Inhibitors of leukotriene A4 hydrolase

1. A compound having the Formula (I):

wherein:

R is i) the group;

r is 0 to 4;

q is 1;

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 3- to 18-membered heteroaryl, or optionally substituted 3- to 18-membered heterocyclyl;

R 3 is —O—;

R 4 is a direct bond;

each R 5a and R 6a are each independently hydrogen and optionally substituted alkyl;

R 7 is —C(R 5b ) 2 —R 15 ;

each R 5b is independently hydrogen or optionally substituted C 1 -C 6 alkyl;

R 15 is selected from the group consisting of C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , optionally substituted aryl, and optionally substituted 3- to 18-membered heteroaryl;

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, optionally substituted aryl, or optionally substituted 3- to 18-membered heteroaryl;

each R 10 and R 11 is independently 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 3- to 18-membered heteroaryl, or optionally substituted 3- to 18-membered heterocyclyl;

R 12 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 2 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 14 is an optionally substituted azetidinyl;

wherein each of the optionally substituted moieties is optionally substituted by one, two, or three substituents independently selected from the group consisting of —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 3 -C 15 cycloalkyl, —C 3 -C 15 cycloalkenyl, C 3 -C 15 cycloalkynyl, -heterocyclic, —F, —Cl, —Br, —I, —OH, —NO 2 , —N 3 , —CN, —NH 2 , oxo, thioxo, —NHR x , —NR x R x , dialkylamino, -diarylamino, -diheteroarylamino, —OR x , —C(O)OR y , —C(O)R y , —C(O)C(O)R y , —OCO 2 R y , —OC(O)R y , OC(O)C(O)R y , —NHC(O)R y , —NHCO 2 R y , —NHC(O)C(O)R y , —NHC(S)NH 2 , —NHC(S)NHR x , —NHC(NH)NH 2 , —NHC(NH)NHR x , —NHC(NH)R x , —C(NH)NHR x , —NR x C(O)R x , —NR x CO 2 R y , —NR x C(O)C(O)R y , —NR x C(S)NH 2 , —NR x C(O)NR x R x , —NR x S(O) 2 NR x R x , —NR x C(S)NHR x , —NR x C(NH)NH 2 , —NR x C(NH)NHR x , —NR x C(NH)R x , —C(NR x )NHR x —S(O) n R y , —NHSO 2 R x , —CH 2 NH 2 , —CH 2 SO 2 CH 3 , —(C═NR x )R x ; -aryl, -arylalkyl, -3- to 18-membered heteroaryl, -3- to 18-membered heteroarylalkyl, -3- to 18-membered heterocycloalkyl, -polyalkoxyalkyl, -polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—R x , or -methylthiomethyl;

R x is selected from the group consisting of hydrogen, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 3 -C 15 cycloalkyl, -aryl, -3- to 18-membered heteroaryl and -3- to 18-membered heterocyclic;

R y is selected from the group consisting of hydrogen, —C 1 -C 12 alkyl, —C 2 -C 12 alkenyl, —C 2 -C 12 alkynyl, —C 3 -C 15 cycloalkyl, -aryl, -3- to 18-membered heteroaryl, -3- to 18-membered heterocyclic, —NH 2 , —NH—C 1 -C 12 alkyl, —NH—C 2 -C 12 alkenyl, —NH—C 2 -C 12 -alkynyl, —NH—C 3 -C 15 cycloalkyl, —NH-aryl, —NH-3- to 18-membered heteroaryl and —NH-3- to 18-membered heterocyclic,

and n is 0, 1 or 2;

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

2. The compound of claim 1 , wherein R 15 is C(O)OR 10 .

3. The compound of claim 1 , wherein R 15 is optionally substituted phenyl.

4. The compound of claim 1 , wherein R 15 is optionally substituted heteroaryl.

5. The compound of claim 1 , wherein R 14 is optionally substituted azetidin-3-yl.

6. The compound of claim 5 , wherein R 14 is:

wherein R 17 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 12 alkyl, C(O)R 10 and C(O)OR 10 .

7. The compound of claim 1 , wherein each R 5a and R 6a are each independently hydrogen, alkyl, haloalkyl or hydroxyalkyl.

8. The compound of claim 1 , wherein R 1a is hydrogen, C(O)OR 10 , C(O)R 10 , C(O)—R 13 —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, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

9. The compound of claim 8 , wherein R 1a is hydrogen, C(O)OR 10 , C(O)R 10 , C(O)—R 13 —N(R 10 )R 11 , optionally substituted C 1 -C 12 alkyl, halo, optionally substituted phenyl, optionally substituted furanyl, optionally substituted thienyl, optionally substituted thiazolyl, or optionally substituted oxazolyl; and wherein R 1b , R 1c , R 1d and R 1e are each hydrogen.

10. The compound of claim 1 selected from the compounds shown in the following Table, or a pharmaceutically acceptable salt thereof:

X

Y

11. The compound of claim 3 , wherein R 15 is phenyl optionally substituted with one or more groups selected from the group consisting of halo, C(O)R 10 , C(O)OR 10 , C(O)—R 13 —N(R 10 )R 11 , S(O) j R 10 , and S(O) j NR 10 R 11 , wherein j is 0, 1 or 2.

12. The compound of claim 1 , wherein r is 0.

13. The compound of claim 1 , wherein each R 9 is independently optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, halo, optionally substituted aryl, or optionally substituted heteroaryl.

14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15. A method of treating an inflammatory or autoimmune disorder in a mammal in need thereof, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the inflammatory or autoimmune disorder is selected from the group consisting of a pulmonary or respiratory tract inflammation and an inflammatory skin condition.

16. The method of claim 15 , wherein the mammal is a human.

17. The method of claim 15 , wherein the inflammatory or autoimmune disorder is a pulmonary or respiratory tract inflammation.

18. The method of claim 15 , wherein the inflammatory disorder is an inflammatory skin condition.

19. The method of claim 18 , wherein the inflammatory skin condition is selected from the group consisting of atopic dermatitis, acne, psoriasis and eczema.

20. The method of claim 17 , wherein pulmonary or respiratory inflammation is a disorder selected from the group consisting of asthma, cystic fibrosis, chronic bronchitis, bronchiolitis, bronchiolitis obliterans, allergic inflammation of the respiratory tract, eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary diseases, adult respiratory distress syndrome, and other non-infectious inflammatory disorders of the lung characterized by eosinophil infiltration.