Inhibitors of leukotriene A4 hydrolase

1. A method of treating cystic fibrosis in a human patient in need thereof, wherein the method comprises administering to the patient an effective amount of a compound having the Formula (I):

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 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 alkynylene 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;

as a single stereoisomer or as a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein R 16 is cyano.

3. The method 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 optionally substituted aryl and optionally substituted heteroaryl.

4. The method of claim 1 , wherein the compound has the Formula (Ia)

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 ; and

wherein z is an integer from 1 to 5.

5. The method of claim 1 , wherein the compound has the Formula (Ib):

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 ; and

wherein z is an integer from 1 to 5.

6. The method of claim 3 , wherein R 17 is optionally substituted heteroaryl.

7. The method of claim 6 , wherein R 17 is an optionally substituted heteroaryl containing one or more ring nitrogen atoms.

8. The method of claim 1 , wherein R 1a is 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, and each of R 1b , R 1c , R 1d , and R 1e is hydrogen.

9. The method of claim 1 , wherein R 4 is a direct bond, an optionally substituted methylene, or an optionally substituted ethylene.

10. The method of claim 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:

X

Y

PhO z

NH 2

PhO z

PhO z

PhO z

PhO z

PhO z

PhO z

—OPh

—OPh

—OPh

—OPh

—OPh

11. The method of claim 1 , wherein R 7 is hydrogen or optionally substituted C 1 -C 6 alkyl.

12. The method of claim 11 , 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 .

13. The method of claim 12 , wherein R 7 is hydrogen or methyl.

14. The method 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 .

15. The method of claim 14 , wherein R 16 is cyano.

16. The method of claim 5 , 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 .

17. The method of claim 16 , wherein R 16 is cyano.

18. The method of claim 17 , wherein each R 21 is independently selected from the group consisting of hydrogen, hydroxyl and halo.

19. The method of claim 7 , wherein R 17 is optionally substituted pyridyl.

20. The method of claim 8 , 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.

21. The method of claim 9 , wherein R 4 is a direct bond.