(Halo-benzo carbonyl)heterobi cyclic p38 linase inhibiting agents
View Patent ↗Compounds described by the chemical formula (I) or pharmaceutically acceptable salts thereof: (I) are inhibitors of p38 and are useful in the treatment of inflammation such as in the treatment of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation
1. A compound represented by chemical formula (I) or a pharmaceutically acceptable salt thereof:
wherein
B is —C 1-6 alkyl-, —C 0-3 alkyl-O—C 0-3 alkyl-, —C 0-3 alkyl-NH—C 0-3 alkyl-, —C 0-3 alkyl-S—C 0-3 alkyl-, —C 0-3 alkyl-PH—C 0-3 alkyl-. —C 0-3 alkyl-C(O)—C 0-3 alkyl-, or a direct bond;
X is —C 1-6 alkyl-, —C 0-3 alkyl-O—C 0-3 alkyl-, —C 0-3 alkyl-NH—C 0-3 alkyl-, —C 0-3 alkyl-S—C 0-3 alkyl-, —C 0-3 alkyl-PH—C 0-3 alkyl-, —C 0-3 alkyl-C(O)—C 0-3 alkyl-, or a direct bond;
R, R 71 , and R 72 each independently is hydrogen, OH, or C 1-4 alkyl, any alkyl optionally substituted with 1-6 groups, each group independently being —OH, —NH 2 , —NH—CH 3 , —N(CH 3 ) 2 , or halogen;
n is 1, 2, 3, or 4;
m is 0, 1, 2, 3, or 4;
n+m is 2, 3, 4, 5, or 6; optionally, one of n CH 2 and one of m CH 2 are bridged by a —C 0-2 alkyl- linkage;
E 1 is CH, N, or CR 6 ;
E 2 is CH2, CHR, NH, NR, O, S, —S(O)—, or —S(O)2—;
R 1 is halogen or C 1-4 alkyl;
R 2 , R 3 , R 4 , and R 6 are each independently halogen, Cl4alkyl, or hydrogen; and
R 5 is H, CH 3 , or CH 2 CH 3 .
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof wherein
X is —C 0-3 alkyl-S—C 0-3 alkyl-.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, whereinm
X is —C 0-3 alkyl-S—C 0-3 alkyl-; and
B is a direct bond.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein
E 1 is N; and
E 2 is NR.
5. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof; wherein
E 1 is N;
E 2 is NR; and
one of n CH 2 and one of m CH 2 are bridged by a C 0-2 alkyl- linkage.
6. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein
E 1 is N; and
E 2 is 0.
7. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein
E 1 is N; and
E 2 is CHR.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X is —C 0-3 alkyl-S—C 0-3 alkyl-; and
B is NH.
9. The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein
E 1 is CH; and
E 2 is NR.
10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
X is —C 0-3 alkyl-S—C 0-3 alkyl-; and
B is —C 0-3 alkyl-O—C 0-3 alkyl-.
11. The compound according to claim 1 , represented by
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .