Inhibitors of leukotriene A4 hydrolase
View Patent ↗The present invention is directed to compounds encompassed by the Formula (I): pharmaceutical compositions thereof, methods for inhibiting LTA-4 hydrolase, and methods for the treatment of a disease and disorder which is ameliorated by the inhibition of LTA4 h activity. Non-limiting examples of such diseases and conditions include inflammatory and autoimmune diseases and disorders.
1. A compound having the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R is the group:
r is 0 to 4;
R 1a , R 1b , R 1c , R 1d and R 1e are each independently hydrogen, OR 10 , C(O)OR 10 , C(O)R 10 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
R 3 is —O—;
R 4 is a direct bond, —O—R 12a , an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 3 to C 12 alkynylene chain;
R 7 is selected from the group consisting of hydrogen, OR 10 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
each R 9 is independently —OR 10 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, halo, aryl, or heteroaryl;
each R 10 and R 11 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
or R 10 and R 11 , together with the nitrogen to which they are attached, form an optionally substituted N-heterocyclyl or an optionally substituted N-heteroaryl;
R 12a is an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 3 to C 12 alkynylcnc chain;
each R 13 is independently a direct bond, an optionally substituted straight or branched C 1 to C 12 alkylene chain, an optionally substituted straight or branched C 2 to C 12 alkenylene chain, or an optionally substituted straight or branched C 3 to C 12 alkynylene chain; and
R 16 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 ,N(R 10 )C(O)N(R 10 )R 11 , NR 10 R 11 , and N(R 10 )C(O)R 10 ;
each R 17 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , S(O) j R 10 , S(O) j NR 10 R 11 , C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , NR 10 R 11 , and N(R 10 )C(O)R 10 ;
wherein w is an integer from 1 to 3; and
j is 0, 1, or 2.
2. The compound of claim 1 , wherein R 16 is cyano; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein w is 1 and R 17 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and C(O)R 20 , wherein R 20 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein the compound has the Formula (Ia):
or a pharmaceutically acceptable salt thereof;
wherein each R 19 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , S(O) j R 10 , S(O) j NR 10 R 11 ; C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , NR 10 R 11 , and N(R 10 )C(O)R 10 ;
wherein z is an integer from 1 to 5.
5. The compound of claim 4 , wherein z is 1 or 2, and each R 19 is independently selected from the group consisting of hydrogen, hydroxyl, halo, optionally substituted C 1 -C 4 alkyl, C(O)R 10 , C(O)OR 10 , NO 2 , S(O) j R 10 and S(O) j NR 10 R 11 ; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4 , wherein R 16 is cyano; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein the compound has the Formula (Ib):
or a pharmaceutically acceptable salt thereof;
wherein each R 21 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR 10 , NO 2 , S(O) j R 10 , S(O) j NR 10 R 11 ; C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , N(R 10 )C(O)N(R 10 )R 11 , NR 10 R 11 , and N(R 10 )C(O)R 10 ;
wherein z is an integer from 1 to 5.
8. The compound of claim 7 , wherein z is 1 or 2, and each R 21 is independently selected from the group consisting of hydrogen, hydroxyl, halo, optionally substituted C 1 -C 4 alkyl, C(O)R 10 , C(O)OR 10 , NO 2 , S(O) j R 10 and S(O) j NR 10 R 11 ; or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein each R 21 is independently selected from the group consisting of hydrogen, hydroxyl and halo, or a pharmaceutically acceptable salt thereof.
10. The compound of claim 3 , wherein R 17 is optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein R 17 is an optionally substituted heteroaryl containing one or more ring nitrogen atoms; or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 , wherein R 17 is optionally substituted pyridyl; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 7 , wherein R 16 is cyano; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein R 1a is selected from the group consisting of hydrogen, C(O)OR 10 , C(O)R 10 , optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 3 -C 15 cycloalkyl, optionally substituted C 3 -C 15 cycloalkenyl, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein R 1a is selected from the group consisting of hydrogen, C(O)OR 10 , C(O)R 10 , optionally substituted alkyl, halo, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted thiazolyl, and optionally substituted oxazolyl; and wherein R 1b , R 1c , R 1d and R 1e are each hydrogen, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein R 4 is a direct bond, an optionally substituted methylene or an optionally substituted ethylene, or a pharmaceutically acceptable salt thereof.
17. The compound of claim 16 , wherein R 4 is methylene, or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof.
19. The compound of claim 18 , wherein R 7 is hydrogen, C 1 -C 6 alkyl optionally substituted with OR 10 , or C 1 -C 6 alkyl optionally substituted with NR 10 R 11 , or a pharmaceutically acceptable salt thereof.
20. The compound of claim 19 , wherein R 7 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 selected from the following compounds, or a pharmaceutically acceptable salt thereof:
X
Y
PhO
NH 2
PhO
PhO
PhO
PhO
PhO
PhO
OPh
—OPh
—OPh
—OPh
—OPh
—OPh
22. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
23. The compound of claim 4 , wherein r is 0 and R 4 is a direct bond; or a pharmaceutically acceptable salt thereof.
24. The compound of claim 7 , wherein r is 0 and R 4 is a direct bond; or a pharmaceutically acceptable salt thereof.
25. The compound of claim 10 , wherein r is 0 and R 4 is a direct bond; or a pharmaceutically acceptable salt thereof.
26. The compound of claim 18 , wherein r is 0 and R 4 is a direct bond; or a pharmaceutically acceptable salt thereof.