Compounds for the treatment of inflammatory disorders
View Patent ↗This invention relates to compounds of the Formula (I): or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, TNF-α or combinations thereof.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein:
M is —(C(R 30 )(R 40 )) m —, wherein m is 1;
T is selected from the group consisting of R 21 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 3 , —C(O)R 4 , —C(O)OR 3 , —C(O)NR 24 R 25 , —C(O)NR 24 OR 3 , —C(O)SR 3 , —NR 24 R 25 , —NR 25 C(O)R 4 , —NR 25 C(O)OR 3 , —NR 25 C(O)NR 24 R 25 , —NR 25 C(O)NR 24 OR 3 , —SR 3 , —S(O) x NR 24 R 25 , —S(O) x NR 25 OR 3 , —CN, —P(O)(R 24 )(OR 24 ), —P(O)(OR 24 )(OR 24 ), —C(R 4 )(═N(OR 3 )), —C(O)—AA—NR 24 R 25 and —C(O)—AA—NR 25 OR 3 ,
wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of T is independently unsubstituted or substituted with one to five independently selected R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below;
V is selected from the group consisting of alkyl, R 21 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 3 , —C(O)R 4 , —(CR 23 R 24 ) n1 C(O)OR 3 , —C(O)NR 24 R 25 , —(CR 23 R 24 ) n1 C(O)NR 25 OR 3 , —C(O)SR 3 , —NR 24 R 25 , —NR 25 C(O)R 4 , —NR 25 C(O)OR 3 , —NR 25 C(O)NR 24 R 25 , —NR 25 C(O)NR 24 OR 3 , —SR 3 , —S(O) x NR 24 R 25 , —S(O) x NR 25 OR 3 , —CN, —P(O)(R 24 )(OR 24 ), —P(O)(OR 24 )(OR 24 ), —C(R 4 )(═N(OR 3 )), —C(O)—AA—NR 24 R 25 and —C(O)—AA—NR 25 OR 3 ,
wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of V is independently unsubstituted or substituted with one to three independently selected R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below;
W is —(CH 2 )—;
X is unsubstituted phenyl;
U is —O—(CH 2 )—;
n is 0 to 2;
n is 0 to 2;
x is 0 to 2;
AA is
wherein R 31 and R 32 are the same or different and are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, —NR 24 R 25 , —(CH 2 ) 3 NH(C═NH)NH 2 , —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 SH, —CH 2 S—SCH 2 CH(NH 2 )C(O)OCH, —CH 2 CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 CH 2 CH(OH)CH 2 NH 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 (CH 3 ), —CH 2 CH 2 SCH 3 , —CH 2 OH, —CH(OH)(CH 3 ),
or R 31 and R 32 , together with the N to which R 31 is attached and the C to which R 31 is attached, form a 5-membered ring which is unsubstituted or independently substituted with a hydroxyl group;
R 1 is selected from the group consisting of unsubstituted quinolyl, alkyl-substituted quinolyl and aryl-substituted quinolyl;
each R 2 , R 4 and R 5 is the same or different and each is independently selected from the group consisting of H, halo, alkyl, R 22 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 6 , —C(O)R 7 , —C(O)OR 6 , —NR 24 R 25 , —NR 24 C(O)R 25 , —N(═C—O—NR 24 R 25 ), —NR 24 S(O) 2 R 25 ,
wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R 2 , R 4 and R 5 is independently unsubstituted or substituted with one to four independently selected alkyl, R 22 -substituted alkyl or R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 22 moieties below;
each R 3 is the same or different and is independently selected from the group consisting of H, alkyl, R 22 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 6 , —C(O)R 7 , —C(O)OR 6 , —NR 24 R 25 , —NR 24 C(O)R 25 , —N(═C—O—NR 24 R 25 ) and —NR 24 S(O) 2 R 25 ,
each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R 3 is independently unsubstituted or substituted with one to four independently selected alkyl, R 22 -substituted alkyl or R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 22 moieties below;
each R 6 is independently selected from the group consisting of H, alkyl and —OCF 3 ;
each R 7 is independently selected from the group consisting of H, alkyl, heteroaryl and —CF 3 ;
each R 20 is independently selected from the group consisting of: alkyl, R 21 -substituted alkyl, —OR 3 , halo, —CN, —NO 2 , —NR 24 R 25 , C(O)R 3 , —C(O)OR 3 , —C(O)NR 24 R 25 , —S(O) x NR 24 R 25 , —S(O) x R 5 , —CF 3 , —OCF 3 , —CF 2 CF 3 , —C(═NOH)R 3 , aryl, halo-substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —N(R 25 )S(O) x R 5 , —N(R 25 )C(O)R 5 , and —N(R 25 )C(O)NR 24 R 25 ,
wherein each of the aryl, halo-substituted aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of R 20 is independently unsubstituted or substituted with one to four independently selected R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 23 moieties below,
or two R 20 groups taken together with the carbon to which both R 20 groups are attached is
R 21 is one to three substituents independently selected from the group consisting of: —OR 3 , halo, —CN, —NO 2 , —NR 24 R 25 , —C(O)R 3 , —C(O)OR 3 , —C(O)NR 24 R 25 , —S(O) x NR 24 R 25 , SO x R 5 , —CF 3 , —OCF 3 , —CF 2 CF 3 , —C(═NOH)R 3 , R 23 -substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —N(R 25 )S(O) x R 5 , —N(R 25 )C(O)R 5 , and —N(R 25 )C(O)NR 24 R 25 ;
wherein each of the aryl, halo-substituted aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups of R 21 is independently unsubstituted or substituted with one to four independently selected R 23 moieties which can be the same or different, each R 23 moiety being independently selected from the group of R 23 moieties below,
or two R 21 groups taken together with the carbon to which both R 21 groups are attached is
each R 22 is independently selected from the group consisting of: halo, alkynyl, aryl, heteroaryl, —OR 24 , —(C 1 -C 6 alkyl)-OR 24 , —CN, —NO 2 , —NR 24 R 25 , —C(O)R 23 , —C(O)OR 23 , —C(O)NR 24 R 25 , —S(O) x NR 24 R 25 , —S(O) x R 23 , —CF 3 , —OCF 3 , —CF 2 CF 3 , —C(═NOH)R 23 , —N(R 24 )S(O) x R 25 , —N(R 24 )C(O)R 25 , and —N(R 24 )C(O)NR 24 R 25 ,
or two R 22 groups taken together with the carbon to which both R 22 groups are attached is
each R 23 is independently selected from the group consisting of H, hydroxyl, halo and alkyl,
each R 24 is independently selected from the group consisting of H and alkyl;
each R 25 is independently selected from the group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl, —NR 24 R 24 , —(C 1 to C 6 alkyl)NR 24 N 24 , —CF 3 and —S(O) x R 23 ;
each R 26 is independently selected from the group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl and —NR 3 R 4 ;
R 27 is independently selected from the group consisting of heteroaryl, heterocycloalkyl and —NR 24 R 25 ;
R 30 is independently selected from the group consisting of H and R 20 substituent groups above;
R 40 is independently selected from the group consisting of H and R 20 substituent groups above,
or R 30 and R 40 , taken together with the carbon to which R 30 and R 40 are attached, is
with the proviso that at least one of V or T is selected from the group consisting of —C(O)N(R 3 )(OR 4 ), —C(O)OR 3 and —C(O)NR 24 R 25 .
2. The compound according to claim 1 , wherein R 30 is H or —(C 1 -C 6 )alkyl.
3. The compound according to claim 1 , wherein R 40 is H or —(C 1 -C 6 )alkyl.
4. The compound according to claim 1 , wherein T is selected from the group consisting of —C(O)R 4 , —C(O)OR 3 , —C(O)NR 23 R 25 , and —C(O)NR 23 OR 3 .
5. The compound according to claim 4 , wherein T is —C(O)R 4 in which R 4 is a pyrrolidinyl ring that is unsubstituted or substituted with one to three R 22 moieties which are each independently selected from the group consisting of —OR 24 , —(C 1 -C 6 alkyl)-OR 24 and —NR 23 R 24 .
6. The compound according to claim 4 , wherein T is —C(O)OR 3 in which R 3 is alkyl.
7. The compound according to claim 4 wherein T is —C(O)NR 23 R 25 in which R 23 is H or alkyl and R 25 is H, alkyl or —(C 1 to C 6 alkyl)NR 23 N 24 .
8. The compound according to claim 4 , wherein T is —C(O)NR 23 OR 3 in which R 23 is H or alkyl and R 3 is H or alkyl.
9. The compound according to claim 1 , wherein V is —C(O)NR 23 OR 3 in which R 23 is H or alkyl and R 3 is H or alkyl.
10. The compound according to claim 1 , wherein V is —C(O)OR 3 in which R 3 is alkyl.
11. The compound according to claim 1 , wherein n is 1.
12. The compound according to claim 1 , wherein R 1 is unsubstituted quinolyl.
13. The compound according to claim 1 , wherein R 1 is alkyl-substituted quinolyl.
14. The compound according to claim 1 , wherein R 1 is aryl-substituted quinlyol.
15. The compound according to claim 14 , wherein R 1 is phenyl-substituted quinolyl.
16. The compound according to claim 1 , wherein R 2 is H.
17. The compound according to claim 1 , wherein each R 3 is independently H, alkyl or aryl.
18. The compound according to claim 1 , wherein each R 4 is independently H, alkyl or aryl.
19. The compound according to claim 1 , wherein each R 5 is independently H, alkyl or aryl.
20. The compound according to claim 1 , wherein each R 20 is independently selected from the group consisting of alkyl, R 21 -substituted alkyl, —OR 3 , halo, —CN, —NO 2 , —NR 3 R 4 , —C(O)OR 3 , —S(O) x R 5 , —CF 3 , —OCF 3 , aryl, heteroaryl, cycloalkyl, wherein each of the aryl, heteroaryl and cyoloalkyl groups of R 20 is independently unsubstituted or substituted with one to four independently selected R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 23 moieties.
21. The compound according to claim 20 , wherein R 20 is a heteroaryl group selected from the group consisting of pyrazinyl, pyrrolyl, pyridyl and morpholinyl.
22. The compound according to claim 20 , wherein R 20 is a cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl and cyclohexyl.
23. The compound according to claim 20 , wherein each R 20 moiety is selected from the group consisting of —(C 1 -C 6 )alkyl and aryl.
24. The compound according to claim 1 , wherein
M is —(C(R 30 )(R 40 )) m —, wherein m is 1;
V is —C(O)OR 3 or —C(O)NR 25 OR 3 ;
T is R 21 -substituted alkyl, —CN, —C(O)OR 3 , —C(O)NR 25 OR 3 , —C(O)NR 24 R 25 , —C(O)R 4 or —C(R 4 )(═N(OR 3 ));
W is —(CH 2 )—;
X is unsubstituted phenyl;
R 1 is unsubstituted quinolyl, alkyl-substituted quinolyl and aryl-substituted quinolyl; and
R 2 is H.
25. The compound according to claim 24 , wherein R 30 is H or —(C 1 -C 6 )alkyl, and R 40 is H or —(C 1 -C 6 )alkyl.
26. The compound according to claim 24 , wherein T is selected from the group consisting of —C(O)R 4 , —C(O)OR 3 , —C(O)NR 23 R 25 , and —C(O)NR 23 OR 3 .
27. The compound according to claim 26 , wherein T is —C(O)OR 3 or —C(O)NR 23 R 25 .
28. The compound according to claim 24 , wherein V is —C(O)NR 23 OR 3 in which R 23 is H or alkyl and R 3 is H or alkyl.
29. The compound according to claim 24 , wherein R 3 is H or alkyl and R 4 is H or alkyl.
30. The compound according to claim 24 , wherein R 1 is aryl-substituted quinolyl.
31. The compound according to claim 30 , wherein R 1 is phenyl-substituted quinolyl.
32. The compound according to claim 24 , wherein each R 3 is independently H, alkyl or aryl, wherein the alkyl or aryl groups can be unsubstituted or substituted with one to four independently selected R 22 moieties.
33. The compound according to claim 24 , wherein each R 4 is independently H, alkyl or aryl.
34. The compound according to claim 24 , wherein each R 5 is independently H, alkyl or aryl.
35. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or isomer thereof.
36. A compound according to claim 35 , which is selected from the group consisting of
or a pharmaceutically acceptable salt, solvate or isomer thereof.
37. A compound represented by Formula (I):
or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein:
M is —(C(R 30 )(R 40 )) m —, wherein m is 1;
T is selected from the group consisting of R 21 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 3 , —C(O)R 4 , —C(O)OR 3 , —C(O)NR 24 R 25 , —C(O)NR 24 OR 3 , —C(O)SR 3 , —NR 24 R 25 , —NR 25 C(O)R 4 , —NR 25 C(O)OR 3 , —NR 25 C(O)NR 24 R 25 , —NR 25 C(O)NR 24 OR 3 , —NR 25 S(O) x R 3 , —SR 3 , —S(O) x NR 24 R 25 , —S(O) x NR 25 OR 3 , —CN, —P(O)(R 24 )(OR 24 ), —P(O)(OR 24 )(OR 24 ), —C(R 4 )(═N(OR 3 )), —C(O)—AA—NR 24 R 25 and —C(O)—AA—NR 25 OR 3 ,
wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of T is independently unsubstituted or substituted with one to five independently selected R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below;
V is selected from the group consisting of alkyl, R 21 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 3 , —C(O)R 4 , —(CR 23 R 24 ) n1 C(O)OR 3 , —C(O)NR 24 R 25 R —(CR 23 R 24 ) n1 C(O)NR 25 OR 3 , —C(O)SR 3 , —NR 24 R 25 , —NR 25 C(O)R 4 , —NR 25 C(O)OR 3 , —NR 25 C(O)NR 24 R 25 , —NR 25 C(O)NR 24 OR 3 , —NR 25 S(O) x R 3 , —SR 3 , —S(O) x NR 24 R 25 , —S(O) x NR 25 OR 3 , —CN, —P(O)(R 24 )(OR 24 ), —P(O)(OR 24 )(OR 24 ), —C(R 4 )(═N(OR 3 )), —C(O)—AA—NR 24 R 25 and —C(O)—AA—NR 25 OR 3 ,
wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of V is independently unsubstiuted or substituted with one to three independently selected R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below;
W is —(CH 2 )—;
X is unsubstituted phenyl;
U is —O—(CH 2 )—;
n1 is 0 to 2;
x is 0 to 2;
AA is
wherein R 31 and R 32 are the same or different and are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, —NR 24 R 25 , —(CH 2 ) 3 NH(C═NH)NH 2 , —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 SH, —CH 2 S—SCH 2 CH(NH 2 )C(O)OH, —CH 2 CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , —(CH 2 ) 4 NH 2 , —CH 2 CH 2 CH(OH)CH 2 NH 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 (CH 3 ), —CH 2 CH 2 SCH 3 , —CH 2 OH, —CH(OH)(CH 3 ),
or R 31 and R 32 , together with the N to which R 31 is attached and the C to which R 31 is attached, form a 5-membered ring which is unsubstituted or independently substituted with a hydroxyl group;
R 1 is selected from the group consisting of unsubstituted quinolyl, alkyl-substituted quinolyl and aryl-substituted quinolyl;
each R 2 , R 4 and R 5 is the same or different and each is independently selected from the group consisting of H, halo, alkyl, R 22 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 6 , —C(O)R 7 , —C(O)OR 6 , —NR 24 R 25 , —NR 24 C(O)R 25 , —N(═C—O—NR 24 R 25 ), —NR 24 S(O) 2 R 25 ,
wherein each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R 2 , R 4 and R 5 is independently unsubstituted or substituted with one to four independently selected alkyl, R 22 -substituted alkyl or R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 22 moieties below,
each R 3 is the same or different and is independently selected from the group consisting of H, alkyl, R 22 -substituted alkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, —OR 6 , —C(O)R 7 , —C(O)OR 6 , —NR 24 R 25 , —NR 24 C(O)R 25 , —N(═C—O—NR 24 R 25 ) and —NR 24 S(O) 2 R 25 ,
each of the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl and heteroaryl groups of R 3 is independently unsubstituted or substituted with one to four independently selected alkyl, R 22 -substituted alkyl or R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 22 moieties below;
each R 6 is independently selected from the group consisting of H, alkyl and —OCF 3 ;
each R 7 is independently selected from the group consisting of H, alkyl, heteroaryl and —CF 3 ;
each R 20 is independently selected from the group consisting of: alkyl, R 21 -substituted alkyl, —OR 3 , halo, —CN, —NO 2 , —NR 24 R 25 , —C(O)R 3 , —C(O)OR 3 , —C(O)NR 24 R 25 , —S(O) x NR 24 R 25 , —S(O) x R 5 , —CF 3 , —OCF 3 , —CF 2 CF 3 , —C(═NOH)R 3 , aryl, halo-substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —N(R 25 )S(O) x R 5 , —N(R 25 )C(O)R 5 , and —N(R 25 )C(O)NR 24 R 25 ,
wherein each of the aryl, halo-substituted aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups of R 20 is independently unsubstituted or substituted with one to four independently selected R 22 moieties which can be the same or different, each R 22 moiety being independently selected from the group of R 23 moieties below,
or two R 20 groups taken together with the carbon to which both R 20 groups are attached is
R 21 is one to three substituents independently selected from the group consisting of: —OR 3 , halo, —CN, —NO 2 , —NR 24 R 25 , —C(O)R 3 , —C(O)OR 3 , —C(O)NR 24 R 25 , —S(O) x NR 24 R 25 , —SO x R 5 , —CF 3 , —OCF 3 , —CF 2 CF 3 , —C(═NOH)R 3 , R 23 -substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, —N(R 25 )S(O) x R 5 , —N(R 25 )C(O)R 5 , and —N(R 25 )C(O)NR 24 R 25 ;
wherein each of the aryl, halo-substituted aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups of R 21 is independently unsubstituted or substituted with one to four independently selected R 23 moieties which can be the same or different, each R 23 moiety being independently selected from the group of R 23 moieties below,
or two R 21 groups taken together with the carbon to which both R 21 groups are attached is
each R 22 is independently selected from the group consisting of: halo, alkynyl, aryl, heteroaryl, —OR 24 , —(C 1 -C 6 alkyl)—OR 24 , —CN, —NO 2 , —NR 24 R 25 , —C(O)R 23 , —C(O)OR 23 , —C(O)NR 24 R 25 , —S(O) x NR 24 R 25 , —S(O) x R 23 , —CF 3 , OCF 3 , —CF 2 CF 3 , —C(═NOH)R 23 , —N(R 24 )S(O) x R 25 , —N(R 24 )C(O)R 25 , and —N(R 24 )C(O)NR 24 R 25 ,
or two R 22 groups taken together with the carbon to which both R 22 groups are attached is
each R 23 is independently selected from the group consisting of H, hydroxyl, halo and alkyl;
each R 24 is independently selected from the group consisting of H and alkyl;
each R 25 is independently selected from the group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl, —NR 24 R 24 , —(C 1 to C 6 alkyl)NR 24 N 24 , —CF 3 and —S(O) x R 23 ;
each R 26 is independently selected from the group consisting of H, hydroxyl, alkyl, hydroxyalkyl, aryl, cycloalkyl, heteroaryl and —NR 3 R 4 ;
R 27 is independently selected from the group consisting of heteroaryl, heterocycloalkyl and —NR 24 R 25 ;
R 30 is independently selected from the group consisting of H and R 20 substituent groups above;
R 40 is independently selected from the group consisting of H and R 20 substituent groups above,
or R 30 and R 40 , taken together with the carbon to which R 30 and R 40 are attached, is
with the provisos that at least one of V or T is selected from the group consisting of —C(O)N(R 3 )(OR 4 ), —C(O)OR 3 and —C(O)NR 24 R 25 , and when one of T or V is —NR 25 S(O) x R 3 , the other of T or V is not —C(O)NR 25 OR 3 .
38. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable addition salt, solvate or isomer thereof, in combination with a pharmaceutically acceptable carrier.
39. A pharmaceutical composition for the treatment of inflammation in a subject, comprising an effective amount of a combination of a compound of claim 1 or a pharmaceutically acceptable salt, solvate or isomer thereof, an anti-inflammatory agent different from the compound of claim 1 and a pharmaceutically acceptable carrier.
40. A compound according to claim 36 , which is:
41. A compound having the structure: