5-lipoxygenase-activating protein (FLAP) inhibitors

1. A compound of Formula (B):

wherein,

Z is selected from N(R 1 ), S(O) m , CR 1 ═CR 1 , —C≡C—, C(R 1 ) 2 [C(R 2 ) 2 ] n , [C(R 2 ) 2 ] n C(R 1 ) 2 O, OC(R 1 ) 2 [C(R 2 ) 2 ] n , [C(R 2 ) 2 ] n C(R 1 ) 2 S(O) m , S(O) m C(R 1 ) 2 [C(R 2 ) 2 ] n , [C(R 2 ) 2 ] n C(R 1 ) 2 NR 1 , NR 1 C(R 1 ) 2 [C(R 2 ) 2 ] n , [C(R 2 ) 2 ] n O[C(R 1 ) 2 ] n , [C(R 1 ) 2 ] n O[C(R 2 ) 2 ] n , —C(O)NR 2 —, —NR 2 C(O)—, —NR 2 C(O)O—, —OC(O)NR 2 —, —S(O) 2 NR 2 —, —CR 1 ═N—N—, NR 2 C(O)NR 2 —, —OC(O)O—, S(O) 2 NR 2 , or —NR 2 S(O) 2 —,

each R 1 is independently H, CF 3 , or an optionally substituted lower alkyl or two R 1 on the same carbon may join to form an oxo (═O);

each R 2 is independently H, OH, OMe, CF 3 , or an optionally substituted lower alkyl or

two R 2 on the same carbon may join to form an oxo (═O); m is 0, 1 or 2; each n is independently 0, 1, 2, or 3;

Y is H, —CO 2 H, tetrazolyl, —NHS(═O) 2 R 3b , S(═O) 2 N(R 4 ) 2 , OH, —OR 3b , —C(═O)(C 1 -C 5 fluoroalkyl), —C(O)NHS(═O) 2 R 3b , —S(═O) 2 NHC(O)R 4 , CN, N(R 4 ) 2 , —N(R 4 )C(O)R 4 , —C(═NR 3 )N(R 4 ) 2 , —NR 4 C(═NR 3 )N(R 4 ) 2 , —NR 4 C(═CHR 3 )N(R 4 ) 2 , —C(O)NR 4 C(═NR 3 )N(R 4 ) 2 , —C(O)NR 4 C(═CHR 3 )N(R 4 ) 2 , —CO 2 R 3b , —C(O)R 4 , —CON(R 4 ) 2 , —SR 3b , —S(═O)R 3b , —S(═O) 2 R 3b , -L 1 -(substituted or unsubstituted alkyl), -L 1 -(substituted or unsubstituted alkenyl), -L 1 -(substituted or unsubstituted alkynyl), -L 1 -(substituted or unsubstituted cycloalkyl), -L 1 -(substituted or unsubstituted heteroalicyclic group), -L 1 -(substituted or unsubstituted heteroaryl), -L 1 -(substituted or unsubstituted aryl) or -L 1 -C (═NR 4 )N(R 4 ) 2 , -L 1 -NR 4 C(═NR 4 )N(R 4 ) 2 , -L 1 -NR 4 C(═CHR 3 )N(R 4 ) 2 ;

where L 1 is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroalicyclic group, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, a substituted or unsubstituted heteroalkynyl, or substituted or unsubstituted aryl;

where each substituent is L s R s , wherein each L s is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O) 2 —, —NHC(O)—, —C(O)NH—, S(═O) 2 NH—, —NHS(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—, —C(O)O—, —OC(O)—, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —C 1 -C 6 fluoroalkyl, heteroaryl, aryl, or heteroalicyclic group; and each R s is independently selected from H, halogen, —N(R 4 ) 2 , —CN, —NO 2 , N 3 , —S(═O) 2 NH 2 , lower alkyl, lower cycloalkyl, —C 1 -C 6 -fluoroalkyl, heteroaryl, or heteroalkyl;

each R 3 is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; each R 3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R 4 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R 3b and R 4 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;

R 6 is L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heteroalicyclic group), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl);

L 2 is O, S, —S(═O), —S(═O) 2 , C(O), or —CH(OH);

R 7 is H or substituted or unsubstituted alkyl;

R 5 is H, halogen, —N 3 , —CN, —NO 2 , -L 6 -(substituted or unsubstituted C 1 -C 6 alkyl), -L 6 -(substituted or unsubstituted C 2 -C 6 alkenyl), -L 6 -(substituted or unsubstituted heteroaryl), or -L 6 -(substituted or unsubstituted aryl), wherein L 6 is a bond, O, S, —S(═O), S(═O) 2 , NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), —NHC(O)NH—, or —C(O)NH;

R 11 is L 7 -L 10 -G 6 ; wherein

L 7 is a bond, —O, —S, —S(═O), —S(═O) 2 , —NH, —C(O), —C(O)NH, —NHC(O), (substituted or unsubstituted C 1 -C 6 alkyl), or (substituted or unsubstituted C 2 -C 6 alkenyl);

L 10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group);

G 6 is H, CN, SCN, N 3 , NO 2 , halogen, OR 9 , —C(═O)CF 3 , —C(═O)R 9 , —SR 8 , —S(═O)R 8 , —S(═O) 2 R 8 , N(R 9 ) 2 , tetrazolyl, —NHS(═O) 2 R 8 , —S(═O) 2 N(R 9 ) 2 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CHR 10 )N(R 9 ) 2 , -L 5 -(substituted or unsubstituted alkyl), -L 5 -(substituted or unsubstituted alkenyl), -L 5 -(substituted or unsubstituted heteroaryl), or -L 5 -(substituted or unsubstituted aryl), wherein L 5 is —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or

G 6 is W-G 7 , wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl);

and G 7 is H, tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , OH, —OR 8 , —C(═O)CF 3 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CHR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═NR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═CHR 10 )N(R 9 ) 2 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , or —S(═O) 2 R 8 , -L 5 -(substituted or unsubstituted alkyl), -L 5 -(substituted or unsubstituted alkenyl), -L 5 -(substituted or unsubstituted heteroalkyl), -L 5 -(substituted or unsubstituted heteroaryl), -L 5 -(substituted or unsubstituted heteroalicyclic group), or -L 5 -(substituted or unsubstituted aryl), wherein L 5 is —NH, —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O);

R 12 is L 3 -X-L 4 -G 1 , wherein,

L 3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclic group;

X is a bond, O, —C(═O), —CR 9 (OR 9 ), S, —S(═O), —S(═O) 2 , —NR 9 , —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 9 C(O)NR 9 —, heteroaryl, aryl, —NR 9 C(═NR 10 )NR 9 —, —NR 9 C(═NR 10 )—, —C(═NR 10 )NR 9 —, —OC(═NR 10 )—, or —C(═NR 10 )O—;

L 4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

G 1 is tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , —OR 9 , —C(═O)CF 3 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CHR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═NR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═CHR 10 )N(R 9 ) 2 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , —S(═O) 2 R 8 , -L 5 -(substituted or unsubstituted alkyl), -L 5 -(substituted or unsubstituted alkenyl), -L 5 -(substituted or unsubstituted heteroaryl), or -L 5 -(substituted or unsubstituted aryl), wherein L 5 is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or

G 1 is W-G 5 , where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl;

G 5 is tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , OH, —OR 8 , —C(═O)CF 3 , —C(O)NHS(═O) 2 R 8 , —S(═O) 2 NHC(O)R 9 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═NR 10 )N(R 9 ) 2 , —NR 9 C(═CHR 10 )N(R 9 ) 2 , —C(O)NR 9 C(═NR 10 (R 9 ) 2 , —C(O)NR 9 C(═CHR 10 )N(R 9 ) 2 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , or —S(═O) 2 R 8 ;

each R 8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;

each R 9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or

two R 9 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

R 8 and R 9 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; and

each R 10 is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl;

or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:

Z is [C(R 2 ) 2 ] n C(R 1 ) 2 O.

3. The compound of claim 2 , wherein:

Y is H, —CN, -L 1 -(substituted or unsubstituted alkyl), -L 1 -(substituted or unsubstituted heteroaryl), or -L 1 -(substituted or unsubstituted aryl); and L 1 is a bond.

4. The compound of claim 3 , wherein:

Y is -L 1 -substituted or unsubstituted heteroaryl.

5. The compound of claim 4 , wherein:

Y is a substituted or unsubstituted heteroaryl selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

6. The compound of claim 5 , wherein:

R 7 is an unsubstituted alkyl.

7. The compound of claim 6 , wherein:

R 6 is L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted aryl);

L 2 is a bond, O, S, —S(O) 2 , —C(O), —CH(OH), or substituted or unsubstituted alkyl.

8. The compound of claim 7 , wherein:

X is a bond.

9. The compound of claim 8 , wherein:

L 3 is a bond.

10. The compound of claim 9 , wherein:

L 4 is a bond, or (substituted or unsubstituted alkyl).

11. The compound of claim 10 , wherein:

G 1 is tetrazolyl, —OR 9 , —C(═O)CF 3 , CN, N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 .

12. The compound of claim 11 , wherein:

G 1 is CO 2 H.

13. The compound of claim 12 , wherein:

L 7 is a bond; and

L 10 is (substituted or unsubstituted aryl).

14. The compound of claim 13 , wherein:

G 6 is H, ON, SON, N 3 , NO 2 , halogen, OR 9 , —C(═O)CF 3 , —C(═O)R 9 , tetrazolyl, or -L 5 -(substituted or unsubstituted alkyl).

15. The compound of claim 14 , wherein:

R 11 is L 7 -L 10 -W-G 7 .

16. The compound of claim 15 , wherein:

W is (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group).

17. The compound of claim 16 , wherein:

G 7 is H, halogen, ON, NO 2 , N 3 , CF 3 , OCF 3 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 fluoroalkyl, tetrazolyl, —OH, —OR 8 , —C(═O)CF 3 , —ON, —CO 2 R 9 , —C(O)R 9 , or —CON(R 9 ) 2 .

18. The compound of claim 1 , wherein the compound is an inhibitor of 5-lipoxygenase-activating protein (FLAP).

19. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.