
R 5β is a carbon-carbon linked heteroaryl selected from the group consisting of furanyl, benzofuranyl, pyrimidinyl, oxazolyl, thienyl, benzothienyl, indolyl, pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, triazolopyridinyl, quinolinyl, purinyl, and isoquinolinyl.
17. The compound of claim 16 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 6α , R 3β and R 6β are hydrogen;
R 4α is carboxymethoxy;
R 3α , R 5α , R 2β and R 4β are methoxy; and
R 5β is 5-(benzothien-2-yl).
18. The compound of claim 16 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 6α , R 3β and R 6β are hydrogen;
R 4α is carboxymethoxy;
R 3α , R 5α , R 2β and R 4β are methoxy; and
R 5β is thienyl.
19. The compound of claim 16 or its pharmaceutically acceptable salt or ester, wherein:
R 2α , R 6α , R 3β and R 6β are hydrogen;
R 4α is carboxymethoxy;
R 3α , R 5α , R 2β and R 4β are methoxy; and
R 5β is indolyl.
20. The compound of claim 1 wherein the compound is selected from the group consisting of 4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-benzoic acid methyl ester,
4-[3-{2,4-Dimethoxy-5-(thiophen-2-yl)-phenyl}propynoyl]-benzoic acid,
{4-[3-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester, and
{4-[3-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid.
21. 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 or 20 together with one or more pharmaceutically acceptable carrier.
22. A method for the treatment of an inflammatory disorder mediated by VCAM-1, comprising administering 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 or 20 , wherein the disorder is arthritis.
23. A method for the treatment of an inflammatory disorder mediated by 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 or 20 , wherein the disorder is rheumatoid arthritis.
24. A method for the treatment of an inflammatory disorder mediated by 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 or 20 , wherein the disorder is asthma.
25. A method for the treatment of an inflammatory disorder mediated by 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 or 20 , wherein the disorder is allergic rhinitis.