CN101331117A - 5-lipoxygenase-activating protein (FLAP) inhibitors - Google Patents

5-lipoxygenase-activating protein (FLAP) inhibitors Download PDF

Info

Publication number
CN101331117A
CN101331117A CNA2006800412077A CN200680041207A CN101331117A CN 101331117 A CN101331117 A CN 101331117A CN A2006800412077 A CNA2006800412077 A CN A2006800412077A CN 200680041207 A CN200680041207 A CN 200680041207A CN 101331117 A CN101331117 A CN 101331117A
Authority
CN
China
Prior art keywords
pyridin
compound
dimethyl
indol
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2006800412077A
Other languages
Chinese (zh)
Other versions
CN101331117B (en
Inventor
J·H·哈奇森
P·P·普来斯特
M·默伦
J·F·依凡斯
B·A·史蒂安
J·R·罗普
李逸炜
J·E·祖尼克
J·M·阿鲁达
N·S·史塔克
M·哈达奇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Panmira Pharmaceuticals LLC
Original Assignee
Amira Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/553,946 external-priority patent/US7977359B2/en
Application filed by Amira Pharmaceuticals Inc filed Critical Amira Pharmaceuticals Inc
Publication of CN101331117A publication Critical patent/CN101331117A/en
Application granted granted Critical
Publication of CN101331117B publication Critical patent/CN101331117B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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

5-lipoxygenase-activating protein (FLAP) inhibitors
Related application
This application is U.S. provisional application No. 60/734,030, entitled "5-lipoxygenase activating protein (FLAP) inhibitor", filed on 4.11.2005; U.S. provisional application No. 60/747,174, filed on 12.5.2006, entitled "5-lipoxygenase activating protein (FLAP) inhibitors"; and U.S. provisional application No. 60/823,344 filed on 23/8/2006, entitled "inhibitors of 5-lipoxygenase activating protein (FLAP), the entire contents of which are incorporated herein by reference.
Field of the invention
Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with 5-lipoxygenase-activating protein (FLAP) activity.
Prior Art
The protein 5-lipoxygenase activating protein (FLAP) is involved in the pathway of leukotriene synthesis. In particular, 5-lipoxygenase activating protein (FLAP) is responsible for binding arachidonic acid and transferring it to 5-lipoxygenase. See, e.g., Abramovitz, m. et al, eur.j. biochem.215: 105-111(1993). The 5-lipoxygenase can then catalyze the two-step oxygenation and dehydration of arachidonic acid, convert it to the intermediate compound 5-HPETE (5-hydroperoxyeicosatetraenoic acid), and convert the 5-HPETE to leukotriene A in the presence of FLAP4(LTA4)。
Leukotrienes are biological compounds produced from arachidonic acid in the leukotriene synthesis pathway (Samuelsson et al, Science, 220, 568-575, 1983; Cooper, cell, molecular pathway, 2 nd edition, Sinauer Co., Sunderland (MA), 2000). It is synthesized mainly by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and single cells. Leukotrienes are associated with biological effects, including, by way of example only, smooth muscle contraction, leukocyte activation, cytokine secretion, mucosal secretion, and vascular function.
Disclosure of Invention
Presented herein are methods, compounds, pharmaceutical compositions and medicaments for (a) diagnosing, preventing or treating allergic and non-allergic inflammation, (b) controlling signs and symptoms associated with inflammation, and/or (c) controlling proliferative or metabolic disorders. These disorders can arise from genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, and/or traumatic etiologies. In one aspect, the methods, compounds, pharmaceutical compositions, and medicaments described herein comprise a 5-lipoxygenase activating protein (FLAP) inhibitor described herein.
In one aspect, provided herein are compounds of formula (G), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, which antagonize or inhibit FLAP and are useful in treating patients suffering from leukotriene-dependent symptoms or diseases, including but not limited to asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis, allergic responses, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxin shock, proliferative disorders and inflammatory conditions.
Formula (G) is as follows:
Figure A20068004120700201
wherein
Z is selected from [ C (R)1)2]m[C(R2)2]n、[C(R2)2]n[C(R1)2]mO、O[C(R1)2]m[C(R2)2]n、[C(R2)2]nO[C(R1)2]nOr [ C (R)1)2]nO[C(R2)2]nWherein each R1Is independently H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1Can be joined to form a carbonyl (═ O); and each R2Is independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2Can 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);
wherein each substituent on Y or Z is (L)sRs)jWherein each LsIs independently selected from a bond, -O-, -C (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) -or a substituted or unsubstituted C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6Fluoroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; and each RSIs independently selected from H, halogen, -N (R)4)2、-CN、-NO2、N3、-S(＝O)2NH2Substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, -C1-C6Fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
R6Is 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 heterocycles), L2- (substituted or not)Substituted heteroaryl) or L2- (substituted or unsubstituted aryl) in which L2A bond, O, S, -S (O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl) or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein
L3is 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-；
L4Is a bond or a substituted or unsubstituted alkyl group;
G1is 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)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) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O) -, -C (O) NH, -C (O) O or-OC (O);
or G1Is W-G5Wherein W is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaryl, and G 5Is 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)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
each R9Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; or two R9The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9May together form a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
R5is H, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted O-C1-C6An alkyl group;
R11is L7-L10-G6Wherein L is7Is a bond, -C (O) NH, -NHC (O) or (substituted or unsubstituted C)1-C6Alkyl groups); l is10Is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycle);
G6is OR9、-C(＝O)R9、-C(＝O)OR9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -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 1O)N(R9)2、-L5- (substituted or unsubstituted alkyl), -L5- (substituted or unsubstituted alkenyl), -L5- (substituted or unsubstituted heteroaryl) or-L5- (substituted or unsubstituted aryl) in which L5is-O-, C (═ O), S, S (═ O), S (═ O)2-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G6Is W-G7Wherein W is (substituted or unsubstituted heterocycle), (substituted or unsubstituted aryl) or (substituted or unsubstituted heteroaryl), and G7Is H, halogen, CN, NO2、N3、CF3、OCF3、C1-C6Alkyl radical, C3-C6Cycloalkyl, -C1-C6Fluoroalkyl, 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)R8or-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 heterocycles) or-L5- (substituted or unsubstituted aryl) in which L5Is 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 R11Comprising at least one (unsubstituted or substituted) aromatic moiety and at least one (unsubstituted or substituted) cyclic moiety, wherein the (unsubstituted or substituted) cyclic moiety is an (unsubstituted or substituted) heterocyclic moiety or an (unsubstituted or substituted) heteroaryl, and R 11Is not thienyl-phenyl;
R12is H, (substituted or unsubstituted C1-C6Alkyl group), (substituted or unsubstituted C3-C6Cycloalkyl groups);
or an active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.
With respect to any and all embodiments (e.g., formula (G), formula (G-I), and formula (G-II)), substituents can be selected from a subset of the listed alternatives. For example, in some embodiments, Z is [ C (R)2)2]nC(R1)2O。
In further or alternative embodiments, Y is- (substituted or unsubstituted heteroaryl) or- (substituted or unsubstituted aryl), and G6Is W-G7。
In further or alternative embodiments, Y is- (substituted or unsubstituted heteroaryl).
In a further or alternative embodiment, Y is selected from the group consisting of pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo [1, 2-a ] pyridyl and furopyridyl, wherein Y is substituted or unsubstituted.
In further or alternative embodiments, Y is selected from the group consisting of pyridyl or quinolyl, wherein Y is substituted or unsubstituted.
In further or alternative embodiments, R6Is L2- (substituted or unsubstituted alkyl) or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O) or substituted or unsubstituted alkyl.
In further or alternative embodiments, X is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9。
In further or alternative embodiments, G1Is 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)R8or-S (═ O)2R8。
In further or alternative embodiments, L3Is unsubstituted alkyl; x is a bond; l is4Is a bond; and G1is-C (O) OR9。
In further or alternative embodiments, R9Is H or unsubstituted alkyl.
In further or alternative embodiments, L10Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and G6Is W-G7Wherein W is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle.
In further or alternative embodimentsIn the examples, L10Is a substituted or unsubstituted aryl group.
In further or alternative embodiments, L3Is unsubstituted alkyl; x is a bond; l is4Is a bond; and G1is-OR9。
In further or alternative embodiments, G1Is W-G5Wherein W is a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl.
Any combination of the groups described above with respect to the various variables is intended to be encompassed herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill to provide chemically stable compounds, and that they can be synthesized by techniques known in the art and set forth herein.
In one aspect, provided herein are compounds selected from among:
3- [ 3-tert-butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -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 ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-2); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid 6-hydroxy-hexyl ester (compound 1-3); 1- [ 3-tert-butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-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) -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) -1H-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 (compounds 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) -1H-indole (compound 1-8); 5- {2- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -1, 1-dimethyl-ethyl } - [1, 3, 4] oxadiazol-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- (pyridin-2-ylmethoxy) -1H-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 (compounds 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-propionylguanidine (compound 1-15); 3- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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); - [ 3-tert-butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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-butylsulfanyl-1- (4-pyrazin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-5); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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 ] -2, 2-dimethyl-propionic acid (compound 2-7); 3- [3- (3, 3-dimethyl-butyryl) -5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-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) -1H-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-dimethyl-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-dimethyl-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, 2-dimethyl-propionic acid (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 ] -2, 2-dimethyl-propionic acid (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 ] -2, 2-dimethyl-propionic acid (compound 2-19); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methyl-pyridazin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-20); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methyl-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (2-methyl-thiazol-4-ylmethoxy) -1H-indol-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-dimethyl-butyryl) -5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-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, 2-dimethyl-propionic acid (compound 2-27); 3- [3- (3, 3-dimethyl-butyryl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (2-methyl-thiazol-4-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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); 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (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-dimethyl-propionic acid (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-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 ] -2, 2-dimethyl-propionic acid (compound 2-34); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-35); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methyl-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-39); 3- [ 3-tert-butylsulfanyl-1- [4- (3, 5-dimethyl-isoxazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-41); 3- [ 3-tert-butylsulfanyl-1- [4- (3-methyl-3H-imidazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-43); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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 ] -2, 2-dimethyl-propionic acid (compound 2-55); 3- [ 3-tert-butylsulfanyl-1- [4- (6-hydroxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-62); 3- [ 3-tert-butylsulfanyl-1- [4- (6-cyano-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-64); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-65); 3- [ 3-tert-butylsulfanyl-1- [4- (2-methoxy-pyrimidin-5-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-67); 3- [ 3-tert-butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-68); 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 acid (compound 2-73); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-76); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-77); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-78); 3- [ 3-tert-butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-82); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-84); 3- [ 3-tert-butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-85); 3- [ 3-tert-butylsulfanyl-1- [4- (5-carbamoyl-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-87); 3- [ 3-tert-butylsulfanyl-1- [4- (5-cyano-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-88); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methoxy-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-89); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methyl-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-90); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-91); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-92); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methyl-1H-imidazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-93); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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, 2-dimethyl-propionic acid (compound 2-95); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-96); 3- [ 3-tert-butylsulfanyl-1- [4- (6-carbamoyl-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-97); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-98); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-99); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (6-methoxy-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-100); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (6-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-101); 3- { 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-102); 3- { 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-103); 3- { 3-tert-butylsulfanyl-5- (6-cyclopropyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-104); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-105); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-106); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-107); 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 acid (compound 2-108); 3- { 3-tert-butylsulfanyl-5- ((S) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-109); 3- { 3-tert-butylsulfanyl-5- ((R) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-110); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- ((S) -1-pyridin-2-yl-ethoxy) -1H-indol-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-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-112); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -5- ((S) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-113); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-114); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- ((S) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-115); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-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) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-117); 3- { 3-tert-butylsulfanyl-5- (3-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-118); 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 acid (compound 2-119); 3- { 3-tert-butylsulfanyl-5- (3, 5-dimethyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-120); 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-121); 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-122); 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-123); 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-124); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-125); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (5-ethyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-126); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-127); 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 acid (compound 2-128); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-129); 3- [ 3-tert-butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -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) -1H-indol-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-dimethyl-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 ] -2, 2-dimethyl-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 acid (compound 2-134); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-135); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-136); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-137); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-138); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-139); 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 acid (compound 2-140); 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 acid (compound 2-141); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-142); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-143); 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 acid (compound 2-144); 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 acid (compound 2-145); 3- { 3-tert-butylsulfanyl-5- (7-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-146); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (7-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-147); 3- [ 3-tert-butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-148); 3- { 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-149); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-150); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-151); 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 acid (compound 2-156); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (3-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-157); 3- { 3-tert-butylsulfanyl-5- (3-methyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-158); 3- { 3-tert-butylsulfanyl-5- (3, 5-dimethyl-pyridin-2-ylmethoxy) -1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-159); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-160); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-161); 3- { 3-tert-butylsulfanyl-5- (4-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-162); 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 acid (compound 2-163); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-164); 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 acid (compound 2-165); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (6-methyl-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-166); 3- { 3-tert-butylsulfanyl-5- (6-methyl-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-167); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methyl-pyridazin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-168); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridazin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-169); 3- [ 3-isobutyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-170); 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 acid (compound 2-171); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -3- (2-methyl-propane-2-sulfonyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-172); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -3- (2-methyl-propane-2-sulfinyl) -5- (pyridin-2-ylmethoxy) -1H-indol-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-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-174); 3- { 3-tert-butylsulfanyl-5- (imidazo [1, 2-a ] pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-175); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (imidazo [1, 2-a ] pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-176); 3- { 3-tert-butylsulfanyl-5- (imidazo [1, 2-a ] pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-177); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-178); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methyl-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-179); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-180); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-181); 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 acid (compound 2-182); 3- { 3-tert-butylsulfanyl-5- (2, 5-dimethyl-2H-pyrazol-3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-183); 3- { 3-tert-butylsulfanyl-5- (1, 5-dimethyl-1H-pyrazol-3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-184); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridazin-3-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-185); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridazin-3-yl) -benzyl ] -5- (5-ethyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-186); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-187); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-188); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-189); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-190); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-191); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-192); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-193); 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 acid (compound 2-194); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-195); 3- [ 3-tert-butylsulfanyl-1- [3- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-196); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-197); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-198); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-199); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-200); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-201); 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 acid (compound 2-202); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-203); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (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-tert-butylsulfanyl-1- [3- (4-methoxy-tetrahydro-pyran-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-206); 3- [ 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- (4-pyridin-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-207); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4-pyridin-3-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-210); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4-pyridin-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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-dimethyl-propionic acid (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-dimethyl-propionic acid (compound 2-214); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-215); 3- [ 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-216); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-217); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-218); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-219); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-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-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indol-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-dimethyl-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-dimethyl-propionic acid (compound 2-224); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (2-methoxypyridin-5-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-225); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (3-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-226); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-227); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (3-fluoropyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-228); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-229); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (4-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-230); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (pyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-231); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-232); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-233); 3- [ 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-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 ] -2, 2-dimethyl-propionic acid (compound 3-1); 3- [ 3-tert-butylsulfanyl-1- [6- (4-methoxy-phenyl) -pyridin-3-ylmethyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 3-2); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [6- (4-trifluoromethoxy-phenyl) -pyridin-3-ylmethyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 3-3); 3- [ 3-tert-butylsulfanyl-1- [5- (4-methoxy-phenyl) -pyridin-2-ylmethyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 3-4); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [5- (4-trifluoromethoxy-phenyl) -pyridin-2-ylmethyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 3-5); 3- { 3-tert-butylsulfanyl-5-isopropyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 4-1); and 3- { 3-tert-butylsulfanyl-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-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 of treating inflammation in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein.
In yet another aspect, provided herein is a method of treating asthma in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound described herein. In a further or alternative embodiment, provided herein is a method of treating asthma in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound provided herein, e.g., any compound of formula (G), formula (G-I), or formula (G-II), wherein Z is [ C (R), wherein Z is2)2]nC(R1)2O。
In another aspect are compounds presented in any of figures 8, 9, 10 or 11, or pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, which antagonize or inhibit FLAP and are useful in treating patients suffering from leukotriene-dependent symptoms or diseases, including but not limited to asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis, allergic responses, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions.
In another aspect are compounds presented in any of tables 1, 2, 3 or 4, or pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, which antagonize or inhibit FLAP and are useful in treating patients suffering from leukotriene-dependent symptoms or diseases, including but not limited to asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis, allergic responses, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxic shock, proliferative disorders and inflammatory conditions.
In further or alternative embodiments, any compound of formula (G), formula (G-I), or formula (G-II) may be an inhibitor of 5-lipoxygenase activating protein (FLAP), while in yet further or alternative embodiments, such an inhibitor is selective for FLAP. In still further or alternative embodiments, such inhibitors have an IC of less than 50mM in the FLAP binding assay50。
In further or alternative embodiments, any of the compounds of formula (G), formula (G-I), or formula (G-II) may be included in a pharmaceutical composition or medicament for use in treating a leukotriene-dependent or leukotriene mediated condition or disease in a patient.
In another aspect, inflammatory conditions include, but are not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung 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 skin or lymphatic tissue. In other aspects, metabolic disorders include, but are not limited to, bone remodeling, wasting, or augmenting. In other aspects, such symptoms are iatrogenic, and the increase or abnormal localization of leukotrienes can result from other therapies or medical or surgical procedures.
In other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein can be used to prevent cell activation of 5-lipoxygenase, while in other aspects the methods, compounds, pharmaceutical compositions, and medicaments described herein can be used to limit the formation of leukotrienes. In other aspects, such methods, compounds, pharmaceutical compositions, and medicaments can comprise a FLAP inhibitor disclosed herein for the treatment of asthma by (a) reducing the concentration of leukotrienes in certain body tissues or throughout the body of the patient, (b) modulating the activity of enzymes or proteins in the patient, wherein such enzymes or proteins are involved in the leukotriene pathway, such as, for example, 5-lipoxygenase activating proteins or 5-lipoxygenase, or (c) combining the effects of (a) and (b). In still other aspects, the methods, compounds, pharmaceutical compositions, and medicaments described herein can be used in conjunction with other medical treatments or surgical modalities.
In one aspect is a method of reducing/inhibiting leukotriene synthesis activity of 5-lipoxygenase activating protein (FLAP) in a mammal comprising administering to the mammal at least once an effective amount of a compound of any of formula (G), formula (G-I), or formula (G-II).
In further or alternative embodiments, any "G" group of formula (G), formula (G-I), or formula (G-II) (e.g., G)1、G5、G6、G7) Is any group designed to tailor the physical and biological properties of a molecule. Such tailoring/modification is achieved using groups that modulate the acidity, basicity, lipophilicity, solubility, and other physical properties of the molecule. Physical and biological properties modulated by such modification of "G" include, by way of example only, solubility, in vivo absorption, and in vivo metabolism. In addition, in vivo metabolic effects, by way of example only, may include control of PK properties in vivo, targeted external activity,with potential toxicity of cypP450 interactions, drug-drug interactions, and the like. Further, the modification of "G" allows for in vivo efficacy of the customized compounds, for example, by modulating the binding of specific and non-specific proteins to plasma proteins and lipids and in vivo tissue distribution. In addition, such customization/modification of the "G" allows the design of compounds that are selective for 5-lipoxygenase activating proteins over other proteins. In further or alternative embodiments, "G" is L 20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In further or alternative embodiments, the drug includes, by way of example only, a leukotriene receptor antagonist and an anti-inflammatory agent. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, affinity moiety groups allow site-specific binding and include, but are not limited to, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands.
In another aspect is a method of modulating, directly or indirectly, including reducing and/or inhibiting 5-lipoxygenase activating protein activity in a mammal, 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 (G-I), or formula (G-II).
In another aspect is a method of modulating, directly or indirectly, including reducing and/or inhibiting leukotriene activity in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I) or formula (G-II).
In another aspect is a method of treating leukotriene-dependent or leukotriene mediated conditions or diseases, comprising administering to the mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II).
In another aspect is a method of treating inflammation, 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 (G-I), or formula (G-II).
In another aspect is a method of treating a respiratory 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 (G-I), or formula (G-II). In a further embodiment of this aspect, the respiratory disease is asthma. In further embodiments of this aspect, respiratory tract disorders include, but are not limited to, adult dyspnea syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, normocapnia, childhood developed asthma, adult developed asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma.
In another aspect is a method of 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 (G-I), or formula (G-II). In further embodiments of this aspect, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.
In another aspect is a method of preventing an increase in mucosal secretion and/or 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 formula (G), formula (G-I), or formula (G-II).
In another aspect is a method of treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, comprising administering to the mammal an effective amount of a compound having the structure of any of formula (G), formula (G-I), or formula (G-II).
In another aspect is a method of treating organ reperfusion injury following organ ischemic and/or endotoxic shock comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any of formula (G), formula (G-I) or formula (G-II).
In another aspect is a method of reducing vascular pinching in a mammal 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 (G-I), or formula (G-II).
In another aspect is a method of reducing or preventing increased blood pressure in a mammal 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 (G-I), or formula (G-II).
In another aspect is a method of preventing recruitment of eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or single cells 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 (G-I), or formula (G-II).
A further aspect is a method of preventing or treating abnormal bone remodeling, wasting or augmentation, illustratively including diseases or conditions of osteopenia, osteoporosis, buhui's disease, cancer and other 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 (G-I) or formula (G-II).
In another aspect is a method of preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis, comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any of formula (G), formula (G-I), or formula (G-II).
In another aspect is a method of treating a CNS disorder 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 (G-I), or formula (G-II). CNS disorders include, but are not limited to, multiple sclerosis, parkinson's disease, alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema, and head injury.
A further aspect is a method of treating cancer 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 (G-I), or formula (G-II). Types of cancer may include, but are not limited to, pancreatic cancer and other solid or hematological tumors.
In another aspect is a method of treating endotoxic and septic shock which comprises administering to the mammal at least once an effective amount of at least one compound having the structure of any of formula (G), formula (G-I) or formula (G-II).
In another aspect is a method of treating rheumatoid arthritis and osteoarthritis 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 (G-I), or formula (G-II).
In another aspect is a method of preventing an increase in GI 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 (G-I), or formula (G-II). By way of example only, such diseases include chronic gastritis, eosinophilic gastroenteritis and gastric motor dysfunction.
A further aspect is a method of treating kidney 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 (G-I), or formula (G-II). By way of example only, such diseases include glomerulonephritis, cyclosporin-induced renal failure reperfusion.
In another aspect is a method of preventing or treating acute or chronic renal insufficiency, 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 (G-I), or formula (G-II).
In another aspect is a method of treating type II diabetes, 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 (G-I), or formula (G-II).
In another aspect is a method of reducing an inflammatory aspect of an acute infection in one or more solid organs or tissues, such as a kidney with acute pyelonephritis.
In another aspect is a method of preventing or treating an acute or chronic condition involving recruitment or activation of eosinophils, 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 (G-I), or formula (G-II).
In another aspect is a method for preventing or treating acute or chronic erosive disorders of the gastrointestinal tract or motor dysfunction caused by nonsteroidal anti-inflammatory drugs, including selective or non-selective cyclooxygenase-1 or-2 inhibitors, 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 (G-I), or formula (G-II).
A further aspect is a method of preventing or treating 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 having the structure of any of formula (G), formula (G-I), or formula (G-II).
In another aspect is a method of treating an inflammatory response of the skin 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 (G-I), or formula (G-II). Such inflammatory responses of the skin include, for example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scars. In another aspect is a method of reducing psoriatic lesions in the skin, joints or other tissues or organs comprising administering to the mammal an effective amount of a first compound having the structure of any of formula (G), formula (G-I) or formula (G-II).
A further aspect is a method of treating cystitis, including, by way of example only, interstitial cystitis, 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 (G-I), or formula (G-II).
A further aspect is a method of treating a metabolic syndrome, 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 (G-I), or formula (G-II).
In a further aspect is a method of treating liver and kidney syndrome 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 (G-I), or formula (G-II).
In another aspect is the use of any compound of formula (G), formula (G-I) or formula (G-II) in the manufacture of a medicament for treating an inflammatory disease or condition in an animal, wherein the activity of at least one leukotriene protein contributes to the pathology and/or symptomology of the disease or condition. In a specific embodiment of this aspect, the leukotriene pathway protein is 5-lipoxygenase activating protein (FLAP). In another or further embodiment of this aspect, the inflammatory disease or condition is a respiratory, cardiovascular or proliferative disease.
In any of the aforementioned aspects, is a further embodiment, wherein the administration is enteral, parenteral, or both, and wherein (a) the effective amount of the compound is administered to the mammal in a conventional manner; and/or (b) an effective amount of the compound is administered orally to the mammal; and/or (c) an effective amount of the compound is administered to the mammal intravenously; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound is administered nasally; or (f) an effective amount of the compound is administered to the mammal by injection; and/or (g) an effective amount of the compound is administered topically (dermally) to the mammal; and/or (h) an effective amount of the compound is administered by ocular administration; and/or (i) an effective amount of the compound is rectally administered to the mammal.
In any of the aforementioned aspects, is a further embodiment, wherein the mammal is a human, including embodiments wherein (a) the human has symptoms of asthma, or one or more other symptoms selected from the group consisting of allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood developed asthma, adult developed asthma, cough variant asthma, occupational asthma, steroid-resistant asthma or seasonal asthma, or chronic obstructive pulmonary disease, or pulmonary hypertension, or interstitial lung fibrosis. In any of the aforementioned aspects, is a further embodiment, wherein the mammal is an animal model with inflamed lungs, embodiments of which are provided herein.
In any of the aforementioned aspects, is a further embodiment that includes a single administration of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over a one day period; (iii) continuously; or (iv) continuously.
In any of the aforementioned aspects, is a further embodiment that includes multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered in a single dose; (ii) the time between doses is every 6 hours; (iii) the compound is administered to the mammal every 8 hours. In further or alternative embodiments, the method comprises a drug discontinuation period, wherein administration of the compound is temporarily discontinued, or the dose of the compound administered is temporarily reduced; at the end of the drug withdrawal period, compound dosing was resumed. The length of the drug withdrawal period may vary from 2 days to 1 year.
In any of the aforementioned aspects relating to the treatment of leukotriene-dependent diseases or conditions, is a further embodiment which comprises the administration of at least one further agent, each agent being administered in any order, for example, comprising an anti-inflammatory agent, a different compound having any of the structures of formula (G), formula (G-I) or formula (G-II), CysLT1Receptor antagonists or CysLT1/CysLT2A dual receptor antagonist. In further or alternative embodiments, CysLT1The antagonist is selected from Montelukast (Singulair)TM: [1- [ [1- [3- [2- [ (7-chloro-2-quinolinyl) ]Vinyl radical]Phenyl radical]-3- [2- (1-hydroxy-1-methyl-ethyl) phenyl]-propyl radical]Mercapto methyl group]Cyclopropyl group]Acetic acid), miscellaneous Lu Ka Si (zafirlukast) (Acclate)TM: 3- [ [ 2-methoxy-4- (o-toluenesulfonylaminoyl) carbamoyl) phenyl]Methyl radical]-1-methyl-1H-indol-5-yl]Cyclopentyl carbamate), or pranlukast (Onon)TM: 4-oxo-8- [ p- (4-phenylbutoxy) benzamido]-2-tetrazol-5-yl) -4H-1-benzopyran).
In further or alternative embodiments, anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory drugs, such as cyclooxygenase inhibitors (COX-1 and/or COX-2), lipoxygenase inhibitors, and steroids, such as prednisone or dexamethasone. In further or alternative embodiments, the anti-inflammatory agent is selected from the group consisting of
Figure A20068004120700441
Ashacol (Asacol),
Figure A20068004120700442
Sulfasalazine, Daypro, etodolac, mefenamic acid, salofak, suxol such as methylprednisolone (Solu-Mekrol), aspirin, indomethacin (Indocin)TM) Rofecoxib (Vioxx)TM) Celecoxib (celecoxib) (Celebrex)TM) Wedgesbeib (Bextra)TM) Diclofenac (diclofenac), etodolac (etodolac), ketoprofen (ketoprofen), floridine (Lodine), Mobic (Mobic), nabumetone (nabumetone), naproxen (naproxen), pyrilamine (piroxicam), West Standon (Celestone), prednisone, Deltapine (Deltasone), or any general equivalent thereof.
In any of the aforementioned aspects relating to the treatment of proliferative disorders including cancer,is a further embodiment which comprises administering at least one additional agent selected from the group consisting of Artuzumab (alemtuzumab), arsenic trioxide, asparaginase (pegylated or not), Bevacizumab (bevacizumab), Ceramima (cetuximab), platinum is a compound such as cisplatin, Clarithrombine (cladribine), Dorithromycin/Doxorubicin/Edararubicin, Iminotique (irinotecan), Fladarabine (fludarabine), 5-fluorouracil, Rotunib (gemtuzumab), aminomethopterin, PaclitaxelTMTaxol, temozolomide (temozolomide), thioguanine, or a drug class including hormones (antiestrogens, antiandrogens, or gonadotropin releasing hormone analogues), interferons, such as alpha-interferon, nitrogen mustards, such as busulfan or chlorambucil or nitrogen mustards, retinoids, such as tretinoin (tretinoin), topoisomerases inhibitors, such as illinoenothein or topotecan, tyrosine kinase inhibitors, such as gefinitib or imatinib (imatinib), or agents for treating signs or diseases caused by such therapies, including isopurinol, filgrastim (filgrastim), geleinil (granitron)/danesetron (ondansetron)/palonomycin (droxynol), or drugs for treating signs or diseases caused by such therapies, including isopurinol, filgraginosin (genistein)/pinostimul (androl), palonomycin (pinolene).
In any of the aforementioned aspects directed to therapy of a transplanted organ or tissue or cell, is a further embodiment, comprising administering at least one additional agent selected from the group consisting of azathioprine, corticosteroid, cyclophosphamide, cyclosporine, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, or thymocyte protein.
In any of the aforementioned aspects relating to therapy of interstitial cystitis, is a further embodiment which comprises administering at least one additional agent selected from the group consisting of dimethyl sulfoxide, omalizumab, and pentasaccharide polysulfate.
In any of the aforementioned aspects directed to therapy of a bone condition, is a further embodiment which comprises administering at least one additional agent selected from the group consisting of minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analog, and the cathepsin K inhibitor dronabinol.
In any of the aforementioned aspects related to preventing or treating inflammation, are further embodiments, comprising: (a) monitoring inflammation in a mammal; (b) measuring bronchoconstriction in a mammal; (c) measuring eosinophil and/or basophil and/or dendritic cells and/or neutrophils and/or single cell and/or lymphocyte recruitment in a mammal; (d) monitoring mucosal secretions in a mammal; (e) measuring mucosal edema in a mammal; (e) measure LTB 4Calcium ionophore-stimulated blood levels in mammals; (f) measuring LTE4The amount in urinary excretion of a mammal; or (g) identifying the patient by measuring leukotriene-driven inflammatory biomarkers, such as LTB4、LTC4、Il-6、CRP、SAA、MPO、EPO、MCP-1、MIP-α、sICAM、Il-4、Il-13。
In any of the aforementioned aspects relating to the prevention or treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, is a further embodiment, which comprises identifying the patient by screening for leukotriene gene singleness. In further or alternative embodiments, the plain type of leukotriene gene is a leukotriene pathway gene, whereas in yet further or alternative embodiments, the plain type of leukotriene gene is a 5-lipoxygenase activating protein (FLAP) plain type.
In any of the aforementioned aspects relating to the prevention or treatment of leukotriene-dependent or leukotriene mediated diseases or symptoms, is a further embodiment, which comprises identifying the patient by monitoring the patient for any of:
i) at least one leukotriene-related inflammatory biomarker; or
ii) at least one functional marker response to a leukotriene modifier; or
iii) at least one leukotriene-related inflammatory biomarker, in response to at least one functional marker of a leukotriene modifier.
In further or alternative embodiments, the leukotriene-related inflammatory biomarker is selected from the group consisting of LTB4Cysteaminyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-alpha, sICAM, IL-6, IL-4, and IL-13, however in yet further or alternative embodiments the functional marker response is significant lung volume (FEV 1).
In any of the aforementioned aspects relating to the prevention or treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, is a further embodiment, which includes identifying a patient by any of the following:
i) screening the patient for at least one leukotriene gene SNP and/or simple type, including SNPs in the insert or expression sequence positions; or
ii) monitoring the patient for at least one leukotriene-related inflammatory biomarker; or
iii) monitoring the patient for at least one functional marker response to the leukotriene modifier.
In further or alternative embodiments, the leukotriene gene SNP or simple type is a leukotriene pathway gene. In still further or alternative embodiments, the leukotriene gene SNP or simple type is a 5-lipoxygenase activating protein (FLAP) SNP or simple type. In further or alternative embodiments, the leukotriene-related inflammatory biomarker is selected from the group consisting of LTB 4Cysteaminyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-alpha, sICAM, IL-6, IL-4, and IL-13, however in yet further or alternative embodiments the functional marker response is significant lung volume (FEV 1).
In any of the aforementioned aspects relating to the prevention or treatment of leukotriene-dependent or leukotriene mediated diseases or symptoms, is a further embodiment, which comprises identifying the patient by at least two of:
i) screening the patient for at least one leukotriene gene SNP or simple type;
ii) monitoring the patient for at least one leukotriene-related inflammatory biomarker;
iii) monitoring the patient for at least one functional marker response to the leukotriene modifier.
In further or alternative embodiments, the leukotriene gene SNP or simple type is a leukotriene pathway gene. In still further or alternative embodiments, the leukotriene gene SNP or simple type is a 5-lipoxygenase activating protein (FLAP) SNP or simple type. In further or alternative embodiments, the leukotriene-related inflammatory biomarker is selected from the group consisting of LTB4Cysteaminyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-alpha, sICAM, IL-6, IL-4, and IL-13, however in yet further or alternative embodiments the functional marker response is significant lung volume (FEV 1).
In any of the aforementioned aspects relating to the prevention or treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, is a further embodiment, which comprises identifying the patient by:
i) screening the patient for at least one leukotriene gene SNP or simple type; and
ii) monitoring the patient for at least one leukotriene-related inflammatory biomarker; and
iii) monitoring the patient for at least one functional marker response to the leukotriene modifier.
In further or alternative embodiments, the leukotriene gene SNP or SNP isThe pure form is a leukotriene pathway gene. In still further or alternative embodiments, the leukotriene gene SNP or simple type is a 5-lipoxygenase activating protein (FLAP) SNP or simple type. In further or alternative embodiments, the leukotriene-related inflammatory biomarker is selected from the group consisting of LTB4Cysteaminyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-alpha, sICAM, IL-6, IL-4, and IL-13, however in yet further or alternative embodiments the functional marker response is significant lung volume (FEV 1).
In another aspect is the prevention or treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, comprising administering to a patient an effective amount of a FLAP modulator, wherein the patient has been identified using the information obtained by:
i) Screening the patient for at least one leukotriene gene SNP or simple type; and
ii) monitoring the patient for at least one leukotriene-related inflammatory biomarker; and
iii) monitoring the patient for at least one functional marker response to the leukotriene modifier.
In further or alternative embodiments, the FLAP modulator is a FLAP inhibitor. In further or alternative embodiments, the leukotriene gene SNP or simple type is a leukotriene pathway gene. In still further or alternative embodiments, the leukotriene gene SNP or simple type is a 5-lipoxygenase activating protein (FLAP) SNP or simple type. In further or alternative embodiments, the leukotriene-related inflammatory biomarker is selected from the group consisting of LTB4Cysteaminyl leukotriene, CRP, SAA, MPO, EPO, MCP-1, MIP-alpha, sICAM, IL-6, IL-4, and IL-13, however in yet further or alternative embodiments the functional marker response is significant lung volume (FEV 1). In further or alternative embodiments, information from three diagnostic methods may be used in the algorithm, wherein the information is analyzed to identify a patient in need of treatment with a FLAP modulator As well as the therapeutic regimen and the type of FLAP modulator used.
In any of the aforementioned aspects, the leukotriene-dependent or leukotriene mediated disease or condition is including, but not limited to, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis, anaphylaxis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, and endotoxic shock.
Certain chemical terms
Unless otherwise indicated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The definition of the terms of the standardization sector can be found in the literature references, including Carey and Sundberg "4 th edition of higher organic chemistry, volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacological methods within the skill of the art are employed. In this application, the use of "or" is intended to mean "and/or" unless stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "includes," "including," and "included," is not limiting.
"alkoxy" refers to a (alkyl) O-group, wherein alkyl is as defined herein.
"alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group comprising at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group comprising at least two carbon atoms and at least one carbon-carbon double bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
An "alkyl" moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the specified range; e.g., "1 to 10 carbon atoms" means that the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition of the invention also covers the occurrence of the term "alkyl" where no numerical range is specified). Alkyl groups may also be "lower alkyl" groups having 1 to 5 carbon atoms. The alkyl group of the compounds described herein may be referred to as "C 1-C4Alkyl "or similar nomenclature. By way of example only, "C1-C4Alkyl "means one to four carbon atoms in the alkyl chain, meaning that the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are in no way 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" means-N (alkyl)xHyWherein x and y are selected from the group consisting of x-1, y-1, and x-2, y-0. When x is 2, the alkyl groups taken together may optionally form a cyclic ring.
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, alkenyl groups begin with the atom-C (R) ═ C-R, where R refers to the remainder of the alkenyl group, which may be the same or different. Non-limiting examples of alkenyl include-CH ═ CH, -C (CH)3)＝CH、-CH＝CCH3and-C (CH)3)＝CCH3. The alkenyl moiety group may be branched, straight chain, or cyclic (in which case it is also referred to as "cycloalkenyl").
The term "alkynyl" refers to an alkyl type wherein the first two atoms of the alkyl group are in a triple bond. That is, alkynyl groups begin with the atom-C.ident.C-R, where R refers to the remainder of the alkynyl group, which may be the same or different. Non-limiting examples of alkynyl groups include-C ≡ CH, -C ≡ CCH3and-C ≡ CCH2CH3. The "R" portion of the alkynyl moiety may be branched, straight-chain or cyclic.
"amide" is a chemical moiety having the formula-C (O) NHR or-NHC (O) R, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon), and heteroalicyclic (bonded via a ring carbon). The amide may be an amino acid or molecule linked to any compound of formula (A), formula (B), formula (C), formula (D), formula (F) or formula (H), thus forming a prodrug. Any amine or carboxyl side chain on the compounds described herein may be amidated. Procedures and specific groups for making such amides are known to the skilled artisan and can be readily referenced to reference data sources such as Greene and Wuts, organic synthetic protecting groups, 3 rd edition, 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 having at least one ring with a conjugated pi-electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). This term includes monocyclic or fused ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The term "carbocyclic group" refers to compounds containing one or more covalently closed ring structures, and the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom other than carbon.
The term "bond" or "single bond" refers to a chemical bond between two atoms, or two partial groups when the atoms joined by the bond are considered part of a larger substructure.
"cyano" refers to the group-CN.
The term "cycloalkyl" refers to a monocyclic or polycyclic group that contains only carbon and hydrogen, and can be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups comprise groups having 3 to 10 ring atoms. Illustrative cycloalkyl groups include the following partial groups:
Figure A20068004120700491
Figure A20068004120700501
the term "ester" refers to a chemical moiety having the formula-COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon), and heteroalicyclic (bonded via a ring carbon). Any hydroxyl or carboxyl side chain on the compounds described herein can be esterified. Procedures and specific groups for making such esters are known to the skilled artisan and can be readily referenced to reference data sources such as Greene and Wuts, organic synthetic protecting groups, 3 rd edition, John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety. "halo" or "halogen" terms mean fluoro, chloro, bromo, or iodo.
The terms "haloalkyl", "haloalkenyl", "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures which are substituted with one or more halo groups or with combinations thereof. The terms "fluoroalkyl" and "fluoroalkoxy" include, respectively, haloalkyl and haloalkoxy, wherein halo is fluorine.
The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl groups having one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.
The term "heteroaryl" or "heteroaromatic" refers to an aryl group that contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom. Polycyclic heteroaryl groups may be fused or unfused. Illustrative heteroaryl groups include the following partial groups:
Figure A20068004120700502
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 4 to 10 atoms in its ring system, with the proviso that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups contain groups having only 4 atoms in their ring systems, but aromatic heterocyclic groups must have at least 5 atoms in their ring systems. Heterocyclic groups include benzo-fused rings. An example of a 4-membered heterocyclic group is a mononitrocyclyl group (derived from a mononitrocyclo). An example of a 5-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 quinolyl. Examples of non-aromatic heterocyclic groups are tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, hexahydropyridinyl, morpholinyl, thiomorpholinyl, thiohexacyclic, hexahydropyrazinyl, monoazatetracyclic, glycidyloxy, thiiranyl, homopiperidinyl, oxyheptacyclyl, thioheptacyclyl, oxaheptacycloalkenyl, diazacyclocycloalkenyl, thiazaheptacycloalkenyl, 1, 2, 3, 6-tetrahydropyridinyl, 2-dihydropyrrolyl, 3-dihydropyrrolyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, dihydropyrazolyl, dithiohexacyclic, dithiopentacyclic, dihydropyranyl, dihydrothienyl, dihydrofuranyl, tetrahydropyrazolyl, thiolyl, etc, A dihydroimidazolyl group, a tetrahydroimidazolyl group, a 3-azabicyclo [3.1.0] hexyl group, a 3-azabicyclo [4.1.0] heptanyl group, a 3H-indolyl group, and an -functional group. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridyl. The foregoing groups, when derived from the groups listed above, may be C-linked or N-linked where possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, the groups derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (both C-linked). Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (═ O) moieties, such as tetrahydropyrrole-2-ones.
By "heteroalicyclic" group is meant a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur, i.e., a non-aromatic heterocyclic group. These groups may be fused with aryl or heteroaryl groups. Heterocycloalkyl, also known as a heteroalicyclic group, illustrative examples of which include:
Figure A20068004120700511
Figure A20068004120700521
the term heteroalicyclic also includes all ring forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides.
The term "membered ring" can include any ring structure. The term "member" is intended to mean the number of atoms of the backbone that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings, while cyclopentyl, pyrrole, furan and thiophene are 5-membered rings.
"isocyanato" refers to an-NCO group.
"isothiocyanato" refers to the-NCS group.
"thiol" refers to an (alkyl) S-group.
The term "moiety" refers to a particular segment or functional group of a molecule. Chemical moiety groups are often considered to be chemical entities embedded in or attached to a molecule.
"sulfinyl" refers to-S (═ O) -R where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through ring carbons), and heteroalicyclic (bonded through ring carbons).
"Sulfonyl" means-S (═ O) 2-R, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and heteroalicyclic (bonded via a ring carbon).
"thiocyanato" refers to a-CNS group.
The term "optionally substituted" or "substituted" means that the indicated group can be individually and independently substituted with one or more other groups selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanic acidRadicals, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl, and amino, including mono-and di-substituted amino, and protected derivatives thereof. For example, an optional substituent may be LSRSWherein each LSIs independently selected from a bond, -O-, -C (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 C1-C6Alkyl) or- (substituted or unsubstituted C2-C6Alkenyl); and each RSIs independently selected from H, (substituted or unsubstituted lower alkyl), (substituted or unsubstituted lower cycloalkyl), heteroaryl or heteroalkyl. Protecting groups which may form protective derivatives of the above substituents are known to the skilled person and can be referred to reference data, such as Greene and Wuts, above.
The compounds presented herein may have one or more stereogenic centers, and each center may exist in either the R or S configuration. The compounds presented herein are meant to include all diastereomeric, symmetric and epimeric forms, as well as suitable mixtures thereof. If desired, the stereoisomers may be obtained by methods known in the art, for example separation of the stereoisomers by chiral chromatography columns.
The methods and formulations described herein include the use of N-oxides, crystalline forms (also referred to as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of any of formula (G), formula (G-I), or formula (G-II), as well as active metabolic products of these compounds having the same type of activity. In some cases, 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 as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvate forms of the compounds presented herein are also considered to be disclosed herein.
Certain medical terms
The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no sustained adverse effect on the general health of the patient being treated.
The term "agonist" as used herein refers to a molecule, such as a compound, drug, enzyme activator or hormone modulator, that enhances 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, drug, enzyme inhibitor or hormone modulator, that reduces or prevents the action of another molecule, or the activity of a receptor site.
The term "asthma" as used herein refers to any condition of the lung characterized by a variation in the flow of the lung air associated with airway constriction of whatever cause (intrinsic, extrinsic or both; allergic or non-allergic). The term asthma may be used in conjunction with one or more adjectives to indicate a cause.
As used herein, the term "Bone disease" refers to diseases or conditions of Bone including, but not limited to, inappropriate Bone remodeling, wasting or augmenting, Bone deficiency, osteomalacia, Bone fibrosis, and buhui de's disease [ Garcia, "leukotriene B4 stimulates osteoclast Bone wasting in vitro and in vivo", J Bone Miner res.1996; 11: 1619-27].
As used herein, the term "cardiovascular disease" refers to a disease affecting the heart or blood vessels or both, including but not limited to: irregular rhythm; atherosclerosis and its sequelae; angina pectoris; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury following blood deprivation in the brain, heart or other organ or tissue; endotoxin, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; (ii) shock; vasoconstriction (including associated migraine); vascular abnormalities, inflammation, insufficiency restricted to a single organ or tissue [ Lotzer K et al, "5-lipoxygenase pathway in arterial wall biology and atherosclerosis", Biochim Biophys Acta 2005; 1736: 30-7; helgadottir A et al, "genes encoding proteins which activate 5-lipoxygenase confer risk of myocardial infarction and stroke", Nat Genet.2004, month 3; 36(3): 233-9, Epub 2004, 2 months and 8 days; [ Heise CE, Evans JF et al, "characterization of the human cysteaminoyl leukotriene 2 receptor", J Biol chem.2000, 9/29 days; 275(39): 30531-6].
The term "cancer" as used herein refers to abnormal growth of cells that tend to proliferate in an uncontrolled manner, and in some cases metastasize (spread). Types of Cancer include, but are not limited to, solid tumors (such as bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma), or hematologic tumors (such as leukemia) [ Ding XZ et al, "novel anti-pancreatic Cancer agents, LY 293111", anti-Cancer agents, 6 months 2005; 16 (5): 467-73. retrospective; Chen X et al, "overexpression of 5-lipoxygenase in rats and human esophageal adenocarcinoma and the inhibitory effect of ghetton (zileuton) and celecoxib (celecoxib) on carcinogenesis", Clin Cancer res.2004, 10 months 1; 10 (19): 6703-9 ].
The term "carrier" as used herein refers to a relatively non-toxic chemical compound or agent that facilitates incorporation of the compound into a cell or tissue.
As used herein, "co-administration" or similar terms, is intended to encompass the administration of a selected therapeutic agent to a single patient, and is intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.
The term "skin disorder" as used herein refers to a skin (skin) disorder. Such skin disorders include, but are not limited to, proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, glioblastomas, contact dermatitis eczema, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, urticaria [ Wedi B et al, "pathophysiological role of leukotrienes in skin disorders: potential therapeutic associations ", biodrugs.2001; 15(11): 729-43].
The term "diluent" refers to a chemical compound used to dilute a compound of interest prior to delivery. Diluents may also be used to stabilize the compound as they provide a more stable environment. Salts that are dissolved in a buffer solution (which may also provide pH control or maintenance) are utilized as diluents in the art, including but not limited to phosphate buffered saline solutions.
As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound being administered that will alleviate the signs of one or more of the diseases or conditions being treated to some extent. The result may be a reduction and/or alleviation of the signs, signs or causes of a disease, or any other desired alteration of an organism's system. For example, an "effective amount" for therapeutic use is the amount of the composition comprising a compound as disclosed herein that is required to provide a clinically significant decrease in the signs of disease. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies.
As used herein, the terms "potentiate" or "enhancing" mean increasing or prolonging the desired effect, whether in effect or duration. Thus, with respect to potentiating the effect of a therapeutic agent, the term "potentiate" refers to the ability to increase or prolong the effect of other therapeutic agents on the system, whether in terms of efficacy or duration. As used herein, a "potentiating effective amount" refers to an amount sufficient to potentiate the action of another therapeutic agent in the desired system.
As used herein, the term "enzymatically cleavable linker" refers to an labile or cleavable linkage that is degradable by one or more enzymes.
As used herein, the term "fibrosis" or "fibrotic condition" refers to conditions that follow acute or chronic inflammation and are associated with abnormal accumulation of cells and/or collagen, and includes, but is not limited to, fibrosis of individual organs or tissues, such as heart, kidney, joints, lung or skin, and includes conditions such as idiopathic pulmonary fibrosis and cryptofibrillary pneumocystitis [ charsenau RP et al, "eicosanoids: mediators and therapeutic targets "Clin Sci (Lond)" in fibrotic lung disease 6 months 2005; 108(6): 479-91].
The term "iatrogenic" means a leukotriene-dependent or leukotriene mediated condition, disorder or disease caused by or exacerbated by medical or surgical therapy.
The term "inflammatory disorder" refers to a disease or condition characterized by one or more of pain (dolor), from the production of noxious substances and irritation of nerves, heat (calor), from vasodilation, redness (rubor), from vasodilation and increased blood flow), swelling (tumors, from excessive inflow or restricted outflow of fluids), and loss of function (functional disease, which may be partial or complete, temporary or permanent). Inflammation takes a variety of forms, and includes, but is not limited to, inflammation of one or more of the following: acute, adhesion, atrophy, mucositis, chronic, hard, diffuse, disseminated, exudative, fibrinous, fibrosis, lesion, granuloma, hyperplasia, hypertrophy, interstitial space, metastasis, necrosis, occlusion, parenchyma, plasticity, productivity, hyperplasia, pseudomembranous, purulent, sclerosing, seroformable, serous, simple, specific, subacute, chemoconcentrated, toxic, traumatic, and/or ulcerative. Inflammatory conditions further include, without limitation, blood vessels (polyarteritis, temporal arteritis); joints (arthritis: crystalline, bone, psoriasis, reactive, rheumatic, lypus); gastrointestinal tract (disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus) [ Harrison's internal medicine principle, 16 th edition, edited KasperDL et al; McGraw-Hill Press ].
The term "interstitial cystitis" refers to a condition characterized by lower abdominal discomfort, frequent and frequent painful urination, which is not caused by anatomical abnormalities, infections, toxins, trauma, or tumors [ bouchelouuche K et al, "cysteinyl leukotriene D4 receptor antagonist montelukast (montelukast) for the treatment of interstitial cystitis", J urolol 2001; 166: 1734].
As used herein, the term "leukotriene-driven mediator" refers to a molecule capable of being produced in a patient, which may be caused by stimulation of leukotrienes by overproducing cells, such as LTB, by way of example only4、LTC4、LTE4Cysteaminyl leukotriene, single cell inflammatory protein (MIP-1 alpha), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), single cell chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM), Myeloperoxidase (MPO), eosinophil-peroxoxygenase (EPO), and general inflammatory molecules such as interleukin-6 (Il-6), C-reactive protein (CRP), and serum amyloid A protein (SAA).
As used herein, the term "leukotriene-related mediator" refers to a molecule capable of being produced in a patient, which may be caused by stimulation of leukotrienes by overproducing cells, such as LTB, by way of example only 4、LTC4、LTE4Cysteaminyl leukotriene, single cell inflammatory protein (MIP-1 alpha), interleukin-8 (IL-8), interleukin-4 (IL-4), interleukin-13 (IL-13), single cell chemoattractant protein (MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM), Myeloperoxidase (MPO), eosinophil-peroxoxygenase (EPO), and general inflammatory molecules such as interleukin-6 (Il-6), C-reactive protein (CRP), and serum amyloid A protein (SAA).
The term "leukotriene-dependent" as used herein refers to the absence or degree of occurrence of symptoms or conditions in the absence of one or more leukotrienes.
The term "leukotriene-mediated" as used herein refers to a symptom or condition that may occur in the absence of leukotrienes, but may occur in the presence of one or more leukotrienes.
As used herein, the term "leukotriene-responsive patient" refers to a patient who has been identified by either the FLAP simple type of genotyping, or the genotyping of one or more other genes in the leukotriene pathway, and/or by the development of a phenotype in the patient, by either a previous positive clinical response to another leukotriene modulator, including, by way of example only, zileuton (Zyflo) (Zyflo) TM) Montelukast (Singulair)TM) Pranlukast (Onon)TM) Miscellaneous LUOCAST (zafirlukast) (Acclate)TM) And/or by driving the distribution profile of mediators, which exhibit excessive leukotriene stimulation of inflammatory cells, by their leukotrienes, which may advantageously respond to leukotriene modulator therapy.
The terms "kit" and "article of manufacture" are used synonymously as synonyms.
A "metabolic product" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized by an organism. The term "active metabolic product" refers to a biologically active derivative of the compound that is formed when the compound is metabolized by an organism. As used herein, the term "metabolized biologically" refers to the sum of processes by which a particular substance is altered by an organism (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes). Thus, enzymes may produce specific structural changes to a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, whereas the enzyme -diphosphoglucosyluronyltransferase catalyzes the transfer of activated aldonic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolic effects can be derived from the pharmacological basis of therapeutics, 9 th edition, McGraw-Hill (1996). The metabolic products of the compounds disclosed herein can be identified either by administration of the compounds to a host, analysis of tissue samples obtained from the host, or by culturing the compounds in vitro as hepatocytes, and analysis of the resulting compounds. Both methods are well known in the art.
The term "modulate" as used herein means to interact with a target, whether directly or indirectly, to alter a target activity, including, by way of example only, to enhance a target activity, inhibit a target activity, limit a target activity, or prolong a target activity.
The term "modulator" as used herein refers to a molecule, whether direct or indirect, that interacts with a target. Interactions include, but are not limited to, agonist and antagonist interactions.
As used herein, the term "neurogenic disease" or "neurological disorder" refers to a condition that alters the structure or function of the brain, spinal cord or peripheral nerve system, including, but not limited to, alzheimer's disease, cerebral edema, cerebral ischemia, multiple sclerosis, neuropathy, parkinson's disease, as found after blunt or surgical trauma (including post-operative cognitive dysfunction and spinal cord or brainstem injury), and the neuropathic aspects of the disorder, such as degenerative disc disease and sciatica. The capitalized language "CNS" refers to disorders in which the central nervous system (i.e., brain and spinal cord) [ Sugaya K et al, "novel anti-inflammatory treatment strategy in Alzheimer's disease", Jpn J Pharmacol.2000, month 2; 82(2): 85-94 parts of; yu Gl et al, "montelukast cysteaminoylleukotriene receptor-1 antagonist, dose-and time-dependently protected against local cerebral ischemia in mice", pharmacology.2005 month 1; 73(1): 31-40, Epub 2004, 9 months and 27 days; [ ZhangWP et al, "neuroprotective effects of ONO-1078 leukotriene receptor antagonists on local cerebral ischemia in rats", Acta Pharmacol sin.2002, 10 months; 23(10): 871-7].
As used herein, the term "eye disease" or "ocular disease" refers to a disease that affects one or both eyes, as well as potentially surrounding tissues. Eye or ocular diseases include, but are not limited to, conjunctivitis, retinitis, scleritis, uveitis, allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis [ Toryama S., "Effect of leukotriene B4 receptor antagonist on experimental autoimmune uveitis in white rats", Nippon Ganka GakkaiZasshi.6 months 2000; 104(6): 396-40 parts by weight; [ Chen F et al, "treatment of S-antigen uveitis with lipoxygenase and cyclooxygenase inhibitors", Ophthalmic Res.1991; 23(2): 84-91].
As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, meaning that the substance can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the ingredients included in the composition.
The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutically acceptable salts can be obtained by reacting any compound of formula (G), formula (G-I) or formula (G-II) with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts may also be obtained by reacting any compound of formula (G), formula (G-I) or formula (G-II) with a base to form a salt, such as an ammonium salt, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, an organic base, such as dicyclohexylamine, N-methyl-D-glucosamine, 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 herein means a product resulting from the mixing 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, e.g. any compound of formula (G), formula (G-I) or formula (G-II), and the co-agent are administered to the patient simultaneously in a single entity or dosage form. The term "non-fixed combination" means that the active ingredients, e.g. any compound of formula (G), formula (G-I) or formula (G-II), and the co-agent are administered to the patient as separate entities, whether simultaneous, concurrent or sequential, without specific intervening time constraints, wherein such administration provides effective amounts of the two compounds in the body of the patient. The latter also applies to cocktail therapies, for example the administration of three or more active ingredients.
The term "pharmaceutical composition" refers to any mixture of a compound of formula (G), formula (G-I) or formula (G-II) with other chemical ingredients such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Various techniques for administering compounds exist in the art, including but not limited to: intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.
"prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. It may be bioavailable, for example, by oral administration, whereas the parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Examples of prodrugs, without limitation, are any compounds of formula (G), formula (G-I) or formula (G-II) which are administered as esters ("prodrugs") to aid transport across cell membranes where aqueous solubility is detrimental to mobility, but which are then metabolically hydrolyzed to carboxylic acids, which are the active entities, where the degree of hydrolysis is beneficial once inside the cell. Another embodiment of a prodrug can be a short (poly-amino acid) bound to an acid group, where it is metabolized biologically to reveal the active moiety.
The term "respiratory disease" as used herein refers to a disease that affects organs involved in breathing such as the nose, throat, larynx, trachea, bronchi and lungs. Respiratory diseases include, but are not limited to, asthma, adult dyspnea syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood developed asthma, adult developed asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia [ Evans JF, "cysteinyl leukotriene (CysLT) pathway in allergic rhinitis", international allergy 2005; 54: 187-90); kemp JP., "leukotriene receptor antagonist for treatment of asthma", idrugs.2000, 4 months; 3(4): 430-41; riccionii G et al, "the effects of two different leukotriene receptor antagonists Montelukast and miscellaneous Lutkast on quality of life: 12-week randomized study ", Allergy asset astm proc.2004, months 11-12; 25(6): 445-8].
The term "patient" or "suffering" is intended to encompass mammals as well as non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian species: humans, non-human primates, such as chimpanzees, and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; livestock animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
As used herein, the terms "treat," "treating," or "treatment" include reducing or ameliorating a sign of a disease or condition, preventing another sign, ameliorating or preventing a metabolic cause to which the sign is associated, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, reducing the disease or condition, causing regression of the disease or condition, resolving the condition caused by the disease or condition, or halting the sign of the disease or condition, whether prophylactically and/or therapeutically.
Other objects, features, and advantages of the methods and compositions described herein will become apparent from the detailed description that follows. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. All references, including patents, patent applications, and publications, cited herein are hereby incorporated by reference in their entirety.
Drawings
Fig. 1 presents illustrative reaction schemes for synthesizing the compounds described herein.
Fig. 2 presents illustrative reaction schemes for the synthesis of compounds described herein.
Fig. 3 presents illustrative reaction schemes for synthesizing the compounds described herein.
Fig. 4 presents illustrative reaction schemes for synthesizing the compounds described herein.
Fig. 5 presents illustrative reaction schemes for synthesizing the compounds described herein.
Fig. 6 presents illustrative reaction schemes for synthesizing the compounds described herein.
Fig. 7 presents illustrative reaction schemes for synthesizing the compounds described herein.
Fig. 8 presents an illustrative example of the compounds described herein.
Fig. 9 presents an illustrative example of the compounds described herein.
Fig. 10 presents an illustrative example of the compounds described herein.
Fig. 11 presents an illustrative example of the compounds described herein.
Figure 12 presents an illustrative schematic of the use of the compounds and methods described herein to treat patients.
Figure 13 presents an illustrative schema for treating patients using the compounds and methods described herein.
Figure 14 presents an illustrative schematic of the use of the compounds and methods described herein to treat patients.
Detailed Description
Illustrative biological Activity
Leukotrienes (LT) are potent contractile and inflammatory mediators released from the cell membrane by arachidonic acid and activated by 5-lipoxygenase, 5-lipoxygenase activating protein, LTA4Hydrolase and LTC4The action of the synthetase is converted into leukotriene. The leukotriene synthesis pathway or 5-lipoxygenase pathway involves a series of enzymatic reactions in which arachidonic acid is converted to leukotriene LTB4Or cysteaminoylleukotrienes, LTC4、LTD4And LTE4. This pathway occurs primarily in the nuclear envelope and has been described. See, e.g., Wood, JW et al, j.exp.med., 178: 1935-1946, 1993; Peters-Golden, am.j.respir.crit.care med.157: S227-S232, 1998; drazen et al, edited five lipoxygenase products in asthma, in lung biology in health and disease, Vol.120, Chapter 1, 2 and 7, Marcel Dekker NY, 1998. Protein components specific to the leukotriene synthesis pathway include 5-lipoxygenase (5- LO), 5-lipoxygenase activating protein, LTA4Hydrolase and LTC4And (3) synthesizing enzyme. The synthesis of leukotrienes has been described in the literature, e.g., Samuelsson et al, Science, 220, 568-575, 1983; Peters-Golden, "cytobiology of the 5-lipoxygenase pathway" Am J Respir CritCare Med 157: S227-S232 (1998). Leukotrienes are synthesized directly from arachidonic acid by different cells, including eosinophils, neutrophils, basophils, lymphocytes, macrophages, single cells, and mast cells. Excess LTA4E.g., from activated neutrophils, may enter the cell via a transcellular route. Most cells in the body have LTA4Hydrolases, thus producing LTB4. Platelets have LTC with endothelial cells4Synthesising enzymes, so when passing through the transcellular pathway, LTA4Upon presentation, LTC can be made4。
Arachidonic acid is a polyunsaturated fatty acid and is found primarily in the cell membrane of body cells. In the presence of inflammatory stimuli from outside the cell, calcium is released and binds to phospholipase A2(PLA2) and 5-LO. Cell activation causes PLA2And 5-LO from the cytoplasm to the endoplasmic reticulum and/or nuclear cell membrane, wherein in the presence of released arachidonic acid is converted to epoxide LTA via a 5-HPETE intermediate 4. Depending on the cell type, LTA4LTC capable of immediate nuclear binding4Synthetase conversion to LTC4Or by cytolytic LTA4Conversion to LTB by action of hydrolytic enzymes4。LTB4Is exported from the cell by a yet uncharacterized transporter and can activate other cells, or the cells in which they are made, to bind to one of two G protein-coupled receptors (GPCRs), i.e., BLT, via high affinity1R or BLT2R。LTC4Is exported to the blood via MRP-1 anion pump and is rapidly converted to LTD by the action of gamma-glutamyl transpeptidase4Then LTD4Is converted into LTE by the action of a dipeptidase4。LTC4、LTD4And LTE4Is a general termIs cysteaminoyl leukotriene (or A slow-reacting substance previously called anaphylaxis, SRS-A). Cysteaminyl leukotrienes activate other cells, or the cells in which they are made, via high affinity binding to one of the two GPCRs, CysLT1R or CysLT2R。CysLT1Receptors are found in human airway eosinophils, neutrophils, macrophages, mast cells, B-lymphocytes, and smooth muscle, and cause bronchoconstriction. Zhu et al, Am J Respir Cell Mol Biol Epub Aug 25 (2005). CysLT2The receptor is located in human airway eosinophils, macrophages, mast cells, human pulmonary vascularity, fig. aeeroa et al, Clin Exp Allergy 33: 1380-1388(2003).
Involvement of leukotrienes in disease or condition
The involvement of leukotrienes in disease is well described in the literature. See, e.g., Busse, clin. exp. allergy 26: 868-79, 1996; o' Byrne, Chest 111 (supplement 2): 27S-34S, 1977; sheftell, f.d. et al, Headache, 40: 158-163, 2000; klickstein et al, j.clin.invest, 66: 1166 1170, 1950; davidson et al, ann.rheum.dis, 42: 677-679, 1983. Leukotrienes produce a significant inflammatory response in human skin. Evidence for the involvement of leukotrienes in human disease has been found in psoriasis where leukotrienes have been detected in psoriatic lesions (Kragballe et al, Arch. Dermatol., 119: 548-.
For example, inflammatory responses have been shown to reflect three types of changes in local blood vessels. The initial change is an increase in vessel diameter, which results in increased local blood flow, and results in increased temperature, redness, and decreased blood flow velocity, particularly along the surface of small vessels. The second change is activation of endothelial cells lining the blood vessels to express adhesion molecules that promote the binding of circulating leukocytes. The combination of slowing blood flow and the resulting adhesion molecules allows leukocytes to attach to the endothelium and migrate into the tissue, a process known as extravasation. These changes are triggered by cytokines and leukotrienes produced by activated macrophages. Once inflammation has begun, the first cells attracted to the site of infection are typically neutrophils. It is then a single cell, which differentiates into more tissue macrophages. In the post-inflammatory phase, other white blood cells, such as eosinophils and lymphocytes, also enter the infected site. The third major change in local blood vessels is increased vascular permeability. Instead of being tightly bound together, endothelial cells lining the vessel wall become detached, leading to the exit of fluids and proteins from the blood and their local accumulation in tissues (see Janeway et al, immunobiology: immunization in health and disease is a system, 5 th edition, Garland publication, New York, 2001).
LTB4Relatively weak contractions of isolated airways and lung parenchyma are produced and these contractions are partially blocked by cyclooxygenase inhibitors, indicating that the contraction is secondary to the release of prostaglandins. However, LTB4Has been shown to be an effective chemotactic agent for primary particles of eosinophils and mast cells, and LTB4Recipient BLT 1-/-knockout mice are protected from eosinophilic inflammation and allergic airway reactions mediated by T-cells. Miyahara et al JImmunol 174: 4979-4784; (Weller et al J Exp Med 201: 1961-.
Leukotriene C4And D4For an effective smooth muscle contractant, bronchoconstriction is promoted in a variety of species, including humans (Dahlen et al, Nature, 288: 484-. These compounds have profound hemodynamic effects, cause coronary pinching, and cause decreased cardiac output efficiency (Marone et al, in leukotriene biology, compiled by R.Levi and R.D.Krell, Ann.New York Acad.Sci.524: 321-333, 1988). However, leukotrienes also act as angiotensin converting agents, with significant differences existing for different vascular beds. Leukotrienes have been reported to contribute to cardiac reperfusion injury following myocardial ischemia (Barst and Mullane, Eur. J. Pharmacol., 114: 383-387, 1985; Sasaki et al, C ardiovasc.Res.，22：142-148，1988)。LTC4And LTD4Will directly increase vascular permeability, perhaps by promoting the retraction of microvascular endothelial cells, via CysLT2Activation of the receptor and possibly other yet unidentified CysLT receptors [ Lotzer et al Arterioscler Thromb Vasc Biol 23: e32-36 (2003)]。LTB4In two atherosclerotic mouse models, low density receptor lipoprotein receptor deficiency (LDLr-/-) and apolipoprotein E-deficiency (ApoE-/-) mice, enhanced atherosclerotic progression (Aiello et al, Arterioscler Thromb Vasc Biol 22: 443. 449 (2002); Subbarao et al, Arterioscler Trromb Vasc Biol 24: 369. 375 (2004); Heller et al, Circulation 112: 578. 586 (2005); LTB. mu.4It has also been shown to increase human single cell chemoattractant protein (MCP-1), a known enhancer of atherosclerotic progression (Huang et al, Ateriosorter Thromb Vasc Biol 24: 1783-1788 (2004).
The role of FLAP in the leukotriene synthesis pathway is significant because FLAP, in conjunction with 5-lipoxygenase, carries out the first step in the leukotriene synthesis pathway. Thus, the leukotriene synthesis pathway provides a variety of targets for compounds useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions, including, for example, vascular and inflammatory disorders, proliferative diseases, and noncancerous disorders.
Leukotriene-dependent or leukotriene mediated conditions treated using the methods, compounds, pharmaceutical compositions and medicaments described herein include, but are not limited to, bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, skin diseases and disorders, ocular diseases and disorders, cancer and other proliferative diseases and disorders, respiratory diseases and disorders, and non-cancerous disorders.
Treatment options
Leukotrienes are known to contribute to airway inflammation in patients with asthma. CysLT1Receptor antagonists, e.g. Montelukast)(SingulairTM) Has 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: 1020-1028(2002)]。CysLT1The R antagonist Pranlukast (onanlukast) (Onon)TM) And miscellaneous road card last (zafirlukast) (Acclate)TM) Has also proven effective in asthma.
A variety of drugs have been designed to inhibit leukotriene formation, including the 5-lipoxygenase inhibitor zileuton (Zyflo)TM) Efficacy in asthma has been demonstrated, Israel et al Ann inter 119: 1059-1066(1993). The 5-lipoxygenase inhibitor ZD2138 showed efficacy in inhibiting the decline in FEV1 due to asthma induced by aspirin, Nasser et al, Thorax, 49; 749-756(1994). The following leukotriene synthesis inhibitors have demonstrated efficacy in asthma: specific inhibitors of MK-0591, 5-lipoxygenase activating protein (FLAP), Brideau et al, ca.j. physiol. pharmacol.70: 799-807(1992), specific inhibitors of MK-886, 5-lipoxygenase activating protein (FLAP), Friedman et al Am Rev Respir Dis., 147: 839-844(1993), and specific inhibitors of BAY X1005, 5-lipoxygenase activating protein (FLAP), Fructmann et al, pharmacological action 38: 188-195(1993).
FLAP inhibition will reduce LTB from single cells, neutrophils and other cells involved in vascular inflammation4Thus reducing atherosclerotic progression. The FLAP inhibitor MK-886 has been shown to reduce the vasoconstrictive response following angioplasty in porcine carotid injury models, Provost et al Brit J Pharmacol 123: 251-258(1998). MK-886 has also been shown to suppress femoral endangium hyperplasia in the photochemical pattern of endothelial-injured white rats, Kondo et al Thromb Haemost 79: 635-639(1998). 5-lipoxygenase inhibitor Gereteton (zileuton) has been shown to reduce renal ischemia in a rat model, Nimesh et al Mol Pharm 66: 220-227(2004).
FLAP modulators have been used to treat a variety of diseases or conditions, including, by way of example only, (i) inflammation (see, e.g., L)eff AR et al, "discovery of leukotrienes and development of anti-leukotriene agents", AnnAllergy Asthma Immunol 2001; 86 (supplement 1) 4-8; riccionii G et al, "progress on therapy with anti-leukotriene drugs", Ann Clin Lab Sci.2004, 34 (4): 379-870; (ii) respiratory diseases including asthma, adult dyspnea syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, carbon dioxide hyperventilation, childhood developed asthma, adult developed asthma, cough variant asthma, occupational asthma, steroid resistant asthma, seasonal asthma (see, e.g., Riccioni et al, Ann.Clin.Lab.Sci., v34, 379-; (iii) chronic obstructive pulmonary diseases including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis (see, e.g., Kostikas K et al, "leukotriene B4 in respiratory condensate and sputum supernatant exhaled in patients with COPD and asthma", Chest 2004; 127: 1553-9); (iv) increased mucosal secretion and/or edema in a disease or condition (see, e.g., Shahab R et al, "prostaglandin, leukotriene and perennial rhinitis", J Larynggol Otol., 2004; 118; 500-7); (v) vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke (see, e.g., Jala et al, trends Immunol., v25, 315-; (vi) reducing organ reperfusion injury following organ ischemic and/or endotoxin shock (see, e.g., Matsui N et al, "protective Effect of the 5-lipoxygenase inhibitor aclidinicacid (ardisiaquinone) A on liver ischemic-reperfusion injury in rats," plantaMed.8.2005; 71 (8): 717-20); (vii) reducing pinching of blood vessels (see, e.g., Stanke-Labesque F et al, "inhibition of leukotriene synthesis with MK-886 prevents blood pressure elevation and reduces norepinephrine-induced contractility in L-NAME-treated white rats", BrJPharmacol.9 months 2003; 140 (1): 186-94); (viii) reduce Or to prevent an increase in blood pressure (see, e.g., Stanke-Labesque F et al, "inhibition of leukotriene synthesis with MK-886 prevents blood pressure increases in L-NAME-treated white rats and reduces norepinephrine-induced contractility", Br J Pharmacol.2003, month 9; 140 (1): 186-94, and Walch L et al, "pharmacological evidence of a novel cysteinyl-leukotriene receptor subtype in human pulmonary artery smooth muscle", Br J Pharmacol.2002, month 12; 137 (8): 1339-45); (ix) preventing recruitment of eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or single cells (see, e.g., Miyahara N et al, "leukotriene B4 receptor-1 is essential for the mediated recruitment of CD8+ T cells and airway-responsive allergens", Immunol.2005, 4, 15, 174 (8): 4979-84); (x) Abnormal bone modification, loss or augmentation, including osteopenia, osteoporosis, Bergesician's disease, cancer and other diseases (see, e.g., Anderson GI et al, "inhibition of leukotriene function modulates microparticle-induced changes in bone cell differentiation and activity," Biomed Mater Res.2001; 58 (4): 406) 140, (xi) ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis (see, e.g., Lambian et al, Arch. Opthalli., v121, 615-620(2003)), (xii) CNS disorders including, but not limited to, multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine (see, e.g., Carza hova D et al, "asthma in the annual and adolescent stages using leukotriene plus migraine receptor antagonists of leukotrienes activities",'s receptor, headache.2002, 11-12 months; 42(10): 1044-7; sheftell F et al, "Montelukast in migraine prophylaxis: potential role for leukotriene modifier "", Headache.2000, 2 months; 40(2): 158-63); (xiii) Peripheral neuropathy/neuropathic pain, spinal cord injury (see, e.g., Akpek EA et al, "study of treatment of glands in experimental acute spinal cord injury. Effect on arachidonic acid metabolites", spine.1999, 1/15 days; 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, e.g., Poff and Balazy, curr. drug targets Inflamm. Allergy, v3, 19-33(2004), and Steele et al, cancer epidemiology and prevention, v8, 467-483 (1999); (xv) endotoxic and septic shock (see, e.g., Leite MS et al, "mechanism for increasing survival following lipopolysaccharide-induced endotoxic shock in mice consuming an olive oil rich diet," Shock.2005-2 months; 23 (2): 173-8), (xvi) rheumatoid and osteoarthritis (see, e.g., Alten R et al, "Long-acting LTB by BIIL 284 in patients with rheumatoid arthritis4Receptor antagonist inhibition of leukotriene B4The induced CD11B/CD18(Mac-1) performance ", Ann Rheum Dis.2004, month 2; 63(2): 170-6); (xvii) Prevention of increased GI disease, by way of example only, includes chronic gastritis, eosinophilic gastroenteritis and gastric motor dysfunction (see, e.g., Gyomber et al, J Gastroenterol Heapatol, v11, 922-; (xviii) Kidney diseases include, by way of example only, glomerulonephritis, cyclosporin-induced renal reperfusion (see, e.g., Kidney int. by Guasch et al, v56, 261-267; Butterly et al, v57, 2586-2593 (2000); Guasch A et al "MK-591 rapidly restores glomerular size selectivity and reduces proteinuria in human glomerulonephritis", Kidney Iht.1999; 56: 261-7; Buttery DW et al "role of leukotriene in cyclosporin-induced renal", Kidney Iht.2000; 57: 2586-93); (xix) Preventing or treating acute or chronic renal insufficiency (see, e.g., Maccarrone M et al, "activation of 5-lipoxygenase and associated cell membrane lipid peroxidation in hemodialysis patients", J Am Soc Nephrol.1999; 10: 1991-6); (xx) Type II diabetes (see, e.g., Valdiiviroso et al, v16, 85-94 (2003)), (xxi) reducing the inflammatory aspects of acute infections in one or more solid organs or tissues, such as the kidney with acute pyelonephritis (see, e.g., Tardif M et al, L-651, 39 2, "an effective leukotriene inhibitor, controlling inflammatory processes in E.coli pyelonephritis", Antericrob Agents Chemother.1994, 7 months; 38(7): 1555-60); (xxii) Prevention or treatment of acute or chronic disorders involving recruitment or activation of eosinophils (see, e.g., Quack I et al, "eosinophilic gastroenteritis in young girls-Long-term remission under Monte Carst", BMCGastroterol et al, 2005; 5: 24; xxiii) prevention or treatment of acute or chronic erosive diseases or motor dysfunction of the gastrointestinal tract caused by nonsteroidal anti-inflammatory drugs, including selective or non-selective cyclooxygenase-1 or-2 inhibitors (see, e.g., Marusova IB et al, "CysLT 1 receptor blocker sodium Monte-Loca (monte Lukast) potential gastroprotective effect in aspirin-induced injury of the gastric mucosa in white rats," Eksp in Farmakol, 2002; 65: 16-8, and Gyomber E et al, "Lipase inhibitors and leukotriene antagonists" acute and hemorrhagic gastric mucosal injury in white rats in the pattern of gastric ulcer and gastric mucosal injury in white rats, j. gastroentrol.hepatol, 1996, 11, 922-7), and Martin St et al, "gastric motor dysfunction: is the cause of eosinophilic mural gastritis? ", Eur J gastroenterol. hepatol., 2005, 17: 983-6; (xxiv) Treatment of type II Diabetes (see, e.g., Valdiielso JM et al, "inhibition of 5-lipoxygenase activating protein reduces proteinuria in diabetic rats", J Nephrol.2003 1-2 months; 16 (1): 85-94; Parlapianano C et al, "correlation between release of glycoheme and polymorphonuclear leukotriene B4 in people with Diabetes mellitus," Diabetes Res ClinPract.1999 10 months; 46 (1): 43-5; (xxv) treatment of metabolic syndrome, including, by way of example only, familial Mediterranean fever (see, e.g., Bentancur AG et al, "urinary leukotriene B4" in familial Mediterranean fever, Atin Exp Rheumull.2004 7-8 months; 22(4 supplement 34 "S638; and" renal coper with renal syndrome "and renal syndrome (see, e.g., Calla GL.) treatment of renal syndrome and renal syndrome (see, e.g., prevention of renal syndrome and renal syndrome, renal syndrome B GL., and renal syndrome treatment of renal syndrome, prostagladins Leukotes Fatty acids, 4 months 2003; 68(4): 263-5 ]。
Several inhibitors of FLAP 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; Steinhibler, curr. Med. chem.6 (1): 71-85, 1999; Riendeau, Bioorg Med. Chem. lett., 15 (14): 3352-5, 2005; Flam and et al, mol. Pharmacol.62 (2): 250-6, 2002; Folco et al, am. J. Respir. karst. 2, 2246, 293, 2000; Hakoma et al, (2, 2246, 293, 2000-18).
Identification of leukotriene synthetic pathway inhibitors
Novel FLAP inhibitors, which are effective, either alone or in combination with other drugs, and which cause minimal negative side effects, are developed and tested for their benefit in treating leukotriene-dependent or leukotriene mediated diseases or conditions. Inhibitors of the leukotriene synthesis pathway described herein may be targeted at any step of this pathway to prevent or reduce leukotriene formation. Such leukotriene synthesis inhibitors, for example, can be inhibited at the FLAP or 5-LO levels, thus minimizing the formation of various products in the leukotriene pathway, thus reducing the amount of such compounds available in the cell. Leukotriene synthesis inhibitors can be identified based on their ability to bind to proteins in the leukotriene synthesis pathway. For example, FLAP inhibitors may be identified based on their binding to FLAP.
Compound (I)
Compounds of formula (G), formula (G-I) and formula (G-II):
compounds of formula (G), formula (G-I) and formula (G-II), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs and pharmaceutically acceptable solvates thereof, antagonize or inhibit FLAP and are useful in treating patients suffering from leukotriene-dependent or leukotriene mediated symptoms or diseases, including but not limited to asthma, myocardial infarction, cancer and inflammatory conditions.
The formula (G-I) is as follows:
wherein
Z is selected from N (R)1)、S(O)m、CR1＝CR1、-C≡C-、C(R1)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、NR1C(R1)2[C(R2)2]n、[C(R2)2]nO[C(R1)2]n、[C(R1)2]nO[C(R2)2]n、-C(O)NR2-、-NR2C(O)-、-NR2C(O)O-、-OC(O)NR2-、-S(O)2NR2-、-CR1＝N-N-、NR2C(O)NR2-、-OC(O)O-、S(O)2NR2or-NR2S(O)2-, wherein each R1Is independently H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1Can be joined to form a carbonyl (═ O); and each R2Is independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2Can be joined to form a carbonyl (═ O); m is 0, 1 or 2; each n is independently 0, 12 or 3;
y is-L1- (substituted or unsubstituted aryl); -L1- (substituted or unsubstituted heteroaryl); -L1- (substituted or unsubstituted non-aromatic heterocycle) with the proviso that when the heteroatom is directly bound to Z, the non-aromatic heterocycle is substituted; wherein L is 1Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, -C (O), C (R)8)(OH)、C(R8)(OMe)、C(＝NOH)、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；
Wherein each substituent on Y or Z is (L)SRS)jWherein each LSIs independently selected from a bond, -O-, -C (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)-、C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6Fluoroalkyl, heteroaryl, aryl, or heterocycle; and each RSIs independently selected from H, halogen, -N (R)4)2、-CN、-NO2、N3、-S(＝O)2NH2Lower alkyl, lower cycloalkyl, -C1-C6Fluoroalkyl, heteroaryl, or heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
each R3Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
each R3bIs independently selected from substituted or unsubstituted lower alkyl,Substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl;
each R4Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R4The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R 3bAnd R4May together form a 5-, 6-, 7-or 8-membered heterocyclic ring;
each R4bIs independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; substituted or unsubstituted heteroaryl substituted or unsubstituted heterocycle;
R6is 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 heterocycles), L2- (substituted or unsubstituted heteroaryl) or L2- (substituted or unsubstituted aryl) in which L2A bond, O, S, -S (O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl) or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein
L3is a bond or a substituted or unsubstituted alkyl group;
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 an aryl group;
L4is a bond orSubstituted or unsubstituted alkyl;
G1is 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)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), -L 5- (substituted or unsubstituted heteroaryl) or-L5- (substituted or unsubstituted aryl) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O);
or G1Is W-G5Wherein W is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaryl, and G5Is 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)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;
each R9Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R9The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9May together form a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
R5is H, halogen, -N3、-CN、-ONO2、-L6- (substituted or unsubstituted C)1-C6Alkyl), -L6- (substituted or unsubstituted C)2-C6Alkenyl), -L6- (substituted or unsubstituted heteroaryl) or-L6- (substituted or unsubstituted aryl) in which L6Is a bond, O, S, -S (O), S (O) 2NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) NH-or-C (O) NH;
R11is L7-L10-G6Wherein L is7Is a bond, -O, -S (═ O)2-NH, -C (O) NH, -NHC (O), - (substituted or unsubstituted C1-C6Alkyl) or (substituted or unsubstituted C2-C6Alkenyl); l is10Is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (b), (c) and (d)Substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycle); g6Is H, CN, SCN, N3、NO2Halogen, OR9、-C(＝O)CF3、-C(＝O)R9、-C(＝O)OR9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -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 or unsubstituted aryl) in which L5is-NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O);
or G6Is W-G7Wherein W is (substituted or unsubstituted heterocycle) or (substituted or unsubstituted heteroaryl), and G7Is H, halogen, CN, NO2、N3、CF3、OCF3、C1-C6Alkyl radical, C3-C6Cycloalkyl, -C1-C6Fluoroalkyl, 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)R8or-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 heterocycles) or-L5- (substituted or unsubstituted aryl) in which L5Is 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 L10Is phenyl or thiophenyl, Y is- (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) and Z is [ C (R)2)2]nC(R1)2When O is, then G6Is W-G7(ii) a And is
R12Is H, (substituted or unsubstituted C1-C6Alkyl group), (substituted or unsubstituted C3-C6Cycloalkyl groups).
With respect to any and all embodiments (e.g., formula (G), formula (G-I), and formula (G-II)), the substituents are selected from the list of alternatives. For example, in one embodiment, the non-aromatic heterocycle of Y is selected from the group consisting of quinolizine, dioxine, piperidine, morpholine, thiazine, tetrahydropyridine, hexahydropyrazine, oxazinone, dihydropyrrole, dihydroimidazole, tetrahydrofuran, dihydrooxazole, ethylene oxide, tetrahydropyrrole, tetrahydropyrazole, dihydrothiophenone, tetrahydroimidazolone, tetrahydropyrrolone, dihydrofuranone, dioxolanone, thiazolidine, hexahydropyridone, tetrahydronaphthalene, tetrahydroquinoline, tetrahydrothiophene, and thiazahepta rings.
In a further embodiment, the non-aromatic heterocycle of Y is selected from the group consisting of the following structures:
Figure A20068004120700731
by way of example only, the non-aromatic heterocyclic ring of Y is selected from
Figure A20068004120700732
In further or alternative embodiments, a "G" group (e.g., G)1、G5、G6、G7) Is any group designed to tailor the physical and biological properties of a molecule. Such tailoring/modification is achieved using groups that modulate the acidity, basicity, lipophilicity, solubility, and other physical properties of the molecule. Physical and biological properties modulated by such modification of "G" include, by way of example only, solubility, in vivo absorption, and in vivo metabolism. Furthermore, in vivo metabolic effects, by way of example only, may include control of PK properties in vivo, targeted extrinsic activity, with potential toxicity of cypP450 interactions, drug-drug interactions, and the like. Further, the modification of "G" allows for in vivo efficacy of the customized compounds, for example, by modulating the binding of specific and non-specific proteins to plasma proteins and lipids and in vivo tissue distribution. In addition, such customization/modification of the "G" allows the design of compounds that are selective for 5-lipoxygenase activating proteins over other proteins.
In further or alternative embodiments, "G" is L20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In further or alternative embodiments, the drug includes, by way of example only, leukotrienesReceptor antagonists and anti-inflammatory agents. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, affinity moiety groups allow site-specific binding and include, but are not limited to, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands.
The formula (G-II) is as follows:
Figure A20068004120700741
wherein
Z is selected from N (R)1)、S(O)m、CR1＝CR1、-C≡C-、C(R1)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、NR1C(R1)2[C(R2)2]n、[C(R2)2]nO[C(R1)2]n、[C(R1)2]nO[C(R2)2]n、-C(O)NR2-、-NR2C(O)-、-NR2C(O)O-、-OC(O)NR2-、-S(O)2NR2-、-CR1＝N-N-、NR2C(O)NR2-、-OC(O)O-、S(O)2NR2or-NR2S(O)2-, wherein each R1Is independently H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1Can be joined to form a carbonyl (═ O); and each R2Is independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2Can be joined to form a carbonyl (═ O); m is 0, 1 or 2; each n is independently 0, 1, 2 or 3;
y is-L1- (substituted or unsubstituted aryl); -L1- (substituted or unsubstituted heteroaryl); -L 1- (substituted or unsubstituted non-aromatic heterocycle) with the proviso that when the heteroatom is directly bound to Z, the non-aromatic heterocycle is substituted; wherein L is1Is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, -C (O), C (R)8)(OH)、C(R8)(OMe)、C(＝NOH)、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；
Wherein each substituent on Y or Z is (L)SRS)jWherein each LSIs independently selected from a bond, -O-, -C (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)-、C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6Fluoroalkyl, heteroaryl, aryl, or heterocycle; and each RSIs independently selected from H, halogen, -N (R)4)2、-CN、-NO2、N3、-S(＝O)2NH2Lower alkyl, lower cycloalkyl, -C1-C6Fluoroalkyl, heteroaryl, or heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
each R3Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
each R3bIs independently selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or benzyl;
each R4Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R 4The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R3bAnd R4May together form a 5-, 6-, 7-or 8-membered heterocyclic ring;
each R4bIs independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl;
substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;
R6is 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 heterocycles), L2- (substituted or unsubstituted heteroaryl) or L2- (substituted or unsubstituted aryl) in which L2A bond, O, S, -S (O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl) or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein
L3Is a bond or a substituted or unsubstituted alkyl group;
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 an aryl group;
L4is a bond or a substituted or unsubstituted alkyl group;
G1is 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)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) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O);
or G1Is W-G5Wherein W is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaryl, and G5Is 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)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl;
each R9Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R9The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9May together form a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
R5is H, halogen, -N3、-CN、-ONO2、-L6- (substituted or unsubstituted C)1-C6Alkyl), -L6- (substituted or unsubstituted C)2-C6Alkenyl), -L6- (substituted or unsubstituted heteroaryl) or-L 6- (substituted or unsubstituted aryl) in which L6Is a bond, O, S, -S (O), S (O)2NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) NH-or-C (O) NH;
R11is L7-L10-G6Wherein L is7Is a bond, -O, -S (═ O)2-NH, -C (O) NH, -NHC (O), (substituted or unsubstituted)C1-C6Alkyl) or (substituted or unsubstituted C2-C6Alkenyl);
L10is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycle);
G6is H, CN, SCN, N3、NO2Halogen, OR9、-C(＝O)CF3、-C(＝O)R9、-C(＝O)OR9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -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 or unsubstituted aryl) in which L5is-NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O);
or G6Is W-G7Wherein W is (substituted or unsubstituted heterocycle) or (substituted or unsubstituted heteroaryl), and G 7Is H, halogen, CN, NO2、N3、CF3、OCF3、C1-C6Alkyl radical, C3-C6Cycloalkyl, -C1-C6Fluoroalkyl, 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(＝NR 10)N(R9)2、-C(O)NR9C(＝CR 10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-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 heterocycles) or-L5- (substituted or unsubstituted aryl) in which L5Is 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 L10Is phenyl or thiophenyl, Y is- (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl) and Z is [ C (R)2)2]nC(R1)2When O is, then G6Is W-G7(ii) a And is
R12Is H, (substituted or unsubstituted C1-C6Alkyl group), (substituted or unsubstituted C3-C6Cycloalkyl groups).
With respect to any and all embodiments (e.g., formula (G), formula (G-I), and formula (G-II)), substituents can be selected from a subset of the listed alternatives. For example, in some embodiments, Z is [ C (R)2)2]nC(R1)2And O. In further or alternative embodimentsIn the examples, Y is- (substituted or unsubstituted heteroaryl), - (substituted or unsubstituted aryl), and G 6Is W-G7. In further or alternative embodiments, Y is-L1- (substituted or unsubstituted alkyl), -L1- (substituted or unsubstituted cycloalkyl), -L1- (substituted or unsubstituted heterocycle), -L1- (substituted or unsubstituted heteroaryl), -L1- (substituted or unsubstituted non-aromatic heterocycle) with the proviso that when the heteroatom is directly bound to Z, the non-aromatic heterocycle is substituted; -L1- (substituted or unsubstituted aryl). In further or alternative embodiments, Y is heteroaryl selected from the group consisting of pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl.
In further or alternative embodiments, R 6Is L2- (substituted or unsubstituted alkyl) or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O), -CH (OH) or substituted or unsubstituted alkyl. In further or alternative embodiments, R7Is L3-X-L4-G1(ii) a Wherein L is3Is a bond; and X is a bond, O, -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9. In further or alternative embodiments, G1Is 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、-S(＝O)2R8。
In further or alternative embodiments, the non-aromatic heterocycle of group Y may be selected from the group consisting of quinolizine, dioxine, piperidine, morpholine, thiazine, tetrahydropyridine, hexahydropyrazine, oxazinone, dihydropyrrole, dihydroimidazole, tetrahydrofuran, dihydrooxazole, ethylene oxide, tetrahydropyrrole, tetrahydropyrazole, dihydrothiophenone, tetrahydroimidazolone, tetrahydropyrrolone, dihydrofuranone, dioxolanone, thiazolidine, hexahydropyridone, tetrahydronaphthalene, tetrahydroquinoline, tetrahydrothiophene, and thiazahepta rings. In further or alternative embodiments, the non-aromatic heterocyclic ring of the group Y may be selected from the group consisting of:
Figure A20068004120700791
in further or alternative embodiments, "G" (e.g., G)1、G5、G6、G7) Is L20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In further or alternative embodiments, the drug includes, by way of example only, a leukotriene receptor antagonist and an anti-inflammatory agent. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists And CysLT1 antagonists. In further or alternative embodiments, affinity moiety groups allow site-specific binding and include, but are not limited to, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands.
In further or alternative embodiments, any "G" group of formula (G), formula (G-I), or formula (G-II) (e.g., G)1、G5、G6、G7) Is any group designed to tailor the physical and biological properties of a molecule. Such tailoring/modification is achieved using groups that modulate the acidity, basicity, lipophilicity, solubility, and other physical properties of the molecule. Physical and biological properties modulated by such modification of "G" include, by way of example only, solubility, in vivo absorption, and in vivo metabolism. Furthermore, in vivo metabolic effects, by way of example only, may include control of PK properties in vivo, targeted extrinsic activity, with potential toxicity of cypP450 interactions, drug-drug interactions, and the like. Further, the modification of "G" allows for in vivo efficacy of the customized compounds, for example, by modulating the binding of specific and non-specific proteins to plasma proteins and lipids and in vivo tissue distribution. In addition, such customization/modification of the "G" allows the design of compounds that are selective for 5-lipoxygenase activating proteins over other proteins. In further or alternative embodiments, "G" is L 20-Q, wherein L20Is an enzymatically cleavable linker and Q is a drug or affinity moiety. In further or alternative embodiments, the drug includes, by way of example only, a leukotriene receptor antagonist and an anti-inflammatory agent. In further or alternative embodiments, leukotriene receptor antagonists include, but are not limited to, CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further or alternative embodiments, affinity moiety groups allow site-specific binding and include, but are not limited to, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands.
Any combination of the groups described above with respect to the various variables is intended to be encompassed herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill to provide chemically stable compounds, and that they can be synthesized by techniques known in the art and set forth herein.
Formula (G) is as follows:
Figure A20068004120700801
wherein
Z is selected from [ C (R)1)2]m[C(R2)2]n、[C(R2)2]n[C(R1)2]mO、O[C(R1)2]m[C(R2)2]n、[C(R2)2]nO[C(R1)2]nOr [ C (R)1)2]nO[C(R2)2]nWherein each R1Is independently H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1Can be joined to form a carbonyl (═ O); and each R2Is independently H, OH, OMe, CF 3Or optionally substituted lower alkyl, and two R on the same carbon2Can 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);
wherein each substituent on Y or Z is (L)SRS)jWherein each LSIs independently selected from a bond, -O-, -C (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) -or a substituted or unsubstituted C1-C6Alkyl radical、C2-C6Alkenyl, -C1-C6Fluoroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; and each RSIs independently selected from H, halogen, -N (R)4)2、-CN、-NO2、N3、-S(＝O)2NH2Substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, -C1-C6Fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
R6is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L 2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heterocycles), L2- (substituted or unsubstituted heteroaryl) or L2- (substituted or unsubstituted aryl) in which L2A bond, O, S, -S (O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl) or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein
L3is 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-；
L4Is a bond or a substituted or unsubstituted alkyl group;
G1is 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)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) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O);
or G1Is W-G5Wherein W is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaryl, and G5Is 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)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
Each R9Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; or two R9The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9May together form a 5-, 6-, 7-or 8-membered heterocyclic ring, and each R10Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
R5is H, halogen, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted O-C1-C6An alkyl group;
R11is L7-L10-G6Wherein L is7Is a bond, -C (O) NH, -NHC (O) or (substituted or unsubstituted C)1-C6Alkyl groups); l is10Is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycle);
G6is OR9、-C(＝O)R9、-C(＝O)OR9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -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 or unsubstituted aryl) in which L5is-O-, C (═ O), S, S (═ O), S (═ O) 2-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O)
Or G6Is W-G7Wherein W is (substituted or unsubstituted heterocycle), (substituted or unsubstituted aryl) or (substituted or unsubstituted heteroaryl), and G7Is H, halogen, CN, NO2、N3、CF3、OCF3、C1-C6Alkyl radical, C3-C6Cycloalkyl, -C1-C6Fluoroalkyl, 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)R8or-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 heterocycles) or-L5- (substituted or unsubstituted aryl) in which L5Is 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 R11Comprising at least one (unsubstituted or substituted) aromatic moiety and at least one (unsubstituted or substituted) cyclic moiety, wherein the (unsubstituted or substituted) cyclic moiety is an (unsubstituted or substituted) heterocyclic moiety or an (unsubstituted or substituted) heteroaryl, and R 11Is not thienyl-phenyl;
R12is H, (substituted or unsubstituted C1-C6Alkyl group), (substituted or unsubstituted C3-C6Cycloalkyl groups);
or an active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.
With respect to any and all embodiments (e.g., formula (G), formula (G-I), and formula (G-II)), substituents can be selected from a subset of the listed alternatives. For example, in some embodiments, Z is [ C (R)2)2]nC(R1)2O。
In further or alternative embodiments, Y is- (substituted or unsubstituted heteroaryl) or- (substituted or unsubstituted aryl), and G6Is W-G7。
In further or alternative embodiments, Y is- (substituted or unsubstituted heteroaryl).
In a further or alternative embodiment, Y is selected from the group consisting of pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo [1, 2-a ] pyridyl and furopyridyl, wherein Y is substituted or unsubstituted.
In further or alternative embodiments, Y is selected from the group consisting of pyridyl or quinolyl, wherein Y is substituted or unsubstituted.
In further or alternative embodiments, R6Is L2- (substituted or unsubstituted alkyl) or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O) or substituted or unsubstituted alkyl.
In further or alternative embodiments, X is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9。
In further or alternative embodiments, G1Is 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)R8or-S (═ O)2R8。
In further or alternative embodiments, L3Is unsubstituted alkyl; x is a bond; l is4Is a bond; and G1is-C (O) OR9。
In further or alternative embodiments, R9Is H or unsubstituted alkyl.
In further or alternative embodiments, L10Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and G6Is W-G7Wherein W is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle.
In further or alternative embodiments, L10Is a substituted or unsubstituted aryl group.
In further or alternative embodiments, L3Is unsubstituted alkyl; x is a bond; l is4Is a bond; and G1is-OR9。
In further or alternative embodiments, G1Is W-G5Wherein W is a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl.
Any combination of the groups described above with respect to the various variables is intended to be encompassed herein. It is to be understood that substituents and substitution patterns on the compounds provided herein can be selected by one of ordinary skill to provide chemically stable compounds, and that they can be synthesized by techniques known in the art and set forth herein.
Further embodiments of formula (G), formula (G-I) and formula (G-II) include, but are not limited to, the compounds shown in FIGS. 8-11 and tables 1-4.
TABLE 1N- (aryl-heteroaryl) indolecarboxylic acid metathesis
Figure A20068004120700851
Compound # R1 R2 R4 M+H
1-1 Pyridin-2-ylmethyl Pyridin-2-yl C(O)NH2 579
1-2 Pyridin-2-ylmethyl 2-methoxypyridin-5-yl CO2Et 638
1-3 Pyridin-2-ylmethyl 2-methoxypyridin-5-yl C(O)(CH2)6OH See experiment
1-4 Pyridin-2-ylmethyl Pyridin-2-yl OH 552
1-5 Pyridin-2-ylmethyl Pyridin-3-yl OH 552
1-6 Pyridin-2-ylmethyl Thiazol-2-yl OH 558
1-7 Pyridin-2- ylmethyl 1, 3, 4-oxadiazol-2-yl OH 543
1-8 Pyridin-2-ylmethyl 2-methoxypyridin-5- yl 1, 3, 4-oxadiazol-2-yl 634
1-9 Pyridin-2-ylmethyl 2-methoxypyridin-5- yl 1, 3, 4-oxadiazol-2-ylamines 649
1-10 Pyridin-2-ylmethyl 2-methoxypyridin-5-yl N-pyrazin-2-yl-propionamide 687
1-11 Pyridin-2-ylmethyl 2-methoxypyridin-5-yl N-thiazol-2-yl-propionamide 692
Compound # R1 R2 R4 M+H
1-12 Pyridin-2-ylmethyl 2-methoxypyridin-5-yl N-pyridin-3-yl-propionamide 686
1-13 Pyridin-2-ylmethyl 2-methoxypyridin-5-yl C(O)NH(CH2CH2NMe2) 680
1-14 Pyridin-2- ylmethyl 1, 3, 4-oxadiazol-2-ylamines CH3 556
1-15 Quinolin-2-ylmethyl 5-fluoro-pyridin-2-yl C(O)NHC(＝NH)NH2 689
TABLE 2N- (aryl-heteroaryl) indoles with N- (aryl-heterocyclic) indoles
Figure A20068004120700861
Compound # R1 Position of R2 R3 M+H
2-1 Pyridin-2-ylmethyl 4 2-thiazolyl group 2-methyl-2-propylthio 586
2-2 Pyridin-2-ylmethyl 4 2-pyrimidinyl radicals 2-methyl-2-propylthio 581
2-3 Pyridin-2-ylmethyl 4 3-pyridyl group 2-methyl-2-propylthio 580
2-4 Pyridin-2-ylmethyl 4 4-pyrimidinyl radicals 2-methyl-2-propylthio 581
2-5 Pyridin-2-ylmethyl 4 2-pyrazinyl radical 2-methyl-2-propylthio 581
2-6 Pyridin-2-ylmethyl 4 6-methoxy-3-pyridazinyl 2-methyl-2-propylthio 611
2-7 Pyridin-2-ylmethyl 4 2-amino-4-pyridazinyl 2-methyl-2-propylthio 596
2-8 Pyridin-2-ylmethyl 4 2-thiazolyl group 3, 3-dimethylbutyryl 596
2-9 Pyridin-2-ylmethyl 4 2-thiazolyl group H 498
2-10 Pyridin-2-ylmethyl 4 2-thiazolyl group Acetyl group 501
2-11 Pyridin-2-ylmethyl 4 3-methoxy-6-pyridazinyl H 523
Compound # R1 Position of R2 R3 M+H
2-12 Pyridin-2-ylmethyl 4 3-methoxy-6-pyridazinyl Acetyl group 565
2-13 Pyridin-2-ylmethyl 4 3-methoxy-6-pyridazinyl Ethyl radical 551
2-14 Pyridin-2-ylmethyl 4 2-thiazolyl group 3, 3-dimethylbut-1-yl 582
2-15 Pyridin-2-ylmethyl 4 2-thiazolyl group Cyclopropyl carbonyl group 566
2-16 Pyridin-2-ylmethyl 4 2-thiazolyl group Cyclobutyl carbonyl 580
2-17 Pyridin-2-ylmethyl 4 3-hydroxy-6-pyridazinyl 2-methyl-2-propylthio 597
2-18 Pyridin-2-ylmethyl 4 4-pyridyl group 2-methyl-2-propylthio 580
2-19 Pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 610
2-20 Pyridin-2-ylmethyl 4 2-methyl-4-pyridazinyl 2-methyl-2-propylthio 595
2-21 Pyridin-2-ylmethyl 4 5-methyl-thiazol-2-yl 2-methyl-2-propylthio 600
2-22 Pyridin-2-ylmethyl 4 2-thiazolyl group Cyclobutylmethyl group 566
2-23 2-methylthiazol-4-yl 4 2-methoxy-4-pyridazinyl 2-methyl-2-propylthio 631
2-24 2-methylthiazol-4-yl 4 2-thiazolyl group 2-methyl-2-propylthio 606
2-25 2-methylthiazol-4-yl 4 2-thiazolyl group H 518
2-26 2-methylthiazol-4-yl 4 2-thiazolyl group 3, 3-dimethylbutyryl 616
2-27 2-methylthiazol-4-yl 4 2-methoxy-4-pyridazinyl H 543
2-28 2-methylthiazol-4-yl 4 2-methoxy-4-pyridazinyl 3, 3-dimethylbutyryl 641
Compound # R1 Position of R2 R3 M+H
2-29 Pyridin-2-ylmethyl 4 2-thiazolyl group Ethyl radical 526
2-30 Benzothiazol-2-yl 4 2-thiazolyl group 2-methyl-2-propylthio 667
2-31 2-methylthiazol-4-yl 4 2-pyrimidinyl radicals 2-methyl-2-propylthio 601
2-32 Benzothiazol-2-yl 4 2-pyrimidinyl radicals 2-methyl-2-propylthio 637
2-33 Pyridin-2-ylmethyl 4 1- (pyridin-2-ylmethyl) -2-methyl-imidazol-4-yl 2-methyl-2-propylthio 674
2-34 Pyridin-2-ylmethyl 4 2, 4-Dimethylthiazol-5-yl 2-methyl-2-propylthio 614
2-35 Pyridin-2-ylmethyl 4 5-fluoro-thiazol-2-yl 2-methyl-2-propylthio 604
2-36 Pyridin-2-ylmethyl 4 5-trifluoromethyl-thiazol-2-yl 2-methyl-2-propylthio
2-37 Pyridin-2-ylmethyl 4 2-methyl-thiazol-4-yl 2-methyl-2-propylthio
2-38 Pyridin-2-ylmethyl 4 2-methyl-thiazol-5-yl 2-methyl-2-propylthio
2-39 Pyridin-2-ylmethyl 4 4-methyl-thiazol-2-yl 2-methyl-2-propylthio 600
2-40 Pyridin-2-ylmethyl 4 Isoxazol-4-yl 2-methyl-2-propylthio
2-41 Pyridin-2-ylmethyl 4 3, 5-dimethyl-isoxazol-4-yl 2-methyl-2-propylthio 600
2-42 Pyridin-2-ylmethyl 4 2-methyl-imidazol-4-yl 2-methyl-2-propylthio
2-43 Pyridin-2-ylmethyl 4 1-methyl-imidazol-5-yl 2-methyl-2-propylthio 583
Compound # R1 Position of R2 R3 M+H
2-44 Pyridin-2-ylmethyl 4 1-methyl-imidazol-4-yl 2-methyl-2-propylthio
2-45 Pyridin-2-ylmethyl 4 Imidazol-4-yl 2-methyl-2-propylthio
2-46 Pyridin-2-ylmethyl 4 4-methyl-imidazol-5-yl 2-methyl-2-propylthio
2-47 Pyridin-2-ylmethyl 4 5-methoxypyridin-2-yl 2-methyl-2-propylthio 610
2-48 Pyridin-2-ylmethyl 4 Pyridin-2-yl 2-methyl-2-propylthio
2-49 Pyridin-2-ylmethyl 4 Pyrazol-4-yl 2-methyl-2-propylthio
2-50 Pyridin-2-ylmethyl 4 1-methyl-pyrazol-4-yl 2-methyl-2-propylthio
2-51 Pyridin-2-ylmethyl 4 3-methyl-pyrazol-4-yl 2-methyl-2-propylthio
2-52 Pyridin-2-ylmethyl 4 5-methyl-1, 2, 4-oxadiazol-3-yl 2-methyl-2-propylthio
2-53 Pyridin-2-ylmethyl 4 2-methyl-1, 3, 4-oxadiazol-5-yl 2-methyl-2-propylthio
2-54 Pyridin-2-ylmethyl 4 1, 3, 4-oxadiazol-2-yl 2-methyl-2-propylthio
2-55 Pyridin-2-ylmethyl 4 1, 3, 4-Monooxadiazol-2-yl 2-methyl-2-propylthio 587
2-56 Pyridin-2-ylmethyl 4 3-methyl-pyrazol-5-yl 2-methyl-2-propylthio
2-57 Pyridin-2-ylmethyl 4 1, 2, 3-Monooxadiazol-4-yl 2-methyl-2-propylthio
Compound # R1 Position of R2 R3 M+H
2-58 Pyridin-2-ylmethyl 4 1-tetrazolyl 2-methyl-2-propylthio
2-59 Pyridin-2-ylmethyl 4 2-tetrazolyl radical 2-methyl-2-propylthio
2-60 Pyridin-2-ylmethyl 4 1-methyl-tetrazol-5-yl 2-methyl-2-propylthio
2-61 Pyridin-2-ylmethyl 4 2-methyl-tetrazol-5-yl 2-methyl-2-propylthio
2-62 Pyridin-2-ylmethyl 4 2-pyridon-5-yl 2-methyl-2-propylthio 596
2-63 Pyridin-2-ylmethyl 4 Pyridin-3-yl 2-methyl-2-propylthio
2-64 Pyridin-2-ylmethyl 4 2-cyanopyridin-5-yl 2-methyl-2-propylthio 606
2-65 Pyridin-2-ylmethyl 4 2-trifluoromethylpyridin-5-yl 2-methyl-2-propylthio 648
2-66 Pyridin-2-ylmethyl 4 2-acetamidopyridin-5-yl 2-methyl-2-propylthio
2-67 Pyridin-2-ylmethyl 4 2-methoxypyrimidin-5-yl 2-methyl-2-propylthio 611
2-68 Pyridin-2-ylmethyl 4 2-Methoxythiazol-4-yl 2-methyl-2-propylthio 616
2-69 3-fluoro-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-70 3-fluoro-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-71 4-fluoro-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-72 5-fluoro-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
Compound # R1 Position of R2 R3 M+H
2-73 5-methyl-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 625
2-74 5-cyano-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-75 5-methoxy-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-76 5-Ethyl-pyridin-2-ylmethyl 4 4-methoxypyridin-2-yl 2-methyl-2-propylthio 638
2-77 Quinolin-2-ylmethyl 4 4-methoxypyridin-2-yl 2-methyl-2-propylthio 660
2-78 6-Fluoroquinolin-2-ylmethyl 4 4-methoxypyridin-2-yl 2-methyl-2-propylthio 678
2-79 Quinolin-2-ylmethyl 3 5-Fluoropyridin-2-yl 2-methyl-2-propylthio
2-80 Quinolin-2-ylmethyl 3 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-81 Quinolin-2-ylmethyl 3 5-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio
2-82 5-methyl-pyridin-2-ylmethyl 4 3-Fluoropyridin-2-yl 2-methyl-2-propylthio 612
2-83 Quinolin-2-ylmethyl 3 2-trifluoromethylpyridin-5-yl 2-methyl-2-propylthio
2-84 5-Ethyl-pyridin-2-ylmethyl 4 3-Fluoropyridin-2-yl 2-methyl-2-propylthio 627
2-85 Quinolin-2-ylmethyl 4 3-Fluoropyridin-2-yl 2-methyl-2-propylthio 648
Compound # R1 Position of R2 R3 M+H
2-86 Quinolin-2-ylmethyl 3 2-ethoxypyridin-5-yl 2-methyl-2-propylthio
2-87 Pyridin-2-ylmethyl 4 5-carboxamido-pyridin-2-yl 2-methyl-2-propylthio 623
2-88 Pyridin-2-ylmethyl 4 5-cyanopyridin-2-yl 2-methyl-2-propylthio 605
2-89 Pyridin-2-ylmethyl 4 5-Methoxythiazol-2-yl 2-methyl-2-propylthio 616
2-90 Pyridin-2-ylmethyl 4 2-methyl-pyridin-5-yl 2-methyl-2-propylthio 594
2-91 Pyridin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 670
2-92 Pyridin-2-ylmethyl 4 2-ethoxythiazol-4-yl 2-methyl-2-propylthio 631
2-93 Pyridin-2-ylmethyl 4 4-methyl-imidazol-2-yl 2-methyl-2-propylthio 583
2-94 Pyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 624
2-95 Pyridin-2-ylmethyl 4 6-methoxypyridin-2-yl 2-methyl-2-propylthio 610
2-96 Pyridin-2-ylmethyl 4 5-methoxypyridin-3-yl 2-methyl-2-propylthio 610
2-97 Pyridin-2-ylmethyl 4 2-carboxamido-pyridines-5-yl 2-methyl-2-propylthio 624
2-98 Pyridin-2-ylmethyl 4 5-methyl-pyridin-2-yl 2-methyl-2-propylthio 594
Compound # R1 Position of R2 R3 M+H
2-99 6-fluoro-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 628
2-100 6-methoxy-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 640
2-101 6-methyl-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 624
2-102 5-methyl-pyridin-2-ylmethyl 4 2-trifluoromethyl-pyridin-5-yl 2-methyl-2-propylthio 662
2-103 5-methyl-pyridin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 662
2-104 6-cyclopropyl-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 650
2-105 5-methyl-pyridin-2-ylmethyl 4 5-methyl-pyridin-2-yl 2-methyl-2-propylthio 608
2-106 5-methyl-pyridin-2-ylmethyl 4 6-methoxy-pyridazin-3-yl 2-methyl-2-propylthio 625
2-107 5-methyl-pyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 639
2-108 5-chloro-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 644
2-109 S-1- (pyridin-2-yl) -1-ethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 684(M+Na)
2-110 R-1- (pyridin-2-yl) -1-ethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 663
2-111 S-1- (pyridin-2-yl) -1-ethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 624
Compound # R1 Position of R2 R3 M+H
2-112 R-1- (pyridin-2-yl) -1-ethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 624
2-113 S-1- (pyridin-2-yl) -1-ethyl 4 6-methoxypyridin-2-yl 2-methyl-2-propylthio 625
2-114 R-1- (pyridin-2-yl) -1-ethyl 4 6-methoxypyridin-2-yl 2-methyl-2-propylthio 624
2-115 S-1- (pyridin-2-yl) -1-ethyl 4 2-ethoxythiazol-4-yl 2-methyl-2-propylthio 644
2-116 R-1- (pyridin-2-yl) -1-ethyl 4 2-ethoxythiazol-4-yl 2-methyl-2-propylthio 644
2-117 3-methyl-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 624
2-118 3-methyl-pyridin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 662
2-119 3, 5-Dimethylpyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 638
2-120 3, 5-Dimethylpyridin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propanoneRadical of sulfur 676
2-121 Benzothiazol-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 666
2-122 Benzothiazol-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 666
2-123 Benzothiazol-2-ylmethyl 4 2-methoxypyridin-5-yl Cyclobutyl carbonyl 660
2-124 Benzothiazol-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl Cyclobutylmethyl group 646
Compound # R1 Position of R2 R3 M+H
2-125 5-Ethylpyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 638
2-126 5-Ethylpyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 652
2-127 5-Ethylpyridin-2-ylmethyl 4 2-trifluoromethyl-pyridin-5-yl 2-methyl-2-propylthio 676
2-128 5-Ethylpyridin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 677
2-129 5-methylpyridin-2-ylmethyl 4 2-ethoxythiazol-4-yl 2-methyl-2-propylthio 644
2-130 5-methylpyridin-2-ylmethyl 4 2-Methoxythiazol-4-yl 2-methyl-2-propylthio 630
2-131 5-methylpyridin-2-ylmethyl 4 6-methoxypyridin-2-yl 2-methyl-2-propylthio 624
2-132 Pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl Cyclobutylmethyl group 590
2-133 5-methylpyridin-2-ylmethyl 4 2-methoxypyridin-5-yl Cyclobutylmethyl group 604
2-134 5-methylpyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-propan-1-yl 592
2-135 Quinolin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 660
2-136 Quinolin-2-ylmethyl 4 2-trifluoromethyl-pyridin-5-yl 2-methyl-2-propylthio 936
2-137 Quinolin-2-ylMethyl radical 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 698
Compound # R1 Position of R2 R3 M+H
2-138 Quinolin-2-ylmethyl 4 6-methoxy-pyridazin-3-yl 2-methyl-2-propylthio 661
2-139 Quinolin-2-ylmethyl 4 2-BOxopyridin-5-yl 2-methyl-2-propylthio 674
2-140 6-Fluoroquinolin-2-ylmethyl 4 6-methoxypyridin-2-yl 2-methyl-2-propylthio 678
2-141 6-Fluoroquinolin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 678
2-142 6-Fluoroquinolin-2-ylmethyl 4 2-ethoxythiazol-4-yl 2-methyl-2-propylthio 698
2-143 6-Fluoroquinolin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 716
2-144 7-FluoroquineLin-2-ylmethyl 4 2-trifluoromethyl-pyridin-5-yl 2-methyl-2-propylthio 716
2-145 7-Fluoroquinolin-2-ylmethyl 4 5-trifluoromethyl-pyridin-2-yl 2-methyl-2-propylthio 716
2-146 7-Fluoroquinolin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 678
2-147 7-Fluoroquinolin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 692
2-148 6-Fluoroquinolin-2-ylmethyl 4 3-Fluoropyridin-2-yl 2-methyl-2-propylthio 666
2-149 5-methyl-pyridin-2-ylmethyl 4 3-trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 662
2-150 5-Ethyl-pyridin-2-ylmethyl 4 3-trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 676
Compound # R1 Position of R2 R3 M+H
2-151 Quinolin-2-ylmethyl 4 3-trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 698
2-152 Quinolin-2-ylmethyl 3 5-Methoxythiazol-2-yl 2-methyl-2-propylthio
2-153 Quinolin-2-ylmethyl 3 3-methoxy-6-pyridazinyl 2-methyl-2-propylthio
2-154 Quinolin-2-ylmethyl 3 5-fluoro-thiazol-2-yl 2-methyl-2-propylthio
2-155 Quinolin-2-ylmethyl 3 Pyridin-2-yl 2-methyl-2-propylthio
2-156 6-Fluoroquinolin-2-ylmethyl 4 3-trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 716
2-157 3-methylpyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 638
2-158 3-methylpyridin-2-ylmethyl 4 2-trifluoromethylpyridin-5-yl 2-methyl-2-propylthio 662
2-159 3, 5-Dimethylpyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 652
2-160 4-methylpyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 624
2-161 4-methylpyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 638
2-162 4-methylpyridin-2-ylmethyl 4 2-trifluoromethylpyridin-5-yl 2-methyl-2-propylthio 662
2-163 5-methylpyridin-2-ylmethyl 4 5-Trifluoromethylpyridin-2-yl Cyclobutylmethyl group 642
2-164 6-Fluoroquinolin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 692
Compound # R1 Position of R2 R3 M+H
2-165 6-Fluoroquinolin-2-ylmethyl 4 2-trifluoromethylpyridin-5-yl 2-methyl-2-propylthio 716
2-166 6-Methylquinolin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 674
2-167 6-Methylquinolin-2-ylmethyl 4 5-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 712
2-168 Quinolin-2-ylmethyl 4 3-methylpyridazin-6-yl 2-methyl-2-propylthio 645
2-169 Quinolin-2-ylmethyl 4 3-ethoxypyridazin-6-yl radicals 2-methyl-2-propylthio 675
2-170 Quinolin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-1-propyl 628
2-171 6-Fluoroquinolin-2-ylmethyl 4 3-methoxypyridazin-6-yl 2-methyl-2-propylthio 679
2-172 Pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio-S, S-dioxide 642
2-173 Pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylsulfanyl S-oxide 626
2-174 N-oxido-pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 626
2-175 Imidazo [1, 2-a ]]Pyridin-2-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 649
2-176 Imidazo [1, 2-a ]]Pyridin-2-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 663
2-177 Imidazo [1, 2-a ]]Pyridin-2-ylmethyl 4 5-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 687
Compound # R1 Position of R2 R3 M+H
2-178 R-1- (pyridin-2-yl) -1-ethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 638
2-179 6-Fluoroquinolin-2-ylmethyl 4 3-methylpyridazin-6-yl 2-methyl-2-propylthio 663
2-180 5-methylisoxazol-3-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 614
2-181 5-methylisoxazol-3-ylmethyl 4 2-ethoxypyridin-5-yl 2-methyl-2-propylthio 628
2-182 5-methylisoxazol-3-ylmethyl 4 5-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 652
2-183 1, 3-dimethylpyrazol-5-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 627
2-184 1, 5-dimethylpyrazol-3-ylmethyl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio 627
2-185 6-Fluoroquinolin-2-ylmethyl 4 3-ethoxypyridazin-6-yl radicals 2-methyl-2-propylthio 693
2-186 5-Ethylpyridin-2-ylmethyl 4 3-ethoxypyridazin-6-yl radicals 2-methyl-2-propylthio 653
2-187 5-Ethylpyridin-2-ylmethyl 4 3-methoxypyridazin-6-yl 2-methyl-2-propylthio 639
2-188 6-Fluoroquinolin-2-ylmethyl 4 5-Fluoropyridin-2-yl 2-methyl-2-propylthio 666
2-189 R-1- (pyridin-2-yl) -1-ethyl 4 5-Fluoropyridin-2-yl 2-methyl-2-propylthio 612
2-190 6-Fluoroquinolin-2-ylmethyl 4 2-ethoxypyridin-6-yl 2-methyl-2-propylthio 692
Compound # R1 Position of R2 R3 M+H
2-191 R-1- (pyridin-2-yl) -1-ethyl 4 2-ethoxypyridin-6-yl 2-methyl-2-propylthio 638
2-192 5-methylpyridin-2-ylmethyl 4 5-Fluoropyridin-2-yl 2-methyl-2-propylthio 612
2-193 5-methylpyridin-2-ylmethyl 4 2-ethoxypyridin-6-yl 2-methyl-2-propylthio 638
2-194 6-Fluoroquinolin-2-ylmethyl 4 2-trifluoromethylpyridin-5-yl 2-methylpropan-1-yl 684
2-195 Pyridin-2-ylmethyl 3 5-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 648
2-196 Pyridin-2-ylmethyl 3 2-methoxypyridin-5-yl 2-methyl-2-propylthio 610
2-197 Quinolin-2-ylmethyl 4 5-Fluoropyridin-2-yl 2-methyl-2-propylthio 648
2-198 Quinolin-2-ylmethyl 4 2-ethoxypyridin-6-yl 2-methyl-2-propylthio 674
2-199 Pyridin-2-ylmethyl 4 2-ethoxypyridin-6-yl 2-methyl-2-propylthio 624
2-200 6-Fluoroquinolin-2-ylmethyl 4 2-trifluoromethylpyridin-6-yl 2-methyl-2-propylthio 716
2-201 Pyridin-2-ylmethyl 4 5-Fluoropyridin-2-yl 2-methyl-2-propylthio 598
2-202 5-methylpyridin-2-ylmethyl 4 2-trifluoromethylpyridin-6-yl 2-methyl-2-propylthio 662
2-203 Quinolin-2-ylmethyl 4 2-trifluoromethylpyridin-6-yl 2-methyl-2-propylthio 698
Compound # R1 Position of R2 R3 M+H
2-204 Pyridin-2-ylmethyl 4 2-trifluoromethylpyridin-6-yl 2-methyl-2-propylthio 648
2-205 Quinolin-2-ylmethyl 4 2-thiazolyl group 2-methyl-2-propylthio 636
2-206 Pyridin-2-ylmethyl 3 4-Methoxytetrahydropyran-4-yl 2-methyl-2-propylthio 617
2-207 6-Fluoroquinolin-2-ylmethyl 4 Pyridin-2-yl 2-methyl-2-propylthio 648
2-208 5-Ethylpyridin-2-ylmethyl 4 Pyridin-3-yl 2-methyl-2-propylthio 608
2-209 Quinolin-2-ylmethyl 4 Pyridin-3-yl 2-methyl-2-propylthio 630
2-210 6-Fluoroquinolin-2-ylmethyl 4 Pyridin-3-yl 2-methyl-2-propylthio 648
2-211 5-methylpyridin-2-ylmethyl 4 Pyridin-2-yl 2-methyl-2-propylthio 594
2-212 5-Ethylpyridin-2-ylmethyl 4 Pyridin-2-yl 2-methyl-2-propylthio 608
2-213 Quinolin-2-ylmethyl 4 Pyridin-2-yl 2-methyl-2-propylthio 630
2-214 5-methylpyridin-2-ylmethyl 4 Pyridin-3-yl 2-methyl-2-propylthio 594
2-215 5-methylpyridin-2-ylmethyl 4 4-methoxypyridin-2-yl 2-methyl-2-propylthio 624
2-216 Quinolin-2-ylmethyl 4 3-methoxypyridin-2-yl 2-methyl-2-propylthio 660
2-217 5-methylpyridin-2-ylmethyl 4 3-methoxypyridin-2-yl 2-methyl-2-propylthio 624
2-218 5-Ethylpyridin-2-ylmethyl 4 3-methoxypyridin-2-yl 2-methyl-2-propylthio 638
Compound # R1 Position of R2 R3 M+H
2-219 5-methylpyridin-2-ylmethyl 4 4-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 663
2-220 5-Ethylpyridin-2-ylmethyl 4 4-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 677
2-221 Quinolin-2-ylmethyl 4 4-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio 698
2-222 5-methylpyridin-2-ylmethyl 4 5-Fluoropyridin-3-yl 2-methyl-2-propylthio 613
2-223 5-Ethylpyridin-2-ylmethyl 4 5-Fluoropyridin-3-yl 2-methyl-2-propylthio 626
2-224 Quinolin-2-ylmethyl 4 5-Fluoropyridin-3-yl 2-methyl-2-propylthio 649
2-225 2, 3-dimethylpyridin-6-yl 4 2-methoxypyridin-5-yl 2-methyl-2-propylthio
2-226 2, 3-dimethylpyridin-6-yl 4 3-trifluoromethylpyridin-2-yl 2-methyl-2-propylthio
2-227 2, 3-dimethylpyridin-6-yl 4 4-Trifluoromethylpyridin-2-yl 2-methyl-2-propylthio
2-228 2, 3-dimethylpyridin-6-yl 4 3-fluoroPyridinyl-2-yl radical 2-methyl-2-propylthio
2-229 2, 3-dimethylpyridin-6-yl 4 5-Fluoropyridin-3-yl 2-methyl-2-propylthio
2-230 2, 3-dimethylpyridin-6-yl 4 4-methoxypyridin-2-yl 2-methyl-2-propylthio
2-231 2, 3-dimethylpyridin-6-yl 4 Pyridin-3-yl 2-methyl-2-propylthio
Compound # R1 Position of R2 R3 M+H
2-232 5-methylpyridin-2-ylmethyl 4 2-methoxypyridin-3-yl 2-methyl-2-propylthio
2-233 5-Ethylpyridin-2-ylmethyl 4 2-methoxypyridin-3-yl 2-methyl-2-propylthio
2-234 Quinolin-2-ylmethyl 4 2-methoxypyridin-3-yl 2-methyl-2-propylthio
TABLE 3N- (heteroaryl-aryl) and N- (heteroaryl-heteroaryl) indoles
Compound # R2 M+H
3-1 2- (2-methoxypyridin-5-yl) -pyridin-5-yl 611
3-2 2- (4-methoxyphenyl) -pyridin-5-yl 610
3-3 2- (4-trifluoromethoxyphenyl) -pyridin-5-yl 664
3-4 5- (4-methoxyphenyl) -pyridin-2-yl 610
3-5 5- (4-trifluoromethoxyphenyl) -pyridin-2-yl 664
TABLE 4N- (aryl-heteroaryl) indoles with non-aryl C5 substituents
Figure A20068004120701041
Compound # R1 R2 R4 M+H
4-1 OH 2-methoxypyridin-5-yl H 519
4-2 Isopropyl group 2-methoxypyridin-5-yl H 545
Synthesis of Compounds
Compounds of formula (G), formula (G-I) and formula (G-II) described in the preceding paragraphs can be synthesized using standard synthetic techniques known to the skilled artisan, or using methods known in the art and using the methods described herein. In addition, the solvents, temperatures, and other reaction conditions set forth herein may vary according to the skilled artisan.
The starting materials described in the preceding paragraphs for the synthesis of compounds of formula (G), formula (G-I) and formula (G-II) may be synthesized or may be obtained from commercial sources such as, but not limited to, Aldrich chemical company (Milwaukee, Wis.) or Sigma chemical company (St.Louis, Mo.). The compounds described herein, and other related compounds having various substituents, can be synthesized using techniques and materials known to the skilled artisan, such as those described in March, advanced organic chemistry, 4 th edition (Wiley 1992); carey and Sundberg, advanced organic chemistry, 4 th edition, volumes A and B (Plenum 2000, 2001), and Green and Wuts, organic synthetic protecting groups, 3 rd edition, (Wiley 1999) (all of which are incorporated herein by reference in their entirety). With respect to the general methods of preparing compounds as disclosed herein, one may derive from reactions known in the art, and the reactions may be modified using appropriate reagents and conditions as will be apparent to the skilled artisan, to introduce various moieties as found in the formulae provided herein. The following synthetic methods may be used as guidance.
By reaction of electrophiles with nucleophiles to form covalent linkages
The compounds described herein can be modified using various electrophiles or nucleophiles to form novel functional groups or substituents. Table 6, entitled "examples of covalent linkages and precursors thereof," is a selection of examples listing covalent linkages and precursor functional groups that would result and can be used as a guide for variations that can employ combinations of electrophiles and nucleophiles. The precursor functional groups are shown as electrophilic groups and nucleophilic groups.
Table 5: examples of covalent linking and precursors thereof
Covalently linked product Electrophiles Nucleophilic agents
Carboxylic acid amides Activated esters Amines/anilines
Carboxylic acid amides Acyl azides Amines/anilines
Carboxylic acid amides Acyl halides Amines/anilines
Esters as pesticides Acyl halides Alcohols/phenols
Esters as pesticides Acylacetonitriles Alcohols/phenols
Carboxylic acid amides Acylacetonitriles Amines/anilines
Imines Aldehydes Amines/anilines
Hydrazone compounds Aldehydes or ketones Hydrazines
Oximes Aldehydes or ketones Hydroxy amines
Alkyl amines Alkyl halides Amines/anilines
Esters as pesticides Alkyl halides Carboxylic acids
Thioethers Alkyl halides Thiols
Ethers Alkyl halides Alcohols/phenols
Thioether Alkyl sulfonic acid esters Thiols
Esters as pesticides Alkyl sulfonic acid esters Carboxylic acids
Ethers Alkyl sulfonic acid esters Alcohols/phenols
Esters as pesticides Anhydrides Alcohols/phenols
Carboxylic acid amides Anhydrides Amines/anilines
Thiophenols Aryl halides Thiols
Aryl amines Aryl halides Amines as herbicides
Thioether Azindines Thiols
Dihydroxy borane esters Dihydroxy borane compounds Glycols
Carboxylic acid amides Carboxylic acids Amines/anilines
Esters as pesticides Carboxylic acids Alcohols
Hydrazines Hydrazides Carboxylic acids
N-acylureas or anhydrides Carbodiimides Carboxylic acids
Esters as pesticides Diazoalkanes Carboxylic acids
Thioether Epoxide compound Thiols
Thioether Halogen-based acetamides Thiols
Aminotriazines Halogen-based triazines Amines/anilines
Triazinyl ethers Halogen-based triazines Alcohols/phenols
Amidines Imide esters Amines/anilines
Urine products Isocyanates Amines/anilines
Carbamates Isocyanates Alcohols/phenols
Sulfur urine Isothiocyanates Amines/anilines
Thioether Maleic imideAmines as herbicides Thiols
Phosphorous acid esters Phosphorylamine acid esters Alcohols
Silyl ethers Silyl halides Alcohols
Alkyl amines Sulfonic acid esters Amines/anilines
Thioether Sulfonic acid esters Thiols
Esters as pesticides Sulfonic acid esters Carboxylic acids
Ethers Sulfonic acid esters Alcohols
Sulfonamides Sulfonyl halides Amines/anilines
Sulfonic acid esters Sulfonyl halides Phenols/alcohols
Use of protecting groups
In the reaction described, it may be necessary to protect reactive functional groups, such as hydroxyl, amine, imine, thio or carboxyl groups, where these are required in the final product, to avoid their undesired participation in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. Each protecting group is preferably removable by different means. Protecting groups that cleave under completely different reaction conditions are required for differential removal. The protecting group can be removed by acid, base and hydrogenolysis. Some groups, such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl, are acid labile and can be used to protect carboxyl and hydroxyl reactive moieties in the presence of an amine group protected with a Cbz group (which can be removed by hydrogenolysis) and an Fmoc group (which is base labile). The carboxylic acid and hydroxyl reactive moieties can be blocked with base labile groups such as, but not limited to, methyl, ethyl and acetyl groups in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates, which are both acid and base stable but can be removed hydrolytically.
The carboxylic acid and hydroxyl reactive moieties may also be blocked by a hydrolytically removable protecting group, such as benzyl, while the amine groups capable of hydrogen bonding to acids may be blocked by a base labile group, such as Fmoc. The carboxylic acid reactive moiety may be protected by conversion to a simple ester compound, as exemplified herein, or it may be blocked by an oxidatively removable protecting group, such as 2, 4-dimethoxybenzyl, while the co-existing amine groups may be blocked by fluoride-labile silyl carbamates.
Allyl blocking groups can be used in the presence of acid-and base-protecting groups, are therefore stable, and can then be removed by metal or pi-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected by a Pd 0-catalyzed reaction in the presence of an acid-labile tert-butyl carbamate or a base-labile amine acetate protecting group. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional groups are available for reaction.
Typically, the blocking/protecting group may be selected from:
Figure A20068004120701081
other protecting groups, plus detailed descriptions of techniques applicable to the generation and removal of protecting groups, are described in Greene and Wuts, organic synthetic protecting groups, 3 rd edition, John Wiley & Sons, New York, NY, 1999, and Kocienski, protecting groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference in their entirety.
Indole-containing compounds can be prepared using standard literature procedures, such as those described in kattritzky, "handbook of heterocyclic chemistry" Pergamon press, Oxford, 1986; pindur et al, J.HeterocyclicChem., Vol.25, 1, 1987, and Robinson "Fisher indole Synthesis", found in John Wiley & Sons, Chichester, New York, 1982, each of which is incorporated herein by reference in its entirety.
A non-limiting example of a synthetic route for indole compounds of formula (G), formula (G-I) and formula (G-II) is shown in accordance with reaction scheme I shown in FIG. 1, wherein a 4-substituted aniline (I-1) can be converted to its corresponding hydrazine (I-2) using standard procedures. Reaction of hydrazine (I-2) with an appropriately substituted ketone (I-3) under standard Fisher-indoxylation conditions produces indole (I-4). Indole (I-6) is due to the reaction of (I-4) with benzyl halide (I-5) (or tosylate (OTs) orMethane Sulfonates (OMs)), by N-alkylation 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 (i.e. Z is MeO), the methyl group can be removed under standard conditions, for example using BBr 3In solvents, e.g. CH2Cl2To obtain phenol (I-7). The phenol may be alkylated with an electrophile (YX) to provide the alkylated product (I-8). Alternatively, in the case where the 5-substituent on the indole ring is, for example, a halide or trifluoromethanesulfonate (OTf; I-7), it can be coupled with a wide variety of reagents using coupling reactions mediated by standard metals well known to those familiar with organic synthesis techniques to give alternative compounds of structure (I-6). This chemistry is described in general organometallic chemistry II, volume 12, Pergamon, eds by Abel, Stone and Wilkinson. The Z substituent of indole (I-6) can be further modified using standard chemical procedures. In addition, when R is7Or R6In the case of bromine or iodine, standard cross-coupling reactions allow the introduction of a variety of functional groups using procedures well known in the art of organic synthesis. Then, when R is7For H, under certain conditions, a strong base such as nBuLi can be used to lithiate in a regioselective manner, and then this anion can be condensed with an electrophile to introduce a substitution on the C-2 basis (see Hasan et al, J. org. chem., 46, 157-164, 1981).
Another non-limiting example of a synthetic route for compounds of formula (G), formula (G-I) and formula (G-II) is shown according to reaction scheme II in FIG. 2. Starting with hydrazine I-2, N-alkylation with benzyl halide (or tosylate or mesylate; I-5) using the conditions described above, provides the hydrazine derivative (II-1). Reaction with an appropriately substituted ketone (I-3) using standard Fisher's indolisation conditions affords indole (I-6).
Another non-limiting example of a synthetic route for compounds of formula (G), formula (G-I) and formula (G-II) is shown in FIG. 2 according to reaction scheme III, where 3-H-indole (III-1) can be made directly using the procedure described above, or alternatively, it can be made by dissolving it in a solventSuch as CH2Cl2Medium humidity AlCl3Treatment, prepared from 3-thioindole. Functionalization at the 3-position can be achieved using a variety of reactions and procedures to allow the introduction of a wide range of substituents. By way of example only, in Lewis acids such as AlCl3Acylation with chlorinated acyl (or anhydride) in the Presence of an acid group allows introduction of an acyl group (I-6; R)6C (o) R'), see Murakami et al, heterocyles, v14, 1939-. Starting with (III-1), and by way of example only, using a sulfenic acid chloride in a suitable solvent, compounds of general structure (III-2) can be prepared, wherein R is6Is SR "(Raban, j. org. chem., v45, 1688, 1980). Similar chemistry using indole (III-3) can be performed or, alternatively, a diaryl disulfide can be used in DMF in the presence of a base such as NaH to yield (III-4) (Atkinson et al, Synthesis, 480-481, 1988). Electron deficient olefins with 3-H indoles (III-1) or (III-3) in Lewis acids (e.g. Yb (OTf) 3.3H2O) allowing the installation of a 3-alkyl substituent of the general structure (III-2) or (III-4) (wherein R is6Is a substituted alkyl group; see Harrington and Kerr, Synlett, 1047-. Alternatively, indole (III-3) may be reacted with benzyl derivative (I-5) in warm DMF to give (III-4), wherein R6Is a substituted benzyl group (Jacobs et al, J.Med.chem., v36, 394-409, 1993).
Further synthesis of indole and indole type compounds
Other non-limiting examples of synthetic strategies for the indole or indole-like skeleton of compounds of formula (G), formula (G-I) and formula (G-II) include modifications to the various syntheses of the indole, including but not limited to; Batco-Leimgruber indole synthesis, Reissert indole synthesis, Hegedus indole synthesis, Fukuyama indole synthesis, Sugasawa indole synthesis, Bischler indole synthesis, Gassman indole synthesis, Fischer indole synthesis, Japp-Klingemann indole synthesis, Buchwald indole synthesis, Larock indole synthesis, Bartoli indole synthesis, Castro indole synthesis, Hemetsberger indole synthesis, Mori-Ban indole synthesis, Madelung indole synthesis, Nenitzescu indole synthesis, and other reactions not named. Non-limiting examples of such synthetic methods are shown in FIGS. 3-7.
Other forms of the Compounds
Compounds of formula (G), formula (G-I) and formula (G-II) may be prepared as pharmaceutically acceptable acid addition salts, which is one type of pharmaceutically acceptable salt, by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic 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, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, lauryl sulfuric acid, gluconic acid, glutamic acid, naphthoic acid, salicylic acid, stearic acid, and muconic acid.
Alternatively, the compounds of formula (G), formula (G-I) and formula (G-II) may be prepared as pharmaceutically acceptable base addition salts, which are one type of pharmaceutically acceptable salt, by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, butanetriethanolamine, N-methylglucamine, and the like, and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
The compounds of formula (G), formula (G-I) and formula (G-II) may be formulated as pharmaceutically acceptable salts, which are formed when an acidic proton is present in the parent compound, whether replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion or an aluminium ion; or coordinated with an organic base. In addition, salt forms of the disclosed compounds can be made using salts of starting materials or intermediates.
It will be understood that reference to a pharmaceutically acceptable salt includes the solvent addition or crystalline forms thereof, particularly solvates or polymorphs. Solvates contain an amount of solvent, whether stoichiometric or non-stoichiometric, and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds of formula (G), formula (G-I) and formula (G-II) may conveniently be made or formed during the processes described herein. By way of example only, hydrates of the compounds of formula (G), formula (G-I) and formula (G-II) may conveniently be prepared by recrystallisation from an aqueous/organic solvent mixture using an organic solvent including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.
The compounds of formula (G), formula (G-I) and formula (G-II) may be in various forms including, but not limited to, amorphous forms, milled forms and nano-particulate forms. Furthermore, the compounds of formula (G), formula (G-I) and formula (G-II) include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability and solubility. Factors such as recrystallization solvent, rate of crystallization and storage temperature can cause the single crystal form to dominate.
The compounds of formula (G), formula (G-I) and formula (G-II) in their unoxidized form may be prepared from N-oxides of compounds of formula (G), formula (G-I) and/or formula (G-II) by treatment with a reducing agent such as, but not limited to, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromides and the like, in a suitable inert organic solvent such as, but not limited to, ethyl-ponan, ethanol, aqueous dioxane and the like, at from 0 ℃ to 80 ℃.
The compounds of formula (G), formula (G-I) and formula (G-II) may be formulated as prodrugs. Prodrugs are generally prodrugs that, upon administration to a patient and subsequent absorption, are converted to the active or more active species via a process such as conversion by metabolic pathways. Some prodrugs have chemical groups present on the prodrug that render the drug less active and/or impart solubility or some other property to the drug. Once the chemical group has been cleaved from the prodrug and/or modified, the active drug is produced. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. It may be bioavailable, for example, by oral administration, whereas the parent is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
Prodrugs can be designed as reversible drug derivatives for use as modifiers to enhance drug delivery to site-specific tissues. To date, the design of prodrugs has increased the effective aqueous solubility of therapeutic compounds to target regions where water is the predominant solvent. See, e.g., 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-; larsen and h.bundgaard, int.j.pharmaceuticals, 37, 87 (1987); larsen et al, iht. j. pharmaceuticals, 47, 103 (1988); sinkula et al, j.pharm.sci., 64: 181-210 (1975); t.higuchi and v.stella, a.c.s. argument are listed prodrugs as novel delivery systems, volume 14; roche, a bioreversible carrier in drug design, american society of medicine and Pergamon press, 1987, all incorporated herein in their entirety.
In addition, prodrug derivatives of the compounds of formula (G), formula (G-I) and formula (G-II) can be prepared by methods known to the skilled worker (see, for example, Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985, for further details). By way of example only, suitable prodrugs can be prepared by reacting the underivatized compounds of formula (G), formula (G-I) and formula (G-II) with suitable carbamoylating agents, such as, but not limited to, 1-acyloxyalkyl carbonate, p-nitrophenyl carbonate, and the like. Prodrug forms of the compounds described herein, wherein a prodrug is metabolized in vivo to produce a derivative as set forth herein, are included within the scope of the claims. Indeed, some of the compounds described herein may be another derivative or a prodrug of the active compound.
At positions on the aromatic ring portion of the compounds of formula (G), formula (G-I) and formula (G-II), various metabolic reactions are readily acceptable, and thus incorporation of appropriate substitutions on the aromatic-based ring structure, such as, for example, halogens, can reduce, minimize or eliminate this metabolic pathway.
The compounds described herein may be labeled isotopically (e.g., using a radioisotope) or by another means including, but not limited to, using a chromophore or a fluorescent moiety, a bioluminescent label or a chemiluminescent label. The compounds of formula (G), formula (G-I) and formula (G-II) may have one or more stereogenic centers, and each center may be present in either the R or S configuration. The compounds presented herein include all diastereomeric, symmetric and epimeric forms, and appropriate mixtures thereof. The compounds of formula (G), formula (G-I) and formula (G-II) can be prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Although resolution of the symmetrical isomers can be performed using covalent diastereomeric derivatives of the compounds described herein, dissociative complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and can be readily separated by exploiting these dissimilarities. Diastereomers may be separated by chiral chromatography, or preferably by separation/resolution techniques based on differences in solubility. The optically pure isomer is then recovered, along with the resolving agent, by any practical method that does not cause racemization. Techniques applicable to resolving stereoisomeric mixtures of compounds from their racemic mixtures are described in more detail in Jean Jacques, Andre Collet, Samuel H.Wilen, "isomers, racemates and resolution", John Wiley & Sons, 1981, the entire contents of which are incorporated herein by reference.
In addition, the compounds and methods provided herein can exist as geometric isomers. The compounds and methods provided herein include all cis, trans, ipsilateral, contralateral, trans (entgegen) (E) and cis (zusammen) (Z) isomers, as well as suitable mixtures thereof. In some cases, the compounds may exist as tautomers. All tautomers that are encompassed within the formulae described herein are provided by the compounds and methods herein. In other embodiments of the compounds and methods provided herein, mixtures of symmetric isomers and/or diastereomers resulting from a single preparation step, combination, or interconversion can also be used for the applications described herein.
The route of administration
Suitable routes of administration include, but are not limited to, intravenous, oral, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections, to name a few.
Alternatively, the compound may be administered topically rather than systemically, e.g., by direct injection of the compound into an organ, often in depot or sustained release formulations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, we can target drug delivery by administering the drug systemically, such as liposomes coated with organ-specific antibodies. The liposomes will target the organ and be selectively absorbed by it. In addition, the drug may be provided in a rapid release formulation, in a long-term release formulation, or in an intermediate release formulation.
Pharmaceutical compositions/formulations
Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration selected. Any of the well known techniques, carriers and excipients may be used as appropriate and as is apparent in the art. Summary of the pharmaceutical compositions described herein, see, e.g., Remington: pharmaceutical sciences and practices, nineteenth edition (Easton, Pa.: Mack publishing company, 1995); hoover, John e., Remington's pharmaceutical science, Mack publishing company, 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 edition (Lippincott Williams & Wilkins1999), which are incorporated herein by reference in their entirety.
Provided herein are pharmaceutical compositions comprising a compound of formula (G), formula (G-I), or formula (G-II), and a pharmaceutically acceptable diluent, excipient, or carrier. Furthermore, the compounds described herein may be administered in pharmaceutical compositions wherein the compound of formula (G), formula (G-I) or formula (G-II) is mixed with other active ingredients, as is the case in combination therapy.
As used herein, a pharmaceutical composition refers to a mixture of any compound of formula (G), formula (G-I) or formula (G-II) with other chemical ingredients, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients. Pharmaceutical compositions facilitate the administration of compounds to organisms. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound of any of formula (G), formula (G-I), or formula (G-II) provided herein is administered as a pharmaceutical composition to a mammal having the disease or condition to be treated. The mammal is preferably a human. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the patient, the efficacy of the compound used, and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of a mixture.
For intravenous injection, the compound of formula (G), formula (G-I) or formula (G-II) may be formulated in aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, ringer's solution or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such saturants are generally known in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.
For oral administration, the compounds of formula (G), formula (G-I) or formula (G-II) can be readily formulated by combining the active compound with pharmaceutically acceptable carriers or excipients well known in the art. Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, if desired after addition of suitable auxiliaries, and treating the mixture of granules to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as: corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose; or others, such as: polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
Sugar-coated tablet cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyltetrahydropyrrolone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. 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 which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in admixture 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 may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, a stabilizer may be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal or sublingual administration, these compositions may take the form of tablets, dragees or gels, formulated in a conventional manner. Parenteral injection 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 compositions of any of formula (G), formula (G-I) or formula (G-II) may be in a form suitable for parenteral injection, as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Furthermore, suspensions of the active compounds may be prepared in a suitable manner as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension may also optionally contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
Any compound of formula (G), formula (G-I) or formula (G-II) can be administered topically, and can be formulated into a variety of compositions that can be administered topically, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, penetration enhancers, buffers and preservatives.
Formulations suitable for transdermal administration of a compound having any of the structures of formula (G), formula (G-I) or formula (G-II) may be presented using transdermal delivery devices and transdermal delivery patches, and may be presented as a lipophilic emulsion or as a buffered aqueous solution dissolved and/or dispersed in a polymer or adhesive. Such patches may be constructed for continuous, pulsatile or on-demand delivery of the medicament. Further, transdermal delivery of any of the compounds of formula (G), formula (G-I) or formula (G-II) can be achieved using iontophoresis, etc. In addition, transdermal patches may provide controlled delivery of any compound of formula (G), formula (G-I) or formula (G-II). The rate of absorption can be slowed by rate controlling cell membranes, or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers may be used to increase absorption. The absorption enhancer or carrier may include absorbable pharmaceutically acceptable solvents to aid passage through the skin. For example, a transdermal device is in the form of a bandage comprising a backing, a reservoir containing a compound, optionally accompanied by a carrier, optionally with a rate-controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and a means of securing the device to the skin.
For administration by inhalation, any of the compounds of formula (G), formula (G-I) or formula (G-II) may be in the form of, for example, an aerosol, mist or powder. Pharmaceutical compositions of any of formula (G), formula (G-I) or formula (G-II) may conveniently be delivered in the form of an aerosol spray presentation from a pressurised pack or nebuliser, with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be measured via a valve provided to deliver a metered amount. By way of example only, capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
Any compound of formula (G), formula (G-I) or formula (G-II) may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel-like suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerin, and synthetic polymers such as polyvinyl tetrahydropyrrolone, PEG and the like. In suppository forms of these compositions, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.
Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration selected. Any of the well known techniques, carriers and excipients may be used as appropriate and as is apparent in the art. Pharmaceutical compositions comprising any compound of formula (G), formula (G-I) or formula (G-II) may be manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, coating, entrapping or compressing methods.
Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent or excipient, and as active ingredient any compound of formula (G), formula (G-I) or formula (G-II) as described herein, in free acid or free base form, 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 referred to as polymorphs), and active metabolic products of these compounds having the same type of activity. In some cases, 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 as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvate forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions may contain other pharmaceutical or medical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solubility promoters, salts for regulating the osmotic pressure and/or buffers. In addition, the pharmaceutical compositions may also comprise other therapeutically valuable substances.
A method of preparing a composition comprising a compound described herein, comprising formulating such compound 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, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or solutions containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semisolid compositions include, but are not limited to, gels, suspensions, and creams. These compositions may be in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of non-toxic, auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
Compositions comprising any compound of formula (G), formula (G-I), or formula (G-II) can illustratively be in liquid form, wherein the agent is present as a solution, as a suspension, or both. Typically, 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 in particulate form, suspended in a liquid matrix. In some embodiments, the liquid composition may comprise a gel formulation. In other embodiments, the liquid composition is aqueous.
Useful aqueous suspensions may also contain one or more polymeric substances as suspending agents. Useful polymers include water soluble polymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water insoluble polymers such as cross-linked carboxyl containing polymers. Useful compositions may also comprise mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbon polymers (carbomers), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymers, sodium alginate and dextran.
Useful compositions may also contain a solubilizing agent to aid in the solubility of any compound of formula (G), formula (G-I) or formula (G-II). The term "pro-solvent" generally includes agents that cause the formation of a micellar or true solution of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, may be used as solubilizing agents, as may ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.
Useful compositions may also include one or more pH adjusting or buffering agents including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; alkalies such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris (hydroxymethyl) aminomethane; and buffers such as citrate/dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases and buffers are added in amounts necessary to maintain the pH of the composition within an acceptable range.
Useful compositions may also require an amount to bring the osmolality of the composition within an acceptable range, comprising one or more salts. Such salts include those having sodium, potassium or ammonium cations with chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or acid sulfite 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 materials such as mercurophene (merfen) and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as alkoxyammoniumchloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.
Still other useful compositions may include one or more surfactants to enhance physical stability, or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers such as octylphenyl ether 10, octylphenyl ether 40.
Still other useful compositions may include one or more antioxidants, if desired, to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
The aqueous suspension composition may be packaged in a single dose non-reclosable container. Alternatively, multiple dose reclosable containers may be used, in which case preservatives are typically added to the composition.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as N-methyl tetrahydropyrrolone, may also be employed, often at the expense of greater toxicity. Alternatively, the compounds may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained release materials are established and are well known to the skilled artisan. Sustained release capsules, depending on their chemical nature, release the compound over a period of weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, other strategies for protein stabilization may be employed.
All of the formulations described herein may benefit from antioxidants, metal chelators, thiol containing compounds, and other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentasaccharide polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) a combination thereof.
Medicine taking method and therapeutic administration method
The compounds of formula (G), formula (G-I) and formula (G-II) are useful in the preparation of medicaments for the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions. Furthermore, a method of treating any of the diseases or conditions described herein in a patient in need of such treatment involves administering a pharmaceutical composition containing at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, to the patient in a therapeutically effective amount.
Compositions containing the compounds described herein can be administered for prophylactic and/or therapeutic treatment. In therapeutic applications, these 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 signs of the disease or condition. The amount effective for this use will depend on the severity and duration of the disease or condition, previous therapy, the patient's health, weight and response to the drug, and the judgment of the treating physician. It is considered well within the skill of the art to determine such therapeutically effective amounts by routine experimentation, including but not limited to dose escalation clinical trials.
In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to infection or at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this application, the correct amount will also depend on the health status, weight, etc. of the patient. It is considered well within the skill of the art to determine such prophylactically effective amounts by routine experimentation, including but not limited to dose escalation clinical trials. When used in a patient, an effective amount for this use will depend on the severity and duration of the disease, disorder or condition, previous therapy, the patient's health and response to the drug, and the judgment of the treating physician.
In the case where the patient's symptoms are not improved, the administration of the compound may be administered in a chronic manner, i.e., over an extended period of time, including the entire life span of the patient, at the discretion of the physician, to improve or otherwise control or limit the signs of the patient's disease or symptoms.
In the case where the patient's condition does improve, the administration of the compound may be administered continuously, at the discretion of the physician; alternatively, the dose of drug administered may be temporarily reduced or temporarily suspended for a specified length of time (i.e., a "drug holiday"). The length of the drug withdrawal period may vary between 2 days and 1 year, including, by way of example only, 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 drug cessation can be 10% -100%, by way of example only, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
Once improvement of the patient's symptoms has occurred, a maintenance dose is administered if necessary. The dose or frequency of administration, or both, can then be reduced as a function of the indication to the extent that the improved disease, disorder or symptom is maintained. However, upon any recurrence of the signs, the patient may require intermittent treatment on a long-term basis.
The amount of a particular agent corresponding to such amount will vary depending upon factors such as the particular compound, the disease state and its severity, the identity (e.g., body weight) of the patient or host to be treated, but nonetheless can be routinely determined in a manner known in the art, depending upon the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the patient or host being treated. In general, however, the dose employed for treatment of adult humans is typically in the range of 0.02 to 5000 mg per day, preferably 1 to 1500 mg per day. The desired dose may conveniently be presented in a single dose, or administered simultaneously in separate doses (or over a short period of time), or at appropriate intervals, for example two, three, four or more sub-doses per day.
The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of the correct dosage. In unit dosage form, a formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose can be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packed tablets or capsules, and powders in vials or ampoules. The aqueous suspension composition may be packaged in a single dose non-reclosable container. Alternatively, multiple dose reclosable containers may be used, in which case preservatives are typically added to the composition. By way of example only, 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.
A daily dosage suitable for any compound of formula (G), formula (G-I) or formula (G-II) described herein is about 0.01 to 2.5 mg/kg, based on body weight. The daily dosage required in larger mammals, including but not limited to humans, is in the range of about 0.5 mg to about 100 mg, and may conveniently be administered in divided doses, including but not limited to up to four times a day, or in extended release form. Suitable unit dosage forms for oral administration contain from about 1 mg to 50 mg of the active ingredient. The foregoing ranges are merely indicative, as the number of variables relating to individual therapeutic regimens is large, and considerable drift from these suggested values is not unusual. Such dosages may vary depending upon a number of variables, not limited to the activity of the compound employed, the disease or condition to be treated, the mode of administration, the amount required of the individual patient, the severity of the disease or condition being treated, and the judgment of the practitioner.
Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures, including but not limited to LD, in cell cultures or experimental animals50(dose lethal to 50% of the population) and ED50(in a therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it may be LD 50With ED50The ratio between them. Compounds that exhibit high therapeutic indices are preferred. Data from cell culture assays and animal studies can be used to formulate a range of doses for use in humans. The dosage of such compounds is preferably within the circulating concentration range, which includes ED with minimal toxicity50. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
Use of FLAP modulators for the prevention and/or treatment of leukotriene dependence or leukotriene mediated pathways Disease or symptom of
Treatment of leukotriene-dependent or leukotriene mediated diseases or conditions is designed to modulate the activity of FLAP. Such modulation, by way of example only, may include inhibition or antagonism of FLAP activity. For example, a FLAP inhibitor may be administered to reduce leukotriene synthesis in an individual, or possibly down-regulate or reduce the expression or availability of FLAP mRNA or a specific conjugative variant of FLAP mRNA. Down-regulation or reduction of the expression or availability of the native FLAP mRNA or specific zygosity variant minimizes the expression or activity of defective nucleic acids or specific zygosity variants and thereby minimizes the impact of defective nucleic acids or specific zygosity variants.
According to one aspect, the compositions and methods described herein, including compositions and methods for treating, preventing, reversing, halting or slowing the progression of, or treating the signs of, a leukotriene-dependent or leukotriene mediated disease or condition once it becomes clinically significant, by administering to the patient any compound of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II). The patient may already have, or be at risk of developing, a leukotriene-dependent or leukotriene mediated disease or condition when administered. The indication of leukotriene-dependent or leukotriene mediated disease or symptoms in a patient can be determined by the skilled artisan and is described in standard texts.
The activity of the 5-lipoxygenase activating protein may be modulated, directly or indirectly, in the mammal by administering (at least once) to the mammal an effective amount of at least one compound of any of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising a compound of any of formula (G), formula (G-I) or formula (G-II). Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of 5-lipoxygenase activating protein. Furthermore, leukotriene activity in a mammal can be directly or indirectly modulated, including reduced and/or inhibited, by administering (at least once) an effective amount of at least one of any of the compounds of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any of the compounds of formula (G), formula (G-I), or formula (G-II) to the mammal. Such modulation includes, but is not limited to, reducing and/or inhibiting the activity of 5-lipoxygenase activating protein.
Preventing and/or treating leukotriene-dependent or leukotriene mediated diseases or conditions may comprise administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II). For example, prevention and/or treatment of an inflammatory disease or condition may comprise administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising a compound of any of formula (G), formula (G-I), or formula (G-II). Leukotriene-dependent or leukotriene mediated diseases or conditions are treatable by a method comprising administering to a mammal at least once an effective amount of at least one compound of any formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II), and include, but are not limited to, bone diseases and disorders, cardiovascular diseases and disorders, inflammatory diseases and disorders, skin diseases and disorders, ocular diseases and disorders, cancer and other proliferative diseases and disorders, respiratory diseases and disorders, and noncancerous disorders.
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of treating a respiratory disease comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising a compound of any of formula (G), formula (G-I), or formula (G-II). For example, the respiratory disease may be asthma; see Riccioni et al, Ann.Clin.Lab.Sci., v34, 379-387 (2004). In addition, respiratory diseases may include, but are not limited to, adult dyspnea syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, equi-carbon dioxide hyperventilation, childhood developed asthma, adult developed asthma, cough variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, allergic rhinitis, vascular response, endotoxin shock, fibrosis, pulmonary fibrosis, allergic disease, chronic inflammation, and adult dyspnea syndrome.
Included in such treatment methods, by way of example only, is a method of preventing chronic obstructive pulmonary disease comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II). In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation and cystic fibrosis.
Included in such treatment methods, by way of example only, is a method of increasing 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 (G-I), or formula (G-II) or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of preventing or treating vasoconstriction, atherosclerosis and its sequelae 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 (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II); see Jala et al Trends in Immunol, v25, 315-.
By way of example only, included in the prophylactic/therapeutic methods described herein is a method of reducing cardiac reperfusion injury following myocardial ischemia and/or endotoxic shock comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of reducing vascular pinching in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of reducing or preventing an increase in blood pressure in a mammal comprising administering to the mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of preventing recruitment of eosinophils and/or basophils and/or dendritic cells and/or neutrophils and/or single cells comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of preventing or treating abnormal bone remodeling, wasting or augmentation, illustratively diseases or conditions such as osteopenia, osteoporosis, buerger's disease, cancer and other diseases, comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II).
Included in the methods of prevention/treatment described herein are, by way of example only, methods of preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis, which comprise administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II); see lamb et al, arch, v121, 615-.
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of preventing a CNS disorder comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising a compound of any of formula (G), formula (G-I), or formula (G-II). CNS disorders include, but are not limited to, multiple sclerosis, parkinson's disease, alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain, spinal cord injury, cerebral edema, and head injury.
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of treating cancer comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II). Types of cancer may include, but are not limited to, pancreatic cancer, and other solid or hematological tumors, see Poff and Balazy, curr. drug Targets in inflammation. allergy, v3, 19-33(2004), and Steele et al, cancer epidemiology and prevention, v8, 467-483 (1999).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of preventing endotoxic and septic shock which comprise administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the methods of prevention/treatment described herein are, by way of example only, methods of preventing rheumatoid arthritis and osteoarthritis comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the methods of prevention/treatment described herein are methods of preventing increased GI disease, by way of example only, comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II). Such GI diseases include, by way of example only, Inflammatory Bowel Disease (IBD), colitis, and crohn's disease.
By way of example only, included in the prophylactic/therapeutic methods described herein are methods of reducing inflammation while also preventing transplant rejection, or preventing or treating tumors, or accelerating wound healing, comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of preventing or treating rejection or dysfunction in a transplanted organ or tissue comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of treating type II diabetes, which comprise administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising a compound of any of formula (G), formula (G-I), or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of treating an inflammatory response of the skin comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II). Such inflammatory responses of the skin include, for example, psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing and scarring. In another aspect is a method of reducing psoriatic lesions in the skin, joints or other tissues or organs comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any of formula (G), formula (G-I) or formula (G-II).
Included in the prophylactic/therapeutic methods described herein are, by way of example only, methods of treating a metabolic syndrome, such as familial mediterranean fever, comprising administering to a mammal at least once an effective amount of at least one compound of any of formula (G), formula (G-I), or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I), or formula (G-II).
Combination therapy
In certain instances, at least one compound of any of formula (G), formula (G-I), or formula (G-II) may be suitably administered, in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds herein is inflammation, then an anti-inflammatory agent may be suitably administered, in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein, with another therapeutic agent that also has therapeutic benefit (which also includes therapeutic regimens). By way of example only, in a context involving administration of one of the compounds described herein to treat asthma, an increased therapeutic benefit may result from also providing the patient with other asthma treatments or therapies. Overall, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be simply the addition of the two therapeutic agents, or the patient may experience a synergistic benefit.
It is known to the skilled artisan that when drugs are used in therapeutic combinations, the therapeutically effective dose may vary. Methods for experimentally determining therapeutically effective doses of drugs and other agents for use in combination therapeutic regimens are described in the literature. For example, the use of metronomic dosing, i.e. providing more frequent, lower doses to minimize toxic side effects, has been widely described in the literature. A combination therapeutic regimen may encompass a therapeutic regimen wherein administration of the FLAP or 5-LO inhibitor described herein is initiated before, during, or after treatment with the second agent described above and continues until any time during treatment with the second agent, or after treatment with the second agent is terminated. It also includes treatments wherein the FLAP or 5-LO inhibitor described herein is administered concurrently or at different times and/or at decreasing or increasing intervals during the treatment, in combination with a second agent. Combination therapy further includes periodic therapy, which is started and stopped at different times to aid in the clinical management of the patient. For example, the FLAP or 5-LO inhibitors described herein in combination therapy may be administered weekly at the start of treatment, reduced to biweekly, and further reduced as appropriate.
Compositions and methods relating to combination therapy are provided herein. According to one aspect, the pharmaceutical compositions disclosed herein are used to treat leukotriene-dependent or leukotriene mediated symptoms. According to another aspect, the pharmaceutical compositions disclosed herein are used for the treatment of respiratory diseases, where treatment with a FLAP inhibitor, particularly asthma, is required, and induces bronchodilation in a patient. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat a patient having a condition driven by vascular inflammation. In one embodiment, the pharmaceutical compositions disclosed herein are used to treat patients susceptible to Myocardial Infarction (MI).
The combination therapies described herein may be used as part of a particular therapeutic regimen intended to provide the beneficial effects resulting from the co-action of the FLAP inhibitors described herein with co-therapy. It will be appreciated that the dosage regimen for treating, preventing or ameliorating the symptoms sought to be alleviated may be modified depending on a variety of factors. These factors include the type of respiratory disorder and the type of bronchiectasis that the patient suffers from, as well as the age, weight, sex, diet and medical condition of the patient. Thus, the dosage regimen actually employed may vary widely and thus may deviate from the dosage regimens set forth herein.
For the combination therapies described herein, the dosage of the co-administered compounds will, of course, vary depending upon the type of co-drug employed, the particular drug employed, the disease or condition being treated, and the like. In addition, when co-administered with one or more bioactive agents, the compounds provided herein can be administered either simultaneously, or sequentially with the bioactive agent. If administered sequentially, the physician in charge will decide the appropriate order of administering the proteins and co-administering the bioactive agents.
In general, multiple therapeutic agents (one of which is one of the compounds described herein) can be administered in any order or even simultaneously. If simultaneous, multiple therapeutic agents may be provided in a single, unitary form, or in multiple forms (whether in a single pill or in two separate pills, for example only). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. If not the same, the timing between multiple doses may be changed from greater than zero weeks to less than four weeks. Furthermore, the combination methods, compositions, and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations is also envisaged.
In addition, any compound of formula (G), formula (G-I) or formula (G-II) may also be used in combination with procedures that may provide additional or synergistic benefits to the patient. By way of example only, it is contemplated that a patient will find therapeutic and/or prophylactic benefit in the methods described herein, wherein any pharmaceutical composition of formula (G), formula (G-I), or formula (G-II) and/or combination with other therapeutic agents is combined with a gene test to determine whether the individual is a carrier of a mutated gene, which is known to be associated with certain diseases or conditions.
Any compound of formula (G), formula (G-I) or formula (G-II) and combination therapy can be administered before, during or after the onset of the disease or condition, and the timing of administration of the composition containing the compound can vary. Thus, for example, the compounds can be used as prophylactic agents and can be administered continuously to patients having a predisposition to develop a condition or disease to prevent the occurrence of the disease or condition. The compounds and compositions may be administered to the patient during or as soon as possible after the sign is developed. Administration of the compound may be initiated within the first 48 hours of sign development, preferably within the first 6 hours of sign development, and most preferably within 3 hours of sign development. The initial administration can be via any practical route, such as intravenous injection, bolus injection, infusion over a period of 5 minutes to about 5 hours, pill, capsule, transdermal patch, buccal delivery, and the like, or a combination thereof. The compound is preferably administered once feasible after the development of the disease or condition is detected or suspected, and over a period of time necessary to treat the disease, e.g., about 1 month to about 3 months. The length of treatment may vary from patient to patient, and this length may be determined using known criteria. For example, the compound or formulation containing the compound may 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.
For example, a therapy combining any compound of formula (G), formula (G-I) or formula (G-II) with an inhibitor of leukotriene synthesis or leukotriene receptor antagonist, whether acting at the same or other point in the leukotriene synthesis pathway, may prove particularly useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions. Furthermore, by way of example, any combination of a compound of formula (G), formula (G-I) or formula (G-II) with an inflammation inhibitor may prove particularly useful in the treatment of leukotriene-dependent or leukotriene mediated diseases or conditions.
Anti-inflammatory agent
In another embodiment described herein, a method of treating leukotriene dependence or leukotriene locus is providedA method of mediating a condition or disease comprising administering to a patient a compound, pharmaceutical composition or medicament described herein, and in combination with an anti-inflammatory agent, including but not limited to arsotere (artrotec), arsacol (asacol), oraraglan (auralglan), sulfasalazine, Daypro (Daypro), etodolac (etodolac), mefenamic acid, salofuk (salofalk), and lodrol (solumedrol); non-steroidal anti-inflammatory agents, for example, aspirin (Bayer) TM，BufferinTM) Indomethacin (indomethacin) (Indocin)TM) Rofecoxib (Vioxx)TM) Celecoxib (celecoxib) (CELEBREX)TM) Wedgesbeib (Bextra)TM) Diclofenac, etodolac, ketoprofen, flodine, mobicn, nabumetone, naproxen, pyrilamine; and corticosteroids, such as, for example, Cejostoh (celesterone), prednisone, and deltasone. Corticosteroids do not directly inhibit leukotriene production and thus co-administration with steroids may provide additional anti-inflammatory benefits.
Asthma, for example, is a chronic inflammatory disease characterized by hyperphagia of the lung and high responsiveness of the airways. Zhao et al, proteomics research, 7/4/2005. In patients with asthma, leukotrienes are released from mast cells, eosinophils, and basophils. Leukotrienes are involved in the contraction of airway smooth muscle, increase in vascular permeability and mucus secretions, and have been reported to attract and activate inflammatory cells in the asthmatic airways (Siegel et al, eds., basic neurochemistry, molecular, cellular and medical aspects, sixth edition, Lippincott Williams & Wilkins, 1999). Thus, in another embodiment described herein, a method of treating a respiratory disease comprises administering to a patient a compound, pharmaceutical composition or medicament described herein, and in combination with an anti-inflammatory agent.
Leukotriene receptor antagonists
Herein, theIn another embodiment, the method of treating a leukotriene-dependent or leukotriene mediated condition or disease comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with a leukotriene receptor antagonist, including but not limited to CysLT1/CysLT2Dual receptor antagonists, and CysLT1A receptor antagonist. In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with CysLT1/CysLT2A dual receptor antagonist. CysLT1/CysLT2Dual receptor antagonists include, but are not limited to, BAY u9773, Cuthbert et al EP 00791576 (published 27.8.1997), DUO-LT (Galczenski et al, D38, Poster F4, filed by the American thoracic society, 5.2002), and Tsuji et al, org.Biomol.Chem., 1, 3139-. The most appropriate formulation or method of treatment using such a combination may depend on the type of leukotriene-dependent or leukotriene mediated disorder, the period in which the FLAP inhibitor is used to treat the disorder, and CysLT therein, for a particular patient 1/CysLT2Depending on the period of time in which the dual receptor antagonist is used to inhibit the activity of the CysLT receptor. By way of example only, such combination therapy may be used to treat patients suffering from respiratory disorders.
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with CysLT1A receptor antagonist. CysLT1Receptor antagonists include, but are not limited to, miscellaneous Lucifusts (Zafirlukast) ("AcclateTM"), Montelukast (" Singulair ")TM"), Pranlukast (Pranlukast) (" OnonTM") and derivatives or analogs thereof. Such combinations are useful in the treatment of leukotriene-dependent or leukotriene mediated disorders, including respiratory disorders.
FLAP or 5 as described herein-LO inhibitors and CysLT1Receptor antagonists or bis-CysLT1/CysLT2Co-administration of receptor antagonists may have therapeutic benefit over and above that derived from either FLAP or 5-LO inhibitors or CysLT1The benefit of the R antagonist alone. In cases where substantial inhibition of leukotriene production has an undesirable effect, this pathway goes through pre-inflammatory LTB 4Improvement of action with cysteinyl leukotrienes, and binding to CysLT1Blockade of receptors and/or bis-CysLT1/CysLT2Partial inhibition of receptor blockade may provide substantial therapeutic benefits, particularly for respiratory diseases.
Other combination therapies
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as a proliferative disorder, including cancer, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein, in combination with at least one additional agent selected from the group consisting of atlas (alemtuzumab), arsenic trioxide, asparaginase (pegylated or not), bevacizumab, cetuximab (cetuximab), platinum-based compounds such as cisplatin, cladribine (cladribine), daunorubicin/doxorubicin/idarubicin, illinoenotrexecutan (irxeotecan), fraxagabine (udflarabine), 5-fluorouracil, substantivity marb (geutbamab), methotrexate, paclitaxathicin (Paclitaxel), and PaclitaxelTMPaclitaxel, temozolomide (temozolomide), thioguanine, or a class of drugs including hormones (antiestrogens, antiandrogens, or gonadotropin releasing hormone analogs), interferons, such as alpha-interferon, nitrogen mustards, such as busulfan or chlorambucil or nitrogen mustard, retinoids, such as tretinoin (tretinoin), topoisomerases inhibitors, such as irinotecan or topotecan, tyrosine kinase inhibitors, such as gefinitib or Imatinib (Imatinib), or agents for treating signs or symptoms of disease caused by such therapy, including Isopurine alcohol, filgrastim, granisetron, ondansetron, palonosetron, trinabinol, and drobinol.
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as a transplanted organ or tissue or cell therapy, comprises administering to a patient a compound, pharmaceutical composition or agent described herein in combination with at least one other agent selected from the group consisting of
Figure A20068004120701311
Examples of suitable excipients include, but are not limited to, heparin, corticosteroids, cyclophosphamide, cyclosporine, dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus, and thymoglobulin.
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as atherosclerosis, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein, and with at least one other agent selected from the group consisting of HMG-CoA reductase inhibitors (e.g., statins, in their lactonized or dihydroxyseco-cyclic acid forms, and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (lovastatin); simvastatin (simvastatin), simvastatin, especially the ammonium or calcium salt thereof; pravastatin, especially the sodium salt thereof; fluvastatin, especially the sodium salt thereof; atorvastatin, especially the calcium salt thereof; nisivastatin, also known as NK-104; rosuvastatin (rosuvastatin)); agents having both lipid-altering and other pharmaceutical activities; HMG-CoA synthetase inhibitors; cholesterol absorption inhibitors such as also kitasalbrom (ezetimibe); cholesteryl Ester Transfer Protein (CETP) inhibitors, such as JTT-705 and CP529,414; a squalene cyclooxygenase inhibitor; squalene synthetase inhibitors (also known as squalene synthetase inhibitors); acyl-coenzyme a: cholesterol Acyltransferase (ACAT) inhibitors, including selective inhibitors of ACAT-1 or ACAT-2, as well as dual ACAT-1 and-2 inhibitors; microsomal triglyceride transfer protein (MTP) inhibitors; proprocol (probucol); nicotinic acid; a bile acid sequestrant; LDL (low density lipoprotein) receptor elicitors; platelet aggregation inhibitors, such as glycoprotein IIb/IIIa fibrinogen receptor antagonists with aspirin; human peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, including compounds commonly referred to as the tagatose class (glitazones), such as troglitazone (troglitazone), pioglitazone (pioglitazone) and cetoglitazone (rosiglitazone), and including compounds referred to as the thiazolidinediones included in this structural class, and PPAR γ agonists outside the thiazolidinedione structural class; PPAR α agonists, such as clofenate, fenofibric acid esters (fenofibric acid esters), including micronized fenofibric acid esters (fenofibric acid esters) and gemfibrozil; PPAR bis alpha/gamma agonists such as 5- [ (2, 4-dioxo-5-thiazolidinyl) methyl ] -2-methoxy-N- [ [4- (trifluoromethyl) phenyl ] methyl ] -benzamide, known as KRP-297; vitamin B6 (also known as pyridoxine) and pharmaceutically acceptable salts thereof, such as the HCl salt; vitamin B12 (also known as cyanocobalamin acid); 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; a beta-blocker; vasopressin II antagonists such as losartan; inhibitors of vasopressin converting enzymes, such as ananapril (enalapril) and captopril (captopril); calcium channel blockers such as nifedipine (nfidipine) and dititazam (dithzam); an endothelial antagonist; agents that enhance the expression of ABC1 gene; FXR and LXR ligands, both inhibitors and agonists; bisphosphonate compounds, such as sodium alendronate; and cyclooxygenase-2 inhibitors such as rofecoxib and celecoxib.
In another embodiment described herein, a leukotriene-dependent or leukotriene mediated condition is treated orA method of treating a disease, such as stroke, comprising administering to a patient a compound, pharmaceutical composition or medicament as described herein, in combination with at least one other agent selected from a COX-2 inhibitor; nitric oxide synthase inhibitors such as N- (3- (aminomethyl) benzyl) ethyl; rho kinase inhibitors such as sudadi (fasudil); angiotensin type II-1 receptor antagonists including candesartan (candesartan), losartan (losartan), irbesartan (irbesartan), eprosartan (eprosartan), telmisartan (telmisartan) and valsartan (valsartan); glycogen synthase kinase 3 inhibitors; sodium or calcium channel blockers, including lobenidine (crotenetine); p38MAP kinase inhibitors, including SKB 239063; inhibitors of prostacyclin AX-synthase, including obergarel (isbogrel), okara (ozagrel), ridogrel (ridogrel), and darcy (dazoxiben); nystatin (HMG CoA reductase inhibitors) including lovastatin, simvastatin (simvastatin), dihydroxysecozastatin (simvastatin), pravastatin (pravastatin), fuvastatin (fluvastatin), atorvastatin (atorvastatin), nisin (nisvastatin) and rosuvastatin (rosuvastatin); neuroprotective agents including free radical scavengers, calcium channel blockers, excitatory amino acid antagonists, growth factors, antioxidants, such as edaravone, vitamin C, TROLOX TMCiticoline and microcyclines, and reactive astrocytic inhibitors such as (2R) -2-propyloctanoic acid; beta adrenergic blockers such as pyrroniol (propranolol), piroctone olamine (nadolol), temolol (timolol), pindolol (pindolol), labetalol (labetalol), metoprolol (metoprolol), atenolol (atenolol), ismolol (esmolol) and acebutolol (acebutolol); NMDA receptor antagonists, including memantine (memantine); NR2B antagonists, such as troxodil (traxoprodil); 5-HTlA agonist; receptor platelet fibrinogen receptor antagonists including tiofiban and lamifiban; a thrombin inhibitor; an antithrombotic agent such as aspergillon Bian (argatroban); antihypertensive agents such as ananapril (enalapril); vasodilators, e.g. ringsA mandelate ester; a nociceptin antagonist; a DPIV antagonist; GABA5 inverse agonists; and selective androgen receptor modulators.
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as pulmonary fibrosis, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with at least one other agent selected from anti-inflammatory agents, such as a corticosteroid, azathioprine or cyclophosphamide.
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as interstitial cystitis, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with at least one other agent selected from dimethylsulfoxide, omalizumab, and pentasaccharide polysulfate.
In another embodiment described herein, a method of treating a leukotriene-dependent or leukotriene mediated condition or disease, such as a bone disorder, comprises administering to a patient a compound, pharmaceutical composition or medicament described herein in combination with at least one other agent selected from the group consisting of minerals, vitamins, bisphosphonates, anabolic steroids, parathyroid hormone or analog, and cathepsin K inhibitors.
CysLT is used for treating leukotrinin-based symptoms or diseases 1 /CysLT 2 Receptor antagonists Of
According to another aspect, the compositions and methods described herein are designed to transmit CysLT1/CysLT2Dual receptor antagonists to block CysLT receptor activity. The term "CysLT antagonist" or "CysLT receptor antagonist" or "leukotriene receptor antagonist" refers to a decrease in Cy sLT is signaled through the therapy of the CysLT receptor. CysLT is typically either LTC4、LTD4Or LTE4. Cysteaminyl leukotrienes are effective smooth muscle contractants, particularly in the respiratory and circulatory systems. These are via at least two cellular receptors, CysLT1And CysLT2The channel is accessed. CysLT1Receptors and CysLT2The receptor is a G-protein coupled receptor with seven putative transmembrane domains, and an intracellular functional site that interacts with G-proteins, Evans et al, prostaglandins and other lipid mediators, 68-69, pages 587-597, (2002). CysLT1/CysLT2Examples of dual receptor antagonists are BAY u9773, Cuthbert et al EP 00791576 (published 27.8.1997), DUO-LT (Galczenski et al, D38, Poster F4, proceedings of the thoracic society of America, 5.2002), and Tsuji et al, org.Biomol.Chem., 1, 3139-.
In certain embodiments, a method of treating a leukotriene-dependent or leukotriene mediated disease or condition comprises administering to a patient a compound, pharmaceutical composition or medicament comprising CysLT1/CysLT2A receptor antagonist. For example, such compounds, pharmaceutical compositions or medicaments may be useful in the treatment and/or prevention of respiratory diseases including, but not limited to, chronic, stable asthma.
Diagnostic method for confirming patient
Screening of "leukotriene-responsive patients" that may be selected for treatment with any compound of formula (G), formula (G-I) or formula (G-II) described herein or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II) or other FLAP modulators may be achieved using the techniques and methods described herein. Such techniques and methods include, by way of example, simplistic type assessment of genes (genotyping), monitoring/measurement of biomarkers (phenotyping), monitoring/measurement of functional markers (phenotyping), which is the display of a patient's response to known modulators of the leukotriene pathway, or any combination thereof.
Genotype analysis: FLAP polytropy
Human FLAP has been purified and clonally propagated and is an 18 kilodalton cell membrane-bound protein that is most highly expressed in human neutrophils. The FLAP gene is located at 13q 12 and has been linked to increased risk for both myocardial infarction and stroke in several populations of individuals. Among the genes encoding FLAP, a variety of polymorphism and simple types have been identified in individuals (U.S. patent application 2005113408; Sayers, Clin. exp. allergy, 33 (8): 1103-10, 2003; Kedda et al, Clin. exp. allergy, 35 (3): 332-8, 2005). The specific FLAP simplex type has been linked to myocardial infarction and stroke in several populations of individuals (Helgadottir A et al, Nature Genet.36: 233-; helgadottir A et al, Am J Hum Genet 76: 505-; lohmussaar E et al, Stroke 36: 731-736 (2005); kajimoto K et al, Circ J69: 1029-1034(2005) previously, polymorphism in certain genes has been shown to correlate with responsiveness to particular therapies, such as cancer responsiveness to particular chemotherapeutic agents (Erichsen et al, br.j. cancer, 90 (4)): 747-51, 2004, Sullivan et al, oncogene, 23 (19): 3328-37, 2004), accordingly, patients considered to be treated with the novel FLAP inhibitors described herein, or a pharmaceutical combination comprising such novel FLAP inhibitors, may be screened, potentially responsive to treatment based on its FLAP polymorphism or simple type.
In addition, polymorphisms in any synthetic or signaling genes specific for the leukotriene pathway can cause patients to be more or less responsive to leukotriene modulator therapy (whether FLAP or 5-LO inhibitors or leukotriene receptor antagonists). The genes specific for leukotriene pathway are 5-lipoxygenase, 5-lipoxygenase-activating protein, LTA4Hydrolase, LTC4Synthetase, LTB4Receptor 1 (BLT)1)、LTB4Receptor 2 (BLT)2) Cysteaminoyl leukotriene receptor 1 (CysLT)1R), cysteaminoyl leukotriene receptor 2 (CysLT)2R). For example, the 5-LO gene has been linked to aspirin intolerance asthma and airway hyperresponsiveness (Choi JH et al HumGenet 114: 337-344 (2004); Kim SH et al allergy 60: 760-765 (2005); genetic variation in the promoter region of 5-LO has been demonstrated to predict clinical response to 5LO inhibitors in asthma (Drazen et al Nature Genetics, 22, 168-170, (1999)). LTC4The synthetase genes have been linked to specific reactivity and asthma (Moissidi I et al Genet Med 7: 406-410 (2005)). CysLT2The receptor has been linked to asthma and idiosyncratic activity (Thompson MD et al, Genetiol 13: 641-649 (2003); Pilai SG et al, Genetiol 14: 627-633 (2004); Park JS et al, Pharmacogenet Genomics 15: 483-492 (2005); Fukai H et al, Genetiol 14: 683-690 (2004)). Any polymorphism or combination of simple types in any leukotriene pathway gene can cause a patient to become more susceptible to alteration of therapy with the aim of reducing leukotriene pathology. The choice of patients who are likely to respond most well to the leukotriene modulator therapies described herein can include knowledge of the polymorphism in the leukotriene pathway genes, as well as knowledge of the expression of leukotriene driven mediators. Patient selection can be performed on the basis of leukotriene pathway genotype alone, phenotype alone (biomarker or functional marker), or any combination of genotype and phenotype.
"Simplex type" as used herein refers to a combination of gene markers ("alleles"). The simple type can include one or more dual genes (e.g., a simple type containing a single SNP), two or more dual genes, three or more dual genes, four or more dual genes, or five or more dual genes. The gene marker is a specific "allele" at the "polymorphic site" associated with the FLAP. Within a population, more than one order on a nucleotide position is possible, referred to herein as a "polymorphic position". In the case of a polymorphic locus that is a single nucleotide in length, the locus is referred to as a single nucleotide polymorphism ("SNP"). For example, if at a particular chromosomal location, one member of the population has an adenine and another member of the population has a thymine at the same position, then that position is a polymorphic position, and more specifically, the polymorphic position is a SNP. Polymorphic sites may allow for differences in the order of substitution, insertion or deletion. With respect to each sequential variation of a polymorphic site, it is referred to herein as a "allele" of the polymorphic site. Thus, in the previous examples, SNPs allow for both adenine and thymine duplers.
Typically, a reference order is referred to as a specific order. The allele that differs from the reference is referred to as the "variant" allele. The term "variant FLAP" as used herein refers to an order that is different from a reference FLAP order, but otherwise substantially similar. The gene markers that constitute the plain type described herein are FLAP variants. In certain embodiments, the FLAP variant is at least about 90% similar to the reference order. In other embodiments, the FLAP variant is at least about 91% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 92% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 93% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 94% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 95% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 96% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 97% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 98% similar to the reference sequence. In other embodiments, the FLAP variant is at least about 99% similar to the reference sequence.
Furthermore, in certain embodiments, the FLAP variant is at least one base different from the reference sequence, while in other embodiments, the FLAP variant is at least two bases different from the reference sequence. In other embodiments, the FLAP variant is at least three bases different from the reference sequence, and in yet other embodiments, the FLAP variant is at least four bases different from the reference sequence.
Other variants may include alterations that affect a polypeptide, such as a FLAP polypeptide. The polypeptide encoded by the reference nucleotide sequence is a "reference" polypeptide having a particular reference amino acid sequence, while the polypeptide encoded by the variant allele is referred to as a "variant" polypeptide having a variant amino acid sequence. FLAP nucleic acid sequence differences may include insertions or deletions of a single nucleotide or more than one nucleotide, resulting in a backbone shift when compared to a reference nucleotide sequence; a change in at least one nucleotide that results in a change in the encoded amino acid; a change of at least one nucleotide, which results in the generation of an early stop codon; deletions of several nucleotides, resulting in the deletion of one or more amino acids encoded by the nucleotides; insertion of one or several nucleotides, such as by unequal recombination or gene transformation, results in disruption of the coding sequence; replication of all or a portion of the sequence; transposition is carried out; or rearrangement of nucleotide sequences, as detailed above. Such a change in order alters the polypeptide encoded by the FLAP nucleic acid. For example, if a change in the nucleic acid sequence results in a backbone shift, the backbone shift may result in a change in the encoded amino acid, and/or may result in the generation of an early stop codon, resulting in the generation of a truncated polypeptide.
For example, polymorphisms associated with susceptibility to Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), stroke, or Peripheral Arterial Occlusive Disease (PAOD) can be synonymous changes in one or more nucleotides (i.e., do not result in a change in amino acid sequence). Such polymorphism may, for example, alter conjugation, decrease or increase expression, affect mRNA stability or transport, or otherwise affect transcription or translation of the polypeptide. The simple forms described below are found more frequently in individuals with MI, ACS, stroke, or PAOD than in individuals without MI, ACS, stroke, or PAOD. Thus, these simple types may have predictive value for detecting susceptibility to MI, ACS, stroke, or PAOD in an individual.
Several variants of the FLAP gene have been reported to be associated with the incidence of myocardial infarction in patients (Hakonasson, JAMA, 293 (18): 2245-56, 2005), plus the FLAP gene marker reported to be associated with the risk of developing asthma, has been described in U.S. Pat. No. 6,531,279. Methods for identifying FLAP sequence variations are described, for example, in U.S. publication No. 2005/0113408 and U.S. patent No. 6,531,279, which are incorporated herein by reference in their entirety.
By way of example only, the simple types associated with susceptibility to myocardial infarction or stroke include markers SG13S99, SG13S25, SG13S377, SG13S106, SG13S32, and SG13S35 at the 13q12-13 positions. Alternatively, the presence of the alleles T, G, G, G, A and G at individual SG13S99, SG13S25, SG13S377, SG13S106, SG13S32, and SG13S35 (simple type B6) is diagnostic of susceptibility to myocardial infarction or stroke. Alternatively, the simple types associated with susceptibility to myocardial infarction or stroke include markers SG13S99, SG13S25, SG13S106, SG13S30 and SG13S42 at position 13q 12-13. Alternatively, the presence of the allele T, G, G, G and A in the individual SG13S99, SG13S25, SG13S 13S106, SG13S30 and SG13S42(B5 only type) is diagnostic of susceptibility to myocardial infarction or stroke. Alternatively, the simple types associated with susceptibility to myocardial infarction or stroke include markers SG13S25, SG13S106, SG13S30, and SG13S42 at positions 13q 12-13. Alternatively, the presence of the allele G, G, G and A in the individual SG13S25, SG13S106, SG13S30 and SG13S42(B4 simple type) is diagnostic of susceptibility to myocardial infarction or stroke. Alternatively, the simple types associated with susceptibility to myocardial infarction or stroke include markers SG13S25, SG13S106, SG13S30 and SG13S42 at position 13q 12-13. Alternatively, the presence of the allele G, G, G and A in the individual SG13S25, SG13S106, SG13S30 and SG13S42(Bs4 only type) is diagnostic of susceptibility to myocardial infarction or stroke. In such embodiments as just described, patients under consideration for treatment with any compound of formula (G), formula (G-I) or formula (G-II) or a pharmaceutical combination comprising any compound of formula (G), formula (G-I) or formula (G-II) as described herein can be screened for potential responsiveness to treatment with any compound of formula (G), formula (G-I) or formula (G-II), based on this simple type.
By way of example only, the simple types associated with susceptibility to myocardial infarction or stroke include markers SG13S99, SG13S25, SG13S114, SG13S89, and SG13S32 at positions 13q 12-13. Alternatively, the presence of the allele T, G, T, G and a in the individual SG13S99, SG13S25, SG13S114, SG13S89 and SG13S32(a5 simple type) is a diagnosis of susceptibility to myocardial infarction or stroke. Alternatively, the simple types associated with susceptibility to myocardial infarction or stroke include markers SG13S25, SG13S114, SG13S89 and SG13S32 at position 13q 12-13. Alternatively, the presence of the allele G, T, G and a in the individual SG13S99, SG13S25, SG13S114, SG13S89 and SG13S32(a4 simple type) is a diagnosis of susceptibility to myocardial infarction or stroke. In such embodiments as just described, patients under consideration for treatment with any compound of formula (G), formula (G-I) or formula (G-II) or a pharmaceutical combination comprising any compound of formula (G), formula (G-I) or formula (G-II) as described herein can be screened for potential responsiveness to treatment with any compound of formula (G), formula (G-I) or formula (G-II), based on this simple type.
Detection of simple types can be achieved by methods known in the art for detecting order in polymorphic location, so that patients can be selected using genotype selection for FLAP, 5-LO, or other leukotriene pathway gene polymorphism. The presence or absence of the leukotriene pathway gene polymorphism, or simple type, can be determined by various methods, including, for example, using enzymatic amplification, restriction fragment length polymorphism analysis, nucleic acid sequencing, electrophoretic analysis of nucleic acids from an individual, or any combination thereof. In certain embodiments, a SNP or simple type of assay may identify a patient that will respond to, or benefit from, treatment with any compound of formula (G), formula (G-I), or formula (G-II). For example, a method of diagnosing susceptibility to myocardial infarction or stroke in an individual includes determining the presence or absence of certain Single Nucleotide Polymorphisms (SNPs) or certain simple types, wherein the presence of the SNPs or simple types is diagnostic of susceptibility to myocardial infarction or stroke.
And (3) phenotype analysis: biomarkers
Patients under consideration for treatment with any compound of formula (G), formula (G-I) or formula (G-II) or a pharmaceutical combination comprising any compound of formula (G), formula (G-I) or formula (G-II) as described herein can be screened for potential responsiveness to treatment based on leukotriene-driven inflammatory biomarker phenotypes.
Patient screening based on leukotriene-driven inflammatory biomarker phenotype can be used as an alternative to, or in addition to, patient screening by simple type detection of leukotriene pathway genes. 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 may be any substance, structure, or process that can be measured in the body or its products, and which can affect or predict outcome or incidence of disease. Biomarkers can be classified as exposure, effect and susceptibility markers. The biomarker may be a physiological endpoint, for example blood pressure, or it may be an analytical endpoint, for example blood glucose or cholesterol concentration. Techniques for monitoring and/or measuring biomarkers include, but are not limited to, NMR, LC-MS/MS, GC-MS/MS, HPLC-MS/MS, FT-MS/MS, ICP-MS/MS,/protein sequencing, nucleic acid sequencing, electrophoresis techniques, immunodetection, immunostaining, in situ hybridization, fluorescent in situ hybridization, PCR, radioimmunoassay, and enzyme immunodetection. Single core acid polymorphism (SNP) has also been used to identify biomarkers for predisposition to certain diseases, as well as susceptibility or responsiveness to drugs, such as chemotherapeutic and antiviral agents. These techniques, or any combination thereof, can be used to screen patients for leukotriene-dependent or leukotriene mediated diseases or symptoms, where such patients can be advantageously treated with any compound of formula (G), formula (G-I), or formula (G-II) or a pharmaceutical combination comprising any compound of formula (G), formula (G-I), or formula (G-II) described herein.
By way of example only, a patient may be selected for treatment with any compound of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical combination comprising any compound of formula (G), formula (G-I) or formula (G-II) as described herein, by screening for enhanced inflammatory blood biomarkers such as, but not limited to, stimulated LTB4、LTC4、LTE4Myeloperoxygenase (MPO), eosinophil-lipoxygenase (EPO), C-reactive protein (CRP), soluble intracellular adhesion molecule (sICAM), single cell chemoattractant protein (MCP-1), single cell inflammatory protein (MIP-1 α), interleukin-6 (IL-6), TH2T cell activator interleukin 4(IL-4) and 13(IL-13) and other inflammatory cytokines. In certain embodiments, patients with inflammatory respiratory disease, including but not limited to asthma and COPD, or patients with cardiovascular disease are selected for their most likely responsiveness to inhibition of leukotriene synthesis, using any of the compounds of formula (G), formula (G-I) or formula (G-II), utilizing a test list of leukotriene-driven inflammatory biomarkers.
And (3) phenotype analysis: functional marker
Patients under consideration for treatment with any compound of formula (G), formula (G-I) or formula (G-II) or a pharmaceutical combination comprising any compound of formula (G), formula (G-I) or formula (G-II) as described herein can be screened for response to known modulators of the leukotriene pathway. Patient screening by assessing functional markers as indicators of patient response to known modulators of the leukotriene pathway can be used as an alternative to, or can be supplemented by, patient screening by simple type detection (genotyping) of leukotriene pathway genes, and/or monitoring/measurement of leukotriene-driven inflammatory biomarker phenotypes. Functional markers may include, but are not limited to, any physical characteristic associated with leukotriene-dependent symptoms or diseases, or knowledge of current or past medication regimens.
By way of example only, assessment of lung volume and/or function may 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 screen patients for such leukotriene-dependent or leukotriene mediated diseases or conditions for treatment with any of the compounds of formula (G), formula (G-I), or formula (G-II) or pharmaceutical compositions or agents comprising any of the compounds of formula (G), formula (G-I), or formula (G-II). Such tests include, but are not limited to, assessment of lung volume and volume, such as tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume, inspiratory volume, functional residual volume, lung capacity, total lung volume, minute volume of breathing, alveolar ventilation, timed lung capacity, and ventilation volume. Methods to measure lung volume versus volume include, but are not limited to, maximum expiratory flow volume curve, forced expiratory volume in 1 second (FEV1), peak expiratory flow rate. In addition, other pulmonary function tests used as functional markers for the patient assessment described herein include, but are not limited to, respiratory muscle capacity, highest inspiratory pressure, highest expiratory pressure, trans-diaphragm pressure, ventilation profile, single breath nitrogen test, lung nitrogen washout, and gas transfer.
In addition, knowledge of the patient's past or current therapeutic regimens may be used as a functional marker to aid in screening patients for treatment of leukotriene-dependent symptoms or diseases using any compound of formula (G), formula (G-I) or formula (G-II) or pharmaceutical compositions or agents comprising any compound of formula (G), formula (G-I) or formula (G-II). By way of example only, such therapeutic regimens may include the use of zileuton (Zyflo), a past or current treatmentTM) Montelukast (Singulair)TM) Pranlukast (Onon)TM) Zafirlukast (zafirlukast) (Acclate)TM)。
Moreover, patients contemplated to be treated with any compound of formula (G), formula (G-I), or formula (G-II) or a pharmaceutical combination comprising any compound of formula (G), formula (G-I), or formula (G-II) as described herein can be screened for functional markers including, but not limited to, reduced eosinophils and/or basophils and/or neutrophils and/or single cells and/or dendritic cells and/or lymphocytes recruitment, reduced mucosal secretion, reduced mucosal edema and/or increased bronchodilation.
Methods for identifying patients in need of treatment for leukotriene-dependent or leukotriene mediated symptoms or diseases, and exemplary, non-limiting methods of treatment, are shown in fig. 12, 13 and 14, in which patient samples are analyzed and the information obtained is used to identify possible treatments. It is contemplated that the skilled artisan will use this message in conjunction with other patient messages including, but not limited to, age, weight, sex, diet, and medical condition to select a treatment. It is also contemplated that each message will be given a specific amount in the decision process. In some embodiments, the information derived from the above diagnostic methods and any other patient information, including but not limited to age, weight, sex, diet, and medical condition, are incorporated into an algorithm for setting forth the treatment method, wherein each message is to be given a specific amount in the decision process.
In some embodiments, patient samples are analyzed for pure types of leukotriene genes, by way of example only, for FLAP-pure types, and the resulting information identifies patients in need of treatment using various therapies. Such methods of treatment include, but are not limited to, administering a therapeutically effective amount of any compound of formula (G), formula (G-I) or formula (G-II) or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II), administering a therapeutically effective amount of any compound of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II), and administering a therapeutically effective amount of a leukotriene receptor antagonist (illustratively CysLT)1/CysLT2Antagonists or CysLT1Antagonists) or administering a therapeutically effective amount of any compound of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicamentAn agent comprising any compound of formula (G), formula (G-I) or formula (G-II) in combination with a therapeutically effective amount of another anti-inflammatory agent. In other embodiments, patient samples are analyzed for leukotriene gene singleness, by way of example only, for FLAP singleness and/or phenotypic biomarker and/or phenotypic functional marker response to leukotriene modifiers. The patient may then be treated using various treatment methods. Such methods of treatment include, but are not limited to, administering a therapeutically effective amount of any compound of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II), and administering a therapeutically effective amount of a leukotriene receptor antagonist (illustratively CysLT) 1/CysLT2Antagonists or CysLT1An antagonist), or administering a therapeutically effective amount of any compound of formula (G), formula (G-I) or formula (G-II), or a pharmaceutical composition or medicament comprising any compound of formula (G), formula (G-I) or formula (G-II), in combination with a therapeutically effective amount of another anti-inflammatory agent. In yet other embodiments, patient samples are analyzed for a simple type of leukotriene gene, by way of example only, for FLAP simple type and phenotypic biomarker and phenotypic functional marker response to leukotriene modifiers. The patient may then be treated using various treatment methods. Such methods of treatment include, but are not limited to, administering a therapeutically effective amount of a FLAP inhibitor, or a pharmaceutical composition or medicament comprising a FLAP inhibitor in combination with a therapeutically effective amount of a leukotriene receptor antagonist (e.g., CysLT1/CysLT2Antagonists or CysLT1Antagonist), or administering a therapeutically effective amount of a FLAP inhibitor, or a pharmaceutical composition or medicament comprising a FLAP inhibitor in combination with a therapeutically effective amount of another anti-inflammatory agent.
Kit/article of manufacture
Kits and articles of manufacture for use in the therapeutic applications described herein are also described herein. Such kits may include a carrier, package, or container that is differentiated to accommodate one or more containers, such as vials, tubes, and the like, each container containing one of the individual components to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container may be made from a variety of materials, such as glass or plastic.
For example, the container may comprise one or more compounds described herein, optionally in a composition, or in combination with another agent as disclosed herein. The container optionally has a sterile access port (e.g., the container may be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound, along with a confirmatory description or label or instructions for its use in the methods described herein.
Kits typically may comprise one or more additional containers, each with one or more different materials (such as reagents, optionally in concentrated form, and/or devices), as desired for use of the compounds described herein from a commercial and use standpoint. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carriers, packages, containers, vials and/or tube labels to list the contents, and/or instructions for use, and package inserts with instructions for use. Typically also contains a set of instructions.
The label may be on or with the container. The label may be on the container when the letters, numbers or other words forming the label are affixed, molded or etched into the container itself; the label may accompany the container when present in a receptacle or carrier (e.g., as a package insert) that also holds the container. The label may be used to indicate that the contents are to be used for a particular therapeutic application. The label may also display directions for use of the contents, such as in the methods described herein.
Detailed description of the preferred embodiments
Examples
These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.
Preparation of intermediates useful in the synthesis of compounds of formula (G), formula (G-I) and formula (G-II)
Starting materials and intermediates for the synthesis of compounds of formula (G), formula (G-I) and formula (G-II) are commercially available or can be synthesized by synthetic methods known in the art or described herein. Some intermediates, such as those shown in table 6, which are used herein and are not commercially available, are prepared as described below. Other intermediates used in the synthesis of compounds of formula (G), formula (G-I) and formula (G-II), not specifically mentioned herein, may be prepared using methods described herein or known in the art.
TABLE 6 intermediates for the synthesis of compounds of formula (G), formula (G-I) and formula (G-II)
Figure A20068004120701431
Figure A20068004120701441
Figure A20068004120701461
Figure A20068004120701481
Route 1:
step 1: BOC protection (Int-10)
3-Monoazatetracyclic carboxylic acid (Sigma Aldrich, 0.25 g, 2.5 mmol) was dissolved in tBuOH (5 mL) and 1N NaOH (2.7 mL, 2.7 mmol). Di-tert-butyl dicarbonate (0.59 g, 2.7 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with water, slowly acidified to pH 4 with 1N HCl, and the mixture was extracted with EtOAc until all product was removed from the aqueous layer by ninhain staining. The combined organic layers were dried, filtered, and concentrated to give the desired product.
Step 2: borane reduction (Int-10)
The acid from step 1 (0.7 g, 3.5 mmol) was dissolved in THF and dissolved in N2The mixture was cooled to 0 ℃. borane-THF complex was added to the solution and the reaction was stirred at room temperature overnight. The reaction was cooled to 0 ℃ and quenched with water. The mixture was extracted 3 times with EtOAc and the combined organic layers were MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was filtered through a silica gel packed column and eluted with EtOAc to give the desired compound.
Step 3 a: br2Bromide formation (Int-10)
Triphenylphosphine (1.7 g, 6.5 mmol) was dissolved in DMF and cooled to 0 ℃. Bromine (0.31 ml, 5.9 mmol) was added slowly and the solution was stirred for 30 min. The alcohol from step 2 (0.32 g, 2.0 mmol) was added to DMF and the reaction was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc3 times, and the combined organic layers are washed with MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was filtered through a silica gel packed column and eluted with EtOAc to give the desired compound.
And step 3 b: i is2Iodide formation (Int-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 dropwise, followed by a solution of iodine (0.88 g, 3.5 mmol) in toluene. The reaction was stirred at room temperature for 15 minutes and then saturated Na was poured in 2CO3In aqueous solution. The organic layer was washed with aqueous sodium thiosulfate, water, and then MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (EtOAc: hexane gradient) to afford the desired product.
And step 3 c: tosylation (Int-21)
(S) - (-) -1- (tert-butoxycarbonyl) -2-tetrahydropyrrolemethanol (1.0 g, 5.0 mmol) was dissolved in pyridine (3 ml) and tosyl chloride (1.0 g, 5.5 mmol) was added. The reaction was stirred at room temperature overnight, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, over MgSO4Dried, filtered, and concentrated. The residue was purified on silica gel (0 to 10% EtOAc in hexanes) to give the desired product.
And step 3 d: mesylation (Int-55)
(R) - α -methyl-2-pyridinemethanol (1.0 g, 8.1 mmol) was dissolved in CH2Cl2(20 ml) and cooled to 0 ℃. Triethylamine (1.7 ml, 12.2 mmol) was added dropwise followed by methanesulfonyl chloride (0.66 ml, 8.4 mmol). The reaction was stirred for 30 minutes and then CH2Cl2Diluted, washed with water, over MgSO4Dried by dehydration, filtered, and concentrated to obtain the desired product.
Route 2:
step 1: amide formation (Int-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 ℃ and chloroacetyl chloride (0.4 ml, 5.0 mmol) was added dropwise. The reaction was stirred at-10 ℃ for 1 hour, then at room temperature for 2 hours, then quenched with water. With CH2Cl2The aqueous layer was extracted and the organic layer was dried, filtered, and concentrated to give the desired product.
Route 3:
step 1: imine formation (Int-20)
Chloroacetophenon (0.5 g, 6.6 mmol) was dissolved in Et2O (10 ml) and cooled to 0 ℃. 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 ℃ for 4 days and then concentrated to give the desired product as a white solid.
Step 2: cyclization (Int-20)
The imine from step 1 (0.3 g, 2.0 mmol) was dissolved in EtOH (4 ml) and cooled to 0 ℃.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 ℃ for 2 hours, then 4N HCl in 1, 4-dioxane (0.5 ml, 2 mmol) was added. The mixture was filtered and the filtrate was concentrated to give the desired product.
Route 4:
step 1: mCPBA oxidation (Int-46)
2, 5-lutidine (5.0 g, 46.7 mmol) was dissolved in CHCl3(125 ml) and cooled to 0 ℃. M-chloroperoxybenzoic acid (70%; 13.9 g, 55.2 mmol) was added and the reaction was stirred at room temperature overnight. Mixing the mixtureBy saturation of Na2CO3Washing with aqueous solution of Na2SO4Dried, filtered and concentrated to give the desired product.
Step 2: acetylation (Int-46)
The N-oxide from step 1 (46.7 mmol) was dissolved in acetic anhydride (25 ml) and heated to reflux at 100 ℃ over one hour. The mixture was cooled to room temperature and ethanol (46.7 mmol) was slowly added to quench the reaction. The solution was evaporated to dryness and purified on silica gel to give the desired product.
And step 3: hydrolysis (Int-46)
The acetate salt from step 2 (46.7 mmol) was dissolved in concentrated HCl (20 ml) and refluxed for 1 hour. The reaction was cooled and evaporated to dryness to give an orange solid which was used directly in the next reaction.
And 4, step 4: SOCl2Chloride formation (Int-46)
The alcohol from step 3 (1.0 g, 8.1 mmol) was dissolved in thionyl chloride (3 ml) and heated at room temperature under N 2Stirred for 30 minutes. The mixture was evaporated to dryness to give the desired product as the hydrochloride salt, which was used directly in the subsequent reaction.
Route 5:
step 1: condensation (Int-60)
P-toluidine (10 g, 60.0 mmol) and triethylamine (8.4 ml, 60.3 mmol) were dissolved in CH at room temperature2Cl2(200 ml). 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 without solvent. After 45 minutes, ice was added to form a precipitate. The mixture was stirred at room temperature overnight. The precipitate is then filtered and dissolved in CH2Cl2In the middle, in1N HCl, brine, over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was recrystallized from ethanol to give the desired quinolinone product.
Step 2: POCl3Chloride formation (Int-60)
Quinolinone from step 1 (3.12 g, 19.6 mmol) in POCl3(10 ml), heat to 90 ℃. Once no starting material remained, the reaction was immediately cooled and concentrated. The residue was taken up in EtOAc and saturated NaHCO3The aqueous solution was diluted and the aqueous layer was extracted with EtOAc. The combined organic material was dried, filtered, and concentrated to give the chloroquinoline product.
Step 3 a: NBS bromide formation (alkyl) (Int-60)
Quinoline (19.6 mmol) from step 2 was heated to 80 ℃ in benzene with NBS (3.6 g, 20.2 mmol) and catalytic dibenzoyl peroxide (200 ml) over 1 hour. The reaction mixture was concentrated and purified on silica gel to give the desired product.
And step 3 b: NBS bromide formation (aryl) (Int-118)
2-aminopyrazine (4 g, 42 mmol) was dissolved in water (2 ml) and DMSO (70 ml) and NBS (7.5 g, 42 mmol) was added at 0 ℃ over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was poured onto ice and extracted 4 times with EtOAc. The combined organic layers were washed with 5% Na2CO3Water and brine, over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired product.
And step 3 c: NCS chloride formation (Int-50)
2-fluoro-6-methylpyridine (1.11 g, 10 mmol), NCS (2.0 g, 15 mmol) and catalytic dibenzoyl peroxide were dissolved in benzene and heated to reflux overnight. The reaction was concentrated and diluted with water and EtOAc. The organic layer was washed with saturated NaHCO3Washing with aqueous solution, dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired product.
Route 6:
step 1: suzuki coupling (Int-71)
In DME/H2To (4-hydroxymethylphenyl) dihydroxyborane (Combi-Blocks; 1.0 g, 6.6 mmol) in O (16 mL, 2: 1) was added 2-bromothiazole (1.2 g, 7.2 mmol) and K2CO3(2.7 g, 19.7 mmol). Make the reactant N2Degassing for 20 minutes. Addition of Pd (PPh)3)4(0.76 g, 0.7 mmol) and the reaction was further degassed for 10 minutes. Then reacting the mixture with N2Heat to 90 ℃ overnight. 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 washed with MgSO4Dried by dehydration, filtered, concentrated, and purified on silica gel (EtOAc: hexanes gradient) to give the desired product.
Step 2 a: f-alkylation (Int-71)
The thiazole from step 1 (0.35 g, 1.8 mmol) was dissolved in THF (15 ml) and dissolved in N2Then cooled to-78 ℃. N-butyllithium (1.6M; 4.6 mL, 7.3 mmol) followed by NFSi (1.2 g, 3.7 mmol) was added dropwise. At-78 ℃ with saturated NH4The reaction was quenched with aqueous Cl and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic material was extracted with MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired compound.
And step 2 b: me-alkylation (Int-72)
The thiazole from step 1 (0.33 g, 1.7 mmol) was dissolved in THF (15 ml) and dissolved in N2Then cooled to-78 ℃. N-butyllithium (1.6M; 4.3 ml, 6.7 mmol) was added dropwise, followed by methyl iodide (0.16, 2.6 mmol). At-78 ℃ with saturated NH4Aqueous Cl solutionThe reaction was quenched and diluted with EtOAc and water. The aqueous layer was extracted twice with EtOAc and the combined organic material was extracted with MgSO4Dried, filtered, and concentrated. The residue was purified on silica gel to give the desired compound.
Route 7:
step 1: formation of acyl chloride (Int 135)
3-phenoxy-benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH2Cl2In (1). 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 acyl chloride.
Route 8:
step 1: alkylation (Int-5)
In CH2Cl2To imidazole (0.41 g, 6.0 mmol) in (b), bromoethyl-ponkan (0.21 g, 2.0 mmol) was added, 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 (Int-74)
To 4-m-tolyl-tetrahydro-pyran-4-ol (2.5 g, 13.0 mmol) in THF (50 ml) at room temperature was added sodium hydride (60%; 0.8 g, 20.0 mmol). Methyl iodide (1.25 ml, 20 mmol) was added and the reaction was stirred for 1 hour. The mixture was quenched with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired compound.
Route 10:
step 1: bromination of
4, 4-dimethyl-pentan-2-one (3.7 ml, 26.3 mmol) in MeOH (2.8 ml) at 0 deg.C andunder a single stream, bromine (1.34 ml, 26.3 mmol) was added. The reaction was slowly warmed to 10 ℃ over 30 minutes to initiate the reaction, then stirred at room temperature for an additional 15 minutes. The reaction was diluted with water and ether and the aqueous layer was extracted three times with ether. The combined organic layers were washed with MgSO4Dried, filtered, and concentrated to give the desired product as a colorless liquid.
Step 2: mercaptan addition
The bromide from step 1 (26.3 mmol) was dissolved in THF (50 ml) and the mixture was cooled to 0 ℃. 2-methyl-2-propanethiol (2.45 ml, 21.6 mmol) was added followed by triethylamine (7.9 ml, 56.8 mmol). The reaction was stirred at room temperature for 18 hours and then diluted with water. The aqueous layer was extracted with ether and the combined organic layers were washed with MgSO 4Dehydration drying, filtration, and concentration to obtain the desired product.
Synthesis of Compounds of formula (G), formula (G-I) and formula (G-II)
Reaction formula A:
Figure A20068004120701541
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
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 were prepared as outlined in reaction formula 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-3-yl) -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 ℃ for 2 days. The mixture was cooled, poured into water (2 l) and extracted with EtOAc (× 6). The organic layer was washed with brine, dried (MgSO) 4) And filtered to give a tan solid (a-1, 114 g), which is used as such in the next step.
Step 2: 4- (pyridin-2-ylmethoxy) -aniline hydrochloride
A-1(114 g) was dissolved in EtOH (1L) and to this was added water (200 mL) KOH (50 g). The solution was heated to 110 ℃ for 2 days, KOH (20 g in 100 ml water) was added, and heating continued for an additional 2 days. The solution was allowed to cool, EtOH was removed in vacuo, and the residue was partitioned between EtOAc and water. After extraction with EtOAc (× 3) in water, the organic layer was washed with brine, dried (MgSO) and concentrated4) And filtering. To this solution, saturated HCl in EtOAc was added and a precipitate formed immediately. The solid was collected by filtration and then dried under vacuum to provide the title compound (a-2, 95 g) as a pink solid.
And step 3: [4- (pyridin-2-ylmethoxy) -phenyl ] -hydrazine dihydrochloride
A-2(95 g) was dissolved in water (1L) at 0 ℃ and NaNO in water (100 mL) was added thereto2(26 g). The diazonium salt is allowed to form over 45 minutes and then slowly poured over Na at 0 deg.C2S2O4(350 g) in a rapidly stirred mixture of water (1 l) and ether (1 l) over a period of 15 minutes. Stirring was continued for 40 minutes, followed by making the mixture basic using concentrated KOH. After extraction with EtOAc (× 2), the organic layer was washed with water, then brine, dried (MgSO) and concentrated 4) And is combined withAnd (5) filtering. To this solution, saturated HCl in EtOAc was added and a precipitate formed immediately. The solid was collected by filtration and then dried under vacuum to provide the title compound as a tan solid (a-3, 75 g).
And 4, step 4: 3- [ 3-tert-Butylthio-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
Toluene (800 ml) was stirred with A-3(75 g) in HOAc (400 ml), ethyl 5- (tert-butylsulfanyl) -2, 2-dimethyl-4-oxo-pentanoate (prepared according to the procedure described in U.S. Pat. No. 5,288,743, 2.22 of 1994; 64 g), NaOAc (40 g) at room temperature for 3 days. The mixture was poured into water and taken up as solid Na2CO3Rendering it alkaline. The mixture was extracted with EtOAc (× 3), then washed with water (× 2), brine, dried (MgSO) and concentrated4) Filtered, and concentrated to give a dark red black oil. Column chromatography of the mother liquor (silica gel packed in hexane; eluting with hexane, then hexane-EtOAc 9: 1 rising to 4: 1) afforded 68 g of the title compound (A-4) as a yellow solid.
And 5: 3- [ 3-tert-Butylthio-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
Reacting 3- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl]Ethyl-2, 2-dimethyl-propionate (A-4; 20.0 g, 45.4 mmol) was dissolved in DMF (150 ml) and dissolved in N2Then cooled to-10 ℃. Sodium hydride (60% dispersion in mineral oil; 2.0 g, 50.0 mmol) was added in portions and the reaction was stirred at-10 ℃ for 45 minutes until the foam had disappeared. To this dark brown red solution, methanesulfonic acid 4- (6-methoxy-pyridin-3-yl) -ester (Int-72; 16.0 g, 54.5 mmol) in DMF was added dropwise. The reaction was then stirred at-10 ℃ for 1 hour and allowed to warm slowly to room temperature. After 16 h, LCMS confirmed the formation of the product. To saturate NH4The reaction was quenched with Cl and diluted with methyl tert-butyl ether (MTBE) and water. The aqueous phase was extracted twice with MTBE. The combined organic layersOver MgSO4Dried by dehydration, filtered, and concentrated, and the crude product was purified by column chromatography to obtain 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 ] -2, 2-dimethyl-propionic acid
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. Aqueous 3N LiOH (56 ml, 168.5 mmol) was added and the reaction was refluxed at 80 ℃ for 2 hours. LCMS confirmed the formation of the product, so the reaction was cooled to rt 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, over MgSO 4Dehydration, drying, filtration, and concentration to give the desired free acid (A-6).
Mass spectrum data 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 are shown in tables 1-4.
Note:
with respect to compounds 1-2, step 6 was not performed.
With respect to compounds 2-62, after step 6, the 6-methoxy-pyridin-3-yl group in the precursor was hydrolyzed with potassium hydroxide to obtain the 6-hydroxy-pyridin-3-yl group in the final product.
With respect to compounds 2-89, it is during step 6 that the 5-fluorothiazolyl group in the precursor is also hydrolyzed to obtain the 5-methoxythiazolyl group in the final product.
With respect to compounds 2-195, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to afford compound a-5 b.
With respect to compound 2-196, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to afford compound a-5 b.
With respect to compound 3-1, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to give compound a-5 b.
With respect to compound 3-2, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to give compound a-5 b.
With respect to compound 3-3, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to give compound a-5 b.
With respect to compound 3-4, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to give compound a-5 b.
With respect to compounds 3-5, after step 5, the Suzuki cross-coupling reaction was performed as described in example 5, step 2 to give compound a-5 b.
With respect to compound 4-1, i) during step 1, 1- (4-isopropylphenyl) hydrazine is used instead of 4-methoxyphenyl hydrazine and 1-iodo-4-bromotoluene is used instead of 4-chloro-phosphonium chloride, ii) steps 3 and 4 are not performed; the product from step 2(C-2) was used directly in step 5, iii) after hydrolysis in step 5, and Suzuki cross-coupling was performed as described in example 5, step 2 to give the final compound.
Reaction formula B:
Figure A20068004120701581
example 2: preparation of Compounds 1-4, Compounds 1-5 and Compounds 1-6
Compounds 1-4, compounds 1-5, and compounds 1-6 were prepared as outlined in reaction scheme B. A detailed description of the reaction conditions shown in equation B describes the synthesis of 1- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2-methyl-propan-2-ol.
Step 1: 4-tert-Butylthio-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 (10.8 ml, 77.4 mmol) and catalytic tetrabutylammonium bromide were dissolved in THF (250 ml) and stirred at room temperature overnight. Silica gel was added and the mixture was concentrated and filtered through a silica gel packed column to obtain the desired product (B-1) which was used without further purification.
Step 2: (3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl) -acetic acid ethyl ester
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 over 24 hours. The reaction mixture was concentrated and combined with EtOAc and saturated NaHCO3The aqueous solution was partitioned. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel (0 to 30% EtOAc in hexanes) to give the desired product (B-2).
And 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 mercaptan (21 ml, 186.7 mmol) at 0 ℃. B-2(6.0 g, 18.7 mmol) was added to CH 2Cl2(21 ml) and the reaction was allowed to warm to room temperature. After 2 hours, the reaction was complete by TLC analysis, so the solution was poured into ice and acidified with 10% aqueous HCl. The aqueous layer was extracted three times with EtOAc and the combined organic material was extracted with MgSO4Dried by dehydration, filtered, and concentrated to obtain the desired product (B-3).
And 4, 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 cooled to 0 ℃. Methylmagnesium chloride (3M; 14 ml, 42.0 mmol) was added dropwise and the reaction was stirred at room temperature for 1 hour. By NH4The reaction was quenched with aqueous Cl and extracted with EtOAc. The combined organic layers were washed with MgSO4Dried by dehydration, filtered, concentrated, and purified on silica gel to give the desired product (B-4).
And 5: 1- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2-methyl-propan-2-ol
To 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, 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 a further 16 hours. The reaction was partitioned between water and diethyl ether, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, over MgSO 4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to obtain the desired product (B-5).
Step 6: 1- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2-methyl-propan-2-ol
To 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, then 1-chloro-4-chloro-toluene (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 overnight. The reaction was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic material was washed with water, over MgSO4Dried by dehydration, filtered, and purified on silica gel (EtOAc: hexane gradient) to give the desired compound (B-6).
Mass spectrum data of the compounds 1 to 4, the compounds 1 to 5 and the compounds 1 to 6 are shown in tables 1 to 4.
Note:
with respect to the compounds 1 to 4, the compounds 1 to 5 and the compounds 1 to 6, after the step 6, Suzuki cross-coupling reaction was carried out as described in the step 2 of example 5 to obtain the compound B-6B.
Reaction formula C:
Figure A20068004120701601
example 3(X ═ Cl): (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester
Step 1: n- (4-chloro-benzyl) -N- (4-methoxy-phenyl) -hydrazine hydrochloride
4-Methoxyphenylhydrazine hydrochloride (10.0 g, 57.3 mmol), 4-chlorobenzyl chloride (9.2 g, 57.2 mmol), tetrabutylammonium bromide (3.7 g, 11.5 mmol) and diisopropylethylamine (20 ml, 115 mmol) in CH2Cl2The solution in (250 ml) was stirred at room temperature for several days. The reaction mixture was diluted with water and the organic layer was MgSO4Dehydrating, drying, filtering, and concentrating. The residue was dissolved in toluene (200 ml) and diethyl ether (100 ml) and 1 equivalent of 4N HCl in dioxane was added at 0 ℃. The mixture was stirred at room temperature for 2 hours and then evaporated to dryness to give the desired product (C-1; X ═ Cl) as 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
Toluene (120 mL) was mixed with C-1 (. about.16 g, 57-3 mmol) in HOAc (66 mL), 5- (tert-butylsulfanyl) -2, 2-dimethyl-4-oxo-pentanoic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 5,288,743 issued 2/22 of 1994; 14.8 g, 57.3Mmol), NaOAc (5.2 g), stirred at room temperature in the dark for 5 days. The mixture was partitioned between EtOAc and water, and the organic layer was partitioned with solid NaHCO 3Stirred together, filtered, and evaporated. The residue was purified on silica gel (0 to 55% CH in hexane)2Cl2) And recrystallizing the isolated product from hexane to obtain the desired product (C-2; x ═ Cl).
And 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 (0.820 g, 6.15 mmol) was suspended in tert-butyl mercaptan (1.8 ml, 16 mmol) and cooled to 0 ℃. C-2(1.0 g, 2.0 mmol) was added to 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 taken up in CH2Cl2Diluted and washed with 10% ice cold aqueous HCl. The aqueous layer was washed with CH2Cl2Extracting three times, and allowing the combined organic substances to act as MgSO4Dried by dehydration, filtered, and concentrated to give the desired product (C-3; X ═ Cl) as a colorless foam.
And 4, step 4: (S) -2- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -2- (2-ethoxycarbonyl-2-methyl-propyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester
3- [1- (4-chloro-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl ] in DMF (2.5 ml)]To ethyl-2, 2-dimethyl-propionate (C-3; 0.5 g, 1.05 mmol) were added N-BOC- (S) -2- (toluene-4-sulfonyloxymethyl) tetrahydropyrrole (0.39 g, 1.10 mmol) and Cs 2CO3(0.69 g, 2.1 mmol). The reaction was stirred at 45 ℃ for 2 hours, then potassium iodide for catalysis was added and the reaction was heated to 60 ℃ overnight. The reaction mixture was diluted with EtOAc, washed with water, and Na2SO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel (0 to 15% EtOAc in hexanes) to give the desired product (C-4; X ═ Cl).
And 5: (S) -2- [ 3-tert-butylsulfanyl-2- (2-carboxy-2-methyl-propyl) -1- (4-chloro-benzyl) -1H-indol-5-yloxymethyl ] -pyrrolidine-1-carboxylic acid tert-butyl ester (1-1)
The ester from step 4 (0.16 g, 0.26 mmol) was dissolved in MeOH (1 ml), THF (1 ml) and water (1 ml). Lithium hydroxide (0.6 g, 1.43 mmol) was added and the reaction was heated for 12 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water, over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel (0 to 40% EtOAc in hexanes) to give the desired product (C-5; X ═ Cl).
Reaction formula D:
Figure A20068004120701621
example 4: compound 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 2-32, compound 2-76, compound 2-80, compound 2-82, compound 2-84, compound 2-85, compound 2-99, compound 2-100, compound 2-101, compound, 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 2-191, compound 2-193, compound 2-197, and compound 2-200, Preparation of 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
Compound 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 2-32, compound 2-76, compound 2-80, compound 2-82, compound 2-84, compound 2-85, compound 2-99, compound 2-100, compound 2-101, compound, 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, the compound 2-221, the compound 2-222, the compound 2-223, the compound 2-224, the compound 2-225, the compound 2-226, the compound 2-227, the compound 2-228, the compound 2-229, the compound 2-230, the compound 2-231, the compound 2-232, the compound 2-233, the compound 2-234, and the compound 4-2 are prepared as shown in reaction formula D. A detailed illustrative example of the reaction conditions shown in equation 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 acid (compound 2-141).
Step 1: 3- { 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-dimethyl-propionic acid ethyl ester
Phenol (C-3, X ═ Br; 35.0 g, 67.5 mmol), bis (pin Kelyl) diboron (Combi-Blocks; 25.0 g, 98.4 mmol) and KOAc (19.9 g, 209.1 mmol) from step 3 of example 3 were dissolved in 1, 4-dioxane (350 ml) and treated with N2Degassed over 30 minutes. Addition of PdCl2dppf (2.5 g, 3.1 mmol) and the reaction mixture was stirred with N2And degassed for an additional 30 minutes. The reaction was heated at 85 ℃ 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, over MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (15% EtOAc in hexanes) to give the desired product (D-1, 33.5 g).
Step 2: 3- { 3-tert-Butylthio-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
D-1(25.34 g, 44.8 mmol), 5-bromo-2-methoxypyridine (Combi-Blocks; 10.9 g, 70.3 mmol) and K were combined 2CO3(15.5 g, 112.1 mmol) was dissolved in DME (300 mL) and water (150 mL) and treated with N2Degassing for 30 minutes. Addition of Pd (PPh)3)4(1.6 g, 1.4 mmol) and reacting the mixture with N2Degassing was carried out for a further 15 minutes. The solution was heated to 80 ℃ overnight, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were washed with water, brine, MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (0 to 8% EtOAc in hexanes) to give the desired product (D-2, 23.7 g).
And step 3: 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 acid ethyl ester
3- { 3-tert-Butylthio-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl in MeCN (75 mL)]-1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl esterTo the ester (D-2; 6.5 g, 11.9 mmol) was added 2-bromomethyl-6-fluoro-quinoline (3.14 g, 13.1 mmol) and Cs2CO3(9.7 g, 29.8 mmol). After LCMS showed the reaction was complete, the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were over MgSO 4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (D-3, 7.6 g).
And 4, step 4: 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 acid
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 ℃ for 6 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water, over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was triturated overnight with hexanes: EtOAc (9: 1) and filtered to give the desired product (D-4, 5.9 g).
Compound 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 2-32, compound 2-76, compound 2-80, compound 2-82, compound 2-84, compound 2-85, compound 2-99, compound 2-100, compound 2-101, compound, Mass spectrum data of 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.
Note:
with respect to compounds 2-33, during step 3, the imidazole was also alkylated to obtain the final product.
With respect to compounds 2-79, during step 4, the ethyl ester of the precursor was also hydrolyzed to obtain the acid in the final product.
With respect to compounds 2-80, the ketone in the precursor is reduced with sodium borohydride after step 3 to obtain the alcohol in the final product.
With respect to compounds 2-100, during step 4, the 6-fluoropyridyl group in the precursor is also hydrolyzed to obtain the 6-methoxypyridyl group in the final product.
For compounds 2-104, after step 3, the 6-bromopyridyl group in the precursor was subjected to the Suzuki cross-coupling reaction as described in example 5, step 2, to give the 6-cyclopropylpyridyl group in the final product.
With respect to compound 4-2, step 3 was not performed.
Reaction formula E:
Figure A20068004120701661
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
Compounds 2-30, compounds 2-64, compounds 2-73, compounds 2-87, compounds 2-88, compounds 2-97, compounds 2-107, and compounds 2-121 are prepared as shown in reaction E. A detailed description of the reaction conditions shown in equation E describes the synthesis of 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 acid (compound 2-73).
Step 1: 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl ] in DMF (2 ml)]To ethyl 2, 2-dimethyl-propionate (C-3; 0.25 g, 0.48 mmol) were added 2-chloromethyl-5-methyl-pyridine hydrochloride (0.13 g, 0.72 mmol), Cs2CO3(0.39 g, 1.21 mmol) and tetrabutylammonium iodide for catalysis. After LCMS showed the reaction was complete, the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were over MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (0 to 15% EtOAc in hexanes) to give additional desired product (E-1, 0.30 g).
Step 2: 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 acid ethyl ester
E-1(0.06 g, 0.10 mmol), 2-methoxy-pyridine-5-dihydroxyborane (0.02 g, 0.14 mmol) and K2CO3(0.03 g, 0.24 mmol) was dissolved in DME (1 mL) and water (0.5 mL) and treated with N 2Degassing for 10 minutes. Addition of Pd (PPh)3)4(0.01 g, 0.01 mmol) and reacting the reaction mixture with N2And degassed for another 10 minutes. The solution was heated to 80 ℃ for 4 hours, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were washed with water, brine, MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (0 to 50% EtOAc in hexanes) to give the desired product (E-2).
And step 3: 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 acid
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 ℃ for 4 hours until no starting material was observed by LCMS. The reaction was diluted with water and EtOAc, acidified to pH 5 with citric acid, and extracted with EtOAc. The combined organic layers were washed with water, over MgSO4Dehydration, drying, filtration, and concentration gave the desired product (F-4).
Mass spectrum data of the compounds 2 to 30, the compounds 2 to 64, the compounds 2 to 73, the compounds 2 to 87, the compounds 2 to 88, the compounds 2 to 97, the compounds 2 to 107 and the compounds 2 to 121 are shown in tables 1 to 4.
Note:
with respect to compounds 2-64, steps 2 and 3 were performed in reverse order.
With respect to compounds 2-87, during step 3, the 5-cyanopyridyl group in the precursor is also hydrolyzed to obtain the 5-carbamoylpyridinyl group in the final product.
With respect to compounds 2-88, steps 2 and 3 were performed in reverse order.
With respect to compounds 2-97, during step 3, the 6-cyanopyridyl group in the precursor is also hydrolyzed to obtain the 6-carbamoylpyridinyl group in the final product.
Reaction formula F:
Figure A20068004120701681
example 6: 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 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 2-4, 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, 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 2-110, compound 2-119, compound 2-120, compound 2-125, compound 2-126, compound 2-127, compound 2-142, compound 2-143, compound, 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, preparation of 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.
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 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 2-4, 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, 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 2-110, compound 2-119, compound 2-120, compound 2-125, compound 2-126, compound 2-127, compound 2-142, compound 2-143, compound, 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 prepared as shown in reaction formula F. A detailed example of the reaction conditions shown in equation F is described for the synthesis of 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 acid (compound 2-140).
Step 1: 3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid ethyl ester
3- [1- (4-bromo-benzyl) -3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl ] in MeCN (25 ml)]To ethyl-2, 2-dimethyl-propionate (C-3; 2.0 g, 3.9 mmol) was added 2-bromomethyl-6-fluoro-quinoline (1.0 g, 4.2 mmol) and Cs2CO3(2.5 g, 7.7 mmol). After LCMS showed the reaction was complete, the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was taken up in EtOAc: recrystallization from hexane gave 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: 3- { 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-dimethyl-propionic acid ethyl ester
F-1(1.0 g, 1.5 mmol), bis ( Kelyl) diboron (Combi-Blocks; 1.1 g, 4.3 mmol) and KOAc (0.44 g, 4.5 mmol) were dissolved in 1, 4-dioxane (15 ml) and heated in a sealed vessel with N 2Degassing for 10 minutes. Addition of PdCl2dppf (0.13 g, 0.16 mmol) and the reaction mixture was stirred with N2And degassed for another 10 minutes. The vessel was sealed and the reaction was heated at 95 ℃ 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, and MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (0 to 20% EtOAc in hexanes) to give the desired product (F-2).
And step 3: 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 acid ethyl ester
F-2(0.25 g, 0.35 mmol), 2-bromo-6-methoxypyridine (0.09 g, 0.48 mmol) and K2CO3(0.15 g, 1.05 mmol) was dissolved in DME (3.5 mL) and water (1.8 mL) and treated with N2Degassing for 10 minutes. Addition of Pd (PPh)3)4(0.06 g, 0.05 mmol) and allowing the reaction mixture to stand N2And degassed for another 10 minutes. The solution was heated to 85 ℃ for 4 hours, then cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were washed with water, brine, MgSO4Dehydrating, drying, filtering, and concentrating. The crude material was purified on silica gel (0 to 25% EtOAc in hexanes) to give the desired product (F-3).
And 4, step 4: 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 acid
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 ℃ for 3.5 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water, over MgSO4Dehydration, drying, filtration, and concentration gave the desired product (F-4).
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 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 2-4, 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, 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 2-110, compound 2-119, compound 2-120, compound 2-125, compound 2-126, compound 2-127, compound 2-142, compound 2-143, compound, 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, mass spectrum data of 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.
Note:
with respect to compounds 2-17, it was during step 4 that the 6-methoxypyridazinyl group in the precursor was also hydrolysed, obtaining the 6-hydroxypyridazinyl group in the final product.
With respect to compounds 2-172, after step 2, the 3-tert-butylthio group in the precursor was oxidized with m-chloroperoxybenzoic acid to obtain the 2-methylpropane-2-sulfonyl group in the final product.
With respect to compound 2-173, the 3-tert-butylthio moiety in the precursor was oxidized with m-chloroperoxybenzoic acid after step 2 to obtain the 2-methylpropane-2-sulfinyl moiety in the final product.
Reaction formula G:
example 7: 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid step 1: 3- { 3-tert-Butylthio-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 acid ethyl ester
Reacting (S) -2- { 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 tert-butyl ester (0.23 g, 0.30 mmol) in CH 2Cl2(1.5 ml). TFA (1.5 ml) was added and the reaction was stirred at room temperature for 10 min until no starting material was observed by TLC analysis. The solution was concentrated in vacuo and the crude product (G-1) was used without further purification.
Step 2: 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
Dissolving G-1(0.30 mmol) in CH2Cl2(1 ml). Diisopropylethylamine (0.5 ml) was added followed by acetic anhydride (33 μ l, 0.35 mmol) and the reaction was stirred at room temperature until no starting material was observed by LCMS. Reacting with CH2Cl2Diluting with MeOH, concentrating, and redissolving in CH2Cl2Washed with water and Na2SO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired product (G-2).
And step 3: 3- {5- ((S) -1-acetyl-2, 3-dihydro-1H-indol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
G-2 (0.05G, 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 ℃ for 6 hours until no starting material was observed by TLC analysis. The reaction was diluted with water, acidified to pH 5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water, over MgSO 4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired product (G-3).
Reaction formula H:
example 8: 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; preparation of Compound 2-132, Compound 2-133, Compound 2-134, Compound 2-163, Compound 2-170, and Compound 2-194
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; compounds 2-132, compounds 2-133, compounds 2-134, compounds 2-163, compounds 2-170, and compounds 2-194 are prepared as shown in reaction scheme H. A detailed description of the reaction conditions shown in reaction scheme H describes the synthesis of 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-124).
Step 1: 3- {5- (benzothiazol-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
Aluminium chloride (0.18 g, 1.37 mmol) was suspended in CH2Cl2(1 ml) and water (19 μ l, 1.0 mmol) was slowly added at room temperature. The mixture was stirred for 5 minutes and then cooled to 0 ℃. 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl]-1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester (0.12 g, 0.17 mmol) was added to CH2Cl2(1 ml) and the reaction was stirred at room temperature for 2 hours. Once no starting material was observed by tlc, water was added and CH was added2Cl2The mixture is extracted. The combined organic layers were washed with water, over MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified to obtain the desired product (H-1).
Step 2: 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
To H-1(0.10 g, 0.17 mmol) in dichloroethane (5 mL) was added cyclobutanecarbonyl chloride (57. mu.L, 0.50 mmol) and aluminum chloride (0.09 g, 0.66 mmol). Reacting the reactant with N2The reaction was heated for 1.5 hours, then cooled to room temperature and quenched with saturated aqueous potassium sodium tartrate. The mixture was extracted with EtOAc and the combined organic layers were washed with MgSO4Dried by dehydration, filtered, concentrated, and purified on silica gel to give the desired product (H-2).
And step 3: 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid ethyl ester
H-2(0.05 g, 0.08 mmol) was suspended in CH2Cl2To a solution, and sodium borohydride (0.03 g, 0.8 mmol) was added dropwise to TFA (1 ml) and CH2Cl2(1 ml). The mixture was stirred at room temperature for 4 hours, then the reaction was quenched with water and basified with solid NaOH pellets. With CH2Cl2The mixture was extracted and the combined organic material was washed with MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel to give the desired product (H-3).
And 4, step 4: 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid
H-3(0.03 g, 0.04 mmol) was dissolved in MeOH (0.5 ml) and THF (0.5 ml). Aqueous lithium hydroxide (1N, 0.5 ml) was added and the reaction was heated at 60 ℃ for 4 hours until no starting material was observed by LCMS. The reaction was diluted with water, acidified to pH 5 with citric acid and extracted with EtOAc. The combined organic layers were washed with water, over MgSO 4Dehydration, drying, filtration, and concentration gave the desired product (H-4).
Mass spectrum data 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 are shown in tables 1-4.
Note:
with respect to compounds 2-8, only steps 1, 2 and 4 were performed.
With respect to compounds 2-9, only steps 1 and 4 were performed.
With respect to compounds 2-10, only steps 1, 2 and 4 were performed.
With respect to compounds 2-11, only steps 1 and 4 were performed.
With respect to compounds 2-12, only steps 1, 2 and 4 were performed.
With respect to compounds 2-15, only steps 1, 2 and 4 were performed.
With respect to compounds 2-16, only steps 1, 2 and 4 were performed.
With respect to compounds 2-25, only steps 1 and 4 were performed.
With respect to compounds 2-26, only steps 1, 2 and 4 were performed.
With respect to compounds 2-27, only steps 1 and 4 were performed.
With respect to compounds 2-28, only steps 1, 2 and 4 were performed.
For compounds 2-123, only steps 1, 2 and 4 were performed.
Reaction formula I:
Figure A20068004120701751
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 1-12, Compound 1-13, Compound 1-14, and Compound 1-15
Compounds 1-1, compounds 1-3, compounds 1-7, compounds 1-8, compounds 1-9, compounds 1-10, compounds 1-11, compounds 1-12, compounds 1-13, compounds 1-14, and compounds 1-15 were prepared as outlined in reaction formula I. A detailed illustrative example of the reaction conditions shown in reaction scheme H is described with respect to 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: 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl ] -2, 2-dimethyl-propionyl chloride
In the suspension in CH2Cl23- [ 3-tert-Butylthio-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl in (5 ml)]To 2, 2-dimethyl-propionic acid (made according to the procedure described in us patent 5,081,138 issued on 1/14 1992; 0.25 g, 0.53 mmol) was added oxalyl chloride (48 μ l, 0.56 mmol) with catalytic DMF. The reaction was stirred at room temperature for 3 hours and then concentrated to give I-1, which was used without further purification.
Step 2: 3- [ 3-tert-butylsulfanyl-1- (4-chloro-benzyl) -5-isopropyl-1H-indol-2-yl ] -N- (2-hydroxy-ethyl) -2, 2-dimethyl-propionamide
In CH2Cl2To I-1(0.18 mmol) in (1), triethylamine (0.1 mL, 0.70 mmol) and 2-aminoethanol (10. mu.L, 0.19 mmol) were added. The reaction was stirred at room temperature for 2 days, then concentrated and purified on silica gel (EtOAc: hexane gradient) to afford the desired product (I-2).
And step 3: 5- {4- [ 3-tert-butylsulfanyl-2- (2, 2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl ] -phenyl } - [1, 3, 4] oxadiazol-2-ylamine
4- [ 3-tert-Butylthio-2- (2, 2-dimethyl-propyl) -5- (pyridin-2-ylmethoxy) -indol-1-ylmethyl in DMF (1 ml)]To benzoic acid hydrazide (0.05 g, 0.10 mmol), add C- (di-imidazol-1-yl) -methylamine (0.08 g, 0.5 mmol)0 mmol) and the reaction was heated at 85 ℃ for 3 hours. The mixture was cooled to rt and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were MgSO4Dehydrating, drying, filtering, and concentrating. The residue was purified on silica gel (EtOAc: hexane gradient) to afford the desired product.
Mass spectrum data of compound 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. NMR data of the compounds 1 to 3 are shown below.
Note:
with respect to the compounds 1 to 3,1H NMR(CDCl3)δ8.6(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).
with respect to compounds 1-7, the hydrazide I-2 was converted to 1, 3, 4-oxadiazol-2-yl I-3 during step 3 using triethyl orthoformate.
With respect to compound 1-8, I) hydrazide I-2 was made directly from ester I-4, ii) during step 3, hydrazide I-2 was converted to 1, 3, 4-oxadiazol-2-yl I-3 using triethyl orthoformate.
With respect to compounds 1-9, I) hydrazide I-2 was prepared directly from ester I-4, ii) hydrazide I-2 was converted to 1, 3, 4-oxadiazol-2-ylamine I-3 during step 3 using cyanogen bromide and sodium bicarbonate.
With respect to compounds 1-14, the hydrazide I-2 was converted to 1, 3, 4-oxadiazol-2-ylamine I-3 during step 3 using C- (di-imidazol-1-yl) -methylene amine.
Example 10: FLAP binding assay
Non-limiting examples of such FLAP binding assays are as follows:
the pellets (1.8X 10) filled with human polymorphonuclear cells9Cells) (biol. special products) were resuspended, lysed, and 100,000 grams of cell membrane were prepared as described (Charles et al mol. Pharmacol, 41, 873-879, 1992). Resuspend 100,000 g of the pelleted cell membrane in Tris-Tween assay buffer (100mM Tris HCl pH 7.4, 140mM NaCl, 2mM EDTA, 0.5mM DTT, 5% glycerol, 0.05% Tween 20) resulted in protein concentrations of 50-100. mu.g/ml. Add 10. mu.l of cell membrane suspension to 96 well microwell plates, 78. mu.l of Tris-Tween buffer, 10. mu.l 3HMK 886 or3H3- [5- (pyridin-2-ylmethoxy) -3-tert-butylsulfanyl-1-benzyl-indol-2-yl]-2, 2-dimethylpropionic acid (or125MK591 derivatives, Eggler et al J. laboratory Compounds and Radiopharmaceuticals, 1994, vXXXIV, 1147) to 30,000cpm, 2 microliters of inhibitor, and incubated at room temperature for 30 minutes. 100 microliters of ice-cold wash buffer was added to the culture mixture. The plates were then filtered and washed 3x with 200 μ l ice-cold Tris-Tween buffer, and the scintillation bottom was sealed. 100 μ l of scintillator was added, shaken for 15 min, and then counted in TopCount. Specific binding was determined, which was defined as total radioactive binding minus non-specific binding in the presence of 10 μ M MK 886. IC (integrated circuit)50Is determined by GraphPad Prism analysis using a drug titration curve.
Example 11: human blood LTB4Inhibition detection
Such human blood LTB4Non-limiting examples of inhibition detection are as follows:
blood was drawn from consenting human volunteers into heparinized tubes and 125 microliters aliquots were added to wells containing 2.5 microliters of drug in 50% DMSO (vehicle) or 2.5 microliters of 50% DMSO. The samples were incubated at 37 ℃ for 15 minutes. 2 microliter of calcium ionophore A23817 (a 50mM DMSO stock was diluted to 1.25mM in Hanks Balanced salt solution (Invitrogen) just before detection), the solutions were mixed and incubated at 37 ℃ for 30 minutes. Samples were centrifuged at 1,000rpm (. about.200 Xg) for 10 minutes at 4 deg.C Plasma was removed and tested using ELISA (test design) for 1: LTB in 100 dilutions4And (4) concentration. Achievement of mediator LTB4The drug concentration at 50% inhibition (IC50) was determined by non-linear regression (GraphPadPrism) of% inhibition versus log drug concentration.
Example 12: rat peritoneal inflammation and edema detection
Non-limiting examples of such rat peritoneal inflammation and edema detection are as follows:
the in vivo efficacy of leukotriene biosynthesis inhibitors was assessed using the rat model of peritoneal inflammation. Male Stepogoni (Sprague-Dawley) white rats (200-. The compounds were administered orally (3 ml/kg in 0.5% methylcellulose vehicle) 2 to 4 hours prior to zymosan injection. One to two hours after zymosan injection, rats were euthanized and the peritoneal cavity was rinsed with 10 ml of Phosphate Buffered Saline (PBS). The resulting fluid was centrifuged at 1,200rpm for 10 minutes. Vascular edema was assessed using a spectrophotometer (absorbance 610 nm) by quantifying the amount of evans blue dye in the supernatant. LTB in supernatant 4The concentration of leukotrienes was determined by ELISA. Achieving 50% inhibition of plasma leakage (Evans blue dye) with peritoneal LTB4And the inhibitory drug concentration of cysteaminyl leukotriene, can be calculated by nonlinear regression (GraphPad Prism) of% inhibition versus log drug concentration.
Example 13: human leukocyte inhibition assay
Non-limiting examples of human leukocyte inhibition assays are as follows:
blood was drawn from consenting human volunteers into heparinized tubes and equal volumes of 3% dextran, 0.9% saline were added. In red blood cellsAfter sedimentation, hypotonic lysis of the remaining erythrocytes was performed and the leukocytes were allowed to sediment at 1000 rpm. Pellet at 1.25x105The cells/ml were resuspended and aliquoted into wells containing 2.5 microliters of 20% DMSO (vehicle) or 2.5 microliters of drug in 20% DMSO. The samples were incubated at 37 ℃ for 5 minutes and 2 microliters of calcium ionophore A23817 were added (immediately before detection, 50mM DMSO stock was diluted to 1.25mM in Hanks Balanced salt solution (Invitrogen)), the solutions were mixed and incubated at 37 ℃ for 30 minutes. The samples were centrifuged at 1,000rpm (-200 x grams) for 10 minutes at 4 ℃, plasma was removed, and 1: LTB in 4 dilutions 4And (4) concentration. Achievement of mediator LTB4The drug concentration at 50% inhibition (IC50) was determined by non-linear regression of% inhibition versus log drug concentration (GraphPad Prism). The compounds presented in tables 1-4 are those with a detection value of 1nM to 5. mu.M in this assay.
Example 14: pharmaceutical composition
Example 14 a: parenteral composition
To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of any water-soluble salt of a compound of formula (G), formula (G-I) or formula (G-II) is dissolved in DMSO and then mixed with 10 ml of 0.9% sterile saline. The mixture is incorporated into dosage unit forms suitable for administration by injection.
Example 14 b: oral composition
To prepare a pharmaceutical composition for oral delivery, 100 mg of any compound of formula (G), formula (G-I) or formula (G-II) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.
Example 14 c: sublingual (hard tablet) compositions
To prepare a pharmaceutical composition for buccal delivery, such as a hard tablet, 100 mg of any compound of formula (G), formula (G-I) or formula (G-II) is mixed with 420 mg of powdered sugar, which is mixed with 1.6 ml of corn syrup, 2.4 ml of distilled water and 0.42 ml of peppermint extract. The mixture was gently blended and poured into molds to form tablets suitable for buccal administration.
Example 14 d: inhalation composition
To prepare a pharmaceutical composition for inhalation delivery, 20 mg of any compound of formula (G), formula (G-I) or formula (G-II) is mixed with 50 mg of anhydrous citric acid and 100 ml of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as an aerosol can, which is suitable for inhalation administration.
Example 14 e: rectal gel composition
To prepare a pharmaceutical composition for rectal delivery, 100 mg of any compound of formula (G), formula (G-I) or formula (G-II) is mixed with 2.5G of methylcellulose (1500mPa), 100 mg of methyl paraben, 5G of glycerol and 100 ml of purified water. The resulting gel mixture is then incorporated into a rectal delivery unit, such as a syringe, which is suitable for rectal administration.
Example 14 f: topical gel compositions
To prepare a pharmaceutical topical gel composition, 100 mg of any compound of formula (G), formula (G-I), or formula (G-II) is mixed with 1.75G of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate, and 100 ml of purified alcohol USP. The gel mixture formed is then incorporated into a container, such as a tube, which is suitable for topical administration.
Example 14 g: ophthalmic solution composition
To prepare a pharmaceutical ophthalmic solution composition, 100 mg of any compound of formula (G), formula (G-I) or formula (G-II) is mixed with 0.9G NaCl in 100 ml of pure water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eyedrop container, which is suitable for ophthalmic administration.
The embodiments and examples set forth herein are presented for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and the scope of the appended claims, all publications, patents and patent applications cited herein are hereby incorporated herein by reference for all purposes.

Claims (21)

1. A compound having the structure of formula (G):
Figure A2006800412070002C1
wherein,
z is selected from [ C (R)1)2]m[C(R2)2]n、[C(R2)2]n[C(R1)2]mO、
O[C(R1)2]m[C(R2)2]n、[C(R2)2]nO[C(R1)2]nOr
[C(R1)2]nO[C(R2)2]nWherein each R1Is independently H, CF3Or optionally substituted lower alkyl, and two R on the same carbon1Can be joined to form a carbonyl (═ O); and each R2Is independently H, OH, OMe, CF3Or optionally substituted lower alkyl, and two R on the same carbon2Can 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);
wherein each substituent on Y or Z is (L)SRS)jWherein each LSIs independently selected from a bond, -O-, -C (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) -or a substituted or unsubstituted C1-C6Alkyl radical, C2-C6Alkenyl, -C1-C6Fluoroalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; and each RSIs independently selected from H, halogen, -N (R)4)2、-CN、-NO2、N3、-S(＝O)2NH2Substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, -C1-C6Fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroalkyl; wherein j is 0, 1, 2, 3 or 4;
R6Is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or not)Substituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heterocycles), L2- (substituted or unsubstituted heteroaryl) or L2- (substituted or unsubstituted aryl) in which L2A bond, O, S, -S (O)2C (O), -CH (OH), -C (substituted or unsubstituted)1-C6Alkyl) or- (substituted or unsubstituted C2-C6Alkenyl);
R7is L3-X-L4-G1Wherein
L3is 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-；
L4Is a bond or a substituted or unsubstituted alkyl group;
G1is 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)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) in which L5is-OC (O) O-, -NHC (O) NH-, -NHC (O) O, -O (O) CNH-, -NHC (O), -C (O) NH, -C (O) O or-OC (O);
or G1Is W-G5Wherein W is substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, or substituted or unsubstituted heteroaryl, and G 5Is 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)NR9C(＝NR10)N(R9)2、-C(O)NR9C(＝CR10)N(R9)2、-CO2R9、-C(O)R9、-CON(R9)2、-SR8、-S(＝O)R8or-S (═ O)2R8；
Each R8Is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
each R9Is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl; or two R9The groups may together form a 5-, 6-, 7-or 8-membered heterocyclic ring; or R8And R9May together form a 5-, 6-, 7-or 8-membered heterocyclic ring, and
each R10Is independently selected from H, -S (═ O)2R8、-S(＝O)2NH2-C(O)R8、-CN、-NO2Heteroaryl or heteroalkyl;
R5is H, halogen, substituted or unsubstituted C1-C6Alkyl, substitutedOr unsubstituted O-C1-C6An alkyl group;
R11is L7-L10-G6Wherein L is7Is a bond, -C (O) NH, -NHC (O) or (substituted or unsubstituted C)1-C6Alkyl groups); l is10Is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heterocycle);
G6is OR9、-C(＝O)R9、-C(＝O)OR9、-SR8、-S(＝O)R8、-S(＝O)2R8、N(R9)2Tetrazolyl, -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 or unsubstituted aryl) in which L5is-O-, C (═ O), S, S (═ O), S (═ O)2-NH, -NHC (O) O, -NHC (O) NH-, -OC (O) O-, -OC (O) NH-, -NHC (O), -C (O) NH, -C (O) O, or-OC (O);
or G6Is W-G7Wherein W is (substituted or unsubstituted heterocycle), (substituted or unsubstituted aryl) or (substituted or unsubstituted heteroaryl), and G7Is H, halogen, CN, NO2、N3、CF3、OCF3、C1-C6Alkyl radical, C3-C6Cycloalkyl, -C1-C6Fluoroalkyl, tetrazolyl and substituted fluoroalkylNHS(＝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)R8or-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 heterocycles) or-L5- (substituted or unsubstituted aryl) in which L5Is 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 R11Comprising at least one (unsubstituted or substituted) aromatic moiety and at least one (unsubstituted or substituted) cyclic moiety, wherein the (unsubstituted or substituted) cyclic moiety is an (unsubstituted or substituted) heterocyclic moiety or an (unsubstituted or substituted) heteroaryl, and R 11Is not thienyl-phenyl;
R12is H, (substituted or unsubstituted C1-C6Alkyl group), (substituted or unsubstituted C3-C6Cycloalkyl groups);
or an active metabolite, or solvate, or pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.
2. The compound of claim 1, wherein Z is [ C (R)2)2]nC(R1)2O。
3. The compound of claim 2, wherein Y is- (substituted or unsubstituted heteroaryl) or- (substituted or unsubstituted aryl), and G6Is W-G7。
4. The compound of claim 1, wherein Y is- (substituted or unsubstituted heteroaryl).
5. The compound of claim 4, wherein Y is selected from the group consisting of pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo [1, 2-a ] pyridyl, thienopyridyl, and furopyridyl, wherein Y is substituted or unsubstituted.
6. The compound of claim 5, wherein Y is selected from the group consisting of pyridyl or quinolyl, wherein Y is substituted or unsubstituted.
7. The compound of claim 1, wherein R6Is L2- (substituted or unsubstituted alkyl) or L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted aryl) in which L2Is a bond, O, S, -S (O)2-C (O) or substituted or unsubstituted alkyl.
8. A compound according to claim 1, wherein X is a bond, O, -C (═ O), -CR9(OR9)、S、-S(＝O)、-S(＝O)2、-NR9、-NR9C(O)、-C(O)NR9。
9. The compound of claim 1, wherein G1Is 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)R8or-S (═ O)2R8。
10. The compound of claim 1, wherein L3Is unsubstituted alkyl; x is a bond; l is4Is a bond; and G1is-C (O) OR9。
11. The compound of claim 10, wherein R9Is H or unsubstituted alkyl.
12. The compound of claim 1, wherein L10Is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and G6Is W-G7Wherein W is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle.
13. The compound of claim 12, wherein L10Is a substituted or unsubstituted aryl group.
14. The compound of claim 1, wherein L 3Is unsubstituted alkyl; x is a bond; l is4Is a bond; and G1is-OR9。
15. The compound of claim 1, wherein G1Is W-G5Wherein W is a substituted or unsubstituted heterocycle or a substituted or unsubstituted heteroaryl.
16. A compound selected from the group consisting of:
3- [ 3-tert-butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -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 ] -2, 2-dimethyl-propionic acid ethyl ester (compound 1-2); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid 6-hydroxy-hexyl ester (compound 1-3); 1- [ 3-tert-butylsulfanyl-1- (4-pyridin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-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) -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) -1H-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 (compounds 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) -1H-indole (compound 1-8); 5- {2- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -1, 1-dimethyl-ethyl } - [1, 3, 4] oxadiazol-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- (pyridin-2-ylmethoxy) -1H-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 (compounds 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-propionylguanidine (compound 1-15); 3- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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); - [ 3-tert-butylsulfanyl-1- (4-pyridin-3-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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-butylsulfanyl-1- (4-pyrazin-2-yl-benzyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-5); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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 ] -2, 2-dimethyl-propionic acid (compound 2-7); 3- [3- (3, 3-dimethyl-butyryl) -5- (pyridin-2-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-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) -1H-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-dimethyl-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-dimethyl-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, 2-dimethyl-propionic acid (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 ] -2, 2-dimethyl-propionic acid (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 ] -2, 2-dimethyl-propionic acid (compound 2-19); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methyl-pyridazin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-20); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methyl-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (2-methyl-thiazol-4-ylmethoxy) -1H-indol-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-dimethyl-butyryl) -5- (2-methyl-thiazol-4-ylmethoxy) -1- (4-thiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-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, 2-dimethyl-propionic acid (compound 2-27); 3- [3- (3, 3-dimethyl-butyryl) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (2-methyl-thiazol-4-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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); 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (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-dimethyl-propionic acid (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-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 ] -2, 2-dimethyl-propionic acid (compound 2-34); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-35); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methyl-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-39); 3- [ 3-tert-butylsulfanyl-1- [4- (3, 5-dimethyl-isoxazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-41); 3- [ 3-tert-butylsulfanyl-1- [4- (3-methyl-3H-imidazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-43); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-47); 3- [ 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- (4- [1, 3, 4] oxadiazol-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-55); 3- [ 3-tert-butylsulfanyl-1- [4- (6-hydroxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-62); 3- [ 3-tert-butylsulfanyl-1- [4- (6-cyano-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-64); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-65); 3- [ 3-tert-butylsulfanyl-1- [4- (2-methoxy-pyrimidin-5-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-67); 3- [ 3-tert-butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-68); 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 acid (compound 2-73); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-76); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-77); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-78); 3- [ 3-tert-butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-82); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-84); 3- [ 3-tert-butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-85); 3- [ 3-tert-butylsulfanyl-1- [4- (5-carbamoyl-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-87); 3- [ 3-tert-butylsulfanyl-1- [4- (5-cyano-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-88); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methoxy-thiazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-89); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methyl-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-90); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-91); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-92); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methyl-1H-imidazol-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-93); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-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, 2-dimethyl-propionic acid (compound 2-95); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-96); 3- [ 3-tert-butylsulfanyl-1- [4- (6-carbamoyl-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-97); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-98); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-99); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (6-methoxy-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-100); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (6-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-101); 3- { 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-102); 3- { 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-103); 3- { 3-tert-butylsulfanyl-5- (6-cyclopropyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-104); 3- [ 3-tert-butylsulfanyl-1- [4- (5-methyl-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-105); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-106); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-107); 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 acid (compound 2-108); 3- { 3-tert-butylsulfanyl-5- ((S) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-109); 3- { 3-tert-butylsulfanyl-5- ((R) -1-pyridin-2-yl-ethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-110); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- ((S) -1-pyridin-2-yl-ethoxy) -1H-indol-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-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-112); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -5- ((S) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-113); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-2-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-114); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- ((S) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-115); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-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) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-117); 3- { 3-tert-butylsulfanyl-5- (3-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-118); 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 acid (compound 2-119); 3- { 3-tert-butylsulfanyl-5- (3, 5-dimethyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-120); 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-121); 3- {5- (benzothiazol-2-ylmethoxy) -3-tert-butylsulfanyl-1- [4- (5-methoxy-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-122); 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutanecarbonyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-123); 3- {5- (benzothiazol-2-ylmethoxy) -3-cyclobutylmethyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-124); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-125); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (5-ethyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-126); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-127); 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 acid (compound 2-128); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-129); 3- [ 3-tert-butylsulfanyl-1- [4- (2-methoxy-thiazol-4-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -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) -1H-indol-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-dimethyl-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 ] -2, 2-dimethyl-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 acid (compound 2-134); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-135); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-136); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-137); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-138); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-139); 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 acid (compound 2-140); 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 acid (compound 2-141); 3- [ 3-tert-butylsulfanyl-1- [4- (2-ethoxythiazol-4-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-142); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-143); 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 acid (compound 2-144); 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 acid (compound 2-145); 3- { 3-tert-butylsulfanyl-5- (7-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-146); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (7-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-147); 3- [ 3-tert-butylsulfanyl-1- [4- (3-fluoro-pyridin-2-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-148); 3- { 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-149); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-150); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (3-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-151); 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 acid (compound 2-156); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (3-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-157); 3- { 3-tert-butylsulfanyl-5- (3-methyl-pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-158); 3- { 3-tert-butylsulfanyl-5- (3, 5-dimethyl-pyridin-2-ylmethoxy) -1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-159); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-160); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (4-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-161); 3- { 3-tert-butylsulfanyl-5- (4-methyl-pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-162); 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 acid (compound 2-163); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-164); 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 acid (compound 2-165); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (6-methyl-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-166); 3- { 3-tert-butylsulfanyl-5- (6-methyl-quinolin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-167); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methyl-pyridazin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-168); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridazin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-169); 3- [ 3-isobutyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-170); 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 acid (compound 2-171); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -3- (2-methyl-propane-2-sulfonyl) -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-172); 3- [1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -3- (2-methyl-propane-2-sulfinyl) -5- (pyridin-2-ylmethoxy) -1H-indol-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-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-174); 3- { 3-tert-butylsulfanyl-5- (imidazo [1, 2-a ] pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-175); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (imidazo [1, 2-a ] pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-176); 3- { 3-tert-butylsulfanyl-5- (imidazo [1, 2-a ] pyridin-2-ylmethoxy) -1- [4- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-177); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-178); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-methyl-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-179); 3- [ 3-tert-butylsulfanyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-180); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-3-yl) -benzyl ] -5- (5-methyl-isoxazol-3-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-181); 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 acid (compound 2-182); 3- { 3-tert-butylsulfanyl-5- (2, 5-dimethyl-2H-pyrazol-3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-183); 3- { 3-tert-butylsulfanyl-5- (1, 5-dimethyl-1H-pyrazol-3-ylmethoxy) -1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-184); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridazin-3-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-185); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridazin-3-yl) -benzyl ] -5- (5-ethyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-186); 3- { 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- [4- (6-methoxy-pyridazin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-187); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-188); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-189); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (6-fluoro-quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-190); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- ((R) -1-pyridin-2-yl-ethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-191); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-192); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-193); 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 acid (compound 2-194); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [3- (5-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-195); 3- [ 3-tert-butylsulfanyl-1- [3- (6-methoxy-pyridin-3-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-196); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-197); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (quinolin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-198); 3- [ 3-tert-butylsulfanyl-1- [4- (6-ethoxypyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-199); 3- { 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-200); 3- [ 3-tert-butylsulfanyl-1- [4- (5-fluoro-pyridin-2-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-201); 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 acid (compound 2-202); 3- { 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 2-203); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [4- (6-trifluoromethyl-pyridin-2-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (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-tert-butylsulfanyl-1- [3- (4-methoxy-tetrahydro-pyran-4-yl) -benzyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-206); 3- [ 3-tert-butylsulfanyl-5- (6-fluoro-quinolin-2-ylmethoxy) -1- (4-pyridin-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-207); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4-pyridin-3-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-210); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4-pyridin-2-yl-benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (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-dimethyl-propionic acid (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-dimethyl-propionic acid (compound 2-214); 3- [ 3-tert-butylsulfanyl-1- [4- (4-methoxy-pyridin-2-yl) -benzyl ] -5- (5-methyl-pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-215); 3- [ 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-216); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-217); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (3-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-218); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-219); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-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-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indol-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-dimethyl-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-dimethyl-propionic acid (compound 2-224); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (2-methoxypyridin-5-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-225); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (3-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-226); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (4-trifluoromethylpyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-227); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (3-fluoropyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-228); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (5-fluoropyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-229); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (4-methoxypyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-230); 3- [ 3-tert-butylsulfanyl-5- (2, 3-dimethyl-pyridin-6-ylmethoxy) -1- (4- (pyridin-2-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-231); 3- [ 3-tert-butylsulfanyl-5- (5-methyl-pyridin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-232); 3- [ 3-tert-butylsulfanyl-5- (5-ethyl-pyridin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 2-233); 3- [ 3-tert-butylsulfanyl-5- (quinolin-2-ylmethoxy) -1- (4- (2-methoxy-pyridin-3-yl) -benzyl) -1H-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 ] -2, 2-dimethyl-propionic acid (compound 3-1); 3- [ 3-tert-butylsulfanyl-1- [6- (4-methoxy-phenyl) -pyridin-3-ylmethyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 3-2); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [6- (4-trifluoromethoxy-phenyl) -pyridin-3-ylmethyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 3-3); 3- [ 3-tert-butylsulfanyl-1- [5- (4-methoxy-phenyl) -pyridin-2-ylmethyl ] -5- (pyridin-2-ylmethoxy) -1H-indol-2-yl ] -2, 2-dimethyl-propionic acid (compound 3-4); 3- { 3-tert-butylsulfanyl-5- (pyridin-2-ylmethoxy) -1- [5- (4-trifluoromethoxy-phenyl) -pyridin-2-ylmethyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 3-5); 3- { 3-tert-butylsulfanyl-5-isopropyl-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 4-1); 3- { 3-tert-butylsulfanyl-5-hydroxy-1- [4- (6-methoxy-pyridin-3-yl) -benzyl ] -1H-indol-2-yl } -2, 2-dimethyl-propionic acid (compound 4-2).
17. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
18. A method of treating inflammation in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.
19. A method of treating a respiratory disease in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.
20. The method of claim 19, wherein Z is [ C (R) ]2)2]nC(R1)2O。
21. A method of treating cardiovascular disease in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.
CN2006800412077A 2005-11-04 2006-10-30 5-lipoxygenase-activating protein (FLAP) inhibitors Expired - Fee Related CN101331117B (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US73403005P 2005-11-04 2005-11-04
US60/734,030 2005-11-04
US74717406P 2006-05-12 2006-05-12
US60/747,174 2006-05-12
US82334406P 2006-08-23 2006-08-23
US60/823,344 2006-08-23
US11/553,946 US7977359B2 (en) 2005-11-04 2006-10-27 5-lipdxygenase-activating protein (FLAP) inhibitors
US11/553,946 2006-10-27
PCT/US2006/042690 WO2007056021A2 (en) 2005-11-04 2006-10-30 5-lipoxygenase-activating protein (flap) inhibitors

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201110179642A Division CN102295637A (en) 2005-11-04 2006-10-30 5-lipoxygenase-activating protein (FLAP) inhibitors

Publications (2)

Publication Number Publication Date
CN101331117A true CN101331117A (en) 2008-12-24
CN101331117B CN101331117B (en) 2012-09-05

Family

ID=40206380

Family Applications (3)

Application Number Title Priority Date Filing Date
CN2006800412077A Expired - Fee Related CN101331117B (en) 2005-11-04 2006-10-30 5-lipoxygenase-activating protein (FLAP) inhibitors
CNA2006800503220A Pending CN101351472A (en) 2005-11-04 2006-11-03 5-lipoxygenase-activating protein (FLAP) inhibitors
CN200680041255.6A Expired - Fee Related CN101535299B (en) 2005-11-04 2006-11-03 5-lipoxygenase-activating protein (flap) inhibitors

Family Applications After (2)

Application Number Title Priority Date Filing Date
CNA2006800503220A Pending CN101351472A (en) 2005-11-04 2006-11-03 5-lipoxygenase-activating protein (FLAP) inhibitors
CN200680041255.6A Expired - Fee Related CN101535299B (en) 2005-11-04 2006-11-03 5-lipoxygenase-activating protein (flap) inhibitors

Country Status (3)

Country Link
CN (3) CN101331117B (en)
UA (1) UA95084C2 (en)
ZA (3) ZA200803421B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102822166A (en) * 2009-11-03 2012-12-12 葛兰素集团有限公司 Processes for the preparation of 5 - lipooxygenase activating protein inhibitors and their intermediates
WO2020003119A1 (en) * 2018-06-25 2020-01-02 Suzhou Mednes Pharma Tech Co., Ltd. Compounds and methods for treatment of hedgehog pathway associated conditions

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60123485A (en) * 1983-12-08 1985-07-02 Yoshitomi Pharmaceut Ind Ltd Indole-3-carboxamide derivative
US5081138A (en) * 1986-12-17 1992-01-14 Merck Frosst Canada, Inc. 3-hetero-substituted-n-benzyl-indoles and prevention of leucotriene synthesis therewith
US5272145A (en) * 1989-08-22 1993-12-21 Merck Frosst Canada, Inc. (Quinolin-2-ylmethoxy)indoles as inhibitors of the biosynthesis of leukotrienes
JP2661841B2 (en) * 1992-07-23 1997-10-08 ファイザー製薬株式会社 Indoline derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102822166A (en) * 2009-11-03 2012-12-12 葛兰素集团有限公司 Processes for the preparation of 5 - lipooxygenase activating protein inhibitors and their intermediates
WO2020003119A1 (en) * 2018-06-25 2020-01-02 Suzhou Mednes Pharma Tech Co., Ltd. Compounds and methods for treatment of hedgehog pathway associated conditions
US11718614B2 (en) 2018-06-25 2023-08-08 Suzhou Mednes Pharma Tech Co., Ltd. Compounds and methods for treatment of hedgehog pathway associated conditions

Also Published As

Publication number Publication date
CN101535299B (en) 2013-09-25
CN101351472A (en) 2009-01-21
CN101535299A (en) 2009-09-16
ZA200803579B (en) 2009-06-24
ZA200803421B (en) 2009-03-25
CN101331117B (en) 2012-09-05
ZA200804748B (en) 2009-03-25
UA95084C2 (en) 2011-07-11

Similar Documents

Publication Publication Date Title
US8710081B2 (en) 5-lipoxygenase-activating protein (FLAP) inhibitors
AU2008247672B2 (en) 5-lipoxygenase-activating protein (FLAP) inhibitors
US8399666B2 (en) 5-lipoxygenase-activating protein (FLAP) inhibitors
TW201402562A (en) 5-lipoxygenase-activating protein (FLAP) inhibitors
US20070225285A1 (en) 5-lipoxygenase-activating protein (flap) inhibitors
US8546431B2 (en) 5-lipoxygenase-activating protein (FLAP) inhibitors
CN101331117A (en) 5-lipoxygenase-activating protein (FLAP) inhibitors
CA3053918A1 (en) Reduction of pro-inflammatory hdl using a leukotriene inhibitor
MX2008005633A (en) 5-lipoxygenase-activating protein (flap) inhibitors

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: PAMIRA PHARMACEUTICALS, INC.

Free format text: FORMER OWNER: AMIRA PHARMACEUTICALS INC.

Effective date: 20120810

C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20120810

Address after: American California

Patentee after: Panmira Pharmaceuticals LLC

Address before: American California

Patentee before: Amira Pharmaceuticals Inc.

CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20120905

Termination date: 20201030

CF01 Termination of patent right due to non-payment of annual fee