MX2008005633A - 5-lipoxygenase-activating protein (flap) inhibitors - Google Patents

5-lipoxygenase-activating protein (flap) inhibitors

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Publication number
MX2008005633A
MX2008005633A MXMX/A/2008/005633A MX2008005633A MX2008005633A MX 2008005633 A MX2008005633 A MX 2008005633A MX 2008005633 A MX2008005633 A MX 2008005633A MX 2008005633 A MX2008005633 A MX 2008005633A
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MX
Mexico
Prior art keywords
pyridin
compound
benzyl
acid
dimethyl
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MXMX/A/2008/005633A
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Spanish (es)
Inventor
H Hutchinson John
Peppi Prasit Petpiboon
Moran Mark
F Evans Jillian
M Arruda Jeannie
Simon Stock Nicholas
Andrew Stearns Brian
Roger Roppe Jeffrey
Yiwei Li
Eleanor Zunic Jasmine
Haddach Mustapha
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Amira Pharmaceuticals Inc
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Publication of MX2008005633A publication Critical patent/MX2008005633A/en

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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 ACTIVATING PROTEIN OF 5-LIPOXYGENASE (FLAP) Field of the Invention Compounds, methods for producing 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 of the invention are described herein. -lipoxygenase (FLAP). Background of the Invention The 5-lipoxygenase activating protein (FLAP) is associated with the leukotriene synthesis pathway. In particular, the 5-lipoxygenase activating protein (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). 5-lipoxygenase can then catalyze the oxygenation of two steps and 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 leukotriene A4 ( LTA4). Leukotrienes are biological compounds formed from arachidonic acid in the synthesis pathway of leukotrienes (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 including, 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 inhibitors of the 5-lipoxygenase activating protein (FLAP) described herein. In an aspect provided herein are compounds of formula (G), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically active 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, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. Formula (G) is the following: wherein, Z is selected from [C (R1) 2] m [C (R2) 2] n, [C (R2) 2] n [C (R1) 2] mO, O [C (R?) 2] m [C (R2) 2] n, [CÍRa lpOICÍR zln, or [CR zlnOICÍRa ln, where each R ^ is independently H, CF3, or an optionally substituted lower alkyl and two R over the same carbon can join to form a carbonyl (= O); 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 0, 1, 2 or 3; Y is H or - (substituted or unsubstituted aryl); or - (heteroaryl substituted or unsubstituted); where each substituent on Y or Z is (LsRs) j- where each Ls is independently selected from a bond, -O-, -C (= O) -, -S-, -S (= O) -, -S ( = O) 2-, -NHC (O) -, -C (O) NH-, S (= O) 2NH-, -NHS (= O) 2, -OC (O) NH-, -NHC (O) O-, -OC (O) O-, -NHC (O) NH-, -C (O) O-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms substituted or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -NO2, N3, -S (= O) NH2, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, fluoroalkyl from 1 to 6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl; where j is 0, 1, 2, 3 or 4; 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 (= O), -S (= O) 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-G ?, where, L3 is a substituted or unsubstituted alkyl; X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2, -NR9, -NRgC (O), -C (O ) NRβ, -NR9C (O) NR9-; L4 is a bond, or a substituted or unsubstituted alkyl; G-, is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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) NR 9 C (= CR 10) N (R 9) 2, -CO 2 R 9, -C (O) R 9, -CON (R 9) 2, -SR 8, -S (= O) R 8, -S (= O) 2R8, -Ls- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), wherein L5 is -OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or -OC (O); or G-, is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9 ) 2, OH, -ORß, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9) CN, N (R9) 2, -N (R9) C (O) 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, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted benzyl or unsubstituted each Rg 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 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 (= O) 2 R 8, -S (= O) 2 NH 2 -C (O) R 8 , -CN, -NO2, heteroaryl, or heteroalkyl; R 5 is H, halogen, alkyl of 1 to 6 carbon atoms substituted or unsubstituted, O-alkyl of 1 to 6 carbon atoms substituted or unsubstituted; Rn is L7-L10-G6, where L7 is a bond, -C (O), -C (O) NH, -NHC (O), or (substituted or unsubstituted alkyl of 1 to 6 carbon atoms); L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl) or (substituted or unsubstituted heterocycle); G6 is OR9, -C (= O) R9, -C (= O) OR9, -SR8I -S (= O) R8, -S (= O) 2R8, N (R9) 2, tetrazolyl, -NHS (= O) 2R8, -S (= O) 2N (R9) 2, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, -C (= O) N (R9) 2, NR9C (O) R9, C (R9) 2C (= O) N (R9) 2-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 heteroaryl or unsubstituted), or -L5- (substituted or unsubstituted aryl), wherein L5 -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, u -OC (O) or G6 is WG, wherein W is (substituted or unsubstituted heterocycle), (substituted or unsubstituted aryl) or a ( substituted or unsubstituted heteroaryl) and G7 is H, halogen, CN, NO2, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, tetrazolyl , -NHS (= O) 2R8, S (= O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O 2NHC (O) R9 > CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR10) N (Rβ) 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, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted alkenyl or unsubstituted), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heterocycle), or -L5- (substituted or unsubstituted aryl), where L5 is a bond , -O-, C (= O), S, S (= O), S (= O) 2, -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O -, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or -OC (O); provided that Rn comprises at least one aromatic moiety (unsubstituted or substituted) and at least one cyclic moiety (unsubstituted or substituted), wherein the cyclic moiety (unsubstituted or substituted) is a heterocyclic group (unsubstituted or substituted) or a heteroaryl group (unsubstituted) or substituted) and Rn is not a thienyl group phenyl; 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. For any and all embodiments (such as, for example, Formula (G), Formula (G-1), and Formula (G-11)), the substituents may be selected from a subset of the alternatives mentioned. For example, in some modalities, Z is [CfRa lnCíRi O. In other modalities or alternative modalities, Y is - (substituted or unsubstituted heteroaryl) or - (substituted or unsubstituted aryl) and G6 is W-G. In other modalities or alternative modalities, Y is - (substituted or unsubstituted heteroaryl). In other alternative embodiments or embodiments, Y is selected from the group consisting of pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl. , benzofuranyl, cinolinyl, indazolyl, i ndolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo [1,2- a] pi-ridyl and furopyridinyl, where Y is substituted or unsubstituted. In other alternative embodiments or modalities, Y is selected from the group consisting of pyridinyl or quinolinyl, wherein Y is substituted or unsubstituted. In other alternative embodiments or embodiments, 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 ( O) 2, -C (O), or substituted or unsubstituted alkyl. In other embodiments or alternative embodiments, X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2, -NR9 > In other embodiments or alternative embodiments, Gi is tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (= O ) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR? O) N (R9) 2, -NR9C (= NR10) N (R9) 2l -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SRβ, -S (= O) Rβ or -S (= O) 2R8. In other embodiments or alternative embodiments, L3 is unsubstituted alkyl; X is a link; L4 is a link; and d is -OR9. In other embodiments or alternative embodiments, Rg is H or unsubstituted alkyl. In other embodiments or alternative embodiments, L10 is a substituted or unsubstituted aryl substituted or unsubstituted heteroaryl and G6 is W-G7 where W is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle. In other embodiments or alternative embodiments, L10 is a substituted or unsubstituted aryl. In other embodiments or alternative embodiments, L3 is unsubstituted alkyl; X is a link; L is a link; and Gi is -OR9. In other embodiments or alternative embodiments, G- is W-G5, where W is a substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl. 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 set forth in the present. In one aspect, provided herein is a compound selected from: 3- [3-tert-butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H- indole-2-yl] -2,2-dimethyl-propionamide (Compound 1-1); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indole-2- acid ethyl ester il] -2,2-dimethyl-propionic (Compound 1-2); 6-hydroxy-hexyl esters of 3- [3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 1-3); 1- [3-tert-Butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1 H -indol-2-yl] -2-methyl-propan-2 -ol (Compound 1-4); 1- [3-tert-Butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1 H -indol-2-yl] -2-methyl-propan-2 -ol (Compound 1-5); 1- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1 H -indol-2-yl] -2-methyl-propan-2 -ol (Compound 1-6); 1- [3-tert-Butylsulfanyl-1- (4- [1, 3,4] oxadiazol-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - 2-methyl-propan-2-ol (Compound 1-7); 3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -2- (2-methyl-2- [1, 3,4] oxadiazol-2-yl-propyl) -5- (pyridin-2-ylmethoxy) -1 H -indole (Compound 1-8); 5-. { 2- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 Hi ndol-2-yl] -1, 1-dimethyl-ethyl} - [1, 3, 4] oxa di azo I -2-ylamine (Compound 1-9); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 , 2-dimethyl-N-pyrazin-2-yl-propionamide (Compound 1-10); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2, 2-dimethyl-N-thiazol-2-yl-propionamide (Compound 1-11); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyrid i n-2-i I methoxy) -1 H -indol-2-yl] -2,2-dimethyl-N-pyridin-3-yl-propionamide (Compound 1-12); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -N - (2-dimethylamino-ethyl) -2,2-dimethyl-propionamide (Compound 1-13); 5-. { 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -phenyl} - [1,3,4] oxadiazol-2-ylamine (Compound 1-14); 3- [3-tert-Butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -N - (2-dimethylamino-ethyl) -2,2-dimethyl-propanoylguanidine (Compound 1-15); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) - 1 H -indo l-2-yl] -2, 2 acid -d imetyl-propion ico (Compound 2-1); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-pyrimidin-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-2); acid - [3-tert-Butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- (pyridin-2-yl-methoxy) -1H-indol-2-yl] -2,2-dimethyl -propionic (Compound 2-3); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-pyrimidin-5-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-4); 3- [3-tert-Butylsu Ifa nor 1-1 - (4-pi razin-2-l-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-5); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) - acid be ni c] -5- (pyrid i n -2-yl methoxy) -1 H-indol-2-yl] -2, 2-d imethyl-propionic acid (Compound 2-6); 3- [1- [4- (5-Amino-pyrazin-2-yl) -benzyl] -3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-7); 3- [3- (3,3-dimethyl-butyryl) -5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1 H -i ndol-2-yl] acid -2, 2-d imethyl propionic acid (Compound 2-8); 2,2-dimethyl-3- [5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -propionic acid (Compound 2-9 ); 3- [3-Acetyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1 H -indol-2-yl] -2,2-dimethyl-propionic acid ( Compound 2-10); 3- [1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-11); 3- [3-acetyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2, 2-d imethyl propionic acid (Compound 2-12); 3- [3-ethyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2 acid -dimethyl propionic (Compound 2-13); 3- [3- (3,3-Dimethyl-butyl) -5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-14); 3- [3-Cyclopropanecarbonyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-15); 3- [3-Cyclobutanecarbonyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-16); 3- [3-tert-Butylsulfanyl-1- [4- (6-hydroxy-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-17); 3- [3-te rc-butylsulfa nor 1-1 - (4-pyrid-n-4-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid 2,2-dimethyl-propionic (Compound 2-18); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-19); 3- [3-tert-Butylsulfanyl-1- [4- (6-methyl-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2, 2-di meti l-prop ion ico (Compound 2-20); 3- [3- te rc-butylsulfa nyl-1- [4- (5-methyl-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-21); 3- [3-Cyclobutylmethyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-22); 3- [3- te rc-butylsulfa nyl-1- [4- (6-me toxy-pyridazin-3-yl) -benzyl] -5- (2-methyl-thiazol-4-ylmethoxy) -1 H- indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-23); 3- [3-tert-Butylsulfanyl-5- (2-methyl-thiazol-4-ylmethoxy) -1- (4- thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-24); 2,2-Dimethyl-3- [5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -propionic acid ( Compound 2-25); 3- [3- (3, 3-d imethyl-butyrol) -5- (2-methyl-thiazol-4-yl-methoxy) -1- (4-thiazol-2-yl-benzyl) -1 H acid -indol-2-yl] -2, 2-d imethyl propionic acid (Compound 2-26); 3- [1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (2-methyl-thiazol-4-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-27); 3- [3- (3,3-dimethyl-butyryl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (2-methyl-thiazole-4-i-methoxy) acid ) - 1 H -in l-2-yl] -2, 2-d-imethyl-propionic acid (Compound 2-28); 3- [3-ethyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-29); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-30); 3- [3-tert-Butylsulfanyl-5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-pyrimidin-2-yl-benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl propionic (Compound 2-31); 3- [5- (benzothiazol-2-ylmet oxy) -3-te rc-butylsulfa nyl-1- (4-pyrimidin-2-yl-benzyl) -1H-indol-2-yl] -2,2- acid dimethyl propionic (Compound 2-32); 3- [3-tert-Butylsulfanyl-1- [4- (2-methyl-3-pyridin-2-ylmethyl- 3H-imidazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-33); 3- [3-tert-Butylsulfanyl-1- [4- (2,4-dimethyl-thiazol-5-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-34); 3- [3-tert-Butylsulfanyl-1- [4- (5-fluoro-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-35); 3- [3-tert-Butylsulfanyl-1- [4- (4-methyl-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-39); 3- [3- te rc-butylsulfa nyl-1- [4 - (3, 5-dimethyl-isoxazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-41); 3- [3-tert-Butylsulfanyl-1- [4- (3-methyl-3H-imidazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-43); 3- [3- te rc-butylsulfa nyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2, 2-d imethyl propionic acid (Compound 2-47); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1 - (4- [1,3,4] thiadiazol-2-yl-benzyl) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-55); 3- [3-tert-Butylsulfanyl-1- [4- (6-hydroxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -i ndol-2-yl] acid -2, 2-di meti l-prop ionic (Compound 2-62); 3- [3-tert-Butylsulfanyl-1- [4- (6-cyano-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-64); acid 3-. { 3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-65); 3- [3-te rc-butylsulfa nyl-1- [4- (2-methoxy-pyrimidin-5-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-67); 3- [3-te rc-butylsulfa nor 1-1 - [4- (2-methoxy-thiazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-68); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1 H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-73); acid 3-. { 3-te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-76); 3- [3-tert-Butylsulfanyl-1- [4- (4-methoxy-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-77); 3 - acid. { 3-te rc-butylsulfa nyl-5- (6-fluo ro-quinolin-2-ylm and oxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzoyl] -1H-indole-2 -il} -2,2-dimethyl-propionic (Compound 2-78); 3- [3-tert-Butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -be n-1] -5- (5-methyl-pyrid i n-2- i I methoxy) acid -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-82); acid 3-. { 3-tert-Butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (3-fluoro-pyridin-2-yl) -benzoyl] -1H-indol-2-yl} -2, 2-d imetil-propion ico (Compound 2-84); 3- [3-tert-Butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-85); 3- [3-tert-Butylsulfanyl-1- [4- (5-carbamoyl-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -i ndol-2-yl] acid -2, 2-d imethyl propionic acid (Compound 2-87); 3- [3- te rc-butylsulfa nyl-1- [4- (5-cyano-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-88); 3- [3- te rc-butylsulfa nyl-1- [4 - (5-methoxy-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -i ndol-2 acid -yl] -2, 2-d imethyl propionic acid (Compound 2-89); 3- [3-te rc-butylsulfa nor 1-1 - [4- (6-methyl-pyrid i n-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-90); acid 3-. { 3- te rc-butylsulfa nyl-5- (pyridin-2-ylmethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-91); 3- [3-tert-Butylsulfanyl-1- [4- (2-ethoxy-thiazol-4-yl) -benzyl] - acid - (pyrid i n-2-i I methoxy) -1 H-indol-2-yl] -2,2-d imethyl propionic acid (Compound 2-92) '; 3- [3-tert-Butylsulfanyl-1- [4- (4-methyl-1 H-imidazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-93); 3- [3-te rc-butylsulfa nyl-1- [4 - (6-e-toxi-pyridin-3-yl) -benzyl] -5- (pyrid i n-2-i I methoxy) -1 H- acid indole-2-yl] -2,2-d imethyl propionic acid (Compound 2-94); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-95); 3- [3-te rc-butylsulfa nyl-1- [4- (5-metoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-96); 3- [3-te rc-butylsulfa nyl-1- [4- (6-carba moi l-pyrid i n-3-i I) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-97); 3- [3-te rc-butylsulfa nyl-1- [4 - (5-methyl-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -i ndol-2- acid il] -2, 2-d imethyl propionic acid (Compound 2-98); acid 3-. { 3-te rc-butylsulfa nyl-5- (6-f luoro-pyridin-2-ylmethoxy) -1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-99); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (6-methoxy-pyridin-2-ylmethoxy) -1H-indole-2 acid -il] -2,2-dimethyl- propionic (Compound 2-100); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (6-methyl-pyridin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-101); acid 3-. { 3-te rc-butylsulfa nyl-5- (5-met il-pyridin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 2-102); acid 3-. { 3-te rc-butylsulfa nyl-5- (5-met il-pyridin-2-ylmethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-103); acid 3-. { 3-tert-Butylsulfanyl-5- (o-cyclopropyl-pyridinyl-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-104); 3- [3-tert-Butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-105); 3- [3- te rc-butylsulfa nyl-1- [4- (6-me toxy-pyridazin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-106); 3- [3-te rc-butylsulfa nor 1-1 - [4- (6-ethoxy-pyrid i n-3-yl) -benzyl]] - 5- (5- met i I -pyrid in -2- i I methoxy) -1 H -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-107); acid 3-. { 3-te rc-butylsulfa ni l-5- (5-chloro-p i rid i n-2-yl methoxy) -1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -indol-2-il} -2,2-dimethyl-propionic (Compound 2-108); acid 3-. { 3-tert-Butylsulfanyl-5 - ((S) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-109); acid 3-. { 3-tert-Butylsulfanyl-5 - ((R) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-110); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5 - ((S) -1-pyridin-2-yl-ethoxy) -1H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-111); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1H- acid indole-2-yl] -2,2-dimethyl-propionic (Compound 2-112); 3- [3-te rc-butylsulfa nyl-1 - [4- (6-methoxy-pyridin-2-yl) -benzyl] -5 - ((S) -1-pyridin-2-yl-ethoxy) - acid 1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-113); 3- [3- te rc-butylsulfa nyl-1- [4- (6-meto xi-pyridin-2-yl) -be n ci l] -5- ((R) -1-pyrid in -2- acid il-ethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-114); 3- [3-tert-Butylsulfanyl-1- [4- (2-ethoxy-thiazol-4-yl) -benzyl] -5 - ((S) -1-pyridin-2-yl-ethoxy) -1 H acid -i ndol-2-yl] -2, 2-d imethyl propion ico (Compound 2-115); 3- [3- te rc-butylsulfa nyl-1- [4 - (2-ethoxy-thiazol-4-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) - acid 1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-116); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) - acid benzyl] -5- (3-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-117); acid 3-. { 3-te rc-butylsulfa ni l-5- (3-methyl-pyrid i n-2-i I methoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-118); acid 3-. { 3-tert-Butylsulfanyl-5- (3,5-dimethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-119); acid 3-. { 3-tert-Butylsulfanyl-5- (3,5-dimethyl-pyridin-2-ylmethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-120); acid 3-. { 5- (benzothiazol-2-ylmethoxy) -3-te rc-butylsulfa or 1-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-121); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1 - [4- (5-methoxy-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2 > 2-dimethyl-propionic (Compound 2-122); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-123); acid 3-. { 5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -i ndol-2-yl} -2, 2-d imethyl propionic acid (Compound 2-124); acid 3-. { 3-te rc-butylsulfa ni l-5- (5-ethyl-pyrid i n-2-i I methoxy) -1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H- Indole-2-il} -2, 2-d imetil-propion ico (Compound 2-125); 3- [3-te rc-butylsulfa nor 1-1 - [4- (6-ethoxy-pyrid i n-3-yl) -benzyl] -5- (5-ethyl-pyridin-2-ylmethoxy) -1H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-126); 3 - acid. { 3-te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4 - (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-127); acid 3-. { 3-tert-Butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-128); 3- [3- te rc-butylsulfa nyl-1- [4- (2-ethoxy-thiazol-4-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1 H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-129); 3- [3- te rc-butylsulfa nyl-1 - [4 - (2-methoxy-thiazol-4-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1 H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-130); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-131); 3- [3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2.2 acid -dimethyl propionic (Compound 2-132); 3- [3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2, 2-d imethyl propionic acid (Compound 2-133); 3- [3-Isobutyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-134); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-135); 3 - acid. { 3-te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-136); acid 3-. { 3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-137); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-138); 3- [3- te rc-butylsulfa nyl-1- [4- (6-etho xi-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H -indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-139); 3 - acid. { 3-te rc-butylsulfa nyl-5- (6-fluo ro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -1 H -indole-2 -il} -2, 2-d meti I-propionic (Compound 2-140); acid 3-. { 3-te rc-butylsulfa nyl-5- (6-f luoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 2-141); 3- [3-te rc-butylsulfa nor I- 1- [4- (2-ethoxy-thiazol-4-yl) -benz I] - acid - (6-Fluoro-quinolin-2-ylmethoxy) -1 H -indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-142); acid 3-. { 3-te rc-butylsulfa nyl-5- (6-f Io-quinolin-2-ylm and oxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-143); acid 3-. { 3-tert-Butylsulfanyl-5- (7-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-144); acid 3-. { 3-tert-Butylsulfanyl-5- (7-fluoro-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-145); acid 3-. { 3- te rc-butylsulfa nyl-5- (7-f luoro-quinolin-2-ylm and oxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indole 2-il} -2,2-dimethyl-propionic (Compound 2-146); 3- [3- te rc-butylsulfa nyl-1- [4 - (6-e-toxi-pyridin-3-yl) -benzyl] -5- (7-fluoro-quinolin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-147); acid 3- [3-te rc-butylsulfa or 1-1 - [4- (3-f I u-ro-pi rid i n-2-i I) -benzyl] -5- (6-fluoro-quinolin-2) -ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-148); acid 3-. { 3- te rc-butylsulfa nyl-5- (5-met il-pyridin-2-ylmethoxy) -1 • [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-149); 3 - acid. { 3-te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl- propionic (Compound 2-150); 3 - acid. { 3- te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1- [4 - (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-151); acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-156); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (3-methyl-pyridin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-157); acid 3-. { 3-te rc-butylsulfa ni l-5- (3-meti l-pyrid i n-2-I methoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H- Indole-2-il} -2,2-dimethyl-propionic (Compound 2-158); acid 3-. { 3-te rc-butylsulfa ni l-5- (3,5-dimeti l-pyrid i n-2-i I methoxy) -1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] - 1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-159); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (4-methyl-pyridin-2-ylmethoxy) -1 H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-160); 3- [3-te-r-butylsulfa nyl-1- [4- (6-e-toxi-pyridin-3-yl) -benzyl] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-161); acid 3-. { 3-tert-Butylsulfan i l-5- (4-methy1-pyrid i n-2-i-methoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-162); acid 3-. { 3-cyclobuti I met i I -5- (5-met i l-pyrid i n-2-i I methoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1 H -indol-2-il} -2,2-dimethyl-propionic (Compound 2-163); 3- [3-te rc-butylsulfa nor 1-1 - [4- (6-ethoxy-pyrid-n-3-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) - 1H-indol-2-yl] -2,2-dimethyl-propionic of (Compound 2-164); acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-165); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (6-methyl-quinolin-2-ylmethoxy) -1 H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-166); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-methyl-quinolin-2-ylmethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-167); 3- [3-tert-buty] Isulfa nyl-1 - [4- (6-methy1-pyrid-azi-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indole -2-yl] -2, 2-d imethyl propionic acid (Compound 2-168); 3- [3-tert-Butylsulfanyl] -1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-169); 3- [3-Isobutyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2 acid, 2-dimethyl-propionic (Compound 2-170); acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) - 1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-171); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -3- (2-methyl-propane-2-sulfonyl) -5- (pyridin-2-ylmethoxy) -1 H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-172); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -3- (2-methyl-propane-2-sulfinyl) -5- (pyridin-2-ylmethoxy) -1 H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-173); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (1-oxy-pyridin-2-ylmethoxy) -1H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-174); acid 3-. { 3-te rc-butylsulfa nyl-5- (imidazo [1,2- a] pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-175); 3- [3-te rc-butylsulfa nyl-1- [4 - (6-etho xi-pyridin-3-yl) -benzyl] -5- (imidazo [1, 2-a] pyrid i n-2- i I methoxy) -1H-indol-2-yl] -2,2-d-imethyl-propionic acid (Compound 2-176); acid 3-. { 3- te rc-butylsulfa nyl-5- (imidazo [1,2- a] pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-177); 3- [3-tert-Butylsulfanyl-1 - [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1 H acid -i ndol-2-yl] -2, 2-d imethyl propionic acid (Compound 2-178); acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1 - [4- (6-methyl-1-pyrid-azi-3-yl) -benzyl] -1H-indol-2-yl } -2, 2-d i meti I- propionic (Compound 2-179); 3- [3- te rc-butylsulfa nyl-1- [4- (6-rpetoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-180); 3- [3-te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridin-3-yl) -benzyl] -5- (5-methyl-isoxazol-3-ylmethoxy) -1 Hi ndol acid -2-il] -2, 2-d meti I-propionic (Compound 2-181); acid 3-. { 3-tert-Butylsulfanyl-5- (5-methyl-isoxazol-3-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-182); acid 3-. { 3- te rc-butylsulfa nyl-5- (2,5-dimethyl-2H-pi-razo I -3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H -indol-2-il} -2,2-dimethyl-propionic (Compound 2-183); acid 3-. { 3-te rc-butylsulfa nyl-5- (1, 5-dimethyl-1H-p1-razol-3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H- Indole-2-il} -2,2-dimethyl-propionic (Compound 2-184); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridazin-3-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-185); 3- [3- te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridazin-3-yl) -benzyl] -5- (5-eti l-pyrid i n-2-ylmethoxy) - 1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-186); 3 - acid. { 3-te rc-butylsulfa ni l-5- (5-eti l-pyrid i n-2-i I methoxy) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1 H -indol-2-il} -2,2-dimethyl-propionic (Compound 2-187); 3- [3-tert-Butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-188); 3- [3-te rc-butylsulfa nyl- 1- [4- (5-f I uoro-pyrid i n-2-i I) -benzyl] -5 - ((R) -1-pyridin-2-acid il-ethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-189); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-2-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-190); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-2-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1 H acid -indol-2-yl] -2, 2-d imethyl propionic acid (Compound 2-191); 3- [3-tert-butyl ulfan i 1-1 - [4- (5-fl uoro-pyrid i n-2-i I) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) acid -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-192); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-2-yl) -benzyl] -5- (5-met i l-pyrid i n-2-i I methoxy) acid 1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-193); acid 3-. { 5- (6-Fluoro-quinolin-2-ylmethoxy) -3-isobutyl-1- [4- (6-tri-fluoro-methyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2, 2-d imethyl propionic (Compound 2-194); acid 3-. { 3-te rc-butylsulfa nyl-5- (pyridin-2-ylmethoxy) -1 - [3- (5-tri-fluoro-methyl-pyridin-2-yl) -benzyl] -1H-indole-2-yl} -2, 2-dimethyl-propionic (Compound 2-195); 3- [3-tert-Butylsulfanyl-1- [3- (6-methoxy-pyridin-3-yl) - acid benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-196); 3- [3- te rc-butylsulfa nyl-1- [4- (5-fl uo-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-197); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-198); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-199); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-f luoro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-200); 3- [3-tert-Butylsulfanyl-1 - [4- (5-fluoro-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-201); acid 3-. { 3-tert-buti Isulfa ni l-5- (5-meti l-pyrid i n-2-i I methoxy) -1 - [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H- Indole-2-il} -2,2-dimethyl-propionic (Compound 2-202); acid 3-. { 3- te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-203); acid 3-. { 3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl- propionic (Compound 2-204); 3- [3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1-indol-2-yl] -2, 2- acid d imetyl-propion ico (Compound 2-205); 3- [3- te rc-butylsulfa nor 1-1 - [3- (4-methoxy-tetrahydro-pi-ra n-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-206); acid 3- [3-te rc-butylsulfa ni I -5- (6-f I uoro-qu i noli n-2-i I methoxy) -1 - (4-pyrid i n-2-i l-benz I ) - 1 H-indol-2-yl] -2, 2-d imethyl propionic acid (Compound 2-207); 3- [3-te rc-butylsulfa nor l-5- (5-eti l-pyridin-2-yl methoxy) -1 - (4-pyridin-3-yl-benzyl) -1H-indole-2-acid il] -2,2-dimethyl-propionic (Compound 2-208); 3- [3-tert-Butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-209), 3- [3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- (4-pyridin-3-yl-benzyl) -1H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-210); 3- [3-tert-Butylsulfan i l-5- (5-methy1-pyrid i n-2-yl methoxy) -1 - (4-pyridin-2-yl-benzyl) -1H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-21); 3- [3- te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - (4-pyridin-2-yl-benzyl) -1H-indol-2-yl] -2 , 2-dimethyl-propionic (Compound 2-212); 3- [3-te rc-butylsulfa nyl-1- (4-pyridin-2-yl-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl acid -propionic (Compound 2-213); 3- [3-te rc-butylsulfa nyl-5- (5-methyl-pyridin-2-ylme-toxy) -1 - (4-pyridin-3-yl-benzyl) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-214); 3- [3-tert-Butylsulfanyl-1 - [4- (4-methoxy-pyridin-2-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-215); 3- [3-te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1- (4 - (3-methoxy-pyridin-2-yl) -benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-216); 3- [3- te rc-butylsulfa nyl-5- (5-methyl-pyridin-2-ylmethoxy) -1 - (4- (3-methoxypyridin-2-yl) -benzyl) -1 H -indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-217); 3- [3- te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indole-2- il] -2,2-dimethyl-propionic (Compound 2-218); 3- [3-tert-Butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-219), 3- [3- te-tert-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - (4- (4- trifluoromethylpyridin-2-yl) -benzyl) -1 H -indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-220); 3- [3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (4- trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-221); 3- [3-te rc-butylsulfa nyl-5- (5-met l-pyridin-2-ylmethoxy) -1 - (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic acid (Compound 2-222), 3- [3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (5 -fluoropyridin-3-yl) -benzyl) -1H-indol-2-yl] -2,2-d-imethyl-propionic acid (Compound 2-223); 3- [3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl-propionic (Compound 2-224); 3- [3-? et-Butylsulfanyl-5- (2,3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (2-methoxypyridin-5-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-225); 3- [3-tert-b u ti Isulfa ni l-5- (2, 3-d imeti l-pyridin-6-i I methoxy) -1- (4- (3-trifluoromethylpyridin-2-yl)] -benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-226); 3- [3-te rc-butylsulfa nyl-5- (2,3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-227); 3- [3- te rc-butylsulfa nyl-5- (2,3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (3-fluoropyridin-2-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-228); 3- [3-tert-Butylsulfanyl-5- (2,3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indole-2- acid il] -2,2-dimethyl- propionic (Compound 2-229); 3- [3-te rc-butylsulfa nor l-5- (2, 3-di met i l-pyrid i n-6-i I methoxy) -1- (4- (4-methoxy pyrid i n-2) -yl) -benzyl) -1H-indol-2-yl] -2, 2-d-meti I-propionic (Compound 2-230); 3- [3-te rc-butylsulfa nyl-5- (2, 3-dimethyl-pyri din-6-ylmet oxy) -1- (4- (pyridin-2-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-231); 3- [3- te rc-butylsulfa nyl-5- (5-met il-pyridin-2-ylm ethoxy) -1 - (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H- indole-2-yl] -2,2-dimethyl-propionic (Compound 2-232); 3- [3- te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-233); 3- [3- te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-d imetil-propion ico (Compound 2-234); 3- [3-tert-Butylsulfanyl-1- (6'-methoxy- [2,3 '] bipyridinyl-5-ylmethyl) -5- (pyridin-2-ylmethoxy) -1 Hi ndol-2-yl] - acid 2, 2-di methyl-propionic ion (Compound 3-1); 3 - [3- te rc-butylsulfa nyl-1- [6- (4-methoxy-phenyl) -pyridin-3-ylmethyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2,2-dimethyl-pro pion ico (Compound 3-2); acid 3-. { 3- te rc-butylsulfa nyl-5- (pyridin-2-ylmethoxy) -1- [6 - (4-tri-fluoro-methoxy-phenyl) -pyridin-3-ylmethyl] -1H-indol-2-yl} -2, 2-d imethyl propionic (Compound 3-3); 3- [3-tert-Butylsulfanyl-1- [5- (4-methoxy-phenyl) -pyridin-2-ylmethyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 3-4); acid 3-. { 3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [5- (4-trifluoromethoxy-phenyl) -pyridin-2-ylmethyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 3-5); acid 3-. { 3- te rc-butylsulfa nyl-5-isopro pil-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 4-1); and acid 3-. { 3-tert-Butylsulfanyl-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -be nci I] - 1 H -indo l-2-yl} -2, 2-d imethyl propionic acid (Compound 4-2). In one aspect, provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein, and a pharmaceutically acceptable excipient. In another aspect, provided herein is a method for treating inflammation in a mammal comprising administering a therapeutically effective amount of a compound provided herein to the mammal in need. In yet another aspect, provided herein is a method of treating asthma in a mammal comprising administering a therapeutically effective amount of a compound provided herein to the mammal in need thereof. In another modality or alternative modality, provided in the present is a method for treating asthma in a mammal comprising the administration, to the mammal in need, of a therapeutically effective amount of a compound provided herein, such as, for example, a compound of any Formula (G), Formula (Gl), or Formula (G-ll), where Z is [C (R2) 2] nC (R1) 2O. In another aspect are the compounds presented in Figures 8, 9, 10 or 11, or their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, which antagonize or inhibit FLAPs. 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, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In another aspect are the compounds presented in any of Tables 1, 2, 3 or 4, or their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates, which antagonize or inhibit the FLAP and they 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, syndrome adult respiratory distress, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions. In other embodiments or alternative embodiments, the compounds of any of Formula (G), Formula (G-1), or Formula (G-ll), can be inhibitors of the 5-lipoxygenase activating protein (FLAP), while even in other modalities or alternative modalities, such inhibitors are selective for 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 (G), Formula (Gl), or Formula (G-ll), 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 cutaneous or lymphatic 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 in, or abnormal location of, 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 cellular activation of 5-lipoxygenase, while in other aspects the methods, compounds, pharmaceutical compositions, and medicaments described in 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 synthesis activity of the leukotrienes 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 (G), Formula (Gl), or Formula (G-ll). In another alternative modality or modality, the "G" group (for example G ,, G5, G6, G7) of any of the Formula (G), Formula (Gl), or Formula (G-ll), is any group that it 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, in vivo metabolism may include, by way of example only, controlling PK properties in vivo, off-site activities, toxicities associated with cypP450 interactions, drug-drug interactions, and the like. In addition, modifications to "G" allow the adequacy of efficacy in vivo of the compound through modulation, by way of 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 embodiments, "G" is L20-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 antagonists of CysLT1 / CysLT2 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 there 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 (G), Formula (Gl), or Formula (G-ll).
In another aspect there are methods for modulating, including reducing and / or inhibiting the 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 (G), Formula (Gl), or Formula (G-ll). In another aspect are methods for treating leukotriene-dependent or 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 the Formula ( G), Formula (Gl), or Formula (G-ll). 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 (G), Formula (Gl), or Formula (G-ll). 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 (G), Formula (Gl), or Formula (G-ll). In another modality of this aspect, the respiratory disease is asthma. In another modality of this aspect 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, allergen-induced asthma, aspirin-sensitive asthma, asthma induced by physical exercise, isocanic hyperventilation, childhood-onset asthma , adult onset asthma, asthma with cough variant, occupational asthma, asthma resistant to steroids, stationary asthma. In another aspect are methods for treating chronic obstructive pulmonary disease 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 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 airway inflammation and cystic fibrosis. In another aspect are methods for preventing secretion and / or increased mucosal edema in a disease or condition comprising administering to the mammal at least once, an effective amount of at least one compound having the structure of any of the Formula (G), Formula (Gl), or Formula (G-ll). In another aspect there are methods to treat vasoconstriction, atherosclerosis and its sequelae, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and Stroke comprising the administration to a mammal of an effective amount of a compound having the structure of any of Formula (G), Formula (G-1), or Formula (G-II). In another aspect are methods for treating organic reperfusion injury following organic ischemia and / or endotoxic shock comprising administration to the mammal at least once of 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 there are methods for reducing 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 (G), Formula (Gl), or Formula (G-ll). In another aspect are methods for decreasing or preventing an increase in blood pressure of 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 the Formula ( G), Formula (Gl), or Formula (G-ll). 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 minus a compound having the structure of any of Formula (G), Formula (G-1), or Formula (G-1). 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 (G), Formula (Gl), or Formula (G-ll). 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 (G), Formula (Gl), or Formula (G-ll). 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 (G), Formula (Gl), or Formula (G-ll). 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 one time, an effective amount of at least one compound having the structure of any of Formula (G), Formula (Gl), or Formula (G-ll). The type of cancer can include, but is 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 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 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 (G), Formula (Gl) , or Formula (G-ll). In another aspect there are methods for preventing augmented Gl diseases 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). 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 (G), Formula (Gl), or Formula (G-ll). Such diseases include, by way of example only, glomerulonephritis, renal ischemic reperfusion by nephrotoxicity due to cyclosporin. In another aspect are methods for preventing or treating acute or chronic renal failure 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 treating type II diabetes comprising administering to the mammal at least one time, 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 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 for preventing or treating acute or chronic disorders involving the recruitment or activation of eosinophils comprising administering to the mammal at least once, an effective amount of minus a compound having the structure of any of Formula (G), Formula (G-1), or Formula (G-1). 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 anti-inflammatory drugs (including selective or non-selective cyclooxygenase-1 or -2 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 (G), Formula (Gl), or Formula (G-ll). In another aspect are methods for the prevention or treatment of 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 (G), Formula (G-1), or Formula (G-1). In another aspect are methods for treating inflammatory skin responses 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 (G), Formula (G-1), or Formula (G-11). Such inflammatory responses of the skin include, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring. In another aspect there are methods to reduce 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 (G), Formula (G-1), or Formula (G-1). In another aspect there 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 the Formula (G), Formula (Gl), or Formula (G-ll). In another aspect 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 (G) , Formula (Gl), or Formula (G-ll). 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 having the structure of any of Formula (G), Formula (Gl), or Formula (G-ll). In another aspect is the use of any compound of Formula (G), Formula (Gl), or Formula (G-ll), in the production of a medicament for treating an inflammatory disease or 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 embodiment of this aspect, the inflammatory diseases or conditions are respiratory, cardiovascular or proliferative diseases. In any of the aspects mentioned above there are other embodiments in which administration is enteric, parenteral, or both, and wherein (a) the effective amount of the compound is administered systemically to the mammal; and / or (b) the effective amount of the compound is orally administered 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 by nasal administration; 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 topically (dermally) administered 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 rectally administered to the mammal. In any of the aspects mentioned above there are other embodiments 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), severe acute asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, asthma induced by physical exercise, isocanic 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 pulmonary inflammation, examples of which are provided herein. In any of the aspects mentioned above there are other embodiments comprising simple administrations of the effective amount of the compound, including other modalities 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) continuously. 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 administers to the mammal every 8 hours; In other modalities or alternative modalities, the method comprises a drug break, where 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 anti-inflammatory, a different compound that has the structure of any of the Formula (G), Formula (G-1), or Formula (G-11), a CysLT ^ receptor antagonist or a dual receptor antagonist of CysLT1 / CysLT2. In other modalities or alternative modalities, the CysLTi antagonist is selected from montelukast (SingulairMT: [1 - [[1- [3- [2 - [(7-chloro-2-quinolyl)] vinyl] phenyl] -3- acid [2- (1-hydroxy-1-methylethyl-ethyl) phenyl] -propyl] sulfanylmethyl] cyclopropyl] acetic acid), zafirlukast (Accolate ™: 3 - [[2-methoxy-4- (o-tolylsulfo nylcarbamoyl)] cyclopentyl ester nyl] methyl] -1-methyl-1 H-indol-5-yl] aminoformic) or pranlukast (Onon ™: 4-oxo-8- [p- (4-phenylbutyloxy) benzoylamino] -2-tetrazole-5- il) -4H-1-benzopyran).
In other alternative modalities or modalities, the anti-inflammatory agent includes, but is not limited to, non-steroidal anti-inflammatory drugs such as a cyclooxygenase inhibitor (COX-1 and / or COX-2), lipoxygenase inhibitors and steroids 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, SoluMedrol, aspirin, indomethacin (Indocin ™), rofecoxib (Vioxx ™) , celecoxib (Celebrex ™), valdecoxib (Bextra ™), diclofenac, etodolac, ketoprofen, Lodine, Mobic, nabumetone, naproxen, piroxicam, Celestone, prednisone, Deltasone, 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), bevacizumab , cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicin / idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel ™, taxol, temozolomide, thioguanine, or classes of drugs that include hormones (an antiestrogen , an antiandrogen, or hormonal analogs that release 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 to treat signals or symptoms induced by this therapy including allopurinol, filgrastim, granisetron / ondansetron / palonosetron, dronabinol. In any of the aforementioned aspects involving organ therapy, 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, cyclosporin, 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, parathyroid hormone or the like, and inhibitors of cathepsin K dronabinol.
In any of the aforementioned aspects that involve the prevention or treatment of inflammation are other modalities comprising: (a) monitoring inflammation in a mammal; (b) measuring bronchoconstriction 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) monitoring mucosal secretion in a mammal; (e) measuring mucosal edema in a mammal; (e) measuring the levels of LTB in the mammalian blood caused with a calcium ionophore; (f) measuring LTE levels in the urinary secretion of a mammal; or (g) identifying a patient by measuring the inflammatory biomarkers driven by leukotrienes such as LTB4, LTC4, 11-6, CRP, SAA, MPO, EPO, MCP-1, MlP-a, sICAMs, II-4, 11-13. In any of the aforementioned aspects involving the prevention of 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 comprising identifying patients monitoring the patient for, either: i) at least one inflammatory biomarker related to leukotriene; or ii) at least one response of the functional marker to a leukotriene modifying agent; 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 the leukotrienes are selected from the group consisting of LTB, cysteinyl-leukotrienes, CRP, SAA, MPO, EPO, MCP-I, MlP-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 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 either: i) tracking the patient for at least one leukotriene gene SNP and / or the haplotype that includes the SNP in locations intronic or exonic; 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 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, cysteinyl-leukotrienes, CRP, SAA, MPO, EPO, MCP-I, MlP-a, sICAM, IL-6, IL-4 and I L-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 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 biomarker inflammatory related to leukotriene; ii) monitoring the patient to 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 the leukotrienes are selected from the group consisting of LTB 4, cysteinyl-leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MlP-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 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 in the following way: i) tracking the patient for at least one gene leukotrienes SNP or haplotype; and ii) 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 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 the leukotrienes are selected from the group consisting of LTB 4, cysteinyl-leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MlP-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 stops at least one leukotriene gene SNP 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 FLAP modulator is a FLAP inhibitor. In other modalities or alternative modalities, the leukotriene gene SNP 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 integrated group for LTB, cysteinyl-leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MlP-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 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-dependent include, but without asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fsis, rhinitis, arthritis, allergy, inflammatory bowel disease, adult respiratory distress syndrome , myocardial infarction, aneurysm, apoplexy, cancer, and endotoxic shock. Certain Chemical Terminology Unless stated otherwise, the following terms used in this application, which includes the specification and claims, have the definitions given below. It should be noted that, as used in the specification and appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly states otherwise. The definition of standard chemical terms can be found in reference to the works, which include, Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4th ED." VOIS A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry are used, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the capacity of the art. In this application, the use of "or" means "and / or" unless otherwise stated. Additionally, the use of the term "including" as well as other forms "include", "includes", and "that includes" is not limiting. An "alkoxy" group refers to a group (alkyl) O-, where alkyl is 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 or 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 carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting 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 whole number in the given range, for example, "1 to 10 atoms" "carbon" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition further comprises 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, "C1-C4 alkyl" indicates that they are one to four carbon atoms in the alkyl chain, ie, the Alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Normal alkyl groups include, but are not limited to, 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. That is, an alkenyl group starts with the atoms -C (R) = C-R, 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 moiety may 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 -C = C-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 can be straight chain, branched, or cyclic. An "amide" is a chemical moiety with the Formula -C (O) NHR or -NHC (O) R, wherein R is selected from the 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 (G), Formula (G-1), or Formula (G-11), 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 and 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 larger 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 10 ring atoms. Illustrative examples of cycloalkyl groups include the following moieties: CD-OO. CO and the like.
The term "ester" refers to a chemical moiety with the Formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon) and heteroalicyclic (linked through a ring carbon). Any hydroxy, or carboxyl side chain on the compounds described herein may be esterified. The specific methods and groups for producing such esters are known to those skilled in the art and are readily found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated into the present as a 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 combinations thereof. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which halo is fluorine. The terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from a non-carbon atom, eg, oxygen, nitrogen, sulfur, phosphorus or its combinations The terms "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms 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 O, S and N, wherein each heterocyclic group has from 4 to 10 in its ring system, and with the proviso that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups that have only 4 atoms in their ring system, but the aromatic heterocyclic groups must have at least 5 atoms in your 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, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranoyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanil, 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, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, q u inoxali nilo, naftiridinilo and furopiridinilo. 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 imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached) . 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 The radicals may be fused with an aryl or heteroaryl Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include: ? .or. .ó, Q. and similar. The term Heteroic acid also includes all ring forms of carbohydrates, including but not limited to, monosaccharides, disaccharides and oligosaccharides. The term "member ring" may comprise any cyclic structure. The term "of members" means the number of skeletal forms that constitute 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 an -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 (= O) -R, wherein 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 "sulfonyl" group refers to a -S (= O) 2 -R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (linked through a ring carbon) and heteroalicyclic (linked to through a ring carbon). A "thiocyanate" group refers to a group -CNS.
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 (= O) -, -S-, -S (= O) -, -S (= O ) 2-, -NH-, -NHC (O) -, -C (O) NH-, S (= O) 2NH-, -NHS (= O) 2, -OC (O) NH-, -NHC ( O) O-, - (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), or - (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); 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 more stereocenters and each center may exist in the R or S configuration. The compounds present herein include all diastereomeric, enantiomeric and epimeric as well as the 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 having the structure of any of Formula (G), Formula (Gl), or Formula (G-ll), as well as active metabolites of these compounds that have 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 does not have a detrimental 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 more adjectives 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, improper bone reconstitution, loss or gain, osteopenia, osteomalacia, osteofibrosis, and Paget's disease [Garcia, "Leukotriene B4 stimulates osteoclastic bone resorption both intro and in vivo", J Bone Miner Res. 1996; 11: 1619-27]. The term "cardiovascular disease," such a coma is used herein to refer to diseases that affect the heart or the blood vessels or both, including but not limited to: arrhythmia; atherosclerosis and its sequelae; angina; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, apoplexy; peripheral obstructive arteriopathy of a limb, organ, or tissue; reperfusion injury followed by cerebral ischemia, heart or other organ or tissue; endotoxic, surgical or traumatic shock; hypertension, vascular heart disease, 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-lipoxygenase activating protein confers risk of myocardial infarction and stroke", Nat Genet March 2004; 36 (3): 233-9. Epub February 8, 2004; [Heise CE, Evans JF et al, "Characterization of the human cysteinil leukotriene 2 receptor", J Biol Chem. 2000 Sep 29; 275 (39): 30531-6]. The term "cancer," as used herein refers to an abnormal development of cells which tend to proliferate in an uncontrolled manner and, in some cases, metastasize (disperse). 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 (thyroid) organs, prostate, skin (melanoma), or hematologic tumors (such as leukemias) [Ding XZ et al., "A novel anti-pancreatic cancer agent , LY293111", Anticancer Drugs. June 2005; 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", Clin Cancer Res. October 1, 2004; 10 (19): 6703-9]. The term "carrier" 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, encompass administration of the selected therapeutic agents to a single patient, and include treatment regimens in which the agents are administered by the same or different route administration route or at the same time or at 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 skin disorders such as, 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 diseases: potential therapeutic implications", BioDrugs. 2001; 15 (11): 729-43]. 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 edema provide pH control or maintenance) are used as diluents in the art, including, but not limited to, a phosphate buffered saline 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 alleviate, to some degree, one or more 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 to provide a clinically significant decrease in the symptoms of the disease. An appropriate "effective" amount in any individual case can be determined using techniques, such as a study in dose scale. The terms "improving" or "improving," as used herein, mean increasing or prolonging either a potential or a desirable effect in power or duration. Thus, with respect to the improvement of the effect of therapeutic agents, the term "improving" 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 "fibrosis" 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 are not limited to to fibrosis of individual organs or tissues such as the heart, kidney, lungs or skin, and includes such disorders as idiomatic pulmonary fibrosis and cryptogenic fibrous alveolitis [Charbeneau RP et al., "Eicosanoids: mediators and therapeutic targets in fibrotic lung disease", Clin Sd (Lond). June 2005; 108 (6): 479-91].
The term "iatrogenic" means a condition, disorder, or disease mediated by leukotrienes or leukotriene-dependent created or made worse by medical or surgical therapy. The term "inflammatory disorders" refers to those diseases or conditions that are characterized by one or more of the pain signals (pain, from the generation of harmful substances that stimulate the nerves), heat (heat, from of vasodilation), redness (flushing, from vasodilatation and increased blood flow), dilation (tumor, excessive entry or restricted fluid output), and loss of function (functio laesa, which may be partial or complete , 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, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrous, focal, granulomatous, Hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymal, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, serplástico, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative. Inflammatory disorders also include, without limitation, those that affect the blood vessels (polyarteritis, 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 Internal Medicine, 16th Edition, Kasper DL, and contributors, 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 cysteinil leukotrine D4 receptor antagonist montelukast for the treatment of interstitial cystitis ", J Urol 2001; 166: 1734]. The term "leukotriene-driven mediators," as used herein, refers to molecules capable of being produced in a patient that may arise from excessive production of leukotriene stimulation of cells, such as, by way of example only , LTB, LTC4, LTE, cysteinyl-leukotrienes, monocyte inflammatory protein (MBP-la), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), chemoattractant protein of monocytes (MCP-1), soluble intracellular adhesion molecule (sICAM, soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and general inflammation molecules such as interleukin-6 (II-6), C-reactive protein (CRP), and serum amyloid A protein (SAA). The term "leukotriene-related mediators," as used herein, refers to molecules capable of being produced in a patient that may arise from the excessive production of leukotriene stimulation of cells, such as, by way of example only , LTB4, LTC4, LTE4, cysteinil- leukotrienes, monocyte inflammatory protein (MBP-la), interleukin-8 (1L-8), interleukin-4 (IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein (MCP-1), molecule of soluble intracellular adhesion (sICAM; soluble ICAM), myeloperoxidase (MPO), eosinophil peroxidase (EPO), and general inflammation molecules such as interleukin-6 (11-6), C-reactive protein (CRP), and amyloid protein A serum (SAA). The term "leukotriene-dependent", as used herein, refers to conditions or disorders that will not occur or will not occur to the same degree, in the absence of one or more leukotrienes. The term "leukotriene-mediated", as used herein, refers to conditions or disorders that may occur in the absence of leukotrienes but may occur in the presence of one or more leukotrienes. The term "patient responsive to leukotrienes", as used herein, refers to a patient that has been identified by the genotype of the FLAP haplotypes, or the genotype of one or more other genes in the pathway. the leukotrienes and / or the patient 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 excessive stimulation of leukotrienes of inflammatory cells, since they probably respond favorably to leukotriene modulating 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" refers to 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 exchanged for an organism In this way, enzymes can produce structural alterations specific to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reducing reactions while uridin diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic acid molecule to aromatic 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, McGraw-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 the analysis of the resulting compounds. Both methods are well known in the art. The term "modular," such a comma is 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 extend the activity of the target. The term "modulator," as used herein, refers 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 "nervous system disorder," as used herein, refers 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, multiple 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 aspects neurological disorders such as degenerative disc disease and sciatica. The acronym "SNC" refers 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. February 2000; 82 (2): 85-94; Yu GL, et al., "Montelukast, a cysteinil leukotriene receptor-1 antagonist, dose-and time-dependently protects against focal cerebral ischemia in mice", Pharmacology. January 2005; 73 (1): 31 -40. Epub September 27, 2004; [Zhang WP, et al., "Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats, Acta Pharmacol Sin. October 2002; 23 (10): 871 -7]." The terms "disease 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, allergic conjunctivitis, spring conjunctivitis, papillary conjunctivitis [Toriyama S., "Effects of leucotriene B4 receptor antagonist on experimental autoimmune uveoretinitis in rats", Nippon Ganka Gakkai Zasshi, June 2000; 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 in the present, refers to a mater ial, such as a vehicle or diluent, that does not abrogate 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 it is contained. 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 any compound of Formula (G), Formula (G-1), or Formula (G-11), 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 any compound of Formula (G), Formula (Gl), or Formula (G-ll), with a base to form a salt such as an ammonium salt, a salt of alkali metal, such as a sodium salt or potassium salt, an alkaline earth metal salt, 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, lysine, and the like, or by other methods known in the art. The term "pharmaceutical combination" as used in present, 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, for example any compound of the Formula (G), Formula (G-1), or Formula (G-11), and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, for example any compound of Formula (G), Formula (G-1), or Formula (G-11), and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially without specific intervening time limits, where such administration provides effective levels of the two compounds in the body of the patient. patient. 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 the Formula (G), Formula (G-1), or Formula (G-1), with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The composition administration techniques of a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and Topical 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 may, for example, be 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 (G), Formula (G-1), or Formula (G-ll), 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 hydrolyzed in a metabolic 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 asthma (extrinsic), non-allergic asthma (intrinsic), severe acute asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, asthma induced by physical exercise, isocapnic hyperventilation, childhood-onset asthma , adult onset asthma, asthma with cough variant, occupational asthma, steroid-resistant asthma, stationary asthma, allergic spring rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, pulmonary fibrosis interstitial and / or airway inflammation and cystic fibrosis, and hypoxia [Evans JF, "The Cysteinil Leukotriene (CysLT) Pathway in Allergic Rhinitis", Allergology International 2005; 54: 187-90); Kemp JP., "Leukotriene receptor antagonists for the treatment of asthma", IDrugs. April 2000; 3 (4): 430-41; Riccioni G, et al., "Effect of the two different leukotriene receptor antagonists, montelukast and zaf? Rlukast, on quality of life: a 12-week randomized study", Allergy Asthma Proc. November-December 2004; 25 (6): 445-8]. The term "subject" or "patient" includes 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 are not limited to, birds and fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human being. The terms "treating", "treating" or "treatment", as used herein, include alleviating, reducing or decreasing the symptoms of a disease or condition, preventing further symptoms, decreasing or preventing the underlying metabolic causes of the conditions. symptoms, inhibiting 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. disease or 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 as a reference in their entirety. Brief Description of the Figures FIG. 1 presents illustrative schemes for the synthesis of compounds described herein. FIG. 2 presents illustrative schemes for the synthesis of compounds described herein. FIG. 3 presents illustrative schemes for the synthesis of compounds described herein. FIG. 4 presents illustrative schemes for the synthesis of compounds described herein. FIG. 5 presents illustrative schemes for the synthesis of compounds described herein. FIG. 6 presents illustrative schemes for the synthesis of compounds described herein. FIG. 7 presents illustrative schemes for the synthesis of compounds described herein. FIG. 8 presents illustrative examples of compounds described herein. FIG. 9 presents illustrative examples of compounds described herein. FIG. 10 presents illustrative examples of compounds described herein. FIG. 11 presents illustrative examples of compounds described herein.
FIG. 12 presents an illustrative scheme for the treatment of patients using the compounds and methods described herein. FIG. 13 presents an illustrative scheme for the treatment of patients using the compounds and methods described herein. FIG. 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 (LTs) 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, LTA hydrolase and LTC4 synthase. The leukotriene synthesis pathway, the 5-lipoxygenase pathway, involves a series of enzymatic reactions in which arachidonic acid is converted into leukotrienes LTB4, or the cysteinyl-leukotrienes, LTC, LTD4, and LTE4. The pathway occurs mainly 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, and collaborators, ed. Five-Lipoxygenase Products in Asthma, Lung Biology in Health and Disease Series, Vol. 120, Chs. 1, 2, and 7, Marcel Dekker, Inc. NY, 1998. Protein components dedicated to the synthesis pathway of leukotrienes include a 5-lipoxygenase (5-LO), a 5-lipoxygenase activating protein, a LTA hydrolase, and an LTC4 synthase. The synthesis of leukotrienes has been described in the literature, for example, by Samuelsson et al., Science, 220, 568-575, 1983; Peters-Golden, "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 of the cells in the body have LTA4 hydrolase so that they can produce LTB. Platelets and endothelial cells have LTC4 synthase, so that they can produce LTC4 when presented 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 arachidonic acid liberated is converted by an intermediate 5-HPETE to the epoxide LTA4. Depending on the type of cell, LTA can be converted immediately into LTC4 by CTL nuclear binding synthase or LTB4 by the action of cystosolic 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), know BLTTR OR BLT2R. LTC4 is exported to the blood by the MRP-1 anion pump and rapidly converted to LTD4 by the action of β-glutamyl transpeptidases and LTD then converted to LTE4 by the action of dipeptidases. LTC, LTD, and LTE4 are collectively known as cysteinyl-leukotrienes (or previously as a slow-reacting substance of anaphylaxis, SRS-A). The cysteinyl leukotrienes activate other cells, or the cells in which they are produced, by binding by high affinity to one of the two GPCRs, namely 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 bronchoconstriction. 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 vasculature pulmonar 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. Allergy 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 and collaborators, 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 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 the cytokines and leukotrienes produced by the 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). LTB produces relatively weak contractions of the isolated trachea and pulmonary parenchyma, and these contractions are partially blocked by cyclooxygenase inhibitors, suggesting that 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 knockout mouse of LTB4 receptor BLT1 - / - is protected from eosinophilic inflammation and allergic airway hyperresponsiveness mediated by 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 bronchoconstriction in a variety of species, including humans (Dahlen et al., Nature, 288). : 484-486, 1980) These compounds have profound hemodynamic effects, contracting the coronary blood vessels, and resulting in the reduction of cardiac output efficiency (Marone et al., In Biology of Leukotrienes, ed. By R. Levi and R.D. Krell, Ann. New York Acad. Sci. 524: 321333, 1988). Leukotrienes also act as vasoconstrictors, however; there are marked differences for the different vascular beds. There are reports suggesting that 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 LTD directly increase vascular permeability probably by promoting the retraction of capillary endothelial cells through activation of the CysLT2 receptor and possibly other CysLT receptors not yet defined [Lotzer et al. Arterioscler Thromb Vase Biol 23: e32-36. (2003)]. LTB4 improves atherosclerotic advancement in two atherosclerotic rat models, namely mice deficient of the low density lipoprotein receptor (LDLr - / -) 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 human monocyte chemoattractant proteins (MCP-1) a known enhancer of atherosclerotic advancement (Huang et al Aterioscler Thromb Vasc Biol 24: 1783-1788 (2004).) The role of FLAP in the synthesis pathway of leukotrienes is significant because FLAP in concert with 5-lipoxygenase carries out the first step in the pathway for the synthesis of leukotrienes.Therefore, the synthesis route of leukotrienes provides a quantity of targets for the compounds useful 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, disease is and bone disorders, diseases and cardiovascular disorders, inflammatory diseases and disorders, diseases and dermatological 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 CysLTi 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, which includes the 5-lipoxygenase inhibitor, zileuton (Zyflo ™) which has been shown to be effective in asthma, Israel et al. Ann Intern Med 119: 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; and collaborators, Ca. J. Physiol. Phannacol. 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 Actions 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 et 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 Haemost 79: 635-639 (1998). The 5-lipoxygenase inhibitor, zileuton has been shown to reduce renal ischemia in a mouse model, Nimesh et al. Mol 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 leukotrienes and the development of antileukotriene agents. ", Ann Allergy Asthma Immunol 2001; 86 (Suppl 1) 4-8; Riccioni G, and collaborators, "Advances in therapi with antileukotriene drugs", Ann Clin Lab Sd. 2004, 34 (4): 379-870; (ii) respiratory diseases including asthma, adult respiratory distress syndrome and allergic 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. Sd., V34, 379-387 (2004)); (iii) chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation and cystic fibrosis (see for example Kostikas K et al., "Leukotriene V4 in exhaled breath condense and sputum supernatant in patients with COPD and asthma ", Chest 2004; 127: 1553-9); (iv) secretion and / or increased mucosal edema in a disease or condition (see for example Shahab R et al, "Prostaglandins, leukotrienes, and perennial rhinitis", J Laryngol Otol., 2004; 118; 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., Vl4, 447-457 (2003)); (vi) reduction of 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 injury in rats", Planta Med. August 2005; 71 (8): 717-20); (vii) reduction of constriction of blood vessels (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-NAME-treated rats" , Br J Pharmacol, September 2003; 140 (1): 186-94); (viii) 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-NAME- treated rats ", Br J Pharmacol, September 2003; 140 (1): 186-94, and Walch L, et al," Pharmacological evidence for a novel cysteinil-leukotriene receptor subtype in human pulmonary artery smooth muscle ", Br J Pharmacol December 2002; 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., "Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8 + T cells and airway hyperresponsiveness ", Immunol April 2005 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 leukotriene function can modulate particulate-induced changes in bone cell differentiation and activity", Biomed Mater Res. 2001; 58 (4): 406-140; (xi) ocular inflammation and allergic conjunctivitis, spring keratoconjunctivitis, and papillary conjunctivitis (see for example Lambíase et al., Arch. Opthalmol., Vl21, 615-620 (2003)); ) 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 Carvalho D, et al., "Asthma plus migraine in childhood and adolescence: prophilactic benefits with leukotriene receptor antagonist", Headache, Nov-Dec 2002; 42 (10): 1044-7; Sheftell F, and collaborators, "Montelukast in the prophilaxis of migraine: a potential role for leukotriene modifiers", Headache. February 2000; 40 (2): 158-63); (xiii) peripheral neuropathy / neuropathic pain, spinal cord injury (see, for example, AkpekEA, et al., "A study of adenosine treatment in experimental acute spinal cord injury." Effect on arachidonic acid metabolites ", Spine, January 1999 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, vd, 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. feberero 2005; 23 (2): 173-8); (xvi) rheumatoid arthritis and osteoarthritis (see for example Alten R, et al, "Inhibition of leukotriene B4-induced CDI 1B / CD18 (Mac-1) expression by BEL 284, a new long acting LTB receptor antagonist, in patients with rheumatoid arthritis ", Ann Rheum Dis. feberero 2004; 63 (2): 170-6); (xvii) prevention of increased Gl diseases, including, by way of example, clinically, chronic gastritis, eosinophilic gastroenteritis, and gastric motor dysfunction, (see for example Gyomber et al., J Gastroenterol Hepatol., v11,922-927 (1996); Quack I and collaborators BMC Gastroenterol vl8,24 (2005); Cuzzocrea S, et al., "5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration", Lab Invest. June 2005; 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.,? 56, 261-267; Butterly et al., v 57, 2586-2593 (2000); Guasch A et al. "MK-591 acutely restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis ", Kidney Int. 1999; 56: 261-7; Butterly DW et al. "A role for leukotrienes in ciclosporine nephrotoxicity", Kidney Int. 2000; 57: 2586-93); (xix) prevention or treatment of acute or chronic renal failure (see for example Maccarrone M, et al, "Activation of 5-lipdxygenase and related cell membrane lipoperoxidation in hemodialysis patients", J Am Soc Nephrol., 1999; 10: 1991- 6); (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 or tissues such as kidney with acute pyelonephritis ( see for example Tardif M, et al., L-651,392, "A potent leukotriene inhibitor, controls inflammatory process in Escherichia coli pielonephritis", Antimicrob Agents Chemother, July 1994; 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 Gastroenterol., 2005; 5:24; (xxiii) prevention or treatment of acute or chronic erosive disease or motor dysfunction of the gastrointestinal tract caused by non-steroidal anti-inflammatory drugs (including selective or non-selective cyclooxygenase-1 or -2 inhibitors) (see for example Marusova IB , and collaborators, "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 chronic gastric haemorrhagic mucosal lesions in ulcer models in the rat ", J. Gastroenterol, Hepatol., 1996, 11, 922-7) and Martin St et al., "Gastric motor dysfunction: is eosinophilic mural gastritis a causative factor?", Eur J Gastroenterol, Hepatol., 2005, 17: 983-6; xxiv) treat type II diabetes (see for example Valdivielso JM, et al, "Inhibition of 5-lipoxygenase activating protein decreases proteinuria in diabetic rats", J Nephrol, Jan-Feb 2003; 16 (1): 85-94; Parlapiano C , and collaborators, "The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 relay in people with diabetes mellitus", Diabetes Res Clin Pract. October 1999; 46 (l): 43-5; (xxv) treatment of metabolic syndromes, including , by way of example only, Family Mediterranean Fever (see for example Bentancur AG, et al., "Uriñe leukotriene B4 in familial Mediterranean fever", Clin Exp Rheumatol. Jul-Aug 2004; 22 (4 Suppl 34): S56-8; and (xxvi) treatment of hepatorenal syndrome (see for example Capella GL., "Anti-leukotriene drugs in the prevention and treatment of hepatorenal syndrome", Prostaglandins Leukot Essent Fatty Acids, April 2003; 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, BioorgMed Chem Lett, 15 (14): 3352-5, 2005; Flamand, et al., Mol.
Pharmacol. 62 (2): 250-6, 2002; Folco, et al., Am. J. Respir. Crit. Care 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 leukotriene-dependent or leukotriene-dependent conditions. The inhibitors of the leukotriene synthesis route described herein can locate any step 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 (G), Formula (Gl) and Formula (G-ll): The compounds of Formula (G), Formula and Formula (G-ll), their pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, active metabolites for pharmaceutical use, pharmaceutically active prodrugs, and pharmaceutically acceptable solvates, antagonize or inhibit FLAP and can be used to treat patients suffering from leukotriene or leukotriene-dependent diseases or conditions, including, but not limited to, asthma, myocardial infarction, cancer, and inflammatory conditions. The Formula (G-l) is the following: wherein, Z is selected from N (Rt), S (O) m, CR ^ CR ,, -C = C-, C (R1) 2 (R2) 2] n, [C (R2) 2] nC ( R1) 2 O, OC (RO2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2S (O) m, S (O) 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 (R,) 2] ", [C (R1) 2] nO [C (R2) 2] n, -C (O) NR2-, -NR2C (O) -, -NR2C (O) O-, -OC (O) NR2-, -S (O) 2NR2-, -CR ^ NN-, NR2C (O) NR2 -, -OC (O) O-, S (O) 2NR2, or -NR2S (O) 2-, where each R-, is independently H, CF3, or an optionally substituted lower alkyl and two RTs on the same carbon can join to form a carbonyl (= O); 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 0, 1, 2, or 3; And it is -Li-íari the substituted or unsubstituted); -L? - (substituted or unsubstituted heteroaryl); -l _? - (substituted or unsubstituted heterocyclic non-aromatic), provided that when the heteroatom is directly linked to Z, the non-aromatic heterocycle is substituted; where is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, -C (O) , C (R8) (OH), C (R8) (OMe), C (= NOH), C (= N0R4b), C (= O) NH, C (= O) NR4b, -NHC (= O), NR4bC (= O), S, S (= O), S (= O) 2, -NHC (= O) NH, or NR4bC (= O) NR4b; where each substituent on Y or Z is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= O) -, -S-, -S (= O) -, -S ( = O) 2-, -NHC (O) -, -C (O) NH-, S (= O) 2NH-, -NHS (= O) 2, -OC (O) NH-, -NHC (O) O-, -OC (O) O-, -NHC (O) NH-, -C (O) O-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, fluoroalkyl of 1 to 6 carbon atoms, heteroaryl, aryl, or heterocycle; and each Rs is independently selected from H, halogen, H, -CN, -NO2, N3, -S (= O) 2 NH 2, 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 (= O) 2R8, -S (= O) 2NH2 -C (O) R8, -CN, -NO2, 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 is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R 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; each R4b is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted, aryl-substituted or unsubstituted cycloalkyl or substituted or unsubstituted benzyl; substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle; R6 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heterocycle), L2- ( substituted or unsubstituted heteroaryl), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= O), -S (= O) 2, C (O), -CH (OH ), - (alkyl from 1 to 8 substituted or unsubstituted carbon atoms), or - (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); R7 is L3-X-L4-Gj, wherein, L3 is a bond, or substituted or unsubstituted alkyl; X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2) -NR9, -NRgC (O), -C (O) NR9, -NR9C (O) NR9-, or aryl; L is a bond, or substituted or unsubstituted alkyl; GT is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3) -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) )2, -NR9C (= CR10) N (R9) 2, -C (O) NRgC (= NR10) N (Rg) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9) -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, -S (= O) 2R8, -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 (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O u -OC (O); or d is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR10) N (R9) 2, -NRgC (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (0) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O 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 lower cycloalkyl, phenyl or benzyl; or two Rg 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 R10 is independently selected from H, -S (= O) 2R8, -S (= O) 2NH2 -C (O) R8, CN, -NO2, heteroaryl, or heteroalkyl; R5 is H, halogen, -N3, -CN, -ONO2, -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 (= O), S (= O) 2, NH, C (O) , -NHC (O) O, -OC (O) NH, -NHC (O), -NHC (O) NH-, or -C (O) NH; Rn is L7-L10-G6, wherein L7 is a bond, -O, -S, -S (O), -S (O) 2, -NH, -C (O), -C (O) NH, -NHC (O), (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), or (substituted or unsubstituted alkenyl of 2 to 6 carbon atoms); Lio is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (aryl) substituted or unsubstituted), or (substituted or unsubstituted heterocycle); G6 is H, CN, SCN, N3, NO2, halogen, OR9, -C (O) CF3, -C (= O) R9, -C (O) OR9, -SR8, -S (= O) R8, - S (O) 2R8, N (R9) 2, tetrazolyl, -NHS (O) 2R8, -S (O) 2N (R9) 2, -C (O) NHS (O) 2R8, -S (O) 2NHC ( O) R9, -C (= O) NCRs) 2, N R9C (O) R9, C (R9) 2C (O) N (R9) 2-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 (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O ), -C (O) NH, -C (O) O or -OC (O); G6 is W-G7, wherein W is (substituted or unsubstituted heterocycle) or a (substituted or unsubstituted heteroaryl) and G7 is H, halogen, CN, NO2, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl of 1 to 8 carbon atoms, tetrazolyl, -NHS (O) 2R8, S (O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C (O) NHS (O) 2R8, -S (O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR, o) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (OR10) N (R9) 2l -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (O) R8, or -S (O) 2R8 , -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heterocycle) , or -L5- (substituted or unsubstituted aryl), where L5 as a bond, -O-, C (= O), S, S (= O), S (= O) 2, -NH, -NHC (O ) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O or -OC (O); with the proviso that when Lio is phenyl or thiophenyl, Y is - (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl), and Z is [C (R2) 2] nC (R1) 2O, then G6 is W- G7; and R12 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms). For any and all embodiments (such as, for example, Formula (G), Formula (G-1), and Formula (G-11)), substituents are selected from an alternative list. For example, in one embodiment, the non-aromatic heterocycle of Y is selected from quinolizines, dioxins, piperidines, morpholines, thiazines, tetrahydropyridines, piperazines, oxazinanones, dihydropyrols, dihydroimidazoles, tetrahydrofurans, dihydrooxazoles, oxiranes, pyrrolidines, pyrazolidines, dihydrothiophenones, imidazolidinones, pyrrolidinones, dihydrofuranones, dioxolanones, thiazolidines, piperidinones, tetrahydronaphthalenes, tetrahydroquinolines, tetrahydrothiophenes, and thiazepanes. In other embodiments, the non-aromatic heterocycle of Y is selected from the group consisting of the following structures: GOES By way of example only, the non-aromatic heterocycle of Y is selected from In another alternative modality or modality, the "G" group (for example G- ?, G5, G6, G7) is any group that is used to adapt 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 "G" modifications 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 only, controlling PK properties in vivo, off-site activities, potential toxicities associated with cypP450 interactions, drug-drug interactions, and the like. Moreover, modifications to "G" allow the adaptation of the in vivo efficacy of the compound through 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 design of selective compounds for the activating protein of 5-lipoxygenase on other proteins. In other embodiments or alternative embodiments, "G" is L20-Q, where L20 is a linker cleavable by enzymatic path and Q is a drug, 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 antagonists CysLT1 / CysLT2 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. The Formula (G-ll) is the following: wherein, Z is selected from NfR, S (O) m, CR., = CR ?, -C = C-, C (R?) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2O, OC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2S (O) m, S (O) mC (R1) 2 [C (R2) 2] n, [C (R2) 2] nC (R1) 2NR1, [CÍRa lnOIC R zln, [C (R1) 2] nO [C (R2) 2] n, -C (O) NR2-, -NR2C (O) -, -NR2C (O) O-, -OC (O) NR2-, -S (O) 2NR2-, -CR ^ NN-, NR2C (O) NR2-, -OC (O) O-, S (O) 2NR2, or -NR2S (O) 2-, where each Ri is independently H, CF3, or optionally lower alkyl substituted and two RTs on the same carbon can be joined to form a carbonyl (= O); 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 0, 1, 2, or 3; And it is - read it replaced or unsubstituted); -substituted or unsubstituted heteroaryl); -L -? - (substituted or unsubstituted heterocyclic non-aromatic), provided that when the heteroatom is directly linked to Z, the non-aromatic heterocycle is substituted; where L ^ is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, -C ( O), C (R8) (OH), C (R8) (OMe), C (= N0H), C (= NOR4b), C (O) NH, C (= O) NR4b, -NHC (O), NR4bC = O), S, S (O), S (O) 2, -NHC (= O) NH, or NR4bC (= O) NR4b; where each substituent on Y or Z is (LsRs) j, where each L3 is independently selected from a bond, -O-, -C (= O) -, -S-, -S (= O) -, -S ( = O) 2-, -NHC (O) -, -C (O) NH-, S (= O) 2NH-, -NHS (= O) 2, -OC (O) NH-, -NHC (O) O-, -OC (O) O-, -NHC (O) NH-, -C (O) O-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, fluoroalkyl of 1 to 6 atoms carbon, heteroaryl, aryl, or heterocycle; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -NO2, N3, -S (= O) 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 (= O) 2R8, -S (= O) 2NH2-C (O) R8, -CN, -NO2, 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 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; each R 4 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, substituted or unsubstituted heterocycle; 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 heteroaryl or unsubstituted), or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= O), -S (= O) 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); R is L3-X-L4-G; where, L3 is a link; or substituted or unsubstituted alkyl; X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2) -NR9, -NR9C (O), -C (O ) NR9, -NR9C (O) NR9-, or aryl; L4 is a bond, or substituted or unsubstituted alkyl; G1 is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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) NR 9 C (= CR 10) N (R 9) 2, -CO 2 R 9, -C (O) R 9, -CON (R 9) 2, -SR 8, -S (= O) R 8, -S (= O) 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 (O ) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O or -OC ( OR); or GT is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (O) 2R8, S (O) 2N (R9) 2, OH , -OR8, -C (O) CF3, -C (O) NHS (O) 2R8, -S (O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NRgC (= NR10) N ( R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (O) R8, or -S (O) 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 lower 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 (O) 2R8, -S (O) 2NH2-C (O) R8, -CN , -NO2, heteroaryl, or heteroalkyl; R5 is H, halogen, -N3, -CN, -ONO2, -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 (= O), S (= O) 2, NH, C (O) , -NHC (O) O, -OC (O) NH, -NHC (O), -NHC (O) NH- or -C (O) NH; Rn is L7-L? O-G6, where L7 is a bond, -C (O), -C (O) 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), (aryl) substituted or unsubstituted), or (heterocycle substituted to unsubstituted); G6 is H, CN, SCN, N3, NO2, halogen, OR9, -C (O) CF3, -C (O) R9, -C (O) OR9, -SR8, -S (O) R8, -S ( = O) 2R8, N (R9) 2, tetrazolyl, -NHS (= O) 2R8, -S (= O) 2N (R9) 2, -C (O) NHS (= O) 2R8, -S (= O ) 2NHC (O) R9, -C (O) N (R9) 2, NR9C (O) R9, C (R9) 2C (= O) N (R9) 2- 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 heteroaryl or unsubstituted), or -L5- (substituted or unsubstituted aryl), where L5 is -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, - NHC (O), -C (O) NH, -C (O) O or -OC (O); or G6 is W-G7, wherein W is (substituted or unsubstituted heterocycle) or (substituted or unsubstituted heteroaryl) and G7 is H, halogen, CN, NO2, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O ) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heterocycle), or -L5- (substituted or unsubstituted aryl) , where L5 is a bond, -O-, C (= O), S, S (= O), S (= O) 2, -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O or -OC (O); provided that when L10 is phenyl or thiophenyl, Y is - (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl), and Z is [C (R2) 2] nC (R1) 2 O, then G6 is W-G7; and R12 is H, (substituted or unsubstituted alkyl of 1 to 6 carbon atoms), (substituted or unsubstituted cycloalkyl of 3 to 6 carbon atoms). For any and all embodiments (such as, for example, Formula (G), Formula (G-1), and Formula (G-11)), substituents may be selected from a subset of the alternatives mentioned. For example, in some embodiments, Z is [C (R2) 2] nC (R1) 2O. In other alternative embodiments or modalities, Y is - (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) and G6 is W-G7. In other alternative embodiments or modalities, Y is ^ - (substituted or unsubstituted alkyl), -L1- (substituted or unsubstituted cycloalkyl), -substituted or unsubstituted -LTiheterocycle), -Lr (substituted or unsubstituted heteroaryl), -lTi substituted or unsubstituted heterocycle unsubstituted) provided that when the heteroatom is directly bonded to Z, the non-aromatic heterocycle is substituted; -L substituted or unsubstituted aryl). In other embodiments or alternative embodiments, Y is heteroaryl selected from the group consisting of pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl . In other alternative embodiments or embodiments, 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 (O) 2, -C (O), -CH (OH), or substituted or unsubstituted alkyl. In other embodiments or alternative embodiments, R is L3-X-L4-G1; where, L3 is a link; and X is a bond, O, -CR9 (OR9), S, -S (= O), -S (= O) 2, -NR9, -NR9C (O), -C (O) NR9. In other embodiments or alternative embodiments, G is tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NRgC (= CR10) N (Rg) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (O) R8, -S (= O) 2R8. In other alternative embodiments or embodiments, the non-aromatic heterocycle of 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 tetrahydronaphthalene, a tetrahydroquinoline, a tetrahydrothiophene, and a thiazepane. In other embodiments or alternative embodiments, the non-aromatic heterocycle of the group Y can be selected from the group consisting of: enzymatically cleavable and Q is' a drug, 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 antagonists CysLT1 / CysLT2 and CysLTI antagonists. In other alternative modalities or modalities, the affinity moiety allows site-specific binding and includes, but is not limited to, antibodies, fragments of antibodies, DNA, RNA, I-siRNA, and ligands. In another modality or alternative modality, the "G" group (for example G ^, G5, G6, G7) of any of the Formula (G), Formula (G-1), or Formula (G-11), is any group that is used to suit 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 modifications to "G" include; by way of example only, solubility, in vivo absorption, and in vivo metabolism. In addition, in vivo metabolism may include, by way of example only, controlling PK properties in vivo, off-site activities, toxicities associated with cypP450 interactions, drug-drug interactions, and the like. In addition, modifications to "G" allow the adequacy of the in vivo efficacy of the compound through modulation, by way of 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 embodiments or alternative embodiments, "G" is L20-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 others Alternative modalities or modalities, leukotriene receptor antagonists include, but are not limited to, dual antagonists CysLT1 / CysLT2 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 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 set forth in the present. The Formula (G) is the following: Z is selected from [C (R1) 2] m [C (R2) 2] n, [C (R2) 2] n [C (R1) 2] mO, OICÍR ^,] m [C (R2) 2] n, [C (R2) 2] nO [C (R1) 2] n, or [C (R1) 2] nO [C (R2) 2] n, where each R- is independently H, CF3, or a optionally substituted lower alkyl and two Ri on the same carbon can be joined to form a carbonyl (= O); and every 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 (= O); m is 0, 1 or 2; each n is independently 0, 1, 2 or 3; Y is H or - (substituted or unsubstituted aryl); or - (substituted or unsubstituted heteroaryl); where each substituent on Y or Z is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= O) -, -S-, -S (= O) -, -S ( = O) 2-, -NHC (O) -, -C (O) NH-, S (= O) 2NH-, -NHS (= O) 2, -OC (O) NH-, -NHC (O) O-, -OC (O) O-, -NHC (O) NH-, -C (O) O-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms substituted or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -NO2, N3, -S (= O) 2NH2, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, fluoroalkyl from 1 to 6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl; where j is 0, 1, 2, 3 or 4; 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 - (heteroaryl substituted or unsubstituted) or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= O), -S (= O) 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-L-G1, wherein, L3 is a substituted or unsubstituted alkyl; X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2, -NR9l -NRgC (O), -C (O) NR9, -NR9C (O) NR9-L4 is a bond, or a substituted or unsubstituted alkyl; d is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2l -OR9, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S ( = O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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) NR 9 C (= CR 10) N (R 9) 2, -CO 2 R 9, -C (O) R 9, -CON (R 9) 2, -SR 8, -S (= O) R 8, -S (= O) 2R8, -Ls- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (O ) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O, or -OC (OR); or G ^ is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N ( R9) C (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR? 0) N (R9) 2, -C (O ) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9) -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; each R9 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 Rg 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 R10 is independently selected from H, -S (= O) 2R8, -S (= O) 2NH2C (O) R8, -CN, -NO2, heteroaryl, or heteroalkyl; R 5 is H, halogen, alkyl of 1 to 6 carbon atoms substituted or unsubstituted, O-alkyl of 1 to 6 carbon atoms substituted or unsubstituted; Rn is L7-L10-G6, where L7 is a bond, -C (O), -C (O) NH, -NHC (O), or (substituted or unsubstituted alkyl of 1 to 6 carbon atoms); L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl) or (substituted or unsubstituted heterocycle); G6 is OR9, -C (= O) R9, -C (= O) OR9, -SR8, -S (= O) R8, -S (= O) 2R8, N (R9) 2, tetrazolyl, -NHS (= O) 2R8, -S (= O) 2N (R9) 2, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, -C (= O) N (R9) 2, NR9C (O) R9, C (R9) 2C (= O) N (R9) 2-C (= NR10) N ( R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (Rg) 2, -L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted aryl or unsubstituted), where L5 -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, u -OC (O) or G6 is WG, wherein W is (substituted or unsubstituted heterocyclic), (substituted or unsubstituted aryl) or a (substituted or unsubstituted heteroaryl) and G7 is H, halogen , CN, NO2, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, tetrazolyl, -NHS (= O) 2R8, S ( = O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N ( R9) 2, -N (R9) C (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2, -NR9C (= CR10) N (R9) 2, -C (O) NRgC (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted alkenyl or unsubstituted), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heterocycle), or -L5- (substituted or unsubstituted aryl), where L5 is a bond , -O-, C (= O), S, S (= O), S (= O) 2, -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O -, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or -OC (O); provided that Rn comprises at least one aromatic moiety (unsubstituted or substituted) and at least one cyclic moiety (unsubstituted or substituted), wherein the cyclic moiety (unsubstituted or substituted) is a heterocyclic group (unsubstituted or substituted) or a heteroaryl group (unsubstituted) or substituted) and Rn is not a thienyl-phenyl group; 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. For any and all embodiments (such as, for example, Formula (G), Formula (G-1), and Formula (G-1)), substituents may be selected from a subset of the alternatives mentioned. For example, in some modalities, Z is [CÍRs InCíRZO. In other embodiments or alternative embodiments, Y is - (substituted or unsubstituted heteroaryl) or - (substituted or unsubstituted aryl) and G6 is W-G7. In other modalities or alternative modalities, Y is - (substituted or unsubstituted heteroaryl). In other embodiments or alternative embodiments, Y is selected from the group consisting of pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo [1,2- a] pyridinyl and furopyridinyl, where Y is substituted or unsubstituted. In other alternative embodiments or modalities, Y is selected from the group consisting of pyridinyl or quinolinyl, wherein Y is substituted or unsubstituted. In other alternative embodiments or embodiments, 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 ( O) 2, -C (O), or substituted or unsubstituted alkyl. In other embodiments or alternative embodiments, X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2l -NR9, -NR9C (O ), -C (O) NR9. In other embodiments or alternative embodiments, d is tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (= O ) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O) 2R8. In other embodiments or alternative embodiments, L3 is unsubstituted alkyl; X is a link; L is a link; and Gi is -C (O) OR9. In other embodiments or alternative embodiments, Rg is H or unsubstituted alkyl. In other embodiments or alternative embodiments, L10 is a substituted or unsubstituted heteroaryl substituted or unsubstituted aryl and G6 is W-G7 where W is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle. In other embodiments or alternative embodiments, L10 is a substituted or unsubstituted aryl. In other embodiments or alternative embodiments, L3 is unsubstituted alkyl; X is a link; L4 is a link; and G-is -OR9. In other embodiments or alternative embodiments, Gi is W-G5, where W is a substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl. 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 set forth in the present. Other embodiments of Formula (G), Formula (G-1) and Formula (G-11), include, but are not limited to, compounds that are shown in Figures 8-11 and Tables 1-4. Table 1. N- (aryl-heteroaryl) indole acid substitutions Table 2. N- (aryl-heteroaryl) indoles N- (aryl -heterocycle) indoles Table 3. N- (heteroaryl-aryl) and N- (heteroaryl-heteroaryl) indoles Table 4. N- (aryl-heteroaryl) indoles with non-aryl substituents C5 Synthesis of the Compounds The compounds of Formula (G), Formula (Gl), and Formula (G-ll), described in the previous section can be synthesized using synthetic techniques known to those skilled in the art or using methods known in the art. technique in combination with methods described herein. In addition, solvents, solvents, temperatures, and other reaction conditions presented herein may vary in accordance with those stipulated by those skilled in the art. The starting material used for the synthesis of the compounds of Formula (G), Formula (Gl), and Formula (G-ll), described in the previous section can be synthesized or obtained from commercial sources, such as, but not limited to a, 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 4a Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999) (which are incorporated herein in their entirety).
General methods for the preparation of the compound as disclosed herein may derive from reactions known in the art, and the reactions may be modified by the use of reagents and appropriate conditions, as would be recognized by one skilled in the art, for the introduction of various remains found in the Formulas as provided herein. As a guide, the following synthesis methods can be used. Formation of Covalent Links by Reaction of an Electrophile with a Nucleophile The compounds described herein can be modify using several electrophiles or nucleophiles to form new groups or substituents. Table 5 entitled "Examples of Covalent Links and their Precursors" lists the selected examples of covalent bonds and precursor functional groups which yield and can be used as a guide to the variety of available electrophilic and nucleophile combinations. The precursor functional groups are shown as electrophilic groups and nucleophilic groups. Table 5: 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, do 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 moieties 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 moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and the groups Fmoc groups, which are labile in front of the base. The reactive carboxylic acid and hydroxy moieties 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 skillful groups against the acid such as t-butyl carbamate or with carbamates that are both stable acids and base but removable by hydrolytic path. The reactive carboxylic acid and hydroxy moieties can also be blocked with removable protective groups by hydrolytic path such as the benzyl group, while the amine groups capable of hydrogen bonding with acids they can be blocked with labile groups in front of the base such as Fmoc. Reactive carboxylic acid moieties may be protected by conversion into simple ester compounds as exemplified herein, or may be blocked with removable protective groups by oxidative path such as 2,4-dimethoxybenzyl, while coexisting amino groups may block with labile silyl carbamates 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 Pd0 catalyzed reaction in the presence of labile t-butyl carbamate protecting groups against the labile acid or acetate amine against 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. The normally protective / blocking groups can be selected from: aillo SÍI £ ¡£ 2 3ÜS £ Me c pMBn trityl acetyl Fmoc Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal 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, which are incorporated herein by reference in their entirety. The 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 by reference in its entirety. A non-limiting example of the method of synthesis towards the indole compounds of Formula (G), Formula (Gl) and Formula (G-II), is shown according to Reaction Scheme I shown in Figure 1, where the 4-substituted anilines (1-1) are can convert into the corresponding hydrazine (1-2) using standard methodology. The reaction of hydrazine (I-2) with an appropriately substituted ketone (I-3) under standard Fisher indiolization conditions gives the indole (I-4). Indole (I-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) it can be coupled with a wide variety of reagents using well-known standard metal-mediated coupling reactions. by 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, standard cross-coupling reactions allow the introduction of a variety of functional groups using procedures well known to those who practice the technique of organic synthesis. In addition, when R7 is H, it is possible, under certain conditions, to lithium regioselectively using a strong base such as nBuLi and then to condense the anion with an electrophile 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 of Formula (G), Formula (G-1) and Formula (G-ll) is shown according to Reaction Scheme II in Figure 2. Starting with hydrazine 1 -2, N-alkylation with a benzyl halide (or tosylate or mesylate; 1-5) using the conditions described above, provides the hydrazine derivative (11-1). Reaction with an appropriately substituted ketone (I-3) using standard Fisher's indole conditions provides the indole (1-6). Another non-limiting example of the method of synthesis towards the compounds of Formula (G), Formula (Gl) and Formula (G-ll) is shown according to Reaction Scheme II in Figure 2, where the 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 wet AICI3 in a solvent such as CH2Cl2. The functionalization at position 3 can be obtained using a variety of reactions and methods 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 Lewis acid such as AICI3, allows the introduction of acyl groups (1-6; R6 = C (O) R ') see Murakami et al. Heterocycles, vl4, 1939-1941, 1980 and the references mentioned therein. Starting with (111-1), and using, by way of example only, sulfonic chlorides in a suitable solvent, compounds of general structure (III-2) where R6 is SR "can be prepared (Raban, J.Org. Chem. ., v45, 1688, 1980.) A similar chemistry using indole (III-3) can be performed or, alternatively, diaryldisulfides can be used in the presence of a base such as NaH in DMF to generate (111-4) ( Atkinson et al., Synthesis, 480-481, 1988.) The reaction of electron-deficient olefins with 3-H Índols (111-1) or (III-3) in the presence of a Lewis acid (such as Yb (OTf) 3.3 H2O) allows the installation of 3-alkyl substituents of general structure (111-2) or (111-4) (where R6 is a substituted alkyl group; see Harrington and Kerr, Synlett, 1047-1048, 1996). Alternatively, the indole (III-3) can react with benzyl derivatives (I-5) in warm DMF to give (III-4) where R6 is a substituted benzyl group (Jacobs et al., J. Med. Chem. , v36, 394-409, 1993). Other Synthesis of Indol Compounds and Indol Type Other non-limiting examples of the synthesis strategy towards indole and indole type scaffolds for the compounds of Formula (G), Formula (G-1) and Formula (G-11), include modifications to several synthesis of Índoles, including, but not limited to; Synthesis of indoles of Batcho-Leimgruber, Synthesis of Indoles of Reissert, Synthesis of Indoles of Hegedus, Synthesis of Indoles of Fukuyama, Synthesis of Indoles of Sugasawa, Synthesis of Indoles of Bischier, Synthesis of Inters of Gassman, Synthesis of Fischer's Indoles, Synthesis of Japp-Klingemann characters, Synthesis of Buchwald characters, Synthesis of Larock's characters, Synthesis of Bartoli's characters, Synthesis of Castro's characters, Synthesis of Hemetsberger's characters, Synthesis of Mod-Ban's characters, Synthesis of Madelun g, Synthesis of Intents of 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 (G), Formula (G-1) and Formula (G-ll), can be prepared as a pharmaceutically acceptable acid addition salt (which is a type of pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but are 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, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid , methanesulfonic acid, ethanesulfonic acid, acid 1, 2-ethanedisulfonic acid, 2-hydroxyethane sulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis ( 3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfonic acid, gluconic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Alternatively, the compounds of Formula (G), Formula (Gl) and Formula (Gil), can be prepared as pharmaceutically acceptable base addition salts (which is a type of pharmaceutically acceptable salt) by reacting the acid form free 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 the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, hydroxide of potassium, sodium carbonate, sodium hydroxide, and the like. The compounds of Formula (G), Formula (G-1) and Formula (G-11), can be prepared in the form of salts pharmaceutically acceptable formed when an acidic proton present in the parent compound 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 active 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 of Formula (G), Formula (G-1) and Formula (G-11), can be conveniently prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds of Formula (G), Formula (G-1) and Formula (G-ll), can be conveniently prepared by recrystallization from 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 forms as well as solvated. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. The compounds of formula (G), Formula (G-1) and Formula (G-II) can be in various forms, including but not limited to, amorphous forms, ground forms and nanoparticulate forms. In addition, the compounds of Formula (G), Formula (G-1) and Formula (G-11), 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. Various factors such as the recrystallization solvent, the rate of crystallization, and the storage temperature can make a single crystal form to dominate. The compounds of k-mule (G), Formula (Gl) and Formula (G-II), in non-oxidized form can be prepared from N-oxides of compounds of Formula (G), Formula (Gl) and / or Formula (G-ll), treating with a reducing agent, such as, but not limited to, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent , such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like of 0 to 80 ° C. The compounds of Formula (G), Formula (G-1) and Formula (G-11) 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 makes it 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. Prodrugs may be designed as derivatives of reversible drugs, for use 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, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. ScL, 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as 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 of Formula (G), Formula (Gl) and Formula (G-ll), can be prepared by methods known to those skilled in the art (for example, for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistiy Letters, Vol. 4, p. 1985). By way of example only, appropriate prodrugs can be prepared by reacting a compound not derived from any of Formula (G), Formula (Gl), or Formula (G-ll), with a suitable carbamylating agent, such as, but not limited to, 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 in present may be a prodrug for another derivative or active compound. The sites on the aromatic ring portion of the compounds of Formula (G), Formula (Gl) and Formula (G-ll), may be susceptible to various metabolic reactions, hence the incorporation of appropriate substituents on ring structures aromatic, such as, by way of example only, aromatics, can reduce, minimize or eliminate this metabolic path. 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 or fluorescent moieties, bioluminescent markers, or chemiluminescent labels. The compounds of Formula (G), Formula (Gl) and Formula (G-ll), may have one or more stereocenters and each center may exist in the R or S configuration. The compounds disclosed herein include all diastereomeric forms, enantiomeric and epimeric as well as their appropriate mixtures. The compounds of Formula (G), Formula (Gl) and Formula (G-ll), 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 the 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 chemical chromatography or, 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 Resolutions," 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 in the present. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers, arising from a single preparation, combination or interconversion step may be useful for the applications described herein. Routes of Administration Appropriate administration routes include, but are not limited to, intravenous, oral administration., rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal and topical. In addition, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injections. Alternatively, the compound can be administered locally rather than systemically, for example by direct injection of the compound into an organ, often in a depot preparation or sustained release formulation. Such long-acting formulations can be administered by implant (e.g. 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 located and captured selectively 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 pharmaceutically. 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, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), which are incorporated herein by reference in their entirety. In the present compositions are provided Pharmaceuticals comprising a compound of any Formula (G), Formula (G-1), or Formula (G-11), and a pharmaceutically acceptable diluent, excipient or carrier. In addition, the compounds described herein can be administered as pharmaceutical compositions where compounds of any of Formulas (G), Formula (G-1), or Formula (G-11) 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 (G), Formula (Gl), or Formula (G-ll), 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 amounts effective for therapeutic use of compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll), provided herein they are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated.Preferably, the mammal is a human.A therapeutically effective amount 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 can be used separately or in combination with one or more therapeutic agents as components of mixtures. For intravenous injections, the compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll) 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 transmucosal 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 of any of Formulas (G), Formula (G-1), or Formula (G-11) can be formulated easily by combining the active compounds with pharmaceutically active carriers or excipients. 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 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 desired, to obtain tablet cores or dragons. The excipients are, in particular, filler materials such as sugars, which include lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) to 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, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer 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 orally include easy-swallow capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Easy to swallow capsules may contain the active components mixed with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or 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 or sublingual administration, the compositions may take the form of tablets, lozenges or 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 (G), Formula (G-1), or Formula (G-11), can be presented in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulation 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. Suitable lipophilic solvents or 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 of any Formula (G), Formula (Gl), or Formula (G-ll), can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pills, medicinal 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 (G), Formula (Gl), or Formula (G-ll), can utilize transdermal delivery devices and transdermal delivery patches and can be lipid emulsions. icas or buffers, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. The patches can be prepared for continuous, pulsatile or on demand administration of pharmaceutical agents. In addition, transdermal administration of the compounds of any of Formulas (G), Formula (G-1), or Formula (G-11), can be achieved by the use of iontophoretic patches and the like. In addition, transdermal patches can provide controlled administration of the compounds of any of Formulas (G), Formula (G-1), or Formula (G-II). 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 vehicles, optionally a rate controlling barrier for administering the compound to the skin of the host at a predetermined and controlled level for a prolonged period of time, and means for securing the device to the skin. For administration by inhalation, the compounds of any of Formulas (G), Formula (G-1), or Formula (G-11), may exist in the form of aerosol, mist or powder. The pharmaceutical compositions of any Formula (G), Formula (Gl), or Formula (G-ll), 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, trichlorofluoromethane, 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 deliver a set amount. Capsules and cartridges of, for example, by way of example only, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and an appropriate powder base such as lactose or starch. Compounds of any of Formulas (G), Formula (G-1), or Formula (G-11), 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, as well as synthetic polymers such as polyvinyl pyrrolidone, 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 pharmaceutically. The correct formulation depends on the chosen route of administration. Any of the well known techniques, vehicles, and excipients appropriate and contemplated in the art can be used. Pharmaceutical compositions comprising a compound of any Formula (G), Formula (Gl), or Formula (G-ll), can be prepared in conventional manner, such as, by way of example only, by mixing, dissolving, granulating processes , dragee preparation, levigation, emulsification, encapsulation, conventional entrapment or compression. The pharmaceutical compositions will include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of any Formula (G), Formula (Gl), or Formula (G-ll), 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, vehicles, adjuvants, such as preserving agents, stabilizers, humectants or emulsifiers, solubility promoters, salts to regulate the osmotic pressure and / or buffers. In addition, the pharmaceutical compositions may also contain other valuable substances for therapeutic use. The methods for the preparation of compositions that comprise the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible 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 may 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 regulating agents, etc. A composition comprising a compound of any Formula (G), Formula (G-1), or Formula (G-11), can illustratively take the form of a liquid wherein the agents are present in solution, in suspension or both. Usually 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. present in the form of a particle, suspended in a liquid matrix. In some embodiments, a liquid 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 (methylmethacrylate), polyacrylamide, polycarbophil, copolymer of acrylic acid / butyl acrylate, sodium alginate and dextran. Useful compositions may also include solubilizing agents to aid in the solubility of a compound of any of Formula (G), Formula (G-1) or Formula (G-11). 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, as are ophthalmically acceptable glycols, polyglycols, for example, polyethylene glycol 400, and glycol ethers.
Useful compositions may also include one or more pH adjusting agents or buffering agents, which include 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 trishydroxymethylaminomethane; 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 normally a preservative is 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 may 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 matrices semipermeable 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) from 0.003% to about 0.02% w / v polysorbate 80, (g) from 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (1) heparin, (j) dextran sulfate, (k) cyclodextrins, (I) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
Methods of Dosage and Treatment Regimens The compounds of Formula (G), Formula (G-1), and Formula (G-11), can be used in the preparation of medicaments for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions. In addition, a method for treating any disease or condition described herein in a subject in need of treatment, involves the administration of pharmaceutical compositions containing at least one compound of any Formula (G), Formula (Gl), or Formula (G-) ll), or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in effective amounts for therapeutic use to the 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, previous therapy, the patient's health status, weight, response to drugs, and the judgment of the attending physician. It is considered within the skill inherent to the technique the determine the amounts effective 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. The amount is defined as a "prophylactically effective amount or dose." 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 effective amounts for prophylactic use by retinal 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 condition of the patient 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 patient's condition improves, a At the discretion of the attending physician, the compounds can be administered continuously; alternatively, the dose of the drug administered may be reduced or temporarily suspended 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 (for example, weight) of the subject or host in need of treatment, but nevertheless can never be determined routinely in a manner known in practice in accordance with 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 normally 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 compositions in aqueous suspension can be packaged in single dose containers with non-reusable closure. Alternatively, you can use the multiple dose containers with reusable closure, in such cases a preservative is normally 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. Appropriate daily doses for the compounds of Formula (G), Formula (G-1), and Formula (G-11), described herein are from about 0.01 to 2.5 mg / kg per body weight. An indicated daily dose in the larger 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 daily 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, as the number of variables with respect to an individual treatment regimen is extensive, 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 experimental animal cell cultures, including, but not limited to, the determination of LD50 (the lethal dose at 50% of the population) and the 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 range of doses 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 Diseases or Conditions or Leukotriene-mediated Therapy of leukotriene-dependent or leukotriene-mediated diseases or conditions is designed to modulate FLAP activity. Modulation may include, for example, inhibiting or antagonizing FLAP activity. For example, you can administering a FLAP inhibitor in order to decrease the synthesis of leukotrienes within the individual, or possibly to down-regulate or decrease the expression or availability of FLAP mRNA or splice variants specific to FLAP mRNA. The down regulation or expression or availability of a native FLAP mRNA 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, reversing, stopping or 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 administering to the subject a compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll). 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 mediated disease or condition. leukotrienes. 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 activation 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 (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-1), to a mammal. 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, which includes reducing and / or inhibiting, by administering (at least once) an effective amount of at least one compound of any Formula (G) , Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll), to a mammal. The 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 (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll). 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 (G), Formula (Gl), or Formula (G). -ll), or pharmaceutical composition or medicament that includes a compound of any Formula (0), Formula (Gl), or Formula (G-II). The leukotriene-dependent or leukotriene-mediated diseases or conditions which can be treated by a method comprising administration to a mammal, at least one time, of an effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G) , Formula (Gl), or Formula (G-ll), include, but are not limited to, bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, dermatological diseases and disorders, eye diseases and disorders, cancer and others. proliferative diseases and disorders, respiratory diseases and disorders, and non-cancerous disorders. As an example only, they are included in the methods H.H- of prevention / treatment described in the present methods for treating respiratory diseases comprising administering to a mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G- ll), or pharmaceutical composition or medicament including a compound of any Formula (G), Formula (Gl), or Formula (G-ll). By way of example only the respiratory disease can be asthma; see Riccioni et al., Ann. Clin. Lab. Sci., 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 , asthma sensitive to aspirin, exercise-induced asthma, isocanic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-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 of treatment are included in 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 (G), Formula (R). Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-11). 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 treatment are included to prevent 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 any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-ll). By way of example only, methods for preventing / treating methods for preventing or treating vasoconstriction, atherosclerosis and its consequences, myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering to a mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (Gl): or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl) ), or Formula (G-ll); see Jala et al., Trends in Immunol, v25, 315-322 (2004) and Mehrabian et al., Curr. Opin. Lipidol., Vl4, 447-457 (2003). By way of example only, methods for prevention / treatment include methods for reducing cardiac reperfusion injury followed by myocardial ischemia and / or endotoxic shock comprising administering to a mammal, at least once, an effective amount of minus a compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-ll) By way of example only, methods for preventing / treating methods for reducing constriction of 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 the methods of prevention / treatment. (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-ll). By way of example only, methods for preventing / treating are included in 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 Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-11). By way of example only, methods for prevention / treatment are included in 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 (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll) By way of example only, methods for the prevention or treatment of remodeling, loss or gain () are included in the prevention / treatment methods, whether it is abnormal, including diseases or conditions such as, for example, osteopenia, osteoporosis, Paget, cancer and other diseases comprising administering to a mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll). By way of example only, methods for preventing / treating eye inflammation and allergic conjunctivitis are included in the methods of prevention / treatment described herein. vernal keratoconjunctivitis, and papillary conjunctivitis comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (GI), or Formula (G-ll), or pharmaceutical composition or medicament which includes a compound of any Formula (G), Formula (G-I), or Formula (G-ll); 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 (G) , Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll). 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 , cerebral edema and head injury. By way of example, technically, methods for the treatment of cancer comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G) are included in the prevention / treatment methods described herein. , Formula (G- I), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-I), or Formula (G-ll). 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 prevention / treatment described herein are included to prevent endotoxic shock and septic shock comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (GI), or Formula (G-ll). By way of example only, methods for prevention / treatment described herein for preventing rheumatoid arthritis and osteoarthritis comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (FIG. G), Formula (G-I), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (GI), or Formula (G-ll). By way of example only, are included in the methods of prevention / treatment described herein methods for preventing the increase of Gl diseases comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (GI), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (GI), or Formula (G-ll). The G-1 diseases include, by way of example only, inflammatory bowel disease (G-ll), 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, comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula ( G), Formula (Gl), or Formula (G-ll). By way of example only, methods for prevention / treatment described herein are included for the prevention or treatment of rejection or dysfunction in a transplanted organ or tissue comprising administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament including a composed of any Formula (G), Formula (G-1), or Formula (G-1). By way of example only, methods of prevention / treatment described herein for treating diabetes type II diabetes comprising administering to the mammal, at least once, an effective amount of at least one compound of either Formula are included in the methods of prevention / treatment described herein. G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll). By way of example only, methods for treating / treating skin inflammatory responses comprising administering to the mammal, at least once, an effective amount of at least one compound of either Formula are included in the methods of prevention / treatment described herein. G), Formula (G-I), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (GI), or Formula (G-ll). Inflammatory responses of the skin include, for 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, which comprise administering to the mammal, at least once, an effective amount of at least one compound of any Formula (G), Formula (R). Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (G-1), or Formula (G-11). By way of example only, methods for the prevention / treatment described herein are methods for the treatment of cystitis, including, by way of example only, interstitial cystitis, which comprise administering to the mammal, at least once, a effective amount of at least one compound of any Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll) 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 (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any Formula (G), Formula (Gl), or Formula (G-ll). Combination Treatments In certain cases, it may be appropriate to administer at least one compound of any Formula (G), Formula (G-1), or Formula (G-11), in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient after 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 that 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 may be administered weekly at the beginning of the treatment, decreasing biweekly, and then decreasing according to the appropriate. 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, wherein 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 that is intended to provide a beneficial effect from the coaction of the FLAP inhibitors described herein and a concurrent treatment. It is understood that the dosage regimen to treat, prevent, or improve 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 type of bronchodilation suffered 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 the co-administered compounds will of course vary depending on the type of co-drug used, the specific drug used, the disease or condition treated, and so on. In addition, when coadministered 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 can 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 I dont know administered simultaneously, the time between multiple doses can 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 was also prevented. In addition, compounds of any Formula (G), Formula (G-1), or Formula (G-11), may also be used in combination with methods that may provide additional or synergistic benefit to the patient. By way of example only, patients are expected to find therapeutic and / or prophylactic benefit in the methods described herein, wherein the pharmaceutical composition of any Formula (G), Formula (GI), or Formula (G-ll), and / or combinations with other therapeutic agents is combined with genetic tests to determine whether an individual is a vehicle of a mutant gene that is known to be correlated with certain diseases or conditions. Compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll), and combination therapies may be administered before, during or after the occurrence of a disease or condition, 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 or 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 (G), Formula (Gl), or Formula (G-ll), with inhibitors of leukotriene synthesis or leukotriene receptor antagonists, acting at the same point or at other points in the leukotriene synthesis pathway, they could prove to be particularly useful for treating leukotriene-dependent or leukotriene-mediated diseases or conditions. In addition, by way of example, therapies that combine compounds of any of Formula (G), Formula (Gl), or Formula (G-ll), with inhibitors of inflammation may prove to be particularly useful for treating leukotriene diseases or conditions. -dependent or mediated by leukotrienes. Anti-Inflammatory Agents In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions include administering to a patient compounds, pharmaceutical compositions, or medicaments described herein in combination with an anti-inflammatory agent. which includes, but is not limited to, artrotec, asacol, auralgan, bluefidin, daypro, etodolac, ponstan, salofalk, and solumedrol; non-steroidal anti-inflammatory agents, for example aspirin (Bayer ™, Amotiguadorin ™), indomethacin (lndocin .TIMM); rofecoxib (VioxxIM), celecoxib (Celebrex ™), valdecoxib (Bextra), diclofenac, etodolac, ketoprofen, lodin, 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 may provide additional anti-inflammatory benefits. As an example, asthma is a chronic inflammatory disease characterized by pulmonary eosinophilia and hyperresponsiveness or respiratory tract. Zhao et al., Proteomics, 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 respiratory tract, in the increase in 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 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 diseases or conditions Dependent or mediated by leukotrienes 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 antagonists of the CysLT1 / CysLT2 receptor and antagonists. of the CysLT Receptor 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 CysLT1 / CysLT2. The dual antagonists of the receptor CysLT1 / CysLT2 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 presented at the American Thoracic Society, May 2002) and Tsuji et al., Org. Biomol. Chem., 1, 3139-3141, 2003. For a particular patient, the most appropriate formulation or method of 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 to treat the disorder and the period of time in which the dual receptor antagonist of CysLT1 / CysLT2 acts to inhibit the activity of the CysLT receptor. As an example only, 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 leukotriene-mediated 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. CysLT !. Antagonists of the CysLTi receptor include, but are not limited to, Zafirlukast ("Accolate ™"), Montelukast ("Singulair ™"), Prankulast ("Onon ™"), and derivatives or analogs thereof. The combinations can be used to treat leukotriene-dependent or leukotriene-mediated disorders, including respiratory disorders. The co-administration of a FLAP or 5-LO inhibitor described herein with a CysLT receptor antagonist! or dual antagonist of the CysLT1 / CysLT2 receptor can have a therapeutic benefit that surpasses the benefit derived from the administration of only a FLAP or 5-LO inhibitor or a CysLTTR 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 receptor blockade and / or the blocking of the dual receiver of CysLTi / CysLT? can provide substantial therapeutic benefits, particularly for respiratory diseases. Other Combination Therapies In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, 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 to not), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicin / idarubicin, irinotecen, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel ™, taxol, temozolomide, thioguanine, or classes of drugs that include hormones (an antiestrogen, an anti-androgen, or gonadotropin-releasing hormone analogs, interferons such as alpha interferon, nitrogen mustards such as busu lfen melphalen or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecen or topotecen, 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 diseases or leukotriene-dependent or leukotriene-mediated 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 or leukotriene-mediated diseases or conditions, such as atherosclerosis, 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 HMG-CoA reductase inhibitors (for example statins in their lactonized or dihydroxy open chain acid forms and pharmaceutically acceptable salts and esters thereof, including, but not limited to a, 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 particular the sodium salt thereof Atorvastatin, in particular the calcium salt of it; nisvastatin, also called NK-104; rosuvastatin); agents that have both lipid modifying effects and other pharmaceutical activities; inhibitors of HMG-CoA synthase; cholesterol absorption inhibitors such as ezetimibe; inhibitors of the cholesterol ester transfer protein (CETP), for example JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalene synthetase inhibitors (also called squalene synthase inhibitors); inhibitors of the aquocenzyme A: cholesterol acyltransferase (ACAT) which include selective inhibitors of ACAT-1 or ACAT-2 as well as 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 lipoproteins); inhibitors of platelet aggregation, for example glycoprotein fibrinogen receptor antagonists llb / llla and aspirin; agonists of the peroxisome proliferator-activated gamma receptor (PPAR?), which include the compounds commonly referred to as glitazones, for example troglitazone, pioglitazone and rosiglitazone and include those compounds included in the structural class known as thiazolidinediones as well as those agonists of PPAR? outside the structural class of the thiazolidinediones; PPARα agonists such as clofibrate, fenofibrate including micronized fenofibrate, and gemfibrozil; dual agonists a /? of PPARs such as 5 - [(2,4-dioxo-5-thiazolidinyl) methyl] -2-methoxy-N - [[4- (tri-fluoro-methyl) -phene-nyl] -methyl] -benzamide, known as KRP-297; vitamin B6 (also known as pyridoxine) and pharmaceutically acceptable salts thereof such as the NCI salt; b12 vitamin (also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or ester 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; calcium channel blockers such as nifedipine and diltiazam; endotelian antagonists; agents that increase the expression of the ABC1 gene; FXR and LXR ligands that include both inhibitors and agonists; bisphosphonate compounds such as sodium alendronate; and cyclooxygenase-2 inhibitors 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; nitric oxide synthase inhibitors, such as N- (3- (aminomethyl) benzyl) acetamidine; Rho kinase inhibitors, such as fasudil; angiotensin II type-1 receptor antagonists, including candesarten, losarten, irbesartan, eprosarten, telmisarten and valsarten; inhibitors of glycogen synthase kinase 3; sodium or calcium channel blockers, including crobenetin; inhibitors of p38 MAP kinase, including 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 open-chain dihydroxy acid, pravastatin, fluvastatin, atorvastatin, nisvastatin, and rosuvastatin; neuroprotectors, which include free radical scavengers, calcium channel blockers, excitatory amino acid antagonists, growth factors, antioxidants, such as edaravone, vitamin C, TROLOX ™, citicoline and minicycline, and reactive astrocyte inhibitors, such as (2R) -2-propyloctanoic acid; β-andrenergic blockers, such as propranolol, nadolol, timoloi, pindolol, labetalol, metoprolol, atenolol, esmolol and acebutolol; NMDA receptor antagonists, including memantine; NR2B antagonists, such as traxoprodil; 5-HTIA agonists; fibrinogen platelet receptor antagonists, including tirofiben and lamifiban; thrombin inhibitors; antithrombotics, such as argatroben; antihypertensive agents, such as enalapril; vasodilators, such as cyclohellate; 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 dimethylsulfoxide, omalizumab, and pontosan polysulfate. In another embodiment described herein, methods for the treatment of leukotriene-dependent or leukotriene-mediated diseases or conditions, such as bone disorder therapy, comprise administering compounds, pharmaceutical compositions, or medications to a patient. described herein in combination with at least one additional agent selected from the group consisting of minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or the like, and cathepsin K inhibitors. Treatment of Leukotriene-Based Diseases or Diseases Using Antagonists of the Receiver of CvsLTi / CvsLT? According to another aspect, the compositions and methods described herein are designed to administer a dual antagonist of the CysLT1 / 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 CysLT signaling through the CysLT receptors. Normally CysLT refers to LTC4, LTD4 or LTE4. Cysteinyl leukotrienes are potent building agents of smooth muscle, particularly in respiratory and circulatory systems. These are measured by at least two cellular receptors, CysLTi and CysLT2. The CysL ^ receptor and the CysLT2 receptors are receptors coupled to protein G with seven putative transmembrane regions and an intracellular domain that interacts with proteins G, Evans et al., Prostag landins and Other Lipid Mediators, 68- 69, p587-597, (2002). Examples of dual receptor antagonists of CysLT! / CysLT2 BAY u9773, Cuthbert et al.
EP 00791576 (published on August 27, 1997), DUO-LT (Galczenski et al., D38, Poster F4 presented at the American Thoracic Society, May 2002) and Tsuji et al., Org. Biomol. Chem., 1, 3139-3141, 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 drugs comprising a receptor antagonist. of CysLT1 / CysLT2. As an 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 (G), Formula (Gl), or Formula (G-ll), or pharmaceutical compositions or Medications described herein that include compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll), or other FLAP moctulators, 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 (phenotype analysis), monitoring / measurement of functional markers (analysis of phenotypes), which indicate the patient's response 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 at 13q12 and the gene has been linked to an increased risk of myocardial infarction and stroke in several populations. A number of polymorphisms and haplotypes have been identified in the gene encoding FLAP (U.S. Patent Application 2005113408; Sayers, Clin. Exp. Allergy, 33 (8) 1 103-10, 2003; Kedda, et al., Clin. Exp. Allergy, 35 (3): 332-8, 2005). Particular haplotypes of FLAP have been linked to myocardial infarction and stroke in various populations (Helgadottir A and collaborators Nature Genet, 36: 233-239 (2004), Helgadottir A and collaborators Am J Hum Genet 76: 505-509 (2004); Lohmussaar E et al Stroke 36: 731-736 (2005); Kajimoto K et al Circ J 69: 10291034 (2005) Previously, it has been shown that polymorphisms in certain genes correlate with the response to given therapies, 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): 3328-37, 2004). Therefore, patients who are 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. Furthermore, polymorphisms in any of the synthetic or signaling genes dedicated to the leukotriene pathway could determine a patient that had more or less response to leukotriene modulating therapy (both FLAP or 5-LO inhibitors and receptor antagonists). leukotrienes). The genes dedicated to the leukotriene pathway are those of 5-lipoxygenase, 5-lipoxygenase activation protein, LTA4 hydrolase, LTC synthase, LTB4 receptor 1 (BLT-i), LTB4 receptor 2 (BLT2), receptor 1 of cysteinyl-leukotrienes (CysLT? R), cysteinyl-leukotriene receptor 2 (CysLT2R). For example, the 5-LO gene has been linked to asthma intolerant to aspirin and airway hyperresponsiveness (Choi JH et al. Hum Genet 114: 337-344 (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 5-LO inhibitor in asthmatics (Drazen et al., Nature Genetics, 22, p168170, (1999 The LTCa synthase gene has been linked to atopy and asthma (Moissidis I et al., Genet Med 7: 406-410 (2005).) The CysLT2 receptor has been linked to asthma. and atopy (Thompson MD and collaborators Pharmacogenetics 13: 641-649 (2003); Pillai SG and collaborators Pharmacogenetics 14: 627-633 (2004); Park JS and collaborators Pharmacogenet Genomics 15: 483492 (2005); Fukai H and collaborators Pharmacogenetics 14: 683-690 (2004) .Any polymorphism in any gene of the leukotriene pathway or combination of polymorphisms or haplotypes could lead to altered sensitivity of the patient to therapy aimed at reducing the pathological effects of leukotrienes. Patients who could respond better to leukotriene modulator therapies described herein may include knowledge of polymorphisms in leukotriene pathway genes and also knowledge of the expression of mediators managed by leukotrienes.The selection of patients could be made by taking as base only the genotype of the leukotriene pathway, only the phenotype (biomarkers om functional arcators) 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 is possible more than one sequence 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. it 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 in the present "allele" of the polymorphic site. SNP allows an adenine allele and a thymine allele Normally, a reference sequence refers to a particular sequence.The alleles that differ from the reference are called "variant" alleles.The term "FLAP variant" as used herein, it 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 sequence of reference. 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 structure change; 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 stop codon; 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 gene conversion, 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 nucleic acid sequence causes a change in structure, the change in structure may result in a change in the encoded amino acids, and / or can result in the generation of a premature stop codon, causing the generation of a truncated polypeptide. By way of example, a polymorphism associated with a susceptibility to myocardial infarction (Ml), 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 Ml, ACS, stroke or PAOD than in individuals without Ml, ACS, stroke or PAOD. Therefore, these haplotypes may have predictive values to detect a susceptibility to Ml, 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): 224556, 2005), and FLAP gene markers have been described associated with the risk 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 in its entirety. By way of example only, a haplotype associated with a susceptibility to myocardial infarction or stroke comprises markers SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42 at loci 13q 12-13. Or, the presence of alleles T, G, G, G, A and G in SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42, respectively (the 136 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 SG13S42 at loci 13q12-13. Or, the presence of alleles T, G, G, G and A at 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 SG13S32 at locus 13q12-13 locus. Or, the presence of alleles G, G, G and A in SG13S25, SG13S106, SG13S30 and SG13S32, 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. Or, the presence of alleles G, G, G and A in SG13S25, SG13S106, SG13S30 and SG13S32, respectively (the haplotype Bs4), is diagnosis of susceptibility to myocardial infarction or stroke. In the embodiments just described, patients under consideration for treatment with compounds of any Formula (G), Formula (Gl), or Formula (G-ll), or combinations of drugs described herein including compounds of any Formula (G), Formula (Gl), or Formula (G-ll), can be monitored to determine the potential response for treatment with compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll) , 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 13q12-13. Or, the presence of alleles T, G, T, G and A in SG13S99, SG13S25, SG13S114, SG13S89 and SG13S32, respectively (haplotype A4), 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, SG13S114, SG13S89 and SG13S32, respectively (the A4 haplotype), is diagnostic of susceptibility to myocardial infarction or stroke. In the recently described modalities, patients who are under consideration for treatment with compounds of any of Formulas (G), Formula (Gl), or Formula (G-II), or combinations of drugs described herein that include compounds of any of Formulas (G), Formula (Gl), or Formula ( G-ll), can be monitored to determine the potential response for treatment with compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll), based on the haplotypes. Haplotype detection can be achieved by methods known in the art to detect sequences at polymorphic sites, and therefore patients can be selected using FLAP genotype selection, 5-LO or other polymorphisms of the leukotriene path gene. The presence or absence of a polymorphism or haplotype of the leukotriene path gene 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 respond to, or derive benefit from, treatment with compounds of any Formula (G), Formula (G-1), or Formula (G-11). 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 certain haplotypes, where the presence of the SNP or the haplotype is diagnostic of susceptibility to myocardial infarction or stroke. Phenotype Analysis: Biomarkers Patients under consideration for treatment with compounds of any of Formulas (G), Formula (Gl), or Formula (G-ll), or combinations of drugs described herein including compounds of any of the Formulas (G), Formula (Gl), or Formula (G-ll), can be monitored to determine the potential response for treatment based on inflammatory phenotype biomarkers 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 detecting the haplotype of the leukotriene path 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. The biomarkers can be physiological titration parameters, for example blood pressure, or they can be analytical titration parameters, for example blood glucose, or cholesterol concentrations. The techniques used to monitor and / or measure the biomarkers include, but are not limited to, NMR, LC-MS, LCMS / MS, GC-MS, GC-MS / MS, HPLC-MS, HPLC-MS / MS, FT-MS, FT-MS / MS, ICP-MS, ICP-MS / MS, peptide / protein sequencing, nucleic acid sequencing, electrophoresis techniques, immunoassays, immunoblotting, in-situ hybridization, fluorescence in situ hybridization, PCR, radio-immunoassays, and enzyme immunoassays. Single nucleotide polymorphisms (SNPs) have also been useful for the identification of biomarkers to determine the propensity 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 compounds of any Formula (G), Formula (Gl), or Formula (G-ll), or combinations of drugs described herein that include compounds of any of Formula (G), Formula (Gl), or Formula (G-ll).
By way of example only, patients may be selected for treatment with compounds of any of Formula (G), Formula (Gl), or Formula (G-ll), or combinations of drugs described herein that include compounds of any of Formula (G), Formula (Gl), or Formula (G-ll), by monitoring to identify increased blood inflammatory biomarkers such as, but not limited to, LTB4, LTC, stimulated LTE4, myeloperoxidase (MPO), eosinophil peroxidase (EPO) , C-reactive protein (CRP), soluble intracellular adhesion molecule (sICAM), monocyte chemoattractant protein (MCP-1), monocyte inflammatory protein (MIP-1a), interleukin-6 (IL-6), interleukin 4 activator of TH2 T cells (IL-4), and 13 (I L-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 inhibition of leukotriene synthesis using compounds of any Formula (G), Formula (Gl), or Formula (G-ll), by using a panel of inflammatory biomarkers driven by leukotrienes. Phenotype Analysis: Functional Markers Patients under consideration for treatment with compounds of any of Formula (G), Formula (G-1), or Formula (G-11), or combinations of drugs described herein which include compounds of any of Formula (G), Formula (G-1), or Formula (G-11), can be monitored to determine the response to known modulators of the leukotriene path. 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, patient monitoring by detection of the gene haplotype. the trajectory of leukotrienes (analysis of the genotype) and / or monitoring / measurement of biomarkers (analysis of phenotypes), 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 leukotriene-dependent or leukotriene-mediated diseases or conditions, for treatment, using compounds of either Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical compositions or medicaments that include compounds of any of Formula (G), Formula (G-1), or Formula (G-11). 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, volume respiratory minute, alveolar ventilation, maximum vital capacity, and ventilatory capacity. The method of measuring lung volumes and capacities includes, but is not limited to, maximum expiratory flow-volume curve, forced expiratory volume in 1 second (FEV1), maximum expiratory flow rate. 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, transdiaphragmatic pressure, ventilation distribution, nitrogen simple inspiration, pulmonary nitrogen washing, and gas transfer. In addition, 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 Formula (G), Formula (G-1), or Formula (G-11), or compositions Pharmaceuticals or medicaments including compounds of any of Formula (G), Formula (G-1), or Formula (G-11). By way of example only, treatment regimens may include current or past treatments using zileuton (Zyflo ™), montelukast (Singulair ™), pranlukast (Onon ™), zafirlukast (Accolate ™). Also, patients who are under consideration for treatment with compounds of any of Formula (G), Formula (Gl), or Formula (G-ll), or combinations of drugs described herein include compounds of any of Formula ( G), Formula (Gl), or Formula (G-ll), can be monitored for functional markers, including, 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 mucosal edema, 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. It is expected that those with experience in the technique 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, information obtained from previously described diagnostic methods 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. The methods of treatment include, but are not limited to, administering a therapeutically effective amount of a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), administering a therapeutically effective amount of a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament including a compound of any of Formula (G), Formula (Gl), in combination with a therapeutically effective amount of a leukotriene receptor antagonist (by way of example, CysLT1 / CysLT2 antagonist or CysLTi antagonist), or administering a therapeutically effective amount of a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), in combination with a therapeutically effective amount of another anti-inflammatory agent. In other embodiments, a sample from a patient is analyzed to determine haplotypes of the leukotriene gene, for example only FLAP haplotypes, and / or biomarkers of phenotypes, and / or functional responses of the phenotype tag to modifying agents. Then, the patient can be treated using various methods of treatment. The methods of treatment include, but are not limited to, administering a therapeutically effective amount of a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition or medicament that includes a compound of any of Formula (G), Formula (G-I), or Formula (G-ll), administering a therapeutically effective amount of a compound of any of Formula (G), Formula (Gl), or Formula (G-ll) ), or pharmaceutical composition or medicament including a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), in combination with a Therapeutically effective amount of a leukotriene receptor antagonist (by way of example, CysLT1 / CysLT2 antagonist or CysLT antagonist, or administering a therapeutically effective amount of a compound of any of Formula (G), Formula (Gl), or Formula (G-ll), or pharmaceutical composition to medicament that includes a compound of any of Formulas (G), Formula (Gl), or Formula (G-ll), in combination with a therapeutically effective amount of another anti-inflammatory agent. In yet other embodiments, a sample from a patient is analyzed to determine haplotypes of the leukotriene gene, for example only FLAP haplotypes, and biomarkers of phenotypes, and / or functional responses of the phenotype marker to modifying agents. , the patient can be treated using various methods of treatment.The 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 a therapeutically effective amount of a FLAP inhibitor, or a pharmaceutical composition or medicament that includes a FLAP inhibitor, in combination with a therapeutically effective amount of a leukotriene receptor antagonist (by way of example, CysLT1 / CysLT2 antagonist or CysLT! antagonist), or administering a therapeutically effective amount of a FLAP inhibitor, or a pharmaceutical composition or medicament that includes a FLAP inhibitor, in combination with a therapeutically effective amount 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 that is compartmentalized to receive 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 package (s) may comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The containers optionally have a sterile access port (for example the container can be a bag or vial of intravenous solution having a stopper 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.
Typically, a device may 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 are not limited to, buffers, diluents, filters, needles, syringes; Carrier, package, container, vial and / or tube labels that mention the contents and / or instructions for use, and package leaflets with instructions for use. Normally, a set of instructions will also be included. A label may be on or associated with the container. A label can be on a container when the letters, numbers or other characters that form the label adhere, mold or engrave on the container itself; A label may be associated with a package when it is present within a receptacle or carrier that also holds the package, for example, a package insert. A label can be used to indicate that the content 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 provided 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 (G), Formula (Gl), and Formula (G-ll) The starting materials and intermediates used in the synthesis of the compounds of formula (G), Formula (Gl) , and Formula (G-ll) 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 used in the synthesis of the compounds of Formula (G), Formula (Gl), and Formula (G-ll), can be prepared using the methods described herein or known in the technique. Table 6. Intermediates used in the synthesis of the compounds of Formula (G), Formula (G-1), and Formula (G-1) Route 1: Step 1: BOC Protection (lnt-10) 3-azetidinecarboxylic acid (Sigma Aldrich, 0.25 g, 2.5 mmol) was dissolved in tBuOH (5 mL) and 1 N 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 1N HCl, and the mixture was extracted with EtOAc until all of 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 MgSO 4, 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 of 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 MgSO 4, 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 l2 (lnt-73) (6-Bromo-pyridin-3-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 poured into aq Na2CO3. saturated. The organic layer was washed with aqueous sodium thiosulfate, water, then dried over MgSO, filtered and 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 toluenesulfonyl chloride was added (1.0 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, filtered and concentrated. The 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) was dissolved in CH2Cl2 (20 ml) and cooled to 0 ° C. Triethylamine (1.7 ml, 122 mmol), followed by methanesulfonyl chloride (0.66 ml, 8.4 mmol) dropwise. The reaction was stirred for 30 minutes, and then diluted with CH2Cl2, washed with water, dried over MgSO4, filtered and concentrated to obtain the desired product. Route 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 stirred at -10 ° C for 1 hour, then at room temperature for 2 hours, followed by rapid cooling with water. The aqueous layer was extracted with CH2Cl2, and the organic layers were dried, filtered and concentrated to give the desired product. Route 3: Step 1: Formation of Imine (lnt-20) Chloroacetonitrile (0.5 g, 6.6 mmol) was dissolved in Et2O (10 mL) and cooled to 0 ° C. EtOH (0.43 ml, 7.3 mmol) was added, followed by 4N HCl in 1,4-dioxane (15 ml, 59.6 mmol). The reaction was stirred at 0 ° C for 4 days, and then concentrated to Give the desired product in the form of a white solid.
Step 2: Cyclization (lnt-20) The imine 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 HCl was added 4N in 1,4-dioxane (0.5 ml, 2 mmol). The mixture was filtered, and the filtrate was concentrated to give the desired product. Step 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 was added (70%, 13.9 g, 55.2 mmol), and the reaction was stirred overnight at room temperature. The mixture was washed with saturated aqueous Na2CO3, 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 acetic anhydride (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 added slowly to quench the reaction. The solution was evaporated to dryness and purified on silica gel to give the desired product. Step 3: Hydrolysis (nt-46) The acetate from Step 2 (46.7 mmol) was dissolved in HCl concentrated (20 ml) and refluxed for 1 hour. The reaction was cooled and evaporated to dryness to give an orange solid, which was used directly in the next reaction. Step 4: Chloride Formation with SOCI2 (nnt-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 as a hydrochloride salt, which was used directly in subsequent reactions. Route 5: Step 1: Condensation (lnt-60) p-Toluidine (10 g, 60.0 mmol) and triethylamine (8.4 mL, 60.3 mmol) were dissolved in CH2Cl2 (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 CH2CI2, 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: Formation of chloride 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 saturated aqueous NaHCO3, 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% Na2CO3, water, and brine, dried over MgSO4, 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-methylpyridine (1.11 g, 10 mmol), NCS (2.0 g, 15 mmol), and catalytic benzoyl peroxide were dissolved in benzene and heated to reflux during the night. The reaction it was concentrated and diluted with water and EtOAc. The organic layer was washed with saturated aqueous NaHCO3, 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 / H2O (16 ml, 2: 1) was added 2-bromothiazole (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 was added (0.76 g, 0.7 mmol) 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 MgSO, filtered, concentrated and purified on silica gel (Gradient EtOAc: hexanes) to give the desired product. Step 2a: F-Alkylation (lnt-71) Thiazole from Step 1 (0.35 g, 1.8 mmol) was dissolved in THF (15 ml) and cooled to -78 ° C in N2, n-butyllithium (1.6M) was added. 4.6 ml, 7.3 mmol) dropwise, followed by NFSi (1.2 g, 3.7 mmol). The reaction was cooled rapidly to -78 ° C with saturated aqueous NH Cl, and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organics were dried over MgSO, 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-butyl lithium (1.6 M; 4. 3 ml, 6.7 mmol) dropwise, followed by iodomethane (0.16, 2.6 mmol). The reaction was cooled rapidly to -78 ° C with saturated aqueous NH 4 Cl, and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc, and the combined organics were dried over MgSO 4, filtered and concentrated. The residue was purified on silica gel to give the desired compound. Route 7: Step 1: Formation of acid chloride (Int 135) 3-Phenoxy-benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH 2 Cl 2, oxalyl chloride (0.32 g, 0.25 mmol) was added, followed by 1-2 drops of DMF. The reaction was stirred at room temperature, and then concentrated to give the desired acid chloride. Route 8: Step 1: Alkylation (int-5) To imidazole (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.
Route 9: Step 1: Methylation (lnt-74) To 4-m-tolyl-tetrahydro-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. Iodomethane (1.25 ml, 20 mmol) was added, and the reaction was stirred for 1 hour. The mixture was rapidly cooled 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. Route 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 during minutes to start the reaction, and then stirred at room temperature for another 15 minutes. The reaction was diluted with water and diethyl ether, and the aqueous layer was extracted with diethyl ether three times. The combined organic layers were dried over MgSO 4, filtered and concentrated to give the desired product as a colorless liquid. Step 2: Addition of thiol 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 during 18 hours, then diluted with water. The aqueous layer was extracted with diethyl ether, and the combined organic layers were dried over MgSO 4, filtered and concentrated to give the desired product. Synthesis of Compounds of Formula (G), Formula (G-1) and Formula (G-ll) Reaction Scheme A: X = Bro B (OH) 2 Example 1: Preparation of Compound 1-2, Compound 2- 19, Compound 2-21, Compound 2-35, Compound 2-62, Compound 2-89, Compound 2-195, Compound 2-196, Compound 2-206, Compound 3-1, Compound 3-2, Compound 3 3, Compound 3-4, Compound 3-5, and Compound 4-1. Compounds 1-2, Compound 2-19, Compound 2-21, Compound 2-35, Compound 2-62, Compound 2-89, Compound 2-195, Compound 2-196, Compound 2206, Compound 3-1, Compound 3-2, Compound 3-3, Compound 3-4, Compound 3 -5, and Compound 4-1, were prepared as detailed in Reaction Scheme A. A detailed illustrative example of the reaction conditions shown in Reaction Scheme A is described for the synthesis of 3- [3- tert -Butylsulfanyl-1- [4- (6-methoxy-pyridin-34) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-19). Step 1: N- [4- (pyridin-2-ylmethoxy) -phenyl] -acetamide A mixture of 4-acetamidophenol (Sigma-Aldrich; 73.6 g), 2-chloromethylpyridine hydrochloride (80 g) and cesium carbonate (320 g) in DMF (1 L) was stirred at 70 ° C for 2 days. The mixture was cooled, poured into water (2 I) and extracted with EtOAC (x6). The organic layers were washed with brine, dried (MgSO) and filtered to give a tan solid (A-1, 114 g) which was used as such in the next Step. Step 2: 4- (Pyridin-2-ylmethoxy) -phenylamine hydrochloride A-1 (114 g) was dissolved in EtOH (1 L) 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 heating was continued 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 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 (A-2.95 g) as a pink solid.
Step 3: [4- (Pyridin-2-ylmethoxy) -phenyl] -hydrazine A-2 dihydrochloride (95 g) was dissolved in water (1 L) at 0 ° C and NaNO2 (26 g) in water was added thereto. (100 ml). The diazonium salt was formed, for 45 minutes and then poured slowly for 15 minutes in a rapidly stirred mixture of Na 2 S 2 O 4 (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 concentrated KOH. 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 was formed immediately. Collection of the residues by filtration followed by vacuum drying gave the title compound as a tan solid (A-3.75 g).
Step 4: Ethyl ester of 3 [3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid A-3 (75 g), 5 - ethyl (t-butylthio) -2,2-dimethyl-4-oxo-pentanoate (prepared according to the procedures described in US Pat. No. 5,288,743 issued 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 Na2CO3. The mixture was extracted with EtOAc (x3), then washed with water (x2), brine, dried (MgSO), 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 solid yellow. Step 5: Ethyl ester of 3- [3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -indo I -2-yl] -2,2-dimethyl-propionic Ethyl ester of 3- [3-tert-butylsulfanyl-5- (pyridin-2-yl methoxy) -1H-indol-2-yl] -2 was dissolved , 2-d imethyl propionic acid (A-4, 20.0 g, 45.4 mmol) in DMF (150 ml) and cooled to -10 ° C in N2. Sodium hydride (60% dispersion in mineral oil, 2.0 g, 50.0 mmol) was added in portions, and the reaction was stirred at -10 ° C for 45 minutes until the foam disappeared. To this dark brown-red solution was added 4- (6-methoxypyridin-3-yl) -benzylester of methanesulfonic acid (lnt-72; 16.0 g, 54.5 mmol) in DMF drop a drop. The reaction was then stirred at -10 ° C for 1 hour and allowed to warm to room temperature slowly. After 16 hours, the LCMS confirmed the formation of the product. The reaction was quenched with saturated NH4CI and diluted with tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. The combined organic layers were dried over MgSO 4, 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-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2,2-Dimethyl-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 LCMS 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 MgSO 4, filtered and concentrated to give the desired free acid (A-6). The mass spectrometric data of Compounds 1-2, Compound 2-19, Compound 2-21, Compound 2-35, Compound 2-62, Compound 2-89, Compound 2195, Compound 2-196, Compound 2-206, Compound 3-1, Compound 3-2, Compound 3-3, Compound 3-4, Compound 3-5, and Compound 4-1 is that they are shown in Tables 1-4. Notes: For compound 1-2, step 6 was not performed. For compound 2-62, after step 6, the 6-methoxy-pyridin-3-yl in the precursor was hydrolyzed with potassium hydroxide to give the 6-hydroxy-pyridin-3-yl in the final product. For compound 2-89, during step 6, THF 5-fluorothiazoyl in the precursor was hydrolyzed edemas to give 5-methoxythiazolyl in the final product. For compound 2-195, after step 5, a Suzuki cross-coupling reaction was performed to give compound A-5b, as described in Example 5, step 2. For compound 2-196, after step 5 , a Suzuki cross-coupling reaction was performed to give compound A-5b, as described in Example 5, step 2. For compound 3-1, after step 5, a Suzuki cross-coupling reaction was performed to give compound A-5b, as described in Example 5, step 2. For compound 3-2, after step 5, a Suzuki cross-coupling reaction was performed to give compound A-5b, as described in Example 5, step 2. For compound 3-3, after step 5, a reaction of Suzuki cross coupling was performed to give compound A-5b, as described in Example 5, step 2. For compound 3-4, after step 5, a Suzuki cross-coupling reaction was performed to give compound A- 5b, as described in Example 5, step 2. For compound 3-5, after step 5, a cross-coupling Suzuki reaction was performed to give compound A-5b, as described in Example 5, step 2. For compound 4-1, i) during step 1, 1- (4-isopropylphenyl) hydrazine was used in place of 4-methoxyphenylhydrazine, and 1-iodo-4-bromomethylbenzene was used in place of 4-chlorobenzylchloride , ii) steps 3 and 4 were not carried out; the product of step 2 (C-2) was used directly in step 5, iii) after hydrolysis in step 5, a Suzuki cross-coupling reaction was performed to give the final compound, as described in Example 5 , step 2. Reaction Scheme B: Ck XL ^ co2et B-5 6-6 Pdí Pha) ,, X R = cßH4-X. & - * > X = BP0 B (0H) 2 Example 2: Preparation of Compound 1-4, Compound 1-5, and Compound 1-6. Compound 1-4, Compound 1-5 and Compound 1-6 were prepared as detailed in Reaction Scheme B. A detailed illustrative example of the reaction conditions shown in Reaction Scheme B is described for the synthesis from 1 - [3- te rc-butylsulfa nyl-1- (4-chloro-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol . Step 1: 4-tert-Butylsulfanyl-3-oxo-butyric acid ethyl ester Ethyl 4-chloroacetoacetate (7.5 ml, 51.9 mmol), 2-methyl-2-propanethiol (5.6 ml, 49.7 mmol), triethylamine were 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 was used without further purification. Step 2: Ethyl ester of (3-tert-butylsulfanyl-5-methoxy-1H-indol-2-11) -acetic acid 4-Methoxyphenylhydrazine hydrochloride (7.7 g, 44.1 mmol) and B-1 (7.4 g, 33.9 mmol) were dissolved in 2-propanol (150 mL) and heated to reflux for 24 hours. The reaction mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO 4, 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 MgSO, filtered and concentrated to give the desired product (B-3). Step 4: 3-tert-Butylsulfanyl-2- (2-hydroxy-2-methyl-propyl) -1H-indol-5-ol B-3 (2.2 g, 7.0 mmol) was dissolved in THF (70 mL) and it was 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 aqueous NH CI and extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, concentrated and purified on silica gel to give the desired product (B-4). Step 5: 1- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol A B-4 (0.18 g, 0 , 61 mmol) in 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 minutes. 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 MgSO, filtered and concentrated. The residue was purified on silica gel to give the desired product (B-5). Step 6: 1 - [3-te rc-butylsu If ani 1-1 - (4-c-loro-be nci I) -5- (pyrid-n-2-ylmethoxy) -1H-indol-2-yl] - 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 for the night. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The The combined organics were washed with water, dried over MgSO 4, filtered, concentrated, and purified over silica gel (Gradient EtOAc: hexanes) to give the desired compound (B-6).
The mass spectrometry data of Compound 1-4, Compound 1-5, and Compound 1-6, are shown in Tables 1-4. Notes: For compound 1-4, Compound 1-5, and Compound 1-6, after step 6, a cross-coupling Suzuki reaction was performed) to give compound B-6b, as described in Example 5 , step 2, Reaction Scheme C: Example 3 (X = CI): (S) -243-tert-Butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indole tert-butylester -5-yloxymethyl] -pyrrolidine-1-carboxylic acid Step 1: N- (4-chloro-benzyl) -N- (4-methoxy-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 diisopropylethylamine (20 mL, 115 mmol) in CH2Cl2 (250 mL) was stirred at room temperature for several days . The reaction mixture was diluted with water and the organic layer was dried over MgSO 4, 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 = CI) in the form of a purple solid. Step 2: 3- [1- (4-Chloro-benzyl) -3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl] -2,2-dimethyl-propionic acid ethyl ester C-1 was stirred (-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 issued February 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 solid NaHCO3, 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) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl] -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) was added in CH2Cl2 (2.4 mL), 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 CH2CI2, the combined organics were dried over MgSO4, filtered and concentrated to give the desired product (C-3; X = C1) as a colorless foam. Step 4: (S) -2- [3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-tert-butylester -iloxymethyl-pyrrolidin-1-carboxylic acid 3- [1- (4-Chloro-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-11] -2,2-dimethyl acid ethyl ester -propionic (C-3; 0.5 g, 1.05 mmol) in DMF (2.5 ml) was added N-BOC- (S) -2- (toluene-4-sulfonyloxymethyl) pyrrolidine (0.39 g, 1.10 mmol), and Cs2CO3 ( 0.69 g, 2.1 mmol). The reaction was stirred at 45 ° C for 2 hours, and then catalytic potassium iodide was added and the reaction heated to 60 ° C at night. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2SO, 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-methylpropyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl-tert-butylester ] -pyrrolidin-1-carboxylic acid (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 seen 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 MgSO, 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). Diagram of Reaction D: Example 4: Preparation of Compounds 2-23, Compound 2- 24, Compound 2-31, Compound 2-32, Compound 2-33, Compound 2-76, Compound 2-77, Compound 2-78, Compound 2-79, Compound 2-80, Compound 2-81, Compound 2-82, Compound 2-84, Compound 2-85, Compound 2-99, Compound 2-100, Compound 2-101, Compound 2-104, Compound 2-108, Compound 2-122, Compound 2-135, Compound 2-141, Compound 2-148, Compound 2-149, Compound 2-150, Compound 2-151, Compound 2-156, Compound 2-183, Compound 2-184, Compound 2-188, Compound 2-189, Compound 2-190, Compound 2-191, Compound 2-192, Compound 2-193, Compound 2-197, Compound 2-198, Compound 2-199, Compound 2-200, Compound 2-201, Compound 2-202, Compound 2-203, Compound 2-204, Compound 2-205; Compound 2-207, Compound 2-208, Compound 2-209, Compound 2-210, Compound 2-211, Compound 2-212, Compound 2-213, Compound 2-214, Compound 2-215, Compound 2-216, Compound 2-217, Compound 2-218, Compound 2-219, Compound 2-220, Compound 2-221, Compound 2-222, Compound 2-223, Compound 2-224, Compound 2-225, Compound 2-226, Compound 2-227, Compound 2-228, Compound 2-229, Compound 2-230, Compound 2-231, Compound 2-232, Compound 2-233, Compound 2-234, and Compound 4-2. Compounds 2-23, Compound 2-24, Compound 2-31, Compound 2-32, Compound 2-33, Compound 2-76, Compound 2-77, Compound 2-78, Compound 2-79, Compound 2-80 , Compound 2-81, Compound 2-82, Compound 2-84, Compound 2-85, Compound 2-99, Compound 2-100, Compound 2-101, Compound 2-104, Compound 2-108, Compound 2-122, Compound 2-135, Compound 2-141, Compound 2-148, Compound 2-149, Compound 2-150, Compound 2-151, Compound 2-156, Compound 2-183, Compound 2-184, Compound 2-188, Compound 2-189, Compound 2-190, Compound 2-191, Compound 2-192, Compound 2-193, Compound 2-197, Compound 2-198, Compound 2-199, Compound 2-200, Compound 2-201, Compound 2-202, Compound 2-203, Compound 2-204, Compound 2-205; Compound 2-207, Compound 2-208, Compound 2-209, Compound 2-210, Compound 2-211, Compound 2-212, Compound 2-213, Compound 2-214, Compound 2-215, Compound 2-216, Compound 2-217, Compound 2-218, Compound 2-219, Compound 2-220, Compound 2-221, Compound 2-222, Compound 2-223, Compound 2-224, Compound 2-225, Compound 2-226, Compound 2-227, Compound 2-228, Compound 2-229, Compound 2-230, Compound 2-231, Compound 2-232, Compound 2-233, Compound 2-234, and Compound 4-2, were prepared as shown in Reaction Scheme D. A detailed illustrative example of the reaction conditions shown in the Reaction Scheme D is described for the synthesis of 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2- 141). Step 1: Ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5-hydroxy-1- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzyl] -1H-indol-2-yl } -2, 2-di meti I -propion ico 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 to 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 MgSO 4, filtered and concentrated. The crude material was purified on silica gel (15% EtOAc in hexanes) to give the desired product (D-1, 33.5 g). Step 2: Ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5-hydroxy-1- [4- (6-methoxy-pyridin-3-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 DME (300 ml) and water (150 ml) were degassed with N2 for 30 minutes. Pd (PPh3) 4 (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 MgSO, 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 ester of 3- acid. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-yl-ethoxy) -1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic A 3-ethyl ester. { 3-tert-butylsulfanyl-5-hydroxy-1- [4- (6- methoxy-pyridin-3-yl) -benzyl] -1 H -indole-2-l} -2, 2-d imethyl propionic 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 Cs2CO3 (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 4, filtered and concentrated. The residue was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (D-3, 7.6 g). Step 4: acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxypyridin-341) -benzyl] -1H-indol-2-yl} -2, 2-dimethyl-propionic D-3 (6.58 g, 9.3 mmol) was dissolved in MeOH (36 mL), THF (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 seen 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 MgSO 4, filtered and concentrated. The residue was triturated with hexane: EtOAc (9: 1) overnight, and filtered to give the desired product (D-4, 5.9 g). The mass spectrometry data for Compounds 2-23, Compound 2-24, Compound 2-31, Compound 2-32, Compound 2-33, Compound 2-76, Compound 277, Compound 2-78, Compound 2-79, Compound 2-80, Compound 2-81, Compound 2-82, Compound 2-84, Compound 2-85, Compound 2 -99, Compound 2-100, Compound 2-101, Compound 2-104, Compound 2-108, Compound 2-122, Compound 2-135, Compound 2-141, Compound 2-148, Compound 2-149, Compound 2-150, Compound 2-151, Compound 2-156, Compound 2-183, Compound 2-184, Compound 2-188, Compound 2-189, Compound 2-190, Compound 2-191, Compound 2-192, Compound 2-193, Compound 2-197, Compound 2-198, Compound 2-199, Compound 2-200, Compound 2-201, Compound 2-202, Compound 2-203, Compound 2-204, Compound 2-205; Compound 2-207, Compound 2-208, Compound 2-209, Compound 2-210, Compound 2-211, Compound 2-212, Compound 2-213, Compound 2-214, Compound 2-215, and Compound 4-2, are shown in Tables 1-4. Notes: For compound 2-33, during step 3, the imidazole was also alkylated to give the final product. For compound 2-79, during step 4, the ethyl ester of the precursor was further hydrolyzed to give the acid in the final product. For compound 2-80, after step 3, the ketone in the precursor was reduced with sodium borohydride to give the alcohol in the final product. For compound 2-100, during step 4, the 6-fluoropyridinyl in the precursor was further hydrolyzed to give the 6-methoxypyridinyl in the final product. For compound 2-104, after step 3, a Suzuki cross-coupling reaction was performed on the 6-bromopyridinyl in the precursor to give the 6-cyclopropylpyridinyl in the final product, as described in Example 5, step 2. For compound 4-2, step 3 was not performed. Reaction Scheme E: Example 5: Preparation of Compound 2-30, Compound 2-64, Compound 2-73, Compound 2-87, Compound 2-88, Compound 2-97, Compound 2-107, and Compound 2-121. Compound 2-30, Compound 2-64, Compound 2-73, Compound 2-87, Compound 2-88, Compound 2-97, Compound 2-107, and Compound 2-121, were prepared as shown in Reaction Scheme E. A detailed illustrative example of the reaction conditions shown in Reaction Scheme E is described for the synthesis of acid 3- [ 3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 , 2-dimethyl-propionic (Compound 2-73). Step 1: Ethyl 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- (6-fluoroquinolin-2-ylmethoxy) -1H-indol-2-yl) -2,2- dimethyl-pro pion ico To the ethylester of 3- [1- (4-bromo-benzyl) -3-fer-butylsulfanyl-5-hydroxy-1H-indol-2-yl] -2,2-dimethyl-propionic acid (C -3; 0.25 g, 0.48 mmol) in DMF (2 ml) was added 2-chloromethyl-5-methyl-pyridine hydrochloride (0.13 g, 0.72 mmol), Cs2CO3 (0.39 g, 1.21 mmol), and catalytic tetrabutylammonium iodide . 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 4, filtered and concentrated. The crude material was purified on silica gel (0 to 15% EtOAc in hexanes) to give a additional product (E-1, 0.30 g). Step 2: Ethyl ester of 3- acid. { 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 E-1 (0.06 g, 0.10 mmol), 2-methoxy-pyridine-5-boronic acid (0.02 g, 0.14 mmol), and K2CO3 (0.03 g, 0.24 mmol) in DME were dissolved. (1 ml) and water (0.5 ml) and degassed with N2 for 10 minutes. Pd (PPh3) (0.01 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 4, 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- [4- (6-methoxypyridin-2-yl) -benzyl] -1H-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 seen by LCMS. The reaction was diluted with water and EtOAc, acidified to pH 5 with citric acid and extracted with EtOAc. The organic layers The combined extracts were washed with water, dried over MgSO 4, filtered and concentrated to give the desired product (F-4). The mass spectrometry data for compound 2-30, Compound 2-64, Compound 2-73, Compound 2-87, Compound 2-88, Compound 2-97, Compound 2107, and Compound 2-121, are shown in Table 1-4. Notes: For compound 2-64, steps 2 and 3 were performed in the reverse order. For compound 2-87, during step 3, the 5-cyanopyridyl in the precursor was hydrolyzed edemas to give the 5-carbamoylpyridyl in the final product. For compound 2-88, steps 2 and 3 were performed in the reverse order. For compound 2-97, during step 3, the 6-cyanopyridyl in the precursor was hydrolyzed edemas to give the 6-carbamoylpyridyl in the final product. Reaction Scheme F: Example 6: Preparation of Compounds 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2-17, Compound 2-18, Compound 2-20, Compound 2-34, Compound 2-39, Compound 2-41, Compound 2-43, Compound 2-47, Compound 2-55, Compound 2-65, Compound 2.67, Compound 2-68, Compound 2-90, Compound 2-91, Compound 2-92, Compound 2-93, Compound 2-94, Compound 2-95, Compound 2-96, Compound 2-98, Compound 2-102, Compound 2-103, Compound 2-105, Compound 2-106, Compound 2-109, Compound 2-110, Compound 2-111, Compound 2-112, Compound 2-113, Compound 2-114, Compound 2-115, Compound 2-116, Compound 2-117, Compound 2-118, Compound 2-119, Compound 2-120, Compound 2-125, Compound 2-126, Compound 2-127, Compound 2-128, Compound 2-129, Compound 2-130, Compound 2-131, Compound 2-136, Compound 2-137, Compound 2-138, Compound 2-139, Compound 2-140, Compound 2-142, Compound 2-143, Compound 2-144, Compound 2-145, Compound 2-146, Compound 2-147, Compound 2-157, Compound 2-158, Compound 2-159, Compound 2-160, Compound 2-161, Compound 2-162, Compound 2-164, Compound 2-165, Compound 2-166, Compound 2-167, Compound 2-168, Compound 2-169, Compound 2-171, Compound 2-172, Compound 2-177, Compound 2-174, Compound 2-175, Compound 2-176, Compound 2-177, Compound 2-178, Compound 2-179, Compound 2-180, Compound 2-181, Compound 2-182, Compound 2-185, Compound 2-186, and Compound 2-187. Compound 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2-17, Compound 2-18, Compound 220, Compound 2-34, Compound 2-39, Compound 2-41, Compound 2-43, Compound 2-47, Compound 2-55, Compound 2-65, Compound 2 -67, Compound 2-68, Compound 2-90, Compound 2-91, Compound 2-92, Compound 2-93, Compound 294, Compound 2- 95, Compound 2-96, Compound 2-98, Compound 2-102, Compound 2-103, Compound 2-105, Compound 2-106, Compound 2-109, Compound 2-110, Compound 2-111, Compound 2- 112, Compound 2-113, Compound 2-114, Compound 2-115, Compound 2-116, Compound 2-117, Compound 2-118, Compound 2-119, Compound 2-120, Compound 2-125, Compound 2-126, Compound 2-127, Compound 2-128, Compound 2-129, Compound 2-130, Compound 2-131, Compound 2-136, Compound 2-137, Compound 2-138, Compound 2-139, Compound 2-140, Compound 2-142, Compound 2-143, Compound 2-144, Compound 2-145, Compound 2-146, Compound 2-147, Compound 2-157, Compound 2-158, Compound 2-159, Compound 2-160, Compound 2-161, Compound 2-162, Compound 2-164, Compound 2-165, Compound 2-166, Compound 2-167, Compound 2-168, Compound 2-169, Compound 2-171, Compound 2-172, Compound 2-177, Compound 2-174, Compound 2-175, Compound 2-176, Compound 2-177, Compound 2-178, Compound 2-179, Compound 2-180, Compound 2-181, Compound 2-182, Compound 2-185, Compound 2-186, and Compound 2-187, were prepared as shown in Reaction Scheme F. A detailed illustrative example of the reaction conditions shown in Reaction Scheme F is described for Acid synthesis 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinoline-2-) ylmethoxy) -1- (4- (6-methoxy-pyridin-2-yl) -benzyl] -1H-indol-2-yl) -2,2-dimethyl-propionic acid (Compound 2-140).
Step 1: Ethyl 3- [1- (4-bromo-benzyl) -3-tert-butylsulphanyl-5- (6-fluoroquinol n-2-ylmethoxy) -1H-indol-2-yl] -2 , 2-dimethyl-propionic acid To 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1 H-indol-2-yl] -2,2-dimethyl-propionic acid ethyl ester (C) -3; 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-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1 - [4- (4,4,5,5-tetramethyl- (1,3,2] dioxaborolan-2-yl) - benzyl] -1H-indol-2-yl] -2,2-dimethylpropionic F-1 (1.0 g, 1.5 mmol), bis (pinacolato) diboron (Combi-Blocks, 1.1 g, 4.3 mmol) was dissolved, and KOAc ( 0.44 g, 4.5 mmol) in 1,4-dioxane (15 ml) and degassed with N2 for 10 minutes in a sealed flask. PdCl2dppf (0.13 g, 0.16 mmol) was added, and the reaction mixture was degassed for another 10 minutes with N2. The vessel was sealed and the reaction was heated at 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 MgSO 4, 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: 3- (3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- (4- (6-methoxy-pyridin-2-yl) -benzyl] -1-ethyl ester H-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 K2CO3 (0.15 g, were dissolved. 1.05 mmol) in DME (3.5 ml) 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 others 10 minutes The solution was heated to 85 ° C for 4 hours, 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 were dried over MgSO 4, 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-methoxypyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic F-3 (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 seen 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 MgSO, filtered and concentrated to give the desired product (F-4). The mass spectrometry data for compound 2-1, Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2-17, Compound 2-18, Compound 2-20, Compound 2-34, Compound 239, Compound 2-41, Compound 2-43, Compound 2-47, Compound 2-55, Compound 2-65, Compound 2-67, Compound 2- 68, Compound 2-90, Compound 2-91, Compound 2-92, Compound 2-93, Compound 2-94, Compound 2-95, Compound 296, Compound 2-98, Compound 2-102, Compound 2-103, Compound 2-105, Compound 2-106, Compound 2-109, Compound 2-110, Compound 2-111, Compound 2-112, Compound 2-113, Compound 2-114, Compound 2-115, Compound 2-116, Compound 2-117, Compound 2-118, Compound 2-119, Compound 2-120, Compound 2-125, Compound 2-126, Compound 2-127, Compound 2-128, Compound 2-129, Compound 2-130, Compound 2-131, Compound 2-136, Compound 2-137, Compound 2-138, Compound 2-139, Compound 2-140, Compound 2-142, Compound 2-143, Compound 2-144, Compound 2-145, Compound 2-146, Compound 2-147, Compound 2-157, Compound 2-158, Compound 2-159, Compound 2-160, Compound 2-161, Compound 2-162, Compound 2-164, Compound 2-165, Compound 2-166, Compound 2-167, Compound 2-168, Compound 2-169, Compound 2-171, Compound 2-172, Compound 2-173, Compound 2-174, Compound 2-175, Compound 2-176, Compound 2-177, Compound 2-178, Compound 2-179, Compound 2-180, Compound 2-181, Compound 2-182, Compound 2-185, Compound 2-186, and Compound 2-187, are shown in Tables 1-4.
Notes: For compound 2-17, during step 4, the 6-methoxypyridazinyl in the precursor was further hydrolysed to give the 6-hydroxypyridazinyl in the final product. For compound 2-172, after step 2, the 3-tert-butylsulfanyl in the precursor was oxidized with m-chloroperoxybenzoic acid to give the 2-methylpropane-2-sulfonyl in the final product.
Reaction Scheme G: Rl,, R2 TFA R1. , R2 1R.3 boc CHA ¿Pr8NH.CH2Clí G-l Example 7: Acid 3-. { 5 - ((S) -1-Acetyl-2,3-dihydro-1 H -indol-2-ylmethoxy) -3-tert-butylsulfanyl-1 - [4- (6-methoxy-pyridazin-3-yl) - benc il] -1 H -indol -2-il} -2, 2-d i meti I -propion ico Step 1: Ethyl ester of 3- acid. { 3-tert-Butylsulfanyl-5 - [(S) -1- (2,3-dihydro-1H-indol-2-yl) methoxy] -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic Tert-butylester of (S) -2- acid was dissolved. { 3-tert-Butylsulfanyl-2- (2-ethoxycarbonyl-2-methyl-propyl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-indol-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 seen by TLC analysis. The solution was concentrated in vacuo, and the crude product (G-1) was used without further purification. Step 2: Ethyl ester of 3- acid. { 5 - ((S) -1-Acetyl-2,3-dihydro-1 H -indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) - benzyl] -1 H -indol -2-il} -2, 2-d i got I -propionic G-1 (0.30 mmol) was dissolved in CH 2 Cl 2 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, redissolved in CH2Cl2 and washed with water, dried over Na2SO, filtered and concentrated. The residue was purified on silica gel to give the desired product (G-2). Step 3: Acid 3-. { 5 - ((S) -1-Acetyl-2,3-dihydro-1 H -indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) - benzyl] -1H-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 mL), 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 seen 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 MgSO, filtered and concentrated. The residue was purified on silica gel to give the desired product (G-3). Reaction Scheme H: H-l H-2 H-3 H-4 Example 8: Preparation of 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 2-22, Compound 2-25, Compound 2-26, Compound 2-27, Compound 2-28, Compound 2-29, Compound 2-123, Compound 2-124; Compound 2-132, Compound 2.133, Compound 2-134; Compound 2-163, Compound 2-170 and Compound 2-194. Compounds 2-8, Compound 2-9, Compound 2-10, Compound 2-11, Compound 2-12, Compound 2-13, Compound 2-14, Compound 2-15, Compound 216, Compound 2-22, Compound 2-25, Compound 2-26, Compound 2-27, Compound 2-28, Compound 2-29, Compound 2-123, Compound 2-124; Compound 2-132, Compound 2-133, Compound 2-134; Compound 2-163, Compound 2-170, and Compound 2-194, were prepared as shown in Reaction Scheme H. A detailed illustrative example of the reaction conditions that shown in Reaction Scheme H is described for the synthesis of acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-124). Step 1: Ethyl ester of 3- acid. { 5- (Benzothiazol-2-ylmethoxy) -1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic Aluminum chloride (0.18 g, 1.37 mmol) was suspended in CH 2 Cl 2 (1 mL), and water (19 ul, 1.0 mmol) was added slowly at room temperature. The mixture was stirred for 5 minutes, and then cooled to 0 ° C. Ethyl ester of 3- acid was added. { 5- (Benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic acid (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 or TLC was observed, water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water, dried over MgSO 4, filtered and concentrated. The residue was purified to give the desired product (H-1). Step 2: Ethyl ester of 3- acid. { 5- (Benzothiazol-2-ylmethoxy) -3-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-pro pion ico 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 in N2 for 1.5 hours, and then cooled to room temperature and cooled rapidly with saturated aqueous sodium potassium tartrate. The mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO 4, filtered, concentrated and purified on silica gel to give the desired product (H-2).
Step 3: Ethyl ester of 3- acid. { 5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -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, and then quenched with water and basified with solid NaOH pellets. The mixture was extracted with CH2Cl2, and the combined organics were dried over MgSO, filtered and concentrated. The residue was purified on silica gel to give the desired product (H-3). Step 4: Acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic H-3 (0.03 g, 0.04 mmol) was dissolved in MeOH (0.5 mL) and THF (0.5 ml). Aqueous lithium hydroxide (1 N, 0.5 ml) was added, and the reaction was heated at 60 ° C for 4 hours until no more starting material was seen 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). The mass spectrometric data for compounds 2-8, Compound 2-9, Compound 2-10, Compound 2-11, Compound 2-12, Compound 2-13, Compound 214, Compound 2-15, Compound 2-16 , Compound 2-22, Compound 2-25, Compound 2-26, Compound 2-27, Compound 2-28, Compound 2-29, Compound 2-123, Compound 2-124; Compound 2-132, Compound 2-133, Compound 2-134; Compound 2-163, Compound 2-170, and Compound 2-194, are shown in Tables 1-4. Notes: For compound 2-8, only steps 1, 2 and 4 were performed.
For compound 2-9, only steps 1 and 4 were performed. For compound 2-10, only steps 1, 2 and 4 were performed. For compound 2-11, only Steps 1 and 4 were performed.
For compound 2-12, only Steps 1, 2 and 4 were performed. For compound 2-15, only Steps 1, 2 and 4 were performed. For compound 2-16, only Steps 1, 2 and 4 were performed. For compound 2-25, only Steps 1 and 4 were performed.
For compound 2-26, only Steps 1, 2 and 4 are made. For compound 2-27, only Steps 1 and 4 were performed.
For compound 2-28, only Steps 1, 2 and 4 were performed. For compound 2-123, only Steps 1, 2 and 4 were performed. Reaction Scheme I: 1-1 i 1-2 1-4 (EtO ^ CH O ' Example 9: Preparation of Compound 1-1, Compound 1-3, Compound 1-7, Compound 1-8, Compound 1-9, Compound 1-10, Compound 1-11, Compound 112, Compound 1-13, Compound 1 -14 and Compound 1-15. Compound 1-1, Compound 1-3, Compound 1-7, Compound 1-8, Compound 1-9, Compound 1-10, Compound 1-11, Compound 1-12, Compound 1-13, Compound 1-14 and Compound 1-15., were prepared as delineated in Reaction Scheme I. A detailed illustrative example of the reaction conditions shown in Reaction Scheme H is describes For the synthesis of 3-. { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl] -N- (2-hydroxy-ethyl) -2,2-dimethyl-propionamide. Step 1: Chloride of 3-. { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl] -2,2-dimethyl-propionyl To 3- acid. { 3- te rc-butylsulfa nyl-1- (4-chloro-benzyl) -5-isopropyl-1 H-indol-2-yl] -2,2-dimethyl-propionic acid (prepared according to the procedure described in the patent No. 5,081,138 issued January 14, 1992, 0.25 g, 0.53 mmol) in CH2Cl2 (5 ml) was suspended, 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 was used without further purification. Step 2: 3- { 3-tert-Butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1 H -indol-2-yl] -N- (2-h id roxy-ethyl) -2, 2-di metí I - propyone A 1 (0.18 mmol) in CH 2 Cl 2 was added with tritylamine (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 (1-2). Step 3: 5- { 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -phenyl) - (1, 3,4] oxadiazole- 2-ilamine A 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -benzoic acid hydrazide (0.05 g, 0.10 mmol) in DMF (1 ml) was added C- (Di-imidazol-1-yl) -methyleneamine (0.08 g, 0.50 mmol), and the reaction was heated at 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 MgSO, filtered and concentrated. The residue was purified on silica gel (gradient EtOAc: hexane) to give the desired product.
The mass spectrometry data for the compounds 1-1, Compound 1-7, Compound 1-8, Compound 1-9, Compound 1-10, Compound 1-11, Compound 1-12, Compound 1-13, and Compound 1-14, are shown in Tables 1-4. The NMR data for compound 1-3 are shown below. Notes: For compound 1-3, 1H-NMR (CDCI3) d 8.6 (d, 1H), 8.31 (d, 1H), 7.70 (m, 2H), 7.57 (d, 1H), 7.38 (d, 2H) , 7.32 (d, 1H), 7. 20 (m, 1H), 7.08 (d, 1H), 6.80 (m, 4H), 5.41 (s, 2H), 5.27 (s, 2H), 3.96 (t, 5H), 3.57 (t, 2H), 3.27 (s, 2H), 1.57-1.20 (m, 23H). For compound 1-7, during step 3, hydrazide 1-2 was converted to 1, 3,4-oxadiazol-2-yl I-3 using triethyl orthoformate. For compound 1-8, i) hydrazide 1-2 was produced directly from ester 1-4, ii) during step 3, hydrazide 1-2 was converted to 1,4-oxadiazol-2-yl 1 -3 using triethyl orthoformate. For compound 1-9, i) hydrazide 1-2 was produced directly from ester 1-4, i) during step 3, hydrazide 1-2 was converted to 1,3,4-oxadiazol-2-ylamine 1-3 using cyanogen bromide and sodium bicarbonate. For compound 1-14, during step 3, hydrazide 1-2 was converted to 1,3,4-oxadiazol-2-ylamine 1-3 using C- (di-imidazol-1-yl) -methyleneamine. Example 10: FLAP Binding Assays A non-limiting example of the FLAP binding assay is as follows: The packed human polymorphonuclear cell granules (1.8 x 109 cells) (Biological Specialty Corporation) were resuspended, used and 100,000 g were prepared as as described (Charleson et al., Mal. Pharmacol, 41, 873-879, 1992). 100,000 xg granulated membranes were resuspended in Tris-Tween assay buffer (100 mM Tris HCl pH 7.4, 140 mM NaCl, 2 mM EDTA, 0.5 mM DTT, 5% glycerol, 0.05% Tween 20) to give a protein concentration of 50-100 ug / ml. Ten ul of membrane suspension were added to a 96-well Milipore place, 78 μl of Tris-Tween buffer, 10 μl of 3H MK886 or 3H 3- [5- (pyrid-2-ylmethoxy) -3-tert-butylthio -1-benzyl-indol-2-yl] -2,2-dimethylpropionic (or derivative 125IMK591 Eggler et al., J. Labelled Compounds and Radiopharmaceuticals, 1994, vXXXIV, 1147)) up to -30,000 cpm, 2 μl of inhibitor and incubated for 30 minutes at room temperature. One hundred μl of buffer washed on ice was added to the incubation mixture. The plates were then filtered and washed 3x with 200 μl of ice-cold Tris-Tween buffer, the scintillation bases were sealed, 100 μl of scintillant was added, shaken for 15 minutes then counted in a TopCount. Specific binding was determined as defined as total radioactive binding minus non-specific binding in the presence of 10 μM MK886. The Cl50 were determined using Graphpad prism analysis of drug titration curves. Example 11: Human Blood LTB4 Inhibition Assay A non-limiting example of this LTB inhibition assay of human blood is as follows: Blood was extracted from healthy human volunteers with their consent into heparinized tubes and 125 μl aliquots were added to wells containing 2.5 μl 50% DMSO (vehicle) to 2.5 μl drug in 50% DMSO. The samples were incubated for 15 minutes at 37 ° C. 2 μl of calcium ionophore A23817 (from a stock of 50 mM DMSO diluted only before the test in Hanks balanced salt solution (Invitrogen)) up to 1.25 mM were 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: 100 dilution was assayed for LTB concentration using ELISA (Assay Designs). Drug concentrations to obtain 50% inhibition (Cl50's) of vehicular LTB are determined by non-linear regression (Graphpad Prism) of% inhibition versus log of drug concentration. Example 12: Rat peritoneal inflammation and edema test One non-limiting example of this rat peritoneal inflammation and the edema test is as follows: The in vivo efficacy of leukotriene biosynthesis inhibitors was evaluated using a rat model of inflammation peritoneal Male Sprague-Dawley 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 (iv) injection of staining Evans blue (2 ml 1.5% solution) 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 left to die, and the peritoneal cavity was flooded with 10 ml of phosphate buffered saline (PBS) solution.The resulting fluid was centrifuged at 1,200 rpm for 10 minutes.The vascular edema was evaluated by quantifying the amount of staining Evans blue in the supernatant using a spectrophotometer (Absorbance 610 nm) The concentration of LTB and cysteinyl leukotrienes in the supernatant were determined by ELISA.The concentrations of the drug to obtain 50% leakage inhibition plasma (Evans blue stain) and the inhibition of peritoneal LTB4 and cysteinyl leukotrienes could be calculated by non-linear regression (Graphpad Prism) of% inhibition versus 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 extracted from human volunteers with their consent into heparinized tubes 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 resuspended at 1.25 x 10 5 cells / ml and aliquoted in wells containing 2.5 μl of 20% DMSO (vehicle) or 2.5 μl of drug in 20% DMSO. The samples were incubated for 5 minutes at 37 ° C and 2 μl of calcium ionophore A23817 (from a stock of 50 mM DMSO diluted only before the test in Hanks balanced salt solution (Invitrogen)) up to 1.25 mM was added. they mixed the solutions 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 assayed for the concentration of LTB using ELISA (Assay Designs). Drug concentrations to obtain 50% inhibition (Cl50's) of vehicular LTB were determined by non-linear regression (Graphpad Prism) of% inhibition versus concentration log of the drug The compounds presented in Tables 1-4 had assays of 1 nM to 5 μM with this assay. Example 14: Pharmaceutical Compositions Example 14a: 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 (G), Formula (GI), or Formula (G) -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 by injection. Example 14b: Oral Composition To prepare a pharmaceutical composition for oral administration, 100 mg of any compound of Formula (G), Formula (G-1), or Formula (G-11), were mixed with 750 mg of starch. The mixture was incorporated in an oral dosage form, such as a hard gelatin capsule, which is suitable for oral administration. Example 14c: Sublingual composition (hard tablet) To prepare a pharmaceutical composition for oral administration, such as a hard tablet, mix 100 mg of any compound of Formula (G), Formula (Gl), or Formula (G-ll) , 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 Pour into a mold to form a seal suitable for buccal administration. Example 14d: Composition for inhalation To prepare a pharmaceutical composition for administration by inhalation, 20 mg of any compound of Formula (G), Formula (G-4), or Formula (G-ll), are mixed with 50 mg of citric acid anhydrous 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 14e: Rectal Gel Composition To prepare a pharmaceutical composition for rectal administration, 100 mg of any compound of Formula (G), Formula (Gl), or Formula (G-ll), is 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 14f: Topical gel composition To prepare a topical pharmaceutical gel composition, 100 mg of any compound of Formula (G), Formula (Gl), or Formula (G-ll), is mixed with 1.75 g of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate and 100 ml of purified USP alcohol. The mixture in The resulting gel is then incorporated into containers, such as tubes, which are suitable for topical administration. Example 14g: Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of any compound of Formula (G), Formula (Gl), or Formula (G-ll), are mixed with 0.9 g of NaCl in 100 ml of purified water and filtered 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 in 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 (21)

  1. CLAIMS A compound having the structure of Formula (G): wherein, Z is selected from [C (R?) 2] m [C (R2) 2] n, [C (R2) 2] n [C (R?) 2] mO, O [C (R1) 2 ] m [C (R2) 2] n, or [C (R1) 2] nO [C (R2) 2] n, where each Ri is independently H, CF3, or an optionally substituted lower alkyl and two R- \ on the same carbon can be joined to form a carbonyl (= OR); 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 0, 1, 2 or 3; Y is H or - (substituted or unsubstituted aryl); or - (substituted or unsubstituted heteroaryl); where each substituent on Y or Z is (LsRs) j, where each Ls is independently selected from a bond, -O-, -C (= O) -, -S-, -S (= O) -, -S ( = O) 2-, -NHC (O) -, -C (O) NH-, S (= O) 2NH-, -NHS (= O) 2, -OC (O) NH-, -NHC (O) O-, -OC (O) O-, -NHC (O) NH-, -C (O) O-, -OC (O) -, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms carbon, fluoroalkyl of 1 to 6 atoms substituted or unsubstituted carbon, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; and each Rs is independently selected from H, halogen, -N (R4) 2, -CN, -NO2, N3, -S (= O) 2NH2, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, fluoroalkyl from 1 to 6 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl; where j is 0, 1, 2, 3 or 4; 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 (= O), -S (= O) 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, wherein, L3 is a substituted or unsubstituted alkyl; X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2, -NRβ, -NRβC (O), -C (O) NR 9, -NR 9 C (O) NR 9-; L is a bond, or a substituted or unsubstituted alkyl; Gi is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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) NR 9 C (= CR 10) N (R 9) 2, -CO 2 R 9, -C (O) R 9, -CON (R 9) 2, -SR 8, -S (= O) R 8, -S (= O) 2R8, -Ls- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl), or -L5- (substituted or unsubstituted aryl), where L5 is -OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O , u -OC (O); or d is W-G5, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl and G5 is H, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, OH, -OR8, -C (= O ') CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9 ) C (O) R9, -C (= NR10) N (R9) 2, -NR9C (= NR10) N (R9) 2l -NR9C (= CR10) N (R9) 2, -C (O) NR9C (= NR10) N (R9) 2, -C (O) NR9C (= CR10) N (R9) 2, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O 2R8; each R8 is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; each R9 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 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 (= O) 2R8, -S (= O) 2NH2 -C (O) R8, -CN, -NO2, heteroaryl, or heteroalkyl; R 5 is H, halogen, alkyl of 1 to 6 carbon atoms substituted or unsubstituted, O-alkyl of 1 to 6 carbon atoms substituted or unsubstituted; Rn is L7-L10-G6, where L7 is a bond, -C (O), -C (O) NH, -NHC (O), or (substituted or unsubstituted alkyl of 1 to 6 carbon atoms); L10 is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl) or (substituted or unsubstituted heterocycle); G6 is OR 9, -C (= O) Rβ, -C (= O) OR 9, -SR 8, -S (= O) R 8, -S (= O) 2R 8, N (R 9) 2, tetrazolyl, -NHS ( = O) 2R8, -S (= O) 2N (R9) 2, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9 > -C (= O) N (R9) 2, NR9C (O) R9, C (R9) 2C (= O) N (R9) 2-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 aryl or unsubstituted), wherein L5 -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, u -OC (O) or G6 is WG, wherein W is (substituted or unsubstituted heterocycle), (substituted or unsubstituted aryl) or a (substituted or unsubstituted heteroaryl) and G7 is H, halogen, CN, NO2, N3, CF3, OCF3, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, fluoroalkyl of 1 to 6 carbon atoms, tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, OH, -OR8, -C (= O) CF3, -C ( O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8, or -S (= O) 2R8, -L5- (substituted or unsubstituted alkyl), -L5- (substituted alkenyl or unsubstituted), -L5- (substituted or unsubstituted heteroalkyl), -L5- (substituted or unsubstituted heteroaryl), -L5- (substituted or unsubstituted heterocycle), or -L5- (substituted or unsubstituted aryl), where L5 is a bond, -O-, C (= O), S, S (= O), S (= O) 2, -NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or -OC (O); provided that Rn comprises at least one aromatic moiety (unsubstituted or substituted) and at least one cyclic moiety (unsubstituted or substituted), wherein the cyclic moiety (unsubstituted or substituted) is a heterocyclic group (unsubstituted or substituted) or a heteroaryl group ( unsubstituted or substituted) and Rn is not a thienyl-phenyl group; 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.
  2. 2. The compound according to claim 1, characterized in that Z is [C (R2) 2] nC (R1) 2O.
  3. 3. The compound according to claim 2, characterized in that Y is - (substituted or unsubstituted heteroaryl) or - (substituted or unsubstituted aryl) and G6 is W-G7.
  4. 4. The compound according to claim 1, characterized in that Y is - (substituted or unsubstituted heteroaryl).
  5. 5. The compound according to claim 4, characterized in that Y is selected from the group consisting of pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl. , indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazi nile, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo [1, 2-a] pi-ridyl, thiophenopyridinyl and furopyridinyl, where Y is substituted or unsubstituted.
  6. 6. The compound according to claim 5, characterized in that Y is selected from the group consisting of pyridinyl or quinolinyl, wherein Y is substituted or unsubstituted.
  7. The compound according to claim 1, characterized in that R6 is L2- (substituted or unsubstituted alkyl), or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl), where L2 is a bond, OR , S, -S (O) 2, -C (O) or alkyl replaced or unsubstituted.
  8. 8. The compound according to claim 1, characterized in that X is a bond, O, -C (= O), -CR9 (OR9), S, -S (= O), -S (= O) 2, -NR9, -NR9C (O), -C (O) NR9.
  9. 9. The compound according to claim 1, characterized in that G ^ is tetrazolyl, -NHS (= O) 2R8, S (= O) 2N (R9) 2, -OR9, -C (= O) CF3, -C (O) NHS (= O) 2R8, -S (= O) 2NHC (O) R9, CN, N (R9) 2, -N (R9) C (O) 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, -CO2R9, -C (O) R9, -CON (R9) 2, -SR8, -S (= O) R8 or -S (= O) 2R8.
  10. 10. The compound according to claim 1, characterized in that L3 is unsubstituted alkyl; X is a link; l_4 is a link; and G is -C (O) OR9. .eleven.
  11. The compound according to claim 10, characterized in that R9 is H or unsubstituted alkyl.
  12. The compound according to claim 1, characterized in that L10 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and G6 is W-G7, where W is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle.
  13. 13. The compound according to claim 12, characterized in that L10 is a substituted or unsubstituted aryl.
  14. 14. The compound according to claim 1, characterized in that L3 is unsubstituted alkyl; X is a link; L4 it is a link; and G ^ is -OR9.
  15. The compound according to claim 1, characterized in that Gi is W-G5, where W is a substituted or unsubstituted heterocycle or substituted or unsubstituted heteroaryl.
  16. 16. A compound characterized in that it is selected from: 3- [3-tert-3- [3- te rc-butylsulfa nyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-yl) ilme toxy) -1H-indol-2-yl] -2, 2 -dimethyl-propionamide (Compound 1-1); 3- [3-tert-Butylsulfanyl-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ethyl ester ] -2,2-dimethyl-propionic (Compound 1-2); 6-hydroxy-hexyl esters of 3- [3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indole -2-yl] -2,2-dimethyl-propionic (Compound 1-3); 1- [3-te rc-butylsulfa nyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan -2-ol (Compound 1-4); 1- [3-te rc-butylsulfa nyl-1- (4-pyridin-3-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan -2-ol (Compound 1-5); 1- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1 H -indole-2-yl] -2-methyl-propan- 2-ol (Compound 1-6); 1- [3-tert-Butylsulfanyl-1- (4- [1, 3, 4] oxadiazole -2-i-benz I) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2-methyl-propan-2-ol (Compound 1-7); 3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -2- (2-methyl-2- [1,4] oxadiazole-2-yl- propyl) -5- (pyridin-2-ylmethoxy) -1 H-indole (Compound 1-8); 5-. { 2- [3-te rc-butylsulfa or 1-1 - [4- (6-methoxy-pyrid i n-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2 -yl] -1,1-dimethyl-ethyl} - [1,3,4] oxadiazol-2-ylamine (Compound 1-9); 3- [3-te rc-butylsulfa or 1-1 - [4- (6-m-ethoxy-pyrid-n-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-N-pyrrazin-2-yl-propionamide (Compound 1-10); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2, 2-dimethyl-N-thiazol-2-yl-propionamide (Compound 1-11); 3- [3- te rc-butylsulfa nyl-1- [4 - (6-me toxy-pyridin-3-yl) -benzyl] -5- (pyrid i n-2-i I methoxy) -1 H -ind or I -2-yl] -2, 2-di methi I- N -pyrid i n -3-yl-propionamide (Compound 1-12); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -N- (2-dimethylamino-ethyl) -2,2-dimethyl-propionamide (Compound 1-13); 5-. { 4- [3-tert-Butylsulfanyl-2- (2,2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl] -phenyl} - [1,3,4] oxadiazol-2-ylamine (Compound 1-14); 3- [3- te rc-butylsulfa nyl-1- [4- (5-f luoro-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -N- (2-dimethylamino-ethyl) -2,2-dimethyl-propanoylguanidine (Compound 1-15); 3- [3- te rc-butylsulfa nyl-5- (pyridin-2-ylme toxy) -1- (4-thiazol-2-yl-benzyl) - 1 H -indol-2-yl] - acid 2,2-d imethyl propionic acid (Compound 2-1); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-) acid pi rim id i n-2-l-benz I) -1 H-indol-2-yl] -2,2-d imethyl propionic acid (Compound 2-2); acid - [3-tert-Butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- (pyridin-2-yl-methoxy) -1 H -indol-2-yl] -2,2-dimethyl -propionic (Compound 2-3); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-pyrimidin-5-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-4); 3- [3- te rc-butylsulfa nyl-1- (4-pyrazin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl acid -propionic (Compound 2-5); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-6); 3- [1- [4- (5-Amino-pyrazin-2-yl) -benzyl] -3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-7); 3- [3- (3,3-Dimethyl-butyryl) -5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-8); 2,2-dimethyl-3- [5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -propionic acid (Compound 2-9 ); 3- [3-Acetyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1 H -indol-2-yl] -2,2-dimethyl-propionic acid ( Compound 2-10); 3- [1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -indol-2-yl] -2,2-dimethyl- acid propionic (Compound 2-11); 3- [3-acetyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2 acid -dimethyl-propionic (Compound 2-12); 3- [3-et i 1-1 - [4- (6-methoxy-pyrid azi n -3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H -ind or l-2 acid -yl] -2, 2-d imethyl propionic acid (Compound 2-13); 3- [3- (3,3-Dimethyl-butyl) -5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-14); 3- [3-cyclopropancarbonyl-5- (pyridin-2-ylmethoxy) -1 - (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-15); 3- [3-Cyclobutanecarbonyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid ( Compound 2-16); 3- [3-te rc-butylsulfa nyl-1- [4- (6-hydroxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-17); 3- [3-tert-Butylsulfanyl-1- (4-pyridin-4-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-18); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-19); 3- [3-tert-Butylsulfanyl-1- [4- (6-methyl-pyridazin-3-yl) - acid benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-20); 3- [3- te rc-butylsulfa nyl-1- [4- (5-methyl-t-aiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-d imethyl propionic acid (Compound 2-21); 3- [3-Cyclobutylmethyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound) 2-22); 3- [3-te rc-butylsulfa nyl-1- [4- (6-me toxi-pyridazin-3-yl) -benzyl] -5- (2-methyl-thiazol-4-ylmethoxy) -1H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-23); 3- [3-tert-Butylsulfanyl-5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl-propionic (Compound 2-24); 2,2-Dimethyl-3- [5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -propionic acid ( Compound 2-25); 3- [3- (3,3-dimethyl-butyryl) -5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indole-2- acid il] -2,2-dimethyl-propionic acid (Compound 2-26); 3- [1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (2-methyl-thiazole-4-methoxy) -1H-indol-2-yl] -2, 2-dimethyl-propionic acid (Compound 2-27); 3- [3- (3,3-dimethyl-butyryl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (2-methyl-thiazole-4-i-methoxy) acid ) - 1 H-indol-2-yl] -2, 2-d-imethyl-propionic acid (Compound 2-28); 3- [3-ethyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) - acid 1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-29); 3 - acid. { 5- (Benzothiazol-2-ylmethoxy) -3-te rc-butylsulfa nyl-1- [4 - (6-methoxy-pyridazin-3-yl) -benzyl] -1 H -indole-2-yl} -2,2-dimethyl-propionic (Compound 2-30); 3- [3- te rc-butylsulfa nyl-5- (2-methyl-thiazol-4-ylmethoxy) -1 - (4-pyrimidin-2-yl-benzyl) -1H-indol-2-yl] -2 , 2-dimethyl-propionic (Compound 2-31); 3- [5- (Benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- (4-pyrimidin-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-32); 3- [3-te rc-butylsulfa nyl-1- [4 - (2-methyl-3-pyridin-2-ylmethyl-3H-imidazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) acid ) -1 H -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-33); 3- [3-tert-Butylsulfanyl-1- [4- (2,4-dimethyl-thiazol-5-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-34); 3- [3-te rc-butylsulfa nyl-1- [4 - (5-f I uoro-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-35); 3- [3-tert-Butylsulfanyl-1- [4- (4-methyl-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-39); 3- [3-te rc-butylsulfa nyl-1- [4- (3, 5-dimethyl-isoxazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-41); 3- [3-te rc-butylsulfa nor 1-1 - [4- (3-methyl-3H-i midazol-4-y) I) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-43); 3- [3-te rc-butylsulfa nyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2, 2-d imetil-propion ico (Compound 2-47); 3- [3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4- [1,3,4] thiadiazol-2-yl-benzyl) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-55); 3- [3-tert-Butylsulfanyl-1 - [4- (6-hydroxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-62); 3- [3-te rc-butylsulfa nyl-1- [4- (6-cyano-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-64); acid 3-. { 3-te rc-butylsulfa nyl-5- (pyridin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-1-pyrid-n-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-65); 3- [3-tert-Butylsulfanyl-1- [4- (2-methoxy-pyrimidin-5-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-67); 3- [3-tert-Butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-d imethyl propionic acid (Compound 2-68); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) - acid benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-73); acid 3-. { 3-tert-buty Isulfa ni l-5- (5-eti l-pyrid i n-2-yl methoxy) -1 - [4- (4-methoxy-pyridin-2-yl) -benzyl] -1 H- Indole-2-il} -2,2-dimethyl-propionic (Compound 2-76); 3- [3-tert-Butylsulfanyl-1- [4- (4-methoxy-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-77); acid 3-. { 3-tert-Butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzoyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-78); 3- [3- te rc-butylsulfa nyl-1- [4- (3-fl uoro-pyridin-2-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol acid -2-yl] -2,2-dimethyl-propionic (Compound 2-82); acid 3-. { 3-tert-buti Isulfa ni l-5- (5-etl-pyrid n-2-i I methoxy) -1 - [4- (3-fluoro-pyridin-2-yl) -benzoyl] -1H -indol-2-il} -2,2-dimethyl-propionic (Compound 2-84); 3- [3-tert-Butylsulfanyl-1 - [4 - (3-f I uoro-pyrid i n-2-i I) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-85); 3- [3-tert-Butylsulfanyl-1 - [4- (5-carbamoyl-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] -2 acid , 2-dimethyl-propionic (Compound 2-87); 3- [3-tert-Butylsulfanyl-1- [4- (5-cyano-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2, 2-d imethyl propion ico (Compound 2-88); 3- [3-te rc-butylsulfa nyl-1- [4 - (5-methoxy-thiazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indole-2- acid il] -2, 2-d imethyl propionic acid (Compound 2-89); 3- [3-tert-buty] Isulfa nor 1-1 - [4- (6-methyl-1-pyrid-n-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-90); acid 3-. { 3-te rc-butylsulfa nyl-5- (pyridin-2-ylmethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2, 2-d meti I-propionic (Compound 2-91); 3- [3-te rc-butylsulfa nyl-1- [4 - (2-ethoxy-thiazol-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-92); 3- [3-te rc-butylsulfa nor I- 1- [4- (4-methyl-1 H-imidazol-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-93); 3- [3-te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-94); 3- [3-te rc-butylsulfa nyl-1 - [4- (6-me-toxi-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-95); 3- [3-tert-b u ti Isulfa nyl- 1- [4- (5-methoxy-pyridn-3-yl-free] -5- (pyrid i n-2-i I methoxy) - 1 H -i ndol-2-yl] -2, 2-d imethyl propionic acid (Compound 2-96); 3- [3-te rc-butylsulfa nyl-1- [4- (6-ca rb-amyl-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-97); 3- [3-tert-Butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-98); acid 3-. { 3-te rc-butylsulfa nyl-5- (6-fluo ro-pyridin-2-ylme toxy) -1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-99); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (6-methoxy-pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-100); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (6-methyl-1-pyrid-n-2-I-methoxy) -1 acid H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-101); acid 3-. { 3-tert-butylsulfan i l-5- (5-methy1-pyrid i n-2-i I methoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H- Indole-2-il} -2,2-dimethyl-propionic (Compound 2-102); acid 3-. { 3-te rc-butylsulf or l-5- (5-methyl-1-pyridin-2-yl methoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole 2-il} -2,2-dimethyl-propionic (Compound 2-103); 3 - acid. { 3-te rc-butylsulfa nyl-5- (o-cyclop ropil-pyridin t-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-104); 3- [3-tert-Butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl] - acid 5- (5-methyl-pyridin-2-ylmethoxy) -1 H -indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-105); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-106); 3- [3-te rc-butylsulfa nyl-1- [4 - (6-etho xi-pyridin-3-yl) -benzyl] -5- (5-met i l-pyrid i n-2-ylmethoxy) acid -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-107); acid 3-. { 3-tert-Butylsulfanyl-5- (5-chloro-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-108); acid 3-. { 3-tert-Butylsulfanyl-5 - ((S) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-109); acid 3-. { 3-te rc-butylsulfa ni l-5 - ((R) -1-pyrid i n-2-yl-ethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H -indol-2-il} -2,2-dimethyl-propionic (Compound 2-110); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5 - ((S) -1-pyridin-2-yl-ethoxy) - 1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-111); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1 H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-112); 3- [3-te rc-butylsulfa nyl-1- [4- (6-metoxy-pyridin-2-yl) -benzyl] -5 - ((S) -1-pyridin-2-yl-ethoxy) acid -1H-indol-2-yl] -2,2-dimethyl- propionic (Compound 2-113); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) - acid 1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-114); 3 - [3- te rc-butylsulfa nyl-1 - [4- (2-ethoxy-thiazol-4-yl) -benzyl] -5 - ((S) -1-pyridin-2-yl-ethoxy) - 1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-115); 3- [3-tert-Butylsulfanyl-1- [4- (2-ethoxy-thiazol-4-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-116); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (3-methyl-pyridin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-117); acid 3-. { 3-te rc-butylsulfa ni l-5- (3-meti l-pyrid i n-2-i I methoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H- Indole-2-il} -2,2-dimethyl-propionic (Compound 2-118); acid 3-. { 3-te rc-butylsulfa nyl-5- (3, 5-dimethyl-pyridin-2-ylm and oxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indole 2-il} -2,2-dimethyl-propionic (Compound 2-119); acid 3-. { 3-te rc-butylsulfa nyl-5- (3,5-d imethyl-pyri din-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole- 2-il} -2,2-dimethyl-propionic (Compound 2-120); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-te rc-butylsulfa nyl-1- [4 - (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-121); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3- te rc-butylsulfa nyl-1- [4 - (5-methoxy-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-122); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-123); acid 3-. { 5- (Benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2, 2-d imethyl propionic acid (Compound 2-124); 3 - acid. { 3-te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -i ndol-2- il} -2, 2-d imethyl propionic acid (Compound 2-125); 3- [3-tert-butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (5-ethyl-pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic acid (Compound 2-126); acid 3-. { 3- te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-127); acid 3-. { 3-tert-Butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (5-trif-Ioromethyl-pyridin-2-yl) -benzyl] - 1H - indo l-2-il} -2, 2-d methyl I-propionic (Compound 2-128); 3- [3-te rc-butylsulfa nyl-1- [4 - (2-ethoxy-thiazole -4-yl) -benzyl] -5- (5-methylpyridin-2-methylmethoxyl) acid 1 H -indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-129); 3- [3-tert-Butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) - acid benzyl] -5- (5-methy1-pyrid i n-2-i-methoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-130); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-131); 3- [3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyrid i n-2-i-methoxy) -1 H-indol-2-yl acid ] -2, 2-d imethyl propionic acid (Compound 2-132); 3- [3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2, 2-d imethyl propionic acid (Compound 2-133); 3- [3-Isobutyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-134); 3- [3-te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-135); acid 3-. { 3- te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-136); acid 3-. { 3- te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1 - [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-137); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] - acid 2, 2-d imethyl propion ico (Compound 2-138); 3- [3-te rc-butylsulfa nor I- 1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-139); acid 3-. { 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 (Compound 2-140); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-fluo ro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-141); 3- [3-te rc-butylsulfa nyl-1- [4 - (2-ethoxy-thiazol-4-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-142); 3 - acid. { 3-te rc-butylsulfa nyl-5- (6-f luoro-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 2-143); acid 3-. { 3- te rc-butylsulfa nyl-5- (7-fluo-ro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-144); acid 3-. { 3-te rc-butylsulfa nyl-5- (7-fluo ro-q uinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-145); acid 3-. { 3- te rc-butylsulfa nyl-5- (7-fluo-ro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 2-146); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (7-fluoro-quinolin-2-I-methoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-147); 3- [3-te rc-butylsulfa nyl-1- [4 - (3-f I u-ro-pi-ridin-2-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) acid 1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-148); acid 3-. { 3- te rc-butylsulfa nyl-5- (5-methyl-pyridin-2-ylme toxy) -1 - [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-149); acid 3-. { 3- te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-150); acid 3-. { 3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1 - [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-151); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-fluo-ro-quinolin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-156); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (3-methyl-pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-157); 3 - acid. { 3- te rc-butylsulfa nyl-5- (3-methyl-pyridin-2-ylmethoxy) -1 - [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-158); acid 3-. { 3-tert-Butylsulfanyl-5- (3,5-dimethyl-pyridin-2-ylmethoxy) - 1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-159); 3- [3-te rc-butylsulfa nyl-1- [4- (6-me-toxi-pyridin-3-yl) -benzyl] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-160); 3- [3-te rc-butylsulfa nyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-161); acid 3-. { 3-tert-Butylsulfanyl-5- (4-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-1-pyrid-n-2-yl) -benzyl] -1H-indole-2- íl} -2,2-dimethyl-propionic (Compound 2-162); acid 3-. { 3-Cyclobutylmethyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-163); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1 H-indole-2 acid -yl] -2,2-dimethyl-propionic acid (Compound 2-164); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-fluo ro-quinolin-2-ylmethoxy) -1 - [4- (6-trif luoro-met-pyridin-3-yl) - be ncil] -1 H -indol-2-íl} -2,2-dimethyl-propionic (Compound 2-165); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (6-methyl-quinolin-2-ylmethoxy) -1H- acid indole-2-yl] -2,2-dimethyl-propionic (Compound 2-166); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-methyl-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-1-pyrid-n-2-yl) -benzyl] -1H-indole 2-il} -2,2-dimethyl- propionic (Compound 2-167); 3- [3- te rc-butylsulfa nyl-1- [4- (6-methyl-pyridazin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-168); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridazin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H -i nd or I-2- acid i I] -2, 2-di meti I -propion ico (Compound 2-169); 3- [3-isobutyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2 acid -dimethyl-propionic (Compound 2-170); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-f I uoro-q uinolin-2-ylme toxy) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1 H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-171); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -3- (2-methyl-propane-2-sulfonyl) -5- (pyridin-2-ylmethoxy) -1 H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-172); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -3- (2-methyl-propane-2-sulfinyl) -5- (pyridin-2-ylmethoxy) -1H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-173); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (1-oxy-pyridin-2-ylmethoxy) -1H-indole-2 acid -yl] -2,2-dimethyl-propionic (Compound 2-174); acid 3-. { 3-te rc-butylsulfa nyl-5- (imidazo [1,2- a] pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indole -2-il} -2,2-dimethyl-propionic (Compound 2-175); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5- (imidazo [1, 2-a] pyrid] n-2-i I methoxy acid ) - 1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-176); acid 3-. { 3- te rc-butylsulfa nyl-5- (imidazo [1,2-a] pyridin-2-ylmethoxy) -1 - [4 - (5-tri-fluoro-methyl-pyridin-2-yl) -benzyl] -1H- Indole-2-il} - 2,2-dimethyl-propionic (Compound 2-177); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-3-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1 H acid -i nd or I-2- i I] -2, 2-di meti I -pro pion ico (Compound 2-178); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-fluo ro-quinolin-2-ylmethoxy) -1- [4- (6-methyl-pyridazin-3-yl) -benzyl] -1 H -indole-2- il} -2,2-dimethyl-propionic (Compound 2-179); 3- [3-tert-Butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-180); 3- [3- te rc-butylsulfa nyl-1- [4 - (6-etho xi-pyridin-3-yl) -benzyl] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H-indole acid -2-yl] -2,2-dimethyl-propionic (Compound 2-181); acid 3-. { 3-tert-Butylsulfanyl-5- (5-methyl-isoxazol-3-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-182); acid 3-. { 3-tert-Butylsulfanyl-5- (2,5-dimethyl-2H-pyrazol-3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indole-2- il} -2,2-dimethyl-propionic (Compound 2-183); acid 3-. { 3-tert-Butylsulfanyl-5- (1, 5-dimethyl-1 H-pyrazole-3-) L-methoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-184); 3- [3- te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridazin-3-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-185); 3- [3-te-tert-butylsulfa nyl-1- [4- (6-e-toxi-pyridazin-3-yl) -benzyl] -5- (5-ethyl-1-pyrid-n-2-i-methoxy) acid ) - 1 H -indol-2-yl] -2,2-di-methylopropionic (Compound 2-186); acid 3-. { 3-te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 2-187); 3- [3-tert-Butylsu Ifa nor 1-1 - [4 - (5-f I uoro-pyrid i n-2-i I) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) acid ) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-188); 3- [3-tert-Butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl] -5 - ((R) -1-pyrid i n-2-M-ethoxy) - acid 1H-indol-2-yl] -2, 2-d-meti I-propionic (Compound 2-189); 3- [3- te rc-butylsulfa nyl-1- [4 - (6-etho xi-pyridin-2-yl) -benzyl] -5- (6-fluoro-quinolin-2-ylmethoxy) -1 H- acid indole-2-yl] -2, 2-d-meti I-propionic (Compound 2-190); 3- [3- te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridin-2-yl) -benzyl] -5 - ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-191); 3- [3-tert-Butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl] -5- (5-methyl-1-pyrid-n-2-i-methoxy) -1 acid H-indol-2-yl] -2,2-dimethyl- propionic (Compound 2-192); 3- [3- te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridin-2-yl) -benzyl] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic (Compound 2-193); acid 3-. { 5- (6-Fluoro-quinolin-2-ylmethoxy) -3-isobutyl-1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-194); acid 3-. { 3-te rc-butylsulfa nyl-5- (pyridin-2-ylme toxy) -1- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-195); 3- [3- te rc-butylsulfa nyl-1 - [3- (6-methoxy-pyridin-3-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] acid] -2,2-dimethyl-propionic (Compound 2-196); 3 - [3-te rc-butylsulfa nor 1-1 - [4- (5-fl uoro-pyrid i n-2-i I) -benzyl] -5- (quinolin-2-ylmethoxy) -1 H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-197); 3- [3-tert-Butylsulfanyl-1- [4- (6-ethoxy-pyridin-2-yl) -benzyl] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-198); 3- [3- te rc-butylsulfa nyl-1- [4- (6-e-toxi-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl acid ] -2,2-dimethyl-propionic (Compound 2-199); acid 3-. { 3- te rc-butylsulfa nyl-5- (6-f luoro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 2-200); 3 - [3- te rc-butylsulfa nor 1-1- [4 - (5-f luoro-pyridin-2-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-201); acid 3-. { 3-tert-Butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-202); 3 - acid. { 3-te rc-butylsulfa nyl-5- (quinolin-2-ylme toxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-203); acid 3-. { 3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 2-204); 3- [3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1 - (4-thiazol-2-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-205); 3- [3-te rc-butylsulfa acid or 1-1 - [3- (4-methoxy-tet rah id ro-pi ran-4-yl) -benzyl] -5- (pyridin-2-ylmethoxy) -1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-206); 3- [3-te rc-butylsulfa nyl-5- (6-f luoro-quinolin-2-ylmethoxy) -1- (4-pyridin-2-yl-benzyl) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 2-207); 3- [3- te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - (4-pyridin-3-yl-benzyl) -1H-indol-2-yl] -2 , 2-dimethyl-propionic (Compound 2-208); 3- [3-tert-Butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- acid (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-d imethyl-propionic acid (Compound 2-209), 3- [3-te rc-butylsulfa nyl-5- (6 -f I uoro-q uinolin-2-ylmethoxy) -1- (4-pyridin-3-yl-benzyl) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-210); 3- [3-tert-buty] Isulfa nor I -5- (5- met i l-pyridin-2-yl methoxy) -1 - (4-pyridin-2-yl-benzyl) -1H-indole-2 -yl] -2,2-dimethyl-propionic (Compound 2-211); 3- [3-tert-Butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4-pyridin-2-yl-benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl propionic (Compound 2-212); 3- [3-tert-Butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-213); 3- [3-tert-Butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1 - (4-pyridin-3-yl-benzyl) -1H-indol-2-yl] -2.2 acid -dimethyl-propionic (Compound 2-214); 3- [3-tert-Butylsulfanyl-1 - [4- (4-methoxy-pyridin-2-yl) -benzyl] -5- (5-methyl-1-pyrid-n-2-ylmethoxy) -1 H- acid indole-2-yl] -2,2-dimethyl-propionic (Compound 2-215); 3- [3- te rc-butylsulfa nyl-5- (quinolin-2-ylme toxy) -1 - (4- (3-methoxy-pyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2,2-dimethyl-propionic (Compound 2-216); 3- [3-tert-Bu ti Isulfa ni l-5- (5-meti l-pyrid i n-2-i I methoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl] -2,2-dimethyl- propionic (Compound 2-217); 3- [3-te rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - (4- (3-methoxypyridin-2-yl) -benzyl) -1 H -indole-2 acid -yl] -2,2-d imethyl propionic acid (Compound 2-218); 3- [3-te-r-butylsulfa nor l-5- (5-methyl-pyrid-n-2-ylmethoxy) -1 - (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H- acid indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-219), 3- [3- te-tert-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1 - ( 4- (4-trif luoromethyl pyrid i n-2-yl) -benzyl) -1 H -indol-2-yl] -2,2-di-methyl-1-propionic acid (Compound 2-220); 3- [3-te rc-butylsulfa nyl-5- (quinolin-2-ylmethoxy) -1 - (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl] -2 , 2-dimethyl-propionic (Compound 2-221); 3- [3-tert-Butylsulfan i l-5- (5-methy1-pyrid i n-2-i I methoxy) -1 - (4- (5-fluoropyridin-3-yl) -benzyl) - acid 1 H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-222), 3- [3-te-rc-butylsulfa nyl-5- (5-ethyl-pyridin-2-ylmethoxy) - 1- (4- (5-fluoropyridin-3-yl) -benzyl) -1 H -indole-2-yl] -2,2-dimethyl-propionic acid (Compound 2-223); 3- [3-tert-Butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (5-f I or gold pyrid i n-3-yl) -benzyl) -1 H-indole-2 acid -yl] -2, 2-d imethyl propionic acid (Compound 2-224); 3- [3-? et-b u ti Isulfa ni l-5- (2, 3-d-meti l-pyrid i n-6-Imethoxy) -1- (4- (2-methoxypyridin-5-) il) -benzyl) -1H-indol-2-yl] -2, 2-d-meti I-propionic (Compound 2-225); » 3- [3-tert-Butylsulfanyl-5- (2,3-d.methyl-pyridin-6-ylmethoxy) -1- (4- (3-trifluoromethylpyridin-2-yl) -benzyl) -1H- acid indole-2-yl] -2,2-dimethyl-propionic (Compound 2-226); 3- [3-te rc-butylsulfa nyl-5- (2,3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-227); 3- [3-te rc-butylsulfa nyl-5- (2,3-dimethyl-pyridin-6-ylm and oxy) -1- (4- (3-fluoropyridin-2-yl) -benzyl) -1 H acid -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-228); 3- [3-te rc-butylsulfa nyl-5- (2,3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indole- 2-yl] -2,2-dimethyl-propionic (Compound 2-229); 3- [3-tert-buty] Isulfa ni l-5- (2, 3-di met i l-pyrid i n-6-i I methoxy) -1- (4- (4-methoxypyridin-2-yl) -benzyl) -1 H -indol-2-yl] -2,2-dimethyl-propionic (Compound 2-230); 3- [3-tert-buty] Isulfa ni l-5- (2, 3-di met i l-pyrid i n-6-i I methoxy) -1 - (4- (pyrid i n-2-yl) -benz I) - 1 H -indo l-2-yl] -2, 2-d imethyl propionic acid (Compound 2-231); 3- [3-tert-Butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indole-2- acid il] -2,2-dimethyl-propionic (Compound 2-232); 3- [3-tert-butyl] Isulfa ni l-5- (5-etl-pyrid n-2-ylmethoxy) -1 - (4- (2-methoxy-pyridin-3-yl) -benzyl) ) -1H-indol-2-yl] -2,2-dimethyl-propionic (Compound 2-233); 3- [3-tert-Butylsulfanyl-5- (quinolin-2-methoxy) -1- (4- (2- methoxy-pyridin-3-yl) -benzyl) -1 H -indol-2-yl] -2,2-dimethyl-propionic acid (Compound 2-234); 3- [3-tert-Butylsulfanyl-1- (6'-methoxy- [2,3 '] bipyridinyl-5-ylmethyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl] - acid 2,2-dimethyl-propionic (Compound 3-1); 3- [3- te rc-butylsulfa nyl-1- [6 - (4-methoxy -fe or I) -pi-rid-n-3-ylmethyl] -5- (pyridin-2-ylmethoxy) -1 H- indole-2-yl] -2,2-dimethyl-propionic acid (Compound 3-2); acid 3-. { 3-tert-Butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [6- (4-tri-fluoro-methoxy-phenyl) -pyridin-3-ylmethyl] -1H-indol-2-yl} -2, 2-d imethyl propionic acid (Compound 3-3); 3- [3-te rc-butylsulfa nor 1-1 - [5- (4-methoxy-phen il) -pi-rid-n-2-ylmethyl] -5- (pyridin-2-ylmethoxy) -1H-indole -2-yl] -2,2-dimethyl-propionic acid (Compound 3-4); acid 3-. { 3-te rc-butylsulfa nyl-5- (pyridin-2-ylme toxy) -1 - [5- (4-tri-fluoro-methoxy-phenyl) -pyridin-2-ylmethyl] -1H-indol-2-yl } -2,2-dimethyl-propionic (Compound 3-5); acid 3-. { 3-tert-Butylsulfanyl-5-isopropyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl] -1 H -indole-2-yl} -2, 2-d imethyl propionic acid (Compound 4-1); and acid 3-. { 3-tert-Butylsulfanyl-5-hydroxy-1 - [4- (6-methoxy-pyridin-3-yl) -benzyl] -1H-indol-2-yl} -2,2-dimethyl-propionic (Compound 4-2).
  17. 17. A pharmaceutical composition characterized in that it comprises an effective amount of a compound according to claim 1 and an excipient pharmaceutically acceptable.
  18. 18. A method characterized in that it serves to treat inflammation in a mammal comprising administration to the mammal in need thereof, of a therapeutically effective amount of a compound according to claim 1.
  19. 19. A method for treating respiratory disease in a mammal characterized in that it comprises administering to the mammal in need thereof, a therapeutically effective amount of a compound according to claim 1.
  20. 20. The method according to claim 19, characterized in that Z is [C (R2) 2] nC (R1) 2O.
  21. 21. A method for treating cardiovascular disease in a mammal characterized in that it comprises administering to the mammal in need thereof, a therapeutically effective amount of a compound according to claim 1.
MXMX/A/2008/005633A 2005-11-04 2008-04-30 5-lipoxygenase-activating protein (flap) inhibitors MX2008005633A (en)

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US60/734,030 2005-11-04
US60/747,174 2006-05-12
US60/823,344 2006-08-23
US11553946 2006-10-27

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