Asthma and allergic inflammation modulators
View Patent ↗Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of inflammatory and immune-related diseases and conditions. In particular, the invention provides compounds which modulate the function and/or expression of proteins involved in atopic diseases, inflammatory conditions and cancer. The subject compounds are carboxylic acid derivatives.
1. A compound having the formula (XVI):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
Y is —S(O) 2 —;
X is —O—;
R 2 is a substituted or unsubstituted benzene ring;
R 3 and R 5 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, hetero(C 2 -C 8 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, —NR′R″, —OR′, —NO 2 , —CN, —C(O)R′, —CO 2 R′, —(O)NR′R″, —C 1 -C 4 )alkylene-C(O)NR′R″, —(O) m R′, —S(O) k NR′R″, —OC(O)OR′, —OC(O)R′, —C(O)NR′R″, N(R′″)C(O)NR′R″, —(R″)C(O)R′ and —N(R″)C(O)OR′;
R 4 is selected from the group consisting of —C(O)NR 12 R 13 and —NHC(O)-alkyl;
R 6 is selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, hetero(C 2 -C 8 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, —NR′R″, —NO 2 , —CN, —C(O)R′, —CO 2 R′, —C(O)NR′R″, —(C 1 -C 4 )alkylene-C(O)NR′R″, —S(O) m R′, —S(O) k NR′R″, —OC(O)OR′, —OC(O)R′, —OC(O)NR′R″, —N(R′″)C(O)NR′R″, —N(R″)C(O)R′and —N(R″)C(O)OR′;
R 10 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, hetero(C 2 -C 8 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, —C(O)R′, —CO 2 R′, —C(O)NR′R″, —S(O) m R′ and —S(O) k NR′R″;
L is a divalent linkage selected from the group consisting of a single bond, (C 1 -C 6 )alkylene and (C 2 -C 4 )heteroalkylene;
Z is —CO 2 R 12 ;
R 12 and R 13 are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, hetero(C 2 -C 8 )alkyl, aryl, aryl(C 1 -C 4 )alkyl and heteroaryl;
each R 14 is independently selected from the group consisting of halogen, (C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, —OR′, —NR′R″, —NO 2 , —CN, —C(O)R′ and aryl;
each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, cyclo(C 3 -C 8 )alkyl, aryl and aryl(C 1 -C 4 )alkyl;
each subscript k is independently 0, 1 or 2;
each subscript m is independently 0, 1, 2 or 3; and
the subscript n is 0, 1, 2, 3 or 4.
2. The compound of claim 1 , wherein R 6 is selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, aryl(C 1 -C 4 )alkyl, —NR′R″, —NO 2 , —CN, —C(O)R′, —CO 2 R′, —C(O)NR′R″, —C 1 -C 4 )alkylene-C(O)NR′R″, —OC(O)OR′, —OC(O)R′, —OC(O)NR′R″, —N(R′″)C(O)NR′R″, —N(R″)C(O)R′ and —N(R″)C(O)OR′.
3. The compound of claim 1 , wherein R 4 is —HHC(O)-cyclo(C 5 -C 7 )alkyl.
4. The compound of claim 1 , wherein R 2 is a substituted benzene ring and at least one substituent on the benzene ring is selected from the group consisting of halogen, —OCF3, —OCH3, —(C 1 -C 5 )alkyl, —CN, and —NO 2 .
5. The compound of claim 4 , wherein R 2 is a benzene ring substituted with at least one halogen.
6. The compound of claim 5 , wherein R 2 is a benzene ring substituted with at least one chlorine.
7. The compound of claim 1 , wherein R 4 is —C(O)NH—(C 1 -C 4 )alkyl.
8. The compound of claim 7 , wherein R 6 is selected from the group consisting of hydrogen, halogen, (C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, —NO 2 , —CN, —C(O)R′, —CO 2 R′, —C(O)NR′R″, —(C 1 -C 4 )alkylene-C(O)NR′R″, —N(R′″)C(O)NR′R″, —N(R″)C(O)R′ and —N(R″)C(O)OR′.
9. The compound of claim 8 , wherein R 2 is a substituted benzene ring and at least one substituent on the benzene ring is selected from the group consisting of halogen, —OCF 3 , —OCH 3 , —(C 1 -C 5 )alkyl, —CN, and —NO 2 .
10. The compound of claim 1 having the formula (XVII):
or a pharmaceutically acceptable salt or prodrug thereof.
11. The compound of claim 10 , wherein R 10 is hydrogen.
12. The compound of claim 11 , wherein R 4 is —C(O)NH—(C 1 -C 4 )alkyl, and R 6 is hydrogen.
13. The compound of claim 12 , wherein R 2 is a benzene ring substituted with 1, 2, or 3 chlorine atoms.
14. The compound of claim 10 , wherein -L-Z taken together are —CH 2 COOH.
15. The compound of claim 14 , wherein the subscript n is 1 or 2.
16. The compound of claim 15 , wherein R 14 is —OCH 2 CH 3 or —OCH 3 .
17. The compound of claim 10 , wherein R 3 , R 5 and R 6 are each hydrogen.
18. The compound of claim 1 , having the formula (XVIII):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 4 is —C(O)NH—(C 1 -C 4 )alkyl; and
the subscript q is 0, 1, 2, 3, 4, 5 or 6.
19. The compound of claim 18 , wherein each R 14 is independently selected from the group consisting of (C 1 -C 6 )alkyl, halogen, fluoro(C 1 -C 4 )alkyl, —C(O)R′, aryl and —OR′ and subscript n is 2 or 3.
20. The compound of claim 1 , wherein the formula is selected from the group consisting of
or pharmaceutically acceptable salt or prodrug thereof.
21. The pharmaceutically acceptable salt or prodrug of a compound of claim 20 .
22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 .
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 20 .
24. The compound of claim 1 , wherein the formula is
or pharmaceutically acceptable salt or prodrug thereof.
25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 24 .