MX2008005632A - 5-lipoxygenase-activating protein (flap) inhibitors - Google Patents
5-lipoxygenase-activating protein (flap) inhibitorsInfo
- Publication number
- MX2008005632A MX2008005632A MXMX/A/2008/005632A MX2008005632A MX2008005632A MX 2008005632 A MX2008005632 A MX 2008005632A MX 2008005632 A MX2008005632 A MX 2008005632A MX 2008005632 A MX2008005632 A MX 2008005632A
- Authority
- MX
- Mexico
- Prior art keywords
- substituted
- unsubstituted
- compound
- alkyl
- nr9c
- Prior art date
Links
- 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 title claims abstract description 16
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Abstract
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.
Description
INHIBITORS OF THE 5-LIPOXYGENASE ACTIVATING PROTEIN (FLAP)
Field of the Invention Compounds for the production of such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods for using such compounds to treat or prevent diseases or conditions associated with the activity of the activator protein are described herein. lipoxygenase (FLAP, for its acronym in English). Background of the Invention The activating protein of 5-lipoxygenase (FLAP) is associated with the leukotriene synthesis pathway. In particular, the activating protein of 5-lipoxygenase (FLAP) is responsible for the binding of arachidonic acid and its transfer to 5-lipoxygenase. See, for example, Abramovitz, M. et al., Eur. J. Biochem. 215: 105-111 (1993). The 5-lipoxygenase can then catalyze the oxygenation of two steps and the dehydration of arachidonic acid, converting it into the intermediate compound 5-HPETE (5-hydroperoxy-eicosatetraenoic acid), and in the presence of FLAP converting 5-HPETE into Leucotri.eno A4 (LTA). Leukotrienes are biological compounds formed from arachidonic acid in the pathway of leukotriene synthesis (Samuelsson et al., Science, 220, 568-575, 1983; Cooper, The Cell, A Molecular Approach, 2nd Ed. Sinauer Associates, Inc., Sunderland (MA), 2000). They are synthesized essentially by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes have been implicated in biological actions that include, by way of example only, smooth muscle contraction, leukocyte activation, cytokine secretion, mucus secretion, and vascular function. Brief Description of the Invention Methods, compounds, pharmaceutical compositions, and medicaments are presented herein to (a) diagnose, prevent, or treat allergic and non-allergic inflammation, (b) control signals and symptoms that are associated with inflammation, and / or (c) control proliferative or metabolic disorders. These disorders can arise from genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, and / or traumatic etiology. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise the inhibitors of the 5-lipoxygenase activating protein (FLAP) described herein. In one aspect are the compounds of formula (A), their pharmaceutically acceptable salts, N-oxides acceptable for pharmaceutical use, active metabolites for pharmaceutical use, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, which antagonize and inhibit FLAP and can be used to treat patients suffering from leukotriene-dependent conditions or diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, dyspneic syndrome adult respiratory, myocardial infarction, aneurysm, apoplexy, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In one embodiment, formula (A) is the following:
wherein, Z is selected from C (R1) 2 [C (R2) 2] n, [C r R Z R C R R i i, [C (R 2) 2] n O [C (R 1) 2] n, [C (R ,) 2] nO [C (R2) 2] n, where each Rn is independently H, CF3, or an optionally substituted lower alkyl and two R: on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently 0, 1, 2, or 3; Y is H, -. ^ - (substituted or unsubstituted alkyl); or l_i- (substituted or unsubstituted alkenyl), - L 1 - (a Iq uini I or substituted or unsubstituted), -L-, - (substituted or unsubstituted cycloalkyl), -. ^ - (substituted heteroaryl or unsubstituted), -l_i- (substituted or unsubstituted aryl); wherein l_i is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, heteroalkenyl substituted or unsubstituted substituted, a substituted or unsubstituted or substituted aryl I or substituted heteroalkynyl; where each substituent is (LsRs) j, where each L., is independently selected from a bond, -O-, -C (= 0), -S-, -S (= 0) -, -S (= 0) 2-, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, "-C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryloyl or a heteroalicyclic group, and each R5 is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2 , lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl or heteroalkyl, where j is 0, 1, 2, 3 or 4, each R3 is independently selected from H, -S (= 0) 2R8, - S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl, each R3 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; is independently selected from H, alkyl substituted or unsubstituted lower, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R4 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3 and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L_2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted C-alkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkuenyl), L2- ( substituted or unsubstituted heteroalicyclic group), l_2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (alkyl of 1 to 6 'substituted or unsubstituted carbon atoms), or - (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); R7 is selected from: (ii) L3-X-L4-G2, wherein, L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted aryl, unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclic group; X is -NR9C (0), -C (0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO -, -ON = CH-, -N R9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -N R9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) - or -C (= NR10) O;
l_4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G2 is H, tetrazolyl, -NHS (= 0) 2 8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (O) NR9C (= NR10) N (R9) 2, -C (0) NR9C (= CRON (R9) 2, -002R9, -C (0) R9, -CON (R9) 2, -SR3, -S (= 0) R8, -S (= 0) 2R5, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O) , -C (0) NH, -C (0) 0 or -OC (O), or G2 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -ORB, -C (= 0) CF3 > -CN, N (R9) 2, - N (R9) C (0) R9, -C (= NRON (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CRON (R9) 2, -C (O) NR9C (= NR10) N (Rs) 2, -C (0) N
RsC (= CR10) N (R9) 2, -C02R8, -C (0) R8, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R10 is independently selected from H, -S (= 0) 2 e, -S (= 0) 2NH2 -C (0) R8 , -CN, -N02, heteroaryl or heteroalkyl; or (iv) L3-X-L4-G4, where L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted or substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0) NR9, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10 ) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) - or -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G4 is -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CRio) N (R9) 2, (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted aryl or unsubstituted), where L5 is -NHC (0) 0, -0 (0) CNH-, - (O) CO- or -OC (O);
or G4 is -l_5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -0 ( 0) CNH-, - NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (; 70) CF3, -CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8 , -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted) , -L6- (substituted or unsubstituted heteroaryl), or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH or C (0) NH; Rii is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (0) 2, -NH, -C (O), -C (0) NH, -NHC (O), (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl) or (heteroalicyclic group substituted or unsubstituted); and G6 as H, CN, SCN, N3, N02, halogen, OR9, -C (0) NHR9, -NHC (0) R9, -C (= 0) CF3, C (= 0) R9, -SR8, - S (= 0) R8, -S (= 0) 2R8, N (R9) 2, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) N1-1S ( = 0) 2R8, -S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R10) 2, -NR9C (= CRig) N (R9) )2; R12 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms); or R7 and R12 can form a 4- to 8-membered heterocyclic ring; or its active metabolite, or solvate, or pharmaceutically acceptable salt, or acceptable prodrug for pharmaceutical use. In other embodiments or alternative embodiments of the compounds of formula (A), Z is [C (R2) 2] nC (R1) 20. In other embodiments or alternative embodiments of the compounds of formula (A), Y is -l_i- (substituted or unsubstituted aryl) or substituted or unsubstituted -Li-isheteroaryl). In other embodiments or alternative embodiments of the compounds of formula (A), it is a bond or a substituted or unsubstituted alkyl. In other embodiments or alternative embodiments of the compounds of formula (A), R6 is H, 'L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted aryl), L2- (substituted or unsubstituted cycloalkyl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH) or - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted ). In other embodiments or alternative embodiments of the compounds of formula (A), R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted ryl) or L2- (substituted or unsubstituted cycloalkyl), where L2 is a bond, O, S, -S (= 0) 2, -C (O), -CH (OH) or - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted). In other alternative embodiments or modalities, R-12 is H. In other embodiments or alternative embodiments of the compounds of formula (A), R7 is L3-X-L4-G2, where L3 is a substituted or unsubstituted alkyl; X is -NR9C (0), -C (0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -NR9C (0 ) Nri9-, heteroaryl, aryl, -C (= NR10) NR9-, -OC (= NR10) - or -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; G2 is H, tetrazolyl, -OR9, -0 (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C02R9, -C (0) R9, -CON (R9) ) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -C (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O). In other embodiments or alternative embodiments of the compounds of formula (A), X is -NR9C (0), -C (0) NR9, -OC (0) NR9, -NR9C (0) 0-, NR9C (0) NR9 -, heteroaryl or aryl. In other embodiments or alternative embodiments of the compounds of formula (A), G2 is H, tetrazolyl, -OR9, -C (= 0) CF3, -CN, -N (R9) 2, -N (R9) C (0 ) R9, -C02R9, -C (0) R9 or -CON (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (A), R7 is L3-X-L4-G4, where L3 is a substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, S (= 0), -S (= 0) 2, -NR9l -NR9C (0), -C (0) NR9 , -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -N R9C (0) N R9-, heteroaryl, aryl; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; G4 is -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0-, -Q ( 0) CNH-, - (O) CO- or -OC (O); or G4 is -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0-, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G4 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2: OH, -OR8, -C (= 0) CF3, -CN, N (R9) 2, -N (R9) C (0) R9, -C02R9, -C (0) R9, -CON (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (A), G4 is -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl). In other embodiments or alternative embodiments of the compounds of formula (A), L5 is -C (0) NH or -C (0) 0. In other embodiments or alternative embodiments of the compounds of formula (A), X is a bond, O, -C (= 0), -CR9 (OR9), -NR9, -NR9C (0), -C (0) NR9 , -OC (0) NR9 > - NR9C (0) 0-, -NR9C (0) NR9-, heteroaryl or aryl. In other embodiments or alternative embodiments of the compounds of formula (A), X is a bond, -C (= 0), -CR9 (OR9), -C (0) NR9, heteroaryl or aryl. In other embodiments or alternative embodiments, G4 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, OH, -OR8, -C (= O ) 0F3, -CN, N (R9) 2, -N (R9) C (0) R9, -CO2R9, -C (0) R9 or -CON (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (A), L7 is a bond, -O, -C (O), -C (0) NH, -NHC (O), (alkyl of 1 to 6 carbon atoms) substituted or unsubstituted carbon); L 0 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl); and G6 is H, CN, SCN, N3, N02, halogen, OR9, -C (= 0) CF3, C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 , N (R9) 2, -tetrazolyl, NHS (= 0) 2R8, -S (= 0) 2N (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (A), L7 is a bond; and Li0 is (substituted or unsubstituted aryl). In other embodiments or alternative embodiments of the compounds of formula (A), G6 is H, CN, SCN, N3, N02, halogen, OR9, -C (= 0) CF3, -C (= 0) R9 or --N ( R9) 2. In another aspect are the compounds of formula (B), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates, which antagonize or inhibit FLAP and can be used to treat patients suffering from leukotriene-dependent conditions or diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, infarction of the myocardium, aneurysm, apoplexy, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In one embodiment, formula (B) is the following:
in which Z is selected from CíR ^ .Cíf ^ Jn, [C (R2) 2] nC (R1) 20, OC (R) 2 [C (R2) 2] n, where each R ^ is independently H, CF3 , or an optionally substituted lower alkyl and two Rs on the same carbon can be joined to form a carbonyl (= 0); and each R2 is independently H, OH, OMe, CF3, or an optionally substituted lower alkyl and two R2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently 0, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -OR3b, -C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -CON (R4) 2, - SR3b, -S (= 0) R3b, -S (= 0) 2R3b, -. ^ - (substituted or unsubstituted alkyl); or -. ^ - (substituted or unsubstituted alkenyl), substituted or unsubstituted), -l_i- (substituted or unsubstituted cycloalkyl), - [. ^ - (substituted or unsubstituted heteroaryl), -l_i- (substituted or not substituted); where is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, heteroalkenyl substituted or unsubstituted substituted, a substituted or unsubstituted heteroalkynyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0), -S-, -S (= 0) -, -S (= 0) 2- , -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl heteroaryl, aryl or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02l N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl heteroaryl or heteroalkyl; where j is 0, 1, 2, 3 04; each R3 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; each R3b 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 cycloalkyl, phenyl or benzyl; or two R4 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3 and R can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (group substituted or unsubstituted heteroalicyclic), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0 ) 2, C (O), -CH (OH), - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or - (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); R7 is H, unsubstituted alkyl or alkyl substituted with a substituent selected from OH, alkoxy of 1 to 6 carbon atoms, C (0) OH and C (0) 0 (alkyl of 1 to 6 carbon atoms); R5 is H, halogen, -N3, -CN, -ON02, -L6- (substituted or unsubstituted C1-C6 alkylaryl), -L6- (C1 to C6 alkenyl substituted or unsubstituted) substituted), -L6- (substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH , C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH or C (0) NH; R11 is H, (substituted or unsubstituted alkyl) or (substituted or unsubstituted cycloalkyl); Ri2 is H or L3-X-L4-GL where 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, heteroaryl substituted or unsubstituted, substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NRgC (O), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -N R9C (0) N R9-,
-N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= N1R10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; Gi is tetrazolyl, halogen, -NHS (= 0) 2R3, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O ) NR 9 C (= NR10) N (R9) 2, -C (O) NR 9 C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), where L5 is -OC (0) 0-, -NHC ( 0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -0 (0) 0 or -0C (0); each R3 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R-, 0 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2C (0 ) R8, -CN, -N02, heteroaryl. or heteroalkyl; or its active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug. In other embodiments or alternative embodiments of the compounds of formula (B), Z is C (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 20. In other embodiments or alternative embodiments of the compounds of formula (B), Y is H, -C02H, tetrazolyl, OH, -OR3b, -C02R3b, -C (0) R4, -CON (R4) 2, -L-, - (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted heteroaryl), -l_i- (substituted or unsubstituted aryl); and L-, it's a link. In other embodiments to alternative embodiments of the compounds of formula (B), Y is H, -CN, -Li- (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted heteroaryl) or -l_i- (aryl substituted or unsubstituted); and it is a link. In other embodiments or alternative embodiments, R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted aryl), L2- (substituted or unsubstituted cycloalkyl), where L2 is a bond, O, S , -S02, -C (O), -CH (OH) or substituted or unsubstituted alkyl of 1 to 6 carbon atoms. In other alternative embodiments or embodiments of the compounds of formula (B), Rn is H. In other embodiments or alternative embodiments of the compounds of formula (B), R7 is unsubstituted alkyl. In other embodiments or alternative embodiments of the compounds of formula (B), R12 H or L3-X-L4-GL where: L3 is a bond, substituted or unsubstituted alkyl or (substituted or unsubstituted aryl); X is a bond, O, -C (= 0), -CR9 (0R9), S, -S (= 0), -S (= 0) 2, -N R9, -NReC (O), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C ( 0) NR9-, -N (R9) O (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) or -C (= NRio) 0; and l_4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl. In other embodiments or alternative embodiments of the compounds of formula (B), R12 is L.3-X-L4-G! wherein: L3 is a (substituted or unsubstituted aryl); X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) NR9-, -NR9C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) - or -C (= NRio) 0; and L4 is a bond or (substituted or unsubstituted alkyl). In other embodiments or alternative embodiments of the compounds of formula (B), X is a bond, O, -C (= 0), - CR9 (OR9), -NR9, -NReC (O), -C (0) NR9 , -OC (0) NR9, - NR9C (0) 0- or -NR9C (0) NR9-. In other embodiments or alternative embodiments of the compounds of formula (B), X is a bond, O, -C (= 0) or -C (0) NR9. In other embodiments or alternative embodiments of the compounds of formula (B), G is tetrazolyl, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, - C02R9, - C (0) R9 to -CON (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (B), X is a bond, O, -C (= 0), -CR9 (OR9), -NR9C (0), -C (0) NR9, -OC (0) NR9, - NR9C (0) 0- or -NR9C (0) NR9-; and L4 is a bond or (substituted or unsubstituted alkyl). In other embodiments or alternative embodiments of the compounds of formula (B), R9 is independently selected from H, substituted or unsubstituted substituted or unsubstituted cycloalkyl alkyl. In other embodiments or alternative embodiments of the compounds of formula (B), R7 is an alkyl substituted with a substituent selected from OH, alkoxy of 1 to 6 carbon atoms, C (0) OH and C (0) 0 (alko ilo of 1 to 6 carbon atoms). In other embodiments or alternative embodiments of the compounds of formula (B), R n is H, (substituted or unsubstituted alkyl) or substituted or unsubstituted cycloalkyl); and R 2 is H. In other embodiments or alternative embodiments of the compounds of formula (B), R-, 2 is L 3 -X-L 4 -GL where: L 3 is a bond, substituted or unsubstituted aryl, substituted heteroalicyclic group or not replaced; X is a bond, O, -C (= 0), -CR9 (OR9), -NReC (O), -C (0) NR9, -OC (0) NR9 or -NR9C (0) 0-; The is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and G-, is halogen, -OR9, -C (= 0) CF3, -C (0) NHS (= 0) 2R9, -S (= 0) 2NHC (0) R9, -ON, -N (R9) 2, -N (R9) C (0) R92, - C02R9, -C (0) R9, -CON (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl ), where L5 is -00 (0) 0-, -NHC (O) NH-, -NHC (0) 0, - 0 (O) ONH-, -NHC (O), -C (0) NH, - C (0) 0 u -OC (O). In other embodiments or alternative embodiments of the compounds of formula (B), L3 is substituted or unsubstituted aryl or substituted or unsubstituted heteroalicyclic group. In another aspect are the compounds of formula (H), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates, which antagonize or inhibit FLAP and can be used to treat patients suffering from leukotriene-dependent conditions or diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, infarction of myocardium, aneurysm, apoplexy, cancer, endotoxic shock, proliferative disorders and inflammatory conditions.
In one embodiment, the formula (H) is as follows:
wherein Z is selected from C (R9) 2 [C (R2) 2] i, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2], [C ( R2) 2] n [C (R9) 2]., Wherein each R, is independently H, CF3, or an optionally substituted lower alkyl and two on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is -C02H, -CONH2, -C (= 0) N (R4b) 2, -C02R4b, -0R3b, -C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (= NOH ) R 4, -C (= NOR 3b) R 4b, -Li- (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted alkenyl), -L 1 - (substituted or unsubstituted alkynyl), -. (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroaryl), -. ^ - (substituted or unsubstituted heteroalicyclic group) or -L1- (substituted or unsubstituted aryl); where is -C (= 0), CR8OH, CR8OMe, C (= NOH), C (= NOR4b), C (= 0) NH, C (= 0) NR4b, -NHC (= 0), NR4bC (= 0 ), S, S (= 0), S (= 0) 2, -NHC (= 0) NH or NR4bC (= 0) NR4b;
where each substituent on Y or Z is (i_sRs) i, where each Ls is independently selected from a bond, -NH, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2-, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkenyl alkyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl heteroaryl or heteroalkyl; where j is 0, 1, 2, 3 or 4; each R3 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; each R3b 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 cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; or two R4 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or Rib and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; each R3b is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted benzyl; substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalicyclic group; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heteroalicyclic group) or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2 , C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl) or - (substituted or unsubstituted C 2-6 alkenyl); R7 is L3-X-L4-G-1, where: L3 is a bond or substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NR9C (0), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C ( 0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NRI0) - or -C (= NR10) O; L4 is a bond or substituted or unsubstituted alkyl; G, is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, - S (= 0) 2N HC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2l -NR9C (= NR10) N ( R9) 2,
-NR9C (= CR10) N (R9) 2, -C (0) NRsC (= NRio) N (Rs) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R8, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 u -OC (O); each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and Rg can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R 0 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2 -C (0) R8 , -CN, -N02, heteroaryl to heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted) , -L6- (substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted rhyla), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, or -C (0) NH; R11 is L7-Li0-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted 6-carbon alkenyl); Lio 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 heteroalicyclic group) or not substituted); G6 is H, CN, SCN, N3, N02, halogen, OR9, -C (= 0) CF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 , N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2Re,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= R10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (aryl) substituted or unsubstituted), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O); or G6 is W-G7, wherein W as (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl) ) and G7 is H, halogen, CN, N02, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl, tetrazolyl, -NHS (= 0) 2R8, S ( = 0) 2N (R9) 2, OH, -ON, -C (= 0) CF3, -C (0) NHS (= 0) 2R3, -S (= 0) 2NHC (0) R9, CN, N ( R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR8C (= CR 0) N (R9) 2, -C (O) NR8C (= NR10) N (R9) 2, -C (O) NR8C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2l -SR8, -S (= 0) R8 to -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl) substituted), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or -L5- (substituted or unsubstituted aryl), where L5 is a bond, -O-, C (= 0), S, S (= 0), S (= 0) 2, -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC ( 0) NH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); R12 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms); or its active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug. In other embodiments or alternative embodiments of the compounds of formula (H), Z is [C (R2) 2] nC (R) 20. In other alternative embodiments or embodiments of the compounds of formula (H), Y is -C02H, -CONH2, -C (= 0) N (R4b) 2l -C02R4b, -OR3bj C (= 0) (fluoroalkyl from 1 to 6 carbon atoms), -C (= NOH) R4b, -C (= NOR3b) R4b, -Li- (substituted or unsubstituted alkyl), substituted or unsubstituted), -L4- (substituted or unsubstituted heteroaryl) or substituted or not replaced). In other embodiments or alternative embodiments of the compounds of formula (H), Y is -C02H, -CONH2, -C (= 0) N (R4b) 2, -C02R4b, -OR3, -C (= NOH) R4b, - C (= NOR3b) R4b, substituted or unsubstituted), -. ^ - (substituted or unsubstituted heteroaryl), or - ^ - (substituted or unsubstituted aryl). In other embodiments to alternative embodiments of the compounds of formula (H), it is -C (= 0), CR8OH, CR8O e, C (= NOH), C (= NOR4b), C (= 0) NH, C (= 0) NR4b, -NHC (= 0) or NR4bC (= 0). In other embodiments or alternative embodiments of the compounds of formula (H), R6 is L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (0) 2, -C (O), -CH (OH) or substituted or unsubstituted alkyl. In other embodiments or alternative embodiments of the compounds of formula (H), R12 is H. In other embodiments or alternative embodiments of the compounds of formula (H), R is L7-L10-G5; and L7 is a link. In other embodiments or alternative embodiments of the compounds of formula (H), G6 is W-G7, where W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl). In other embodiments or alternative embodiments of the compounds of formula (H), G6 is W-G7, where W is (substituted or unsubstituted aryl) or a (substituted or unsubstituted heteroaryl). In other embodiments or alternative embodiments of the compounds of formula (H), G7 is H, halogen, CN, N02, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl from 1 to 6 carbon atoms, tetrazolyl, -OH, -OR8, -C (= 0) CF3, -CN, -C02R9, -C (0) R9 or -CON (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (H), L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted aryl) ); and G6 is H, CN, SON, N3, N02, halogen, -OR9, -C (= 0) CF3, -C (= 0) R9, tetrazolyl or -L5- (substituted or unsubstituted alkyl). In other embodiments or alternative embodiments of the compounds of formula (H), L 0 is a bond, (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted aryl). In other embodiments or alternative embodiments of the compounds of formula (H), G6 is H, CN, SCN, N3, N02, halogen, -OR9, -C (= 0) CF3, -C (= 0) R9, tetrazolyl or - L5- (substituted or unsubstituted alkyl). In other embodiments or alternative embodiments of the compounds of formula (H), L3 is a bond. In other embodiments or alternative embodiments of the compounds of formula. (H), L4 is a bond or substituted or unsubstituted alkyl; G is H, tetrazolyl, - NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3I - C (0) NHS (= 0) 2R8, S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (0) NR9C (= CRio) N (R9) 2, -C02R9, -C (0) R9 or -CON (R9) 2. In other embodiments or alternative embodiments of the compounds of formula (H), X is a bond. In other embodiments to alternative embodiments of the compounds of Formula (H), L 4 is substituted or unsubstituted alkyl. In other embodiments or alternative embodiments of the compounds of formula (H), G ^ is H, tetrazolyl, -OR9, -C (= 0) CF3, -CN, -C02R9 or -CON (R9) 2. Any combination of the groups described above for the various variables is contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to give compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those established at the moment. In one aspect, a compound selected from: 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-chloro-benzyl) -1H-indo-1-yl] -2, 2-dimethyl-propionic (Compound 1-1); 3- [5 - ((S) -2-tert-Butoxycarbonylamino-2-phenyl-ethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 1-2); 315 - ((R) -2-tert-Butoxycarbonylamino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-cl-oro-be ncyl) -1 H -indole-2-? 11 -2, 2 acid -dimethyl propionic (Compound 1-3); 3-15 - ((S) -2-amino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-ind ol-2-yl] -2, 2- acid dimethyl propionic (Compound 1-4); 3- [5 - ((S) -2-amino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-lndol-2-yl] -2,2-dimethyl acid -propionic (Compound 1-5); 345 - ((R) -2-Acetylamino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-6); 3- [5 - ((S) -2-Acetylamino-2-phenyl-ethoxy) -3- te r-butylsulfa nyl-1 - (4-chloro-benzyl) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 1-7); 3- [5 - [(3-Butoxycarbonylamino-p-ropilcarbamoyl) -methoxy] -3- te r -butylsulfa nor 1-1- (4-chloro-benzyl) -1H-indol-2-yl] -2, 2-dimethyl-propionic (Compound 1-8); 3- [5 - [(3-amino-) propylcarbamoyl) -methoxy] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indo1-2-yl] -2,2- acid dimethyl propionic (Compound 1-9); Acid { 3-tert-Butylsulfanyl- (4-chloro-benzyl) -5- [2- (4-fluoro-phenyl) -2-oxo-ethoxy] -1H-indo-1-2-yl} -2, 2 -d i m e ti I -propionic (Compound 1-10); Acid { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- [2- (4-fluoro-phen1) -2-hydroxy-ethoxy] -1H-indol-2-yl] -2, 2-dimethyl-propionic (Compound 1-11); 3- (3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-. {2- (4-fluoro-pheny1) -2 - [(Z) -hydroxyimino] -ethoxy} acid. -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 1-12); Acid (3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-. {2- (4-fluoro-pheny1) -2 - [(Z) -methoxyimino] -ethoxy} -1-H-indo-1-yl) -2,2-dimethyl-propionic acid (Compound 1-13); 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy] -1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid ester (Compound 1-14 ); Ethyl ester of 3- [3-tert-bu ti isulfa nyl-1 - (4-chlorobenzyl) -5-cy to nomethoxy-1 H -indo1-2-yl] -2,2-dimethyl -propionic (Compound 1-15); 3- [5- (benzylcarbamoyl-methoxy) -l- (4-bromo-benzyl) -3-tert-butylsulfanyl-1H-indole-2-yl] ethyl ester -2,2-dimethyl-propionic (Compound 1-16): 3- [3-tert-Butylsulfanyl-5-carboxymethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2 acid -l] -2, 2-dimethyl-propionic (Compound 1-17); 3- [3-tert-Butylsulfanyl-5- (2-hydroxy-propoxy) -1- (4-thiazole-2-yl- benzyl) -1H-indol- 2- il] -2,2-dimethyl-propionic (Compound 1-18); 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-19); 3- [3-tert-Butylsulfanyl-5- (1-carbamoyl-1-methyl-ethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl-propionic (Compound 1-20); Acid
3- [3-tert-Butylsulfanyl-5- (1-carboxy-1-methylethoxy-1- (4-thiazol-2-yl-benzyl) -H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-21): 3-, 3- tert -butylsulfanyl-5- (2-methoxyropoxy-1- [4- (6-methoxy-pyridin-3-yl) benzyl-1H-indole- 2-yl.) -2,2-dimethyl-propionic (Compound 1-22); Acid 3-. { 3-tert-Butylsulfanyl-5- (2-hydroxy-propoxy-1 - [4- (6-methoxy-pyridin-3-yl) benzyl] -1H-indol-2-yl.} -2, 2- dimethyl-propionic (Compound 1-23); 3-, {3-tert-Butylsulfanyl-5- (2-hydroxy-2-methyl-propoxy-1 [4- (6-methoxy-pyridin-3-yl)} benzyl] -1H-indol-2-yl.} -2,2-dimethyl-propionic (Compound 1-24); 3-, {3-tert-butylsulfanyl-5- (2-hydroxy-3,3) -dimethyl-butoxy-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic acid (Compound 1-25); 3- (3-tert-Butylsulfanyl-5- [2- (4-fluoro-phenyl) -2-hydroxy-ethoxy-1 - [4- (6-methoxy-pyridin-3-yl) benzyl acid; l] -1 H -indol-2-yl.} -2,2-dimethyl-propionic acid (Compound 1-26); 3-, {3-tert-Butylsulfanyl-5-carbamoylmethoxy-1-ethyl ester (4-thiazol-2-yl-benzyl) -1H-indol-2-yl} -2,2-dimethyl-propionic acid (Compound 1-27); 2- [3-tert-butylsulfanyl-1 - (4 -chloro-benzyl) -2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] acetamide (Compound 2-1); 2- [3-tert-butylsulfanyl-2- (2-hydroxy) 2-methyl-propyl) -1-pyridin-4-ylmethyl-indol-5-yloxy] -acet amide (Compound 2-2); 2- [3-tert-ButylsulfanM] -1 - (4-cyano-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-Moxy] -acetamide (Compound 2-3); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1- (4-iodo-benzyl) -1 H -indole-5-yloxyl-acetamide (Compound 2-4); 2- [3-tert-butylsulfanyl-3- (2-hydroxy-2-methyl-propyl) -1- (4-iodo-benzyl) -1H-indol-5-yloxy-acetamide (Compound 2-4); 2- [3-tert-Butylsulfanyl] -1-cyclopropylmethyl-2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -acetamide (Compound 2-5); 2- [3-tert-Butylsulfanyl] -1 - (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] -N, N-diethyl- Acetamide (Compound 2-6); 2- [3-tert-Butylsulfanyl-2- (2-hydrophenyl) -acetamide (Compound 2-7); 2- [3-tert-Butylsulfanyl] -1 - (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] -N- (4-chloro) -benzyl) -N-pyridin-3-α-acetamide (Compound 2-8); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1-pyridin-4-ylmethyl-1H-indol-5-yloxy] -N-cyclopropyl-acetamide (Compound 2) 9); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1- (4-iodo-benzyl) -1H-indol-5-yloxyl-N- (4-iodo-benzyl) ) -acetamide (Compound 2-10); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1 - (4-pyridin-3-yl-benzyl) -1 H -indol-5-yloxy] -acetamide ( Compound 2-l); 2- [3-tert-Butylsuifanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy-acetic acid (Compound 2-12); Ethyl 2- [3-tert-butylsulfanyl- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-jondo-5-yloxy] -acetic acid ester (Compound 2) -13); 1 -13-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (2-hydroxy-2-methyl-propoxy) -1H-indol-2-yl] 2-methyl-propan-2 -ol (Compound 2-14); 143-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (2-hydroxy-propoxy) -1H-indol-2-yl] -2-methy1-propan-2-ol (Compound 2- fifteen); 1 - [3-tert-Butylsulfanyl-1 - (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] - propan-2-one (Compound 2-16); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1 H-indol-2-yl] -N- (2-d-methylamino-etl) -2, 2-dimethyl-propionamide (Compound
3-1); 5- (2-3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -1,1-dimethyl-ethyl) - [ 1,3,4] oxadiazol-2-ylamine
(Compound 3-2); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-methoxy) -1H-indol-2-yl] -2,2-dimethyl-N-thiazole- 2-yl-propionamide (Compound 3-3); N-. { 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-d-methyl- propionylj-formamide (Compound 3-4); 2-. { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -2- [2-methyl-2- (5-methyl- [1, 2,4] oxadiazol-3-11) -propill-1 H -indole-5-yloxymethyl) -quinoline (Compound 3-5); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinol-n-2-ylmethoxy) -1 H -indole-2-yl] -2, 2-dimethyN -pyridin-3-11-propionamide (Compound 3-6); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-methoxy) -1H-indol-2-yl] -2,2-dimethyl-N-pyraz n-2-yl-propionamide (Compound 3-7); 4- (2-Isobutyl-3,5-diisopropyl-indol-1-methylmethyl) -benzoic acid (Compound 4-1); N- (2-hydroxy-ethyl) -4- (2-isobutyl-3,5-diisopropyl-indol-1-methylene) -benzamide (Compound 4-2); N- (2-dimethylamino-ethyl) -4- (2-isobutyl-3,5-diiso-propyl-indol-1-methyl) -benzamide (Compound 4-3); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5-pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid (Compound 4-4); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5-pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid methyl ester (Compound 4-5); 4- [2- (2,2-Dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid (Compound 4-6); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy-indol-ylmethyl] -N- (2-dimethylamino-ethyl) -benzamide (Compound 4- 7); 1- [3-tert-Butylsulfanyl-1-methyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol (Compound 5-1); 1 - (3- [3-tert-Butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl-azetidin-1 -11) - ethanone (Compound 5-2): 1 - [3-tert-Butylsulfanyl-1-cyclopropylmethyl-5- (pyridin-2-ylmethoxy) -1H-indol-211] -2-methyl-propan-2-ol ( Compound 5-3): 1- [3-tert-Butylsulfanyl-1-cyclobutylmethyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol (Compound 5-4); 4- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy-indol-1-ylmethyl] -N-cyclopropyl-benzamide ( Compound 5-5): 4- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy-indol-1-ylmethyl] -N- (2- hydroxyethyl) -benzamide (Compound 5-6); 2- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1- il] -acetamide (Compound 5-7 ). In one aspect, there is provided a pharmaceutical composition comprising an effective amount of a compound provided herein, and a pharmaceutically acceptable excipient.
In another aspect, a method for treating inflammation in a mammal is provided herein, which comprises administering an effective amount of a compound provided herein to the mammal in need thereof. In one aspect, a method for treating a respiratory disease in a mammal is provided herein, which comprises administering an effective amount of a compound provided herein to the mammal in need thereof. In yet another aspect, a method for treating asthma in a mammal is provided herein, which comprises administering an effective amount of a compound described herein to the mammal in need thereof. In another aspect are the compounds presented in Figures 8, 9, 10, or 11, or their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutical active metabolites, pharmaceutically acceptable proteinaceous, and pharmaceutically acceptable solvates, which antagonize or inhibit FLAP and can be used to treat patients suffering from leukotriene-dependent diseases or conditions, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, apoplexy, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In another aspect are the compounds presented in any of Tables 1, 2, 3, 4 or 5 or their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, which antagonize or inhibit FLAP and may be used to treat patients suffering from leukotriene-dependent conditions or diseases, including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In other embodiments or alternative embodiments of any of the aforementioned compounds of formulas (A), formulas (B), formulas (C), formulas (D), formulas (F) and formulas (H), the heteroalicyclic group Y can be selected from a quinolizine, a dioxin, a piperidine, a morpholine, a thiazine, a tetrahydropyridine, a piperazine, an oxazinanone, a dihydropyrrole, a dihydroimidazole, a tetrahydrofuran, a dihydroxazole, an oxirane, a pyrrolidine, a pyrazolidine, a dihydrothiophenone, an imidazolidinone , a pyrrolidinone, a dihydrofuranone, a dioxolanone, a thiazolidine, a piperidinone, a tetrahydronaphthyridine, a tetrahydroquinoline, tetrahydrothiophene, and a thiazepane. In other alternative modalities, the group heteroalicyclic group can be selected from the group consisting of:
In other embodiments or alternative embodiments, the compounds of any of formula (A), formula (B), Formula
(C), formula (D), formula (F) or formula (H), can be inhibitors of the 5-lipoxygenase activating protein (FLAP), while even in other modalities or alternative modalities, such inhibitors are selective for the FLAP. Even in other modalities or alternative modalities, such inhibitors have an Cl50 below 50 microM in the FLAP binding assay. In other embodiments or alternative embodiments, the compounds of any of formula (A), formula (B), formula (C), formula
(D), formula (F) or formula (H), may be included in pharmaceutical compositions or medicaments used to treat a condition or disease mediated by leukotrienes or leukotriene-dependent in a patient. In another aspect inflammatory conditions include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, aortic aneurysm, myocardial infarction, and stroke. In other aspects, proliferative disorders include, but are not limited to, cancer and non-cancerous disorders, including, but not limited to, those involving lymphatic skin tissues. In other aspects, metabolic disorders include, but are not limited to, bone reconstitution, loss or gain. In other aspects, such conditions are iatrogenic and the increases or abnormal localization of the leukotrienes can be induced by other therapies or medical or surgical procedures. In other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein may be used to prevent the cellular activation of 5-lipoxygenase, while in other aspects the methods, compounds, pharmaceutical compositions, and medicaments described in the present can be used to limit the formation of leukotrienes. In other aspects, such methods, compounds, pharmaceutical compositions, and medicaments may comprise FLAP inhibitors disclosed herein for the treatment of asthma (a) by decreasing the concentrations of leukotrienes in certain tissue or tissues of the body or in the entire body of a patient, (b) modulating the activity of enzymes or proteins in a patient where such enzymes or proteins are involved in the leukotriene pathway such as, by way of example, the activating protein of 5-lipoxygenase or 5-lipoxygenase, or (c) combining the effects of (a) and (b). In yet other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein may be used in combination with other medical treatments or surgical modalities. In one aspect are methods for reducing / inhibiting the leukotriene synthesis activity of the 5-lipoxygenase activating protein (FLAP) in a mammal comprising administering to the mammal at least one time, an effective amount of a compound having the structure of any of formula (A), formula (B), formula (C), formula (D), Formula (F) or formula (H). In another alternative modality or modality, the group "G" (for example G ,, G2, G4, G5, G6, G7) of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), is any group that is used to adapt the physical and biological properties of the molecule. Such adaptations / modifications are obtained using any group that modulates the acidity, basicity, lipophilicity, solubility and other physical properties of the molecule. The physical and biological properties modulated by such "G" modifications include, by way of example only, solubility, in vivo absorption, and in vivo metabolism. In addition, the in vivo metabolism may include, by way of example only, controlling the PK properties in vivo, the activities out of site, the toxicities associated with the interactions of cypP450, drug-drug interactions, and the like. In addition, modifications to "G" allow the adequacy of the in vivo efficacy of the compound through the modulation, for example, of the binding of the specific and non-specific protein to the plasma proteins and the tissue distribution in vivo. . In addition, such modifications / modifications to "G" allow the design of selective compounds for the activating protein of 5-lipoxygenase on other proteins. In other modalities or alternative modalities, "G" is L2o-Q. where L20 is an enzymatically cleavable linker and Q is a prodrug, or an affinity moiety. In other alternative modalities or modalities, the drug includes, by way of example only, leukotriene receptor antagonists and anti-inflammatory agents. In other alternative modalities or modalities, leukotriene receptor antagonists include, but are not limited to, dual CysLTI / CysLT2 antagonists and CysLTI antagonists. In other alternative embodiments or modalities, the affinity moiety allows site-specific binding and includes, but is not limited to, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands. In another aspect are methods for modulating, which include reducing and / or inhibiting the activity of the activating protein that of 5-lipoxygenase, directly or indirectly, in a mammal comprising administration to the mammal at least once, of an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect there are methods for modulating, which include reducing and / or inhibiting leukotriene activity in a mammal, directly or indirectly, comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), Formula (C), formula (D); formula (F) or formula (H). In another aspect are methods for treating leukotriene-dependent leukotriene-dependent conditions or diseases, comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula ( A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for treating the inflammation comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula ( C), formula (D), formula (F) or formula (H). In another aspect are methods for treating respiratory diseases comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula ( C), formula (D), formula (F) or formula (H). In another modality of this aspect, the respiratory disease is asthma. In another modality of this aspect the respiratory disease includes, but is not limited to, adult respiratory distress syndrome and allergic asthma (extrinsic), non-allergic asthma (intrinsic), acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, asthma induced by allergens, aspirin-sensitive asthma, asthma induced by physical exercise, isocanic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, spheroidal-resistant asthma, stationary asthma. In another aspect are methods for treating chronic obstructive pulmonary disease comprising administration to the mammal at least once, of an effective amount of at least one compound having the structure of any of formula (A), formula (B) , formula (C), Formula (O), formula (F) formula (H). In another embodiment of this aspect, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or inflammation of the upper tracts and cystic fibrosis. In another aspect are methods for preventing secretion and / or increased mucosal edema in a disease or condition comprising administration to the mammal at least once of an effective amount of at least one compound having the structure of any of the formula (A), formula (B), Formula (C), formula (O), formula (F) or formula (H). In another aspect there are methods to treat vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and apoplexy comprising the administration to the mammal of an effective amount of a compound having the structure of any of the formula (A), formula (B), formula (C), formula (D), Formula (F) or formula (H). In another aspect there are methods to treat les & of organic reperfusion following organic ischemia and / or endotoxic shock comprising administering to the mammal at least once, an effective amount of at least one compound having the structure of any of formula (G), formula (Gl) ), or formula (G-ll). In another aspect are methods for reducing the constriction of blood vessels in a mammal comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for decreasing or preventing an increase in blood pressure of a mammal comprising administering to the mammal at least once, an effective amount of at least one compound having any structure of formula (A) , formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for preventing the recruitment of eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes comprising administration to the mammal at least once., of an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for the prevention or treatment of abnormal bone reconstitution, loss or gain, including diseases or conditions such as, by way of example, osteopenia, osteoporosis, Paget's disease, cancer and other diseases comprising administration to the mammal of at least one time, of an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) . In another aspect are methods for preventing ocular inflammation and allergic conjunctivitis, spring keratoconjunctivitis, and papillary conjunctivitis comprising administration to the mammal at least once, of an effective amount of at least one having the structure of any of the formula ( A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for treating CNS disorders comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). CNS disorders include, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy / neuropathic pain, spinal cord injury, edema brain and head injury. In another aspect are methods for the treatment of cancer comprising administering to the mammal at least once, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). The type of cancer may include, but not limited to, pancreatic cancer and other solid or hematologic tumors. In another aspect are methods for treating endotoxic shock and septic shock comprising administering the mammal at least once, of an effective amount of at least one compound having the structure of any of formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H). In another aspect there are methods for treating rheumatoid arthritis and osteoarthritis comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for preventing augmented Gl diseases comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). Such diseases include, by way of example only, chronic gastritis, eosinophilic gastroenteritis, and gastric motor dysfunction. In another aspect are methods for treating kidney diseases comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula ( C), formula (D), formula (F) or formula (H). Such diseases include, by way of example only, glomerulonephritis, renal ischemic reperfusion by nephrotoxicity due to cyclosporine. In another aspect are methods for preventing or treating acute or chronic renal failure comprising administration to the mammal at least once, of an effective amount of at least one compound having the structure of any of formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for treating type II diabetes comprising administering to the mammal at least once, of an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), Formula (F) or formula (H). In another aspect there are methods to decrease the inflammatory aspects of acute infections within one or more solid organs or tissues such as the kidney with acute pyelonephritis. In another aspect there are methods of preventing to treat acute to chronic disorders involving the recruitment or activation of eosinophils comprising the administration to the mammal at least once of an effective amount of at least one compound having the structure of either of formula (A), formula (B), formula (C), formula (O), formula (F) or formula (H). In another aspect are methods for preventing or treating acute or chronic erosive disease or motor dysfunction of the gastrointestinal tract caused by non-steroidal antiinflammatory drugs (including selective or non-selective cyclooxygenase- or 2-selective inhibitors) comprising administration to the mammal of at least one time, of an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) . In another aspect there are methods for preventing or treating rejection or dysfunction in a transplanted organ or tissue comprising administration to the mammal at least once of an effective amount of at least one compound having the structure of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for treating inflammatory skin responses comprising administering to the mammal at least one time, an effective amount of at least one compound having the structure of any of formula (A), formula (B) , formula (C), formula (D), formula (F) or Formula (H). Such inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring. In another aspect are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, which comprises administering to the mammal an effective amount of a first compound having the structure of any of formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for the treatment of cystitis, including, by way of example only, interstitial cystitis, comprising administration to the mammal at least once, of an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect there are methods for the treatment of metabolic syndromes such as Familial Mediterranean Fever comprising administering to the mammal at least once, an effective amount of at least one compound having the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In another aspect are methods for treating hepatorenal syndrome comprising administering to the mammal at least one time, an effective amount of at least one compound that fills the structure of any of formula (A), formula (B), formula (C), formula (D), formula (F) or Formula (H). In another aspect is the use of any compound of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), in the production of a medicament for treating a disease or inflammatory condition in an animal in which the activity of at least one leukotriene protein contributes to the pathology and / or symptoms of the disease or condition. In one embodiment of this aspect, the leukotriene pathway protein is the 5-lipoxygenase activating protein (FLAP). In another modality of this aspect, inflammatory diseases or conditions are respiratory, cardiovascular or proliferative diseases. In any of the aspects mentioned above there are other embodiments in which the administration is enteric, parenteral, or both, and where (a) the effective amount of the compound is administered systemically to the mammal; and / or (b) the effective amount of the compound is administered orally to the mammal; and / or (c) the effective amount of the compound is administered intravenously to the mammal; and / or (d) the effective amount of the compound is administered by inhalation; and / or (e) the effective amount of the compound is administered nasally; or and / or (f) the effective amount of the compound is administered by injection to the mammal; and / or (g) the effective amount of the compound is administered topically (dermally) to the mammal; and / or (h) the effective amount of the compound is administered by ophthalmic administration; and / or (i) the effective amount of the compound is administered rectally to the mammal. In any of the aspects mentioned above there are other modalities in which the mammal is a human being, including modalities where (a) the human being has an asthmatic condition or one or more other conditions selected from the group consisting of allergic asthma (extrinsic) ), non-allergic asthma (intrinsic), acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, asthma sensitive to aspirin, asthma induced by physical exercise, sopapnic hyperventilation, childhood-onset asthma, adult-onset asthma, asthma with cough variant, occupational asthma, steroid-resistant asthma, or stationary asthma, or chronic obstructive pulmonary disease, or pulmonary hypertension or interstitial pulmonary fibrosis. In any of the aspects mentioned above there are other embodiments in which the mammal is an animal model for lung inflammation, examples of which are provided herein. In any of the aspects mentioned above there are other modalities comprising simple administrations. of the effective amount of the compound, including other embodiments in which (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times in the radius of a day; (iii) continuously; or (iv) constantly. In any of the aspects mentioned above there are other embodiments comprising multiple administrations of the effective amount of the compound, including other embodiments in which (i) the compound is administered in a single dose; (ii) the time interval between multiple administrations every 6 hours; (iii) the compound is administered to the mammal every 8 hours. In other alternative modalities or modalities, the method comprises a drug break, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; At the end of the drug's rest, the dosage of the compound is resumed. The extension of the drug's rest can vary from 2 days to 1 year. In any of the aspects mentioned above that involve the treatment of leukotriene-dependent diseases or conditions are other modalities comprising the administration of at least one additional agent, each agent can be administered in any order, including, by way of example, an agent antiinflammatory, a different compound having the structure of any of formula (A), formula (B), formula (C), formula (O), formula (F) or formula (H), a CysLTI receptor antagonist, or a dual receptor antagonist of CysLTI / CysLT2. In other alternative modalities or modalities, the CysLTI antagonist is selected from montelukast (Singulaim ™: [[1 - [3- [2 - [(7-chloro-2-quinolyl)] vinyl] phenyl] -3- [2] - (1-hydroxy-1-methyl-1-yl) fen Mi-pro pil] sulf to nylmethyl] cyclopropyl] acetic), zafirlukast (Accolate ™; cyclopentyl ester of 3 - [[2-methoxy-4- (or -tolysulfonylcarbamoyl) phenyl] methyl] -1-methyl-1H-indol-5-yl] aminoformic) or pranlukast (Onon ™: 4-oxo-8- [p- (4-phenylbutyloxy) benzoylamino] -2-tetrazole- 5-yl) -4H-1-benzopyran). In other modalities or alternative modalities, the anti-inflammatory agent includes, but without being limited, non-steroidal anti-inflammatory drugs such as a cyclooxygenase inhibitor (COX-1 and / or COX-2), lipoxygenase inhibitors and spheroids such as prednisone or dexamethasone. In other alternative modalities or modalities, the anti-inflammatory agent is selected from the group consisting of Arthrotec®, Asacol, Auralgan®, Azulfidine, Daypro, etodolac, Ponstan, Salofalk, Solu-Medrol, aspirin, nometacin (IndocinTm), rofecoxib (VioxxTm) , celecoxib (CelebrexTM), valdecoxib (BextraTM), diclofenac, etodolac, ketoprofen, Lodina, Mobic, nabumetone, naproxen, piroxicam, Celestone, prednisone, Deltasona, or any generic equivalent thereof. In any of the aforementioned aspects involving the treatment of proliferative disorders, including cancer, are other modalities comprising the administration of at least one additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or not), bevácizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicinlidarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, PaclitaxelTM, taxol, temozolomide, thioguanine, or classes of drugs that include hormones (an antiestrogen, an antiandrogen, or hormone analogs releasing gonadotropin, interferons such as alpha interferon, nitrogenous mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents for treat signs or symptoms indu This therapy includes allopurinol, filgrastim, granisetron / ondansetron / palonosetron, dronabinol. In any of the aforementioned aspects involving the therapy of organs, or transplanted tissues or cells are other modalities comprising the administration of at least one additional agent selected from the group consisting of azathioprine, corticosteroid, cyclophosphamide, cyclosporine, dacluzimab, mycophenolate mofetil , OKT3, rapamycin, tacrolimus, or thymoglobulin. In any of the aforementioned aspects involving interstitial cystitis therapy are other modalities comprising the administration of at least one additional agent selected from dimethylsulfoxide, omalizumab, and pentosan polysulfate. In any of the aforementioned aspects involving the therapy of bone disorders are other modalities comprising the administration of at least one additional agent selected from the group consisting of minerals, vitamins, bisphosphonates, anabolic steroids, pathoid hormone or anatogos, and inhibitors of the cathepsin K dronabinol. In any of the aforementioned aspects that involve the prevention or treatment of inflammation are other modalities that comprise: (a) monitoring inflammation in a mammal; (b) measuring broncho-constriction in a mammal; (c) measuring the recruitment of eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes and / or lymphocytes in a mammal; (d) monitored mucous secretion in a mammal; (e) measuring mucosal edema in a mammal; (e) measuring the levels of LTB4 in the mammalian blood caused with a calcium ionophore; (f) measuring the levels of LTE4 in the urinary secretion of a mammal; or (g) identifying a patient by measuring inflammatory biomarkers driven by leukotrienes such as LTB, LTC4, IL-6, CRP, SAA, MPO, EPO, MCP-1, α-α, sICAMs, IL-4, IL- 13 In any of the aforementioned aspects that involve the prevention or treatment of diseases or conditions mediated by leukotrienes or leukotriene-dependent are other modalities comprising identifying patients by tracing a leukotriene gene haplotype. In other modalities or alternative modalities the leukotriene gene haplotype is a leukotriene pathway gene, while even in other modalities or alternative modalities, the leukotriene gene haplotype is a 5-lipoxygenase haplotype activating protein (FLAP). In any of the aforementioned aspects that involve the prevention or treatment of diseases or conditions mediated by leukotrienes or leukotriene-dependent are other modalities that comprises identifying patients monitoring the patient for, either: i) at least one inflammatory biomarker related to leukotriene; or ü) at least one response of the functional marker to a leukotriene modifying agent; or iii) at least one inflammatory biomarker related to the leukotrienes and at least one response of the functional marker to a leukotriene modifying agent. In other alternative modalities or modalities, the biomarkers related to leukotrienes are selected from the group consisting of LTB 4 1 cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, α-a, sICA, IL-6, IL-4. , and IL-13, while even in other modalities or alternative modalities, the functional marker response is of a significant lung volume (FEV1). In any of the aforementioned aspects involving the prevention or treatment of diseases or conditions mediated by leukotrienes or leukotriene-dependent are other modalities that comprise identifying patients either: i) tracking the patient for at least one leukotriene gene SNP and / or the haplotype that includes the SNP at intronic or exonic locations; or ii) monitoring the patient for at least one inflammatory biomarker related to leukotriene; or ii) monitoring the patient for at least one response of the functional marker to a leukotriene modifying agent. In other modalities or alternative modalities, the leukotriene SNP gene or haplotype is a gene of the leukotriene pathway. Even in other embodiments or alternative embodiments, the leukotriene gene or SNP haplotype is a 5-lipoxygenase activating protein (FLAP) SNP or haplotype. In other modalities or alternative modalities, the inflammatory biomarkers related to leukotrienes are selected from the group consisting of LTEB4l cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, α-a, sICAM, IL-6, IL- 4, and IL-13, while even in other SAA, MPO, EPO, MCP-1, α-a, sICAM, IL-6, IL-4, and IL-13, even in other modalities or alternative modalities , the response of the functional marker is of a significant pulmonary volume (FEV1). In any of the aforementioned aspects that involve the prevention or treatment of diseases or conditions mediated by leukotrienes or leukotriene-dependent are other modalities that comprise identifying patients through at least two of the following: i) tracing the patient for at least one leukotriene gene SNP or haplotype; ii) monitoring the patient for at least one inflammatory biomarker related to leukotriene; ii) monitoring the patient for at least one response of the functional marker to a leukotriene modifying agent. In other modalities or alternative modalities, the leukotriene SNP gene or haplotype is a gene of the leukotriene pathway. Even in other modalities or alternative modalities, the SNP gene or haplotype is an activating protein of the 5-lipoxygenase (FLAP) SNP or haplotype. In other alternative modalities or modalities, the inflammatory biomarkers related to leukotrienes are selected from the group consisting of LTB 4, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, α-α, sICAM, IL-6, IL -4, and IL-13, while even in other SAA, MPO, EPO, MCP-1, α-a, sICAM, IL-6, IL-4, and IL-13, even in other modalities or modalities alternatives, the response of the functional marker is of a significant lung volume (FEV1). In any of the aforementioned aspects that involve the prevention or treatment of diseases? Leukotriene-mediated or leukotriene-dependent conditions are other modalities that comprise identifying patients in the following way: i) Tracing the patient to at least one leukotriene SNP gene or haplotype; and ii) monitoring the patient for at least one inflammatory biomarker related to leukotriene; and ii) monitoring the patient to stop at least one response of the functional marker to a leukotriene modifying agent. In other modalities or alternative modalities, the leukotriene SNP gene or haplotype is a gene of the leukotriene pathway.
Even in other modalities or alternative modalities, the SNP gene or haplotype is an activating protein of the 5-lipoxygenase (FLAP) SNP or haplotype. In other alternative modalities or modalities, the inflammatory biomarkers related to leukotrienes are selected from the group consisting of LTB 4, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, α-a, sICAM, IL-6, IL -4, and IL-13, while even in other modalities or alternative modalities, the functional marker response is of a significant lung volume (FEV1). In another aspect is the prevention or treatment of diseases or conditions mediated by leukotrienes or leukotriene-dependent comprising the administration to a patient of an effective amount of a FLAP modulator, where patients have been identified using information obtained: i) tracking the patient for at least one leukotriene SNP gene or haplotype; and i) monitoring the patient for at least one inflammatory biomarker related to leukotriene; and ii) monitoring the patient for at least one response of the functional marker to a leukotriene modifying agent. In other modalities or alternative modalities, the FLAP modulator is a FLAP inhibitor. In other modalities or alternative modalities, the leukotriene SNP gene or haplotype is a gene of the leukotriene pathway. Even in other modalities or alternative modalities, the SNP gene or haplotype is an activating protein of the 5-lipoxygenase (FLAP) SNP or haplotype. In other alternative modalities or modalities, the inflammatory biomarkers related to leukotrienes are selected from the group consisting of LTB4, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-0, sICAM, IL-6, IL-4. , and IL-1.3, while even in other modalities or alternative modalities, the functional marker response is of a significant lung volume (FEV1). In other modalities or alternative modalities, the information obtained from the three diagnostic methods can be used in an algorithm in which the information is analyzed to identify patients who need treatment with a FLAP modulator, the treatment regimen, and the type of treatment. FLAP modulator used.
In any of the aforementioned aspects diseases or conditions mediated by leukotrienes or leukotriene-dependents include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, inflammatory bowel disease, dyspneic syndrome adult respiratory, myocardial infarction, aneurysm, apoplexy, cancer, and endotoxic shock.
Certain Chemical Terminology Unless stated otherwise, the following terms used in this application, including the specification and the claims, have the definitions given below. It should be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly states otherwise. The definition of standard chemical terms can be found in reference to the works, which include, Carey & Sundberg "ADVANCED ORGANIC CHEMISTRY 4 * ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used within the capacity of the art. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" as well as other forms "include", "includes", and "including" is not limiting. An "alkoxy" group refers to a group (alkyl) O-, wherein alkyl as defined herein. An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety can be a "saturated alkyl" group, which means that it does not contain alkene to alkyne residues. The alkyl moiety can be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one a carbon-carbon double bond, and an "alkyne" moiety refers to a group composed of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be straight chain, branched, or cyclic. The "alkyl" moiety may have 1 to 10 carbon atoms (as long as it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can consist of ·, carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 0 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group could be a "lower alkyl" having 1 to 5 carbon atoms. The alkyl group of the compounds described herein can be designated as "C 1 -C 4 alkyl" or similar designations. By way of example only, "alkyl of 1 to 4 carbon atoms" indicates that they are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl,! so-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Common alkyl groups include, but are by no means limited, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "alkylamine" refers to the group -N (alkyl) xHy, where x and y are selected from the group x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl groups, taken together, can optionally forming a cyclic ring system. The term "alkenyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. This is ", an alkenyl group begins with the atoms -C (R) = CR, where R refers to the remaining portions of the alkenyl group, which may be the same or different.Non-limiting examples of an alkenyl group include -CH = CH, -C (CH3) = CH, -CH = CCH3 and -C (CH3) = CCH3 The alkenyl residue can be straight chain, branched, or cyclic (in which case it would also be known as a "cycloalkenyl" group). The term "alkynyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond, that is, an alkynyl group starts with the atoms -CEC-R, where R refers to the remaining portions of the alkynyl group, which may be the same or different, non-limiting examples of an alkynyl group include -C = CH, -C = CCH3 and -C = CCH2CH3 .The "R" portion of the alkynyl moiety may be a chain An "amide" is a chemical residue with the formula -C (0) NHR or -NHC (0) R, where R is selected from the group a group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heteroalicyclic (linked through a ring carbon). An amide may be an amino acid molecule or peptide linked to any compound of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), thereby forming a prodrug Any amine, or carboxyl side chain on the compounds described herein can be acidified. The methods and specific groups for producing such amides are known to those skilled in the art and can be easily found in reference sources such as Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety. The term "aromatic" or "aryl" refers to an aromatic group which has at least one ring having a pi electron system and includes both carbocyclic aryl groups (e.g., phenyl) and heterocyclic aryl (or "heteroaryl") or "heteroaromatic") (e.g., pyridine). The term includes fused ring monocyclic or polycyclic groups (i.e., rings that share adjacent pairs of carbon atoms). The term "carbocyclic" refers to a compound which contains one or more covalently closed ring structures, and the atoms that form the ring column are all carbon atoms. The term thus distinguishes carbocyclic heterocyclic rings in which the ring column contains at least one atom that is different from carbon. The term "bond" or "simple bond" refers to a chemical bond between two atoms, or two residues when the atoms bound by the bond are considered part of a large month structure.
A "cyano" group refers to a -CN group. The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen, and may be saturated, partially unsaturated or completely unsaturated. Cycloalkyl groups include groups having from 3 to 0 ring atoms. Illustrative examples of cycloalkyl groups include the following moieties: A.? > . . co .00 > -. ? . . or .0 ·? ·? · 00, and the like The term "ester" refers to a chemical moiety with the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon) and heteroalicyclic (linked through a carbon, ring). Any hydroxy, or carboxyl side chain on the compounds described herein may be esterified. The specific methods and groups for producing such asters are known to those skilled in the art and are easily found in reference sources such as Greene & Wuts, Protective Groups in Organic Synthesis, 3"Ed., John Wiley &Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety, the term" halo "or, alternatively, "halogen" means fluoro, chloro, bromo or iodo The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with their The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which halo as "The terms" heteroalkyl "" heteroalkenyl "and" heteroalkynyl "include optionally substituted alkyl, alkenyl and alkynyl radicals and has one or more atoms of the skeletal chain selected from a different carbon atom, for example, oxygen, nitrogen, sulfur, phosphorus or combinations thereof, the terms "heteroa rilo" or, alternatively, "heteroarom" Alphabet "refers to an aryl group including a month or hetero ring selected from nitrogen, oxygen and sulfur. A "heteroaromatic" or "heteroaryl" moiety containing N refers to an aromatic group in which at least one of the ring skeleton atoms is a nitrogen atom. The polycyclic heteroaryl group can be fused or non-fused. Illustrative examples of heteroaryl groups include the following moieties:
and similar. The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms each selected from 0, S and N, where each heterocyclic group fills from 4 to 10 in its ring system, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. The non-aromatic heterocyclic groups include groups having only At atoms in their ring system, but the aromatic heterocyclic groups must have at least 5 atoms in their ring system. Heterocyclic groups include benzo fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a five-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranoyl, dihydrofuranoyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino. , thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H pyranyl, dioxanyl, 1,3-dioxolantium, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranoyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.OThexanyl, 3-azab] cyclo [4.1, 0] -heptanyl,
3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranoyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The above groups, as derived from the aforementioned groups, can be attached to C or attached to N where such binding is possible. For example, a pyrrole derivative group can be pyrrol-1-yl (N-linked) or pyrrole-3-yl (C-linked). In addition, a group derived from imidazole can be midazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked) ). Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo moieties (= 0) such as pyrrolidin-2-one. A "heteroalicyclic" group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur, ie non-aromatic heterocyclic groups. The radicals can be fused with an aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups, also referred to as heteroalicyclic groups, include:
The term "heteroalicyclic" further includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.
The term "member ring" may encompass any cyclic structure. The term "of members" means the amount of atoms of the skeleton that constitutes the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings. An "isocyanate" group refers to a -NCO group. An "isothiocyanate" group refers to a group -NCS. A "mercaptyl" group refers to a group (alkyl) S-. The term "residue" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded or bound to a molecule. A "sulfinyl" group refers to a -S (= 0) -R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon) and heteroalicyclic (linked to trues of a ring carbon) A "sulfonyl" group refers to a -S (= 0) 2-R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon ) and heteroalicyclic (linked through a ring carbon) A "thiocyanate" group refers to a -CNS group. The term "optionally substituted" or "substituted" means that the reference group may be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulphone, arylsulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, perhaloalkyl, perfluoroalkyl, silyl, and amino, including mono- and di-substituted amino groups, and their derivatives protected. By way of example, a further substituent may be LSRS, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0 ) 2-, -NH-, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC ( 0) 0-, - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or - (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); and each Rs is independently selected from H, (substituted or unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalkyl), heteroaryl, or heteroalkyl. Protecting groups that can form the protective derivatives of the above substituents are known in the art and can be found in references such as Greene &; Wuts, previous. The compounds presented herein may have one or several stereocenters and each center may exist in the R or S configuration. The compounds present herein include all diastereomeric, enantiomeric and epimeric forms as well as appropriate mixtures thereof. Stereoisomers can be obtained, if desired, by methods known in the art such as, for example, the separation of stereoisomers by chiral chromatographic columns. The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein may exist in unsolvated form as well as solvated with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds present herein are also considered disclosed herein. Certain pharmaceutical terminology The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means that it has no persistent harmful effect on the general health of the subject being treated. The term "agonist" as used herein, refers to a molecule such as a compound, a drug, an enzyme activator or a hormonal modulator which improves the activity of another molecule or the activity of a receptor site.
The term "antagonist," as used herein, refers to a molecule such as a compound, a drug, an enzyme activator or a hormonal modulator which decreases, or prevents the action of another molecule or the activity of a receiving site. The term "asthma" as used herein refers to any disorder of the lungs characterized by variants in pulmonary gas flow associated with airway constriction of any cause (intrinsic, extrinsic, or both; not allergic). The term asthma can be used with one or adjective wings to indicate the cause. The term "bone disease," as used herein, refers to a disease or condition of the bones, including, but not limited to, inappropriate bone reconstitution, loss or gain, osteopenia, osteomalacia, osteofibrosis, and bone disease. Paget [Garcia, "Leucotriene B4 stimulates osteoclastic bone resorption both intro and in vivo", J Bone Miner Res. 1996; 11: 1619-27] The term "cardiovascular disease," as used herein refers to diseases affecting the heart to blood vessels or both, including but not limited to: arrhythmia, atherosclerosis and its sequelae, angina, myocardial ischemia, myocardial infarction, cardiac or vascular aneurysm, vasculitis, stroke, peripheral obstructive arteriopathy of a limb, a organ, or a tissue, reperfusion injury followed by cerebral ischemia, heart or other organ or tissue, endotoxic shock, surgical or traumatic, hypertension, heart disease vascular, heart failure, abnormal blood pressure; shock; vasoconstriction (including those associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue. [Lotzer K et al., "The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis," Biochim Biophys Acta 2005; 1736: 30-7; Helgadottir A et al., "The gene encoding 5-lipoxigenoase activating protein confers risk of myocardial infarction and stroke", Nat Genet, 2004 Mar, 36 (3): 233-9, Epub 2004 Feb 8; [Heise CE, Evans JF et al., "Characterization of the human cysteinyl leucotriene 2 receptor", J Biol Chem. 2000 Sep 29; 275 (39): 30531-6.] The term "cancer," as used herein refers to a abnormal development of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (disperse). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, large intestine, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, or other endocrine organs) (thyroid), prostate, skin (melanoma), or hematologic tumors (such as leukemias) [Ding XZ et al., "A novel anti-cancer pancreatic agent, LY293111", Anticancer Drugs, 2005 Jun; 16 (5) : 467-73 Review, Chen X et al., "Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis", an Cancer Res. 2004 Oct 1; 10 (19): 6703 The term "vehicle" as used herein, refers to relatively non-toxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues, the terms "co-administration" or the like, as used herein, they encompass the administration of therapeutic agents euticos selected to a single patient, and include treatment regimens in which agents are administered by the same route or a different route of administration or at the same time or in a different time. The term "dermatological disorder," as used herein refers to a skin disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory disorders of such skin, atopic dermatitis, bullous disorders, collagenous disorders, contact eczema dermatitis, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, urticaria [Wedi B et al., "Pathophysiological role of leukotrienes in dermatological díseases: potential therapeutic implications", BioDrugs. 2001; 15 (11): 729-431.
The term "diluent" refers to chemical compounds that are used to dilute the compound of interest before its administration. The diluents can also be used to stabilize the compounds because they can provide a more stable environment. Salts dissolved in buffer solutions (which also provide pH control or maintenance) are used as diluents in the art, including, but not limited to, a saline phosphate buffer solution. The terms "effective amount" or "effective amount for therapeutic use," as used herein, refers to a sufficient amount of an agent or a compound that is administered which will relieve, to some degree, one or a month symptoms of the disease or condition being treated. The result may be the reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein that provides a clinically significant decrease in the symptoms of the disease. An "effective" amount appropriate in any individual case can be determined using techniques, such as a dose scale study. The terms "improve" or "improvement," as used herein, mean to increase or prolong either a potential effect to a duration. Thus, with respect to the improvement of the effect of therapeutic agents, the term "what improvement" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents in a system. An "effective amount that improves", as used herein, refers to an amount adequate to improve the effect of another therapeutic agent in a suitable system. The term "enzymatically cleavable linker," as used herein refers to unstable or degradable linkers that can be degraded by one or more enzymes.
The terms "flbrosis" or "fibrous disorder," as used herein, refers to conditions that follow acute or chronic inflammation and are associated with abnormal accumulation of cells and / or collagen and include but not limited to fibrosis. of individual organs or tissues such as the heart, kidney, lungs to skin, and includes such disorders as idiomatic pulmonary fibrosis and cryptogenic fibrous alveoitis [Charbeneau RP et al., "Eicosanoids: mediators and therapeutic targets in fibrotic lung disease", Clin Sci (Lond) .2005 Jun; 108 (6): 479-911. The term "iatrogenic" means a condition, disorder, or leukotriene-dependent or leukotriene-dependent disease created or aggravated by medical or surgical therapy. The term "inflammatory disorders" refers to those diseases or conditions that are characterized by a month or so of the pain signals (pain, from the generation of harmful substances that stimulate the nerves), heat (heat, from of vasodilatation), flushing (flushing, from vasodilatation and increased blood flow), dilation (tumor, excessive entry or restricted fluid output), and loss of function (functio laesa, which may partially or completely , temporary or permanent). Inflammation takes many forms and includes, but is not limited to, inflammation that is one or more of the following: acute, adhesive, atrophic, carral, chronic, cirrhosic, diffuse, disseminated, exudative, fibrinous, fibrous, focal, granulomatous, hyperplastic , hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymal, plastic, productive, proliferative, pseudomembranous, purulent, sclerosing, serplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative. Inflammatory disorders also include, without limitation, those that affect the blood vessels (polyarthritis, temporal arteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter); gastrointestinal tract (disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus) [Harrison's Principles of Intemal Medicine, 16th Edition, Kasper DL, et al., Editors; McGraw-Hill, publishers]. The term "interstitial cystitis" refers to a disorder characterized by lower abdominal pain, frequent and sometimes painful urination, infection, toxins, trauma or tumors [Bouchelouche K et al., The cysteinyl leukotrine D4 receptor antagonist montelukast for the treatment of interstitial cystitis ", J Ural 2001; 166: 1734.] The term" mediators driven by leukotrienes, "as used herein, refers to molecules capable of being produced in a patient that may arise from excessive production of stimulation. by leukotrienes of the cells, such as, by way of example only, LTB4, LTC4, LTE4, cysteinyl leukotrienes, monocyte inflammatory protein (??? -? a,), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM, soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and molecules of in general flammation such as interleukin-6 (IL-6), C-reactive protein (CRP), and serum amyloid A protein (SAA). The term "leukotriene-related mediators," as used herein, refers to molecules to molecules capable of being produced in a patient that may arise from the excessive production of stimulation by leukotrienes of the cells, such as, by way of example only, LTB4, LTC4, LTE4, cysteinyl leukotrienes, monocyte inflammatory protein (MIP-10.), interleukin-8 (I L-8), interleukin-4 (IL-4), interleukin-13 (IL-13) , monocyte chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM, soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and general inflammation molecules such as interleukin-6 (IL-6), C-reactive protein (CRP), and serum amyloid A protein) (SAA). The term "leukotriene-dependent", as used herein, refers to conditions or disorders that would not occur or would not occur to the same degree, in the absence of one or several leukotrienes. The term "leukotriene-mediated", as used herein, refers to conditions or disorders that could occur in the absence of leukotrienes but may occur in the presence of one or more leukotrienes. The term "Vpacnt responsive to leukotrienes", as used herein, refers to a patient who has been identified by the genotype of the FLAP haplotypes, or the genotype of one or more other genes in the pathway of the leukotrienes and / or by the patients phenotype either by previous positive clinical response to another leukotriene modulator, including, by way of example only, zileuton (Zyflo ™), montelukast (Singulair ™), pranlukast (Onon ™), zafirlukast ( Accolate ™), and / or by its profile of mediators driven by leukotrienes that indicate the excessive stimulation of leukotrienes of inflammatory cells, since they probably respond in a favorable way to the leukotriene modulator therapy.The terms "equipment" and "article of production" "are used as synonyms" A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized The term "active metabolite" is referred to as "metabolite". It is a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized", as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism . In this way, enzymes can produce structural alterations specific to a compound. For example, cytochrome P450 catalyzes a variety of oxidant and reducing reactions while uridin diphosphate glucuronyltransferases catalyze the transfer of an activated giucuronic acid molecule to aroma- ms alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. More information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McG raw-Hill (1996). The metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with liver cells in vitro and analysis of the resulting compounds. Both methods are well known in the art. The term "modular," as used herein, means interacting with a target either directly or indirectly to alter the activity of the target, including, by way of example only, to improve target activity, to inhibit the activity of the target, to limit the activity of the target, or to stop the activity of the target. The term "modulator," as used herein, rs to a molecule that interacts with a target, either directly or indirectly. Interactions include, but are not limited to, the interactions of an agonist and an antagonist. The terms "neurodegenerative disease" or "disorder of the nervous system," as used herein, rs to conditions that alter the structure or function of the brain, spinal cord or peripheral nervous system, including but not limited to, Alzheimer's disease, cerebral edema, cerebral ischemia, sclerosis, neuropathies, Parkinson's disease, those found after surgical trauma (including post-surgical cognitive dysfunction and injury to the brainstem or spinal cord), as well as neurological aspects of disorders such as degenerative and sciatic disc disease. The acronym "SNC" rs to disorders of the central nervous system, ie, spinal cord and brain [Sugaya K, et al., "New anti-inflammatory treatment strategy in Alzheimer's Disease", Jpn J Pharmacol. 2000 Feb; 82 (2): 85-94; Yu GL, et al., "Montelukast, a cysteinil leucotriene receptor-! Antagonist, dose-and time-dependently protects against focal ischemia cerebrol in mice", Pharmacology. 2005 Jan; 73 (1): 31 -40.
Epub 2004 Sep 27; [Zhang WP, et al., "Neuroprotective effect of ONO-1078, a leucotriene receptor antagonist, on focal ischemia cerebrol in rats," Acta Pharmacol Sin. 2002 Oct; 23 (10); 871 -7]. ocular "or" ophthalmic disease, "as used herein, refers to diseases that affect the eye or eyes and potentially the surrounding tissues as well.Ocular or ophthalmic diseases include, but are not limited to, conjunctivitis, retinitis, scleritis , uveitis, conjunctivitis, spring conjunctivitis, papillary conjunctivitis [Toriyama S., "Effects of leucotriene B4 receptor antagonist on experimental autoimmune uveoretinitis in rats", Nippon Ganka Gakkai Zasshi, 2000 June; 104 (6): 396-40; [Chen F , et al., "Treatment of S antigen uveoretinitis with lipoxygenase and cyclo-oxygenase inhibitors", Ophthalmic Res. 1991; 23 (2): 84-91.] By "pharmaceutically acceptable," as used herein, refers to a material, such as a vehicle or dilutes nte, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which this content.
The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity or properties of the compound, pharmaceutically acceptable salts can be obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Further pharmaceutically acceptable salts can be obtained by reacting a compound described herein, with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium salt or potassium salt, a salt alkaline earth metal, such as a calcium salt or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine, Usin, and similar, or by other methods known in the art. The term "pharmaceutical combination" as used herein, means a product resulting from the mixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, eg ex. any compound of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), and a co-agent, are both administered to a patient simultaneously in the form of a simple entity or dosage. The term "non-fixed combination" means the active ingredients, for example any compound of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), and a co-agent, are administered to a patient as separate entities either concurrently, concurrently or sequentially without specific intervening time limits, where such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients. The term "pharmaceutical composition" refers to a mixture of any compound of formula (A), formula (B), formula (C), formula (D), formula (F) formula (H), with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. The multiple techniques of administration of a compound exist in the art including, but without limitation: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. A "prodrug" refers to an agent that becomes the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They can, for example, ester bioavailable by oral administration while the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions on the parent drug. An example, without limitation, of a prodrug would be any compound of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), which is administered in the form of an ester (the "prodrug") to facilitate transmission through a cell membrane where the solubility in water is harmful to mobility but which is then metabolically hydrolysed to the carboxylic acid, the active entity, once inside the cell where the solubility in water is beneficial. Another example of a prodrug could be a short peptide (polyamino acid) linked to an acid group where the peptide is metabolized to reveal the active moiety. The term "respiratory disease," as used herein, refers to diseases that affect organs that are involved in breathing, such as the nose, throat, larynx, trachea, bronchi, and lungs. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, severe acute asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, asthma sensitive to Aspirin, asthma induced by physical exercise, isocanic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, spheroidal-resistant asthma, stationary asthma, allergic spring rhinitis, allergic rhinitis perennial, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or upper tract inflammation and cystic fibrosis, and hypoxia [Evans JF, "The Cysteinil Leucotrienes (CysLT) Pathway in Allergic Rhinitis", Allergology International 2005; 54: 187-90); Kemp JP., "Leukotriene receptor antagonists for the treatment of asthma", Drugs. 2000 April; 3 (4): 430-41; Riccioni G, et al., "Effect of the two different leukotriene receptor antagonists, montelukast and zafirlukast, on quality of life: a 12-week randomized study", Allergy Asthma Proc. 2004 Nov-Dec; 25 (6): 445-81. The term "subject" or "patient" encompasses mammals and non-mammals Examples of mammals include, but are not limited to, any member of the class of Mammals: humans, non-human primates such as chimpanzees, and other species of apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs, domestic animals such as rabbits, dogs, and cats, laboratory animals that include rodents, such as rats, mice and guinea pigs, and the like Examples of non-mammals include, but not be limited to, Maros and fish and the like In one embodiment of the methods and compositions provided herein, the mammal is a human being, the terms "tatar", "treating" or "treatment", such as used in the present, include alleviating, reducing or decreasing the symptoms of a disease or condition, preventing further symptoms, decreasing or preventing the underlying metabolic causes of the symptoms, inhibit the disease or condition, for example, by stopping the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition; condition either prophylactically and / or therapeutically. Other objects, features and advantages of the methods and compositions described herein will be apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art. from this detailed description. All references mentioned herein, including patents, patent applications, and publications, are incorporated by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 presents illustrative schemes for the synthesis of compounds described herein. Figure 2 presents illustrative schemes for the synthesis of compounds described herein.
Figure 3 presents illustrative schemes for the synthesis of compounds described herein. Figure 4 presents illustrative schemes for the synthesis of compounds described herein. Figure 5 presents illustrative schemes for the synthesis of compounds described herein. Figure 6 presents illustrative schemes for the synthesis of compounds described herein. Figure 7 presents illustrative schemes for the synthesis of compounds described herein. Figure 8 presents illustrative examples of compounds described herein. Figure 9 presents illustrative examples of compounds described herein. Figure 10 presents illustrative examples of compounds described herein. Figure 11 presents illustrative examples of compounds described herein. Figure 12 presents an illustrative scheme for the treatment of patients using the compounds and methods described herein. Figure 13 presents an illustrative scheme for the treatment of patients using the compounds and methods described herein. Figure 14 presents an illustrative scheme for the treatment of patients using the compounds and methods described herein. Detailed Description of the Invention Illustrative Biological Activity Leukotrienes (LT) are powerful contractile and inflammatory mediators produced by the release of arachidonic acid from cell membranes and conversion to leukotrienes by the action of 5-lipoxygenase, activator protein of the 5-lipoxygenase. -lipoxygenase, LTA4 hydrolase and LTC4 synthase. The leukotriene synthesis pathway, or the 5-lipoxygenase pathway, involves a series of enzymatic reactions in which arachidonic acid is converted into leukotrienes LTB l or the cysteinyl leukotrienes, LTC4, LTD4, and LTE4. The way is mainly produced in the nuclear envelope and has been described. See, for example, Wood, JW et al., J. Exp. Med., 178: 1935-1946, 1993; Peters-Golden, Am. J. Respir. Crit. Care Med. 157: S227-S232.1998; Drazen, et al., Ed. Five-Lipoxygenase Products in Asthma, Lung Biology in Health and Disease Series, Vol. 120, Chs. 1, 2, and 7, Marcel Dekker, Inc. NY, 998. Protein components dedicated to the synthesis pathway of leukotrienes include a 5-lipoxygenase (5-LO), a 5-lipoxygenase activating protein, a LTA4 hydrolase, and an LTC synthase. The synthesis of leukotrienes has been described in the literature, for example, by Samuelsson et al., Science, 220, 568-575, 1983; PetersrGolden, "Cell Biology of the 5-Lipoxygenase Pathway" Am J Respir Crit Care Med 157: S227-S232 (1998). Leukotrienes are synthesized directly from arachidonic acid by different cells including eosinophils, neutrophils, basophils, lymphocytes, macrophages, monocytes and mast cells. Excessive LTA4, for example from an activated neutrophil, can enter a cell via a transcellular pathway. Most ace cells in the body have LTA4 hydrolase so that they can produce LTB4. Platelets and endothelial cells have LTC4 synthase, so they can produce LTC4 when they occur with LTA4 through a transcellular pathway. Arachidonic acid is a polyunsaturated fatty acid and is present mainly in the membranes of body cells. After the presentation of the inflammatory stimulus outside the cell, calcium is released and binds to phospholipase A2 (PLA2) and 5-LO. Activation of the cell results in the translocation of PLA2 and 5-LO from the cytoplasm to the endoplasmic reticulum and / or nuclear membranes, where in the presence of FLAP, the released arachidonic acid is converted by an intermediate 5-HPETE to the LTA epoxide . Depending on the type of cell, LTA4 can be converted immediately into LTC by nuclear binding CTL synthase or LTB by the action of cytosolic LTA4 hydrolase. The LTB4 is exported from the cells by a transporter not yet characterized and can activate other cells, or the cell in which it was produced, by binding by high affinity to one of the two receptors coupled to the G protein (GPCRs), ie BLTIR or BLT2R. LTC4 is exported to the blood by the MRP-1 anion pump and rapidly converted to LTE by the action of the dipeptidases. LTC4, LTD and LTE4 are collectively known as cysteinyl leukotrienes (or previously as the slow-reacting substance of anaphylaxis, SRS-A). The cysteinyl leuco.trienos activate other cells, or the cells in which they are produced, by binding by high affinity to one of the two GPCRs, ie CysLTIR or CysLT2R. CysLTI receptors are found in eosinophils, neutrophils, macrophages, mast cells, B-lymphocytes and smooth muscle of the human respiratory tract and induce broncho-constriction. Zhu et al., Am J Respir Cell Mo! Biol Epub August 25 (2005). CysLT2 receptors are located in eosinophils, macrophages, mast cells of the human respiratory tract and in the pulmonary vasculature humane Figueroa et al., Clin Exp Allergy 33: 1380-1388 (2003). Inclusion of Leukotrienes in Diseases or Conditions The inclusion of leukotrienes in diseases is described in detail in the literature. See for example, Busse, Clin. Exp. Alllergy 26: 868-79, 1996; O'Byme, Chest 111 (Supp.2): 27S-34S, 1977; Sheftell, F.D., et al., Headache, 40: 158-163, 2000; Klickstein et al., J. Clin. Invest., 66: 1166-1170, 1950; Davidson et al., Ann. Rheum. Dis., 42: 677-679, 1983. Leukotrienes produce marked inflammatory responses in human skin. Evidence of the inclusion of leukotrienes in a human disease is found in psoriasis, in which leukotrienes have been detected in psoriatic lesions. (Kragballe et al., Arch. Dermatol., 119: 548-552, 1983). For example, inflammatory responses have been suggested to reflect three types of changes in local blood vessels. The essential change is an increase in vascular diameter, which results in an increase in local blood flow, and leads to increased temperature, flushing and a reduction in blood flow velocity, especially along the surfaces of the small blood vessels. The second change is the activation of the endothelial cells that line the blood vessel to express adhesion molecules that promote the binding of circulating leukocytes. The combination of decreased blood flow and induced adhesion molecules allows leukocytes to attach to the endothelium and migrate to tissues, a process known as extravasation. These changes are initiated by cytokines and leukotrienes produced by activated macrophages. Once inflammation has begun, the first cells attracted to the site of infection are, in general, neutrophils. They are followed by monocytes, which differ in more tissue macrophages. In the later stages of inflammation, other leukocytes, such as eosinophils and lymphocytes, also enter the infected site. The third change in local blood vessels is an increase in vascular permeability. Instead of being firmly united, the endothelial cells lining the walls of the blood vessels separate, leading to the release of fluid and proteins from the blood and its local accumulation in the tissue. (See Janeway, et al., Immunobiology: the immune system in health and disease, 5th ed., Garland Publishing, New York, 2001). LTB4 produces relatively weak contractions of the isolated trachea and pulmonary parenchyma, and these contractions are partially blocked by cyclooxygenase inhibitors, suggesting that the contractions are secondary to the release of prostaglandin. However, LTB4 has been shown to be a potent chemotactic agent for eosinophils and progenitors of mast cells and the LTB4 receptor knockout mouse is protected from eosinophilic inflammation and allergic-mediated airway hyperreactivity. T cells. Miyahara et al. J Immunol 174: 4979-4784; (Weller et al J Exp Med 201: 1961-1971 (2005).) Leukotrienes C4 and D4 are potent contractile agents of smooth muscle, promoting broncho-constriction in a variety of species, including humans (Dahlen et al. , Nature, 288: 484-486, 1980.) These compounds have profound hemodynamic effects, contracting coronary blood vessels, and resulting in reduced cardiac output efficiency (Marone et al., In Biology of Leukotrienes, ed. By R. Levi and RD Krell, Ann., New York Acad. Sci. 524: 321-333, 1988), Leukotrienes also act as vasoconstrictors, however, there are marked differences for different vascular beds. leukotrienes contribute to cardiac reperfusion injury following myocardial ischemia (Barst and Mullane, Eur. J. Pharmacol., 114: 383-387, 1985; Sasaki et al., Cardiovasc. Res., 22: 142- 148, 1988.) LTC4 and LTD4 directly increase the vascular permeability probably by promoting the retraction of capillary endothelial cells through activation of the receptor CysLT2 receptor and possibly other CysLT receptors not yet defined [Lotzer et al. Arterioscler Thromb Vasc Biol 23: e32-36. (2003)]. LTB improves atherosclerotic advancement in two atherosclerotic mouse models, ie mice deficient in the low density lipoprotein receptor (LDLr-f-) and deficient in apolipoprotein E (ApoE - / -) (Aiello et al., Arterioscler Thromb Vasc Biol 22: 443-449 (2002); Subbarao et al., Arterioscler Thromb Vasc Biol 24: 369-375 (2004); Heller et al. Circulation 112: 578-586 (2005). LTB4 has also been shown to increase the chemoattractant protein of human monocytes (MCP-1) a known enhancer of atherosclerotic advancement (Huang et al Aterioscler Thromb Vasc Biol 24: 1783-1788 (2004).) The function of FLAP in the pathway of The synthesis of leukotrienes is significant because FLAP in concert with 5-lipoxygenase carries out the first weight in the pathway for the synthesis of leukotrienes.Therefore, the synthesis route of leukotrienes provides a quantity of targets for useful compounds in the treatment of leukotriene-dependent or leukotriene-dependent diseases or conditions, including, by way of example, vascular to inflammatory disorders, proliferative diseases, and non-carcinogenic disorders Leukotriene-mediated or leukotriene-dependent conditions treated using the methods, compounds , pharmaceutical compositions and medicaments described herein, include, but are not limited to, diseases and bone diseases, cardiovascular diseases and disorders, inflammatory diseases and disorders, dermatological diseases and disorders, diseases and eye disorders, cancer and other diseases and proliferative disorders, respiratory diseases and disorders and non-carcinogenic disorders. Treatment Options It is known that leukotrienes contribute to the inflammation of the airways of patients with asthma. Antagonists of the CysLT- receptor, such as montelukast (Singulair ™) have been shown to be effective in asthma and allergic rhinitis [Reiss et al. Arch Intern Med 158: 1213-1220 (1998); Phillip et al. Clin Exp Allergy 32: 10201028 (2002)]. Antagonists of CysLTIR, pranlukast (Onon ™) and zafirlukast, (Accolate ™) have also been shown to be effective in asthma.
A number of drugs have been designed to inhibit the formation of leukotrienes, including the 5-lipoxygenase inhibitor, zileuton (Zyflo ™) which has been shown to be effective in asthma, Israel et al. Ann Intern Med 19: 1059-1066 (1993). The 5-lipoxygenase inhibitor, ZD2138, was shown to be effective in inhibiting the fall of FEV1 resulting in aspirin-induced asthma, Nasser et al., Thorax, 49; 749756 (1994). The following inhibitors of leukotriene synthesis have been shown to be effective in asthma: MK-0591, a specific inhibitor of the 5-lipoxygenase activating protein (FLAP), Brideau, et al., Ca. J. Physiol. Pharmacol. 70: 799-807 (1992), MK-886, a specific inhibitor of the 5-lipoxygenase activating protein (FLAP), Friedman et al. Am Rev Respir Dis., 147: 839-844 (1993), and BAY X1005, a specific inhibitor of the 5-lipoxygenase activating protein (FLAP), Fructmann et al., Agents Action 38: 188-195 (1993) . Inhibition of FLAP will decrease the LTB4 of monocytes, neutrophils and other cells involved in vascular inflammation and thereby decrease atherosclerotic progression. The FLAP inhibitor, MK-886, has been shown to decrease the post-angioplasty vasoconstrictor response in a porcine carotid lesion model Provost of al. Brit J Pharmacol 123: 251-258 (1998). MK-886 has also been shown to suppress intimal hyperplasia of the femoral artery in a photochemical model of rat endothelial injury Kondo et al. Thromb Haemosf 79: 635-639 (1998). The 5-lipoxygenase inhibitor, zileuton has been shown to reduce renal ischemia in a rat model, Nimesh et al. Mot Pharm 66: 220-227 (2004). FLAP modulators have been used for the treatment of a variety of diseases or conditions, including, by way of example only, (I) inflammation (see for example Leff AR et al., "Discovery of leucotrienes and the development of antileucotriene. agents ", Ann Allergy Asthma Immunol 2001; 86 (Suppl 1) 4-8; Riccioni G, et al.," Advances in therapy with antileucotriene drugs ", Ann Clin Lab Sci. 2004, 34 (4): 379-870; (ii) respiratory diseases including asthma, adult respiratory distress syndrome and alargic asthma (extrinsic), non-allergic asthma (intrinsic), severe acute asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, asthma sensitive to aspirin, asthma induced by physical exercise, isocanic hyperventilation, childhood onset asthma, adult onset asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, stationary asthma (see, for example, Riccioni et al., Ann. Clin. Lab. Sci., V34, 379- 387 (2004)) (iii) Chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or inflammation of the upper tracts and cystic fibrosis (see for example Kostikas K et al., "Leucotrienes V4 in exhaled breath condense and sputum supematant in patients with COPD and asthma ", Chest 2004; 127: 1553-9); (V) secretion and / or increased mucosal edema in a disease or condition (see for example Shahab R et al., "Prostaglandins, leucotrienes, and perennial rhinitis", J Latyngol et al., 2004; 18; 500-7 ); (v) vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and apoplexy (see for example Jala et al., Trends in Immunol., v25, 315-322 (2004) and Mehrabian et al. ., Curr.Opin.Lipidol., V14, 447-457 (2003)); (vi) reduction of the organic reperfusion injury followed by organic ischemia and / or endotoxic shock (see for example Matsui N, et al., "Protective effect of the 5-lipoxygenase inhibitor ardisiaquinone A on hepatic ischemia-reperfusion njury in rats ", Planta Med. 2005 Aug; 71 (8): 717-20); (vii) reduction of blood vessel constriction - (see for example Sta nke-Labesq ue F et al., "Inhibition of leucotriene synthesis with MK-886 prevents a rise in blood pressure and reduces noradrenaline-evoked contraction in L-NAME -lreated rats ", Br J Pharmacol, 2003 Sep; 140 (1): 186-94); (vii) decrease or prevention of an increase in blood pressure (see for example Stanke-Labesque F et al., "Inhibition of leukotriene synthesis with MK-886 prevents a rise in blood pressure and reduces noradrenaline-evoked contraction in L-NA E-lreated rats ", Br J Pharmacol, 2003 Sep; 140 (1): 186-94, and Welch L, et al.," Pharmacological evidence for a novel cysteinyl-leucotriene receptor subtype in human pulmonary artery smooth muscle ", Br J Pharmacol, 2002 Die; 137 (8): 1339-45); (ix) prevention of the recruitment of eosinophils and / or basophils and / or dendritic cells and / or neutrophils and / or monocytes (see for example Miyahara N, et al., "Leucotriene B4 receptor-1 essential for allergen-mediated recruitment of CD8 + T cells and airway hyperresponsiveness ", Immunol 2005 Apr 15; 174 (8): 4979-84); (x) abnormal bone reconstitution, loss or gain, including osteopenia, osteoporosis, Paget's disease, cancer and other diseases (see for example Anderson Gl, et al., "Inhibition of leucotriene function can modulate particulate late-induced changes in bone cell differentiation and activity ", Biomed Mater Res. 2001; 58 (4): 406-140; (xi) ocular inflammation and allergic conjunctivitis, spring-like conjunctivitis, and papillary conjunctivitis (see, eg, Lambíase et al., Arch. Opthalmol. , v121, 615-620 (2003)); (xii) CNS disorders, including, but not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine (See, for example, Souza Carvelho D, et al., "Asthma plus migraine in childhood and adolescence: prophilactic benefits with leucotriene receptor antagonist", Headache, 2002 Nov-Dec; 42 (10): 1044-7; Sheftell F, and col., "Montelukast in the pro philaxis of migraine: a potential role for leucotriene modifiers ", Headache. 2000 Feb; 40 (2): 158-63); (xiii) peripheral neuropathy / neuropathic pain, spinal cord injury (see for example Akpek EA, et al., "A study of adenosine treatment in experimental acute spinal cord injury." Effect on arachidonic acid metabolites ", Spine. 1999 Jan 15; 24 (2): 128-32), cerebral edema and head injury; (xiv) cancer, including, but not limited to, pancreatic cancer and other solid or hematological tumors, (see for example Poff and Balazy, Curr. Drug Targets Inflamm. Allergy, v3, 19-33 (2004) and Steele et al. , Cancer Epidemiology &Prevention, v8, 467-483 (1999); (xv) endotoxic shock and septic shock see for example Leite MS et al., "Mechanisms of increased survival after lipopolysaccharide-induced endotoxic shock in mice consuming olive oil -enriched diet ", Shock, 2005 Feb; 23 (2): 173-8); (xvi) rheumatoid arthritis and osteoarthritis (see for example Alten R, et al., "Inhibition of leucotriene arinduced CDIB / CD18 (Mac-) expression by BILL 284, a new long acting LTB4 receptor antagonist, in patients with rheumatoid arthritis", Ann Rheum Dis. 2004 Feb; 63 (2): 170-6); (xvii) prevention of increased Gl diseases, including, by way of example only, chronic gastritis, eosinophilic gastroenteritis, and gastric motor dysfunction, (see for example Gyomber et al., J Gastroenterol Hepatol., v11, 922-927 (1996); Quack I et al., BMC Gastroenterol v18.24 (2005); Cuzzocrea S, et al., "5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration", Lab Invest, 2005 Jun; 85 (6) : 808-22); (xviii) kidney diseases, including, by way of example only, glomerulonephritis, renal ischemic reperfusion by nephrotoxicity due to ciclosporin. (See, for example, Guasch et al Kidney Int., V56, 261-267; Butterly et al., V 57, 2586-2593 (2000); Guasch A et al. "K-591 acutely radical glomerular size selectivity and reduce proteinuria in human glomerulonephritis ", Kidney Int. 1999; 56: 261-7; Butterly DW et al." A role for leukotrienes n ciclosporine nephrotoxicity ", Kidney Int. 2000; 57: 2586-93); (xix) prevention to treatment of acute or chronic renal failure (see for example Maccarrone M, et al., "Activation of 5-lipoxygenase and related cell membrane lipoperoxidation in hemodialysis patients", J Am Soc Nephrol.; 10: 19916); (xx) type II diabetes (see for example Valdivielso et al., v16, 85-94 (2003); (xxi) decrease in the inflammatory aspects of acute infections within one or more solid organs to tissues such as the kidney with pyelonephritis acute (see for example Tardif M, et al., L-651, 392, "A potent leucotriene inhibitor, controls inflammatory process in Escherichia coli pyelonephritis", Antimicrob Agents Chemother 1994 Jul; 38 (7): 1555-60); xxii) prevention or treatment of acute or chronic disorders involving the recruitment or activation of eosinophils (see for example Quack I, et al. "Eosinophilic Gastroenteritis in a Young Girl - Long term remission under montelukast", BMC G astroenterol., 2005 , 5: 24; (xxiii) prevention or treatment of acute or chronic erosive disease or motor dysfunction of the gastrointestinal tract caused by non-spheroidal anti-inflammatory drugs (including selective or non-selective cyclooxygenase-1 or -2 inhibitors) (see for example Marusova IB, et al., "Potential gastroprotective effect of a CysLTI receptor blocker sodium montelukast in aspirin-induced lesions of the rat stomach mucosa", Eksp Klin Farmakol, 2002; 65: 16-8 and Gyomber E, et al., " Effect of lipoxygenase inhibitors and leukotriene antagonists on acute and chronic gastric haemorrhagic mucosa! lesions in ulcer models in the rat ", J. Gastroenterol, Hepatol., 1996, 11, 922-7) and Martin St et al.," Gastric motor dysfunction: the eosinophilic mural gastritis a causative factor? ", Eur J GastroenteroL Hepatol ., 2005, 17: 983-6; (xxiv) to treat type II diabetes (see for example Valdivielso JM, et al., "Inhibition of 5-lipoxygenase activating protein decreases proteinuria in diabetic rats", J Nephrol 2003 Jan-Feb; 16 (1): 85-94; Parlapiano C, et al., "The relationship between glycated hemoglobin and polymorphonuclear leukocyte leucotriene B4 relase in people with diabetes mellitus", Diabetes Res Clin Pract. 1999 Oct; 46 (1): 43 -5; (xxv) treatment of metabolic syndromes, including, by way of example only, Familial Mediterranean Fever (see for example Bentancur AG, et al., "Uriñe leucotriene B4 in familial Mediterranean fever", Clin Exp Rheumatol. Aug; 22 (4 Suppl 34): S56-8; and (xxvi) treatment of hepatorenal syndrome (see for example Capella GL., "Anti-leukotrie It has drugs in the prevention and treatment of heptorenal syndrome, Prostaglandins Leukot Essent Fatty Acids. 2003 Apr; 68 (4): 263-5]. Several FLAP inhibitors have been described (Gillard et al., Can. J. Physiol. Pharmacol., 67, 456-464, 1989; Evans et al., Molecular Pharmacol., 40, 22-27, 1991; Brideau et al. ., Can. J. Physiol. Pharmacol., Musser et al., J. Med. Chem., 35, 2501-2524, 1992; Steinhilber, Curr. Med. Chem. 6 (1): 71-85, 1999; Riendeau, Bioorg Med Chem Lett., 15 (14): 3352-5, 2005; Flamand, et al., Mol.Pharmacol., 62 (2): 250-6, 2002; Folco, et al., Am. J. Respir Care Crit Med 161 (2 Pt 2): S112-6, 2000; Hakonarson, JAMA, 293 (18): 2245-56, 2005). Identification of inhibitors of the leukotriene synthesis pathway
The development and testing of new FLAP inhibitors, which are effective either alone or in combination with other drugs, and which result in minimal negative side effects, would be beneficial in treating diseases or conditions mediated by leukotrienes or leukotriene-dependent. The inhibitors of the leukotriene synthesis route described herein can locate any weight of the pathway to prevent or reduce the formation of leukotrienes. Such inhibitors of leukotriene synthesis can, by way of example, inhibit the level of FLAP, or 5-LO, by minimizing the formation of several products in the leukotriene pathway, thereby decreasing the amounts of such compounds available in the cell. . Inhibitors of leukotriene synthesis can be identified based on their ability to bind to proteins in the leukotriene synthesis pathway. For example, FLAP inhibitors can be identified based on their binding to FLAP.
Compounds of formula (A): Compounds of formula (A), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, antagonize or inhibit FLAP and can be used for treating patients suffering from leukotriene-dependent leukotriene-mediated conditions or diseases, including, but not limited to, asthma, myocardial infarction, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, intestinal disease inflammatory, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders, cancer and inflammatory conditions. In one aspect, the compounds provided herein have a structure of formula (A) which is as follows:
in which, Z is selected from NIR), S (0) n, C (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [ C (R2) 2] n. [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] or [C (R2) 2] nC (R1) 2NR1, NR1C (Ri) 2 [C (R2) 2] n, [C (R2 ) 2] nO [C (R1) 2] n '[C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0, -OC (0) NR2-, -S (0) 2NR2-, -CR ^ NN-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR2S (0 ) 2-, where each R, is independently H, CF3, or an optionally substituted lower alkyl and two Ri on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -OR3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), - 0 (O) NHS (= O) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR C (= CR3) N (R4) 2, -C02R3bl -C (0) R4, -C0N (R4) 2, - SR3b, -S (= 0) R3b, -S (= 0) 2R3b, -. ^ - (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted alkenyl), substituted or unsubstituted), -l_- (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), substituted or unsubstituted -L-! -iheteroaryl), - ^ - (substituted or unsubstituted aryl) or -l_i-C ( = NR4) N (R4) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where | L 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 heteroalk substituted or unsubstituted uilo, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, - -N (R4) 2, -CN, -N02, N3I -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2l -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3 and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (heterocycle) substituted or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), or - (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); R7 is selected from: (i) L3-X-L4-GL where, L3 is unsubstituted or substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalicyclic group; X is a bond, O, -0 (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NReC (O), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) NR9-, heteroaryl, aryl, -NR9C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; G1 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -0 (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2 > -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -C (O) NR90 (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9I -CON (R9) 2, -SR8, -S (= 0) R9, -S (= 0) 2R8 , -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) Ó-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -0 (0) ) 0 u -OC (O); or is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl, and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N ( R9) 2, OH, -OR8, -0 (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, - N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O ) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, SR8, -S (= 0) R8 or -S (= 0) 2R9; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R 0 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; (i¡) L3-X-L4-G2, 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 -NReC (O), -C (0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO -, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, - OC (= NR10) -o -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G2 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10N (R9) 2,
-C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (Ro) 2, -C02R9, -C (0) R9, -CON (R9) 2, - SR9, -S (= 0) R8, -S (= 0) 2R8, substituted or unsubstituted), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- ( substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) Q, -0 (0) CNH-, -NHC (O), -C ( 0) NH, -C (0) 0 or -OC (O); or G2 is W-G5) where W is substituted or unsubstituted aryl or substituted or unsubstituted heteroalicyclic group and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C ( 0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= O R8, O -S (= 0) 2R8, each R8 is independently selected from unsubstituted or substituted lower alkyl, substituted or unsubstituted cycloalkyl lower, phenyl or benzyl, each R9 is independently selected from H, substituted or unsubstituted lower alkyl, cycloalkyl substituted or unsubstituted lower alkyl, phenyl or benzyl, or two R9 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members, or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R-io is selected .independently of H, -S (= 0) 2R8, -S (= 0) 2NH2, -0 (? ) 8, -CN, -N02, heteroaryl or heteroalkyl; (iii) L3-X-L4-G3, where: X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9L -NR9C (0) 0-, -CH = NO -, -ON = CH-, -N R9C (0) N R9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9- , -OC (= NR10) -o -C (= NR10) OR; L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, unsubstituted or substituted alkenyl, substituted or unsubstituted alkynyl, unsubstituted substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted substituted heteroalicyclic group; 1-4 is a substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; G3 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, · -C02R9, -C (0) R9, -CON (R9) 2, -SRe , -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O) , -C (0) NH, -0 (0) 0 or -0C (0), or G3 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3 > -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10 ) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -O (O) NR90 (= CR10) N (R0) 2 , -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8;
each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each L10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; or (iv) L3-X-L4-G3, wherein: L-3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, unsubstituted substituted aryl, unsubstituted or substituted heteroaryl, substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NR9C (0), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C ( 0) NR9-, heteroaryl, aryl, -N (R9) O (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G4 is -C (= NR10) N (R9) 2l -NR9C (= NR10) N (R9) 2,
NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted aryl or unsubstituted), where L5 is -NHC (0) 0, -0 (0) CNN-u -OC (O); or G4 is -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -0 (0 ) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G4 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C ( O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, - S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8 , -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6 - (substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O) , -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; R11 is L7-Lio-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (heteroalicyclic group substituted or unsubstituted); G6 is H, CN, SCN, N3, N02, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R6 , N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (aryl) substituted or unsubstituted), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O);
or G6 is W-G7, where 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 G7 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, - C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- ( unsubstituted or substituted alkenyl), -L8- (substituted or unsubstituted heteroalkyl), -L5- (substituted to unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C ( 0) 0 u -OC (O); R 2 is L8-L9-Ri3, where L8 is a bond, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted C2-C4 alkenyl); L9 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH-, -NHC (0) NH-, -OC (0) 0-, -NHC (O) -, -C (0) NH, -C (0) 0 or -OC (O); R 13 is H, (substituted or unsubstituted C 1-6 alkyl), (substituted or unsubstituted C 3-6 cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group); or R7 and R2 can together form a 4- to 8-membered heterocyclic ring. In an alternative embodiment or additional aspect, the compounds provided herein have a structure of the following formula (A):
in which, Z is selected from N { R), S (0) n, C (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (Ri) 2NRi, NR1C (R1) 2 [C (R2) 2] n, [C (R2) 2] nO [C (R1) 2] n '[C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0 , -OC (0) NR2-, -S (0) 2NR2-, -CRi = NN-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each Ri is independently H, CF3, or an optionally substituted lower alkyl and two Rs on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -N HS (= 0) 2R3b, S (= 0) 2N (R4) 2 > OH, -OR3 l C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N ( R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2 ,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -CON (R4) 2, - SR3b, -S (= 0) R3b, -S (= 0) 2R3b, - ^ - (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted alkenyl), substituted or unsubstituted), -. ^ - (substituted or unsubstituted cycloalkyl), -Li- (substituted or unsubstituted heteroalicyclic group), -l_i- (substituted or unsubstituted heteroaryl), -Lt- (substituted or unsubstituted aryl) or -L -C (= NR4 ) N (R4) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where ?_! 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 heteroalkyl substituted or not substituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02l N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heterocycle or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl), or - (substituted or unsubstituted C 2-6 alkenyl); R7 is selected from: (i) L3-X-L4-GL where, L3 is unsubstituted or substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalicyclic group; X is a bond, O, -0 (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2,
-NR9, -NR9C (0), -C (0) NR9, -S (= 0) 2NR9) -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -NR9C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -0 (0) NHS (= 0) 2R8, -S ( = 0) 2N HC (O) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) )2,
-NR9C (= CR10) N (R9) 2, -C (O) NR90 (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R9, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -0 (0) 0 u -0C (0); or G-, is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroarion and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0 2N (R9) 2, OH, -0R8, -0 (= 0) CF3 > -C (0) NHS (= 0) 2R8, -S (= 0) 2N HC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NRi0) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, SR8, -S (= 0) R8 or -S (= 0) 2R9; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each Ri0 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8 , -CN, -N02, heteroaryl or heteroalkyl; (ii) L3-X-L4-G2, wherein, L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted, substituted or unsubstituted heteroalicyclic group; X is -NR9C (0), -C (0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO -, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, - OC (= NR10) -o -C (= NRio) 0; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G2 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR9, -S (= 0) R8, - S (= 0) 2R8, substituted or unsubstituted), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is - OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G2 is W-G5, where W is substituted or unsubstituted aryl or substituted or unsubstituted heteroalicyclic group and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C ( 0) R9, -C (= NR, o) N (R9) 2, -N R9C (= NR 1 O) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, or -S (= 0 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R-, 0 is selected independently from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) iRB, -C, -N02, heteroaryl or heteroalkyl; (iii) L3-X-L4-G3, where X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) O; L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, unsubstituted substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted substituted heteroalicyclic group; L4 is a substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; G3 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9,
-C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2 , -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or - L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -0 (0) 0 or -OC (O), or G3 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-O (O) NR9C (= CR10) N (R0) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R10 is independently selected from H, -S (= 0) 2 Re, -S (= 0) 2 NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; or (iv) L3-X-L4-G3, wherein, L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, unsubstituted substituted aryl, substituted heteroaryl or unsubstituted, substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (-O), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NRgC (O), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) N R9-, heteroaryl, aryl, -N (R9) O (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR 0) -o -C ( = NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G4 is -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5 - (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -0 (0) CNN-u- OC (O); or G4 is -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted ring), where L5 is -NHC (0) 0, -0 ( 0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G4 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C ( O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, - S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R 0 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), - NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; Rn is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (0), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); L 0 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (heteroalicyclic group substituted or unsubstituted); G6 is H, CN, SCN, N3, N02, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 , N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8, -S (= 0) 2N HC ( 0) R9,
-C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -l_5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, - C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8 - (substituted or unsubstituted alkenyl), -L8- (substituted or unsubstituted heteroalkyl), -L5- (unsubstituted substituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, - C (0) 0 u -OC (O); Ri2 is L8-L9-R13, where L8 is a bond, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted C2-C4 alkenyl); L9 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH-, -NHC (0) NH-, -OC (0) 0-, -NHC (O) -, -C (0) NH, -C (0) 0 or -OC (O); R 13 is H, (substituted or unsubstituted C 1-6 alkyl), (substituted or unsubstituted C 3-6 cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group); or R7 and R2 can together form a 4- to 8-membered heterocyclic ring. In additional or alternative embodiments of the compounds of formula (A), Z is [C (R2) 2] nC (R1) 2- In additional or alternative embodiments of the compounds of formula (A), Y as -Li- (aryl) substituted or unsubstituted). In additional or alternative embodiments of the compounds of formula (A), Y is -L ^ -heteroyl substituted or unsubstituted. In additional or alternative embodiments of the compounds of formula (A), Y is -L ^-substituted or unsubstituted heterocyclic group. In additional or alternative embodiments of the compounds of formula (A), Y is -L1-C (= NR4) N (R4) 2l -L1-NR4C (= NR4) N (R4) 2 or
-L, -NR4C (= CR3) N (R4) 2. In additional or alternative embodiments of the compounds of formula (A), R6 is L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted aryl) or L2- (substituted or unsubstituted cycloalkyl), where L2 is a bond, O, S, -S (0) 2, -C (O), -CH (OH) or (substituted or unsubstituted C 1-6 alkyl). In additional or alternative embodiments of the compounds of formula (A), R7 is L3-X-L-G, where L3 is a (substituted or unsubstituted alkyl); X is a bond O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0) NR9I -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -N (R9) C (0) NR9, heteroaryl, aryl, -N (R9) C (= NR10) NR9, -NR5C (= NR10); -C (= NR10) NR5, -OC (= NR10) -o -C (41R10) O; L4 is a bond, (substituted or unsubstituted alkyl) (substituted or unsubstituted cycloalkyl), substituted or unsubstituted alkenyl, (substituted or unsubstituted alkynyl). G ,, is H, C02H, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS ( = 0) 2R8, -S (= 0) 2NHC (0) 9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NIRGC (= NR10) N (R9) 2l -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR5C (= CR10) N (R9) ) 2, -C02R9, -C (0) R9) -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8, -L5. (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) Q, -0 (0) CNH-, -NHC (O), -C (O) NH, -C (0) 0, or -OC (O): or G ^ is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, C02H. tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R5, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2 , -NR9C (= CR10) N (R9) 2, C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -002R9, -C ( 0) R9, CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups together can form a heterocyclic ring of 5, 6, 7 or 8 members; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members; and each R 0 is independently selected from H, -S (= 0) 2 R 8, -S (= 0) 2 NH 2 -0 (O) R 8, -CN, -N0 2, heteroaryl or heteroalkyl. In additional or alternative embodiments, Gi is H, C02H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C ( 0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, -N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) ) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, C (O) NR9O (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02Rs, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, or -S (= 0) 2R8, od is W-G8 , wherein W is a substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, -C02H. tetrazolyl, NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9l CN, N (R9) 2, -N (R9) C (0) R9, C (= NR10) N (R9) 2l -NR9C (= NR10) N (R9) 2, -NR9C (= CR18) N (R9) 2,
C (O) NR 9 C (= NR 10) N (R 9) 2 1 -C (O) N R 9 C (= C R 10) N (R 9) 2, -C02R 9, -C (0) R 9, CON (R 9) 2, -SR 8 , -S (= 0) R8, or -S (= 0) 2R8. In additional or alternative embodiments, X is a bond -O-, S, -S (O), -S (0) 2, -NR8, -O-NCH, -CH = N-0, -NHC (= 0) or -C (= 0) NH. In additional or alternative embodiments of the compounds of formula (A), R is L7-L 0-W-G7. In additional or alternative embodiments, W is (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group). In additional or alternative embodiments of the compounds of formula (A), R 2 is L 8 -L 9 -R 3, where L 8 is a bond or (substituted or unsubstituted alkyl of 1 to 8 carbon atoms); L9 is a bond, O-, S, -S (O), -S (0) 2, -NH, -C (O) -, - (CH2) -, -NHC (0) 0-, -NHC ( O) - or -C (0) NH; R 13 is H, (substituted or unsubstituted C 1-6 alkyl) or (substituted or unsubstituted C 1-6 cycloalkyl). Any of the combinations of the groups described above for the different variables contemplated herein. It is contemplated that substituents and substitution patterns of the compounds provided herein may be selected by those skilled in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, in addition to those of the art. exposed in the present. Compounds of formula (B) Compounds of formula (B), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, antagonize or inhibit FLAP and can be used to treat patients suffering from conditions or diseases mediated by leukotriene-dependent leukotrienes, including, but not limited to, asthma, myocardial infarction, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, apoplexy, cancer, endotoxic shock, proliferative disorders, cancer and inflammatory conditions. In one aspect, the compounds provided herein have a structure of formula (B) which is as follows:
in which, Z is selected from N R, S (0) ", C (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OCÍR ZICÍRzJzln. [CíRz lnCíR zSíO) ,,,,
S (0) mC (R1) 2 [C (R2) 2] n, [CíRzJzlnCÍR zNR ,, NR1C (R,) 2 [C (R2) 2] n, [CÍRzJzlnOICíR zJn- [CíR zlnOICÍRzJzln, -C (0 ) NR2-, -NRzC (O) -, -NR2C (0) 0, -OC (0) NR2-, -S (0) 2NR2-, -CRi = NN-, NR2C (0) NR2-, -OC ( 0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each R-, is independently H, CF3, or an optionally substituted lower alkyl and two Ri on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -0R3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), - C (0) NHS (= 0) 2R3, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2l -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -CON (R4) 2, - SR3b, -S (= 0) R3b, -S (= 0) 2R3b > -L, - (to Iq or substituted or unsubstituted), -. ^ - (substituted or unsubstituted alkenyl), substituted or unsubstituted), -. ^ - (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), - ^ - (substituted or unsubstituted heteroaryl), -l_i- (substituted or unsubstituted aryl) or -L1-C (= NR4) N (R) 2, -L1-NR4C (= NR) N (R4) 2, -L., - NR4C (= CR3) N (R4) 2; where L1 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 heteroalkyl or unsubstituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heterocycle or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl), or - (substituted or unsubstituted C 2-6 alkenyl); R7 is H or substituted or unsubstituted alkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), - NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; R11 is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); L10 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 heteroalicyclic group) or not substituted); G6 is H, CN, SCN, N3, N02, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 , N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (aryl) substituted or unsubstituted), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, - C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- ( unsubstituted or substituted alkenyl), -L8- (substituted or unsubstituted heteroalkyl), -L5- (substituted to unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), wherein L5 is -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C ( 0) 0 u -OC (O); R 2 is L 3 -X-L 4 -G 1, wherein, L 3 is unsubstituted or substituted alkenyl, substituted or unsubstituted aikinium, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NReC (O), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) )OR; l_3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikinium, unsubstituted or substituted aryl, substituted or unsubstituted heteroaryl or unsubstituted substituted heteroalicyclic group; 1-4 is a substituted or unsubstituted (substituted alkenyl) or substituted or unsubstituted aliquinium; G1 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9I -C (0) R9, -CON (R9) 2, -SR8, - S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5 - (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), - C (0) NH, -0 (0) 0 or -0C (0), or Gi is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -0R8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, - S (= 0) 2NHC (0) R9) CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N ( R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -O (O) NR90 (= CR10) N (R0) 2, -C02R9 , -C (0) R 9 1 -CON (R 9) 2, -SR 8, -S (= 0) R 8 or -S (= 0) 2 R 8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; and each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl. In an alternative embodiment or additional aspect, the compounds provided herein have a structure of the following formula (b): wherein, Z is selected from N (Ri), S (0) n, C (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] ". [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, NR1C (R1) 2 [C (R2) 2] n, [C (R2) 2] nO [C (R1) 2] n '[C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0 , -OC (0) NR2-, -S (0) 2NR2-, -CR ^ NN-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each. is independently H, CF3, or an optionally substituted lower alkyl and two R-sobre on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -0R3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), - C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4I -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N ( R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (O) N R4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -CON (R4) 2, -SR3b, -S (= 0) R3b, -S (= 0) 2R3b, -. ^ - (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted alkenyl), substituted or unsubstituted), -l_i - (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), -. ^ - (substituted or unsubstituted heteroaryl), -Li- (substituted or unsubstituted aryl) or -L1-C ( = NR4) N (R4) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where L 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 heteroalkyl or unsubstituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3 > -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heterocycle or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl), or - (substituted or unsubstituted C 2-6 alkenyl); R7 is H or substituted or unsubstituted alkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), - NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; R 11 is L7-L 0 -G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0 ) NH, -NHC (O), (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); L 0 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (heteroalicyclic group substituted or unsubstituted); G6 is H, CN, SCN, N3, NO2, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8I -S (= 0) R8, -S (= 0) 2R8, N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9 >
-C (= NR10) N (R9) 2, - -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5 - (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -NHC (0) NH-, - OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9I CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -C02R9 , -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- (alkenyl substituted or unsubstituted), -L8- (substituted or unsubstituted heteroalkyl), -L5- (unsubstituted substituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is - NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C (0 ) 0 u -OC (O); R12 is L3-X-L4-G1, wherein, L3 is unsubstituted or substituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NRio ) 0; L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, unsubstituted substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted substituted heteroalicyclic group; L4 is a substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2) -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C ( 0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or - L5- (substituted or unsubstituted), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O ), -C (0) NH, -0 (0) 0 or -0C (0), or Gi is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl substituted and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -0R6, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10 ) N (R9) 2> -NR9C (= CR10) N (R9) 2> -C (O) NR9C (= NR10) N (R9) 2,
-O (O) NR9C (= CR10) N (R0) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl. In additional or alternative embodiments of the compounds of the formula (B), Z is [CR2) 2-C (R1) 20. In additional or alternative embodiments of the compounds of formula (B), Y is Li- (substituted or unsubstituted aryl). In additional or alternative embodiments, Y is -LT-substituted or unsubstituted heteroaryl. In additional or alternative embodiments, Y is is a substituted or unsubstituted heteroalicyclic group. In alternative additional embodiments, Y is -C (= NR4) N (R4) 2: -L1-NR4C (= NR0N (R4) 2,
-L1-NR4C (= CR3) N (R4) 2. In additional or alternative embodiments of the compounds of Formula (B), R6 is L2- (substituted or unsubstituted alkyl), or L2- (substituted or unsubstituted chloroalkyl), L2- (substituted or unsubstituted aryl) where L2 is a bond, O, S, S (0) 2 -C (O), -CH (OH), or (substituted or unsubstituted alkyl). In additional or alternative embodiments of the compounds of formula (B), R-n is L7-L S-W-G7. In additional or alternative embodiments, W is (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group). In additional or alternative embodiments of the compounds of the formula (B), R12 is L3-L4-W-G1 where: I3 is a substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NRg, -NR9C (0), -C (0 ) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -N (R9) C (0) NR9, heteroaryl, aryl, -N (R9) C (= NR10) NR9, -NR9C (= NR10) -, -C (= NR10) NR9, -OC (= NR10) - 0 -C (= NR10) and L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl. In additional or alternative embodiments, G1 is tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF8, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -N R9C (= N R10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0 ) R9, CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, or is W-G5, where W is a (substituted or unsubstituted aryl), substituted heteroalicyclic group or unsubstituted or unsubstituted substituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0 ) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (, R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2l -G (.0) NR9C (= NR1ON (R9) 2, C (0) NR9C (= CR1 ON ( R9) 2, -002R9, C. (O) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R.In additional or alternative embodiments, X, is a bond, -O-, S. -S (O), -S (0) 2. -NR8, -0-N = CH, -CH = N-0, -NHC (= 0) or -C (= 0 ) NH. • Any of the combinations of the groups previously described for the different variables contemplated in this report., the substitution patterns of the compounds provided herein can be selected by those skilled in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, in addition to those set forth in the art. I presented. Compounds of formula (C). The compounds of formula (C), their pharmaceutically acceptable salts, pharmaceutically acceptable oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvents, antagonize or inhibit FLAP and can be used to treat patients suffering from conditions or diseases mediated by eukotriene-dependent leukotrienes, including, but not limited to, asthma, myocardial infarction, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, respiratory distress syndrome adult, myocardial infarction, aneurism, apoplexy, cancer, endotoxic shock, proliferative disorders, cancer and inflammatory conditions. In one aspect, the compounds provided herein have a structure of formula (C) which is as follows:
wherein, Z is selected from NR, S (0) n, C (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2Of [C (R2) 2] nC (R1) 2S (0) m, S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (RI) 2NR1, NR1C (R1) 2 [C (R2) 2] n, [C (R2) 2] nO [C (R1) 2] n '[C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0 ) -, -NR2C (0) 0, -OC (0) NR2-, -S (0) 2NR2-, -CR, = NN-, NR2C (0) NR2-, -OC (0) 0-, S ( 0) 2NR2, or -NR2S (0) 2-, where each R, 'is independently H, CF3, or an optionally substituted lower alkyl and two on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= O); m is 0", 1 or 2, each n is independently -O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2 , OH, -0R3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2l -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2 ,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) N R4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4 > -CON (R4) 2, -SR3b, -S (= 0) R3b, -S (= 0) 2R3b, - [^ - (substituted or unsubstituted alkyl), -l_i- (substituted or unsubstituted alkenyl), substituted or unsubstituted), -L1- (substituted or unsubstituted cycloalkyl), -l_i- (substituted or unsubstituted heteroalicyclic group), -. ^ - (substituted or unsubstituted heteroaryl), -l_i- (substituted or unsubstituted aryl ) or -L -C (= NR) N (R) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4G (= CR3) N (R4) 2, where L 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 substituted heteroalkyl, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl, wherein each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S ( = 0) -, -S (= 0) 2-, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -0C (O) NH-, -NHC (0) 0-, -0C (0) 0-, -NHC (0) NH-, -C (0) 0-, -O'C (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each 3b - is independently selected from unsubstituted or substituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3 and R can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H ,. L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heterocycle), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O) , -CH (OH), - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or - (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); 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 (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NR9C (0), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C ( 0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) OR; 1-4 is a bond, substituted or unsubstituted alkyl, unsubstituted or substituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C ( 0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, _ -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted acyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O ), -C (0) NH, -0 (0) 0 or -0C (0), or G1 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or heteroaryl substituted or not substituted and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -0R8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8> -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -O (O) NR90 (= CR10) N (R0) 2, -C02R9, -C (0) R9, -C0N (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from lower alkyl substituted or not substituted, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R10 is independently selected from H, S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -0N02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (0), - NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; R11 is L7-L 0 -G6, where L7 is a bond, -C (0), -C (0) NH, (substituted or unsubstituted C 1-6 alkyl) or (2-6 alkenyl) carbon atoms substituted or unsubstituted); Lio is a (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group), G6 is tetrazolyl, - NHS (= 0) 2R8, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R8I -C (= NR10) N (R8) 2, -NR9C (= NR10) N ( R9) 2,
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- ( substituted or unsubstituted aryl), where L5 is. -OC (0) 0-, -NH.C (0) NH-, -NHC (0) 0-, 0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) ) 0 u -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, NHS (= 0) 2R8) S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8 , -S (= 0) 2NHC (0) R9, N (R9) 2, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR-10) ) N (R9) 2, -CON (R9) 2,
-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group), or -L5- ( substituted or unsubstituted aryl), where L5 is OC (0) Q-, -NHC (0) NH-, -NHC (0) 0-, 0 (0) CNH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O); and R12 is L8-L9-R13, where L8 is a bond, (substituted or unsubstituted C 1-6 alkyl), or (substituted or unsubstituted C 2- to C 4 alkenyl); L9 is a bond, O, S, -S (= 0), S (= 0) 2., NH-, -C (O) -, -NHC (0) 0, -OC (0) NH, -NHC (ONH-, -OC (0) 0-, -NHC (O) -, -C (0) NH-, -C (0) 0- or -OC (O) -, and R13 is H, (alkyl) 1 to 6 carbon atoms substituted or unsubstituted), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group) ), or R7 and R2 together can form a 4- to 8-membered heterocyclic ring In another aspect, the compounds provided herein have a structure of the following formula (C):
where Z is selected from N ^), S (0) n, C (Ri) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, NR1C (R1) 2 [C (R2) 2] n, [C (R2) 2] nO [C (R1) 2] n '[C (R1) 2] nO [C (R2) 2] "l -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0 , -OC (0) NR2-, -S (0) 2NR2-, -CR ^ NN-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each R-, is independently H, CF3, or an optionally substituted lower alkyl and two Ri on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is O-, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -0R3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), - C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) G (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) .N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2l -C (0) N R4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -CON (R4) 2, - SR3b, -S (= 0) R3b, -S (= 0) 2R3b, - ^ - (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted alkenyl), substituted or unsubstituted), -Li- (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), -L-, - (substituted or unsubstituted heteroaryl), -L-, - (substituted or unsubstituted aryl) or -l_- C (= NR4) N (R) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where L1 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 heteroalkyl or unsubstituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl;
where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2l -OC (0) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02"heteroaryl or heteroalkyl; each R 3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkuenyl), L2- (heterocyclic) substituted or unsubstituted clo), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or non-substituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or - (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); R7 is L3-X-L4-G1, 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 (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NRgC (O), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NRio) -o -C (= Rio ) 0; L4 is a bond, substituted or unsubstituted alkyl, unsubstituted or substituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C ( 0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, '-NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CRi0) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or - L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -0 (0) 0 or -OC (O), or G- \ is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl substituted and G5 is H, tetrazolyl, -NHS (= 0) 2R5, .S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) ) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -O (O) N R90 (= C R10) N ( R0) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted lower alkyl or unsubstituted, substituted or unsubstituted lower cycloalkyl, phenyl or ncilp; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (-0) 2, NH, C (O), - NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; Rii is L7-Li0-G6, wherein, L7 is a bond, -C (O), -C (0) NH, (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6) carbon atoms substituted or unsubstituted); L 0 is a (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group), G6 is tetrazolyl, -NHS (= 0) 2R8, -C (0) NHS (= 0) 2R8l
-S (= 0) 2NHC (0) R8, -C (= NR10) N (R8) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- ( substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0-, 0 (0) CNH-, -NHC (O), -C ( 0) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -ORa, -C (= 0) CF3,
-C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, N (R9) 2, -C (= NR10) N (R9) 2, -NR9C (= NR10) N ( R9) 2, -NR9C (= CR-10) N (R9) 2, -CON (R9) 2,
-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group), or -L5- ( substituted or unsubstituted aryl), where L5 is OC (0) 0-, -NHC (0) NH-, -NHC (0) 0-, 0 (0) CNH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O); and R12 is L8-L9-Ri3, where L8 is a bond, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), or (substituted or unsubstituted alkenyl of 2 to 4 carbon atoms); l_9 is a bond, O, S, -S (= 0), S (= 0) 2-, NH-, -C (O) -, -NHC (0) 0, -OC (0) NH, -NHC (ONH-, -OC (0) 0-, -NHC (O) -, -C (0) NH-, -C (0) 0- or -OC (O) -, and R13 is H, (alkyl) 1 to 6 carbon atoms substituted or unsubstituted), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group) ) or R7 and R2 together can form a 4- to 8-membered heterocyclic ring In further or alternative embodiments of the compounds of formula (C), Z is [C (R2) 2] nC (R1) 20. additional or alternative compounds of formula (C), Y is Li- (substituted or unsubstituted aryl.) In additional or alternative embodiments, Y is -LT-substituted or unsubstituted heteroaryl.In additional or alternative embodiments, Y is - L-substituted or unsubstituted heteroalicyclic group In additional or alternative embodiments, Y is -L1-C (= NR4) N (R4) 2, -L1-NR4C (= NR 4) N (R4) 2) -L1-NR4C (= CR3) N (R4) 2; In additional or alternative embodiments of the compounds of formula (C), R6 is L2- (substituted or unsubstituted alkyl), or L2- (substituted to unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl), where L2 is a link, O, S, -S (0) 2. -C (O), -CHOH) or (substituted or unsubstituted alkyl). In additional or alternative embodiments of the compounds of formula (C), R7 is is L3-X-L4-GL where L3 is a substituted or unsubstituted alkyl; X is a bond O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2; -NR9, -NR9C (0), -C (0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0- , -CH = NO-, -ON = CH-, -N (R9) C (0) NR9, heteroaryl, aryl, -N (R9) O (= NR10) NR9, -NRgC (= NR10) -O ( = NR10) NR9, -OC (= NR.10) -or -0 (= NR10) O; and L4 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), substituted or unsubstituted alkenyl, (substituted or unsubstituted alkynyl). In additional or alternative embodiments, Gi is tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C (0) NFIS (= 0) 2R9, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R8, -C (= NR10) N (R9) 2, -NR9C (= NR10 ) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (0) NR9C (= CR10N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8 or G-, is W-G5, where W is a substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) N HS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (Rs) 2, -SR8, -S (= 0) R9 or -S (= 0) 2R8 . In additional or alternative modalities, X is a bond, -O-, -CR9 (OR9), S, -S (O), S (0) 2.-N R8, -0-N = CH, -CH = N-0, -NHC (= 0) or -C (= 0) NH. In additional or alternative embodiments of the compounds of formula (C), R ,, is L7-L10-G5, where L7 is a bond, (alkyl is 1 to 6 carbon atoms substituted or unsubstituted), Lio- is a ( substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heterocyclic group). In additional or alternative embodiments, G6 is, tetrazolyl, -NHS (= 0) 2R8, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-N R9C (= CR10) N (R9) 2, - L5- (a I I substituted or unsubstituted), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl) , -L5-is -OC (0) 0-. -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O). In additional or alternative embodiments, L 9 is a (substituted or unsubstituted aryl). In additional or alternative embodiments, G6 as W-G7, where W is a (substituted or unsubstituted heteroalicyclic group) or (substituted or unsubstituted heteroaryl) and G7 is tetrazolyl, -NHS (= 0) 2RB, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3. C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R8, N (R9) 2, C (= NR 1 ON (R8) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2 or -CON (R9) 2. -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group), or -l_5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -HC (0 (NH) -, -NHC (0) 0, O (O) CNH, -NHC (O) or -C (0) NH. In additional or alternative embodiments the compounds of formula (C), L9 as a bond (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), L9 is a bond, O, S, -S (= -0), S (= 0) 2 ., NH-.- C (O) -, (CH2) -, -NHC (0) 0-, -NHC (O) - or -C (0) NH; R 3 is H, (alkyl from 1 to 6 substituted or unsubstituted carbon atoms) or (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms) Any of the combinations of the groups described above for the different variables is contemplated herein. and the substitution patterns of the compounds provided herein may be selected by those skilled in the art pare, propo Routing compounds that are chemically stable and that can be synthesized by techniques known in the art, in addition to those set forth herein. Compounds of formula (D) Compounds of formula (D), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, antagonize or inhibit FLAP and can be used to treat patients suffering from conditions or diseases mediated by leukotriene-dependent leukotrienes, including, but not limited to, asthma, myocardial infarction, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, apoplexy, cancer, endotoxic shock, proliferative disorders, cancer and inflammatory conditions. In one aspect, the compounds provided herein have a structure of formula (D) which is as follows:
where Z is selected from -NR, C (0) 0-, -NR ^ C NR ^, -CRI = N-N-, where each is independently H, CF3, or an optionally substituted lower alkyl; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3B, S (= 0) 2N (R4) 2, OH, -OR3B, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), - C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR4C (= CR3) N (R4) 2, -C02R3B, -C (0) R4, -CON (R4) 2, - SR3B, -S (= 0) R3B, -S (= 0) 2R3B, - ^ - (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted alkenyl), substituted or unsubstituted), -L1- ( substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), -. ^ - (substituted or unsubstituted heteroaryl), -. ^ - (substituted or unsubstituted aryl) or -L1-C (= NR4) N (R4) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where L- is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyno, a substituted or unsubstituted heteroalicyclic group, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, a unsubstituted or substituted heteroalkyl, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl from 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02 > heteroaryl or heteroalkyl; each R3 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heterocycle or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl), or - (substituted or unsubstituted C 2-6 alkenyl); R7 is L3-X-L4-G, where 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 heteroaryl or unsubstituted, substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NR9C (0), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C ( 0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= N.Rio) 0; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G3 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8) . -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or - L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -0 (0) 0 or -OC (O); or G3 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2l - N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O ) NR9C (= NR10) N (R9) 2, -O (O) NR90 (= CR10) N (R0) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R10 is independently selected from H, S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O) , -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; Rii is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); L-io is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (group substituted or unsubstituted heteroalicyclic); G6 is H, CN, SCN, N3, N02, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 , N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -l_5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (aryl) substituted or unsubstituted), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, - C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- ( substituted or unsubstituted alkenyl), -L8- (substituted or unsubstituted heteroalkyl), -L5- (substituted heteroaryl to unsubstituted), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, - C (0) 0 u -OC (O); R-i2 is L8-L9-R13, where L8 is a bond, (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (C2-C4 alkenyl substituted or unsubstituted); L9 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH-, -NHC (0) NH-, -OC (0) 0-, -NHC (O) -, -C (0) NH, -C (0) 0 or -OC (O); R 13 is H, (substituted or unsubstituted C 1-6 alkyl), (substituted or unsubstituted C 3-6 cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group);
or R7 and R12 can together form a 4- to 8-membered heterocyclic ring. In a further or alternative aspect, the compounds of the following formula (D) are provided:
where Z is selected from -NRTCÍOJO-, -NR ^ C NR -, -, -CR ^ N-N-, where each is independently H, CF3, or an optionally substituted lower alkyl; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3B, S (= 0) 2N (R4) 2, OH, -OR3B, C (-0) (fluoroalkyl of 1 to 6 carbon atoms), - C (0) NHS (= 0) 2R3B, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR C (= CR3) N (R4) 2, -C02R3B > -C (0) R4, -CON (R4) 2, -SR3B, -S (= 0) R3B, -S (= 0) 2R3B, - ^ - (substituted or unsubstituted alkyl), -l_i- (substituted alkenyl or unsubstituted), substituted or unsubstituted), - ^ - (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), -l_i- (substituted or unsubstituted heteroaryl), -Li- (substituted or unsubstituted aryl) or -L1-C (= NR) N (R) 2, -L1-N R4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where L- 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 heteroalkyl substituted or unsubstituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) ¿, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members;
R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkyl ilo), L2- (heterocycle) substituted or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), or - (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); R7 is L3-X-L4-G1, where, L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted, substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NRgC (O), -C (0 ) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0 ) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) -o -C (= NR10) )OR; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G3 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (0) NR9C (= NR10N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8l -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5 - (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), - C (0) NH, -0 (0) 0 or -OC (O), or G3 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R5, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2> -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -O (O) NR90 (= CR10) N (R0) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8: each R8 is independently selected from unsubstituted or substituted lower alkyl, cycloalkyl lower substituted or unsubstituted, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L6- ( substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), - NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, a -C (0) NH; R is L7-Li0-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); L10 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 heteroalicyclic group) or not substituted); G6 is H, CN, SCN, N3, N02, halogen, ORg, -0 (= 0) OF3,
-C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8, N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -N R9C (= NR10) N (R9) 2,
-NR9C (= CRio) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (aryl) substituted or unsubstituted), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0 ) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3,
-C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -N R9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2 > -SR8l -S (= 0) R8 or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- (substituted or unsubstituted alkenyl), -L8- (substituted or unsubstituted heteroalkyl) , -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is -NH, -NHC (0) 0, -NHC (0) NH- , -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); R 2 is L8-I_9-Ri3 > where L8 is a bond, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted C2-C4 alkenyl); L9 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH-, -NHC (0) NH-, -OC (0) 0-, -NHC (O) -, -C (0) NH, -C (0) 0 or -OC (O); R 13 is H, (substituted or unsubstituted C 1-6 alkyl), (substituted or unsubstituted C 3-6 cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group); or R7 and Ri2 can together form a 4- to 8-membered heterocyclic ring. In additional or alternative embodiments of the compounds of formula (D), Z is -NHC (0) 0-, NHC (0) NH- or -CH = N-N-. In additional or alternative embodiments of the compounds of formula (D), Y is -Lean substituted or unsubstituted. In additional or alternative embodiments, Y is -L substituted or unsubstituted heteroaryl. In additional or alternative embodiments, Y is -L-i-substituted or unsubstituted heteroalicyclic group. In additional or alternative embodiments, Y is L1-C (= NR4) N (R4) 2, L1-NR4C (= NR4) N (R4) 2) -L1-NR4C (= CR3) N (R4) 2.
In additional or alternative embodiments of the compounds of formula (D), R6, is L2-substituted or unsubstituted alkyl), or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl). where L2 is a bond, O, S, -C (O), -CH (OH), or (substituted or unsubstituted alkyl). In additional or alternative embodiments of the compounds of Formula (D), R7 is L3-X-L-G1, where, L3 is a substituted or unsubstituted alkyl); X is a bond O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, - N (R9) C (0) NR9, heteroaryl, aryl, -N (R9) C (= NR10) NR9, -NR9C (= NR10) -, -C (= NR10) NR9, -OC (= NR10) -o -C (= NR10) O; and L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl. In additional or alternative embodiments it is tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C (0) NHS (= 0) 2R6, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, or Gi is W-G5, where W is a (substituted or unsubstituted aryl), substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S ( = 0) 2N (R9) 2, OH, .OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N ( R9) 2, -N (R9) C (0) R9, C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -N R9C (= CR10) N (R9) 2 , -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -002R9, -C (0) R9, -CON (R9) 2, - SR8, -S (= 0) R80 -S (= 0) 2R8. In additional or alternative embodiments, X is a bond, -O-, -CR9 (OR9), S, -S (O), -S (0) 2, -NR8, -O-, N = CH, -CH = N-0, -NHC (= 0) or -C (= 0) NH. In additional or alternative embodiments of the compounds of formula (D), R is L7-Lio-G6, where L is a bond, (alkyl of 1 to 6 carbon atoms, substituted or unsubstituted), and L 0 is a ( substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heteroalicyclic group). In additional or alternative embodiments G6 is tetrazolyl, -NHS (= 0) 2R8, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, -C (= NR10N (R9) 2 , -NR9C (= NR10),
-NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), or L5- (substituted or unsubstituted aryl), Ls is OC (0 ) 0 -.- NHC (0) NH-, -NHC (0) 0. -0 (0) CNH-, -NHC (O), -C (0) NH. -C (0) 0, u -0C (0). In additional or alternative embodiments, L10 is a substituted or unsubstituted aryl. In additional or alternative embodiments G6 is W-G7, where W is (substituted or unsubstituted heteroalicyclic group) or (substituted or unsubstituted heteroaryl) and G7, is, tetrazolyl, -NHS (= 0) 2R8lS (= 0) 2N (R9) 2, OH, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, N (R9) 2l -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2l
-C (O) NR9C (= CR 0) N (R8) 2, -CON (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- ( -substituted or unsubstituted heteroalicyclic group), or -L5- (substituted or unsubstituted aryl), -L5- is -OC (0) 0-, -NHC (0) NH-. -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O). In additional or alternative embodiments of the compounds of formula (D) -L8 is a bond, (substituted or unsubstituted alkyl of 1 to 8 carbon atoms); L9 is a bond, -O-, -S-, -S (O), -S (= 0) 2, -NH-, -C (O), - (H2) -, -NRC (0) 0- , -NHC (O) or -C (0) NH; R 3 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted cycloalkyl of 2 to 6 carbon atoms). Any of the combinations of the groups described above for the different variables is contemplated herein. It is contemplated that substituents and substitution patterns of the compounds provided herein may be selected by those skilled in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art., in addition to those set forth in this report. Compounds of formula (F) Compounds of formula (F), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, antagonize or inhibit FLAP and can be used to treat patients suffering from leukotriene-dependent or leukotriene-mediated diseases or conditions, including but not limited to asthma, myocardial infarction, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis , inflammatory bowel disease, respiratory anxiety syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In one aspect, the compounds provided herein have a structure of the following formula
(F):
wherein, Z is selected from N ^), S (0) n, C (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, NR1C (R) 2 [C (R2) 2] n, [C (R2-) ) 2] nO [C (R1) 2] n- [CíR alnOICÍRa ln. -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0, -OC (0) NR2-, -S (0) 2NR2-, -CR ^ NN-, NR2C (0) NR2- , -0C (0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each R is independently H, CF3l or an optionally substituted lower alkyl and two on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -N HS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -0R3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, .N (R4) 2, -N (R4) C (0) R4, -C (= NR3 ) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -CON (R4) 2, - SR3b, -S (= 0) R3b, -S (= 0) 2R3b, - ^ - (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted alkenyl), substituted or unsubstituted), -L_- (substituted or unsubstituted cycloalkyl), -l_i- (substituted or unsubstituted heteroalicyclic group), -. ^ - (substituted or unsubstituted heteroaryl), -Li- (substituted or unsubstituted aryl) or -L1-C (= NR ) N (R) 2, -L1-NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where L 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 heteroalkyl substituted or unsubstituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0.) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl from 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4; each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3 and R can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heterocycle or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl), or - (substituted or unsubstituted C 2-6 alkenyl); R7 is H or (substituted or unsubstituted alkyl); R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted) , -L6r (substituted or unsubstituted heteroaryl), or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, or -C (0) NH; R is a (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group); and R12 is L8-L9-R13, where Le is a bond, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted C2-C4 alkenyl); L9 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH-, -NHC (0) NH-, -OC (0) 0-, -NHC (O) -, -C (0) NH, -C (0) 0 or -OC (O); R 13 is H, (substituted or unsubstituted C 1-6 alkyl), (substituted or unsubstituted C 3-6 cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group). In a further or alternative aspect, the compounds of the following formula (F) are provided:
where Z is selected from N (Ri), S (0) n, C (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, NR1C (R1) 2 [C (R2) 2] ", [C (R2) 2] nO [C (R1) 2] n- [C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0 , -OC (0) NR2-, -S (0) 2NR2-, -CRrN-N-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR.2S ( 0) 2-, wherein each R- is independently H, CF3, or an optionally substituted lower alkyl and two R-¡on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; m is 0, 1 or 2, each n is independently O, 1, 2 or 3; Y is H, -C02H, tetrazolyl, - HS (= 0) 2R3, S (= 0) 2 (R4) 2, OH, -0R3b, C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), - C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R4) 2, -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2,
-C (0) NR4C (= NR3) N (R4) 2, -C (0) NR C (= CR3) N (R) 2, -C02R3b, -C (0) R4, -CON (R4) 2, -SR3b > -S (= 0) R3b, -S (= 0) 2R3b, - ^ - (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted alkenyl), substituted or unsubstituted), -L -, - (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroalicyclic group), -L- | - (substituted or unsubstituted heteroaryl), -l_i- (substituted or unsubstituted aryl) or -L -C ( = NR) N (R4) 2, -L | -NR4C (= NR) N (R4) 2, -L1-NR4C (= CR3) N (R4) 2; where 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 heteroalkyl substituted or unsubstituted, a substituted or unsubstituted heteroalkenyl or substituted or unsubstituted aryl; where each substituent is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2 -, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, - OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl from 1 to 6 carbon atoms, heteroaryl, aryl, or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where j is 0, 1, 2, 3, or 4;
each R3 is independently selected from H, -S (= 0) 2R3, -S (= 0) 2NH2, -C (0) R3, -ON, -N02, heteroaryl or heteroalkyl; each R3b is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R4 groups to together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heterocycle or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl), or - (substituted or unsubstituted C 2-6 alkenyl); R7 is H or (substituted or unsubstituted alkyl); R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted) , -L6- (substituted or unsubstituted heteroaryl), or -L6- (substituted or unsubstituted rhyla), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH , C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, or -C (0) NH; R-n is a (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group); and R12 is L8-L9-Ri3, where L8 is a bond, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted C2-C4 alkenyl); L9 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH-, -NHC (0) NH-, -OC (0) 0-, -NHC (O) -, -C (0) NH, -C (0) 0 or -OC (O); R 13 is H, (substituted or unsubstituted C 1-6 alkyl), (substituted or unsubstituted C 3-6 cycloalkyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl) or (substituted or unsubstituted heteroalicyclic group). In additional or alternative embodiments of the compounds of formula (F), R7 is a substituted alkyl. In additional or alternative embodiments of the compounds of formula (F), R7 is a mono-substituted alkyl. In additional or alternative embodiments of the compounds of formula (F), R7 is a bi-substituted alkyl. In additional or alternative embodiments of the compounds of formula (F), the substituent of R7 is selected from OH, alkoxy of 1 to 6 carbon atoms, C (O) OH, C (0) 0 (alkyl of 1 to 6 atoms of carbon). Any of the combinations of the groups described above for the different variables contemplated herein. It is contemplated that the substituents and substitution patterns of the compounds provided herein may be selected by those skilled in the art to provide compounds that are chemically stable and that can be synthesized by techniques known in the art, in addition to those of the art. exposed in the present report.
Compounds of formula (H) Compounds of formula (H), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically acceptable active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, antagonize or inhibit FLAP and may be used for treating patients suffering from leukotriene-dependent or leukotriene-mediated diseases or diseases, including but not limited to asthma, myocardial infarction, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, rhinitis, arthritis, allergy, psoriasis, disease inflammatory bowel syndrome, respiratory anxiety syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions.
In one aspect, the compounds provided herein have a structure of the following formula (H) wherein, Z is selected from N (R), S (0) n, C (R 1) 2 [C (R2) 2 ] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] n. [C (R2) 2] nC (R1) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, NR1C (R1) 2 [C (R2) 2] ", [C (R2) 2] nO [C (R1) 2] n '[C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0 , -OC (0) NR2-, -S (0) 2NR2-, -CR ^ NN-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each R ^ is independently H, CF3, or an optionally substituted lower alkyl and two R ^ on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; And it's -C02H. -CONH2, -C (= 0) N (R4b) 2, C02R4b, -0R3b, -C (= 0) (fluoroalkyl of 1 to 6 carbon atoms, -C (= NOH) R4, C (= NOR3b) R b, -l_i- (substituted or unsubstituted alkyl), -l_i- (substituted or unsubstituted alkenyl), - L n - (a Iquini substituted or unsubstituted) (substituted or unsubstituted cycloalkyl),
-L-i-substituted or unsubstituted -Cheteroaryl), -. ^ - (a heteroalicyclic group) or -L1- (substituted or unsubstituted aryl); where Li-is -C (= 0), CR8OH, CR8OMe, C (= NOH), C (= NOR4b), C (= 0) NH, C (= 0) NR4b, -NHC (= 0), NR4bC ( = 0), S, S (= 0), S (= 0) 2, NHC (= 0) NH- or NR4bC (= 0) NR4b, where each substituent in Y or Z is (LsRs) j where each L, is independently selected from a bond, NH, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2-, NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0, -NHC (0) NH-, -C (0) 0-, -OC (0) -alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -ON, -N02, N3, -S (= 0) 2NR2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where) is 0, 1, 2, 3, or 4; each R3 is independently selected from H, from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl, each R3b is independently selected of substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; each R 4 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R groups together can form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R together can form a heterocyclic ring of 5, 6, 7 or 8 members;
each R4b is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted benzyl; unsubstituted or substituted heteroaryl, substituted or unsubstituted heteroalicyclic group; R6 or is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (heteroalicyclic group) substituted or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl) or - (substituted or unsubstituted C 2-6 alkenyl); R7 is L3-X-L4-GL where, I3 is a bond, or substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (O), -S (= 0) 2, -NR9, -NR9C (0), -C (0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, - N (R9) C (0) NR9, heteroaryl, aryl, -N (R9) O (= NR10) NR9. -NR9C (= NR10) -, -C (= NR10) NR9, -OC (= NR10) - or -C (= NR10) O; L4 is a bond or substituted or unsubstituted alkyl; GT is tetrazolyl, -NHS (= 0) 2R9, S (= 0) 2N (R9) 2, -OR9l -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0 ) 2N HC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2 , -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R6, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), wherein L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 u -OC (O); or is W-G8, where W is a (substituted or unsubstituted aryl), substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2 , -N (R9) C (0) R9, C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C ( O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two groups together form a heterocyclic ring of 5, 6, 7 or 8 members; or R8 and R9 together can formally-a heterocyclic ring of 5, 6, 7 or 8 members, each R10 is independently selected from H, S (= 0) 2R8, -S (= 0) NH2 -C (0) RB, -CN, -N02, heteroaryl, or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L5- ( substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, or -C (0) NH; Rii is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); L-io is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (group substituted or unsubstituted heteroalicyclic); G6 is H, CN, SCN, N3, N02, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 , N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-N R9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- ( substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) Q-, -OC (0) NH-, -NHC (O), -C ( 0) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, CN, N02, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl, tetrazolyl, -NHS (= 0) 2R8, S (= 0 ) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, - S (= 0) R8 or .S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), - L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is a bond -O-, C (= 0), S (= 0), S (= 0) 2, -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH , -C (0) 0 u -OC (O); and R 2 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms). In a further or alternative aspect, the compounds of the following formula (H) are provided herein: wherein, Z is selected from NCR,), S (0) n, C (Ri) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20, OC (R1) 2 [C (R2) 2] n. [CíRz INCÍR,) 2S (0) m,
S (0) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, NR1C (R1) 2 [C (R2) 2] n, [C (R2) 2] nO [C (R1) 2] n- [C (R1) 2] nO [C (R2) 2] n, -C (0) NR2-, -NR2C (0) -, -NR2C (0) 0 , -OC (0) NR2-, -S (0) 2NR2-, -CR ^ NN-, NR2C (0) NR2-, -OC (0) 0-, S (0) 2NR2, or -NR2S (0) 2-, where each R < Is independently H, CF3, or an optionally substituted lower alkyl and two R- on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; m is 0, 1 or 2; each n is 0, 1, 2 or 3; And it's -C02H. -CONH2, -C (= 0) N (R4b) 2, C02R4b, -OR3b, -C (= 0) (fluoroalkyl of 1 to 6 carbon atoms, -C (= NOH) R4b, C (= NOR3b) R b, -l_i- (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted alkenyl), - L n - (a Iq uini I or substituted or unsubstituted) -Li (substituted or unsubstituted cycloalkyl), -. ^ - (substituted or unsubstituted heteroaryl), -l_i- (a heteroalicyclic group) or -L1- (substituted or unsubstituted aryl);
where L -, - is -C (= 0), CR8OH, CR8OMe, C (= NOH), C (= NOR4b), C (= 0) NH, C (= 0) NR4b, -NHC (= 0), NR4bC (= 0), S, S (= 0), S (= 0) 2, NHC (= 0) NH- or N R4bC (= 0) N R4b, where each substituent in Y or Z is (LsRs) j where each L is independently selected from a bond, NH, -O-, -C (= 0) -, -S-, -S (= 0) -, -S (= 0) 2-, NHC (O ) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0, -NHC (0) NH-, -C (0) 0-, -OC (0) -alkyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , aryl or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -ON, -N02, N3, -S (= 0) 2NR2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl , or heteroalkyl; where) is 0, 1, 2, 3, or 4; each R3 is independently selected from H, from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl, each R3 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 cycloalkyl, phenyl or benzyl; or two R4 groups together can form a 5, 6, 7 or 8 membered heterocyclic ring; or R3 and R4 together can form a heterocyclic ring of 5, 6, 7 or 8 members; each R4b is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted benzyl; unsubstituted or substituted heteroaryl, substituted or unsubstituted heteroalicyclic group; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), l_2- (heteroalicyclic group) substituted or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl) or - (substituted or unsubstituted C 2-6 alkenyl); R7 is L3-X-L4-GL where, L3 is a bond, or substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (O), -S (= 0) 2, -NRe, -NReC (O), -C (0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, - N (R9) C (0) NR9, heteroaryl, aryl, -N (R9) O (= NR10) NR9. -NR9C (= NR10) -, -C (= NR10) NR9, -OC (= NR10) - or -C (= NR10) O; L4 is a bond or substituted or unsubstituted alkyl; GT is tetrazolyl, -NHS (= 0) 2R9, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2N HC (O) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2l -NR9C (= NR10) N (R9) 2 ,
-NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2,
-C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8I -S (= 0) 2R6 , -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 u -OC (O); or is W-G8, where W is a (substituted or unsubstituted aryl), substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3,
-C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, C (= NR10) N ( R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C ( = CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two groups together form a heterocyclic ring of 5, 6, 7 or 8 members; or R8 and R9 together can formally-a heterocyclic ring of 5, 6, 7 or 8 members, each R10 is independently selected from H, S (= 0) 2R8, -S (= 0) NH2 -C (0) R8, -CN, -N02, heteroaryl, or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted), -L5- ( substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, or -C (0) NH; R11 is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); . Lio 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 heteroalicyclic group) or not substituted); G6 is H, CN, SCN, N3, N02, halogen, OR9, -0 (= 0) OF3, -C (= 0) R9, -SR8, -S (= 0) R8, -S (= 0) 2R8 > N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2 > -C (0) NHS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2,
-NR9C (= CR 0) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- ( substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C ( 0) NH, -C (0) 0 or -OC (O); or G6 is W-G7, where 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 G7 is H, CN, N02, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl, tetrazolyl, -NHS (= 0) 2R8, S (= 0 ) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2 > -SR8, -S (= 0) RB or -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L8- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl) ), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or substituted or unsubstituted), where L5 is a -O-, C (= 0), S (= 0) bond ), S (= 0) 2, -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), - C (0) NH, -C (0) 0 or -OC (O); and R 2 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms). In additional or alternative embodiments of the compounds of formula (H), Z is [C (R2) 2] nC (Ri) 20. In additional or alternative embodiments of the compounds of formula (H). And it's -C02H. -CONH2, -C (= 0) N (R4b) 2, C02R4b, 0R3b C (= 0), (fluoroalkyl of 1 to 6 carbon atoms, -C (= NOH) R4, C (= NOR3b) R4bl -Li - (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted cycloalkyl), -l_i- (substituted or unsubstituted heteroaryl), -l_i- (substituted or unsubstituted heteroalicyclic group), or -l_i- ( substituted or unsubstituted aryl.) In further or alternative embodiments of the compounds of formula (H), G6 is W-G7, where W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted aryl), (substituted heteroalicyclic group or unsubstituted) or a (substituted or unsubstituted heteroaryl) .In additional or alternative embodiments of the compounds of formula (H), Rn is L7-L 0 -G6, and L7 as a bond. the compounds of formula (H), R6 is L2- (substituted or unsubstituted alkyl), or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S , -S (0 ) 2, -C (O), -CH (OH), or (substituted or unsubstituted alkyl). In additional or alternative embodiments of the compounds of formula (H), L3 is a bond.
In additional or alternative embodiments of the compounds of formula (H) G is tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C ( 0) N HS (= 0) 2R8,
-S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2,
-C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, - SR9, -S (= 0) R8, -S (= 0) 2R8. In additional or alternative embodiments of the compounds of formula (H), X is a bond, -O-, -CR9 (OR9), S, -S (O) -, -S (0) 2, -NR8, -NHC (= 0), aryl or -C (= 0) NH. For any and all embodiments (such as, for example, formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), substituents are selected from a list For example, in one embodiment, the heteroalicyclic group of Y is selected from quinolizines, dioxins, piperidines, morpholines, thiazines, tetrahydropyridines, piperazines, oxazinanones, dihydropyrroles, dihydroimidezoles, tetrahydrofurans, dihydrooxazoles, oxiranes, pyrrolidines, pyrazolidines, dihydrothiophenones, imidazolidinones. , pyrrolidinones, dihydrofuranones, dioxolanones, thiazolidines, piperidinones, tetrahydronaphthyridines, tetrahydroquinolines, tetrahydrothiophenes and thiazepanes.
In other modalities, the heteroalicyclic group is selected from the group consisting of the following structures
By way of example only, the heteroalicyclic group of Y is selected from In another embodiment or alternative embodiment, the group "G (for example, G-, G2, G4, G5, G6, G7) is any group that is used for adapting the physical and biological properties of the molecule Such modifications / adaptations are obtained using groups that modulate the acidity, basicity, lipophilicity, solubility and other physical properties of the molecule.The physical and biological properties modulated by such modifications to "G" include , by way of example only, solubility, in vivo adsorption, and in vivo metabolism In addition, in vivo metabolism may include, by way of example Canically, controlling PK properties in vivo, activities outside of localization, associated potential toxicities. with the interactions of cypP450, drug-drug interactions, and the like, moreover, modifications to "G" allow the adaptation of the in vivo efficacy of the compound to after modulation, by way of example, of the binding of the specific and non-specific protein to plasma proteins and the distribution of lipids and tissue in vivo. In addition, such adaptation / modifications to "G" allow the diselium of selective compounds for the activating protein of 5-lipoxygenase on other proteins.
In other modalities or alternative modalities, "G" is L-20-Q, where L20 is an enzymatically cleavable corrector and Q is a drug, or an affinity radical. In other alternative modalities or modalities, the drug includes, by way of example only, leukotriene receptor antagonists and anti-inflammatory agents. In other alternative modalities or modalities, leukotriene receptor antagonists include, but are not limited to, dual CysLTI / CysLT2 antagonists and CysLTI antagonists. In other alternative embodiments or modalities, the affinity moiety allows site-specific binding and includes, but is not limited to, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands: Any combination of the groups described above for the various variables is contemplated in the present. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to give compounds that are chemically stable and that can be synthesized by techniques known in the art, as well as those set forth in the present.
Other embodiments of Formula (A), Formula (B), Formula (C), Formula (D), Formula (F) or Formula (H) include, but are not limited to, compounds shown in Figures 8-11 and tables 1-5.
Table 1. Non-aromatic substituents R1 and chloro / bromo substituents
Table 2. Non-heteroarylated indolic tertiary alcohols
Table 3. Acid Replacements
Table 4. Side chain of 2 carbon atoms
Table 5. Tertiary heteroaryl-indole alcohols In one aspect, there is provided herein a compound selected from: 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-chloro-benzyl) -1 H- acid indo1 -2-yl] -2,2-dimethyl-propionic (Compound 1-1); 3- [5 - ((S) -2-tert-Butoxycarbonylamino-2-phenyl-ethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 1-2); 315 - ((R) -2-tert-Butoxycarbonylamino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-iM-2,2-dimethyl-propionic acid (Compound 1-3); 3-15 - ((S) -2-amino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl- acid propionic (Compound 1-4); 3- [5 - ((S) -2-amino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-1 ndo I -2 - i I] -2 , 2-dimethyl-propionic (Compound 1-5); 345 - ((R) -2-Acetylamino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid ( Compound 1-6); 3- [5 - ((S) -2-Acetylamino-2-phenyl-ethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -H-indol-2-yl] -2,2 acid -dimethyl propionic (Compound 1-7); 3- [5 - [(3-Butoxycarbonylamino-propylcarbamoyl) -methoxy] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2, 2 - acid dimethyl propionic (Compound 1- 8); 3- [5 - [(3-Amino-propylcarbamoyl) -methoxy] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1 H -ndo1 -2-yl] -2,2 acid -dimethyl-propionic (Compound 1-9); Acid { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- [2- (4-fluoro-phenyl) -2-oxo-ethoxy] -1H-indo1-2-yl} -2,2-dimethyl-propionic (Compound 1-10); Acid { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- [2- (4-fluoro-pheny1) -2-hydroxy-ethoxy] -1H-indol-2-yl] -2.2- dimethylpropionic (Compound 1-11); 3- (3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-. {2- (4-fluoro-pheny1) -2 - [(Z) -hydroxyimino] -ethoxy} - 1 H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-12): Acid (3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-. {2- ( 4-fluoro-pheny1) -2 - [(Z) -methoxyimino] -ethoxy} -1H-indo1-2-yl) -2,2-dimethyl-propionic acid (Compound 1-13); - 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-14): Ethyl ester 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-cyanomethoxy-1 H -indole-2-yl] -2,2-dimethyl-propionic acid (Compound 1-15); 3- [5- (Benzylcarbamoyl-methoxy) -1- (4-bromo-benzyl) -3-tert-butylsulfanyl-1H-indol-2-yl] -2,2-dimethyl-propionic acid ester (Compound 1-) 16); 3- [3-tert-Butylsulfanyl-5-carboxymethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-17); 3- [3-tert-Butylsulfanyl-5- (2-hydroxy-propoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2, 2-dimethyl prop ion (Compound 1-18); 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-19); 3- [3-tert-butylsulfanyl-5- (1-carbamoyl-1-methyl-ethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2- acid dimethyl-propionic acid (Compound 1-20); 3- [3-tert-Butylsulfanyl-5- (1-carboxy-1-methylethoxy) -1- (4-tiazole-2-yl- benzyl) -1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 1-21); 3-, 3-tert-Butylsulfanyl-5- (2-methoxy-propoxy) -1- [4- (6-methoxy-pyridin-3-yl) benzyl-1H-indol-2-yl} -2,2-dimethyl-propionic acid (Compound 1-22); 3-tert-Butylsulfanyl-5- (2-hydroxy-propoxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl -propionic (Compound 1-23); 3 ^. {3-tert-Butylsulfanyl-5- (2-hydroxy-2-methyl-propoxy-1 [4- (6-methoxy-pyridin-3-yl) -benzyl) ] -1-hiindol-2-yl.} -2,2-dimethyl-propionic (Compound 1-24); 3-, {3-tert-Butylsulfanyl-5- (2-hydroxU3,3-dimethyl -butoxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl) -1H-indol-2-yl] -2,2-dimethyl-propihoic acid (Compound 1-25); 3-. {3-tert-Butylsulfanyl-5- [2- (4-fluoro-phenyl) -2-hydroxy-ethoxy-1- [4- (6-m ethoxy-pyridin-3-yl) benzyl] -1H-indol-2-yl} -2, 2-dimethyl-propionic (Compound 1-26); Ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 1-27); 2- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -acetamide (Compound 2-1); 2- [3-tert-Butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1-pyridin-4-ylmethyl-indol-5-yloxy] -acetamide
(Compound 2-2); 2- [3-tert-Butylsulfanyl] -1 - (4-cyano-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -acetamide (Compound 2-3); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1 - (4-iodo-benzyl) -1 H -indole-5-yloxy-acetamide (Compound 2-4); 2- [3-tert-butylsulfanyl-3- (2-hydroxy-2-methyl-propyl) -1 - (4-iodo-benzyl) -1H-indol-5-yloxyl-acetamide (Compound 2-4) ); 2- [3-tert-Butylsulfanyl] -1-cyclopropylmethyl-2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] -acetamide (Compound 2-5); 2- [3-tert-Butylsulfanyl] -1 - (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] -N, N-diethyl- Acetamide (Compound 2-6); 2- [3-tert-Butylsulfanyl-1-2- (2-hydrophenyl) -acetamide (Compound 2-7); 2- [3-tert-Butylsulfanyl] -1 - (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5 -loxy] -N- (4 -chloro-benzyl) -N-pyridin-3-yl-acetamide (Compound 2-8); 2- [3-tert-butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1-pyridin-4-methyl-1H-indole-5-yloxy] -N-cyclopropyl-acetamide (Compound 2-9); 2- [3-tert-butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1 - (4-iodo-benzyl) -1 H -indole-5-yloxyl-N- (4 -dodo-benzyl) -acetamide (Compound 2-10); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1- (4-pyridin-3-yl-benzyl) -1 H-indole -5-yloxy] -acetamide (Compound 2-1); 2- [3-tert-Butylsuiphanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-ynol-5-yloxy-acetic acid (Compound) 2-12); Ethyl 2- [3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -acetic acid ester (Compound 2 -13); 1 -13-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (2-hydroxy-2-methyl-propoxy) -1H-indol-2-yl] 2-methyl-propan-2-ol ( Compound 2-14); 143-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (2-hydroxy-propoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol (Compound 2-15); 1 - [3-tert-Butylsulfanyl-1- (4-cl-oro-be-ncyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -propan-2-one ( Compound 2-16); 3- [3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl] -N- (2-dimethylamino-ethyl) -2,2-dimethyl- propionamide (Compound 3-1); 5- (2-3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -1,1-dimethyl-ethyl) - [ 1,3,4] oxadia2ol-2-ylamine (Compound 3-2); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1 H -indol-2-yl] -2,2-d-methyl-N-thiazole -2-α-propionamide (Compound 3-3); N-. { 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionylj-formamide (Compound 3) -4); 2-. { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -2- [2-methyl-2- (5-methyl- [1, 2,4] oxadiazol-3-11) -propyl-1 H-indole -5-yloxymethyl) -quinoline (Compound 3-5); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-M-methoxy) -1H-indol-2-yl] -2,2-dimethyl-N-pyridin-3- 11-propionamide (Compound 3-6); 3- [3-tert-butylsulfan-1 - (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-N -pyrazin-2-1-proponamide (Compound 3-7); 4- (2-Isobutyl-3,5-diisopropyl-indol-1-ylmethyl) -benzoic acid (Compound 4-1); N- (2-hydroxy-ethyl) -4- (2-isobutyl-3,5-diisopropyl-indol-1-iimethyl) -benzamide (Compound 4-2); N- (2-dimethylamino-ethyl) -4- (2-isobutyl-3,5-diisopropyl-indol-1-ylmethyl) -benzamide (Compound 4-3); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5-pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid (Compound 4-4); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5-pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid methyl ester (Compound 4-5); 4- [2- (2,2-Dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid (Compound 4-6); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy-indole-ylmethyl] -N- (2-dimethylamino-ethyl) -benzamide (Compound 4 -7); 1- [3-tert-butylsulfanyl-1-methyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2- ol (Compound 5-1): 1 - (3- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1- Lmetill-azetdin-1-11) -ethanone (Compound 5-2): 1 - [3-tert-butylsulfanyl-1-cyclopropylmethyl-5- (pyridin-2-ylmethoxy) -1H-indole- 211] -2-methy1-propan-2-ol (Compound 5-3); 1- [3-tert-butylsulfanyl-1-cyclobutylmethyl-5- (pyridin-2-ylmethoxy) -1 H -indol-2-yl] -2-methyl-propan-2-ol (Compound 5-4); 4- [3-tert-butyl] sulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy-indol-1-ylmethyl] -N-cyclopropyl-benzamide (Compound 5-5): 4- [3-tert-Butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy-indol-1-ylmethyl] -N- (2 -hydroxy-ethyl) -benzamide (Compound 5-6); 2- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy) -. 1 -yl] -acetamide (Compound 5-7) Synthesis of the Compounds described in the previous sectcan be synthesized using synthesis techniques known to those skilled in the art or using methods known in the art in combinatwith described methods In addit solvents, solvents, temperatures, and other reactcondit presented herein may vary according to those stipulated by those skilled in the art.The starting material used for the synthesis of the compounds described in the sectabove can be synthesized or obtained from commercial sources, ta Like, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds having different substituents can be synthesized using techniques and materials known to those skilled in the art, such as those described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTH ESIS 3rd Ed., (Wiley 1999) (which are incorporated herein in their entirety). The methods for the preparatof the compound as disclosed herein can be derived from known react in the field, and the react can be modified by the use of reagents and appropriate condit, as would be recognized by one skilled in the art, for the introductof several radicals found in the formulas as provided herein. As a guide, the following synthesis methods can be used. Formatof covalent bonds by reactof an electrophile with a nucleophile The compounds described herein can be modified using several electrophiles or nucleophiles to form new groups or substituents. Table 4 entitled "Examples of Covalent Links and their Precursors" lists the selected examples of covalent bonds and precursor functl groups which yield and can be used as a guide to the variety of combinat of electrophiles and nucleophiles available. The precursor functl groups are shown as electrophilic groups and nucleophilic groups. Table 6. Examples of Covalent Links and their Precursors
Use of protecting groups In the reactions described, it may be necessary to protect the reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are convenient in the final product, to avoid their unwanted participation in the reactions. The protecting groups are used to block some or all of the reactive radicals and prevent such groups from participating in the chemical reactions until the protective group is removed. It is preferred that each protecting group be removable by a different means. Protective groups that are cleaved under completely different reaction conditions meet the differential removal requirement. The protecting groups can be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are labile to the acid and can be used to protect the carboxy and hydroxy reactive radicals in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and the groups Fmoc, which are labile in front of the base. Reactive carboxylic acid and hydroxy radicals can be blocked with labile groups against the base such as, but not limited to, methyl, ethyl, and acetyl in the presence of blocked amines with labile groups against the acid such as t-butyl carbamate or with carbamates that are both stable acids and base but removable by hydrolytic route. Reactive carboxylic acid and hydroxy radicals can also be blocked with hydrolytic removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids can be blocked with Miles groups in front of the base such as Fmoc. The reactive carboxylic acid radicals may be protected by conversion into simple ester compounds as exemplified herein, or they may be blocked ester with oxidizing removable protective groups such as coma 2 > 4-dimethoxybenzyl, while the coexisting amino groups can be blocked with silyl carbamates that are weak against fluoride. Allyl blocking groups are useful in the presence of base and acid protecting groups since the former are stable and can be subsequently removed by metal catalysts or pi-acids. For example, a carboxylic acid blocked by allyl can be deprotected with a Pdo-catalyzed reaction in the presence of labile t-butyl carbamate protecting groups against the labile acid or acetate amine versus the base. Even another form of protecting group is a resin to which a compound or intermediate can be attached. As the residue binds to the resin, that functional group becomes blocked and can not react. Once released from the resin, the functional group is available to react. Commonly protective / blocking groups can be selected from:
Boc BMSü triethyl acetyl Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their elimination are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, both of which are incorporated herein by reference in their entirety. Indole-containing compounds can be prepared using the procedures of the standard literature such as those found in Katritzky, "Handbook of Heterocyclic Chemistry" Pergamon Press, Oxford, 1986; Pindur et al., J. Heterocyclic Chem., Vol 25, 1, 1987, and Robinson "The Fisher Indol Synthesis", John Wiley & Sons, Chichester, New York, 1982, each of which is incorporated herein as a reference in its entirety. A non-limiting example of the synthesis method towards the indole compounds described herein, is shown according to the Reaction Scheme 1 shown in Figure 1, where the 4-substituted anilines (1-1) can be converted to the corresponding hydrazine (I-2) using the standard methodology. The reaction of hydrazine (I-2) with an appropriately substituted ketone (1-3) under standard Fisher indiolization conditions gives the indole (I-4). The indole (1-6) arises from the N-alkylation of (I-4) with a benzyl halide (I-5) (or tosylate (OTs) or mesylate (OMs)) in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base such as NaH. In the case where the 5-substituent on the indole ring is methoxy (ie Z is MeO) the methyl group can be removed under standard conditions, for example using BBr3, in a solvent such as CH2Cl2 to give the phenol (I-7) . This phenol can be alkylated using an electrophile (YX) to give the alkylated product (I-8). Alternatively, in the case when the 5-substituent on the indole ring is, for example, a halide or triflate (OTf; 1-7) can be coupled with a wide variety of reagents using standard metal-mediated coupling reactions well known to those skilled in the art of organic synthesis to give the alternative compounds of structure (1-6). This chemistry is described in Comprehensive organometallic Chemistry II, vol 12, Pergamon, edited by Abel, Stone & Wilkinson. The substituent Z of the indole (I-6) can be subsequently modified using standard chemical methods. In addition, when R7 or R6 is a bromine or iodine, the reactions of cross-assembly is to allow the introduction of a variety of functional groups using procedures well known to those who practice the technique of organic synthesis. Moreover, when R7 is, H, it is possible, under certain conditions, to lithium in a regioselective manner using a strong base such as nBuLi and then to condense the anion with an electrolyte to introduce the substituents into C-2 (see Hasan et al., J. Org. Chem., 46, 157-164, 1981). Another non-limiting example of the method of synthesis towards the compounds described herein is shown according to Reaction Scheme II in Figure 2. Starting with Hydrazine I-2, N-alkylation with a benzyl halide (or tosylate) or mesylate, I-5) using the conditions described above, provides the hydrazine derivative (11-1). Reaction with an appropriately substituted ketone (1-1) using standard Fisher's indolization conditions provides the indole (I-6) · Another non-limiting example of the method of synthesis towards the compounds described herein is shown according to the Scheme of reaction li in Figure 2, where 3-H-indoles (111-1) can be prepared directly using the procedures described above or, alternatively, can be prepared from 3-thioindoles by treatment with AIC 3 Wet in a solvent such as CH 2 Cl 2 - Fionalization in the 3-position can be obtained using a variety of reactions and procedures to allow the introduction of a wide range of substituents. By way of example only, acylation using an acid chloride (or anhydride) in the presence of a Léwis acid such as AIC 3, allows the introduction of acyl groups (I-6; = C (O) R ') see Murakami et al. Heterocycles, v14, 1939-1941, 1980 and the references mentioned therein. Starting with (IT-), and using, by way of example only, sulfonic chlorides in a suitable solvent, compounds of general structure (IM-2) where R6 is SR "can be prepared (Raban, J. Org. Chem. , v45, 1688, 1980) A similar chemistry using indole (111-1) can be performed or, alternatively, diaryldisulfides can be used in the presence of a base such as NaH in DMF to generate (III-4) (Atkinson et al., Synthesis, 480-481, 1988.) Reaction of electron deficient olefins with 3-H (111-1) or (111-1) in the presence of a Lewis acid (such as Yb (OTf) 3.3 H20) allows the installation of 3-alkyl substituents of general structure (111-2) or (111-4) (where R6 is a substituted alkyl group, see Harrington &Kerr, Syniett, 1047-1048, 1996). Alternatively, the indole (111-1) can react with benzyl derivatives (I-5) in warm DMF to give (111 -4) where R6 is a substituted benzyl group (Jacobs et al., J. Med. Che m., v36, 394-409, 1993). Other Synthesis of indole and indole compounds Other non-limiting examples of the synthesis strategy towards indole and indole type scaffolds for the compounds described herein, include modifications to several indole syntheses, including, but not limited to; Synthesis of Indoles by Batcho-Leimgruber, Synthesis of Indoles by Reissert, Synthesis of Indoles of Hegedus, Synthesis of IndoLes by Fukuyama, Synthesis of Indoles by Sugasawa, Synthesis of Indoles by Bischler, Synthesis of Indoles by Gassman, Synthesis of Indoles by Físcher, Synthesis of Indoles from Japp-Klingemann, Synthesis of Buchwald characters, Synthesis of Indoles de Larock, Synthesis of Indoles by Bertoli, Synthesis of Indoles de Castro, Synthesis of Indoles by Hemetsberger, Synthesis of Indoles by Mori-Ban, Synthesis of Indoles by Madelun g, Synthesis of Indoles by Nenitzescu, and other reactions without names. Non-limiting examples of such synthesis methods are shown in Figures 3-7. Other Forms of Compounds The compounds of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), can be prepared as an acid addition salt acceptable for pharmaceutical use (which is a type of salt acceptable for pharmaceutical use) by reacting the free base form of the compound with an inorganic or organic acid acceptable for pharmaceutical use, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, masonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, acid trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonyl acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, -naphthalenesulfanic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurel sulfuric acid, glucinio acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Alternatively, the compounds of formula (A), formula (B), Formula (C), formula (D), formula (F) or formula (H), can be prepared as pharmaceutically acceptable base addition salts (the which is a type of pharmaceutically acceptable salt) by reacting the free acid form of the compound with a pharmaceutically acceptable organic or inorganic base, including, but not limited to, organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and similar and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. The compounds of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), can be prepared in the form of pharmaceutically acceptable salts formed when an acidic proton present in the parent compound or is replaced with a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with an organic base. In addition, the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or their crystalline forms, particularly solvates or polymorphs. The solvates contain stoichiometric or non-stoichiometric amounts of a solvent, and can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. The solvates of the compounds described herein may conveniently be prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein can be conveniently prepared by the recrystallization of an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol . In addition, the compounds provided herein may exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. The compounds described herein may be in various forms, including but not limited to, amorphous forms, ground forms and nanoparticulate forms. In addition, the compounds described herein include crystalline forms, also called polymorphs. The polymorphs include the different different glass packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Several factors such as the re-crystallization solvent, the crystallization speed, and the storage temperature can make a single crystal shape predominate. The compounds of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) in non-oxidized form can be prepared from N-oxides of compounds of formula (A) ), Formula (B), Formula (C), Formula (D), Formula (F) or Formula (H), treating with a reducing agent, such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitriyl, ethanol, aqueous dioxane, or the like at 0o to 80 ° C. The compounds provided herein can be prepared in the form of prodrugs. In general, prodrugs are precursors of the drug which, following administration to a subject and subsequent adsorption, are converted to an active species or a more active species by some process, such as conversion via a metabolic pathway. Some prodrugs have a chemical group present in the prodrug that is less active and / or confers solubility or some property to the drug. Once the chemical group has been cleaved and / or modified from the prodrug, the active drug is generated. Prodrugs, in general, are useful because, in some situations, they may be easier to administer than the parent drug. They can, for example, be bioavailable by oral administration while the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions on the parent drug. The prodrugs may be designed as derivatives of reversible drugs, to be used as modifiers to improve the transport of the drug to site-specific tissues. The design of the prodrugs to date has been to increase the effective aqueous solubility of the therapeutic compound to target regions where water is the main solvent. See, for example, Fedorak et al., Am. J. Physiol., 269: G210-218 (1995).; McLoed - et al., Gastroenterol, 106: 405-413 (1994); Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Mt. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Mt. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein by reference. In addition, the prodrug derivatives of compounds provided herein may be prepared by methods known to those skilled in the art (for example, for further details see Saulnier et al., (1994), Biorganic and Medicinal Chemistry Letters, Vol. 4 , P. 1985). By way of example only, the appropriate prodrugs can be prepared by reacting a compound not derived from any of formula (E), formula (EI), or formula (E-ll), with a suitable carbamylating agent, such as, but without limitation, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like. The prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are within the scope of the claims, some of the compounds described herein may be a prodrug for another derivative or active compound. The sites on the aromatic ring portion of the compounds of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) may be susceptible to various metabolic reactions, by thus the incorporation of appropriate substituents in the structures of the aromatic ring, such as, by way of example only, haláguenos, can reduce, minimize or eliminate this metabolic pathway. The compounds described herein can be labeled isotopically (for example with a radioisotope) or by some other means, including, but not limited to, the use of chromophores to fluorescent radicals, bio-luminescent labels, or chemo-luminescent labels. The compounds described herein may have one or more stereo-centers and each center may exist in the R or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric and epimeric forms as well as their appropriate mixtures. The compounds described herein can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of the enantiomers can be carried out using diastereomeric derivatives of the compounds described herein, dissociable complexes (eg, crystalline diastereomeric salts) are preferred. Diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chiral chromatography, preferably by separation / resolution techniques on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of diastereomers of the compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolution", John Wiley and Sons, Inc. ., 1981, incorporated herein by reference in its entirety.
In addition, the compounds and methods provided herein may exist as geometric isomers. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as their appropriate mixtures. In some situations, the compounds may exist as tautomers. All tautomers are included in the formulas described herein provided by the compounds and methods herein. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers, arising from a single step of preparation, combination or inter-conversion may be useful for the applications described herein. Routes of Administration Appropriate routes of administration include, but are not limited to, intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intra-ventricular, intraperitoneal, intra-lymphatic and intra-nasal injections. Alternatively, the compound can be administered locally instead of systemically, for example by direct injection of the compound into a organ, often in a depot preparation or sustained release formulation. Long-acting formulations can be administered by implant (for example subcutaneously or intramuscularly) or by intramuscular injection. In addition, the drug can be administered in a drug delivery system for localization, for example, in a liposome coated with organ-specific antibody. The liposomes will be localized and selectively picked up by the organ. In addition, the drug can be provided in the form of a rapid release formulation, in the form of an extended release formulation or in the form of an intermediate release formulation. Composition / Pharmaceutical Formulation The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the active compounds into preparations that can be used in pharmaceutical form. The correct formulation depends on the chosen route of administration. Any of the well known techniques, vehicles, and appropriate excipients and as are known in the art may be used. A summary of pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th Ed (Easton, Pa .: ack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, N.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed. (Lippincott Williams &Wilkins 1999), which are incorporated herein by reference in their entirety. Pharmaceutical compositions which include a compound described herein and a pharmaceutically acceptable diluent, excipient or carrier are provided herein. In addition, the compounds described herein can be administered as pharmaceutical compositions wherein compounds described herein are mixed with other active components, such as in a combination therapy. A "pharmaceutical composition," as used herein, refers to a mixture of a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) with other chemical components, such as vehicles, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practice, the methods of treatment or use provided herein, the effective amounts for therapeutic use of compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) provided herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. Preferably, the mammal is a human. An effective amount for therapeutic use can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds may be used separately or in combination with one or more therapeutic agents as components of mixtures. For intravenous injections, the compounds described herein can be formulated in aqueous solutions, preferably in compatible buffers for physiological use such as Hank's solution, Ringer's solution, or physiological saline buffer. For trans-mucosal administration, appropriate penetrants for the barrier to permeate are used in the formulation. Penetrants are generally known in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with compatible buffers or excipients for physiological use. The excipients are generally known in the art. For oral administration, the compounds provided herein can be formulated easily by combining the active compounds with vehicles or excipients acceptable for pharmaceutical use. The vehicles allow the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding appropriate auxiliaries, if appropriate. you want, to obtain cores of tablets or dragees. The excipients are, in particular, fillers such as sugars, which include lactose, sucrose, mannitol, sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatine, tragacanth gum, methyl cellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as croscarmellose sodium crosslinked, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with appropriate coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lava solutions, and suitable solvents or mixtures of organic solvents. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations that can be used in oral form include easy-swallow capsules made of gelatin, as well as, sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Soft-fit capsules can contain the active components mixed with fillers such as lactose, binders such as starches and / or lubricants such as talc to magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved to be suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be prepared in appropriate doses for administration. For buccal to sublingual administration, the compositions may take the form of tablets, lozenges to gels formulated in conventional manner. Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) can be presented in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions. in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds can be prepared as appropriate suspensions for oily injection. Solvents to suitable lipophilic vehicles include fatty oils such as sesame oil, or synthetic esters of fatty acids, such as ethyl oleate or triglycerides or liposomes. Aqueous suspensions for injection may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or appropriate agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active component may exist in powder form for reconstitution with an appropriate vehicle, for example sterile, pyrogen-free water, prior to use. The compounds described herein can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, lozenges, medicated bars, balms, creams or ointments. Pharmaceutical compounds may contain solubilizers, stabilizers, tonicity improving agents, buffers and preservatives. Formulations suitable for transdermal administration of compounds having the structure of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) use transdermal delivery devices and patches of transdermal administration and can be lipophilic or buffered emulsions, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. The patches can be elaborated for continuous, pulsatile or on demand administration of the pharmaceutical agents. In addition, transdermal administration of the compounds described herein can be achieved by the use of iontophoretic patches and the like. In addition, transdermal administration of the compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) can be achieved by the use of iontophoretic patches and Similar. In addition, transdermal patches can provide controlled administration of the compounds of any of formula (A), Formula (B), formula (C), formula (D), formula (F) to formula (H). The rate of absorption can be decreased by using speed controlling membranes or by trapping the compound within a polymer or gel matrix. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or vehicle may include pharmaceutically acceptable absorbable solvents to facilitate passage through the skin. For example, transdermal devices are presented in the form of a bandage comprising a support element, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier for delivering the compound to the skin of the host at a predetermined level and controlled for a prolonged period of time, and means to secure the device to the skin. For administration by inhalation, the compounds described herein may exist in the form of aerosol, mist or powder. The pharmaceutical compositions of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) are conveniently administered in the form of an aerosol spray presentation of pressurized containers. or a nebulizer, with the use of an appropriate propellant, for example dichlorodifluoromethane, trichlorofluoro methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by the use of a valve to administer a set amount. Capsules and cartridges of, for example, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mixture of the compound and an appropriate powder base such as lactose or starch. The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal sprays, suppositories, gelatinous suppositories or retention enemas, which contain conventional suppository bases such as cocoa butter or other glycerides, such as thus also synthetic polymers such as polyvinylpyrrolidone, PEG and the like. In suppository forms of the compositions, a low melting point wax is first melted such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter. The pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used in pharmaceutical form. The correct formulation depends on the chosen route of administration. Any of the well-known techniques can be used, vehicles, and excipients appropriate and contemplated in the art. Pharmaceutical compositions comprising a compound described herein may be prepared in conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes. The pharmaceutical compositions will include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound described herein as an active component in the form of free acid or free base, or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers.-All tautomers are included within the scope of the compounds presented herein. In addition, the compounds described herein may exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered disclosed herein. In addition, the pharmaceutical compositions may include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, humectants or emulsifiers, solubility promoters, salts for regulating the osmotic pressure and / or buffers. In addition, the pharmaceutical compositions may also contain other therapeutically valuable substances. Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more excipients or inert carriers, acceptable for pharmaceutical use to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dissipable granules, capsules, seals, and suppositories. Liquid compositions include solutions where a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles or nanoparticles comprising a compound as disclosed herein. The semi-solid compositions include, but are not limited to, gels, suspensions and creams. The compositions can be presented in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, etc. A composition comprising a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) can illustratively take the form of a liquid wherein the agents are present in solution, in suspension or both. Commonly when the composition is administered as a solution or suspension, a first portion of the agent is present in solution and a second portion of the agent is present as a particle, in suspension in a liquid matrix. In some embodiments, a composition may include a gel formulation. In other embodiments, the liquid composition is aqueous. The useful aqueous suspension may also contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, for example hydroxypropylmethylcellulose, and non-water-soluble polymers such as crosslinked polymers containing carboxyl groups. Useful compositions may also comprise a mucoadhesive polymer, selected, for example, from carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, copolymer of acrylic acid / butyl acrylate, sodium alginate and dextran. Useful compositions may also include solubilizing agents to contribute to the solubility of a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). The term "solubilizing agent" generally includes agents that result in the formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, may be useful as solubilizing agents, and may be acceptable glycols for use of ophthalmic, polyglycols, for example polyethylene glycol 400, and glycol ethers. Useful compositions may also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids.; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Acids, bases and buffers are included in a proportion required to maintain the pH of the composition in an acceptable range. Useful compositions may also include one or more salts in a proportion required to bring the osmolality of the composition to an acceptable range. The salts include those containing sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. Other useful compositions may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride. Even other useful compositions may also include one or more surfactants to increase physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylenated fatty acid glycerides and vegetable oils, for example, polyoxyethylenated hydrogenated castor oil (60); and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example octoxynol 10, octoxynol 40. Even other useful compositions may also include one or more antioxidants to increase chemical stability when required. Suitable antioxidants include, solely for the purpose of exemplification, ascorbic acid and sodium metabisulfite. The compositions in aqueous suspension can be packaged in single dose containers with non-reusable closure. Alternatively, multiple dose containers with reusable closure may be used, in such cases a preservative is normally included in the composition. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well known examples of delivery vehicles or vehicles for hydrophobic drugs. Certain organic solvents such as N-methylpyrrolidone can also be used, but usually at the cost of increased toxicity. In addition, the compounds can be administered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known to those skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization can be used. All of the formulations described herein can benefit from antioxidants, metal chelating agents, thiol-containing compounds and other general stabilizing agents. Examples of the stabilizing agents include, but are not limited to: (a) from about 0.5% to about 2% w / v glycerol, (b) from about 0.1% to about 1% w / v methionine, (c) ) from about 0.1% to about 2% w / v of monothioglycerol, (d) about 1 mM EDTA to about 10 mM, (e) from about 0.01% to about 2% w / v of ascorbic acid, (f) of 0.003 % at about 0.02% w / v polysorbate 80, (E) from 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins , (I) pentosan polysulfate and other hepari noids, (m) divalent cations such as magnesium and zinc; (n) combinations thereof. Dosage Methods and Treatment Regimens The compounds of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) can be used in the preparation of medicaments for the treatment of diseases or conditions leukotriene-dependent or mediated by leukotrienes. In addition, a method for treating any disease or condition described herein in a subject in need of such treatment, involves the administration of pharmaceutical compositions containing at least one compound of any formula (A), formula (B), formula (C) , formula (D), formula (F) or formula (H) or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, active metabolite for pharmaceutical use, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in effective amounts for therapeutic use to said subject. The compositions containing the compounds described herein may be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The effective amounts for this use will depend on the severity and course of the disease or condition, the previous therapy, the patient's health status, the weight, the response to the drugs, and the judgment of the attending physician. It is considered within the skill inherent in the art to determine such effective amounts for therapeutic use by routine experimentation (including, but not limited to, a clinical trial of dose escalation). In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder or condition. Said amount is defined as an "effective amount or dose for prophylactic use". In this use, the precise amounts also depend on the patient's health status, weight, and the like. It is considered within the skill inherent in the art to determine such effective amounts for prophylactic use by routine experimentation (including, but not limited to, a clinical trial of dose escalation). When used in a patient, the amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, response to drugs, and judgment. of the doctor in charge. In the event that the patient's condition does not improve, at the discretion of the attending physician, the compounds can be administered chronically, that is, for an extended period of time, which includes throughout the life of a patient, in order to relieve or otherwise control or limit the symptoms of the patient's disease or condition. In the case where the condition of the patient improves, at the discretion of the attending physician, the compounds can be administered continuously; alternatively, the dose of the drug administered may be reduced or suspended temporarily for a certain period of time (ie, a "treatment vacation"). The length of the treatment vacation can vary between 2 days and 1 year, including for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction during the treatment holidays can be 10% -100%, including for example 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%. Once the improvement in the patient's condition has occurred, if necessary, a maintenance dose is applied. Subsequently, the dose or frequency of administration, or both, may be reduced as a function of the symptoms, at a level at which the improvement in the disease, disorder or condition is retained. Patients may, however, require intermittent treatment on a long-term basis following any recurrence of symptoms.
The amount of a given agent that will correspond to such an amount will vary depending on factors such as the particular compound, the disease, condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but nevertheless never it can be routinely determined in a manner known in the art according to the particular circumstances inherent in the case, including, for example, the specific agent administered, the route of administration, the condition treated, and the subject or host treated. In general, however, the dose employed for a treatment in a human adult will commonly be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or for a short period of time) or at appropriate intervals, for example two, three, four or more sub-doses per day. The pharmaceutical composition described herein may be presented in unit dosage forms suitable for simple administration of precise doses. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dosage can be presented in the form of a package containing discrete quantities of the formulation. Non-limiting examples are tablets or capsules, and powders in vials or ampoules. The aqueous suspension compositions can be packaged in single dose containers with non-reusable closure. Alternatively, multiple dose containers with reusable closure may be used, in such cases normally a preservative is included in the composition. For example, formulations for parenteral injection may be presented in unit dosage form, including, but not limited to, ampoules, or in multi-dose containers, with an added preservative. In one embodiment the appropriate daily doses for the compounds described herein are from about 0.01 to 2.5 mg / kg per body weight. An indicated daily dose in the largest mammal, including, but not limited to, humans, is in the range of about 0.5 mg to about 100 mg, conveniently administered in divided doses, including, but not limited to, up to four times day or in the form of extended release. The unit dosage forms suitable for oral administration comprise from about 1 to 50 mg of active component. The preceding ranges are merely suggestive, such as the number of variables with respect to an extensive individual treatment regime, and considerable deviations from such recommended values are usual. The doses may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition treated, and the judgment of the doctor in charge. The toxicity and therapeutic efficacy of the therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD50 (the lethal dose at 50% of the population) and ED50 (the effective dose for therapeutic use in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD50 and ED50. Compounds that exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in the formulation of a dose range for human use. The dose of the compounds is preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dose may vary within this range depending on the dosage form employed and the route of administration used. Use of FLAP Modulators to Prevent and / or Treat Leukotriene-Dependent or Leukotriene-Mediated Diseases or Conditions Therapy of leukotriene-dependent or leukotriene-mediated diseases or conditions is designed to modulate FLAP activity. Said modulation may include, for example, inhibiting or antagonizing FLAP activity. For example, a FLAP inhibitor can be administered in order to decrease the synthesis of leukotrienes within the individual, or possibly to down-regulate or decrease the expression or availability of the FLAP ARMN or specific splice variants of the FLAP ARMN. The down regulation or expression or availability of a native FLAP ARMN or a specific splice variant could minimize the expression or activity of a defective nucleic acid or particular splice variant and thereby minimize the impact of the defective nucleic acid or of the particular splice variant. According to one aspect, the compositions and methods described herein include compositions and methods for treating, preventing, revoking, stopping reducing the progression of leukotriene-dependent or leukotriene-mediated diseases or conditions once they are clinically evident, or treating symptoms associated with or related to leukotriene-dependent or leukotriene-mediated diseases or conditions, by administration to the subject of a compound of any formula (A), formula (B), formula (C), formula (D), formula ( F) or formula (H) or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). The subject may already suffer from a leukotriene-dependent or leukotriene-mediated disease or condition at the time of administration, or be at risk of developing a leukotriene-dependent or leukotriene-mediated disease or condition. The symptoms of leukotriene-dependent or leukotriene-mediated diseases or conditions in a subject can be determined by those skilled in the art and described in standard textbooks. The activity of the 5-lipoxygenase activator protein in a mammal can be modulated directly or indirectly by administering (at least once) an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), to a mammal. Said modulation includes, but is not limited to, reducing and / or inhibiting the activity of the 5-lipoxygenase activation protein. In addition, the activity of leukotrienes in a mammal can be modulated directly or indirectly, including reducing and / or inhibiting, by administering (at least once) an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C) , formula (D), formula (F) or formula (H), to a mammal. Said modulation includes, but is not limited to, reducing and / or inhibiting the activity of the 5-lipoxygenase activation protein. The prevention and / or treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions may comprise administration to a mammal, at least once, of an effective amount of at least one compound of any formula (A), formula (B) , formula (C), formula (D), formula (F) or formula (H), a pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C), formula (D) ), formula (F) or formula (H). For example, the prevention and / or treatment of inflammatory diseases or conditions may comprise administering to a mammal, at least once, an effective amount of at least one compound of any Formula (A), formula (B), formula (C) , formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). The leukotriene-dependent or leukotriene-mediated diseases or conditions which can be treated by a method comprising administering to a mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B) , formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D) ), formula (F) or formula (H), include, but are not limited to, bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, dermatological diseases and disorders, diseases and eye disorders, cancer and other diseases and proliferative disorders , diseases and respiratory disorders, and non-cancerous disorders. By way of example only, methods for prevention / treatment described herein are described for treating respiratory diseases comprising administering to a mammal, at least once, an effective amount of at least one compound of any formula (A) , formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C) ), formula (D), formula (F) or formula (H). By way of example only the respiratory disease can be asthma; see R ^ cioni et a !, Ann. Clin. Lab. ScL, v34, 379-387 (2004). In addition, the respiratory disease may include, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, Aspirin-sensitive asthma, exercise-induced asthma, isocanic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, spheroidal-resistant asthma, seasonal asthma, allergic rhinitis, vascular responses, endotoxic shock, fibrogenesis, pulmonary fibrosis, allergic diseases, chronic inflammation, and adult respiratory distress syndrome. By way of example only, methods for preventing chronic obstructive pulmonary diseases comprising administering to a mammal, at least once, an effective amount of at least one compound of any formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). In addition, chronic obstructive pulmonary diseases include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis. By way of example only, methods for preventing increased mucosal secretion and / or edema in a disease or condition comprising administering to a mammal, at least once, an effective amount of at least one compound of the invention are included in said methods of treatment. any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B) ), formula (C), formula (D), formula (F) or formula (H).
By way of example only, methods for preventing or treating vasoconstrictions, atherosclerosis and their consequences, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering to a mammal, at least, are included in said prevention / treatment methods. once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H); see Jala et al., Trends in Immunol., v25, 315-322 (2004) and Mehrabian et al., Curr. Opin. Upidol., V14, 447-457 (2003). By way of example only, methods for preventing / treating cardiac reperfusion injury followed by myocardial ischemia and / or endotoxic shock comprising administering to a mammal, at least once, an effective amount of at least one dose, are included in said prevention / treatment methods. minus a compound of any formula (A), Formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A) , formula (B), formula (C), formula (D), formula (F) or formula (H). By way of example only, methods for reducing / constricting blood vessels in a mammal comprising administering to a mammal, at least once, an effective amount of at least one compound of any formula are included in said prevention / treatment methods. (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or Formula (H). By way of example only, methods for preventing / treating such methods of decreasing or preventing an increase in blood pressure of a mammal comprising administering to the mammal, at least once, an effective amount of at least one compound of any type are included in said prevention / treatment methods. formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B) , formula (C), formula (D), formula (F) or formula (H). By way of example only, methods for prevention / treatment include methods for preventing the recruitment of monocytes, eosinophils and / or basophils and / or dendritic cells and / or neutrophils comprising administering to a mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). By way of example only, methods for preventing / treating methods for the prevention or treatment of remodeling, abnormal bone loss or gain, including diseases or conditions such as, for example, osteopenia, osteoporosis, Paget's disease, are included in the methods of prevention / treatment. cancer and other diseases comprising administering to a mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). By way of example only, methods for preventing / treating described herein are methods for preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), Formula (C), formula (D), formula (F) or Formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A ), formula (B), formula (C), formula (D), formula (F) or formula (H); see Lambíase et al., Arch. Opthalmol., v121, 615-620 (2003). By way of example only, methods for prevention / treatment described herein are included to prevent CNS disorders comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A) , formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C) ), formula (D), formula (F) or formula (H). CNS disorders include, but are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-surgical cognitive dysfunction, migraine, peripheral neuropathy, neuropathic pain, spinal cord injury, edema brain and head injury. By way of example only, are included in the methods of prevention / treatment described herein for methods of treating cancer comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A) , formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), Formula (B), formula (C) ), formula (D), formula (F) or formula (H). The type of cancer can include, but is not limited to, pancreatic cancer and other solid or hematologic tumors, see Poff and Balazy, Curr. Drug Targets Inflamm. Allergy, v3, 19-33 (2004) and Steele et al., Cancer Epidemiology & Prevention, v8, 467-483 (1999). By way of example only, methods for preventing / treating described herein are methods for preventing endotoxic shock and septic shock comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). By way of example only, methods of prevention / treatment described herein for preventing rheumatoid arthritis and osteoarthritis comprising administering to the mammal, at least once, an elective amount of at least one compound of any formula are included in the prevention / treatment methods described herein. A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or Formula (H). By way of example only, methods of prevention / treatment described herein are included to prevent the increase of Gl diseases comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). Such Gl diseases include, by way of example only, inflammatory bowel disease (EN), colitis and Crohn's disease. By way of example only, methods for prevention / treatment described herein are included for the reduction of inflammation while also preventing the rejection of transplants or for preventing or treating tumors or accelerating the healing of wounds, which comprise administering to the mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or Formula (H), or pharmaceutical composition or medicament including a compound of any formula (A), formula (B), Formula (C), formula (D), formula (F) or formula (H). As an example onlyare included in the methods of prevention / treatment described herein for the prevention or treatment of rejection or dysfunction in a transplanted tissue organ comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B) , formula (C), formula (D), formula (F) or formula (H). By way of example only, methods for preventing / treating described in the present methods for treating type II diabetes, comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (FIG. A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). By way of example only, the methods of prevention / treatment described herein are described for treating inflammatory skin responses comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula ( A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). Such inflammatory responses of the skin include, by way of example, psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing and scarring. In another aspect there are methods for reducing psoriatic lesions in the skin, joints, or other tissues or organs, comprising administering to the mammal, at least once, an effective amount of at least one compound of any formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (ID), formula (F) or formula (H).
By way of example only, methods for the prevention / treatment described herein are described for the treatment of cystitis, which includes, by way of example only, interstitial cystitis, comprising administering to the mammal, at least once, a effective amount of at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). By way of example only, methods for prevention / treatment described herein are included for the treatment of metabolic syndromes such as Familial Mediterranean Fever, which comprise administering to the mammal, at least once, an effective amount of at least one composed of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or pharmaceutical composition or medicament that includes a compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H). Combination Treatments In certain cases, it may be appropriate to administer at least one compound of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds of the present invention is inflammation, then it may be appropriate to administer an anti-inflammatory agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein can be increased by the administration of an adjuvant (i.e., the adjuvant itself may have a minimal therapeutic benefit, but in combination with another agent therapeutic, increases the total therapeutic benefit of the patient). Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein can be increased by the administration of one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) which also has benefit therapeutic. By way of example only, in a treatment for asthma which involves the administration of one of the compounds described herein, the increased therapeutic benefit may result from the provision to the patient with other therapeutic agents or therapies for asthma. In any case, regardless of the disease, disorder or condition treated, the total benefit experienced by the patient may simply be additive to the two therapeutic agents or the patient may experience a synergistic benefit. It is known to those skilled in the art that effective doses for therapeutic use may vary when the drugs are used in combination treatments. Methods for experimentally determining effective doses for therapeutic use of drugs and other agents for use in combination treatments are described in the literature. For example, the use of metronomic doses, that is, provided more frequently, lower doses in order to minimize toxic side effects, has been described extensively in the literature. A combination treatment regimen may encompass treatment regimens where the administration of a FLAP or 5-LO inhibitor described herein is initiated prior to, during, or following treatment with a second agent described above, and continues to any during the treatment with the second agent or after the termination of the treatment with the second agent. This also includes treatments where a FLAP or 5-LO inhibitor described herein and the second agent, used in combination, are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. The combination treatment also includes periodic treatments that start and stop several times to assist the clinical management of the patient. For example, a FLAP or 5-LO inhibitor described herein in the combination treatment can be administered weekly at the beginning of the treatment, decreasing biweekly, and then decreasing accordingly. Compositions and methods for combination therapy are provided herein. According to one aspect, the pharmaceutical compositions described herein are used to treat leukotriene-dependent or leukotriene-mediated conditions. According to another aspect, the pharmaceutical compositions described herein are used to treat respiratory diseases, where treatment with a FLAP inhibitor, in particular asthma, and to induce bronchodilation in a subject is indicated. In one embodiment, the pharmaceutical compositions described herein are used for a subject suffering from a vascular disorder managed by inflammation. In one embodiment, the pharmaceutical compositions described herein are used to treat a subject susceptible to myocardial infarction (MI). The combination therapies described herein may be used as part of a specific treatment regimen which is intended to provide a beneficial effect from the coercion of the FLAP inhibitors described herein and concurrent binding. It is understood that the dosage regimen for treating, preventing, or improving the condition (s) for which relief is sought can be modified according to a variety of factors. These factors include the type of respiratory disorder and the type of bronchodilation experienced by the patient, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen in effect employed may vary widely and therefore deviate from the dosage regimens set forth herein. For the combination therapies described herein, the doses of co-administered compounds of course vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, and so on. In addition, when co-administered with one or more biologically active agents, the compound provided herein may be administered simultaneously with the biologically active agents, or sequentially. If administered sequentially, the attending physician will decide the sequence of appropriate administration of protein in combination with the biologically active agents. In any case, the multiple therapeutic agents (one of which is one of the compounds described herein) can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a simple, unified form, or in multiple forms (by way of example only, as a single pill or as two separate pill). One of the therapeutic agents can be administered in multiple doses, or both can be administered in multiple doses. If they are not administered simultaneously, the time between multiple doses may vary from more than zero weeks to less than four weeks. In addition, the combination methods, compositions and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also envisaged.
In addition, the compounds described herein may also be used in combination with methods that may provide additional or synergistic benefit to the patient. By way of example only, it is expected that patients find therapeutic and / or prophylactic benefit in the methods described herein, wherein the pharmaceutical composition of any formula (A), formula (B), formula (C), formula (D) ), formula (F) or formula (H), and / or combinations with other therapeutic agents is combined with genetic tests to determine if an individual is a vehicle of a mutant gene that is known to be correlated with certain diseases or conditions. Compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), and the combination therapies can be administered before, during or after administration. occurrence of a disease or affection, and the time of administration of the composition containing a compound may vary. Thus, for example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to develop diseases or conditions in order to prevent the occurrence of a disease to condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of symptoms, preferably within the first 48 hours of onset of symptoms, more preferably within the first 6 hours of the onset of symptoms, and with the highest preference within the first 3 hours of the onset of symptoms. The initial administration can be via any practical route, such as, for example, an intravenous injection, a bolus injection, infusion of for 5 minutes to about 5 hours, a pill, a capsule, a transdermal patch, buccal administration, and the like. , or combinations thereof. Preferably, a compound is administered as soon as practicable upon detection or suspicion of the onset of a disease or condition, and for a period of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. The duration of treatment can vary for each subject, and can be determined using the known criteria. For example, the compound or a formulation containing the compound can be administered for at least 2 weeks, preferably from about 1 month to about 5 years, and more preferably from about 1 month to about 3 years. By way of example, the therapies that combine compounds of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), with inhibitors of leukotriene synthesis or Leukotriene receptor antagonists, acting at the same point or at other points in the leukotriene synthesis pathway, could prove to be particularly useful for treating leukotriene-dependent or leukotriene-mediated diseases or conditions. Also, by way of example, therapies that combine compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), with inhibitors of the inflammation may prove to be particularly useful for treating leukotriene-dependent or leukotriene-mediated diseases or conditions. Anti-Inflammatory Agents In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions include administering compounds, pharmaceutical compositions, or medicaments described herein in combination with a patient to a patient. anti-inflammatory agent including, but not limited to, arthrotec, asacol, auralgan, bluefidine, daypro, etodolac, ponstan, salofalk, and solumedrol; non-steroidal anti-inflammatory agents, for example aspirin (Bayer ™, Bufferin ™), indomethacin (Indocin ™), rofecoxib (Vioxx ™), celecoxib (Celebrex ™), valdecoxib (Bextra ™), diclofenac, etodolac, ketoprofen, lodine, mobic, nabumetone, naproxen, piroxicam; and corticosteroids, by way of example celestone, prednisone and deltasone. Corticosteroids do not directly inhibit the production of leukotrienes, therefore co-dosing with steroids could provide additional anti-inflammatory benefits, particularly for respiratory diseases. As an example, asthma is a chronic inflammatory disease characterized by pulmonary eosinophilia and hyper-responsiveness of the respiratory tract. Zhao et al., Proteotnics, July 4, 2005. In patients with asthma, leukotrienes can be released from mast cells, eosinophils and basophils. Leukotrienes are involved in the contraction of the smooth muscle of the airways, in the increase of vascular permeability and mucous secretions, and have been reported to attract and activate inflammatory cells in the airways of asthmatics (Siegel et al. , ed., Basic Neurochemistry, Molecular, Cellular and Medical Aspects, Sixth Ed., Lippincott Williams &Wilkins, 1999). Thus, in another embodiment described herein, methods for the treatment of respiratory diseases include the administration to a patient of compounds, pharmaceutical compositions, or medicaments described herein in combination with an anti-inflammatory agent. Leukotriene Receptor Antagonists In another embodiment described herein, methods for the treatment of leukotriene-dependent or mediated per leukotriene diseases or conditions include the administration to a patient of compounds, pharmaceutical compositions, or medicaments described herein in combination with leukotriene receptor antagonists including, but not limited to, dual CysLTI / CysLT2 receptor antagonists and CysLTI receptor antagonists. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions include the administration to a patient of compounds, pharmaceutical compositions, or medicaments described herein in combination with a dual receptor antagonist. of CysLTI / CysL1 -2. Dual antagonists of the CysLTI / CysLT2 receptor include, but are not limited to, BAY u9773, Cuthbert et al. EP 00791576 (published August 27, 1997), DUO-LT (Galczenski et al., D38, Poster F4 filed in the American Thoracic Society, May 2002) and Tsuji et al., Org. Biomol. Chem., 1, 3139-1141, 2003. For a particular patient, the formulation or method of more appropriate use of the combination treatments may depend on the type of leukotriene-dependent or leukotriene-mediated disorder, the period of time in which it acts the FLAP inhibitor for treating the disorder and the period of time in which the dual antagonist of the CysLTI / CysLT2 receptor activates to inhibit the activity of the CysLT receptor. By way of example only, the combination treatments can be used to treat a patient suffering from a respiratory disorder. In another embodiment described herein, methods for the treatment of leukotriene-dependent or mediated per leukotriene diseases or conditions include the administration to a patient of compounds, pharmaceutical compositions, or medicaments described herein in combination with a receptor antagonist of the present invention. CysLTI. Antagonists of the CysLTI receptor include, but not limited to, Zafirlukast ("Accolaten ™"), Montelukast ("Singulair ™"), Prankulast ("Onon ™"), and derivatives or analogs thereof. The combinations can be used to treat leukotriene-dependent or mid-leukotriene disorders,. which include respiratory disorders. The co-administration of a FLAP or 5-LO inhibitor described herein with a CysLTI receptor antagonist or dual receptor antagonist of CysLTI / CysLT2 may have a therapeutic benefit that exceeds the benefit derived from the administration of only one inhibitor. of FLAP or 5-LO or of a CysLTIR antagonist. In the case where substantial inhibition of leukotriene production has undesired effects, partial inhibition of this pathway through the improvement of the effects of proinflammatory LTB4 and cysteinyl leukotrienes combined with CysLTI receptor blockade and / or dual receptor blockade of CysLTI / CysLT2 can provide substantial therapeutic benefits, in particular for respiratory diseases. Other Combination Therapies In another embodiment described herein, methods for the treatment of leukotriene-dependent or mediated diseases or diseases by leukotrienes, such as proliferative diseases, including cancer, comprise administration to a patient of compounds, pharmaceutical compositions. , or medicaments described herein in combination with at least one additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or not), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicin / idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel ™, taxa ', temozolomide, thioguanine, or classes of drugs that include hormones (an anti-estrogen, an anti-androgen, or homona releasing analogues of gonadotropin, interferons such as alpha interferon, nitrogen mustards such as busul fan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents for treating signs or symptoms induced by therapy including allopurinol, filgrastima, granisetron / ondansetron / palonosetron, dronabinol. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, such as the therapy of transplanted organs, tissues or cells, comprise administration to a patient of compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from the group consisting of azathioprine, a corticosteroid, cyclophosphamide, cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, thymoglobulin. In another embodiment described herein, methods for the treatment of leukotriene-dependent diseases or conditions or. Leukotriene mediated, such as atherosclerosis, comprises administering to a patient compounds, pharmaceutical compositions, or medicaments described herein in combination with at least one additional agent selected from the group consisting of HMG-CoA reductase inhibitors (e.g. statins in their lactonized or open chain dihydroxy acid forms and salts and esters acceptable for pharmaceutical use thereof, including, but not limited to, lovastatin; simvastatin; simvastatin form of open-chain dihydroxy acid, in particular the calcium or ammonium salts thereof; pravastatin, in particular the sodium salt thereof; fluvastatin, in. particularly the sodium salt thereof; atorvastatin, in particular the calcium salt thereof; nisvastatin, also called NK-104; rosuvastatin); agents that have both lipid modifying effects and other pharmaceutical activities; inhibitors of HMG-CoA synthase; inhibitors of cholesterol absorption such as ezetimibe; Cholesterol ester transfer protein (CETP) inhibitors, for example JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalene synthetase inhibitors (also called squalene synthase inhibitors); inhibitors of acyl-coenzyme A: cholesterol acyltransferase (ACAT) which include selective inhibitors of ACAT-1 or ACAT-2 and thus also dual inhibitors of ACAT-1 and-2; inhibitors of the microsomal triglyceride transfer protein (MTP); probucol; niacin; bile acid sequestrants; inducers of the LDL receptor (low density lipoprotein); inhibitors of platelet aggregation, for example glycoprotein fibrinogen receptor antagonists llb / llla and aspirins; agonists of the human peroxisome proliferator-activated gamma receptor (PPARy), which include the compounds commonly referred to as glitazones, for example troglitazone, pioglitazone and rosiglitazone and which include those compounds included within the structural class known as thiazolidinediones as well as those agonists of . PPARy outside the structural class of the thiazolidinediones; PPARα agonists such as clofibrate, fenofibrate including micronized fenofibrate, and gemfibrozil; dual agonists a /? of PPAR such as 5 - [(2,4-dioxo-5-thiazolidinyl) metill-2-methoxy] - N - [[4- (trifluoromethyl) phenyl] rnetyl-benzamide, known as KRP-297; vitamin B6 (also known as pyridoxine) and salts acceptable for pharmaceutical use thereof such as the salt of HCI; vitamin B12 (also known as cyanocobalamin); folic acid or a salt or ester acceptable for pharmaceutical use thereof such as the sodium salt and the methylglucamine salt; antioxidant vitamins such as vitamin C and E and beta carotene; beta blockers; angiotensin II antagonists such as losartan; angiotensin-converting enzyme inhibitors such as enalapril and captopril; Geldo channel blockers such as nifedipine and diltiazam; endotelian antagonists; agents that increase the expression of the ABCT gene; FXR and LXR ligands that include both inhibitors and agonists; bisphosphonate compounds such as sodium alendronate; and inhibitors of cyclooxygenase-2 such as rofecoxib and celecoxib. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, such as stroke therapy, comprise administering to a patient compounds, pharmaceutical compositions, or medicaments described herein. in combination with at least one additional agent selected from the group consisting of COX-2 inhibitors; inhibitors of nitric oxide synthase, such as N- (3- (aminomethyl) benzyl) acetamidine; inhibitors of Rho kinase, such as fasudil; angiotensin II type-1 receptor antagonists, including candesarten, losartan, irbesarten, eprosartan, telmisarten and valsarten; inhibitors of glycogen synthase kinase 3; sodium or calcium channel blockers, including crobenetin; inhibitors of p38 MAP kinase, which include SKB 239063; thromboxane AX synthetase inhibitors, including isbogrel, ozagrel, ridogrel and dazoxiben; Statins (HMG CoA reductase inhibitors), which include lovastatin, simvastatin, simvastatin in the form of dihydroxy-open-chain acid, pravastatin, fluvastatin, atorvastatin, nisvastatin, and rosuvastatin; neuroprotectors, including free radical scavengers, calcium channel blockers, promoter amino acid antagonists, growth factors, antioxidants, such as edaravone, vitamin C, TROLOX ™, citicoline and minicillin, and reactive astrocyte inhibitors, such as acid ( 2R) -2-propyloctanoic; beta-adrenergic blockers, such as propranolol, nadolol, timolol, pindolol, labetalol, metoprolol, atenolol, esmolol and acebutolol; NMDA receptor antagonists, including memantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists; fibrinogen platelet receptor antagonists, including tirofiben and lamifiban; thrombin inhibitors; anti-thrombotic, such as argatroben; anti-hypertensive agents, such as enalapril; vaso-dilators, such as cycllandelate; Nociceptin antagonists; DPIV antagonists; GABA 5 inverse agonists; and selective androgen receptor modulators. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, such as pulmonary fibrosis therapy, comprise administering to a patient compounds, pharmaceutical compositions, or medicaments described in present in combination with at least one additional agent selected from the group consisting of anti-inflammatory agents, such as corticosteroids, azathioprine or cyclophosphamide. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, such as interstitial cystitis therapy, comprise administering to a patient compounds, pharmaceutical compositions, or medicaments described in present in combination with at least one additional agent selected from the group consisting of dimethyl sulfoxide, omalizumab, and pentose polysulfate. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, such as the therapy of toilet disorders, comprise administration to a patient of compounds, pharmaceutical compositions, or medicaments described in present in combination with at least one additional agent selected from the group consisting of minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analogues, and cathepsin K inhibitors. Treatment of diseases or diseases based on Leukotrienes using CysLT1 Receptor Antagonists / CysLT2 According to another aspect, the compositions and methods described herein are designed to deliver a dual antagonist of the CysLTI / CysLT2 receptor to block the activity of the CysLT receptor. The term "CysLT antagonist" or "CysLT receptor antagonist" or "leukotriene receptor antagonist" refers to a therapy that decreases the serialization of CysLTs through the CysLT receptors. Commonly CysLT refers to LTC4, LTD4 or LTE4. Cysteinyl leukotrienes are powerful constrictors of the smooth muscle, particularly in respiratory and circulatory systems. These are measured by at least two cellular receptors, CysLTI and CysLT2. The CysLTI receptor and the CysLT2 receptors are G-protein coupled receptors with seven putative transmembrane regions and an intracellular domain that interacts with G proteins, Evans, et al., Prostaglandins and Other Lipid Mediators, 68-69, p587 -597, (2002). Examples of dual antagonists of the CysLT1 / CysLT2 receptor BAY u9773, Cuthbert et al. EP 00791576 (published August 27, 1997), DUO-LT (Galczenski et al., D38, Poster F4 presented in American Thoracic Society, May 2002) and Tsuji et al., Org. Biomol. Chem., 1, 3139-1141, 2003. In certain embodiments, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions include the administration to patients of compounds, pharmaceutical compositions, or medicaments comprising a CysLTI / CysLT2 receptor antagonist. By way of example, the compounds, pharmaceutical compositions, or medicaments can be used as treatment and / or prevention for respiratory diseases including, but not limited to, chronic stable asthma. Diagnostic Methods for Patient Identification Monitoring of "patients with a response to leukotrienes" that can be selected for treatment with compounds of any formula (A), formula (B), formula (C), formula (D), formula ( F) or formula (H), or pharmaceutical compositions to medicaments described herein that include compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or other FLAP modulators, can be achieved using techniques and methods described herein. Techniques and methods include, for example, haplotype evaluation of the gene (analysis of genotypes), monitoring / measurement of biomarkers (analysis of phenotypes), monitoring / measurement of functional markers (analysis of phenotypes), which indicate the response of the patient to known modulators of the leukotriene pathway, or any combination thereof. Genotype Analysis: FLAP polymorphisms Human FLAP has been purified and cloned and is a 18 kilodalton membrane-bound protein that is mostly expressed in human neutrophils. The FLAP gene is located in i3 i2 and the gene has been linked to an increased risk of myocardial infarction and stroke in several populations. A number of polymorphisms and haplotypes in the gene encoding FLAP have been identified in individuals (U.S. Patent Application 2005113408; Sayers, Clin. Exp. Allergy, 33 (8): 103-10, 2003; Kedda, et al., Clin. Exp. Allergy, 35 (3): 332-8, 2005). HE. have linked particular haplotypes of FLAP to myocardial infarction and stroke in several populations (Helgadottir A of al., Nature Genet, 36: 233-239 (2004), Helgadottir A, et al., Am J Hum Genet 76: 505-509 (2004); Lohmussaar E et al., Stroke 36: 731-736 (2005); Kajimoto K of al. Ciro J 69: 1029-1034 (2005). Previously, it has been shown that polymorphisms in certain genes correlate with the response to therapies. given, for example the response of cancers to particular chemotherapeutic agents (Erichsen, et al., Br. J. Cancer, 90 (4): 747-51, 2004; Sullivan, et al., Oncogene, 23 (19): 3328 -17, 2004.) Therefore, patients under consideration for treatment with the novel FLAP inhibitors described herein, or combinations of drugs including novel FLAP inhibitors, can be monitored to determine the potential response to treatment based on their FLAP polymorphisms, or haplotypes. Any of the synthetic or signaling genes dedicated to the leukotriene pathway could determine a patient that had more or less response to leukotriene modulator therapy (both FLAP or 5-LO inhibitors and leukotriene receptor antagonists). The genes dedicated to the leukotriene pathway are those of 5-lipoxygenase, 5-lipoxygenase activation protein, LTA4 hydrolase, LTC4 synthase, LTB4 receptor 1 (BLT1), LTB4 receptor 2 (BLT2), cysteinyl-1 receptor leukotrienes (CysLTIR), cysteinilleucotriene receptor 2 (CysLT2R). For example, the 5-LO gene has been linked to asthma intolerant to aspirin and to hyper-responsiveness of the airways (Choi JH et al Hum Genet 114: 337-144 (2004); Kim, SH et al., Allergy 60: 760-765 (2005) It has been shown that genetic variants in the 5-LO promoter region predict clinical responses to a 5L0 inhibitor in asthmatics (Drazen et al., Nature Genetics, 22, p168-170, (1999) The LTC4 synthase gene has been linked to atopy and asthma (Moissidis et al., Genet Med 7: 406-410 (2005).) The CysLT2 receptor has been linked to asthma and atopy (Thompson MD et al Pharmacogenetics 13: 641-649 (2003), Pillai SG et al Pharmacogenetics 14: 627-633 (2004), Park JS et al Pharmacogenet Genomics 15: 483-492 (2005), Fukai H et al Pharmacogenetics 14: 683-690 (2004) .Any polymorphism in any gene of the leukotriene pathway or combination of polymorphisms or haplotypes could result in altered sensitivity of the patient to targeted therapy to reduce cir the pathological effects of leukotrienes. The selection of the patients that could respond better to the leukotriene modulator therapies described herein may include knowledge of polymorphisms in the leukotriene pathway genes and also knowledge of the expression of mediators managed by leukotrienes. The selection of patients could be made based only on the genotype of the leukotriene pathway, only the phenotype (biomarkers or functional markers) or any combination of genotype and phenotype. A "haplotype," as described herein, refers to a combination of genetic markers ("alleles"). A haplotype may comprise one or more alleles (eg, a haplotype containing a single SNP), two or more alleles, three or more alleles, four or more alleles, or five or more alleles. Genetic markers are particular "alleles" in "polymorphic sites" associated with FLAP. A nucleotide position in which more than one sequence is possible in a population is referred to herein as the "polymorphic site." When a polymorphic site is a single nucleotide in length, the site is called a single nucleotide polymorphism ("SNP"). For example, if in a particular chromosomal location, a member of a population has an adenine and another member of the population has a thymine in the same position, then this position is a polymorphic site, and, more specifically, the polymorphic site is a SNP. Polymorphic sites can tolerate differences in sequences based on substitutions, insertions or deletions. Each version of the sequence with respect to the polymorphic site is referred to herein as the "allele" of the polymorphic site. Thus, in the previous example, the SNP allows an adenine allele and a thymine allele. Commonly, a reference sequence refers to a particular sequence. Alleles that differ from the reference are called "variant" alleles. The term "FLAP variant" as used herein, refers to a sequence that differs from a reference FLAP sequence, but is otherwise substantially similar. The genetic markers that make up the haplotypes described herein are variants of FLAP. In certain embodiments, the FLAP variants are at least approximately 90% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 91% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 92% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 93% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 94% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 95% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 96% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 97% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 98% similar to a reference sequence. In other embodiments, the FLAP variants are at least approximately 99% similar to a reference sequence. In addition, in certain embodiments the FLAP variants differ from the reference sequence in at least one base, while in other embodiments the FLAP variants differ from the reference sequence in at least two bases. In other embodiments the FLAP variants differ from the reference sequence in at least three bases, and in still other embodiments the FLAP variants differ from the reference sequence in at least four bases. Additional variants may include changes that affect a polypeptide, for example the FLAP polypeptide. The polypeptide encoded by a reference nucleotide sequence is the "reference" polypeptide with a particular reference amino acid sequence, and the polypeptides encoded by allele variants are referred to as "variants" of polypeptides with amino acid sequence variants. Differences in the FLAP sequence of the nucleic acid, when compared to a reference nucleotide sequence, can include the insertion or deletion of a single nucleotide, or more than one nucleotide, resulting in a change in structure; the change of at least one nucleotide, which results in a change in the encoded amino acid; the change of at least one nucleotide, which results in the generation of a premature arrest cation; the deletion of several nucleotides, which results in the deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or conversion of the gene, which results in an interruption of the encoded sequence; the duplication of an entire sequence or part; the transposition; or a rearrangement of a sequence of a nucleotide, as described in detail previously. Changes in the sequence alter the polypeptide encoded by a FLAP nucleic acid. For example, if the change in the nucleic acid sequence causes a change in structure, the change in structure may result in a change in the encoded amino acids, and / or may result in the generation of a premature stop codon, causing generation of a truncated polypeptide. By way of example, a polymorphism associated with a susceptibility to myocardial infarction (MI), acute coronary syndrome (ACS), stroke, or peripheral arterial occlusive disease (PAOD) may be a synonym change in one or more nucleotides (i.e. a change that does not result in a change in the amino acid sequence). Such a polymorphism can, for example, after the splice sites, decrease or increase the expression levels, affect the stability or transport of the mRNA, or otherwise affect the transcription or translation of the polypeptide. The haplotypes described below are found more frequently in individuals with MI, ACS, stroke or PAOD than in individuals without MI, ACS, stroke or PROD. Therefore, these haplotypes can have predictive values to detect a susceptibility to MI, ACS, stroke or PAOD in an individual. Numerous variants of the FLAP gene have been reported to correlate with the incidence of myocardial infarction in patients (Hakonarson, JAMA, 293 (18): 2245-56, 2005), and FLAP gene markers associated with risk have been described. of developing asthma in US Patent 6531279. Methods for identifying variants of FLAP sequences are described in, for example, US Publication No. 2005/0113408, and in US Patent No. 6531279, incorporated herein by reference. its entirety as a reference. By way of example only, a haplotype associated with a susceptibility to myocardial infarction or stroke comprises markers SG13S99, SG13S25, SG13S377, SG13S106, SG13S32 and SG13S35 at loci 13q12-13. 0, the presence of alleles T, G, G, G, A and G in SG13S99, SG13S25, SG13S377, SG13S106, SG13S32 and SG13S35, respectively (the B6 haplotype), is diagnostic of susceptibility to myocardial infarction or stroke. Or, a haplotype associated with a susceptibility to myocardial infarction to apoplexy comprises markers SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42 at loci 13q12-13. Or, the presence of alleles T, G, G, G and A at SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42, respectively (the B5 haplotype), is diagnostic of susceptibility to myocardial infarction or stroke. Or, a haplotype associated with a susceptibility to myocardial infarction or stroke comprises the markers SG13S25, SG13S106, SG13S30 and SG13S42 at locus 13q12-13 locus. Or, the presence of alleles G, G, G and A in SG13S25, SG13S106, SG13S30 and SG13S42, respectively (the B4 haplotype), is diagnostic of susceptibility to myocardial infarction or stroke. Or, a haplotype associated with a susceptibility to myocardial infarction or stroke comprises markers SG13S25, SG13S106, SG13S30 and SG13S32 at loci 13q 12-13. 0, the presence of alleles G, G, G and A in SG13S25, SG13S106, SG13S30 and SG13S32, respectively (the Bs4 haplotype), is a diagnosis of susceptibility to myocardial infarction or stroke. In the recently described modalities, patients under consideration for treatment with compounds of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), or combinations of drugs described in present that include compounds of any formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), can be monitored to determine the potential response to treatment with compounds of either of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), based on the haplotypes.
By way of example only, a haplotype associated with a susceptibility to myocardial infarction or stroke comprises the markers SG13S99, SG13S25, SG13S114, SG13S89 and SG13S32 at loci 13q 12-13. Or, the presence of the T, G, T, G and A alleles in SG13S99, SG13S25, SG13SÜ4, SG13S89 and SG13S32, respectively (the A4 haplotype), is diagnostic of susceptibility to myocardial infarction or stroke. Or, a haplotype associated with a susceptibility to myocardial infarction or stroke comprises the markers SG13S25, SG13S114, SG13S89 and SG13S32 at loci 13q12-13. Or, the presence of alleles G, T, G and A in SG13S25, SG13SÜ4, SG13S89 and SG13S32, respectively (the A4 haplotype), is diagnostic of susceptibility to myocardial infarction or stroke. In the said recently described embodiments, patients under consideration for treatment with compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) ), or combinations of drugs described herein that include compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), can be monitored for determining the potential response to treatment with compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), based on the haplotypes. Haplotype detection can be achieved by methods known in the art to detect sequences in polymorphic sites, and therefore patients can be selected using FLAP genotype selection, 5-LO or other polymorphisms of the leukotriene pathway gene. The presence or absence of a polymorphism or gene haplotype of the leukotriene pathway can be determined by various methods, including, for example, the use of enzymatic amplification, restriction fragment length polymorphism analysis, nucleic acid sequencing, analysis electrophoretic nucleic acid of the individual, or any combination thereof. In certain embodiments, the determination of a SNP or haplotype can identify patients who will respond to, or obtain benefit from, treatment with compounds of any formula (A), formula (B), formula (C), formula (D), formula ( F) or formula (H). By way of example, the methods of diagnosing a susceptibility to myocardial infarction or stroke in an individual, comprise determining the presence or absence of certain single nucleotide polymorphisms (SNPs) or of certain haplotypes, where the presence of the SNP or the haplotype It is a diagnosis of susceptibility to myocardial infarction or stroke. Phenotype Analysis: Reactor Bioma Patients who are under consideration for treatment with compounds described herein or with combinations of drugs described herein that include compounds described herein, can be monitored to determine the potential response to treatment based on Inflammatory biomarkers of phenotype driven by leukotrienes. Patients undergoing monitoring based on inflammatory phenotype biomarkers managed by leukotrienes can be used as an alternative to, or may be complementary to, patient monitoring by detection of the haplotype of the leukotriene pathway gene. The term "biomarker" as used herein refers to a characteristic that can be measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacological responses to therapeutic intervention. Thus a biomarker can be any substance, structure or process that can be measured in the body, or its products, and that can influence or predict the incidence of the result or disease. Biomarkers can be classified into markers of exposure, effect and susceptibility. Biomarkers can be physiological assessment parameters, by way of example blood pressure, or may be analytical assessment parameters, for example blood glucose concentrations, or cholesterol. The techniques used to monitor and / or measure biomarkers include, but are not limited to, NMR, LC-MS, LC-MS / MS, GC-MS, GC-EP / MS, CLAR-MS, CLAR-MS / MS, FT-MS, FT-MS / E, ICP-MS, ICP-MS / MS, peptide / protein sequencing, nucleic acid sequencing, electrophoresis techniques, immunoassays, immunoblotting, in-situ hybridization, in-situ hybridization in situ by fluorescence, PCR, radio-immunoassays, and enzyme immunoassays. Single nucleotide polymorphisms (SNPs) have also been useful for the identification of biomarkers to determine the susceptibility to certain diseases and also the susceptibility or response to drugs such as chemotherapeutic agents and antiviral agents. These techniques, or any combination thereof, can be used to monitor patients to identify leukotriene-dependent or leukotriene-mediated diseases or conditions, where patients can be treated beneficially with the compounds of any of the formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H) described herein or combinations of drugs described herein including compounds of any of the formula (A), formula (B) , formula (C), formula (D), formula (F) or formula (H) described herein.
By way of example only, patients may be selected for treatment with compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described in present or combinations of drugs described herein that include compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein, by monitoring to identify increased blood inflammatory biomarkers such as, but not limited to, LTB4, LTC4, stimulated LTE4, myeloperoxidase (MPO), eosinophil peroxidase (EPO), C-reactive protein (CRP), soluble intracellular adhesion molecule (sICAM), chemo-attractive monocyte protein (MCP-1), monocyte inflammatory protein (MIP-la), interleukin-6 (IL-6), interleukin 4 activator of TH2 T (IL-4) cells, and 13 (IL-) 13) and other inflammatory cytokines. In certain embodiments, patients with inflammatory respiratory diseases, including, but not limited to, asthma and COPD, or with cardiovascular diseases, are selected as those most likely to respond to the inhibition of leukotriene synthesis using compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), by using a panel of inflammatory biomarkers driven by leukotrienes. Phenotype Analysis: Functional Markers Patients under consideration for treatment with compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein or combinations of drugs described herein that include compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described in the present, can be monitored to determine the response to known modulators of the leukotriene pathway. The monitoring of patients by evaluating functional markers as indicators of a patient 's response to known modulators of the leukotriene pathway can be used as an alternative to, or may be complementary with, the monitoring of. patients by detection of the gene haplotype of the leukotriene pathway (genotype analysis) and / or monitoring / measurement of biomarkers (phenotype analysis), monitoring / measurement of inflammatory biomarkers of phenotypes managed by leukotrienes. Functional labels may include, but are not limited to, any physical characteristic associated with a leukotriene-dependent condition or disease, or knowledge of current or past drug treatment regimens. By way of example only, the evaluation of lung volume and / or function can be used as a functional marker for leukotriene-dependent or leukotriene-mediated diseases or conditions, such as respiratory diseases. Pulmonary function tests can be used to monitor patients with such leukotriene-dependent or leukotriene-mediated diseases or conditions, for treatment using compounds of any of the formula (A), formula (B), formula (C), formula (D) , formula (F) or formula (H) described herein or pharmaceutical compositions or medicaments including compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein. Tests include, but are not limited to, assessment of lung volumes and capacities, such as tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume, inspiratory capacity, residual functional capacity, vital capacity, total lung capacity, respiratory minute volume , alveolar ventilation, maximum vital capacity, and ventilation capacity. The method of measuring lung volumes and capacities includes, but is not limited to, peak flow-volume curve expiratory, forced expiratory volume in 1 second (FEV1), maximum expiratory flow. In addition, other pulmonary function tests used as functional markers for patient evaluation described herein include, but are not limited to, respiratory muscle strength, maximal inspiratory pressure, maximal expiratory pressure, trans-diaphragmatic pressure, ventilation distribution, nitrogen simple aspiration, pulmonary nitrogen washing, and gas transfer.
Furthermore, knowledge of the current or past treatment regimen of a patient can be used as a functional marker to aid in the monitoring of patients for the treatment of leukotriene-dependent diseases or conditions using compounds of any of the formula (A), formula (B) ), formula (C), formula (D), formula (F) or formula (H) described herein or pharmaceutical compositions or medicaments including compounds of any of the formula (A), formula (B), formula (C) ), formula (D), formula (F) or formula (H) described herein. By way of example only, treatment regimens may include current or past treatments using zileuton (Zyflo ™), montelukast (Singulair ™), pranlukast (OnonTm), zafirlukast (Accolate ™). Also, patients who are under consideration for treatment with compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein or combinations of drugs described herein that include compounds of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein, can monitored to determine functional markers that intuit, but not limited to, reduced recruitment of eosinophils and / or basophils and / or neutrophils, and / or monocytes, and / or dendritic cells and / or lymphocytes, decreased mucosal secretion, decreased edema of the mucosa, and / or increased bronchodilation. Methods for the identification of a patient in need of treatment for leukotriene-dependent or leukotriene-mediated conditions or diseases, and exemplary, non-limiting treatment methods are shown in Figure 12, Figure 13 and Figure 14, where a sample is analyzed. of a patient and the information obtained is used to identify possible treatment methods. Those with experience in the art are expected to use this information in conjunction with information from another patient, which includes, but is not limited to, age, weight, sex, diet, and medical condition, to choose a treatment method. It is also expected that each piece of information will be given a particular weight in the decision process. In certain modalities, the information obtained from the diagnostic methods described above and any other patient information, including, but not limited to, age, weight, sex, diet, and medical condition, are incorporated into an algorithm used to elucidate a method of treatment, where each piece is given a particular weight in the decision process. In certain embodiments, the sample from a patient is analyzed to determine the haplotypes of the leukotriene gene, for example only haplotypes of FLAP, and the information obtained identifies a patient in need of treatment using various treatment methods. Methods of treatment include, but are not limited to, administering an effective amount for therapeutic use of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein or pharmaceutical composition or medicament including a compound of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein, administering an effective amount for therapeutic use of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described in present or pharmaceutical composition or medicament including a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F). or formula (H) described herein, in combination with an effective amount for therapeutic use of a leukotriene receptor antagonist (by way of example, CysLTI / CysLT2 antagonist or CysLTI antagonist), or administering an effective amount for use Therapeutic of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein, or pharmaceutical composition or medicament that includes a compound of any of formula (A), formula ( B), formula (C), formula (D), formula (F) or formula (H) described herein, in combination with an effective amount for therapeutic use of another anti-inflammatory agent. In other embodiments, a sample from a patient is analyzed to determine the leukotriene deficient haplotypes, for example only FLAP haplotypes, and / or biomarkers of phenotypes, and / or functional responses of the phenotype marker to modifying agents. Then, the patient can be treated using various methods of treatment. Methods of treatment include, but are not limited to, administering an effective amount for therapeutic use of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein or pharmaceutical composition or medicament including a compound of any of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein, administering an effective amount for therapeutic use of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described in present or pharmaceutical composition or medicament including a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein, in combination with an effective amount for therapeutic use of a leukotriene receptor antagonist (by way of example, antagonist of CysLTI / CysLT2 or CysLTI antagonist), or administering an effective amount for therapeutic use of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described herein or medicament pharmaceutical composition including a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H) described in present, in combination with an effective amount for therapeutic use of another anti-inflammatory agent. In still other embodiments, a sample from a patient is analyzed to determine haplotypes of the leukotriene gene, by way of example only FLAP haplotypes, and biomarkers of phenotypes, and / or functional responses of the marker of phenotypes to modifying agents. Then, the patient can be treated using various methods of treatment. Methods of treatment include, but are not limited to, administering an effective amount for therapeutic use of a FLAP inhibitor, or a pharmaceutical composition or medicament that includes a FLAP inhibitor, administering an effective amount for therapeutic use of a FLAP inhibitor, or a pharmaceutical composition or medicament that includes a FLAP inhibitor, in combination with an effective amount for therapeutic use of a leukotriene receptor antagonist (by way of example, CysLTI / CysLT2 antagonist or CysLTI antagonist), or administering an amount effective for therapeutic use of a FLAP inhibitor, or pharmaceutical composition or medicament that includes a FLAP inhibitor, in combination with an effective amount for therapeutic use of another anti-inflammatory agent. Equipment / Articles of Manufacture For use in the therapeutic applications described herein, equipment and articles of manufacture are also described herein. Such equipment may comprise a carrier, package, or container having compartments for receiving one or more containers such as flasks, tubes, and the like, each of the containers comprising one of the separate elements for use in a method described herein. . Suitable containers include, for example, bottles, flasks, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic. For example, the container (s) may comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container (s) optionally has a sterile access port (for example, the container may be a bag or fresh intravenous solution having a filler that can be punctured by a hypodermic injection needle). Such equipment optionally comprises a compound with an identification description or label or instructions that relate to its use in the methods described herein. Commonly, a kit can comprise one or more additional containers, each with one or more of several materials (such as reagents, optionally in concentrated form, and / or devices) convenient from the user and commercial point of view for the use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; labels of carrier, package, container, fresh and / or tube that mention the content and / or instructions for use, and package leaflets with instructions for use. Commonly, a set of instructions is also included. A label may be on or associated with the container. A label can be ester on a container when letters, numbers or other characters that form the label adhere, mold or engrave on the container itself; An ester label may be associated with a container when it is present within a receptacle or carrier that also holds the container, eg, a package insert. A label may be used to indicate that the contents should be used for a specific therapeutic application. The label may also indicate instructions for the use of the content, as in the methods described herein. Examples These examples are given for illustrative purposes only and do not limit the scope of the claims provided herein. Preparation of intermediates used in the synthesis of compounds of formula (A), formula (B), formula (C), formula (O), formula (F) and formula (H) The starting materials and intermediates used in the synthesis of the compounds of Formula (A), formula (B), formula
(C), formula (D), formula (F) and formula (H) are commercially available or can be synthesized by methods known in the art or described herein. The preparation of intermediates, such as, for example, those shown in Table 6, which are used herein and are not commercially available, are described below. Other intermediates that are not specifically mentioned herein and are used in the synthesis of the compounds of formula (A), formula (B), formula (C), formula (D), formula (F) and formula (H), they can be prepared using the methods described herein or known in the art. Table 7. Intermediates used in the synthesis of the compounds of formula (A), formula (B), formula (C), formula
(D), formula (F) and formula (H)
Via 1: Step 1: Protection with BOC (lnt-10) The 3-azetidinecarboxylic acid (Sigma Aldrich, 0.25 g, 2.5 mmol) was dissolved in tBuOH (5 mL) and 1N NaOH (2.7 mL, 2.7 mmol). Di-tert-butyl dicarbonate (0.59 g, 2.7 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction was diluted with water, acidified slowly to pH 4 with 1 NCI NCI, and the mixture was extracted with EtOAc until all the product was removed from the aqueous layer by ninhydrin stain. The combined organic layers were dried, filtered, and concentrated to give the desired product. Step 2: Reduction with borane (lnt-10) The acid from step 1 (0.7 g, 3.5 mmol) was dissolved in THF and cooled to 0 ° C in N2. Borane-THF complex was added to the solution, and the reaction was stirred at room temperature overnight. The reaction was cooled to 0 ° C and quenched with water. The mixture was extracted 3 times with EtOAc, the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was filtered through a plug of silica gel and eluted with EtOAc to give the desired compound. Step 3a: Bromide formation with Br2 (lnt-10) Triphenylphosphine (1.7 g, 6.5 mmol) was dissolved in DMF and cooled to 0 ° C. Bromine (0.31 mL, 5.9 mmol) was added slowly, and the solution was stirred for 30 minutes. The alcohol from step 2 (0.32 g 2.0 mmol) was added in DMF and the reaction was stirred at room temperature overnight. The mixture was diluted with water, extracted 3 times with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was filtered through a plug of silica gel and eluted with EtOAc to give the desired compound. Step 3b: Formation of iodide with 12 (lnt-73) (6-Bromo-pyridin-1-yl) -methanol (0.5 g, 2.7 mmol) was dissolved in toluene (20 mL). Triphenylphosphine (0.9 g, 3.5 mmol) and imidazole (0.4 g, 6.0 mmol) were added, followed by a solution of iodine (0.88 g, 3.5 mmol) in toluene dropwise. The reaction was stirred at room temperature for 15 minutes, and then vened in aq Na2CO3. saturated. The organic layer is washed with sodium thiosulfate aq, water, then dried over MgSO4, concentrated. The crude material was purified on silica gel (Gradient EtOAc: hexanes) to give the desired product. Step 3c: Tosylation (lnt-21) (S) - (+ 1 - (tert-butoxycarbonyl) -2-pyrrolidinemethanol (1.0 g, 5.0 mmol) was dissolved in pyridine (3 mL), and toiuensulfonyl chloride (1.0) was added. g, 5.5 mmol) The reaction was stirred overnight at room temperature, and diluted with water and extracted with EtOAc The combined organic layers were washed with water, dried over MgSO 4, filtered, and concentrated. residue was purified on silica gel (0 to 10% EtOAc in hexanes) to give the desired product Step 3d: Mesylation (lnt-55) (R) -alpha-methyl-2-pyridinemethanol (1.0 g, 8.1 mmol) in CH 2 Cl 2 (20 mL) and cooled to 0 ° C. Triethylamine (1.7 mL, 12.2 mmol) was added, followed by methanesulfonyl chloride (0.66 mL, 8.4 mmol) dropwise. for 30 minutes, and then diluted with CH2Cl2, washed with water, dried over MgSO4, filtered, and concentrated to obtain the desired product. Lane 2: Step 1: Amide formation (lnt-19) Cyclopropylamine (0.35 ml, 5.0 mmol) and triethylamine (0.7 ml, 5.1 mmol) were dissolved in CH2Cl2 (10 ml). The reaction was cooled to -10 ° C and chloroacetyl chloride (0.4 mL, 5.0 mmol) was added dropwise. The reaction was cooled to -10 ° C for 1 hour, then at room temperature for 2 hours, followed by quenching with water. The aqueous layer was extracted with CH2Cl2, and the organic layers were dried, filtered, and concentrated to give the desired product. Track 3: Step 1: Mine formation (lnt-20) Chloroacetonitrile (0.5 g, 6.6 mmol) was dissolved in Et20 (10 mL) and cooled to 0 ° C. EtOH (0.43 mL, 7.3 mmol) was added, followed by 4 N HCl in 1,4-dioxane (15 mL, 59.6 mmol). The reaction is stirred at 0 ° C for 4 days, and then concentrated to give the desired product as a white solid. Step 2: Delation (lnt-20) The mine from step 1 (0.3 g, 2.0 mmol) was dissolved in EtOH (4 mL) and cooled to 0 ° C. 1,3-Diaminopropane (0.17 mL, 2.0 mmol) was added, followed by iPr2NEt (0.35 mL, 2.0 mmol). The reaction was stirred at 0 ° C for 2 hours, and then 4N HCl in 1,4-dioxane (0.5 ml, 2 mmol) was added. The mixture was filtered, and the filtrate was concentrated to give the desired product. Via 4: Step 1: Oxidation with mCPBA (lnt-46) 2,5-lutidine (5.0 g, 46.7 mmol) was dissolved in CHCl 3 (125 mL) and cooled to 0 ° C. M-chloroperoxybenzoic acid (70%) was added; 13.9 g, 55.2 mmol), and the reaction is stirred overnight at room temperature. The mixture was washed with aq Na2CO3.
Saturated, dried over Na2SO4, filtered, and concentrated to give the desired product. Step 2: Acetylation (nnt-46) The N-oxide from step 1 (46.7 mmol) was dissolved in anhydride
acetic acid (25 ml) and heated to reflux at 100 ° C for one hour. The mixture was cooled to room temperature, and ethanol (46.7 mmol) was slowly added to quench the reaction. The solution was evaporated to dryness and purified on silica gel to give the desired product. K) Step 3: Hydrolysis (nt-46) The acetate from Step 2 (46.7 mmol) was dissolved in concentrated HCl (20 mL) and refluxed for 1 hour. The reaction was cooled and evaporated to dryness to give an orange solid, which is used) directly in the next
I5 reaction. Step 4: Formation of chloride with SOCI2 (lnt-46) The alcohol from step 3 (1.0 g, 8.1 mmol) was dissolved in thionyl chloride (3 mL) and stirred at room temperature for 30 minutes in N2. The mixture was evaporated to dryness
to give the desired product in the form of a hydrochloride salt, which is used directly in subsequent reactions. Lane 5: Step 1: Condensation (lnt-60) p-Toluidine (10 g, 60.0 mmol) and triethylamine 25 (8.4 mL, 60.3 mmol) were dissolved in CH 2 Cl 2 (200 mL) at room temperature.
Cinnamoyl chloride (6.5 g, 60.7 mmol) was added, and the reaction was stirred for 1 hour. The reaction was washed with water, dried, filtered and concentrated. To the residue was added aluminum chloride (5 g, 37.5 mmol), which was heated clean. After 45 minutes, ice was added to form a precipitate. The mixture was stirred overnight at room temperature. The precipitate was then filtered and dissolved in CH2Cl2, washed with 1N HCl, brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from ethanol to give the desired quinolinone product. Step 2: Chloride formation with POCI3 (lnt-60) The quinolinone from step 1 (3.12 g, 19.6 mmol) was heated to 90 ° C in POCI3 (10 mL). Once the starting material was finished, the reaction was cooled and concentrated. The residue was diluted with EtOAc and aq NaHCO 3. saturated, and the aqueous layer was extracted with EtOAc. The combined organics were dried, filtered, and concentrated to give the product chloroquinoline. Step 3a: Bromide formation with NBS (Alkyl) (in-60) The quinoline from step 2 (19.6 mmol) was heated to 80 ° C for 1 hour in benzene (200 ml) with NBS (3.6 g, 20.2 mmol) and catalytic benzoyl peroxide. The reaction mixture was concentrated and purified on silica gel to give the desired product. Step 3b: Bromide formation with NBS (Aryl) (lnt-118) 2-Aminopyrazine (4 g, 42 mmol) was dissolved in water (2 ml) and DMSO (70 ml), and NBS (7.5 g, 42 g) was added. mmol) for 1 hour at 0 ° C. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into ice and extracted 4 times with EtOAc. The combined organic layers were washed with 5% Na 2 CO 3, water, and brine, dried over MgSO 4, filtered, and concentrated. The residue was purified on silica gel to give the desired product. Step 3c: Formation of chloride with NCS (lnt-50) 2-Fluoro-6-methy1pyridine (1.11 g, 10 mmol), NCS (2.0 g, 15 mmol), and catalytic benzoyl peroxide were dissolved in benzene and heated to reflux overnight. The reaction is concentrated and diluted with water and. EtOAc. The organic layer was washed with aq. NaHCO 3. saturated, dried, filtered, and concentrated. The residue was purified on silica gel to give the desired product. Route 6: Step 1: Suzuki coupling (lnt-71) To (4-hydroxymethylphenyl) boronic acid (Combi-Blocks, 1.0 g, 6.6 mmol) in DME / H20 (16 ml, 2: 1) 2-bromothiazole was added (1.2 g, 7.2 mmol) and K2CO3 (2.7 g, 19.7 mmol). The reaction was degassed with N2 for 20 minutes. Pd (PPh3) 4 (0.76 g, 0.7 mmol) was added and the reaction was subsequently degassed for 10 minutes. The reaction was then heated to 90 ° C overnight in N2, LCMS confirmed the formation of the product. The reaction was partitioned between water and EtOAc and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on silica gel (Gradient EtO Ac: hexane) to give the desired product. Step 2a: F-Alkylation (lnt-71) Thiazole was dissolved from step 1 (0.35 g, 1.8 mmol) in THF (15 mL) and cooled to -78 ° C in N2, n-butyllithium (1.6 M) was added.; 4.6 ml, 7.3 mmol) dropwise, followed by NFSi (1.2 g, 3.7 mmol). The reaction was warmed to -78 ° C with NH4CI aq. saturated, and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel to give the desired compound. Step 2b: Me-Alkylation (lnt-72) The thiazole from step 1 (0.33 g, 1.7 mmol) was dissolved in THF (15 mL) and cooled to -78 ° C in N2, n-butyllithium (1.6 M; 4.3 mL, 6.7 mmol) dropwise, followed by iodo-methane (0.16, 2.6 mmol). The reaction was warmed to -78 ° C with NH4CI aq. saturated, and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organics were dried over gSO, filtered, and concentrated. The residue was purified on silica gel to give the desired compound. Lane 7: Step 1: Formation of acid chloride (Int 135) 3-Phenoxy-benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH2Cl2, oxalyl chloride (0.32 g, 0.25 mmol) was added, followed by 1- 2 cats of DMF. The reaction was stirred at room temperature, and then concentrated to give the desired acid chloride. Via 8: Step 1: Alkylation (nnt-5) To midazole (0.41 g, 6.0 mmol) in CH 2 Cl 2 was added bromoacetonitrile (0.21 g, 2.0 mmol), and the reaction was refluxed for 30 minutes. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated to give the desired product. Via 9: Step 1: Methylation (nnt-74) To 4-m-tolyl-trahydro-pyran-4-ol (2.5 g, 13.0 mmol) in THF (50 mL) was added sodium hydride (60%; 0.8 g , 20.0 mmol) at room temperature. Iodine-methane (1.25 ml, 20 mmol) was added, and the reaction was stirred for 1 hour. The mixture was warmed with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO 4, filtered, and concentrated. The residue was purified on silica gel to give the desired compound. Lane 10: Step 1: Bromination To 4,4-dimethyl-pentan-2-one (3.7 mL, 26.3 mmol) in MeOH (2.8 mL) at 0 ° C was added bromine (1.34 mL, 26.3 mmol) in a single stream . The reaction was slowly warmed to 10 ° C for 30 minutes to initiate the reaction, and then stirred at room temperature for another 15 minutes. The reaction is diluted with water and diethyl ether, and the aqueous layer is extracted with diethyl ether three times. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product as a colorless liquid. Step 2: A thiol solution The bromide from step 1 (26.3 mmol) was dissolved in THF (50 ml), and the mixture was cooled to 0 ° C. 2-Methyl-2-propanothiol (2.45 mL, 21.6 mmol) was added, followed by triethylamine (7.9 mL, 56.8 mmol). The reaction was stirred at room temperature for 18 hours, then diluted with water. The aqueous layer was extracted with diethyl ether, and the combined organic layers were dried over MgSO, filtered, and concentrated to give the desired product. It is a reation to A:
het-X - c H x Pd (PPh3), f K ~ X = Bf OB (OM) j Example 1: 3- [3-tert-butylsulfanyl-1 - [4- (6-methoxy-pyridin-1-y ) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-maol-2-yl] -2, 2-dimethyl-propionic acid. Step 1: N- [4- (pyridin-2-itmethoxy) -phenyl] -acetamide A mixture of 4-acetamidophenol (Sigma-Aldrich; 73.6g), 2-chloromethylpyridine hydrochloride (80g) and cesium carbonate (320g) ) in DMF (1 L) was stirred at 70 ° C for 2 days. The mixture was cooled, water was poured (2L) and extracted with EtOAC (x6). The organic layers were washed with brine, dried (MgSO 4) and filtered to give a tan solid (A-1, 114g) which was used as such in the next step. Step 2: Hydrochloride 4- (pyridin-2-methoxy) phenylamine A-1 (114 g) was dissolved in EtOH (IL) and to this was added KOH (50 g) in water (200 ml). The solution was heated to 110 ° C for 2 days, KOH (20 g in 100 ml water) was added and the mixture was heated for 2 days. The solution was cooled, the EtOH was removed in vacuo and the residue was partitioned between EtOAc and water. After extraction of the water with EtOAc (x3), the organic layers were washed with brine, dried (MgSO4) and filtered. To this solution, saturated HCl in EtOAc was added and a precipitate formed immediately. Collection of the residues by filtration followed by vacuum drying gave the title compound (A-2, 95 g) as a pink colored solid. Step 3: [4- (pyridin-2-ylmethoxy) -phenyl] -h-drazine dihydrochloride
A-2 (95 g) was dissolved in water (1 L) at 0 ° C and to this was added NaN02 (26 g) in water (100 ml). The diazonium salt was formed for 45 minutes and then poured slowly for 15 minutes in a rapidly stirred mixture of Na2S204 (350 g) in water (1 l_) and ether (1 L) at 0 ° C. Stirring was continued for 40 minutes then the mixture was made basic using KOH conc. After extraction using EtOAc (x2) the organic layers were washed with water, then brine, dried (MgSO4) and filtered. To this solution was added saturated HCl in EtOAc and a precipitate formed immediately. Collection of the residues by filtration followed by vacuum drying gave the title compound as a tan solid (A-1, 75g). Step 4: 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indole-241 J-2, 2-dimethyl-propionic acid ethyl ester, A-3 (75 g), Ethyl 5- (t-butylthio) -2,2-dimethyl-4-oxo-pentanoate (prepared according to the procedures described in U.S. Patent 5,288,743 published February 22, 1994; 64 g, NaOAc (40 g) in toluene (800 ml) and HOAc (400 ml) was stirred at room temperature for 3 days, the mixture was poured into water and made basic with solid Na 2 CO 3 The mixture was extracted with EtOAc (x3), then washed with water (x2), brine, dried (MgSO4), filtered and concentrated to give a dark red-black oil, column chromatography of the mother liquor (silica gel packed in hexanes, eluting with hexane then hexane-EtOAc). 9: 1 raising to 4: 1) gave 68 g of the title compound (A-4), as a yellow solid Step 5: Ethyl 3- [3-tert-butylsulfanyl-1 - [4 - (6-methoxy-pyridin-1-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indol-2-yl] -2,2-dimethyl-propionic Ethyl 3- [3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - ethyl ester was dissolved 2,2-dimethylpropionic (A-4; 20.0 g, 45.4 mmol) in DMF (150 ml) and cooled to -10 ° C in N2, added sodium hydride (60% dispersion in mineral oil, 2.0 g, 50.0 mmol) in portions, and the reaction it was stirred at -10 ° C for 45 minutes until the foam disappeared. To this dark brownish-red solution was added 4- (6-methoxy-pyridin-14) -benzyl ester of methanesulfonic acid (lnt-72; 16.0 g, 54.5 mmol) in DMF dropwise. The reaction was then stirred at -10 ° C for 1 hour and allowed to warm to room temperature slowly. After 16 hours, the LCEM confirmed the formation of the product. The reaction was warmed with saturated NH 4 Cl and diluted with methyl tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude product was purified by column chromatography to give the desired product (A-5). Step 6: 3- [3-tert-Butylsulfanyl-1 - [4- (6-methoxy-pyridin-1-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2 acid -yl] -2,2-dimethy-propionic A-5 (21.5 g, 33.7 mmol) was dissolved in THF (100 mL) and MeOH (100 mL) and stirred until it became a clear solution. The aqueous 3N LiOH solution (56 ml, 168.5 mmol) was added and the reaction was refluxed at 80 ° C for 2 hours. The LCEM confirmed the formation of the product, so the reaction was cooled to room temperature and partitioned between EtOAc and water. The pH of the aqueous solution was adjusted to pH 1 with 10% HCl, and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated to give the desired free acid (A-6). Reaction scheme B:
X = Bro B (OH), Example 2: Preparation of Compound 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2 -8, Compound 2-9, Compound 2-10, Compound 2-l, Compound 2-12, Compound 2-13, Compound 2-14, Compound 2-15, Compound 2-16, Compound 5-1, Compound 5-3, Compound 5-4 and Compound 5-7. Compound 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2-8, Compound 2-9, Compound 2-10 , Compound 2-11, Compound 2-12, Compound 2-13, Compound 2-14, Compound 2-15, Compound 2-16, Compound 5-1, Compound 5-3, Compound 5-4 and Compound 5-7 were prepared as defined in Reaction Scheme B. A detailed illustrative example of the reaction conditions shown in Scheme B is described for the synthesis of 1 - [3-tert-butylsulfanyl-1- (4-chloro- benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol. Step 1: 4-tert-butyl sulfanyl-1-oxo-butyric acid ethyl ester. Ethyl 4-chloroacetoacetate (7.5 ml, 51.9 mmol), 2-methyl-2-propanothiol (5.6 ml, 49.7 mmol), triethylamine was dissolved. (10.8 mL, 77., 4 mmol), and catalytic tetrabutylaluminum bromide in THF (250 mL) and stirred at room temperature overnight. Silica gel was added, and the mixture was concentrated and filtered on a plug of silica gel to obtain the desired product (B-1), which is used without further purification. Step 2: (3-tert-Butylsulfanyl-5-methoxy-4H-indol-2-yl) -acetic acid ethyl ester 4-methoxyphenylhydrazine hydrochloride (7.7 g, 44.1 mmol) and B-1 (7.4 g, 33.9) were dissolved. mmol) in 2-propanol (150 ml) and heated to reflux for 24 hours. The reaction mixture was concentrated and partitioned between EtOAc and aq NaHCO 3. saturated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (0 to 30% EtOAc in hexanes) to give the desired product (B-2). Step 3: (3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl) -acetic acid ethyl ester Aluminum chloride (7.5 g 56.0 mmol) was suspended in tert-butyl thiol (21 mL, 186.7 mmol) at 0 ° C. B-2 (6.0 g, 18.7 mmol) in CH2Cl2 (21 mL) was added, and the reaction was allowed to warm to room temperature. After 2 hours, the reaction was completed by TLC analysis, so the solution was poured on ice and acidified with 10% aqueous HCl solution. The aqueous layer was extracted three times with EtOAc, the combined organics were dried over MgSO4, filtered, and concentrated to give the desired product (B-1). Step 4: 3-tert-butyisulfan-2- (2-hydroxy-2-methyl-propyl) -1H-indole-5-ol | B-1 (2.2 g, 7.0 mmol) was dissolved in THF (70 ml ) and cooled to 0 ° C. Methylmagnesium chloride (3M, 14 mL, 42.0 mmol) was added dropwise, and the reaction was stirred for 1 hour at room temperature. The reaction was quenched with NH4CI aq. and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on silica gel to give the. desired product (B-4). Step 5: 1- [3-tert-Butylsulfanyl-5- (pyrldin-2-ylmeyoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol A B-4 (0.18 g, 0.61 mmol DMF (6 ml) was added cesium carbonate (1.0 g, 3.1 mmol). The reaction was stirred at room temperature for 30 minutes, and then 2-chloromethylpyridine hydrochloride (0.11 g, 0.67 mmol) and tetrabutylammonium iodide (0.05 g, 0.13 mmol) were added, and the reaction was stirred at room temperature for another 16 hours. . The reaction was partitioned between water and diethyl ether, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel to give the desired product (B-5). Step 6: 1 - [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (pyridin-2-methoxy) -1H-indol-2-H] -2-methyl-propan- 2-ol A B-5 (0.05 g, 0.13 mmol) in DMF (3 mL) was added cesium carbonate (0.21 g, 0.65 mmol). The reaction was stirred at room temperature for 30 minutes, and then 1-chloro-4-chloromethylbenzene (0.03 g, 0.20 mmol) and tetrabutylammonium iodide (0.05 g, 0.13 mmol) were added, and the reaction was stirred at room temperature. atmosphere during the night: La. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water, dried over gSO4, filtered, concentrated, and purified on silica gel (Gradient EtOAc: hexanes) to give the desired compound (B-6). Mass spectrometric data of Compound 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2-8, Compound 2-9 , Compound 2-10, Compound 2-11, Compound 2-12, Compound
2-13, Compound 2-14, Compound 2-15, Compound 2-16, Compound 5-1, Compound 5-3, Compound 5-4 and Compound 5-7, are shown in Tables 1-5. Notes: For compound 2-8, during Step 6, both di-substituted nitrogens of the precursor were alkylated to give the final product. For Compound 2-10, during Step 6, both the mono- and di-substituted nitrogens of the precursor were alkylated to give the final product. For Compound 2-11, after step 6, a cross-coupling reaction of Suzuki was performed to give compound B-6b, as described in Example 5, step 2.
For Compound 2-12, after Step 6, the ethyl ester of the precursor was hydrolyzed to give the acid in the final product, as described in Example 1, Step 6. For Compound 2-14, after Step 6 , the ethyl ester of the precursor was treated with methylmagnesium chloride to give the 2-hydroxy-2-methylpropoxy in the final product. For Compound 2-15, after Step 6, the precursor ketone was reduced with sodium borohydride to give the alcohol in the final product, Reaction Scheme C:
Example 3: Preparation of Compound 1-1, Compound 1-2, Compound 1-3, Compound 1-8, Compound 1-10, Compound 1-11, Compound 1-12, Compound 1-13, Compound 1-14, Compound 1-15, Compound 1-16, Compound 4-1, Compound 4-4 and Compound 4-5. Compound 1-1, Compound 1-2, Compound 1-3, Compound 1-8, Compound 1-10, Compound 1-11, Compound 1-12, Compound 1-13, Compound 1-14, Compound 1-15 , Compound 1-16, Compound 4-1, Compound 4-4 and Compound 4-5 were prepared as defined in Scheme C. A detailed illustrative example of the reaction conditions shown in Reaction Scheme C is describes for the synthesis of the (S) -2-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indole-5-tert-butyl ester -yloxymethyl] -pyrrolidin-1-carboxylic acid Step 1: N- (4-chloro-benzyl) -N- (4-m-ethoxy-phenyl) -hydrazine hydrochloride A solution of 4-methoxyphenylhydrazine hydrochloride (10.0 g, 57.3 mmol ), 4-chlorobenzylchloride (9.2 g, 57.2 mmol), tetrabutylammonium bromide (3.7 g, 11.5 mmol), and dilsopropylethylamine (20 mL, 115 mmol) in CH 2 Cl 2 (250 mL) was stirred at room temperature for several days. The reaction mixture was diluted with water and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was placed in toluene (200 ml) and diethyl ether (100 ml), and 1 equivalent of 4N HCl in dioxane was added at 0 ° C. The mixture was stirred at room temperature for 2 hours, and then evaporated to dryness to give the desired product (C-1; X = C1) in the form of a purple solid. Step 2: 3- [1- (4-Chloro-benzyl) -1-tert-butylsulfa- or 1-5-methoxy-1H-indol-2-yl] -2,2-dimethyl-propionic acid ethyl ester. C-1 (-16 g, 57.3 mmol), ethyl 5- (t-butylthio) -2,2-dimethyl-4-oxo-pentanoate (prepared according to the procedure described in U.S. Patent 5,288,743 published on Feb. 22, 1994; 14.8 g, 57.3 mmol), NaOAc (5.2 g) in toluene (120 ml) and HOAc (66 ml) at room temperature in the dark for 5 days. The mixture was partitioned between EtOAc and water, and the organic layer was stirred with NaHCO 3 solid, filtered, and evaporated. The residue was purified on silica gel (0 to 55% CH2Cl2 in hexanes), and the isolated product was recrystallized from hexanes to give the desired product (C-2; X = CI). Step 3: 3- [1- (4-chloro-benzyl) -1-tert-butylsulfanyl-5-hydroxy-1H-indol-2-H1-2,2-dimethyl-propionic acid ethyl ester Aluminum chloride was suspended (0.820 g 6.15 mmol) in tert-butyl thiol (1.8 mL, 16 mmol) and cooled to 0 ° C. C-2 (1.0 g, 2.0 mmol) in CH2Cl2 (2.4 mL) was added, and the reaction was allowed to warm to room temperature. After 3 hours, the reaction was completed by TLC analysis, so the solution was diluted with CH2Cl2 and washed with 10% aqueous HCl solution, cooled on ice. The aqueous layer was extracted three times with CH2Cl2, the combined organics were dried over MgSO2, filtered, and concentrated to give the desired product (C-1).; X = CI) in the form of a colorless foam. Step 4: (S) -243-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-e toxic rbonyl-2-methyl-propyl) -1H-indole-5-tert-butyl ester -iloxymethin-pyrrolidyryl-1-carboxylic acid 3- [1- (4-chloro-benzyl) -1-tert-butylsulfanyl-5-h idroxy-1 H-indol-2-yl] -2-ethyl ester , 2-dimethyl-propionic acid (C-1, 0.5 g, 1.05 mmol) in DMF (2.5 mL) was added N-BOC- (S) -2- (toluene-4-sulfonyloxymethipropyridine (0.39 g, 1.10 mmol), and Cs2C03 (0.69 g, 2.1 mmol) The reaction was stirred at 45 ° C for 2 hours, then catalytic potassium iodide was added and the reaction was heated to 60 ° C overnight.The reaction mixture was diluted with EtOAc, washed with water, dried over Na 2 SO, filtered, and concentrated The residue was purified on silica gel (0 to 15% EtOAc in hexanes) to give the desired product (C-4; X = CI Step 5: (S) -2- [3-tert-Butylsulfanyl-2- (2-carboxy-2-methyl-propH) -1- (4-chloro-benzyl) -1H-tert-butyl ester -indol-5-yloxymethyl-pyrrolidine-1-carboxyHco (1-1) The ester from step 4 (0.16 g, 0.26 mmol) was dissolved in MeOH (1 mL), THF (1 mL), and water (1 mL). Lithium hydroxide (0.6 g, 1.43 mmol) was added, and the reaction was heated for 12 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (0 to 40% EtOAc in hexanes) to give the desired product (C-5; X = CI). Spectrometry data of. Mass of Compound 1-1, Compound 1-2, Compound 1-3, Compound 1-8, Compound 1-10, Compound 1-11, Compound 1-12, Compound 1-13, Compound 1-14, Compound 1- 15, Compound 1-16, Compound 4-1, Compound 4-4 and Compound 4-5, are shown in Tables 1-5. Notes: For compound 1-8, after Step 4, the tetrahydropyrimidine in the precursor was reacted with di-tert-butyl dicarbonate, which produced the opening of the tetrahydropyrimidine ring to generate the BOC-aminopropylcarbamol of the final product. For Compound 1-11, after Step 4, the precursor ketone was reduced with sodium borohydride to give the alcohol in the final product. For Compound 1-12, after step 4, the ketone was reacted with hydroxylamine to give the hydroxyimino of the final product. For Compound 1-13, after weight 4, the ketone was reacted with o-methylhydroxylamine to give the methoxyimino of the final product. For Compound 1-14, Compound 1-15 and Compound 1-16, Step 5 was not performed. For Compound 4-1, i) during Step 1, 1- (4-isopropylphenii) hydrazine was used in place of 4-methoxyphenylhiclrazine and 4- (bromomethyl) benzoate was used in place of 4-chlorobenzyl chloride; i) during Step 2, 2,6-dimethyl-4-heptanone was used in place of ethyl 5- (tert-butylthio) -2,2-dimethyl-4-oxo-pentanoate; ii) Weights 3 and 4 were not made; the product of Step 2 (C-2) was used directly in Step 5. For Compound 4-4, i) during Step 1, 4- (bromomethyl) benzoate was used in place of 4-chlorobenzyl chloride; ii) during Step 2, 1-tert-butylsulfanyl-4,4-dimethyl-pentan-2-one was used in place of ethyl 5- (tert-butylthio) -2,2-dimethyl-4-oxo-penta-noato. For Compound 4-5, i) during Step 1, 4- (bromomethyl) benzoate was used in place of 4-chlorobenzyl chloride; ii) during Step 2, 1-tert-butylsulfanyl-4,4-dimethyl-pentan-2-one was used in place of ethyl 5- (tert-butylthio) -2,2-dimethyl-4-oxo-penta-noato; iii) Step 5 was not carried out. It is a reactive area D:
Example 4: Preparation of Compound 1-17, Compound 1-18, Compound 1-19, Compound 1-20, Compound 1-21, Compound 1.22, Compound 1-23, Compound. 1-24, Compound 1-25, Compound 1-26 and Compound 1-27. Compound 1-17, Compound 1-18, Compound 1-19, Compound 1-20, Compound 1-21, Compound 1-22, Compound 1-23, Compound 1-24, Compound 1-25, Compound 1-26 and Compound 1-27, were prepared as shown in Reaction Scheme D. A detailed illustrative example of the reaction conditions shown in Reaction Scheme D is described for the synthesis of 3- [3-ter- butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-11) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic. Step 1: ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5-hydroxy-1 - [4- (4,4,5,5-tetramethyl- [1,2,2] dioxaborolan-2-yl) -benzyl] -1 H -indole-2- il} -2, 2-dimethylpropionic The phenol of Example 3, step 3 (C-3, X = Br, 35.0 g, 67.5 mmol), bis (pinacolato) diboron (Combi-Blocks, 25.0 g, 98.4 mmol) , and KOAc (19.9 g, 209.1 mmol) was dissolved in 1,4-dioxane (350 mL) and degassed with N2 for 30 minutes. PdCl2dppf (2.5 g, 3.1 mmol) was added, and the reaction mixture was degassed for another 30 minutes with N2. The reaction was heated at 85 ° C overnight. The reaction mixture was partitioned between water and EtOAc, the aqueous layer was extracted three times with EtOAc, the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (15% EtOAc in hexanes) to give the desired product (D-1, 33.5g). Step 2: Ethyl 3- acid ester. { 3-tert-Butylsulfanyl-5-hydroxy-1 - [4- (6-methoxy-pyridin-1-yl) -benzyl] -1H-indol-2-yl} -2, 2-dimethyl-propionic D-1 (25.34 g, 44.8 mmol), 5-bromo-2-methoxypyridine (Combi-blocks, 10.9 g, 70.3 mmol), and K2CO3 (15.5 g, 112.1 mmol) were dissolved in DE (300 ml) and water (150 ml) and degassed with N2 for 30 minutes. Pd (PPh3) (1.6 g, 1.4 mmol) was added, and the reaction mixture was degassed with N2 for another 15 minutes. The solution was heated to 80 ° C overnight, and then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc, the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0 to 8% EtOAc in hexanes) to give the desired product (D-2, 23.7 g).
Step 3: Ethyl 3- acid ester. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-1-yl) -benzyl] -1H-ynol-2-yl} -2, 2-dimethyl-propionic A ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5-hydroxy-1 - [4- (6-methoxy-pyridin-1-yl) -benzyl-1H-indole-24} -2,2-dimethyl-propyanic acid (D-2; 6.5 g, 11.9 mmol) in MeCN (75 mL) was added 2-bromomethyl-6-fluoro-quinoline (3.14 g, 13.1 mmol), and Cs2C03 (9.7 g, 29.8 mmol). The reaction was stirred at room temperature overnight, after which the LCMS showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated. The residue was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (D-1, 7.6g). Step 4: Acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinyl-2- [1-methox) -1- [4- (§-methoxy-p-ridin - '\ - 4') - benc. - '\ H-indo \ -2-yl-2,2-dimethyl-propionic D-1 (6.58 g, 9.3 mmol) was dissolved in MeOH (36 ml), TH F (75 ml), and water (36 ml). ). Lithium hydroxide (2.42 g, 57.7 mmol) was added, and the reaction was heated at 60 ° C for 6 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was triturated with hexane: EtOAc (9: 1) overnight, and filtered to give the desired product (D4)., 5.9g). Mass spemetric data for Compound 1-17, Compound 1-18, Compound 1-19, Compound 1-20, Compound 1-21, Compound 1-22, Compound 1-23, Compound 1-24, Compound 1- 25, Compound 1-26 and Compound 1-27, are shown in Tables 1-5. Notes: For compound 1-17, during step 3, the ethyl ester of the precursor was also hydrolyzed to give the acid in the final product. For compound 1-18, after step 3, the precursor ketone was reduced with sodium borohydride to give the alcohol in the final product. For compound 1-20, after step 3, the cyanomethyl of the precursor was subjected to alkyl to give compound D-3b, which was then hydrolyzed in Step 4 to give the 1-carbamoyl-methylethoxy in the final product. For compound 1-21, after step 3, the cyanomethyl of the precursor was added to give compound D-3b, which was then hydrolyzed in Step 4 to give 1-carboxy-1-methylethoxy in the compound. Final product. For compound 1-22, after step 3, the ketone of the precursor was reduced with sodium borohydride to give the alcohol, which was then subjected to alkyl with iodomethane to give the 2-methoxypropoxy in the final product. For compound 1-23, after Step 3, the precursor ketone was reduced with sodium borohydride to give the alcohol in the final product. For compound 1-25, after Step 3, the precursor ketone was reduced with sodium borohydride to give the alcohol in the final product. For compound 1-26, after Step 3, the precursor ketone was reduced with sodium borohydride to give the alcohol in the final product. For compound 1-27, Step 4 was not performed. Reaction scheme E:
Example 5: 3- [3-tert-Butylsu-l-butyl-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl-5- (5-methyl-pyridin-2-ylmethoxy) -1H -indol-2-yl] -2, 2-dimethyl-propionic acid.
Step 1: 3- [1- (4-bromo-benzyl) -1-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl] ethyl ester 2, 2-dimethyl-propionic
To the ethyl ester of 341- (4-bromo-benzyl) -1-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl] -2,2-dimethyl-prophenic acid (C-3; 0.25 g , 0.48 mmol) in DMF (2 mL) was added 2-cioromethyl-5-methyl-pyridine hydrochloride (0.13 g, 0.72 mmol), Cs2CO3 (0.39 g, 1.21 mmol), and catalytic tetrabutylammonium iodide. The reaction was run at room temperature overnight, after which the LCMS showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0 to 15% EtOAc in hexanes) to give an additional desired product (E-1, 0.30g).
Step 2: 3- (3-tert-Butylsuifanyl-5- [6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-241) -benzyl] - ethyl ester 1 H-indoi-2-yl] -2, 2-dimethyl-propionic E-1 (0.06 g, 0.10 mmol), 2-methoxy-pyridine-5-boronic acid (0.02 g, 0.14 mmol), and K2C03 were dissolved. (0.03 g, 0.24 mmol) in DME (1 mL) and water (0.5 mL) and degassed with N2 for 10 minutes. Pd (PPh3) 4 (0.0.1 g, 0.01 mmol) was added, and the reaction mixture was degassed with N2 for another 10 minutes. The solution was heated to 80 ° C for 4 hours, and then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc, the combined organic layers were washed with water, brine, dried over MgSO, filtered, and concentrated. The crude material was purified on silica gel (0 to 50% EtOAc in hexanes) to give the desired product (E-2).
Step 3: acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [A- (S-methox -pyridin-2-l) -benzyl] - '\ H-indol-2-yl } -2,2-dimethyl-propionic
E-2 (0.22 g, 0.31 mmol) was dissolved in MeOH (0.1 mL), THF (0.1 mL), and water (0.1 mL). Lithium hydroxide, 1N aqueous solution (0.1 ml) was added, and the reaction was heated at 60 ° C for 4 hours until no starting material was observed by LCMS. The reaction was diluted with water and EtOAc, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated to give the desired product (F-4).
Reaction scheme
Example 6: Acid 3-. { 3-Fer-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -IH-indol-2-yl} -2,2-dimethyl-propionic. Step 1: 3- [1- (4-bromo-benzyl) -1-tert-butylsulfanyl-5- (6-fluoro-quinoHn-2-ylmethoxy) -1H-indol-2-yl] ethyl ester 2, 2-climethyl-propionic acid To the ethyl ester of 3- [1- (4-bromo-benzyl) -1-tert-butylsulfanyl-5-hydroxy-1 H-ind or l-2-yl] -2,2 -dimethyl propionic ion (C-1;
2. 0 g, 3.9 mmol) in MeCN (25 mL) was added 2-bromomethyl-6-fluoro-quinoline (1.0 g, 4.2 mmol), and Cs2CO3 (2.5 g, 7.7 mmol). The reaction was stirred at room temperature overnight, after which the LCMS showed that the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated. The residue was recrystallized from EtOAc: hexane to give the desired product (F-1, 1.9 g). The filtrate was concentrated and purified on silica gel (0 to 15% EtOAc in hexanes) to give an additional 1 g of F-1. Step 2: Ethyl ester of 3- acid. { 3-Fer-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4 - (- 4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-H) -benzyl] -1H-indole-241} -2,2-dimethyl-propionic F-1 (1.0 g, 1.5 mmol), bis (pinacolato) diboron (Combi-Blocks, 1.1 g, 4.3 mmol), and KOAc (0.44 g, 4.5 mmol) were dissolved in 1, 4-dioxane (15 ml) and degassed with N2 for 10 minutes in a sealed flask. PdCI2dppf (0.13 g) was added, 0.16 mmol), and the reaction mixture was degassed for another 10 minutes with N2. The vessel was sealed and the reaction was heated to 95 ° C overnight. The reaction mixture was partitioned between water and EtOAc, the aqueous layer was extracted three times with EtOAc, the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0 to 20% EtOAc in hexanes) to give the desired product (F-2). Step 3: Ethyl 3- acid ester. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic F-2 (0.25 g, 0.35 mmol), 2-bromo-6-methoxypyridine (0.09 g, 0.48 mmol), and K2C03 (0.15 g, 1.05 mmol) in DME (3.5 ml) were dissolved. ) and water (1.8 ml) and degassed with N2 for 10 minutes. Pd (PPh3) 4 (0.06 g, 0.05 mmol) was added, and the reaction mixture was degassed with N2 for another 10 minutes. The solution was heated to 85 ° C for 4 hours, and then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc, the combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (F-3). Step 4: acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzH] -1H-indol-2-yl} -2, 2-dimethyl-propionic F-1 (0.22 g, 0.31 mmol) was dissolved in MeOH (1.5 mL), THF (3 mL), and water (1.5 mL). Lithium hydroxide (0.08 g, 1.9 mmol) was added, and the reaction was heated at 60 ° C for 3.5 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated to give the desired product (F-4). Reaction scheme G: p R1 TFA VR2 Rk, -R2 x "^ R3 N boc CHJCI2 H Pr2NEt, CH2CI2 G-1
Example 7: Preparation of Compound 1-4, Compound 1-5, Compound 1-6, Compound 1-7, Compound 1-9 and Compound 5-2.
Compound 1-4, Compound 1-5, Compound 1-6, Compound
1-7, Compound 1-9 and Compound 5-2, were prepared as shown in Reaction Scheme G. A detailed illustrative example of the reaction conditions shown in Reaction Scheme G is described for the synthesis of the acid 3-. { 5 ((S) -1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pindazin-34) -benzyl] -1H -indol-2-íl} -2,2-dimethyl-propionic. Step 1: ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5 - [(S) -1 - (2,3-dihydro-1 H -indol-2-yl) methoxy] -1- [4- (6-methoxy-pyridazin-1-yl) -benzyl] -1H-indol-2-yl} -2, 2-climethyl-propionic Ter-butyl ester of (S) -2- acid was dissolved} 3-tert-Butylsulfanyl-2- (2-ethoxycarbonyl-2-methyl-propyl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-ynol-5-yloxymethyl } -2,3-dihydro-indole-1-carboxylic acid (0.23 g, 0.30 mmol) in CH2Cl2 (1.5 mL). TFA (1.5 ml) was added and the reaction was stirred at room temperature for 10 minutes until no starting material was observed by TLC analysis. The solution was concentrated in vacuo, and the crude product (G-1) was used without further purification. Step 2: Ethyl 3- acid ester. { 5 - ((S) -1-acetyl-2,3-dihydro-1 H-indol-2-ylmethoxy) -1-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-indole-2-yl} -2, 2-dimethyl-propionic G-1 (0.30 mmol) was dissolved in CH 2 Cl 2 (1 mL). Diisopropylethylamine (0.5 ml) was added, followed by acetic anhydride (33 ul, 0.35 mmol), and the reaction was stirred at room temperature until no starting material was seen by LCMS. The reaction was diluted with CH2Cl2 and MeOH, concentrated, re-dissolved in CH2Cl2 and washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel to give the desired product (G-2). Step 3: 3- (5 - ((S) -1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy) -1-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazine -1-yl) -benoyl] -1 H -indol-2-yl.} -2, 2-dimethyl-propionic G-2 (0.05 g, 0.07 mmol) was dissolved in MeOH (0.5 mL), THF (0.5 mi), and water (0.5 ml) Lithium hydroxide (0.03 g, 0.7 mmol) was added, and the reaction was heated at 60 ° C for 6 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated.The residue was purified on silica gel. To give the desired product (G-1).
The mass spectrometry data for Compound 1-4, Compound 1-5, Compound 1-6, Compound 1-7, Compound 1-9 and Compound 5-2, are shown in Tables 1-5. Notes: For Compound 1-4 and Compound 1-5, only steps 1 and 3 were performed.
Reaction scheme H
??? - Example 8: Preparation of Compound 4-6.
Compound 4-6 was prepared as shown in Reaction Scheme H. A detailed illustrative example of the reaction conditions shown in Reaction Scheme H is described for the synthesis of acid 3-. { 5- (benzothiazol-2-ylmethoxy) -1-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -indole-2-yl} -2,2-dimethyl-pr or p ionic (Compound 2-214).
Step 1: ethyl ester of 3- acid. { 5- (Benzothiazol-2-ylmethoxy) -1 - [4- (6-methoxy-pyrldin-1-yl) -benzyl-1H-indol-2-yl} -2,2-dimethyl-propionic Aluminum chloride (0.18 g, 1.37 mmol) was suspended in CH2Cl2 (1 mL), and water (19 mL, 1.0 mmol) was added slowly at room temperature. The mixture was stirred for 5 minutes, and then cooled to 0 ° C. 3-Ethyl ester was added. { 5- (benzothiazol-2-ylmethoxy) -1-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-1-yl) -benzyl] -1 H -indole-2-yl) -2,2- dimethylpropienic (0.12 g, 0.17 mmol) in CH2Cl2 (1 mL), and the reaction was stirred at room temperature for 2 hours. Once no more starting material was observed by TLC, water was added and the mixture was extracted with CH2CI2. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified to give the desired product (H-1).
Step 2: Ethyl 3- acid ester. { 5- (Benzothiazol-2-ylmethoxy) -1-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-1-yl) -benzyl] -1 H-indol-2-yl} -2, 2-dimethyl-propionic A H-1 (0.10 g, 0.17 mmol) in dichloroethane (5 mL) was added cyclobutanecarbonyl chloride (57 ul, 0.50 mmol) and aluminum chloride (0.09 g, 0.66 mmol). The reaction was heated at N2 for 1.5 hours, and then cooled to room temperature and warmed with sodium tartrate and potassium aq. saturated. The mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO, filtered, concentrated, and purified on silica gel to give the desired product (H-2). Step 3: Ethyl 3- acid ester. { 5- (ben zoti azol-2-i I m ethoxy) -1-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-1-yl) -benzyl-1H-indol-2-yl} -2, 2-dimethyl-propionic H-2 (0.05 g, 0.08 mmol) was suspended in CH2Cl2, and sodium borohydride (0.03 g, 0.8 mmol) was added dropwise in TFA (1 mL) and CH2Cl2 (1 mL). ). The mixture was stirred at room temperature for 4 hours, then warmed with water and basified with solid NaOH pellets. The mixture was extracted with CH2Cl2, and the combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel to give the desired product (H-1). Step 4: acid 3-. { 5- (benzotiaz ol-2-i Imethoxy) -1 -c lob uti Itn eti 1-1 - [4- (6-methoxy-p i ridin-3-yl) -benzyl] -1H-indole -2-yl) -2, 2-dimethyl-propionic H-1 (0.03 g, 0.04 mmol) was dissolved in MeOH (0.5 mL) and THF (0.5 mL). Aqueous lithium hydroxide (1N, 0.5 ml) was added, and the reaction was heated at 60 ° C for 4 hours until no more starting material was observed by LCMS. The reaction was diluted with water, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated to give the desired product (H-4).
io Mass spectrometry data for compound 4-6 are shown in tables 1-5. Notes: For compound 4-6, only step 1 was carried out. Reaction scheme I: I5
1-4 1-5 k
(EtO) 3CH
Example 9: Preparation of Compound 3-1, Compound 3-2, Compound 3-3, Compound 3-4, Compound 3-5, Compound 3-6, Compound 3-7, Compound 4-2, Compound 4-3 , Compound 4-7, Compound 5-5 and Compound 5-6. Compound 3-1, Compound 3-2, Compound 3-3, Compound 3-4, Compound 3-5, Compound 3-6, Compound 3-7, Compound 4-2, Compound 4-3, Compound 4-7 , Compound 5-5 and Compound 5-6, were prepared as defined in Reaction Scheme I. A detailed illustrative example of the reaction conditions shown in Reaction Scheme I is described for the synthesis of 3- [ 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-ynol-2-yl] -N- (2-hydroxy-ethyl) -2,2-dimethyl-propionamide. Step 1: 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl] -2, 2-d-methyl-propionyl chloride To the acid 3- [3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1 H-indol-2- [1- 2, 2-dimethyl-propionic acid (prepared according to the procedure described in US Patent 5,081, 138 published on January 14, 1992, 0.25 g, 0.53 mmol) were suspended in CH 2 Cl 2 (5 mL), oxalyl chloride (48 ul, 0.56 mmol) and catalytic DMF were added. The reaction was stirred at room temperature for 3 hours, and then concentrated to give 1-1, which is used without further purification. Step 2: 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl] -N- (2-hydroxy-ethyl) -2, 2-dimethyl -product amide A 1-1 (0.18 mmol) in CH 2 Cl 2 was added triethylamine (0.1 ml, 0.70 mmol) and 2-aminoethanol (10 ul, 0.19 mmol). The reaction was stirred for 2 days at room temperature, and then concentrated and purified on silica gel (Gradient EtOAc: hexanes) to give the desired product (I-2). Step 3: 3- [3-tert-Butylsulfanyl-1- (4-chlorobenzyl) -5- (quinotin-2-ylmethoxy) -11-1-indol-2-yl] -2,2-d-methyl-propionitrile A 1-1 in CH2Cl2 was bubbled with gaseous ammonia for 20 minutes. The reaction was diluted with brine and the organic phase was separated, dried and concentrated. The residue was purified on silica gel to give the desired product (I-4).
Step 4: 2- { 3-tert-Butylsulfanyl-1- (4-chlorobenzyl) -2- [2-methyl-2- (5-methyl- [1,2,4] -oxadiazol-3-yl) propyl-1H-indole-5- Loxymethyl} -quinoline A 1-4 (0.05 g, 0.09 mmol) in ethanol (2 ml) was added hydroxylamine hydrochloride (0.07 g, 1.0 mmol) and potassium hydroxide (0.005 g) and the reaction was refluxed for the night. The reaction mixture was diluted with water and EtOAc and the organic layer was separated, sec6 and concentrated. After purification on silica gel, the intermediate amidine was treated with dimethylacetamide dimethylacetal (2 ml) at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, concentrated and purified on silica gel to give the desired product (I-5) Step 5: 5-. { 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -phenyl} - [1,3,4-Oxadiazol-2-ylamine A I-6 (0.05 g, 0.10 mmol) in DMF (1m1) was added C- (Di-imidazol-14) -methyllenanine (0.08 g, 0.50 mmol) , and the reaction was heated to 85 ° C for 3 hours. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (gradient EtOAc: hexane) to give the desired product (I-7). Mass spectrometric data for Compound 3-1, Compound 3-2, Compound 3-3, Compound 3-4, Compound 3-6, Compound 3-7, Compound 4-2, Compound 4-3, and Compound 5 -5 and Compound 5-6, are shown in Tables 1-5. NMR data for compound 4-7 are shown below. Notes: For compound 4-7, H NMR (CDCl 3) d 8.60 (d, 1H), 7.69 (m, 3H), 7.57 (d, 1H), 7.32 (d, 1H) , 7.20 (m, 1H), 7.01 (d, 1H), 6.85 (m, 4H), 5.46 (s, 2H), 5.28 (s, 2H), 3.49 ( q, 2H), 2.52 (t, 2H), 2.27 (s, 6H), 2.13 (m, 2H), 1.21 (s, 9H), 0.99 (s, 9H). For Compound 3-1, Compound 3-3, Compound 3-4, Compound 3-6, Compound 3-7, Compound 4-2, Compound 4-3, Compound 4-7, Compound 5-5 and Compound 5- 6, only Steps 1 and 2 were performed.
For compound 3-2, only Steps 1, 2 and
. For compound 3-5, only Steps 1 to 4 were performed. Example 10: FLAP Binding Assays A non-limiting example of the FLAP binding assay is as follows: Packaged human polymorphonuclear cell granules (1.8 x 109 cells ) (Biological Specialty Corporation) were resuspended, used and 100,000 g of membranes were prepared as described (Charleson et al., Mol Pharmacol, 41, 873-879, 1992). 100,000 xg granulated membranes were resuspended in Tris-Tween buffer (100 mM Tris HCI pH 7.4, 140 mM NaCl, 2 mM EDTA, 0.5 mM DTT, 5% glycerol, 0.05% Tween 20) to give a protein concentration 50-100 ug / ml. 10 ul of membrane suspension were added to a Millipore 96-well plate, 78 μ? of buffer Tris-Tween, 10 μ? of 3H MK886 or 3H 3- [5- (pyrid-2-ylmethoxy) -1-tert-butylthio-1-benzyl-indol-2-yl] -2,2-dimethyl-propionic acid. (or derivative 125l MK591 Eggler et al., J. Labelled Compounds and Radiopharmaceuticals, 1994, vXXXIV, 1147)) to -30,000 cpm, 2 μ? of inhibitor and incubated for 30 minutes at room temperature. 100 pl of buffer washed on ice was added to the incubation mixture. The plates were then filtered and washed 3x with 200 μ? of frozen Tris-Tween buffer, the scintillation bases were sealed, 100 μ? of twinkle, they were shaken for 15 minutes then counted in a TopCount. The specific binding was determined as defined as a total radioactive binding minus the non-specific binding in the presence of 10 μM MK886. The Cl50 were determined using the Graphpad prism analysis of drug titration curves. Example 11: LTB4 Inhibition Assay of Human Blood A non-limiting example of this inhibition assay of LTB4 from human blood is as follows: Blood was extracted from healthy human volunteers with their consent into heparin-containing tubes and aliquots of 125 were added. μ? to wells that contained 2.5 μ? 50% DMSO (vehicle) at 2.5 μ? of drug in 50% DMSO. The samples were incubated for 15 minutes at 37 ° C. 2 μ? calcium ionophore A23817 (from a stock of 50 mM DMSO diluted only before testing in Hanks balanced salt solution (Invitrogen) up to 1.25 mM), the solutions were mixed and incubated for 30 minutes at 37 ° C. The samples were centrifuged at 1,000 rpm (-200 x g) for 10 minutes at 4 ° C, the plasma was removed and a 1: 100 dilution was tested for LTB4 concentration using ELISA (Assay Designs). Drug concentrations to obtain 50% inhibition (Cl50) of vehicle LTB4 were determined by non-linear regression (Graphpad Prism) of% inhibition versus log of drug concentration.
Example 12: Rat peritoneal inflammation test and edema A non-limiting example of this rat peritoneal inflammation and the edema test is as follows: The in vivo efficacy of the leukotriene biosynthesis inhibitors was evaluated using a rat model of inflammation peritoneai. Sprag ua-Dawley male rats (weighing 200-300 grams) received a single peritoneal (ip) injection of 3 ml of zymosan-containing saline solution (5 mg / ml) followed immediately by an intravenous injection (v. .) Evans blue stain (2 ml of 1.5% solution). The Compounds were administered orally (3 ml / kg in 0.5% methylcellulose vehicle) 2 to 4 hours before zymosan injection. One to two hours after the injection of zymosan, the rats were allowed to die, and the peritoneal cavity was filled with 10 ml of phosphate buffer saline (PBS). The resulting fluid was centrifuged at 1,200 rpm for 10 minutes. Vascular edema was evaluated by quantifying the amount of Evans blue stain in the supernatant using a spectrophotometer (Absorbance 610 nm). The concentration of LTB4 and cysteinyl leukotrienes in the supernatant were determined by ELISA. Drug concentrations to obtain 50% inhibition of plasma leakage (Evans blue staining) and inhibition of LTB4 peritoneai and cysteinyl leukotrienes could be calculated by non-linear regression (Graphpad Prism) of% inhibition against log concentration of the drug .
Example 13: Human Leukocyte Inhibition Assay A non-limiting example of a human leukocyte inhibition assay is as follows:
Blood was drawn from human volunteers with their consent in tubes subjected to heparin and equal volumes of 3% dextran and 0.9% saline were added. After sedimentation of the red blood cells, a hypotonic lysis of the remaining red blood cells was performed and the leukocytes were pelleted at 1000 rpm. The granule was suspended at 1.25 x 10 5 cells / ml and aliquoted in wells containing 2.5 pl of 20% DMSO (vehicle) or 2.5 μm. of -drug in 20% of DMSO. The samples were incubated for 5 minutes at 37 ° C, and 2 pl of calcium ionophore A23817 (from a stock of 50 mM DMSO diluted only before the test in Hanks balanced salt solution (Invitrogen) to 1.25 mM) was added. The solutions were mixed and incubated for 30 minutes at 37 ° C. The samples were centrifuged at 1,000 rpm (-200 x g) for 10 minutes at 4 ° C, the plasma was removed and a 1: 4 dilution was tested for the concentration of LTB using ELISA (Assay Designs). Drug concentrations to obtain 50% inhibition (Cl50) of vehicle LTB4 were determined by non-linear regression (Graphpad Prism) of% inhibition against the log concentration of the drug. The compounds presented in Tables 1-4 had assays of 1 nM to 5 μ? with this essay.
Example 14: Bronchoalveolar lavage procedure in rats A non-limiting example of a bronchoalveolar lavage test in rats is as follows: A lung lavage model with ionophore is used to determine the efficacy of leukotriene biosynthesis inhibitors in the White tissue for respiratory therapy. The compound was administered orally (3 ml / kg in 0.5% methylcellulose vehicle) to Spragua-Dawley rats (weighing 200-100 grams) 2 to 24 hours before lung lavage. At the appropriate time after administration of the compound, the rats were placed in a closed Plexiglas chamber and exposed to C02 for a period of 1-2 minutes or until respiration ceased. Then they were removed and blood was drawn through cardiac puncture. Cervical dislocation is practiced to ensure that rats do not recover from C02. The subjects were then placed on their backs, the trachea exposed by blunt dissection and a 7 ml bolus of phosphate-buffered saline (PBS with 7% DMSO) cooled with ice was instilled., using a 10 ml syringe equipped with a 20 gauge bevel needle tip. After a period of 3 minutes, the fluid was removed, mixed with equal parts of ice-cold methanol and centrifuged at 10,000 xg for 10 minutes at 4 minutes. ° C. The concentrations of LTB4 and cysteinyl leukotrienes in the supernatant were determined by EIA. Drug concentrations to achieve 50% inhibition of pulmonary LTB4 and cysteinyl leukotrienes could be calculated by non-linear regression (Graphpad Prism) of% de. inhibition versus logarithm of drug concentration. Example 15: Pharmaceutical Compositions Example 15a: Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water soluble salt of any compound of formula (E), formula (EI), or formula (E) -ll), were dissolved in DMSO and then mixed with 10 ml of sterile 0.9% saline. The mixture was incorporated into a unit dosage form suitable for administration per injection.
Example 15b: Oral composition 15 To prepare a pharmaceutical composition for oral administration, 100 mg of any compound of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula ( H), were mixed with 750 mg of starch. The mixture was incorporated in an oral dosage form, such as a capsule
of hard gelatin, which is suitable for oral administration.
Example 15c: sublingual composition (hard tablet) To prepare a pharmaceutical composition for oral administration, such as a hard tablet, mix 100 mg of any compound of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), with 420 mg of mixed powdered sugar, with 1.6 ml of light corn syrup, 2.4 ml of distilled water, and 0.42 ml of mint extract. The mixture is mixed gently and poured into a mold to form a seal suitable for buccal administration.
Example 15d: Composition for inhalation To prepare a pharmaceutical composition for administration by inhalation, 20 mg of a compound of any of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% sodium chloride solution. The mixture is incorporated into a unit for administration by inhalation, such as a nebulizer, which is suitable for administration by inhalation.
Example 15e: Rectal gel composition To prepare a pharmaceutical composition for rectal administration, 100 mg of any compound of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), mixed with 2.5 g of methylcellulose (1500 mPa), 100 mg of methyl paraben, 5 g of glycerin and 100 ml of purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration.
Example 15f: Topical gel composition To prepare a topical pharmaceutical gel composition, 100 mg of any compound of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), mixed with 1.75 g of hydroxypropylcellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate and 100 ml of purified USP alcohol. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration. Example 15q: Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of any compound of the formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), mix with 0.9 g of NaCl in 100 ml of purified water and filter using a 0.2 micron filter. The resulting isotonic solution is incorporated into ophthalmic administration units, such as eye drops, which are suitable for ophthalmic administration. The examples and embodiments described herein are for illustrative purposes only and the various modifications or changes suggested by those skilled in the art should be included within the spirit of this application and the scope of the appended claims. All publications, patents and patent applications mentioned herein are incorporated herein by reference for all purposes.
Claims (67)
- CLAIMS 1. A compound that has the structure of formula (A): wherein, Z is selected from C (R1) 2 [C (R2) 2] n, [C (R,) 2] nC (i) 20, [C (R2) 2] nO [C (R1) 2 ] n, [C (R1) 2] nO [C (R2) 2] n, where each R, is independently H, CF3, or an optionally substituted lower alkyl and two R-, on the same carbon can be attached to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -l_i- (substituted or unsubstituted alkyl); or t_i- (substituted or unsubstituted alkenyl), -L_i- (substituted or unsubstituted alkynyl), -L-, - (substituted or unsubstituted cycloalkyl), -l_i- (substituted or unsubstituted heteroaryl), -l_i - (substituted or unsubstituted aryl); where is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, 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 (LsRs) j, where each L., is independently selected from a bond, -O-, -C (= 0), -S-, -S (= 0) -, -S (= 0) 2-, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl from 1 to 6 carbon atoms, heteroaryl, aryl or a heteroalicyclic group; and each R5 is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl or heteroalkyl; where j is 0, 1, 2, 3 or 4; each R3 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; each R3b 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 cycloalkyl, phenyl or benzyl; or two R4 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (cycloalkenyl or unsubstituted or substituted), L2- (group substituted or unsubstituted heteroalicyclic), L2- (substituted or unsubstituted heteroaryl ether), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2, C (O), -CH (OH), - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or - (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); R7 is selected from: (a) L3-X-L4-G2, wherein, L3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted aryl, unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclic group; X is -NRgC (O), -C (0) NR9. -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0) NR9- , heteroaryl, aryl, -N (R9) C (= NR 10) N R9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) - or -C (= NR10) OR; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G2 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (0) NR9C (= CRON (R9) 2, -002R9, -C (0) R9, -CON (R9) 2, -SR3, -S (= 0) R8, -S (= 0) 2R5, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) , or -L5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC ( O), -C (0) NH, -C (0) 0 or -OC (O); or G2 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -ORB, -C (= 0) CF3, -CN, N (R9) 2, -N (Re) C (0) Re. -C (= NRON (R9) 2, -NR9C (= NR10) N (R9) 2l -NR9C (= CRON (R9) 2, -C (O) NR9C (= NR10) N (Rs) 2, -C (0) N RsC (= CR10) N (R9) 2, -C02R8, -C (0) R8, -CON (R9) 2, -SR8, -S (= 0) RB or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring. of 5, 6, 7 or 8 members and each R-io is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2 -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; or (b) L3-X-L4-G4, where l_3 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, heteroaryl substituted or unsubstituted or substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, S (= 0), -S (= 0) 2, -N R9, -NRgC (O), -C (0 ) NR9, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NR10) - or -C (= NR10) O; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G4 is -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CRio) N (Rg) 2, (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (aryl) substituted or unsubstituted), where L5 is -NHC (0) 0, -0 (0) CNH-, - (O) CO- or -OC (O); or G4 is -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -0 ( 0) CNH-, - NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G4 is W-G5l where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N ( R9) 2, OH, -OR8, -C (; 70) CF3, -CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, - NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R-io is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0 ) R8, -CN, -N02, heteroaryl or heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted) , -L6- (substituted or unsubstituted heteroaryl), or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) C \ -OC (0) NH, -NHC (O), -NHC (0) NH or C (0) NH; n is L7-L10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (0) 2, -NH, -C (O), -C (0) NH, -NHC (O), (substituted or unsubstituted alkyl of 1 to 6 carbon atoms) or (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); L10 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 substituted heteroalicyclic group) not substituted); and G6 as H, CN, SCN, N3, N02, halogen, OR9, -C (0) NHR9, -NHC (0) R9, -C (= 0) CF3, C (= 0) R9, -SR8, - S (= 0) R8, -S (= 0) 2R8, N. (R9) 2, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) N 1- 1S (= 0) 2R8, -S (= 0) 2NHC (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR 0) N (R10) 2, -NR9C (= CR1g) N (R9) 2; Ri2 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms); or its active metabolite, or solvate, or pharmaceutically acceptable salt, or acceptable prodrug for pharmaceutical use.
- 2. The compound of claim wherein Z is [C (R2) 2] nC (R1) 20.
- 3. The compound of claim 2, wherein Y is -Li- (substituted or unsubstituted ryl) or-^ - (substituted or unsubstituted heteroaryl).
- 4. The compound of claim 3, wherein! _! is a bond or a substituted or unsubstituted alkyl.
- 5. The compound of claim 1, wherein R6 is L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted aryl) or L2- (substituted or unsubstituted cycloalkyl), wherein L2 is a bond, OR , S, -S (0) 2, -C (O), -CH (OH) or (substituted or unsubstituted C 1-6 alkyl).
- 6. The compound of claim 5, wherein R 2 is H. The compound of claim 6, wherein R7 is L3-X-L4-G2, wherein: L3 is a substituted or unsubstituted alkyl; X is -NReC (O), -C (0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, NR9C (0) 0-, - N (R9) C (0) NR9, heteroaryl, aryl, -C (= NR10) NR9-, -OC (= NR, 0) -o C (= NR10) O; L4 is substituted or unsubstituted alkyl; G2 is H, -ORg, -C (= 0) CF3, -CN, -N (R9) 2, -N (R9) C (0) R9, -CO2R9, -CON (R9) 2, -L5- ( substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where. L5 is -OC (0) O-, -NHC (0) NH-, -NHC (0) 0, -C (0) CNH-, -NHC (O), -C (0) NH, -0 (0) ) 0 u -OC (O); G2 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR, 0) N (R9) 2, - NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, CON (R9) 2, -SR8, -S (= 0) R8 or -S (= 0) 2R5. 8. The compound of claim 7, wherein X is -NR9C (0), -C (0) NR9, -OC (0) N -NR9C (0) 0-, -N (R9) C (0) NR9 , heteroaryl or aryl. 9. The compound of claim 8, wherein G2 is H, -OR9, -C (= 0) CF3, -CN, -N (R9) 2, -N (R9) C (0) 9, -C02R9, -C (0) R9 or -CON (R9) 2. The compound of claim 6, wherein R7 is L3-X-L4-G4, where L3 is a substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NReC (O), -C ( 0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -N (R9) C (0) NR9- , heteroaryl, aryl; L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; G4 is -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0.0 (0) CNH -, - (O) OC-u -OC (O); or G4 is -l_5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0.0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G4 is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroarion, and G5 is H, halogen, tetrazolyl, -NHS (= 0) 2 8, S (= 0) 2N (R9) 2, OH, -OR8, -C (= 0) CF3, -CN, -N (R9) 2, -N (R9) C (0) R9, -C02R9, -C (0) R9, -CON (R9) 2. The compound of claim 10, wherein: X is a bond, O, -C (= 0), -CR9 (OR9), -NR9I-NR9C (0), -C (0) NR9, OC (0 ) NR9, -NR9C (0) 0-, -N (R9) C (0) NR9, heteroaryl, aryl; The compound of claim 11, wherein: G4 is W-G2, wherein W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G5 is H, OH, -OR8, -C (= 0) CF3, -CN, N (R9) 2, -N (R9) C (0) R9, -002R9, -C (0) R9, -CON (R9) 2. The compound of claim 1 (wherein: L7 is a bond, -O, -C (O), -C (0) NH, -NHC (O), (C 1-6 -alkyl substituted or unsubstituted), Lio is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), and G6 is H, CN, SCN, N3, N02, halogen, OR9, NR9C (0), C (0) NR9, C (= 0) CF3, C (= 0) RB, -SR9, -S (= 0) R9, N (R9) 2, tetrazoyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2. The compound of claim 13, wherein: L7 is a bond, and L10 is (substituted or unsubstituted aryl). 15. The compound of claim 14, wherein G6 is H; CN, SCN, N3, N02, halogen, OR9, -NR9C (0), -C (0) NR9, -C (= 0) CF3, -C (= 0) R9, or N (R9) 2. 16. The compound of claim 1, wherein the compound of formula (A) is an inhibitor of the 5-lipoxygenase activating protein (FLAP). 17. The compound of claim 16, wherein the inhibitor is selective for FLAP. 18. The compound of claim 16, wherein the inhibitor has an Cl50 of less than 50 microM at the junction with FLAP. 19. A pharmaceutical composition comprising "an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient." 20. A method for treating inflammation in a mammal comprising administering a therapeutically effective amount of a compound of claim 1 to mammal in need thereof 21. A method for treating respiratory diseases in a mammal comprising administering a therapeutically effective amount of a compound of claim 1 to the mammal in need thereof 22. A method for treating cardiovascular diseases in a mammal comprising administering an effective amount for therapeutic use of a compound of claim 1 to the mammal that needs it, 23. A compound having the structure of formula (B): wherein Z is selected from C (Ri) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 20. OC (Ri) 2 [C (R2) 2] n, where each R-es is independently H, CF3, or an optionally substituted lower alkyl and two on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently O, 1, 2, or 3; Y is H, -C02H, tetrazolyl, -NHS (= 0) 2R3b, S (= 0) 2N (R4) 2, OH, -OR3b, -C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (0) NHS (= 0) 2R3b, -S (= 0) 2NHC (0) R4, -CN, N (R «) 2. -N (R4) C (0) R4, -C (= NR3) N (R4) 2, -NR4C (= NR3) N (R4) 2, -NR4C (= CR3) N (R4) 2, -C (0) NR4C (= NR3) N (R4) 2l -C (0) NR4C (= CR3) N (R4) 2, -C02R3b, -C (0) R4, -COÑ (R4) 2, -SR3b , -S (= 0) R3b, -S (= 0) 2R3b, - ^ - (substituted or unsubstituted alkyl); or -l- (substituted or unsubstituted alkenyl), substituted or unsubstituted), -L-, - (cycloalkyl substituted or unsubstituted), -l- (substituted or unsubstituted heteroaryl), -L ? - (a r i I o substituted or unsubstituted); where is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, 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 (LSRS) ¡, where each Ls is independently selected from a bond, -O-, -C (= 0), -S-, -S (= 0) -, -S (= 0) 2- , -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC (0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl heteroaryl, aryl or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl heteroaryl or heteroalkyl; where j is 0, 1, 2, 3 or 4; each R3 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; each R3b 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 cycloalkyl, phenyl or benzyl; or two R4 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R3b and R "can together form a heterocyclic ring of 5, 6, 7 or 8 members; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heteroalicyclic group) or unsubstituted), L2- (substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2 , C (O), -CH (OH), - (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), or - (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); R7 is H, unsubstituted alkyl or alkyl substituted with a substituent selected from OH, alkoxy of 1 to 6 carbon atoms, C (0) OH and C (0) 0 (alkyl of 1 to 6 carbon atoms); R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 1 to 6 carbon atoms substituted or unsubstituted) , -L6- (substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH or C (0) NH; Rn is H, (substituted or unsubstituted alkyl) or (substituted or unsubstituted cycloalkyl); Ri2 is H or L3-X-L4-GL where 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 heteroaryl or unsubstituted, substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NRgC (O), -C ( 0) NR9, -S (= 0) 2NR9, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -N R9C (0) N R9-, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) N R9-, -OC (= NR10) -o -C (= N1R10) O; l_4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; Gi is tetrazolyl, halogen, -NHS (= 0) 2R3, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3. -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, -C. (= NR10) N (R9) 2, -NRgC (= NR10) N (R9) 2, - N R9C (= CR, 0) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CRi0) N (R9) 2, -C02R9, - C (0) R9, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted alkenyl or unsubstituted), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH , -0 (0) 0 u -OC (O); each R3 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or Ra and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R10 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2 -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; or its active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug. 24. The compound of claim 23, wherein: Z is C (R1) 2iC (R2) 2] n. or [C (R2) 2] eC (R1) 20. 25. The compound of claim 24, wherein: Y is H, C02H, tetrazolyl, OH, OR3b, CN, -C02R3b, -C (0) R4, -CON (R4) 2, -L, - (substituted alkyl or unsubstituted), -L1 - (substituted or unsubstituted heteroaryl), -L? - (a ri I o substituted unsubstituted); l_i is a link. 26. The compound of claim 25, wherein: Y is H, CN, -. ^ - (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted heteroaryl), - L -i- (ary I or substituted or unsubstituted); l_i is a link. 27. The compound of claim 26, wherein: Y is H, CN, -. ^ - (substituted or unsubstituted alkyl), -. ^ - (substituted or unsubstituted heteroaryl). 28. The compound of claim 23, wherein: R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, S (= 0), -S (= 0) 2, C (O), -CH (OH), or substituted or unsubstituted alkyl of 1 to 6 carbon atoms. 29. The compound of claim 23, wherein R ,, is H. 30. The compound of claim 29, wherein R7 is an unsubstituted alkyl. 31. The compound of claim 30, wherein: R12 is L3-X-L4-G1, where l_3 is a bond, substituted or unsubstituted alkyl group, or (substituted or unsubstituted aryl); X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -N R9, -NR9C (0), -C ( 0) NR9, -S (= 0) 2N (R9) 2, -NR9S (= 0) 2, -OC (0) NR9, -NR9C (0) 0-, -CH = NO-, ON = CH-, -N (R9) C (0) R9, -N (R9) C (= NR10) NR9, -NR9C (= NR10, -C (= NR10) NR9, OC (= NR10) -o -C (= NR10) O-; and L4 is a bond, or a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl 32. The compound of claim 31, wherein: X is a bond, O, -C (= 0), - CR9 (OR9), -NR9, -NR9C (0), -C (0) NR9, OC (0) NR9, -NR9C (0) 0-, or -N (R9) C (O) N R9. The compound of claim 32, wherein: Gi is H, halogen, tetrazolyl, -OR9I -C (= 0) CF3, CN, N (R9) 2. -N (R9) C (0) R9, -C02R9, -C (0) R9, or -CON (R9) 2. 34. The compound of claim 33, wherein: X is a bond, O, -C (= 0), -CR9 (OR9), -NR9C (0), -C (0) NR9, -OC (0) NRg, NR9C (0) 0-, or -N (R9) C (0) NR9; and L4 is a bond, or (substituted or unsubstituted alkyl). 35. The compound of claim 34, wherein: each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl. 36. The compound of claim 29, wherein: R7 is an alkyl substituted with a substituent selected from OH, alkoxy of 1 to 6 carbon atoms, C (0) OH, and C (0) 0 (alkyl of 1 to 6 carbon atoms). 37. The compound of claim 36, wherein: R12 is L3-X-14-Gi, where L3 is a bond, substituted or unsubstituted aryl or a substituted or unsubstituted heteroalicyclic group; X is a bond, O, -C (= 0), -CR9 (OR9), -NR9C (0), -C (0) NR9, -OC (0) NR9, -NR9C (0) 0; and L4 is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl; and Gi is halogen, -OR9, -C (= 0) CF3, -0 (0) N HS (= 0) 2R9, -S (= 0) 2NHC (0) R9, CN, N (R9) 2, - N (R9) C (0) R9, -002R9, -C (0) R9, -CON (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), where L5 is -00 (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (O) NH, -C (O ) O u -OC (O). 38. The compound of claim 37, wherein: L3 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroalicyclic group. 39. The compound of claim 23, wherein the compound of formula (B) is an inhibitor of the 5-lipoxygenase activating protein (FLAP). 40. The compound of claim 39, wherein the inhibitor is selective for FLAP. 41. The compound of claim 39, wherein the inhibitor has an Cl50 of less than 50 microM in binding with FLAP. 42. A pharmaceutical composition comprising an effective amount of a compound of claim 23 and a pharmaceutically acceptable excipient. 43. A method for treating inflammations in a mammal that comprises administering a therapeutically effective amount of a compound of claim 23 to the mammal in need thereof. 44. A method for treating respiratory diseases in a mammal wherein it comprises administering a therapeutically effective amount of a compound of claim 23 to the mammal in need thereof. 45. A method for treating cardiovascular diseases in a mammal comprising administering a therapeutically effective amount of a compound of claim 23 to the mammal in need thereof. 46. A compound having the structure of formula (H): wherein Z is selected from C (R9) 2 [C (R2) 2] i, [C (R2) 2] nC (R1) 20, OC (R,) 2 [C (R2) 2], [C (R2) 2] n [C (R9) 2]., Wherein each R, is independently H, CF3, or an optionally substituted lower alkyl and two Rn on the same carbon can be joined to form a carbonyl (= 0); and each R 2 is independently H, OH, OMe, CF 3, or an optionally substituted lower alkyl and two R 2 on the same carbon can be joined to form a carbonyl (= 0); m is 0, 1 or 2; each n is independently 0, 1, 2, or 3; Y is -C02H, -CONH2, -C (= 0) N (R4b) 2, -C02R4b, -OR3, -C (= 0) (fluoroalkyl of 1 to 6 carbon atoms), -C (= NOH) R b, -C (= NOR3b) R4, -Li- (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted alkenyl), -LI- (substituted or unsubstituted alkynyl), - [^ - (substituted cycloalkyl or unsubstituted), - ^ - (substituted or unsubstituted heteroaryl), - ^ - (substituted or unsubstituted heteroalicyclic group) or -Li- (substituted or unsubstituted aryl); where L, is -C (= 0), CR8OH, CR8OMe, C (= NOH), C (= NOR4b), C (= 0) NH, C (= 0) NR4b, -NHC (= 0), NR4bC ( = 0), S, S (= 0), S (= 0) 2. -NHC (= 0) NH or NR4bC (= 0) NR4b; where each substituent on Y or Z is d_5Rs) i, where each Ls is independently selected from a bond, -NH, -O-, -C (= 0) -, -S-, -S (= 0) -, - S (= 0) 2-, -NHC (O) -, -C (0) NH-, S (= 0) 2NH-, -NHS (= 0) 2, -OC (0) NH-, -NHC ( 0) 0-, -OC (0) 0-, -NHC (0) NH-, -C (0) 0-, -OC (O) -, alkenyl alkyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl or heteroalicyclic group; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -N02, N3, -S (= 0) 2NH2, lower alkyl, lower cycloalkyl, fluoroalkyl heteroaryl or heteroalkyl; where j is 0, 1, 2, 3 or 4; each R3 is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2, -C (0) R8, -CN, -N02, heteroaryl or heteroalkyl; each R3b 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 cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; or two R4 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R ^ and R4 can together form a heterocyclic ring of 5, 6, 7 or 8 members; each R3b is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted benzyl; substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroalicyclic group; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted heteroalicyclic group) or unsubstituted), l_2- (substituted or unsubstituted heteroanyl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= 0), -S (= 0) 2 , C (O), -CH (OH), - (substituted or unsubstituted C 1-6 alkyl) or - (substituted or unsubstituted C 2-6 alkenyl); R7 is L3-X-L-GL where; L3 is a bond or substituted or unsubstituted alkyl; X is a bond, O, -C (= 0), -CR9 (OR9), S, -S (= 0), -S (= 0) 2, -NR9, -NR9C (0), -C (0 ) NR9, -S (= 0) 2NR9, -N R9S (= O) 2,. -OC (O) NR9, -NR9C (0) 0-, -CH = NO-, -ON = CH-, -NR9C (0) NR9-, heteroaryl, aryl, -N (R9) C (= NR10) NR9-, -NR9C (= NR10), -C (= NR10) NR9-, -OC (= NRI0) - or -C (= NR10) O; L4 is a bond or substituted or unsubstituted alkyl; G, is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, -C (0) NHS (= 0) 2R8, - S (= 0) 2NHC (0) R9, CN, N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N ( R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NRsC (= NR10) N (Rs) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) RB, -CON (R9) 2, -SR8, -S (= 0) R8, -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -l_5- (substituted or unsubstituted aryl), where L5 is -OC (0) 0-, -NHC (0) NH-, -NHC (0) 0, -0 (0) CNH-, -NHC (O), -C (0) NH, -C (0) 0 u -OC (O); each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R9 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, phenyl or benzyl; or two R9 groups can together form a heterocyclic ring of 5, 6, 7 or 8 members; or R8 and R9 can together form a heterocyclic ring of 5, 6, 7 or 8 members and each R-io is independently selected from H, -S (= 0) 2R8, -S (= 0) 2NH2 -C (0) R8, -CN, -N02, heteroaryl to heteroalkyl; R5 is H, halogen, -N3, -CN, -ON02, -L6- (alkyl of 1 to 6 carbon atoms substituted or unsubstituted), -L6- (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted) , -L6- (substituted or unsubstituted heteroaryl) or -L6- (substituted or unsubstituted aryl), where L6 is a bond, O, S, -S (= 0), S (= 0) 2, NH, C (O), -NHC (0) 0, -OC (0) NH, -NHC (O), -NHC (0) NH-, or -C (0) NH; Rn is l_7-l_10-G6, where L7 is a bond, -O, -S, -S (= 0), -S (= 0) 2, -NH, -C (O), -C (0) NH , -NHC (O), (alkyl of 1 to 6 carbon atoms substituted or unsubstituted) or (alkenyl of 2 to 6 carbon atoms substituted or unsubstituted); Lio 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 heteroalicyclic group) or not substituted); G6 is H, CN, SCN, N3, N02, halogen, OR9, -C (= 0) CF3, -C (= 0) R9, -SR8. -S (= 0) R8, -S (= 0) 2R8, N (R9) 2, tetrazolyl, -NHS (= 0) 2R8, -S (= 0) 2N (R9) 2, -C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, -C (= NR10) N (Re) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (0) 0, -NHC (0) NH-, -OC (0) 0-, -OC (0) NH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); or G6 is W-G7, wherein W as (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl) ) and G7 is H, halogen, CN, N02, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl, tetrazolyl, -NHS (= 0) 2R8, S ( = 0) 2N (R9) 2, OH, -ON, -C (= 0) CF3, -C (0) NHS (= 0) 2R3, -S (= 0) 2NHC (0) R9, CN, N ( R9) 2, -N (R9) C (0) R9, -C (= NR, o) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR8C (= CRi0) N (R9) ) 2, -C (O) NR8C (= NR10) N (R9) 2, -C (O) NR8C (= CR10) N (R9) 2, -C02R9, -C (0) R9, -CON (R9) 2) -SR8, -S (= 0) R8 to -S (= 0) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -l_5- (heteroalkyl) substituted or unsubstituted), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heteroalicyclic group) or -L5- (substituted or unsubstituted aryl), where l_5 is a bond, -O-, C (= 0), S, S (= 0), S (= 0) 2, -NH, -NHC (0) 0, -NHC (0) NH-, -OC (0) 0- , -OC (0) NH-, -NHC (O), -C (0) NH, -C (0) 0 or -OC (O); R 2 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms); or its active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug. 47. The compound of claim 6, wherein Z is [C (R2) 2] nC (R1) 20. 48. The compound of claim 47, wherein: Y is -C02H, -CONH2, C (= 0) N (R4b) 2, -C02R4b, -OR3b, -C (= 0) (1-to-5-chloroalkyl) carbon atoms), C (= NOH) R4b, C (= NOR3b) R4b, -l_i- (substituted or unsubstituted alkyl), -Li- (substituted or unsubstituted cycloalkyl), or - L! - (replaced or unsubstituted). 49. The compound of claim 48, wherein: Y is -C02H, -CONH2, C (= 0) N (R4b) 2, -C02R4b, -0R3b, -C (= NOH) R4b, C (= NOR3b) R4b, substituted or unsubstituted), or -. ^ - (substituted or unsubstituted phenyl). 50. The compound of claim 49, wherein: R6 is L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), or L2- (substituted or unsubstituted aryl) wherein L2 is a bond, O, S, S (= 0), -S (= 0) 2, C (O), -CH (OH), or substituted or unsubstituted alkyl. 51. The compound of claim 50, wherein R, 2 is H. 52. The compound of claim 51, wherein: R ,, is L_7-L10-G6; and L7 is a link. 53. The compound of claim 52, wherein: G6 is W-G7, wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (a substituted heteroalicyclic group) or unsubstituted) or a (substituted or unsubstituted heteroaryl). 54. The compound of claim 53, wherein: G7 is H, halogen, CN, N02, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl of 3 to 6 carbon atoms, tetrazolyl, -OH, -OR8, -C (= 0) CF3, -CN, -C02R9, or CON (R9) 2. 55. The compound of claim 52, wherein: L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted aryl); and G6 is H, CN, SON, N3, N02, halogen, OR9, -C (= 0) CF3. C (= 0) R9, tetrazoyl, or L5- (substituted or unsubstituted alkyl). 56. The compound of claim 46, wherein L3 is a bond. 57. The compound of claim 56, wherein: L4 is a substituted or unsubstituted alkyl or bond; G, is H, tetrazolyl, -NHS (= 0) 2R8, S (= 0) 2N (R9) 2, -OR9, -C (= 0) CF3, C (0) NHS (= 0) 2R8, -S (= 0) 2NHC (0) R9, -CN, -N (R9) 2, -N (R9) C (0) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -C02R9, -C (0) R9, or CON (R9) '2. 58. The compound of claim 57, wherein X is a bond. 59. The compound of claim 58, wherein: is H, tetrazolyl, -OR9, -C (= 0) CF3, CN, -002R9, -C (0) R9, or -CON (R9) 2. 60. The compound of claim 46, wherein the compound of formula (H) is an inhibitor of the 5-lipoxygenase activating protein (FLAP). 61. The compound of claim 60, wherein the inhibitor is selective for FLAP. 62. The compound of claim 60, wherein the inhibitor has an Cl50 of less than 50 microM in binding with FLAP. 63. A pharmaceutical composition, comprising an effective amount of a compound of claim 46 and a pharmaceutically acceptable excipient. 64. A method for treating inflammations in a mammal, comprising administering a therapeutically effective amount of a compound of claim 46 to the mammal in need thereof. 65. A method for treating respiratory diseases in a mammal, comprising administering a therapeutically effective amount of a compound of claim 46 to the mammal in need thereof. 66. A method for treating cardiovascular diseases in a mammal, comprising administering a therapeutically effective amount of a compound of claim 46 to the mammal in need thereof. 67. A compound that is selected from: 3- [3-tert-Butylsulfanyl-5-carbomoylmethoxy-1- (4-chloro-benzyl) -1H-indo1-2-yl] -2,2-dimemethyl acid propionic (Compound 1-1); 3- [5 - ((S) -2-tert-Butoxycarbonyl-amino-2-phenyl-ethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic acid (Compound 1-2); 315 - ((R) -2-tert-butoxycarbonylamino-2-phenylethoxy) -3-tert-butylsulfa nor 1-1- (4-chloro-benzyl) -1H-indol-2-yl 1-2,2- dimethyl propionic (Compound 1-3); 3-15 - ((S) -2-amino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl- acid propionic (Compound 1-4); 3- [5 - ((S) -2-amino-2-phenylketoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-lndol-2-yl] -2 acid, 2-dimethyl-propionic (Compound 1-5); 345 - ((R) -2-Acetylamino-2-phenylethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid ( Compound 1-6); 3- [5 - ((S) -2-Acetylamino-2-phenyl-ethoxy) -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2, 2 acid -dimethyl propionic (Compound 1-7); 3- [5 - [(3-Butoxycarbonylam and non-pro-pilcarbamoyl) -methoxy] -3-te r-butylsulfa nyl-1- (4-chloro-benzyl) -1H-indol-2-yl] -2, 2-dimethyl-propionic (Compound 1-8); 3- [5 - [(3-Amino-propylcarbamoyl) -methoxy] -3-tert-butylsulfanyl-1- (4-chloro-benzyl) -1H-indo1-2-yl] -2,2-dimethyl acid propionic (Compound 1-9); Acid { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- [2 - '(4-fluoro-phenyl) -2-oxo-ethoxy] -1H-indo1-2-yl} -2,2-dimethyl-propionic (Compound 1-10); Acid { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- [2- (4-fluoro-pheny1) -2-hydroxy-ethoxy] -1H-indol-2-yl] -2,2-dimethyl -propionic (Compound 1-11); 3- (3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-. {2- (4-fluoro-pheny1) -2 - [(Z) -hydroxyimino] -ethoxy} - 1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 1-12); Acid (3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-. {2- ( 4-fluoro-pheny1) -2 - [(Z) -methoxyimino] -ethoxy.] -1H-indo1-2-yl) -2,2-dimethyl-propionic acid (Compound 1-13); - [3-tert-Butylsulfanyl-5-carbamoxymethoxy-1- (4-chloro-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-14); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-cyanomethoxy-1H-indo-1-yl] -2,2-dimethyl-propionic acid (Compound 1-15); 3- [5- (Benzylcarbamoyl-methoxy) -1- (4-bromo-benzyl) -3-tert-butylsulfanyl-1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-16); 3- [3-tert-Butylsulfanyl-5-carboxymethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-l] -2,2-d-methyl-propionic acid (Compound 1-17): 3- [3-tert-Butylsulfanyl-5- (2-hydroxy-propoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indole-2-i I] - 2, 2-dimethyl- propionic (Compound 1-18); 3- [3-tert-Butylsulfanyl-5-carbamoylmethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-19); 3- [3-tert-Butylsulfanyl-5- (1-carbamoyl-1-methyl-ethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl-propionic (Compound 1-20); Acid 3- [3-tert-Butylsulfanyl-5- (1-carbobxy-1-methylethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 1-21); Acid 3-} 3-tert-Butylsulfanyl-5- (2-methoxy-propoxy-1- [4- (6-methoxy-pyridin-3-yl) benzyl-1H-indol-2-yl.} -2,2-dimethyl- propionic (Compound 1-22); 3- {3-tert-Butylsulfanyl-5- (2-hydroxy-propoxy-1- [4- (6-methoxy-pyridin-3-yl) benzyl] -1H- indol-2-yl.) -2,2-dimethyl-propionic (Compound 1-23); 3-, {3-tert-Butylsulfanyl-5- (2-hydroxy-2-methyl-propoxy-1 [3 4- (6-methoxy-pyridin-3-yl) benzyl] -1H-indol-2-yl.} -2, 2-dimethyl-propionic acid (Compound 1-24); 3- (3-tert. -butylsulfanyl-5- (2-hydroxy-3,3-dimethyl-butoxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl.} -2, 2-dimethyl-propionic (Compound 1-25): 3-. {3-tert-Butylsulfanyl-5- [2- (4-fluoro-phenyl) -2-hydroxy-ethoxy-1- [4- (6 -methoxy-pyridin-3-yl) benzyl] -1H-indol-2-yl.} - 2, 2-dimethyl-propionic (Compound 1-26); Ethyl ester of 3-. {3-ter-3-acid} butylsulfanyl-5-carbamoylmethoxy-1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl.} -2, 2-dimethyl-propionic acid (Compound 1-27); 2- [3- tert-butylsulfanyl-1- (4-chloro-benzyl) -2-hydroxyl-2 -met.l-propyl) -1H-indol-5-yloxy] acetamide (Compound 2-1); 2- [3-tert-Butylsulfanyl-2- (2-, hydroxy-2-methyl-propyl) -1-pyrid, in-4-ylmethyl-lndol-5-yloxy ] -acetamide (Compound 2-2); 2- [3-tert-Butylsulfanyl] -1- (4-cyano-benzyl) -2- (2-hydroxy-2-methylene-propyl) -1H-indol-5-Moxy] -acetamide ( Compound 2-3); 2- [3-tert-butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1 - (4-iodo-benzyl) -1 H -indole-5-yloxyl-acetamide (Compound 2-4); 2- [3-tert-Butylsulfanyl-3- (2-hydroxy-2-methyl-propyl) -1- (4-iodo-benzyl) -1H-ynol-5-yloxy-acetamide (Compound 2-4 ); 2- [3-tert-Butylsulfanyl] -1-cyclopropylmethyl-2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -acetamide (Compound 2-5); 2- [3-tert-Butylsulfanyl] -1 - (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] -N, N-dimethyl -acetamide (Compound 2-6); 2- [3-tert-Butylsulfanyl-1-2- (2-hydrophenyl) -acetamide (Compound 2-7); 2- [3-tert-Butylsulfanyl] -1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1 H -indole-5-yloxy] -N- ( 4-chloro-benzyl) -N-pyridin-3-yl-acetamide (Compound 2-8); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1-pyridin-4-methyl-1H-ynol-5-yloxy] - N-cyclopropyl acetamide (Compound 2-9); 2- [3-tert-Butylsuifanyl] -2- (2-hydroxy-2-methyl-propyl) -1- (4-iodo-benzyl) -1H-indole-5-yloxyN- (4-iodine -benzyl) -acetamide (Compound 2-10); 2- [3-tert-Butylsulfanyl] -2- (2-hydroxy-2-methyl-propyl) -1- (4-pyridin-3-yl-benzyl) -1 H -indole- 5-yloxy] -acetamide (Compound 2-1); 2- [3-tert-Butylsuifanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy-acetic acid (Compound 2-12); Ethyl 2- [3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -H-indol-5-yloxy] -acetic acid ester (Compound 2-13); 1 -13-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (2-hydroxy-2-methyl-propoxy) -1H-indol-2-yl] 2-methyl-propan-2 -ol (Compound 2-14); 143- te r- buti I its I-1- (4-chloro-benzyl) -5- (2-hydroxyl-propoxy) -1H-indol-2-yl] -2-met 1-propan-2-ol (Compound 2-15); 1 - [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-yloxy] -propan-2- ona (Compound 2-16); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl] -N- (2-d-methyl-methylene-ethyl) -2, 2-dimethy1-proponamide (Compound 3-1); 5- (2-3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -1,1-d-methyl -ethyl) - [1,3,4] oxadiazol-2-ylamine (Compound 3-2); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-N-thiazole-2- il- "propionamide (Compound 3-3); N-. {3- [3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indole-2 -yl] -2,2-dimethyl-propionyl.} -formamide (Compound 3-4); 2-. {3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- [2-methyl -2- (5-methyl- [1,2,4] oxadia2ol-3-11) -propyl-1H-indol-5-yloxymethyl) -quinoline (Compound 3-5); 3- [3-tert-butylsulfanyl] -1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-N-pyridin-3-11-propionamide (Compound 3-6); 3- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-N-pyrazin-2 -yl-propionamide (Compound 3-7): 4- (2-Isobutyl-3,5-diisopropyl-indol-1-methylmethyl) -benzoic acid (Compound 4-1); N- (2-hydroxy-ethyl) -4- (2-isobutyl-3,5-diisopropyl-indol-1-iimethyl) -benzamide (Compound 4-2); N- (2-dimethylamino-ethyl) -4- (2-isobutyl-3,5-diisopropyl-indol-1-ylmethyl) -benzamide (Compound 4-3); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5-pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid (Compound 4-4); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5-pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid methyl ester (Compound 4-5); 4- [2- (2,2-Dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid (Compound 4-6); 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy-indole-ylmethyl] -N- (2-dimethylamino-ethyl) -benzamide (Compound 4- 7); 1- [3-tert-Butylsulfanyl-1-methyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol (Compound 5-1 ); 1 - (3- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl-azetidin-1-11 ) - ethanone (Compound 5-2): 1 - [3-tert-butylsulfanyl-1-cyclopropylmethyl-5- (pyridin-2-ylmethoxy) -1H-indol-211] -2-methyl-propan-2 -ol (Compound 5-3); 1- [3-tert-butylsulfanyl-1-cyclobutylmethyl-5- (pyridin-2-methoxy) -1H-indol-2-yl] -2-methyl-propan -2-ol (Compound 5-4): 4- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy-indole-1-ylmethyl) ] -N-cyclopropyl-benzamide (Compound 5-5): 4- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- (pyridin-2-ylmethoxy-indole -1-ylmethyl] -N- (2-hydroxy-ethyl) -benzamide (Compound 5-6); 2- [3-tert-butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -5- ( pyridin-2-ylmethoxy) -indol-1-yl] -acetamide (Compound 5 -7).
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