Biaryl substituted heterocycle inhibitors of LTA4H for treating inflammation

1. A compound of formula:

wherein

Ar is selected from the group consisting of

phenyl optionally substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, hydroxy, hydroxy(C 1 -C 4 ) alkyl, formyl, formyl(C 1 -C 4 ) alkyl, cyano, cyano(C 1 -C 4 ) alkyl, benzyl, benzyloxy, phenyl, heteroaryl, heterocyclylalkyl, and substituted heteroaryl; and

heteroaryl selected from benzoxazole, benzothiazole, benzimidazole, pyridine, pyrazole, thiophene, furan, and thiazole, wherein said heteroaryl is optionally substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, phenyl, heteroaryl, and heterocyclylalkyl;

X is selected from the group consisting of direct bond, O, NR 1 , CH 2 , CF 2 , CH 2 CH 2 , CH 2 NR 1 , NR 1 CH 2 , CH═CH, C═O, CH 2 C═O, CR 1a R 1b , OCR 1a R 1b , and CR 1a R 1b O;

Ar is attached to X via a ring atom of Ar;

R 1 is selected separately in each occurrence from the group consisting of H and lower alkyl;

R a is selected from the group consisting of H, OH and lower alkyl;

R 1b is selected from the group consisting of H and lower alkyl;

Q is —O—;

n is an integer selected from 1-5;

HET is selected from the group consisting of piperidine and piperazine, wherein said piperidine or piperazine is optionally substituted with one or two substituents independently selected from the group consisting of hydroxyl, carboxy, loweralkyl, benzyl, and benzyloxy; and

taken together ZW is H or

Z is (CH 2 ) 1-10 , in which one (CH 2 ) may optionally be replaced by NR 1 provided that said NR 1 is not at the point of attachment to HET;

W is selected from the group consisting of acyl, hydroxyl, carboxyl, C(O)NHR 4 , COOalkyl, heterocyclyl, heterocyclyl substituted with (C 1 -C 4 ) alkyl, and C(O)NH(OH); and

R 4 is selected from the group consisting of H, (C 1 -C 4 ) alkyl, and phenyl(C 1 -C 4 ) alkyl, with the proviso that when Q is —O—, HET is piperidine, and Ar is phenyl or halo-substituted phenyl, then the Z-W combination is other than H.

2. A compound according to claim 1 wherein X is selected from CH 2 , O and NR 1 .

3. A compound according to claim 1 , wherein HET is piperidin-2-yl.

4. A compound according to claim 1 , wherein HET is selected from the group consisting of

piperidine, piperazine,

piperidine substituted with one or two substituents independently selected from the group consisting of hydroxyl, carboxy, loweralkyl, benzyl, and benzyloxy; and

piperazine substituted with one or two substituents independently selected from the group consisting of carboxy, loweralkyl, benzyl, and benzyloxy.

5. A compound according to claim 1 wherein Ar is

wherein the wavy line indicates the point of attachment to X and R 2 is chosen from hydrogen, halogen, trifluoromethyl, methyl, methoxy, thienyl, furanyl, thiophene, and thienyl or furanyl substituted with halogen, trifluoromethyl, methyl or methoxy.

6. A compound according to claim 1 , wherein Q=O, n=1 or 2, and HET-Z-W is selected from piperidine, piperazine, 4-(piperidin-1-yl)butanoic acid, methyl 3-(piperidin-1-yl)propanoate, methyl 4-(piperidin-1-yl)butanoate, 1-benzylpiperazine, 1-((1,2,4-oxadiazol-5-yl)methyl)piperazine, and 2-(piperidin-1-yl)acetic acid.

7. A compound according to claim 1 , wherein the compound is selected from

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 .

9. A method for inhibiting leukotriene A4 hydrolase comprising contacting the LTA4H enzyme with a therapeutically effective amount of a compound according to claim 1 .

10. A method for treating inflammation comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 .

11. A method according to claim 10 wherein said inflammation is selected from allergic inflammation, acute inflammation and chronic inflammation.

12. A method for treating inflammation comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 and an inhibitor of 5-lipoxygenase activating protein (FLAP).

13. A method for treating inflammation comprising administering to a mammal a therapeutically effective amount of a compound according to claim 1 and a leukotriene B4 (LTB4) antagonist.