5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) INHIBITORS
Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.
1 . A compound of Formula (G):
wherein,
Z is selected from S(O) m , C(R 1 ) 2 S(O) m , S(O) m C(R 1 ) 2 , wherein each R 1 is independently H, CF 3 , or an optionally substituted C 1 -C 6 alkyl; m is 0, 1 or 2;
Y is a (substituted or unsubstituted aryl), or -(substituted or unsubstituted heteroaryl);
R 6 is H, 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 heterocycloalkyl), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(O), —CH(OH), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);
R 7 is L 3 -X-L 4 -G 6 , wherein,
L 3 is a or substituted or unsubstituted alkyl;
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 , —NR 9 C(O)NR 9 —;
L 4 is a bond, a substituted or unsubstituted branched alkyl, a substituted or unsubstituted straight chain alkyl, a substituted or unsubstituted cyclic alkyl, or a substituted or unsubstituted heterocycloalkyl;
G 1 is H, 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 , —NR 9 C(═NR 10 )N(R 9 )C(═O)R 9 , —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 , —C(R 9 ) 2 (OR 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, —OC(O)NH—, —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 heterocycloalkyl or substituted or unsubstituted heteroaryl and G 5 is H, tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , OH; —OR 8 , —C(═O)CF 3 , —C(R 9 ) 2 (OR 9 ), —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 ;
each R 8 is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl;
each R 9 is independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, and substituted or unsubstituted heteroarylmethyl; 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;
R 5 is H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted —O—C 1 -C 6 alkyl;
R 11 is L 7 -L 10 -G 6 , wherein L 7 is a bond, —C(O), —C(O)NH, —NHC(O), or (substituted or unsubstituted C 1 -C 6 alkyl); L 10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycloalkyl);
G 6 is OR 9 , —C(═O)R 9 , —C(═O)OR 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(═O)N(R 9 ) 2 , N R 9 C(O)R 9 , C(R 9 ) 2 C(═O)N(R 9 ) 2 , —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 —O—, C(═O), S, S(═O), S(═O) 2 , —NH, —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 heterocycloalkyl), (substituted or unsubstituted aryl) or a (substituted or unsubstituted heteroaryl) and G 7 is H, halogen, CN, NO 2 , N 3 , CF 3 , OCF 3 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 fluoroalkyl, 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 , —C(R 9 ) 2 (OR 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 heterocycloalkyl), or -L 5 -(substituted or unsubstituted aryl), wherein L 5 is a bond, —O—, C(═O), S, S(═O), S(═O) 2 , —NH, —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O);
provided that R 11 comprises at least one (unsubstituted or substituted) aromatic moiety and at least one (unsubstituted or substituted) cyclic moiety, wherein the (unsubstituted or substituted) cyclic moiety is a (unsubstituted or substituted) heterocycloalkyl group or a (unsubstituted or substituted) heteroaryl group and R 11 is not a thienyl-phenyl group; and
R 12 is H, (substituted or unsubstituted C 1 -C 6 alkyl), (substituted or unsubstituted C 3 -C 6 cycloalkyl);
or glucuronide metabolite, or pharmaceutically acceptable solvate, or pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
2 . The compound of claim 1 , wherein:
Z is S(O) m or C(R 1 ) 2 S(O) m ; and
R 1 is independently H, CF 3 , or an optionally substituted C 1 -C 6 alkyl.
3 . The compound of claim 2 , wherein:
m is 0; and
R 1 is H or methyl.
4 . The compound of claim 3 , wherein:
Y is -(substituted or unsubstituted heteroaryl); and
G 6 is W-G 7 .
5 . The compound of claim 4 , wherein:
Y is a substituted or unsubstituted heteroaryl containing 0-4 nitrogen atoms, 0-1 O atoms and 0-1 S atoms.
6 . The compound of claim 5 , wherein:
Y is selected from the group consisting of 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, imidazo[1,2-a]pyridinyl and furopyridinyl, wherein Y is substituted or unsubstituted.
7 . The compound of claim 6 , wherein:
L 7 is a bond;
L 10 is a (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl); and
W is (substituted or unsubstituted heterocycloalkyl), (substituted or unsubstituted aryl) or a (substituted or unsubstituted heteroaryl).
8 . The compound of claim 7 , wherein:
W is a (substituted or unsubstituted heterocycloalkyl), or a (substituted or unsubstituted heteroaryl).
9 . The compound of claim 8 , wherein:
L 10 is a (substituted or unsubstituted aryl); and
R 12 is H.
10 . The compound of claim 9 , wherein:
W is a (substituted or unsubstituted heterocycloalkyl containing 0-2 nitrogen atoms, 0-1 O atoms and O-1 S atoms) or a (substituted or unsubstituted heteroaryl containing 0-4 nitrogen atoms, 0-1 O atoms and O-1 S atoms).
11 . The compound of claim 10 , wherein:
G 7 is H, halogen, CN, NO 2 , CF 3 , OCF 3 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 1 -C 6 fluoroalkyl, 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 , N(R 9 ) 2 , —N(R 9 )C(O)R 9 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , or —S(═O) 2 R 8 .
12 . The compound of claim 11 , wherein:
W is a substituted or unsubstituted group selected from among 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, imidazo[1,2-a]pyridinyl, furopyridinyl, quinolizinyl, dioxinyl, piperidinyl, morpholinyl, thiazinyl, tetrahydropyridinyl, piperazinyl, oxazinanonyl, dihydropyrrolyl, dihydroimidazolyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrooxazolyl, oxiranyl, pyrrolidinyl, pyrazolidinyl, dihydrothiophenonyl, imidazolidinonyl, pyrrolidinonyl, dihydrofuranonyl, dioxolanonyl, thiazolidinyl, piperidinonyl, tetrahydronaphyridinyl, tetrahydroquinolinyl, tetrahydrothiophenyl, indolinyl, tetrahydroquinolinyl, and thiazepanyl.
13 . The compound of claim 12 , wherein:
R 6 is H, or L 2 -(substituted or unsubstituted alkyl), or L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(O), —S(O) 2 , —C(O), —CR 9 (OR 9 ), or substituted or unsubstituted alkyl.
14 . The compound of claim 13 , wherein:
X is a bond, O, —C(═O), —CR 9 (OR 9 ), S, —S(═O), —S(═O) 2 , —NR 9 , —NR 9 C(═O)—, or —C(O)NR 9 .
15 . The compound of claim 14 , wherein:
G 1 is H, 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 , —N(R 9 )CH 2 CO 2 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 , —NR 9 C(═NR 10 )N(R 9 )C(═O)R 9 , —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 , —C(R 9 ) 2 (OR 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), —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 heterocycloalkyl or substituted or unsubstituted heteroaryl and G 5 is H, tetrazolyl, —NHS(═O) 2 R 8 , S(═O) 2 N(R 9 ) 2 , OH, —OR 8 , —C(═O)CF 3 , —C(R 9 ) 2 (OR 9 ), —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 , —CO 2 R 9 , —C(O)R 9 , —CON(R 9 ) 2 , —SR 8 , —S(═O)R 8 , or —S(═O) 2 R 8 .
16 . The compound of claim 15 , wherein:
R 6 is hydrogen; methyl; ethyl; propyl; prop-2-yl; 2-methylpropyl; 2,2-dimethylpropyl; butyl; tert-butyl; 3-methylbutyl; 3,3-dimethylbutyl; cyclopropylmethyl; cyclobutylmethyl; cyclopentylmethyl; cyclohexylmethyl; benzyl; methoxy, ethoxy, propyloxy; prop-2-yloxy; tert-butyloxy; cyclopropylmethoxy; cyclobutylmethoxy; cyclopentylmethoxy; cyclohexylmethoxy; benzyloxy; cyclopropyloxy; cyclobutyloxy; cyclopentyloxy; cyclohexyloxy; phenoxy; acetyl; 2,2,2-trifluoro-acetyl; propanoyl; 2-methylpropanoyl; 2,2-dimethylpropanoyl; 3-methyl-butanoyl; 3,3-dimethylbutanoyl; 2-ethyl-butanoyl; benzoyl; phenylacetyl; cyclopropylcarbonyl; cyclobutylcarbonyl; cyclopentylcarbonyl; cyclohexylcarbonyl; tert-butylsulfanyl; tert-butyl-sulfinyl; or tert-butylsulfonyl.
17 . The compound of claim 16 , wherein:
G 1 is selected from among H, OH, CN, CO 2 H, CO 2 Me, CO 2 Et, CO 2 NH 2 , CO 2 NHMe, CO 2 N(Me) 2 , CO 2 N(Et) 2 , —NH 2 , —NHMe, —N(Me) 2 , —N(Et) 2 , —NMe(iPr),
18 . The compound of claim 17 , wherein:
L 3 -X-L 4 is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 C(CH 3 )H—, —CH 2 C(CH 2 CH 3 )H—, —CH 2 C(isopropyl)H—, —CH 2 C(tert-butyl)H—, —CH 2 C(CH 3 ) 2 —, —CH 2 C(CH 2 CH 3 ) 2 —, —CH 2 C(CH 3 )(CH 2 CH 3 )—,
19 . The compound of claim 18 , wherein:
R 7 is selected from among
20 . The compound of claim 19 , wherein:
R 7 is selected from among
21 . The compound of claim 16 , wherein:
L 3 is an unsubstituted linear alkyl, branched alkyl, or cycloalkyl;
X is a bond;
L 4 is a bond; and
G 1 is OR 9 or —C(O)OR 9 .
22 . The compound of claim 21 , wherein:
L 3 is methandiyl; ethan-1,2-diyl; propan-1,2-diyl; propan-1,3-diyl; 2-methyl-propan-1,2-diyl; 2-ethyl-propan-1,2-diyl; propan-2,2-diyl; butan-1,2-diyl; butan-1,4-diyl; 2-ethyl-butan-1,2-diyl; 2-propylbutan-1,2-diyl; 3-methylbutan-1,2-diyl; 3,3-dimethylbutan-1,2-diyl; pentan-1,2-diyl; 2-propyl-pentan-1,2-diyl, pentan-1,5-diyl; or hexan-1,6-diyl.
23 . The compound of claim 22 , wherein:
L 3 is 2-methyl-propan-1,2-diyl; or 2-ethyl-butan-1,2-diyl.
24 . The compound of claim 16 , wherein:
L 3 is methandiyl; or ethan-1,2-diyl; and
L 4 is methandiyl; ethan-1,1-diyl; propan-1,1-diyl; 2-methylpropan-1,1-diyl; 2,2-dimethylpropan-1,1-diyl; propan-2,2-diyl; butan-1,1-diyl; butan-2,2-diyl; pentan-1,1-diyl; pentan-2,2-diyl; pentan-3,3-diyl; hexan-3,3-diyl; cyclopropan-1,1-diyl; cyclobutan-1,1-diyl; cyclopentan-1,1-diyl; cyclohexan-1,1-diyl; cycloheptan-1,1-diyl; piperidin-4,4-diyl; tetrahydropyran-4,4-diyl; or tetrahydrothiopyran-4,4-diyl; and
G 1 is —OR 9 , or —CO 2 R 9 .
25 . The compound of claim 24 , wherein:
L 3 is methandiyl;
X is a bond;
L 4 is propan-2,2-diyl; pentan-3,3-diyl; cyclopropan-1,1-diyl; cyclobutan-1,1-diyl; cyclopentan-1,1-diyl; cyclohexan-1,1-diyl; or cycloheptan-1,1-diyl; and
G 1 is —CO 2 R 9 .
26 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.