Spiro compounds for treatment of inflammatory disorders
Provided are compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, in particular asthma. The compounds are of the general Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof: wherein Y, Z and R 1 -R 12 are defined herein.
1 . A compound of Formula IV:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 12a is selected from the group consisting of carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )—C 1 -C 6 straight alkyl, (C(O)NHR 13a )—C 3 -C 6 branched alkyl, (C(O)NHR 13a )—C 2 -C 6 alkenyl, (C(O)NHR 13a )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a —C(O)NR 14a R 5a , NR 15a C(O)R 14a —NR 15a C(O)NR 14a R 15a , —OC(O)NR 14a R 15a , —NR 15a C(O)OR 16a , —S(O) n —R 16a , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14a and —S(O) 2 —NR 14a R 15a ; or
R 12a is selected from the group consisting of hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, and hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14a R 15a , OXO, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a —C(O)—NR 14a R 15a , —NR 15a C(O)R 14a , —NR 15a C(O)NR 14a R 15a , —OC(O)NR 14a R 15a , —NR 15a C(O)OR 16a , —S(O) n —R 16a , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14a and —S(O) 2 —NR 14a R 15a ;
each n is independently 0, 1, or 2;
R 13a is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14a and R 15a are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16a ;
R 14a and R 15a taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16a is selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
2 . The compound of claim 1 in the form of an isolated enantiomer.
3 . The compound of claim 1 wherein R 12a includes a chiral center.
4 . The compound of claim 3 in the form of an isolated diastereomer.
5 . The compound of claim 1 wherein R 12a is selected from the group consisting of carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )—C 1 -C 6 straight alkyl, (C(O)NHR 13a )—C 3 -C 6 branched alkyl, (C(O)NHR 13a )—C 3 -C 8 cyclic alkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , C(O)—NR 14a R 15a and —NR 15a C(O)R 14a .
6 . The compound of claim 1 wherein R 12a is selected from the group consisting of hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , C(O)—N(H)OR 14a , —C(O)—NR 14a R 15a and NR 15a C(O)R 14a .
7 . The compound of claim 1 wherein R 12a is selected from the group consisting of carboxy-C 1 -C 4 straight alkyl and carboxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
8 . The compound of claim 1 wherein R 12a is selected from the group consisting of hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl.
9 . The compound of claim 1 wherein the compound is
or an enantiomer thereof, or a pharmaceutically acceptable salt or prodrug thereof.
10 . The compound of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt or prodrug thereof.
11 . The compound of claim 1 wherein the compound is
or an enantiomer thereof, or a pharmaceutically acceptable salt or prodrug thereof.
12 . A pharmaceutical composition of Formula I
or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier wherein:
Y and Z are independently O, S(O) q , Se(O) q or N(R 13 );
each q is independently 0, 1 or 2;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and —OR 4 , wherein all may be optionally substituted by a hydroxy group;
R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, carboxy, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14 R 15 , oxo, cyano, alkoxycarbonyl, —OR 16 , —C(O)R 16 , —C(O)—NH 2 , —C(O)—N(H)R 14 , —C(O)—N(H)OR 14 , —C(O)—NR 14 R 15 , —NR 15 C(O)R 14 , —NR 15 C(O)NR 14 R 15 , —OC(O)NR 14 R 15 , —NR 15 C(O)OR 16 , —S(O) n —R 16 , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14 and —S(O) 2 —NR 14 R 15 ;
or R 11 and R 12 are independently selected from the group consisting of hydrogen, aryl, heteroaryl and heterocycle, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14 R 15 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16 , —C(O)R 16 , —C(O)—NH 2 , —C(O)—N(H)R 14 , —C(O)—N(H)OR 14 , —C(O)—NR 14 R 15 , —NR 15 C(O)R 14 , —NR 15 C(O)NR 14 R 15 , —OC(O)NR 14 R 15 , —NR 15 C(O)OR 16 , —S(O) n —R 16 , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14 and —S(O) 2 —NR 14 R 15 ;
each n is independently 0, 1, or 2;
R 13 is independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14 and R 15 are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16 ;
R 14 and R 15 taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16 is independently selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy;
with the proviso, that when R 11 and R 12 are heteroaryl, R 11 and R 12 cannot be 2-furyl.
13 . The pharamaceutical composition of claim 12 wherein at least one of R 11 and R 12 is not hydrogen.
14 . The pharamaceutical composition of claim 12 , wherein the compound is of Formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
Y* and Z* are independently O, S(O) q , Se(O) q or N(R 13* );
each q is independently 0, 1 or 2;
R 1* , R 2* , R 3* , R 4* , R 15* and R 6* are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and —OR 14* , wherein all may be optionally substituted by a hydroxy group;
R 7* , R 8* , R 9* and R 10* are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
R 12* is selected from the group consisting of C 1 -C 6 straight alkyl, hydroxy-C 1 -C 6 straight alkyl, polyhydroxy-C 1 -C 6 straight alkyl, carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13* )—C 1 -C 6 straight alkyl, (C(O)NHR 13* )—C 3 -C 6 branched alkyl, (C(O)NHR 13* )—C 2 -C 6 alkenyl, (C(O)NHR 13* )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14* R 15* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16* , —C(O)R 16* , —C(O)—NH 2 , —C(O)—N(H)R 14* , C(O)—N(H)OR 14* , C(O)NR 14* R 15* , —NR 15* C(O)R 14* , —NR 15* C(O)NR 14* R 15* , —OC(O)NR 14* R 15* , NR 15* C(O)OR 16* , —S(O) n —R 16* , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14* and —S(O) 2 —NR 14* R 15* ;
each n is independently 0, 1, or 2;
R 13* is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14* and R 15* are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16* ;
R 14* and R 15* taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16* is independently selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
15 . The pharamaceutical composition of claim 12 , wherein the compound is of Formula III:
or a pharmaceutically acceptable salt, ester or prodrug thereof wherein:
R 1** , R 2** , R 3** , R 4** , R 15** and R 6** are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 straight alkyl, C 1 -C 4 branched alkyl, C 2 -C 6 alkenyl, aryl and —OR 4 ;
R 12** is selected from the group consisting of C 1 -C 6 straight alkyl, hydroxy-C 1 -C 6 straight alkyl, polyhydroxy-C 1 -C 6 straight alkyl, carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13** )—C 1 -C 6 straight alkyl, (C(O)NHR 13** )—C 3 -C 6 branched alkyl, (C(O)NHR 13** )—C 2 -C 6 alkenyl, (C(O)NHR 13** )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, NR 14** R 15** , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16** , —C(O)R 16** , —C(O)—NH 2 , —C(O)—N(H)R 14** , —C(O)—N(H)OR 14** , —C(O)—NR 14** R 15** , NR 15** C(O)R 14** , —NR 15** C(O)NR 14** R 15** , OC(O)NR 14** R 15** , —NR 15** C(O)OR 16** , —S(O) n —R 16** , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14** and —S(O) 2 NR 14** R 15** ;
each n is independently 0, 1, or 2;
R 13** is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14** and R 15** are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16 ;
R 14** and R 15** taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16** is independently selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
16 . The pharmaceutical composition of claim 12 , wherein the compound is of Formula IV:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
R 12a is selected from the group consisting of carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )—C 1 -C 6 straight alkyl, (C(O)NHR 13a )—C 3 -C 6 branched alkyl, (C(O)NHR 13a )—C 2 -C 6 alkenyl, (C(O)NHR 13a )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , C(O)—NR 14a R 15a , NR 15a C(O)R 14a , —NR 15a C(O)NR 14a R 15a , —OC(O)NR 14a R 15a , —NR 15a C(O)OR 16a , —S(O) n —R 16a , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14a and —S(O) 2 —NR 14a R 15a ; or
R 12a is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—, NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , —C(O)—NR 14a R 15a , —NR 15a C(O)R 14a , —NR 15a C(O)NR 14a R 15a , OC(O)NR 14a R 15a , —NR 15a C(O)OR 16a , —S(O) n —R 16a , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14a and —S(O) 2 —NR 14a R 15a ;
each n is independently 0, 1, or 2;
R 13a is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14a and R 15a are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16a ;
R 14a and R 15a taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16a is selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
17 . The pharmaceutical composition of claim 12 wherein the compound is in the form of an isolated enantiomer.
18 . The pharmaceutical composition of claim 12 wherein R 12a includes a chiral center.
19 . The pharmaceutical composition of claim 12 wherein the compound is in the form of an isolated diastereomer.
20 . The pharmaceutical composition of claim 12 wherein R 12a is selected from the group consisting of carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )—C 1 -C 6 straight alkyl, (C(O)NHR 13a )—C 3 -C 6 branched alkyl, (C(O)NHR 13a )—C 3 -C 8 cyclic alkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , C(O)—NR 14a R 15a and NR 15a C(O)R 14a .
21 . The pharmaceutical composition of claim 12 wherein R 12a is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , —C(O)—NR 14a R 15a and NR 15a C(O)R 14a .
22 . The pharmaceutical composition of claim 12 wherein R 12a is selected from the group consisting of carboxy-C 1 -C 4 straight alkyl and carboxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
23 . The pharmaceutical composition of claim 12 wherein R 12a is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl.
24 . The pharmaceutical composition of claim 12 wherein the compound is
or an enantiomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof.
25 . The pharmaceutical composition of claim 12 wherein the compound is:
or a pharmaceutically acceptable salt, ester or prodrug thereof.
26 . The pharmaceutical composition of claim 12 wherein the compound is
or an enantiomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof.
27 . A method of treatment or prophylaxis of an inflammatory condition comprising administering a compound of Formula I, optionally in a pharmaceutically acceptable carrier, to a host at risk of, or suffering from, an inflammatory condition
or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier wherein:
Y and Z are independently O, S(O) q , Se(O) q or N(R 13 );
each q is independently 0, 1 or 2;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and —OR 4 , wherein all may be optionally substituted by a hydroxy group;
R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, carboxy, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14 R 15 , oxo, cyano, alkoxycarbonyl, —OR 16 , —C(O)R 16 , —C(O)—NH 2 , —C(O)—N(H)R 14 , —C(O)—N(H)OR 14 , —C(O)—NR 14 R 15 , —NR 15 C(O)R 14 , —NR 15 C(O)NR 14 R 15 , —OC(O)NR 14 R 15 , —NR 15 C(O)OR 16 , —S(O) n —R 16 , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14 and —S(O) 2 —NR 14 R 15 ;
or R 11 and R 12 are independently selected from the group consisting of hydrogen, aryl, heteroaryl and heterocycle, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14 R 15 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16 , —C(O)R 16 , —C(O)—NH 2 , —C(O)—N(H)R 14 , —C(O)—N(H)OR 14 , —C(O)—NR 14 R 15 , —NR 15 C(O)R 14 , —NR 15 C(O)NR 14 R 15 , —OC(O)NR 14 R 15 , —NR 15 C(O)OR 16 , —S(O) n —R 16 , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14 and —S(O) 2 —NR 14 R 15 ;
each n is independently 0, 1, or 2;
R 13 is independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14 and R 15 are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16 ;
R 14 and R 15 taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16 is independently selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy;
with the proviso, that when R 11 and R 12 are heteroaryl, R 11 and R 12 cannot be 2-furyl.
28 . The method of claim 27 wherein at least one of R 11 and R 12 is not hydrogen.
29 . The method of claim 27 , wherein the compound is of Formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
Y* and Z* are independently O, S(O) q , Se(O) q or N(R 13* );
each q is independently 0, 1 or 2;
R 1* , R 2* , R 3* , R 4* , R 5* and R 6* are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and —OR 14 , wherein all may be optionally substituted by a hydroxy group;
R 7* , R 8* , R 9* and R 10* are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
R 12* is selected from the group consisting of C 1 -C 6 straight alkyl, hydroxy-C 1 -C 6 straight alkyl, polyhydroxy-C 1 -C 6 straight alkyl, carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13* )—C 1 -C 6 straight alkyl, (C(O)NHR 13* )—C 3 -C 6 branched alkyl, (C(O)NHR 13* )—C 2 -C 6 alkenyl, (C(O)NHR 13* )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14* R 15* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16* , —C(O)R 16* , —C(O)—NH 2 , —C(O)—N(H)R 14* , C(O)—N(H)OR 14* , —C(O)—NR 14* R 15* , —NR 15* , C(O)R 14* , —NR 15* C(O)NR 14* R 15* , —OC(O)NR 14* R 15* , NR 15* C(O)OR 16* , —S(O) n —R 16* , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14* and —S(O) 2 —NR 14* R 15* ;
each n is independently 0, 1, or 2;
R 13* is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14* and R 15* are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16* ;
R 14* and R 15* taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16* is independently selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
30 . The method of claim 27 wherein the compound is of Formula III:
or a pharmaceutically acceptable salt, ester or prodrug thereof wherein:
R 1** , R 2** , R 3** , R 4** , R 5** and R 6** are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 straight alkyl, C 1 -C 4 branched alkyl, C 2 -C 6 alkenyl, aryl and —OR 14 ;
R 12** is selected from the group consisting of C 1 -C 6 straight alkyl, hydroxy-C 1 -C 6 straight alkyl, polyhydroxy-C 1 -C 6 straight alkyl, carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 3** )—C 1 -C 6 straight alkyl, (C(O)NHR 3** )—C 3 -C 6 branched alkyl, (C(O)NHR 13** )—C 2 -C 6 alkenyl, (C(O)NHR 13** )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14** R 15** , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, OR 16 , —C(O)R 6 , —C(O)—NH 2 , —C(O)—N(H)R 14** , —C(O)—N(H)OR 14** , —C(O)NR 14** R 15** , —NR 15** C(O)R 14** , —NR 15** C(O)NR 14** R 15** , —OC(O)NR 14** R 15** , —NR 15** C(O)OR 16** , —S(O) n —R 16** , S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14** and —S(O) 2 —NR 14** R 15** ;
each n is independently 0, 1, or 2;
R 13** is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14** and R 15** are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16 ;
R 14** and R 15** taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16** is independently selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
31 . The method of claim 27 wherein the compound is of Formula IV:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
R 12a is selected from the group consisting of carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )—C 1 -C 6 straight alkyl, (C(O)NHR 13a )—C 3 -C 6 branched alkyl, (C(O)NHR 13a )—C 2 -C 6 alkenyl, (C(O)NHR 13a )—C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , —C(O)—NR 14a R 15a NR 15a C(O)R 14a , —NR 15a C(O)NR 14a R 15a , —OC(O)NR 14a R 15a , —NR 15a C(O)OR 16a , —S(O) n —R 16a , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14a and —S(O) 2 —NR 14a R 15a ; or
R 12a is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , C(O)—NR 14a R 15a , —NR 15a C(O)R 14a , —NR 15a C(O)NR 14a R 15a , —OC(O)NR 14a R 15a , —NR 15a C(O)OR 16a , —S(O) n —R 16a , —S(O) 2 —NH 2 , —S(O) 2 —N(H)R 14a and —S(O) 2 —NR 14a R 15a ;
each n is independently 0, 1, or 2;
R 13a is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
R 14a and R 15a are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and —OR 16a ;
R 14a and R 15a taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
R 16a is selected from the group consisting of C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
32 . The method of claim 27 wherein the compound is in the form of an isolated enantiomer.
33 . The method of claim 27 wherein R 12a is selected from the group consisting of carboxy-C 1 -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )—C 1 -C 6 straight alkyl, (C(O)NHR 13a )—C 3 -C 6 branched alkyl, (C(O)NHR 13a )—C 3 -C 8 cyclic alkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N(H)OR 14a , —C(O)—NR 14a R 15a and —NR 15a C(O)R 14a .
34 . The method of claim 27 wherein R 12a is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-C 1 -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, —NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, —OR 16a , —C(O)R 16a , —C(O)—NH 2 , —C(O)—N(H)R 14a , —C(O)—N)OR 14a , —C(O)—NR 14a R 15a and NR 15a C(O)R 14a .
35 . The method of claim 27 wherein the compound is
or an enantiomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof.
36 . The method of claim 27 wherein the compound is:
or a pharmaceutically acceptable salt, ester or prodrug thereof.
37 . The method of claim 27 wherein the compound is:
or an enantiomer thereof, or a pharmaceutically acceptable salt, ester or prodrug thereof.
38 . The method of claim 27 wherein the inflammatory disorder is a respiratory disorder.
39 . The method of claim 27 wherein the inflammatory disorder is asthma or COPD. w