WO2011122815A2 - Novel quinoxaline derivatives - Google Patents

Novel quinoxaline derivatives Download PDF

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Publication number
WO2011122815A2
WO2011122815A2 PCT/KR2011/002115 KR2011002115W WO2011122815A2 WO 2011122815 A2 WO2011122815 A2 WO 2011122815A2 KR 2011002115 W KR2011002115 W KR 2011002115W WO 2011122815 A2 WO2011122815 A2 WO 2011122815A2
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WO
WIPO (PCT)
Prior art keywords
ylthio
quinoxaline
dichloro
tetrazole
thiazole
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PCT/KR2011/002115
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French (fr)
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WO2011122815A3 (en
Inventor
Ho-Sang Moon
Jae-Sung Yang
Mi-Kyung Kim
Jin-Kwan Kim
Jae-Young Lee
So-Mi Kang
Ha-Dong Kim
Chang-Yell Shin
Ye-Hwang Cheong
Eun-Kyoung Yang
Song-Hyen Choi
Young-Soo Park
Eun-Jung Kim
Yu-Na Chae
Eun-Jung Cho
Moon-Ho Son
Soon-Hoe Kim
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Dong-A Pharm.Co.,Ltd.
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Priority claimed from KR1020110026747A external-priority patent/KR20110109917A/en
Application filed by Dong-A Pharm.Co.,Ltd. filed Critical Dong-A Pharm.Co.,Ltd.
Publication of WO2011122815A2 publication Critical patent/WO2011122815A2/en
Publication of WO2011122815A3 publication Critical patent/WO2011122815A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a novel compound represented by the following Chemical Formula 1, a process for preparing it, and its pharmaceutically approved salt comprising it as an active ingredient.
  • diabetes mellitus is a group of metabolic diseases in which a person has high blood sugar, either because the body is not producing enough insulin or because cells are not responding to the insulin that is being produced. More than 90% of the diabetes patients suffer from type 2 diabetes.
  • Currently used therapeutic agents for diabetes include insulin agents, insulin secretion-promoting agents, agents for enhancing sensitivity to insulin, and glucose absorption inhibitors, the goal of which is to reduce blood sugar levels.
  • the drugs suffer from the disadvantages of causing hypoglycemia, weight gain, edema, and having negative effects on the digestive system and being insufficient in efficacy.
  • Such symptomatic treatment for reducing blood sugar levels cannot be expected to fundamentally cure diabetes because it cannot improve the function of the target beta cells.
  • Glucagon-like peptide-1 is a hormone which is secreted by L-cells when they are stimulated by abundant nutrients after meal. This hormone is a kind of incretin hormones and is secreted, together with glucose-dependent insulinotropic polypeptide (GIP), inducing glucose-dependent stimulation of insulin secretion from pancreatic ⁇ -cells (Baggio LL., Drucker DJ., Gastroenterology , 2007(132):2131-2157).
  • GIP glucose-dependent insulinotropic polypeptide
  • GLP-1 possesses physiological functions including increasing insulin secretion after meals, decreasing glucagon secretion, inhibiting gastric juice secretion, retarding gastric emptying in the stomach, lowering food intake, proliferating pancreatic beta cells, and suppressing the death of pancreatic beta cells (Abu-Hamdah R. et. al, J Clin Endocrinol Metab , 2009(94): 1843-1852; KwonDY. et al., J Pharmacol Sci , 2009(111): 361-371).
  • Insulin secretion-promoting agents such as sulfonyl urea
  • GLP-1 was found to have the function of regulating the secretion of both insulin and glucagon, promoting insulin secretion in a glucose-dependent manner, and enhancing the proliferation, production and function of pancreatic beta cells as measured by pre-clinical animal testing (Vilsb ⁇ ll T., Diabetes Obes Metab , 2009(11):11-18; Kwon DY. et al., J Pharmacol Sci , 2009(111):361-371).
  • GLP-1 receptor activation is also expected to show anti-insulin resistance.
  • the direct mechanism of anti-insulin resistance of GLP-1 effectors still remains unclear, but is construed as being, in part, attributed to the secondary action resulting from appetite suppression and blood sugar reduction (Gedulin BR. et al., Endocrinology 2005(146):2069-2076).
  • Incretin mimetics based on the activity of GLP-1 are arising as one of the most attractive targets for developing therapeutics for diabetes because they are anticipated to have the function of increasing insulin secretion, antagonizing insulin resistance, regulating blood sugar levels, and potentiating the function of beta cells.
  • GLP-1 has a half life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP4) (Kim W., Egan JM., Pharmacol Rev, 2008(60):470-512).
  • DPP4 dipeptidyl peptidase-4
  • GLP-1 analogs which are not degraded by blood DPP4.
  • the first medication was exenatide (Byetta®) approved as single therapy for diabetes mellitus type 2 by the FDA in 2005. It was manufactured by Eli Lilly and Company.
  • Liraglutide (Victoza ® ) is a glucagon-like peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of diabetes mellitus type 2. It was first commercialized in Europe in 2009, and then approved by the FDA in Jan. 2010. Recently, the world ⁇ s leading pharmaceutical companies, such as GlaxoSmithKline and Roche, have reported the results of Phase 3 clinical trials and have conducted subsequent development processes. However, the developed drugs are of peptides which are disadvantageous primarily in that the patient must subcutaneously inject themselves with the peptide drugs. To overcome the inconvenience, pharmaceutical companies have made attempts to develop long-lasting Formulations such as those to be injected once a week, a month, etc. Nonetheless, there still remains behind the burden of the drugs for the chronic disease being injections (Lovshin JA., Drucker DJ., Nat Rev Endocrinol, 2009(5):262-269).
  • GLP-1 binds to a GLP-1 receptor which is distributed throughout pancreatic beta-cells and the brain.
  • the GLP-1 receptor belongs to class B of the G-protein coupled receptors (GPCR), a subfamily characterized by a large N-terminal extracellular ligand binding domain that acts to regulate the affinity of ligands for the receptor (Dong M. et al., Mol Endocrinol , 2008(22):1489-1499).
  • GPCR G-protein coupled receptors
  • the cyclobutane derivative Boc5 (Mw 1068) that has the same binding site as the endogenous ligand exhibited appetite suppression, weight loss and blood sugar reduction in both normal and hyperglycemic mice (Chen D. et al., Proc Natl Acad Sci , 2007(104):943-948;GuoJ. et al., PLoS ONE , 2008(3):e2982).
  • the quinoxaline derivative Compound-2 developed by Novo Nordisk, binds to a site different from that for the endogenous ligand to activate the ligand as well as to increase the binding of GLP-1 to the receptor.
  • the present invention provides a novel quinoxaline derivative compound and a method for the preparation thereof.
  • the present invention provide a pharmaceutical composition for the treatment or prevention of diabetes or obesity, comprising the novel quinoxaline derivative compound as an active ingredient functioning to reduce blood sugar levels or subjugate insulin resistance.
  • the present invention pertains to a novel quinoxaline derivative compound having the structure of the following Chemical Formula 1, or a pharmaceutically approved salt thereof.
  • R 1 and R 2 which may be the same or different, are hydrogen, halogen, or halogen-substituted or non-substituted lower alkyl of C 1 ⁇ C 6 ,
  • R 3 is , , , or ;
  • R 6 is hydrogen, hydroxy, a hydroxy-substituted or non-substituted lower alkoxy of C 1 ⁇ C 6 , -OC(O)-R 13 , or -OSO 2 -R 13 wherein R 13 is a lower alkyl of C 1 ⁇ C 6 ;
  • R 7 is a lower alkyl of C 1 ⁇ C 6 having a lower cycloalkyl of C 3 ⁇ C 7 as a substituent, or no substitutents;
  • R 8 and R 9 which may be the same or different, are hydrogen, halogen, a halogen-substituted or non-substituted lower alkyl of C 1 ⁇ C 6 , or a lower alkylthio of C 1 ⁇ C 6 ;
  • X and Y which may be the same or different, are carbon or nitrogen;
  • R 10 is hydrogen, aldehyde, oxime, or -C(O)O-R 14 with the proviso that
  • R 4 is hydrogen, hydroxy, amino, a lower alkyl of C 1 ⁇ C 6 , a lower cycloalkyl of C 3 ⁇ C 7 , phenyl, or -(CH(R 15 ))n-R 16 , wherein the phenyl may be substituted at one or more positions with halogen or a halogen-substituted or non-substituted lower alkyl or alkoxy of C 1 ⁇ C 6 ; n is an integer of 0 to 5; R 15 is a lower alkyl of C 1 ⁇ C 6 ; R 16 is a lower alkylamino or heteroaryl of C 1 ⁇ C 6 , with the proviso that when R 16 is a heteroaryl, this heteroaryl may be substituted at one or more positions with a heteroaryl having a lower alkyl of C 1 ⁇ C 6 , a lower alkoxy of C 1 ⁇ C 6 , or a lower alkyl of C 1 ⁇ C
  • a and B which may be the same or different, are carbon or nitrogen, with the proviso that when B is carbon, R 5 is a hydrogen, hydroxy, amino or a halogen-substituted or non-substituted lower alkyl of C 1 ⁇ C 6 .
  • the present invention relates to the compound represented by Chemical Formula 1 or its pharmaceutically approved salt, wherein the compound selected from the group consisting of;
  • the compounds according to the present invention may have one or more chiral centers and may exist as racemates or individual optical isomers, all of which fall within the scope of the present invention.
  • Examples of the pharmaceutically approved salt of the compound of Chemical Formula 1 include salt of inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid and sulfuric acid, salt of organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid, salt of sulfonic acids such as methanesulfonic acid and para-toluenesulfonic acid, and salt of alkaline metal such as sodium, potassium and lithium. Salt of other well-known acids are also used.
  • inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid and sulfuric acid
  • organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid,
  • the present invention pertains to a method for the preparation of the compound of Chemical Formula 1 or its pharmaceutically approved salt, comprising reacting a compound of Chemical Formula 2 with a thiol compound of Chemical Formula 3 to form a thioether bond therebetween.
  • R 1, R 2 and R 3 are as defined in Chemical Formula 1; and R 3a is a halogen element.
  • A, B, R 4 , and R 5 are as defined in Chemical Formula 1.
  • the method of the present invention may be represented as illustrated in the following Reaction Scheme 1.
  • the thioether bond may be formed by a nucleophilic substitution reaction between the compound of Chemical Formula 2 and the thiol compound of Chemical Formula 3.
  • the compound of Chemical Formula 2 may be synthesized from a quinoxaline derivative or a phenylenediamine derivative.
  • a Suzuki coupling reaction or a Still coupling reaction may be used to form a carbon-carbon bond between a quinoxaline compound substituted at position 3 with hydrogen or hydroxy (a compound of the following Chemical Formula 4) and a substituted thiazole or oxadiazole compound (Chemical Formula 5).
  • the Suzuki coupling reaction may be catalyzed by Pd(PPh 3 ) 4 in the presence of DMF and K 2 CO 3 while the Stille coupling reaction may be conducted with LiCl, CuI, 1,4-dixoane, and Pd(PPh 3 ) 2 Cl 2 (N. Miyauri, A. Suzuki, Chemical Reviews 1995 , 95 , 2457, S. T. Handy, X. Zhang, Organic Letters 2001 , 3 , 233).
  • halogenation subsequent to the introduction of R 3 may be additionally performed to synthesize the compound of Chemical Formula 2.
  • R 1 and R 2 are as defined above; R 3c is halogen or hydroxy, and R 3b is halogen.
  • R A is hydrogen or a protecting group of R 3 selected from among Me 3 Sn-, Bu 3 Sn-, B(OH) 2 - and ; and R 3 is as defined in Chemical Formula 1.
  • a quinoxaline compound substituted at position 3 with halogen or hydroxy may be subjected to nucleophilic substitution with a substituted imidazole or indole compound (Chemical Formula 5).
  • halogenation subsequent to the introduction of R 3 may be further performed to give the compound of Chemical Formula 2.
  • R 6 of the moiety R 3 in the final product compound of Chemical Formula 1 when R 6 of the moiety R 3 in the final product compound of Chemical Formula 1 is not alkoxy, a compound having alkoxy as R 6 may be additionally dealkylated using BBr 3 , HCl or LiCl and then subjected to a nucleophilic substitution reaction with a halogen compound in the final step to yield a desired compound of Chemical Formula 1 in which R 6 is as defined above.
  • R 10 of the moiety R 3 in the final compound of Chemical Formula 1 when R 10 of the moiety R 3 in the final compound of Chemical Formula 1 is not an aldehyde, a compound having an aldehyde as R 10 may be subjected to dehydration condensation using various amines to afford a desired compound of Chemical Formula 1 wherein R 10 is as defined above.
  • the compound of Chemical Formula 2 may be also synthesized from a phenylenediamine derivative.
  • the phenylenediamine derivative-derived compound of Chemical Formula 2 serving as a starting material, may vary.
  • R 3 When R 3 is in the compound of Chemical Formula 1, the compound of Chemical Formula 2 synthesized by condensating 1, 2-phenylenediamine (Chemical Formula 6) with a dioxoethylene derivative (Chemical Formula 7) is used as a starting material.
  • an oxalyl halogen may be further added to synthesize a compound of Chemical Formula 2 wherein R 3a is halogen.
  • the oxalyl halogen include oxalyl chloride.
  • DMF and CH 2 Cl 2 may be employed.
  • R 1, R 2, and R 3 are as defined in Chemical Formula 1.
  • R B is hydroxy or a lower alkoxy of C 1 ⁇ C 6 .
  • R 3 is in the compound of Chemical Formula 1
  • a compound of Chemical Formula 2 which is synthesized by subjecting 1, 2-phenylenediamine (Chemical Formula 6) and a trioxopropylene derivative (Chemical Formula 8) to a condensation reaction, reacting the condensate with a hydrazine hydrate to give a hydrizide compound (Chemical Formula 9), and adding a formic acid derivative (Chemical Formula 10) to the hydrizide compound, was used as a starting material.
  • additional hydrogenation subsequent to the introduction of R 3 may be conducted to give the compound of Chemical Formula 2.
  • the trioxopropylene derivative of Chemical Formula 8 can be reacted with 1, 2-phenylenediamine (Chemical Formula 6) to afford a quinoxaline structure, and may be 3-ethoxy-2,3-dioxopropanic acid.
  • R B is hydroxy or a lower alkoxy of C 1 ⁇ C 6 ; and R C is a lower alkoxy of C 1 ⁇ C 6 .
  • R 1 and R 2 are as defined in Chemical Formula 1.
  • R 7 is as defined in Chemical Formula 1.
  • the thiol compound of Chemical Formula 3 may be commercially available (e.g., from Sigma), or may be prepared by reacting a commercially available amine with di-2-pyridyl thiocarbonate to give an isocyanate (Outt, Pamela E. Journal of Organic Chemistry 1998 , 63 , 5762) and then reacting the isocyanate with metal azide, such as NaN 3 or KN 3 , at 20 ⁇ 100°C in alcohol or water or a mixture thereof (Shin, Kye Jung Bioorganic and Medicinal Chemistry Letters 2000 , 10 , 1421).
  • metal azide such as NaN 3 or KN 3
  • the thiol compound of Chemical Formula 3 may be prepared by reacting isothiocyanate with a commercially available hydrazide at 20 ⁇ 100°C in a solvent, such as alcohol, water, dioxane or a combination thereof, alone or in combination with an alkaline such as NaOH (Graybill, Todd L. Tetrahedron Letters 2002, 43, 5305-5310).
  • a solvent such as alcohol, water, dioxane or a combination thereof, alone or in combination with an alkaline such as NaOH (Graybill, Todd L. Tetrahedron Letters 2002, 43, 5305-5310).
  • a reaction employed in the method of the present invention is accomplished by mixing and stirring a starting material and a reactant in a reaction solvent which has no influences on the reaction.
  • a solvent used to facilitate the nucleophilic substitution reaction and the Suzuki coupling reaction includes alcohols such as methanol, ethers such as dioxane and tetrahydrofuran (THF), aromatic solvents such as benzene and toluene, chlorohydrocarbons such as dichloromethane (MC) and dichloroethane, acetonitrile, dimethylformamide (DMF), and a mixture thereof.
  • the reaction temperatures may be set at 0 ⁇ 150°C.
  • the present invention pertains to a pharmaceutical composition for the treatment or prevention of diabetes or obesity, comprising the novel quinoxaline derivative as an active ingredient, characterized by the activity of reducing blood sugar levels or subjugating insulin resistance.
  • the pharmaceutical composition comprising the novel quinoxaline derivative or a pharmaceutically approved salt thereof as an active ingredient in accordance with the present invention may be Formulated into general medicine forms.
  • the compound of the present invention may be administered in various oral or parenteral dosage forms. Preferred is an oral dosage form.
  • the compound of the present invention may be Formulated in combination with a diluent or an excipient, such as a filter, a thickening agent, a binder, a wetting agent, a disintegrant, a surfactant, etc.
  • Solid agents intended for oral administration of the compound of the present invention may be in the form of tablets, pills, powders, granules, capsules, and the like. These solid agents are Formulated with the quinoxaline derivative or a pharmaceutically approved salt thereof in combination with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, a lubricant, such as magnesium stearate, talc and the like, may also be added.
  • Liquid agents intended for oral administration include suspensions, internal use solutions, emulsions, syrups, and the like.
  • non-oral dosage forms of the compound of the present invention include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions, freeze-dried agents, and suppositories.
  • non-aqueous solutions and suspensions made from propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and esters such as ethyl oleate may be used.
  • the basic materials of suppositories include Witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, and glycerogelatin.
  • the effective dosage of the compound or pharmaceutically approved salt thereof in accordance with the present invention depends on various factors, including the patient ⁇ s weight, age, gender, state of health, diet, the time of administration, the route of administration, the rate of excretion, and the severity of disease.
  • the pharmaceutical composition comprising the quinoxaline derivative or pharmaceutically approved salt of the present invention as an active ingredient may be administered in a single dose or in multiple doses per day, each dose ranging from 0.1 ⁇ 1000 mg/day.
  • This invention provides the novel compound which has the effects on a drop of blood sugar and an improvement of insulin resistance; therefore it may be useful for treatment of metabolic diseases such as diabetes and obesity by regulating the function of glucagon like peptide 1 receptor (GLP 1 receptor) for the disease or disorder carried by GLP 1.
  • GLP 1 receptor glucagon like peptide 1 receptor
  • Figure 1 is a graph that the results of glucose induced insulin secretion of a mouse against the compound of Example 19 shown as the insulin concentration changes in blood plasma until 5 minutes after injecting glucose.
  • Figure 2 is the results of glucose induced insulin secretion of a mouse against the compound of Example 19 shown as an acute insulin response which is the average concentration of insulin in blood plasma to 1 and 5 minutes.
  • Step 3 Preparation of 2-(5-(6,7-dichloro-3-(2-methoxythiazole-5-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
  • Step 4 Preparation of 5-(6,7-dichloro-3-(1-(2-dimethylamino)-ethyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
  • Example 2 The desired form of the compound, 5-(6,7-dichloro-3-(1-3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 2) was obtained in the yield of 24% after preparation of 1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-thiol using N1,N1-dimethylpropane-1,3-diamine in the same method of Example 1.
  • Example 3 The desired form of the compound, 5-(6,7-dicholoro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 3) was obtained in the yield of 22% using 1-methyl-1H-tetrazole-5-thiol in the same method of Example 1.
  • Example 4 The desired form of the compound, 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol (Example 4) was obtained in the yield of 6% by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
  • Example 5 The desired form of the compound, 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 5) was obtained by using propane-1-amine in the same method of Example 1, after synthesizing 1-prophyl-1H-tetrazole-5-thiol.
  • Example 6 The desired form of the compound, 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 6) was obtained in the yield of 18% after synthesizing 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-tetrazole-5-thiol, using 2-(4-methylpiperazine-1)ethanamine in the same method of Example 1.
  • Example 7 The desired form of the compound, 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 7) was obtained in the yield of 15%, using 1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-thiol synthesized by 4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-amine in the same method of Example 1.
  • Example 9 The desired form of the compound, 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 9) was obtained in the yield of 20%, using 1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-thiol synthesized by (3S,4S)-4-methoxy-1-methylpyrrolidine-3-amine in the same method of Example 1.
  • Example 10 The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 10) was obtained in the yield of 16%, using 1-isoprophyl-1H-tetrazole-5-thiol synthesized by propane-2-amine in the same method of Example 1.
  • Example 12 The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate (Example 12) was obtained by using 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol and acetic anhydride synthesized in Example 10 in the same method of Example 4.
  • Example 13 The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate (Example 13) was obtained by using 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol and pentatonic anhydride synthesized in Example 10 in the same method of Example 4.
  • Example 14 The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate (Example 14) was obtained by using 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol and isobutyl anhydride synthesized in Example 10 in the same method of Example 4.
  • Example 16 The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole (Example 16) was obtained in the yield of 11%, using 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol (56 mg, 0.28 mmol) synthesized by 2-methoxy-5-(3,6,7-trichloroquinoxaline-2-yl)thiazole (50 mg, 0.14 mmol) and 1-methylpiperidine-4-amine in the same method of Example 1.
  • Example 17 The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 17) was obtained in the yield of 16%, using 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-ylthio)quinoxaline-2-yl)-2-methoxythiazole (20 mg, 0.04 mmol) synthesized in Example 16 in the same method of Example 1.
  • Example 18 The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole (Example 18) was obtained in the yield of 16%, using 1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-thiol (64 mg, 0.28 mmol) synthesized by 2-methoxy-5-(3,6,7-trichloroquinoxaline-2-yl)thiazole (50 mg, 0.14 mmol) and 1-(1-methylpiperidine-4-yl)ethanamine in the same method of Example 1.
  • Example 21 The desired form of the compound, 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol (Example 21) was obtained by using 1-amino-1H-tetrazole-5-thiol (AKOS company) which is available to buy commercially in the same method of Example 1.
  • AKOS company 1-amino-1H-tetrazole-5-thiol
  • Example 25 The desired form of the compound, 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate (Example 25) was obtained by using 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol and propane-1-sulfonyl chloride in the same method of Example 4.
  • Step 1 Preparation of ethyl 6,7-dichloro-3-hydroxyquinoxaline-2-carboxylate
  • Step 3 Preparation of 2-cyclopentylmethyl-5-(3,6,7-trichloroquinoxaline-2-yl)-1,3,4-oxathiazole
  • Step 4 Preparation of 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio-2-yl)-1,3,4-oxathiazole
  • Step 2 Preparation of 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidne-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
  • Example 31 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methlypiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 31) was obtained by using 0.2289 mmol of 2,6,7-trichloro-3-(2-ethyl-1H-imidazole-1-yl)quinoxaline and 0.45 mmol of 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol synthesized in step 1 in the same method of Example 1.
  • Example 32 The desired form of the compound, 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine (Example 32) was obtained by using 2-ethyl-4-methylimidazole and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 31.
  • Example 33 The desired form of the compound, 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 33) was obtained by using 2-ethyl-4-methylimidazole and 1-(1-methlypiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
  • Example 35 The desired form of the compound, 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline (Example 35) was obtained by using 2-ethylimidazole and 1-prophyl-1H-tetrazole-5-thiol in the same method of Example 31.
  • Example 36 The desired form of the compound, 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 36) was obtained by using 2-isoprophylimidazole and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
  • Example 37 The desired form of the compound, 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline (Example 37) was synthesized by using 2-isoprophylimidazole and 1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-thiol in the same method of Example 31.
  • Example 40 The desired form of the compound, 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 40) was obtained by using 2-isoprophylthioimidazole and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
  • Step 2 Preparation of 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
  • Example 43 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine (Example 43) was obtained by using 0.2002 mmol of 2,6,7-trichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline and 0.40 mmol of 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol synthesized in step 1 in the same method of Example 1.
  • Example 48 methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate
  • Example 48 The desired form of the compound, methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate (Example 48) was obtained by using methyl-1H-indole-3-carboxylate and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 49 The desired form of the compound, 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 49) was obtained by using 1H-indole-3-carbaldehyde and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 53 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde (Example 53) was synthesized by using 5-fluoro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
  • Example 54 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde
  • Example 54 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde (Example 54) was synthesized by using 6-bromo-1H-indole-3-carbaldehyde and 4-amino-4H-1,2,4-triazole-3-thiol in the same method of Example 54.
  • Example 55 6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 55) was synthesized by using 6-bromo-1H-indole-carbaldehyde and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 56 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 56) was synthesized by using 6-fluoro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
  • Example 57 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde (Example 57) was synthesized by using 6-nitro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
  • Example 58 5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 58) was synthesized by using 5-chloro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
  • Example 59 1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile (Example 59) was synthesized by using 5-cyano-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
  • Example 60 6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 60) was synthesized by using 6-bromo-1H-indole-3-carbaldehyde and 1-isoprophyl-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 61 The desired form of the compound, 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 61) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-isoprophyl-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 62 1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
  • Example 62 The desired form of the compound,1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 62) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 5-amino-4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
  • Example 63 The desired form of the compound, 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 63) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 64 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
  • Example 64 The desired form of the compound, 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 64) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-thiol in the same method of Example 64.
  • Example 65 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
  • Example 65 The desired form of the compound, 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 65) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 66 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
  • Example 68 The desired form of the compound, 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 68) was obtained by using 2,3,6-trichloroquinoxaline and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 1.
  • Example 69 The desired form of the compound, 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 69) was obtained by using 2,3,6-trichloroquinoxaline and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 1.
  • Example 70 The desired form of the compound, 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol (Example 70) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 1.
  • Example 71 The desired form of the compound, 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol (Example 71) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 1.
  • Example 74 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde
  • Example 74 The desired form of the compound, 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde (Example 74) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 6-fluoro-1H-indole-3-carbaldehyde in the same method of Example 43.
  • Example 76 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde
  • Example 76 The desired form of the compound, 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde (Example 76) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline, 6-fluoro-1H-indole-3-carbaldehyde, and 1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • Example 77 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
  • Example 77 The desired form of the compound, 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 77) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline, 6-fluoro-1H-indole-3-carbaldehyde, and 1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-thiol in the same method of Example 43.
  • a human GLP-1 receptor expression vector (Origene, USA) was transiently transfected, together with a DNA construct, containing four copies of the cAMP-response element, capable of inducing the expression of firefly luciferase, and a DNA construct expressing renilla luciferase (Promega, USA), into Chinese hamster ovary (CHO) cells with the aid of Lipofectamine Plus reagent (Invitrogen, USA). After transfection of three hours, the medium was replaced with ⁇ -MEM (Minimum essential media; Invitrogen, USA) supplemented with 10% fetal bovine serum.
  • ⁇ -MEM Minimum essential media; Invitrogen, USA
  • a dual luciferase assay reagent Promega, USA was added to the medium in which the cells were submerged while firefly luciferase and renilla luciferase activities were measured.
  • the renilla luciferase activity was used to modulate the efficiency of transfection.
  • the compounds of the present invention were tested at multiple concentrations. Based on these multiple test results, a concentration showing 50% of the maximum effect of the positive control exenatide (American Peptide, USA) (EC 50 ) was calculated using a non-linear regression analysis method. Relative activity of each compound at a concentration of 1 ⁇ M to the maximum effect of the positive control is expressed as percentage in Table 1.
  • the insulin secretion induced was evaluated as the activity of the compounds (enzyme immunoassay).
  • KRBH (Krebs-Ringer Bicarabonate HEPES) buffer was prepared with reference to a previous publication (Hou ZQ. et al., Mol Cell Endocrinol , 2008(291):71-78). Insulin was quantitatively analyzed using a rat insulin enzyme immunoassay kit (Shibayagi, Japan; ALPCO, USA). For quantitative protein assay, a BCA reagent (Pierce, USA) was used according to the protocol of the manufacturer ⁇ s.
  • rat beta-cells were incubated for one hour with glucose-free KRBH buffer to deplete nutrients.
  • KRBH containing 11.1 mM glucose and the phosphodiesterase inhibitor Ro-20-1724 (Calbiochem, USA) was added a compound with which the cells were then treated for 30 min.
  • a sample was taken from the supernatant and quantitatively measured for the insulin released from the beta-cells.
  • the cells were lysed and a portion taken from the cell lysate was quantitatively measured for protein.
  • the measured amount of insulin was corrected according to the amount of protein.
  • the ability of the compounds of the present invention is expressed as a percentage of the maximum effect of the positive control exenatide (American Peptide, USA) in Table 1.
  • the compounds tested ranged in the relative insulin secretion activity from 0 to 80%.
  • the glucose-stimulated insulin secretion activity of the compounds in seven-week old male mice was evaluated as an index indicating anti-diabetes activity (enzyme immunoassay).
  • mice were starved for 16 ⁇ 17 hrs before experiments.
  • the compound of the present invention was orally administered 30 min before the injection of glucose.
  • a glucose solution (1 g/kg/10 ml) was injected into the mice via the tail vein.
  • Blood samples were taken from the intraorbital vein immediately before the injection of glucose and 1 and 5 min before the injection of glucose, and placed in heparinized tubes, followed by centrifugation.
  • the plasma thus obtained were quantitatively analyzed for insulin using a mouse insulin analysis kit (Shibayagi, Japan). The results are shown in FIG. 1.
  • AIR Acute Insulin Response
  • Example 19 When the compound of Example 19 according to the present invention was orally administered at a dose of 100 mg/kg, as seen in FIG. 1, the insulin concentration was increased up to 2.9 ⁇ 0.5 ng/ml at 1 min after glucose injection, which was 1.6-fold greater than that of the control (1.6 ⁇ 0.2 ng/ml). As is understood from data of FIG. 2, the acute insulin response of the compound was measured to be 2.3 ⁇ 0.2 ng/ml which was 1.6-fold greater than that of control (1.5 ⁇ 0.1 ng/ml).

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Abstract

This invention relates to a novel compound represented by the following Chemical Formula 1, a process for preparing it, and its pharmaceutically approved salt comprising it as an active ingredient. The compound of this invention is GLP 1 receptor regulating low molecular weight compound useful for treatment of metabolic diseases such as diabetes and obesity by regulating the function of glucagon like peptide 1 receptor (GLP 1 receptor) for the disease or disorder carried by GLP 1 since it has the effects on a drop of blood sugar and an improvement of insulin resistance.

Description

NOVEL QUINOXALINE DERIVATIVES
This invention relates to a novel compound represented by the following Chemical Formula 1, a process for preparing it, and its pharmaceutically approved salt comprising it as an active ingredient.
<Chemical Formula 1>
Figure PCTKR2011002115-appb-I000001
The incidence of diabetes mellitus is rapidly increasing throughout the world. A report of the International Diabetes Federation has it that the number of diabetes mellitus patients in the world is expected to explosively increase from the 246 million as of 2007 to 435 million in 2030. Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body is not producing enough insulin or because cells are not responding to the insulin that is being produced. More than 90% of the diabetes patients suffer from type 2 diabetes. Currently used therapeutic agents for diabetes include insulin agents, insulin secretion-promoting agents, agents for enhancing sensitivity to insulin, and glucose absorption inhibitors, the goal of which is to reduce blood sugar levels. However, the drugs suffer from the disadvantages of causing hypoglycemia, weight gain, edema, and having negative effects on the digestive system and being insufficient in efficacy. Such symptomatic treatment for reducing blood sugar levels cannot be expected to fundamentally cure diabetes because it cannot improve the function of the target beta cells. (Philippe J., Raccah D., Int J Clin Pract, 2009(63): 321-332).
Glucagon-like peptide-1 (GLP-1) is a hormone which is secreted by L-cells when they are stimulated by abundant nutrients after meal. This hormone is a kind of incretin hormones and is secreted, together with glucose-dependent insulinotropic polypeptide (GIP), inducing glucose-dependent stimulation of insulin secretion from pancreatic β-cells (Baggio LL., Drucker DJ., Gastroenterology, 2007(132):2131-2157). GLP-1 possesses physiological functions including increasing insulin secretion after meals, decreasing glucagon secretion, inhibiting gastric juice secretion, retarding gastric emptying in the stomach, lowering food intake, proliferating pancreatic beta cells, and suppressing the death of pancreatic beta cells (Abu-Hamdah R. et. al, J Clin Endocrinol Metab, 2009(94): 1843-1852; KwonDY. et al., J Pharmacol Sci, 2009(111): 361-371). Insulin secretion-promoting agents, such as sulfonyl urea, have limitations in regards to regulating blood sugar due to their inability to regulate the abnormal secretion increase of glucagon and cause hypoglycemia due to glucose-independent insulin secretion whereas GLP-1 was found to have the function of regulating the secretion of both insulin and glucagon, promoting insulin secretion in a glucose-dependent manner, and enhancing the proliferation, production and function of pancreatic beta cells as measured by pre-clinical animal testing (VilsbØll T., Diabetes Obes Metab, 2009(11):11-18; Kwon DY. et al., J Pharmacol Sci, 2009(111):361-371).
In addition, it was reported that repeat administration of exenatide for six weeks to insulin-resistant rats subjugated insulin resistance to some degree. Hence, GLP-1 receptor activation is also expected to show anti-insulin resistance. The direct mechanism of anti-insulin resistance of GLP-1 effectors still remains unclear, but is construed as being, in part, attributed to the secondary action resulting from appetite suppression and blood sugar reduction (Gedulin BR. et al., Endocrinology 2005(146):2069-2076).
Incretin mimetics based on the activity of GLP-1 are arising as one of the most attractive targets for developing therapeutics for diabetes because they are anticipated to have the function of increasing insulin secretion, antagonizing insulin resistance, regulating blood sugar levels, and potentiating the function of beta cells.
However, once in the circulation, GLP-1 has a half life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP4) (Kim W., Egan JM., Pharmacol Rev, 2008(60):470-512). To overcome this disadvantage, many pharmaceutical companies have developed GLP-1 analogs which are not degraded by blood DPP4. The first medication was exenatide (Byetta®) approved as single therapy for diabetes mellitus type 2 by the FDA in 2005. It was manufactured by Eli Lilly and Company.
Liraglutide (Victoza®) is a glucagon-like peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of diabetes mellitus type 2. It was first commercialized in Europe in 2009, and then approved by the FDA in Jan. 2010. Recently, the world`s leading pharmaceutical companies, such as GlaxoSmithKline and Roche, have reported the results of Phase 3 clinical trials and have conducted subsequent development processes. However, the developed drugs are of peptides which are disadvantageous primarily in that the patient must subcutaneously inject themselves with the peptide drugs. To overcome the inconvenience, pharmaceutical companies have made attempts to develop long-lasting Formulations such as those to be injected once a week, a month, etc. Nonetheless, there still remains behind the burden of the drugs for the chronic disease being injections (Lovshin JA., Drucker DJ., Nat Rev Endocrinol, 2009(5):262-269).
To exert its physiological activity, GLP-1 binds to a GLP-1 receptor which is distributed throughout pancreatic beta-cells and the brain. Structurally, the GLP-1 receptor belongs to class B of the G-protein coupled receptors (GPCR), a subfamily characterized by a large N-terminal extracellular ligand binding domain that acts to regulate the affinity of ligands for the receptor (Dong M. et al., Mol Endocrinol, 2008(22):1489-1499). Thus, it is very difficult to develop low-molecular weight ligands for this class receptor compared to those for other class GPCR, and there have been no reports of successfully developing such low-molecular weight ligands into drugs, so far (Hoare SR., Drug Discov Today, 2005(10):417-427). With GLP-1 stood in the spotlight of the art, research results of low-molecular weight ligands, although rare, have been reported. Keen attention is expected to be paid to the low-molecular weight ligands.
According to the research reports, the cyclobutane derivative Boc5 (Mw 1068) that has the same binding site as the endogenous ligand exhibited appetite suppression, weight loss and blood sugar reduction in both normal and hyperglycemic mice (Chen D. et al., Proc Natl Acad Sci, 2007(104):943-948;GuoJ. et al., PLoS ONE, 2008(3):e2982). The quinoxaline derivative Compound-2, developed by Novo Nordisk, binds to a site different from that for the endogenous ligand to activate the ligand as well as to increase the binding of GLP-1 to the receptor. Its mechanism is suggested to increase insulin release only at high glucose levels (Knudsen LB. et al., Proc Natl Acad Sci, 2007(104):937-942; Irwin N. et al., Eur J Pharmacol, 2009, doi:10.1016/j.ejphar.2009.11.022). Also, these two compounds were found to have different binding sites in the receptor as assayed by virtual molecular modeling of the GLP-1 receptor (Lin F., Wang R., J Mol Model, 2009(15):53-65). In recent, Lilly has reported a GLP-1 receptor full agonist having an EC50 of 660 nM, opening the possibility of developing low-molecular weight drugs acting on the GLP-1 receptor (Kyle W. Sloop, Diabetes, 2010(59):3099-3107).
It is an object of the present invention to provide a novel quinoxaline derivative compound and a method for the preparation thereof.
It is another object of the present invention to provide a pharmaceutical composition for the treatment or prevention of diabetes or obesity, comprising the novel quinoxaline derivative compound as an active ingredient functioning to reduce blood sugar levels or subjugate insulin resistance.
In order to accomplish the above objects, the present invention provides a novel quinoxaline derivative compound and a method for the preparation thereof.
Also, the present invention provide a pharmaceutical composition for the treatment or prevention of diabetes or obesity, comprising the novel quinoxaline derivative compound as an active ingredient functioning to reduce blood sugar levels or subjugate insulin resistance.
Below, a detailed description will be given of the present invention.
In accordance with an aspect thereof, the present invention pertains to a novel quinoxaline derivative compound having the structure of the following Chemical Formula 1, or a pharmaceutically approved salt thereof.
<Chemical Formula 1>
Figure PCTKR2011002115-appb-I000002
Wherein,
R1 and R2, which may be the same or different, are hydrogen, halogen, or halogen-substituted or non-substituted lower alkyl of C1~C6,
R3 is
Figure PCTKR2011002115-appb-I000003
,
Figure PCTKR2011002115-appb-I000004
,
Figure PCTKR2011002115-appb-I000005
, or
Figure PCTKR2011002115-appb-I000006
;
wherein R6 is hydrogen, hydroxy, a hydroxy-substituted or non-substituted lower alkoxy of C1~C6, -OC(O)-R13, or -OSO2-R13 wherein R13 is a lower alkyl of C1~C6; R7 is a lower alkyl of C1~C6 having a lower cycloalkyl of C3~C7 as a substituent, or no substitutents; R8 and R9, which may be the same or different, are hydrogen, halogen, a halogen-substituted or non-substituted lower alkyl of C1~C6, or a lower alkylthio of C1~C6; X and Y, which may be the same or different, are carbon or nitrogen; R10 is hydrogen, aldehyde, oxime, or -C(O)O-R14 with the proviso that X is carbon, wherein R14 is a lower alkyl of C1~C6; R11 and R12, which may be the same or different, are hydrogen, halogen, cyano, nitro, a lower alkyl of C1~C6, or a lower alkoxy of C1~C6;
R4 is hydrogen, hydroxy, amino, a lower alkyl of C1~C6, a lower cycloalkyl of C3~C7, phenyl, or -(CH(R15))n-R16, wherein the phenyl may be substituted at one or more positions with halogen or a halogen-substituted or non-substituted lower alkyl or alkoxy of C1~C6; n is an integer of 0 to 5; R15 is a lower alkyl of C1~C6; R16 is a lower alkylamino or heteroaryl of C1~C6, with the proviso that when R16 is a heteroaryl, this heteroaryl may be substituted at one or more positions with a heteroaryl having a lower alkyl of C1~C6, a lower alkoxy of C1~C6, or a lower alkyl of C1~C6 as a substituent; and
A and B, which may be the same or different, are carbon or nitrogen, with the proviso that when B is carbon, R5 is a hydrogen, hydroxy, amino or a halogen-substituted or non-substituted lower alkyl of C1~C6.
Moreover, the present invention relates to the compound represented by Chemical Formula 1 or its pharmaceutically approved salt, wherein the compound selected from the group consisting of;
(1) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(2) 5-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(3) 5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(4) 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
(5) 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(6) 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(7) 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(8) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(9) 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(10) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(11) 1-(5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
(12) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate;
(13) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate;
(14) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate;
(15) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(16) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
(17) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(18) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
(19) 5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(20) 5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(21) 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
(22) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-imidizol-2-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(23) 5-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(24) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
(25) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate;
(26) 5-(3-(4-amino-5-trifluoromethyl)-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
(27) 5-(6,7-dichloro-3-(4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(28) 5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
(29) 5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(30) 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1,3,4-oxathiazole;
(31) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
(32) 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl) quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
(33) 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
(34) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
(35) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline;
(36) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
(37) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline;
(38) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline;
(39) 6,7-dichloro-2-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-3-(2-(methylthio)-1H-imidazole-1-yl)quinoxaline;
(40) 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
(41) 6,7-dichloro-2-(2-methyl-4-(trifluoromethyl)-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
(42) 6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
(43) 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
(44) 6,7-dichloro-2-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline;
(45) 2-(5-(6,7-dichloro-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
(46) 6-chloro-1-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
(47) 6-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
(48) methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate;
(49) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
(50) 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
(51) 6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
(52) (E)-6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde oxime;
(53) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde;
(54) 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde;
(55) 6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
(56) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(57) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde;
(58) 5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
(59) 1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile;
(60) 6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
(61) 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(62) 1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(63) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(64) 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(65) 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(66) 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(67) 6,7-dichloro-2-(6-chloro-5-fluoro-1H-benzo[d]imidazole-1-yl)-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline;
(68) 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(69) 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
(70) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
(71) 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
(72) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
(73) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
(74) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
(75) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-7-trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(76) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
(77) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
(78) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol.
The compounds according to the present invention may have one or more chiral centers and may exist as racemates or individual optical isomers, all of which fall within the scope of the present invention.
Examples of the pharmaceutically approved salt of the compound of Chemical Formula 1 include salt of inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid and sulfuric acid, salt of organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid, salt of sulfonic acids such as methanesulfonic acid and para-toluenesulfonic acid, and salt of alkaline metal such as sodium, potassium and lithium. Salt of other well-known acids are also used.
In accordance with another aspect thereof, the present invention pertains to a method for the preparation of the compound of Chemical Formula 1 or its pharmaceutically approved salt, comprising reacting a compound of Chemical Formula 2 with a thiol compound of Chemical Formula 3 to form a thioether bond therebetween.
<Chemical Formula 2>
Figure PCTKR2011002115-appb-I000007
Wherein, R1, R2 and R3 are as defined in Chemical Formula 1; and R3a is a halogen element.
<Chemical Formula 3>
Figure PCTKR2011002115-appb-I000008
Wherein A, B, R4, and R5 are as defined in Chemical Formula 1.
The method of the present invention may be represented as illustrated in the following Reaction Scheme 1.
<Reaction Scheme 1>
Figure PCTKR2011002115-appb-I000009
In the reaction scheme, the thioether bond may be formed by a nucleophilic substitution reaction between the compound of Chemical Formula 2 and the thiol compound of Chemical Formula 3.
In the method of the present invention, the compound of Chemical Formula 2 may be synthesized from a quinoxaline derivative or a phenylenediamine derivative. When the compound of Chemical Formula 2 is synthesized from a quinoxaline derivative, a Suzuki coupling reaction or a Still coupling reaction may be used to form a carbon-carbon bond between a quinoxaline compound substituted at position 3 with hydrogen or hydroxy (a compound of the following Chemical Formula 4) and a substituted thiazole or oxadiazole compound (Chemical Formula 5). The Suzuki coupling reaction may be catalyzed by Pd(PPh3)4 in the presence of DMF and K2CO3 while the Stille coupling reaction may be conducted with LiCl, CuI, 1,4-dixoane, and Pd(PPh3)2Cl2 (N. Miyauri, A. Suzuki, Chemical Reviews 1995, 95, 2457, S. T. Handy, X. Zhang, Organic Letters 2001, 3, 233). When the compound of Chemical Formula 4 is substituted at position 3 with hydroxy, halogenation subsequent to the introduction of R3 may be additionally performed to synthesize the compound of Chemical Formula 2.
<Chemical Formula 4>
Figure PCTKR2011002115-appb-I000010
Wherein, R1 and R2 are as defined above; R3c is halogen or hydroxy, and R3b is halogen.
<Chemical Formula 5>
Figure PCTKR2011002115-appb-I000011
Wherein, RA is hydrogen or a protecting group of R3 selected from among Me3Sn-, Bu3Sn-, B(OH)2- and
Figure PCTKR2011002115-appb-I000012
; and R3 is as defined in Chemical Formula 1.
When the compound of Chemical Formula 2 is synthesized from a quinoxaline derivative, a quinoxaline compound substituted at position 3 with halogen or hydroxy (Chemical Formula 4) may be subjected to nucleophilic substitution with a substituted imidazole or indole compound (Chemical Formula 5). When the compound of Chemical Formula 4 has hydroxy as a substituent at position 3, halogenation subsequent to the introduction of R3 may be further performed to give the compound of Chemical Formula 2.
In this context, when R6 of the moiety R3
Figure PCTKR2011002115-appb-I000013
in the final product compound of Chemical Formula 1 is not alkoxy, a compound having alkoxy as R6 may be additionally dealkylated using BBr3, HCl or LiCl and then subjected to a nucleophilic substitution reaction with a halogen compound in the final step to yield a desired compound of Chemical Formula 1 in which R6 is as defined above. On the other hand, when R10 of the moiety R3
Figure PCTKR2011002115-appb-I000014
in the final compound of Chemical Formula 1 is not an aldehyde, a compound having an aldehyde as R10 may be subjected to dehydration condensation using various amines to afford a desired compound of Chemical Formula 1 wherein R10 is as defined above.
As mentioned above, the compound of Chemical Formula 2 may be also synthesized from a phenylenediamine derivative. Depending on R3 of the final compound of Chemical Formula 1, the phenylenediamine derivative-derived compound of Chemical Formula 2, serving as a starting material, may vary.
When R3 is
Figure PCTKR2011002115-appb-I000015
in the compound of Chemical Formula 1, the compound of Chemical Formula 2 synthesized by condensating 1, 2-phenylenediamine (Chemical Formula 6) with a dioxoethylene derivative (Chemical Formula 7) is used as a starting material. For the final compound having a hydroxy at position 3, an oxalyl halogen may be further added to synthesize a compound of Chemical Formula 2 wherein R3a is halogen. Examples of the oxalyl halogen include oxalyl chloride. For reaction with oxalyl halogen, DMF and CH2Cl2 may be employed.
<Chemical Formula 6>
Figure PCTKR2011002115-appb-I000016
Wherein, R1, R2, and R3 are as defined in Chemical Formula 1.
<Chemical Formula 7>
Figure PCTKR2011002115-appb-I000017
Wherein, RB is hydroxy or a lower alkoxy of C1~C6.
When R3 is
Figure PCTKR2011002115-appb-I000018
in the compound of Chemical Formula 1, a compound of Chemical Formula 2 which is synthesized by subjecting 1, 2-phenylenediamine (Chemical Formula 6) and a trioxopropylene derivative (Chemical Formula 8) to a condensation reaction, reacting the condensate with a hydrazine hydrate to give a hydrizide compound (Chemical Formula 9), and adding a formic acid derivative (Chemical Formula 10) to the hydrizide compound, was used as a starting material. In the case where hydroxy is located at position 3 of the final compound, additional hydrogenation subsequent to the introduction of R3 may be conducted to give the compound of Chemical Formula 2.
The trioxopropylene derivative of Chemical Formula 8 can be reacted with 1, 2-phenylenediamine (Chemical Formula 6) to afford a quinoxaline structure, and may be 3-ethoxy-2,3-dioxopropanic acid.
<Chemical Formula 8>
Figure PCTKR2011002115-appb-I000019
Wherein, RB is hydroxy or a lower alkoxy of C1~C6; and RC is a lower alkoxy of C1~C6.
<Chemical Formula 9>
Figure PCTKR2011002115-appb-I000020
Wherein, R1 and R2 are as defined in Chemical Formula 1.
<Chemical Formula 10>
Figure PCTKR2011002115-appb-I000021
Wherein, R7 is as defined in Chemical Formula 1.
When R3 is
Figure PCTKR2011002115-appb-I000022
in the compound of Chemical Formula 1, the synthesis of the compound of Chemical Formula 2 from 1,2-phenylenediamine (Chemical Formula 6) is represented as illustrated in the following Reaction Scheme 2:
<Reaction Scheme 2>
Figure PCTKR2011002115-appb-I000023
The thiol compound of Chemical Formula 3 may be commercially available (e.g., from Sigma), or may be prepared by reacting a commercially available amine with di-2-pyridyl thiocarbonate to give an isocyanate (Outt, Pamela E. Journal of Organic Chemistry 1998, 63, 5762) and then reacting the isocyanate with metal azide, such as NaN3 or KN3, at 20~100℃ in alcohol or water or a mixture thereof (Shin, Kye Jung Bioorganic and Medicinal Chemistry Letters 2000, 10, 1421).
Alternatively, the thiol compound of Chemical Formula 3 may be prepared by reacting isothiocyanate with a commercially available hydrazide at 20~100℃ in a solvent, such as alcohol, water, dioxane or a combination thereof, alone or in combination with an alkaline such as NaOH (Graybill, Todd L. Tetrahedron Letters 2002, 43, 5305-5310).
Each reaction employed in the method of the present invention is accomplished by mixing and stirring a starting material and a reactant in a reaction solvent which has no influences on the reaction. A solvent used to facilitate the nucleophilic substitution reaction and the Suzuki coupling reaction includes alcohols such as methanol, ethers such as dioxane and tetrahydrofuran (THF), aromatic solvents such as benzene and toluene, chlorohydrocarbons such as dichloromethane (MC) and dichloroethane, acetonitrile, dimethylformamide (DMF), and a mixture thereof. As for the reaction temperatures, they may be set at 0~150℃.
In accordance with a further aspect thereof, the present invention pertains to a pharmaceutical composition for the treatment or prevention of diabetes or obesity, comprising the novel quinoxaline derivative as an active ingredient, characterized by the activity of reducing blood sugar levels or subjugating insulin resistance.
The pharmaceutical composition comprising the novel quinoxaline derivative or a pharmaceutically approved salt thereof as an active ingredient in accordance with the present invention may be Formulated into general medicine forms. In clinical practice, the compound of the present invention may be administered in various oral or parenteral dosage forms. Preferred is an oral dosage form. Typically, the compound of the present invention may be Formulated in combination with a diluent or an excipient, such as a filter, a thickening agent, a binder, a wetting agent, a disintegrant, a surfactant, etc.
Solid agents intended for oral administration of the compound of the present invention may be in the form of tablets, pills, powders, granules, capsules, and the like. These solid agents are Formulated with the quinoxaline derivative or a pharmaceutically approved salt thereof in combination with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, a lubricant, such as magnesium stearate, talc and the like, may also be added. Liquid agents intended for oral administration include suspensions, internal use solutions, emulsions, syrups, and the like. In addition to a simple diluent such as water or liquid paraffin, various excipients, such as wetting agents, sweetening agents, aromatics, preservatives and the like may be contained in the liquid agents for the oral administration of the compound of the present invention. Also, non-oral dosage forms of the compound of the present invention include sterile aqueous solutions, non-aqueous solutions, suspensions and emulsions, freeze-dried agents, and suppositories. For injections, non-aqueous solutions and suspensions made from propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and esters such as ethyl oleate may be used. The basic materials of suppositories include Witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, and glycerogelatin.
The effective dosage of the compound or pharmaceutically approved salt thereof in accordance with the present invention depends on various factors, including the patient`s weight, age, gender, state of health, diet, the time of administration, the route of administration, the rate of excretion, and the severity of disease. In general, the pharmaceutical composition comprising the quinoxaline derivative or pharmaceutically approved salt of the present invention as an active ingredient may be administered in a single dose or in multiple doses per day, each dose ranging from 0.1 ~ 1000 mg/day.
This invention provides the novel compound which has the effects on a drop of blood sugar and an improvement of insulin resistance; therefore it may be useful for treatment of metabolic diseases such as diabetes and obesity by regulating the function of glucagon like peptide 1 receptor (GLP 1 receptor) for the disease or disorder carried by GLP 1.
Figure 1 is a graph that the results of glucose induced insulin secretion of a mouse against the compound of Example 19 shown as the insulin concentration changes in blood plasma until 5 minutes after injecting glucose.
Figure 2 is the results of glucose induced insulin secretion of a mouse against the compound of Example 19 shown as an acute insulin response which is the average concentration of insulin in blood plasma to 1 and 5 minutes.
This invention will now be described by reference to the following examples which merely illustrative and which are not construed as a limitation of the scope of this invention.
It could be demonstrated that the analysis of synthesized compound used Varian 400MHz spectrometer and Agilent 1100 series LC/Mass to verify 1H NMR spectrum.
Example 1: 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
Step 1: Preparation of 2-methoxy-5-(3,6,7-trichloroquinoxaline-2-yl)thiazole
2,3,6,7-tetrachloroquinoxaline (1 mmol), 2-methoxy-5-(tributylstannyl)thiazole (1 mmol), lithium chloride, cooper(I) iodide, and Pd(PPh3)2)Cl2 were dissolved in 5 ml of dioxane and stirred for 6 hours in the temperature of 95℃. After the reaction, 500 mg of activated carbon was added and stirred for 10 minutes and concentrated after filtration using ethylacetate with celite. The condensed rudiment was applying to silica gel chromatography (EtOAc : Hexane = 1 : 10) and synthesized 2-methoxy-5-(3,6,7,-trichloroquinoxalin-2-yl)thiazole substituted 3-position.
1H NMR (CDCl3, 400MHz) 9.05(s, 1H), 8.81(s, 1H), 8.15(s, 1H), 7.76(s, 1H), 4.47(t, 2H, J=6.4Hz), 2.83(t, 2H, J=6.4Hz), 2.19(s, 6H).
MS(ESI+) m/z 453.1(M+1)
Step 2: Preparation of 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol
1 mg of N1, N1-dimethlethan-1,2-diamine and 1 mmol of di-2-pyridyl thiamocarbonate were dissolved in dichloromethane for 2 hours and stirred. It was extracted by using 50 ml of ethylacetate and adding water to the reactant. Organic solvents were cleansed by using water (30 ml X 2) and brine (30 ml) and separated. The intermediate of 2-isothiocyanato-N, N-dimethylethanamine was synthesized by removing water using magnesiumsulfat anhydrous from the separated organic solvents and removing ethylacetate through filtration and decompression. 1 mmol of the synthesized 2-isocyanato-N, N-dimethylethanamine and 1 mmol of sodium azide were stirred with 2 ml of 2-propanol and 2 ml of water for 3 hours in the temperature of 80℃. The solvent was removed by reducing pressure after acidification using 2N HCl. The desired form of the compound, 1-(2-dimethylamino)ethyl)-1H-tetrazole-5-thiol was obtained in the yield of 84% by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
1H NMR (CDCl3, 400MHz) 9.05(s, 1H), 8.81(s, 1H), 8.15(s, 1H), 7.76(s, 1H), 4.47(t, 2H, J=6.4Hz), 2.83(t, 2H, J=6.4Hz), 2.19(s, 6H)
MS(ESI+) m/z 453.1(M+1)
Step 3: Preparation of 2-(5-(6,7-dichloro-3-(2-methoxythiazole-5-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
2-methoxy-5-(3,6,7-trichloroquinoxaline-2-yl)thiazole (50 mg, 0.14 mmol) prepared by step 1 and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol (48 mg, 0.28 mmol), N-ethyl-N-isoprophylpropane-2-amine (73 ul, 0.42 mmol) synthesized in step 2 were reacted using 5 mg of N,N-dimethylformamide as a solvent for 2 hours in the temperature of 80℃, then the reactant was cooled down at room temperature. It was extracted by using 50 ml of ethylacetate after adding water to the reactant above. Organic solvents were cleansed by using water (30 ml X 2) and brine (30 ml) and separated. Water was removed from the separated organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. The desired form of the compound, 2-(5-(6,7-dichloro-3-(2-methoxythiazole-5-yl)quinoxalin-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine was obtained in the yield of 17% by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
1H NMR (CDCl3, 400MHz) 8.18(s, 1H), 8.08(s, 1H), 7.70(s, 1H), 4.46(t, 2H, J=6.4Hz), 4.18(s, 3H), 2.84(t, 2H, J=6.4Hz), 2.19(s, 3H)
MS(ESI+) m/z 483.1(M+1), 505.0(M+Na), 521.0(M+K)
Step 4: Preparation of 5-(6,7-dichloro-3-(1-(2-dimethylamino)-ethyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
2-(5-(6,7-dichloro-3-(2-methoxythiazole-5-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine (20 mg, 0.04 mmol) and BBr3 (20 mg, 2eq) were reacted with 2ml of dichloromethane as a solvent for 1 hour at room temperature, and methanol was added to the reactant. It was extracted by using 20 ml of ethylacetate, adding water after stirring for 10 minutes. Organic solvents were cleansed by using water (10 ml X 2) and brine (10 ml) and separated. Water was removed from the separated organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. The desired form of the compound, 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 1) was obtained in the yield of 18% by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
1H NMR (CDCl3, 400MHz) 8.12(s, 1H), 7.89(s, 1H), 7.72(s, 1H), 4.46(t, 2H, J=6.4Hz), 2.85(t, 2H, J=6.4Hz), 2.20(s, 3H).
MS(ESI+) m/z 468.9(M+1)
Example 2: 5-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 2) was obtained in the yield of 24% after preparation of 1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-thiol using N1,N1-dimethylpropane-1,3-diamine in the same method of Example 1.
N1,N1-dimethylpropane-1,3-diamine
MS(ESI+) m/z 188.1(M+1)
5-(6,7-dichloro-3-(1-(3-dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (CDCl3, 400MHz) 8.12(s, 1H), 7.87(s, 1H), 7.70(s, 1H), 4.46(t, 2H, J=7.0Hz), 2.30(t, 2H, J=7.0Hz), 2.16~2.12(m, 2H), 2.12(s, 6H)
MS(ESI+) m/z 483.1(M+1)
Example 3: 5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dicholoro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 3) was obtained in the yield of 22% using 1-methyl-1H-tetrazole-5-thiol in the same method of Example 1.
1H NMR (CD3OD, 400MHz) 8.15(s, 1H), 8.05(s, 1H), 7.80(s, 1H), 4.13(s, 3H)
MS(ESI+) m/z 434.1(M+Na)
Example 4: 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol
5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (50 mg, 0.12 mmol), 1-bromopropane-2-ol (167 mg, 10 eq), and potassium carbonate (167 mg, 10 eq) synthesized in Example 3 were reacted with 2 mg of N,N-dimethylformamide as a solvent for 2 hours in the temperature of 80℃, then the reactant was cooled down at room temperature. It was extracted by using 50 ml of ethylacetate after adding water to the reactant. Organic solvents were cleansed by using water (10 ml X 2) and brine (10 ml) and separated. Water was removed from the separated organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. The desired form of the compound, 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol (Example 4) was obtained in the yield of 6% by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
1H NMR (CDCl3, 400MHz) 8.10(s, 1H), 8.08(s, 1H), 7.70(s, 1H), 4.24~4.21(m, 1H), 4.10(s, 3H), 4.05(dd, 1H, J=14Hz, J=2.4Hz), 3.75~3.69(m, 1H), 1.24(d, 2H, J=3.6Hz)
MS(ESI+ )m/z 492.0(M+Na)
Example 5: 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 5) was obtained by using propane-1-amine in the same method of Example 1, after synthesizing 1-prophyl-1H-tetrazole-5-thiol.
1-prophyl-1H-tetrazole-5-thiol
MS(ESI+) m/z 143.1(M-1)
5-(6,7-dichloro-3-(1-prophyl-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
MS(ESI+) m/z 438.0(M-1)
Example 6: 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 6) was obtained in the yield of 18% after synthesizing 1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-tetrazole-5-thiol, using 2-(4-methylpiperazine-1)ethanamine in the same method of Example 1.
1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 227.1(M-1)
5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (CDCl3, 400MHz) 8.12(s, 1H), 7.89(s, 1H), 7.72(s, 1H), 4.49(t, 2H, J=6.2Hz), 2.92(t, 2H, J=6.2Hz), 2.58~2.42(m, 4H), 2.40~2.30(m, 4H), 2.24(s, 3H)
MS(ESI+) m/z 524.1(M+1)
Example 7: 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 7) was obtained in the yield of 15%, using 1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-thiol synthesized by 4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-amine in the same method of Example 1.
1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 269.1(M-1)
5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (CD3OD, 400MHz) 8.17(s, 1H), 8.09(s, 1H), 7.76(s, 1H), 4.20~3.70(m, 5H), 3.10~2.95(m, 1H), 2.50~2.30(m, 8H), 2.15(s, 3H)
MS(ESI+ )m/z 566.1(M+1)
Example 8: 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 8) was obtained in the yield of 19%, using 1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-thiol synthesized by 1-ethylpiperidine-3-amine in the same method of Example 1.
1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 212.1(M-1)
5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-thiazole-2-ol
1H NMR (DMSO-d6, 400MHz) 8.27(s, 1H), 8.12(s, 1H), 7.85(s, 1H), 4.67~4.60(m, 1H), 3.14~3.11(m, 1H), 2.78~2.75(m, 1H), 2.40~2.23(m, 3H), 2.04~1.70(m, 3H), 1.51~1.23(m, 2H), 0.81(t, 3H, J=7.0Hz).
MS(ESI+) m/z 509.1(M+1)
Example 9: 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 9) was obtained in the yield of 20%, using 1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-thiol synthesized by (3S,4S)-4-methoxy-1-methylpyrrolidine-3-amine in the same method of Example 1.
1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 214.1(M-1)
5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (CD3OD, 400MHz) 8.17(s,1 H), 8.06(s, 1H), 7.78(s, 1H), 4.30~4.20(m, 1H), 3.21~3.20(m, 1H), 2.97(s, 3H), 2.97~2.83(m, 2H), 2.40~2.36(m, 1H), 2.36(s, 3H)
MS(ESI+) m/z 509.0(M-1)
Example 10: 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 10) was obtained in the yield of 16%, using 1-isoprophyl-1H-tetrazole-5-thiol synthesized by propane-2-amine in the same method of Example 1.
1-isoprophyl-1H-tetrazole-5-thiol
MS(ESI+) m/z 143.0(M-1)
5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (CD3OD, 400MHz) 8.17(s, 1H), 8.07(s, 1H), 7.73(s, 1H), 4.97~4.94(m, 1H), 1.60(d, 6H, J=7.2Hz).
MS(ESI+ )m/z 462.0(M+Na)
Example 11: 1-(5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol
5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (50 mg, 0.12 mmol), 1-bromopropane-2-ol (167 mg, 10 eq), and potassium carbonate (167 mg, 10 eq) synthesized in Example 10 were reacted with 2 ml of N,N-dimethylformamide as a solvent for 2 hours in the temperature of 80℃, then the reactant was cooled down at room temperature. It was extracted by using 50 ml of ethylacetate after adding water to the reactant. Organic solvents were cleansed by using water (10 ml X 2) and brine (10 ml) and separated. Water was removed from the separated organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. The desired form of the compound, 1-(5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol (Example 11) was obtained in the yield of 17% by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
1H NMR (DMSO-d6, 400MHz) 8.32(s, 1H), 8.31(s, 1H), 7.87(s, 1H), 5.14(d, 1H, J=5.2Hz), 4.90~4.87(m, 1H), 4.03~3.96(m, 1H), 3.89~3.85(m, 1H), 3.78~3.73(m, 1H), 1.49(d, 6H, J=6.0Hz), 1.12(d, 3H, J=4.8Hz)
MS(ESI+) m/z 520.1(M+Na)
Example 12: 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate
The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate (Example 12) was obtained by using 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol and acetic anhydride synthesized in Example 10 in the same method of Example 4.
1H NMR (CDCl3, 400MHz) 8.54(s, 1H), 8.14(s, 1H), 7.69(s, 1H), 4.95-4.75(m, 1H), 2.73(s, 3H), 1.64(d, 6H, J=7.2Hz)
MS(ESI+) m/z 482.0(M+1)
Example 13: 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate
The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate (Example 13) was obtained by using 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol and pentatonic anhydride synthesized in Example 10 in the same method of Example 4.
1H NMR (CDCl3, 400MHz) 8.55(s, 1H), 8.14(s, 1H), 7.69(s, 1H), 4.95-4.75(m, 1H), 3.09(t, 2H, J=7.2Hz), 1.76~1.72(m, 2H), 1.64(d, 6H, J=7.2Hz), 1.47~1.42(m, 2H), 0.96(t, 3H, J=7.2Hz).
MS(ESI+) m/z 524.1(M+1), 546.1(M+Na)
Example 14: 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate
The desired form of the compound, 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate (Example 14) was obtained by using 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol and isobutyl anhydride synthesized in Example 10 in the same method of Example 4.
1H NMR (CDCl3, 400MHz) 8.54(s, 1H), 8.14(s, 1H), 7.69(s, 1H), 4.95-4.75(m, 1H), 3.90-3.75(m, 1H), 1.64(d, 6H, J=6.4Hz), 1.30(d, 6H, J=6.4Hz)
MS(ESI+ )m/z 510.1(M+1), 532.1(M+Na)
Example 15: 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 15) was obtained in the yield of 16%, using 1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-thiol synthesized by 1-ethylpiperidine-4-amine in the same method of Example 1.
1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 212.1(M-1)
5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (DMSO-d6, 400MHz) 8.28(s, 1H), 8.13(s, 1H), 7.80(s, 1H), 4.66~4.59(m, 1H), 3.33~3.30(m, 1H), 2.96~2.93(m, 1H), 2.40~2.32(m, 2H), 2.19~2.08(m, 3H), 2.01~1.90(m, 3H), 0.97(t, 3H, J=7.2Hz)
MS(ESI+) m/z 509.1(M+1)
Example 16: 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole
The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole (Example 16) was obtained in the yield of 11%, using 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol (56 mg, 0.28 mmol) synthesized by 2-methoxy-5-(3,6,7-trichloroquinoxaline-2-yl)thiazole (50 mg, 0.14 mmol) and 1-methylpiperidine-4-amine in the same method of Example 1.
1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 198.1(M-1)
5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole
1H NMR (CDCl3, 400MHz) 8.19(s, 1H), 8.09(s, 1H), 7.62(s, 1H), 4.42~4.38(m, 1H), 4.19(s, 3H), 2.98~2.94(m, 2H), 2.46~2.42(m, 2H), 2.28(s, 3H), 2.06~2.00(m, 4H)
MS(ESI+) m/z 509.0(M+1)
Example 17: 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 17) was obtained in the yield of 16%, using 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-ylthio)quinoxaline-2-yl)-2-methoxythiazole (20 mg, 0.04 mmol) synthesized in Example 16 in the same method of Example 1.
1H NMR (CDCl3, 400MHz) 8.13(s, 1H), 7.89(s, 1H), 7.64(s, 1H), 4.43~4.38(m, 1H), 2.99~2.96(m, 2H), 2.50~2.30(m, 2H), 2.28(s, 3H), 2.04~2.01(m, 4H)
MS(ESI+) m/z 495.1(M+1)
Example 18: 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole
The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole (Example 18) was obtained in the yield of 16%, using 1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-thiol (64 mg, 0.28 mmol) synthesized by 2-methoxy-5-(3,6,7-trichloroquinoxaline-2-yl)thiazole (50 mg, 0.14 mmol) and 1-(1-methylpiperidine-4-yl)ethanamine in the same method of Example 1.
1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 226.1(M-1)
5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole
1H NMR (CDCl3, 400MHz) 8.16(s, 1H), 8.09(s, 1H), 7.63(s, 1H), 4.40~4.30(m, 1H), 4.19(s, 3H), 3.00~2.77(m, 2H), 2.15(s, 3H), 2.00~1.61(m, 4H), 1.61(d, 3H, J=6.4Hz), 1.35~1.07(m, 3H)
MS(ESI+) m/z 537.2(M+1)
Example 19: 5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 19) was obtained in the yield of 16%, using 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole synthesized in Example 18 in the same method of Example 2.
1H NMR (CD3OD, 400MHz) 8.16(s, 1H), 8.05(s, 1H), 7.75(s, 1H), 4.64~4.61(m, 1H), 3.08~2.96(m, 2H), 2.41(s, 3H), 2.36~1.93(m, 4H), 1.60(d, 3H, J=6.8Hz), 1.41~1.28(m, 3H)
MS(ESI+) m/z 523.1(M+1), 545.1(M+Na)
Example 20: 5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 20) was obtained in the yield of 15%, using 1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-thiol synthesized by using (1-methylpiperidine-4-yl)methanamine in the same method of Example 1.
1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-thiol
MS(ESI+) m/z 212.1(M-1)
5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
1H NMR (CD3OD, 400MHz) 8.18(s, 1H), 8.06(s, 1H), 7.78(s, 1H), 4.42(d, 2H, J=7.2Hz), 3.05~3.02(m, 2H), 2.41(s, 3H), 2.30~1.73(m, 4H), 1.44~1.29(m, 3H)
MS(ESI+) m/z 509.1(M+1)
Example 21: 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol (Example 21) was obtained by using 1-amino-1H-tetrazole-5-thiol (AKOS company) which is available to buy commercially in the same method of Example 1.
1H NMR (CD3OD, 400MHz) 8.17(s, 1H), 8.04(s, 1H), 7.87(s, 1H)
MS(ESI+) m/z 411.0(M-1)
Example 22: 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-imidizol-2-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-imidizol-2-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 22) was obtained by using 1-(2-(dimethylamino)ethyl)-1H-imidazole-2-thiol synthesized by using 1H-imidazole-2-thiol in the same method of Example 1.
1H NMR (CD3OD, 400MHz) 8.14(s, 1H), 8.08(s, 1H), 7.77(s, 1H), 7.65(s, 1H), 7.30(s, 1H), 4.21(t, 2H, J=6.8Hz), 2.72(t, 2H, J=6.8Hz), 2.19(s, 6H)
MS(ESI+) m/z 467.1(M+1)
Example 23: 5-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 23) was obtained by using 4-isoprophyl-5-mercapto-4H-1,2,4-triazole-3-ol in the same method of Example 1.
1H NMR (DMSO-d6, 400MHz) 12.37(s, 1H), 12.10(s, 1H), 8.30(s, 1H), 8.06(s, 1H), 8.04(s, 1H), 4.15-4.08(m, 1H), 1.33(d, 6H, J=6.4Hz)
MS(ESI+) m/z 453.0(M-1)
Example 24: 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 24) was obtained after synthesizing 4-isoprophyl-4H-1,2,4-triazole-3-thiol using 2-isothiocyanato in the same method of Example 1.
4-isoprophyl-4H-1,2,4-triazole-3-thiol
MS(ESI+) m/z 142.1(M-1)
5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol
MS(ESI+) m/z 437.0(M-1)
Example 25: 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate
The desired form of the compound, 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate (Example 25) was obtained by using 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol and propane-1-sulfonyl chloride in the same method of Example 4.
MS(ESI+) m/z 545.0(M+1), 567.0(M+Na)
Example 26: 5-(3-(4-amino-5-trifluoromethyl)-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(3-(4-amino-5-trifluoromethyl)-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol (Example 26) was obtained by using 4-amino-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol in the same method of Example 1.
1H NMR (DMSO-d6, 400MHz) 8.30(s, 1H), 8.12(s, 1H), 7.84(s, 1H), 6.29(s, 2H)
Example 27: 5-(6,7-dichloro-3-(4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 27) was obtained by using 4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol in the same method of Example 1.
MS(ESI+) m/z 515.0(M-1)
Example 28: 5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 28) was obtained after synthesizing 4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-thiol by using 1,2-dichloro-4-isothiocyanatobenzene in the same method of Example 1.
4-isoprophyl-4H-1,2,4-triazole-3-thiol
MS(ESI+) m/z 244.1(M-1)
5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol
MS(ESI+) m/z 541.0(M-1)
Example 29: 5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 29) was obtained after synthesizing 4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-thiol by using 1-isotiocyanato-4-(trifluoromethyl)benzene in the same method of Example 1.
4-(4-(trifluoromethy)phenyl)-4H-1,2,4-triazole-3-thiol
MS(ESI+) m/z 244.2(M-1)
5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol
MS(ESI+) m/z 539.0(M-1)
Example 30: 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1,3,4-oxathiazole
Step 1: Preparation of ethyl 6,7-dichloro-3-hydroxyquinoxaline-2-carboxylate
8.08 g of diethyl 2-oxomalonate was added to 8.22 g of 4,5-dichlorobenzene-1,2-thiamine (Alfa Aesar Company) available to buy commercially after dissolved in 70 ml of DMF and 46 ml of AcOH. After the reaction, the desired compound of ethyl 6,7-dichloro-3-hydrocyquinoxaline-2-carboxylate (12.75 g) was synthesized by filtration and drying the produced solid after adding 100 ml of water.
1H NMR (CDCl3, 400MHz) 8.04(s, 1H), 7.54(s, 1H), 4.51(q, 2H, J=7.2Hz), 1.44(t, 3H, J=7.2Hz)
Step 2: Preparation of 6,7-dichloro-3-hydroxyquinoxaline-2-carbohydrazide
6.96 mmol of ethyl 6,7-dichloro-3-hydroxyquinoxaline-2-carboxylate was dissolved in 70 ml of ethanol, and heated to 90℃. When the solution was cleared, 34.83 mmol hydrazine hydrade was added and stirred for 2 hours in the temperature of 90℃. After the reaction, the desired compound of 6,7-dichloro-3-hydroxyquinoxaline-2-carbohydrazide was synthesized by filtering the generated solid and cleansing it with normal-hexane.
MS(ESI+) m/z 273.0(M+1)
Step 3: Preparation of 2-cyclopentylmethyl-5-(3,6,7-trichloroquinoxaline-2-yl)-1,3,4-oxathiazole
0.18 mmol of 6,7-dichloro-3-hydroxyquinoxaline-3-carbohyrazide and 0.18 mmol of 2-cyclopentyl acetic acid synthesized in step 2 were dissolved in 2 ml of phosphorous oxychloride and reflux-stirred for 6 hours. After the reaction, it was poured in iced water and stirred for 12 hours. The desired compound of 2-cyclopentylmethyl-5-(3,6,7-trichloroquinoxaline-2-yl)-1,3,4-oxathiazole was obtained by filtering of the generated solid.
MS(ESI+) m/z 383.0(M+1)
Step 4: Preparation of 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio-2-yl)-1,3,4-oxathiazole
2-cychlopentylmethyl-5-(3,6,7,-trichloroquinoxaline-2-yl)-1,3,4-oxathiazole (50 mg, 0.13 mmol) and 1-cychloprophyl-1H-tetrazole-5-thiol (37 mg, 0.26 mmol) manufactured in step 3 were reacted with 2 ml of N,N-dimethylacetamide as a solvent in the presence of N-ethly-N-isopropane-2-amine (0.05 ml, 0.285 mmol) for 2 hours in the temperature of 90℃. It was extracted by using 20 ml of ethylacetate, adding water after cooling down at room temperature. Organic solvents were cleansed by using water (10 ml X 2) and brine (10 ml) and separated. Water was removed from the separated organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1,3,4-oxathiazole (Example 30) was obtained by purifying with silica gel column chromatography using methanol and dichloromethane as developing solvents.
1H NMR (DMSO-d6, 400MHz) 8.30(s, 1H), 7.79(s, 1H), 3.69(m, 1H), 3.06(d, 2H, J=7.2Hz), 2.47(m, 1H), 1.94~1.13(m, 12H)
MS(ESI+) m/z 489.1(M+1), 511.1(M+Na)
Example 31: 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
Step 1: Preparation of 2,6,7-trichloro-3-(2-ethyl-1H-imidazole-1-yl)quinoxaline
0.7465 mmol of 2,3,6,7-trichloroquinoxaline and 1.5 mmol of 2-ethylimidazole was dissolved in 7.5 ml of dimethylformamide and stirred all night in the temperature of 90℃. After reaction, it was extracted by using ethylacetate, adding water. Water was removed from the organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. 2,6,7-trichloro-3-(2-ethyl-1H-imidazole-1-yl)quinoxaline was synthesized by crystallization using hexane/ethlyacetate.
1H NMR (CDCl3, 400MHz) 8.28(s, 1H), 8.25(s, 1H), 7.36(s, 1H), 7.30(s, 1H), 2.90~3.0(m, 2H), 1.34(t, 3H, J=7.6Hz)
Step 2: Preparation of 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidne-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methlypiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 31) was obtained by using 0.2289 mmol of 2,6,7-trichloro-3-(2-ethyl-1H-imidazole-1-yl)quinoxaline and 0.45 mmol of 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol synthesized in step 1 in the same method of Example 1.
1H NMR (CDCl3, 400MHz) 8.15(s, 1H), 7.82(s, 1H), 7.29(s, 1H), 7.20(s, 1H), 4.38(m, 1H), 2.98~3.01(m, 2H), 2.74(q, 2H, J=7.6Hz), 2.33~2.44(m, 2H), 2.31(s, 3H), 2.15~2.00(m, 4H), 1.29(t, 3H, J=7.6Hz)
Example 32: 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl) quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
The desired form of the compound, 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine (Example 32) was obtained by using 2-ethyl-4-methylimidazole and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.12(s, 1H), 7.89(s, 1H), 6.93(s, 1H), 4.41~4.45(m, 2H), 2.78~2.81(br, 2H), 2.68(q, 2H, J=7.6Hz), 2.29(s, 3H), 2.18(s, 6H), 1.20~1.28(m, 3H)
Example 33: 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 33) was obtained by using 2-ethyl-4-methylimidazole and 1-(1-methlypiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.12(s, 1H), 7.80(s, 1H), 6.99(s, 1H), 4.30~4.40(m, 1H), 2.95~3.01(m, 2H), 2.71(q, 2H, J=7.6Hz), 2.37~2.42(m, 2H),2.30(s, 3H), 2.28(s, 3H), 1.90~2.10(m, 4H), 1.18~1.28(m, 3H)
Example 34: 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline (Example 34) was obtained by using 2-ethylimidazole and 1-isoprophyl-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.22(s, 1H), 7.95(s, 1H), 7.48(s, 2H), 4.76~4.82(m, 1H), 2.99~3.08(m, 2H), 1.66(d, 6H, J=6.4Hz), 1.50~1.60(m, 3H)
Example 35: 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline (Example 35) was obtained by using 2-ethylimidazole and 1-prophyl-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.13(s, 1H), 7.84(s, 1H), 7.27(s, 1H), 7.19(s, 1H), 4.31(t, 2H, J=7.2Hz), 2.72(q, 2H, J=7.6Hz), 1.93~1.98(m, 2H), 1.27(t, 3H, J=7.6Hz), 0.91(t, 3H, J=7.2Hz)
Example 36: 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 36) was obtained by using 2-isoprophylimidazole and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.17(s, 1H), 7.83(s, 1H), 7.26(s, 1H), 7.22(s, 1H), 4.40~4.50(br, 1H), 3.00~3.11(br, 2H), 2.90~3.00(m, 1H), 2.05~2.44(m, 9H), 1.30(d, 6H, J=6.8Hz)
Example 37: 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline (Example 37) was synthesized by using 2-isoprophylimidazole and 1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (DMSO-d6, 400MHz) 8.56(s, 1H), 8.14(s, 1H), 7.67(s, 1H), 7.14(s, 1H), 4.49(t, 1H, J=14.8Hz), 3.00(quint, 1H, J=27.2Hz), 2.74~2.66(m, 2H), 2.61~2.49(m, 2H), 2.08(s, 3H), 1.76~1.70(m, 4H), 1.67~1.50(m, 3H), 1.22~1.19(m, 6H)
Example 38: 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 38) was synthesized by using 2-isoprophylimidazole and 1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (DMSO-d6, 400MHz) 8.54(s, 1H), 8.23(s, 1H), 7.64(s, 1H), 7.15(s, 1H), 5.20(s, 1H), 4.13(s, 1H), 4.03~4.02(m, 2H), 3.75~3.74(m, 2H), 3.02(m, 1H), 2.30(s, 4H) 2.07~2.01(m, 4H), 1.99(s, 3H), 1.24~1.21(m, 6H).
MS(ESI+ )m/z 575.2(M+1)
Example 39: 6,7-dichloro-2-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-3-(2-(methylthio)-1H-imidazole-1-yl)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-3-(2-(methylthio)-1H-imidazole-1-yl)quinoxaline (Example 39) was obtained by using 2-methylthioimidazole and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
MS(ESI+ )m/z 508.1(M+1)
Example 40: 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 40) was obtained by using 2-isoprophylthioimidazole and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.19(s, 1H), 7.99(s, 1H), 7.39(s, 1H), 7.36(s, 1H), 4.50~4.70(br, 1H), 3.60~3.71(m, 1H), 3.10~3.31(br, 2H), 2.10~2.60(m, 9H), 1.27(d, 6H, J=6.4Hz)
Example 41: 6,7-dichloro-2-(2-methyl-4-(trifluoromethyl)-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-methyl-4-(trifluoromethyl)-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline (Example 41) was obtained by using 2-methyl-4-trifluoromethylimidazole and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 31.
1H NMR (CDCl3, 400MHz) 8.16(s, 1H), 7.85(s, 1H), 7.77(s, 1H), 4.55~4.70(br, 1H), 3.10~3.21(br, 2H), 2.47(s, 3H), 2.30~2.50(br, 7H), 2.12~2.27(br, 2H)
Example 42: 6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline (Example 42) was obtained in the same method of Example 31.
6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline
MS(ESI+ )m/z 441.2(M-1)
Example 43: 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
Step 1: Preparation of 2,6,7-trichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl) quinoxaline
1.6797 mmol of 2,3,6,7-tetrachloroquinoxaline, 2.0 mmol of 4-azaindole, and 6.7 mmol of K2CO3 were dissolved in 9.0 ml of dimethylformamide and stirred all night at room temperature. After reaction, it was extracted by ethylacetate, adding water. Water was removed from the organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. 2,6,7-trichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline was synthesized by using the condensed rudiment applying to silica gel chromatography (EtOAc : Hexane = 1 : 5).
1H NMR (CDCl3, 400MHz) 8.64(d, 1H, J=5.2Hz), 8.46~8.54(br, 1H), 8.30~8.34(br, 1H), 8.27(s, 1H), 8.23(s, 1H), 7.54~7.60(br, 1H), 7.40~7.45(br, 1H)
Step 2: Preparation of 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine (Example 43) was obtained by using 0.2002 mmol of 2,6,7-trichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline and 0.40 mmol of 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol synthesized in step 1 in the same method of Example 1.
1H NMR (CDCl3, 400MHz) 8.68~8.69(m, 1H), 8.25(s, 1H), 8.17(s, 1H), 8.14(s, 1H), 7.76(s, 1H), 7.33~7.37(m, 2H), 5.10~5.25(br, 2H), 3.55~3.70(br, 2H), 2.65~2.80(br, 6H)
Example 44: 6,7-dichloro-2-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline (Example 44) was obtained by using 5-methoxy-4-azaindole and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 8.55(s, 1H), 8.11(s, 1H), 7.80(d, 1H, J=8.8Hz), 7.93(d, 1H, J=4.0Hz), 7.79(s, 1H), 6.90(d, 1H, J=3.2Hz), 6.74(d, 1H, J=8.8Hz), 4.48~4.55(m, 1H), 4.03(s, 3H), 1.54(d, 6H, J=7.2Hz)
Example 45: 2-(5-(6,7-dichloro-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine
The desired form of the compound, 2-(5-(6,7-dichloro-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine (Example 45) was obtained by using 5-methoxy-4-azaindole and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 8.11(s, 1H), 7.95(d, 1H, J=8.8Hz), 7.87(d, 1H, J=3.2Hz), 7.83(s, 1H), 6.87(d, 1H, J=3.6Hz), 6.73(d, 1H, J=8.8Hz), 4.50~4.63(br, 2H), 4.02(s, 3H), 2.90~3.00(br, 2H), 2.28(s, 6H)
Example 46: 6-chloro-1-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde
The desired form of the compound, 6-chloro-1-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (Example 46) was obtained by using 6-chloro-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde and 5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 10.68(s, 1H), 10.46(s, 1H), 8.73(s, 1H), 8.58(s, 1H), 8.22(s, 1H), 8.09(s, 1H), 8.02(s, 1H), 4.20~4.30(m, 1H), 1.52(d, 6H, J=6.8Hz)
Example 47: 6-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde
The desired form of the compound, 6-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (Example 47) was obtained by using 6-chloro-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
MS(ESI+ )m/z 518.0(M+1)
Example 48: methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate
The desired form of the compound, methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate (Example 48) was obtained by using methyl-1H-indole-3-carboxylate and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 8.42(s, 1H), 8.23~8.26(m, 1H), 8.12(s, 1H), 7.79(s, 1H), 7.50~7.59(m, 1H), 7.34~7.40(m, 2H), 5.00~5.20(br, 2H),3.95(s,3H), 3.50~3.70(br, 2H), 2.60~2.90(br, 6H)
Example 49: 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 49) was obtained by using 1H-indole-3-carbaldehyde and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
MS(ESI+) m/z 513.1(M+1), 535.1(M+Na)
Example 50: 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde
The desired form of the compound, 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 50) was synthesized by using 6-bromo-1H-indole-3-carbaldehyde and 5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthiol in the same method of Example 43.
1H NMR (DMSO-d6, 400MHz) 8.85 s, 1H), 8.59(s, 1H), 8.36(s, 1H), 8.17(d, 1H, ), 8.04(s, 1H), 7.57(s, 1H), 5.75(s, 1H), 1.89(s, 3H), 1.39~1.37(m, 3H)
MS(ESI+ )m/z 660.0(M+1)
Example 51: 6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde
The desired form of the compound, 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 50) was synthesized by using 6-bromo-1H-indole-3-carbaldehyde and 5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 8.56(s, 1H), 8.34(s, 1H), 8.31~8.28(m, 1H), 8.20(s, 1H), 7.90(s, 1H), 7.73(s, 1H), 7.55(d, 1H, J=10.4Hz), 4.49~4.45(m, 1H), 1.56~1.52(m, 6H)
Example 52: (E)-6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde oxime
0.12 mmol of 6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-carbaldehyde and 0.12 mmol of hydroxy chloride was reacted by using 2 ml of pyridine as a solvent for 2 hours at room temperature. It was extracted by adding water to the reactant and using 50 ml of ethylacetate. Organic solvents were cleansed and separated by using water (10 ml X 2) and brine (10 ml). Water was removed from the organic solvent by using magnesiumsulfat anhydrous and ethylacetate was removed by filtration and decompression. The desired compound of (E)-6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde oxime (Example 52) was synthesized by applying to silica gel chromatography using methanol and dichloromethane as the developing solvents.
1H NMR (DMSO-d6, 400MHz) 11.1(s, 1H), 9.19(s, 1H), 8.50(s, 1H), 8.45(s, 1H), 8.30(s, 1H), 8.11(s, 1H), 7.49(d, 1H, J=8.8Hz), 4.49~4.50(m, 1H), 1.42~1.40(m, 6H)
MS(ESI+ )m/z 599.9(M+Na)
Example 53: 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde
1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde (Example 53) was synthesized by using 5-fluoro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
1H NMR (DMSO-d6, 400MHz) 9.19(s, 1H), 8.99(s, 1H), 8.52(s, 1H), 8.18(s, 1H), 7.94(d, 1H, J=11.6Hz), 7.81(q, 1H, J=13.6Hz), 7.31(t, 1H, J=2.4Hz), 4.52(quint, 1H, J=2Hz), 1.42(d, 1H, J=6.8Hz)
MS(ESI+) m/z 523.0(M+Na)
Example 54: 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde
1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde (Example 54) was synthesized by using 6-bromo-1H-indole-3-carbaldehyde and 4-amino-4H-1,2,4-triazole-3-thiol in the same method of Example 54.
1H NMR (DMSO-d6, 400MHz) 8.89 s, 1H), 8.84(s, 1H), 8.55(s, 1H), 8.21(s, 1H), 8.18(d, 1H, J=12Hz),7.99(s, 1H), 7.56(d, 1H, J=12Hz), 6.00(s, 2H)
MS(ESI+) m/z 533.9(M+1)
Example 55: 6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde
6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 55) was synthesized by using 6-bromo-1H-indole-carbaldehyde and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 43.
1H NMR (DMSO-d6, 400MHz) 10.19(s, 1H), 8.92(s, 1H), 8.58(s, 1H), 8.20(d, 1H, J=8.4Hz), 8.14(s, 1H), 8.11(s, 1H), 7.61(d, 1H, J=8.4Hz), 4.51~4.50(m, 1H), 2.95~2.94(m, 4H), 2.18(s, 3H), 2.03~2.01(m, 4H)
MS(ESI+) m/z 639.0(M+Na)
Example 56: 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 56) was synthesized by using 6-fluoro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 10.17(s, H), 8.57(s, 1H), 8.39(s, 1H), 8.18(s, 1H), 7.89(s, 1H), 4.51~4.52(m, 1H), 1.56~1.52(m, 6H)
MS(ESI+) m/z 523.1(M+Na)
Example 57: 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde
1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde (Example 57) was synthesized by using 6-nitro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
MS(ESI+) m/z 550.0(M+Na)
Example 58: 5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde
5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 58) was synthesized by using 5-chloro-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
MS(ESI+) m/z 541.0(M+Na)
Example 59: 1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile
1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile (Example 59) was synthesized by using 5-cyano-1H-indole-3-carbaldehyde and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
MS(ESI+) m/z 530.0(M+Na)
Example 60: 6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde
6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde (Example 60) was synthesized by using 6-bromo-1H-indole-3-carbaldehyde and 1-isoprophyl-1H-tetrazole-5-thiol in the same method of Example 43.
1H NMR (CDCl3, 400MHz) 10.18(s, 1H), 8.31~8.28(m, 1H), 8.22(s, 1H), 7.89(s, 1H), 7.71(s, 1H), 7.57~7.55(m, 1H), 4.79(quint, 1H, J=12Hz), 1.63(s, 3H), 1.58(s, 3H)
Example 61: 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 61) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-isoprophyl-1H-tetrazole-5-thiol in the same method of Example 43.
1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
MS(ESI+) m/z 502.2(M+1)
Example 62: 1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound,1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 62) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 5-amino-4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
MS(ESI+) m/z 516.1(M+1)
Example 63: 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 63) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
MS(ESI+) m/z 531.0(M+1)
Example 64: 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 64) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-thiol in the same method of Example 64.
1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
MS(ESI+) m/z 545.1(M+1)
Example 65: 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 65) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 43.
1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
MS(ESI+) m/z 556.1(M+1)
Example 66: 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 66) was obtained by using 6-fluoro-1H-indole-3-carbaldehyde and 4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-thiol in the same method of 43.
1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
MS(ESI+) m/z 546.2(M+1)
Example 67: 6,7-dichloro-2-(6-chloro-5-fluoro-1H-benzo[d]imidazole-1-yl)-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline
The desired form of the compound, 6,7-dichloro-2-(6-chloro-5-fluoro-1H-benzo[d]imidazole-1-yl)-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline (Example 67) was obtained by using 6-chloro-5-fluoro-benzo[d]imidazole and 4-isoprophyl-4H-1,2,4-triazole-3-thiol in the same method of Example 43.
MS(ESI+) m/z 508.0(M+1)
Example 68: 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 68) was obtained by using 2,3,6-trichloroquinoxaline and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 1.
MS(ESI+) m/z 459.1(M-1)
Example 69: 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol (Example 69) was obtained by using 2,3,6-trichloroquinoxaline and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 1.
MS(ESI+) m/z 435.1(M+1),4 57.0(M+Na)
Example 70: 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol (Example 70) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 1.
MS(ESI+) m/z 493.1(M-1), 494.9(M+1), 517.0(M+Na)
Example 71: 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol (Example 71) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 1.
MS(ESI+) m/z 467.0(M-1), 469.0(M+1), 491.0(M+Na)
Example 72: 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde
The desired form of the compound, 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde (Example 72) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 6-fluoro-1H-indole-carbaldehyde in the same method of Example 43.
MS(ESI+) m/z 557.0(M+1), 579.0(M+Na)
Example 73: 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde
The desired form of the compound, 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde (Example 73) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 6-fluoro-1H-indole-3-carbaldehyde in the same method of Example 43.
MS(ESI+) m/z 557.1(M+1), 579.0(M+Na)
Example 74: 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde (Example 74) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 6-fluoro-1H-indole-3-carbaldehyde in the same method of Example 43.
MS(ESI+) m/z 531.1(M+1), 553.1(M+Na)
Example 75: 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-7-trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-7-trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 75) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline, 6-fluoro-1H-indole-3-carbaldehyde, and 1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-thiol in the same method of Example 43.
MS(ESI+) m/z 531.2(M+1), 553.0(M+Na)
Example 76: 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde (Example 76) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline, 6-fluoro-1H-indole-3-carbaldehyde, and 1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-thiol in the same method of Example 43.
MS(ESI+) m/z 545.0(M+1), 567.0(M+Na)
Example 77: 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde
The desired form of the compound, 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde (Example 77) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline, 6-fluoro-1H-indole-3-carbaldehyde, and 1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-thiol in the same method of Example 43.
MS(ESI+) m/z 545.0(M+1)
Example 78: 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol
The desired form of the compound, 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol (Example 78) was obtained by using 2,3-dichloro-6-trifluoromethylquinoxaline and 1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-thiol in the same method of Example 43.
MS(ESI+) m/z 493.1(M-1), 495.0(M+1), 516.9(M+Na)
Experimental Example 1: Assay for Ability to Activate Human Glucagon Like Peptide 1 Receptor
An experiment was designed as follows. When applied to the cells in which the human glucagon like peptide-1 receptor was transiently expressed, the compounds of the present invention activated the receptor so as to increase the level of cyclic adenosine-3`, 5`-monophosphate (cAMP), which thus stimulated the cAMP response element (CRE) to increase the activity of luciferase. Thus, an increase of luciferase activity was evaluated as the ability of the compound to activate the GLP-1 receptor.
In all of the following experiments, Below, 6,7-dichlroro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline of Novo Nordisk (Compound 2; GLP-1 agonist, BIOTREND Chemicals AG, Germany), known as a low-molecular weight compound able to activate the GLP-1 receptor, was used as a control (Knudsen LB. et al., Proc Natl Acad Sci, 2007(104):937-942).
A human GLP-1 receptor expression vector (Origene, USA) was transiently transfected, together with a DNA construct, containing four copies of the cAMP-response element, capable of inducing the expression of firefly luciferase, and a DNA construct expressing renilla luciferase (Promega, USA), into Chinese hamster ovary (CHO) cells with the aid of Lipofectamine Plus reagent (Invitrogen, USA). After transfection of three hours, the medium was replaced with α-MEM (Minimum essential media; Invitrogen, USA) supplemented with 10% fetal bovine serum. After incubation for six hrs, one volume of a dual luciferase assay reagent (Promega, USA) was added to the medium in which the cells were submerged while firefly luciferase and renilla luciferase activities were measured. The renilla luciferase activity was used to modulate the efficiency of transfection.
The compounds of the present invention were tested at multiple concentrations. Based on these multiple test results, a concentration showing 50% of the maximum effect of the positive control exenatide (American Peptide, USA) (EC50) was calculated using a non-linear regression analysis method. Relative activity of each compound at a concentration of 1 μM to the maximum effect of the positive control is expressed as percentage in Table 1.
Out of the compounds of Examples, as seen in Table 1, 71 compounds according to the present invention were found to range in EC50 from 50 nM to 1,000 nM with superiority over Compound-2 of Novo Nordisk (2,506 nM). The relative activity of these compounds at a concentration of 1 μM ranged from 40 to 100 % of that of the positive control.
Experimental Example 2: Assay for Selectivity for Human Glucagon Like Peptide-2 Receptor and Glucagon Receptor
An experiment was designed as follows. When applied to the cells in which the human glucagon like peptide-2 receptor or the glucagon receptor, both belonging to the same family, was transiently expressed, the compounds of the present invention activated the receptor so as to increase the level of cyclic adenosine-3`, 5`-monophosphate (cAMP), which thus stimulated the cAMP response element (CRE) to increase the activity of luciferase. Thus, an increase of luciferase activity was evaluated as the ability of the compound to activate the GLP-1 receptor.
The same procedure as in the assay for ability to activate human glucagon like peptide 1 receptor of Example 1 was repeated, with the exception that a human glucagon like peptide-2 receptor or glucagon receptor expression vector (Origene, USA) was transiently overexpressed, and glucagon like peptide-2 and glucagon (Sigma, USA) were used as positive controls. The ability of each compound at a concentration of 3 μM to activate the glucagon like peptide-2 receptor or the glucagon receptor is expressed as percentage of the maximum reactivity of the positive controls in Table 1.
As is apparent from data of Table 1, most of the compounds suggested in the Examples exhibited no activities or only a low activity on the glucagon receptor and the glucagon like peptide-2 receptor. Hence, the compounds of Examples having excellent activity for the GLP-1 receptor were found to exhibit specific selectivity for the GLP-1 receptor over the two similar receptors.
Experimental Example 3: Assay for Insulin Secretion Using Rat Beta-Cell Line
When the compounds of the present invention were applied to the rat beta-cell line (INS-1), the insulin secretion induced was evaluated as the activity of the compounds (enzyme immunoassay).
KRBH (Krebs-Ringer Bicarabonate HEPES) buffer was prepared with reference to a previous publication (Hou ZQ. et al., Mol Cell Endocrinol, 2008(291):71-78). Insulin was quantitatively analyzed using a rat insulin enzyme immunoassay kit (Shibayagi, Japan; ALPCO, USA). For quantitative protein assay, a BCA reagent (Pierce, USA) was used according to the protocol of the manufacturer`s.
In detail, rat beta-cells were incubated for one hour with glucose-free KRBH buffer to deplete nutrients. To KRBH containing 11.1 mM glucose and the phosphodiesterase inhibitor Ro-20-1724 (Calbiochem, USA) was added a compound with which the cells were then treated for 30 min. A sample was taken from the supernatant and quantitatively measured for the insulin released from the beta-cells. The cells were lysed and a portion taken from the cell lysate was quantitatively measured for protein. The measured amount of insulin was corrected according to the amount of protein. The ability of the compounds of the present invention is expressed as a percentage of the maximum effect of the positive control exenatide (American Peptide, USA) in Table 1.
As seen in Table 1, the compounds tested ranged in the relative insulin secretion activity from 0 to 80%. Of them, the compound with selectivity for the GLP-1 receptor induced insulin secretion at a relative rate of from 20 to 80%, which is higher than Compound-2 of Novo Nordisk.
Experimental Example 4: Assay for Glucose-Stimulated Insulin Secretion in Mice
The glucose-stimulated insulin secretion activity of the compounds in seven-week old male mice (C57BL/6 mice) was evaluated as an index indicating anti-diabetes activity (enzyme immunoassay).
Experimental mice were starved for 16~17 hrs before experiments. The compound of the present invention was orally administered 30 min before the injection of glucose. A glucose solution (1 g/kg/10 ml) was injected into the mice via the tail vein. Blood samples were taken from the intraorbital vein immediately before the injection of glucose and 1 and 5 min before the injection of glucose, and placed in heparinized tubes, followed by centrifugation. The plasma thus obtained were quantitatively analyzed for insulin using a mouse insulin analysis kit (Shibayagi, Japan). The results are shown in FIG. 1.
As Acute Insulin Response (AIR) values, mean values of the insulin concentrations secreted over a time period from 1 to 5 min after glucose administration were calculated (Winzell MS,
Figure PCTKR2011002115-appb-I000024
, Diabetes, 2004(53):S215-219), and the results are shown in FIG. 2.
When the compound of Example 19 according to the present invention was orally administered at a dose of 100 mg/kg, as seen in FIG. 1, the insulin concentration was increased up to 2.9±0.5 ng/ml at 1 min after glucose injection, which was 1.6-fold greater than that of the control (1.6±0.2 ng/ml). As is understood from data of FIG. 2, the acute insulin response of the compound was measured to be 2.3±0.2 ng/ml which was 1.6-fold greater than that of control (1.5±0.1 ng/ml).
Table 1
Result of Remedial effect and Selectivity evaluation
　 Human GLP
1 Receptor Insulin secretion in Beta cells Selectivity Evaluation (% @ 3 μμM)
Human GLP2 Receptor Human Glucagon Receptor
% @ 1 μμM EC50(nM)
compound-2 - 2,506 13.1 0 0
1 80.6 303.2 69.3 3.1(2.4c@1uM) 1.1(0.8c@1uM)
2 62.1 157.7 38.9 11.2(0.5 c @1uM) 4.9(0.0 c %@1uM)
3 68.6 535.6 40.4 0 0
4 76.6 660.1 56.5 0.0(0.9 c %@1uM) 0.0(0.0 c %@1uM)
5 81.6 330.5 49.1 1.6 1.6
6 81.4 328.4 78.3 0.2 0
7 80.3 395.7 54.2 0.2 0
8 62.8 380.9 27.2 0.6 7
9 97.2 202 49.6 3.2 6.9
10 70 464.6 44.7 4.3 7.1
11 76 450.7 31.9 16.9(0.0 c %@1uM) 9.5(0.6 c %@1uM)
12 109.8 177.3 12.4 4 0
13 105.6 166.6 39 3.4 0.6
14 102.5 181.9 30.3 3.2(0.8 c %@1uM) 0.8(0.4 c %@1uM)
15 80.3a(0.3uM) 63.1 58.9 0.0(0.0a%@0.3uM) 0.0(0.0a%@0.3uM)
16 83.8 416.7 43.9 0 0
17 72.6 234.8 26.1 3.1(1. c %@1uM) 3.1(0.0 c %@1uM)
18 75.8 399.6 56.4 0 1.5
19 98.3 122.1 48.2 1.5(0.7 c %@1uM) 1.6(0.9 c %@1uM)
20 99.5 86.5 61.8 3.8 1
21 63.8 758.2 14.1 0 2.7
22 58.9 770.6 11.6 0.9 0
23 61.9 695.5 29.7 0 0
24 51 956.5 43.6 0 5
25 52.3 920.8 11.2 - -
26 57.6 787.1 22.7 7.7(0.8 c %@1uM) 5.4(0.7 c %@1uM)
27 62.4 660.8 　 - -
28 58.6 717 　 - -
29 61.2 391.1 16.1 0.6 0
30 56.2 831.6 30.4 0 0
31 104.3 163.5 31.5 29.2(18.6c%@1uM) 13.9(0.0c%@1uM)
32 61.4 723.9 　 35.1(7.5 c %@1uM) 0.0(0.0 c %@1uM)
33 92.7 199 40.9 27.1(15.5c%@1uM) 0.0(0.0c%@1uM)
34 53.6 889.7 23 14.9(3.9 c %@1uM) 0.0(0.0 c %@1uM)
35 64.7 678.1 　 - -
36 112 326.6 　 2.2 c %@1uM 6.8 c %@1uM
37 77.4 546.4 21.7 14.0(0.0 c %@1uM) 11.5(1.8 c %@1uM)
38 31.1a(0.3uM) ND 　 0.5 c %@1uM 5.1 c %@1uM
39 38.8a(0.3uM) ND 　 - -
40 38.8a(0.3uM) ND 　 - -
41 29.6a(0.3uM) ND 　 - -
42 61.9 661.2 15.2 9.2(0.0 c %@1uM) 4.4(2.9 c %@1uM)
43 68.3 222.6 29 11.5(0.0 c %@1uM) 4.6(0.0 c %@1uM)
44 48.7 1060.4 31.4 - -
45 75.2 392.6 4.9 - -
46 58.2 729.3 　 - -
47 71.7 221.3 29.5 20.1(0.5 c %@1uM) 5.9(0.5 c %@1uM)
48 60.9 655.3 　 2.5(0.0 c %@1uM) 0.0(0.0 c %@1uM)
49 69.6 449.5 21.2 2 5.6
50 41.4 ND 13.2 - -
51 73.9 431.1 18.2 - -
52 60.9 396.1 18.8 - -
53 56.4 759.4 13.7 2.1 1.3
54 64.3 658.1 24.1 - -
55 54.8a(0.3uM) 257.9 10.8 - -
56 94.5 132.4 9.5 2.5(0.6 c %@1uM) 1.5(1.4c%@1uM)
57 106.4 240.2 0 14.2(11.7c%@1uM) 6.5(6.4c%@1uM)
58 61.7 658 21.3 - -
59 63.7 518.9 11b(10uM) - -
60 43.4a(0.3uM) ND 　 - -
61 65 544.2 27.5 - -
62 79.2 379.8 0 - -
63 90.2 105.9 15 5.1(5.1 c %@1uM) 3.3(2.6 c %@1uM)
64 105.8 64.8 11.6 3.1(7.2 c %@1uM) 1.3(3.7 c %@1uM)
65 86.4a(0.3uM) 67 0 - -
66 62.0a(0.3uM) 189.1 0 - -
67 107.4 290.7 29 15.0(5.1 c %@1uM) 7.6(1.3 c %@1uM)
68 72.8 340.5 30.1 25.7(3.3 c %@1uM) 8.8(2.1 c %@1uM)
69 60.7 680.6 11.8 - -
70 91.9 149.2 0 66.1(8.6 c %@1uM) 5.1(3.7 c %@1uM)
71 87.9 155.8 39.2 64.8(11.4c%@1uM) 3.2(10.2 c %@1uM)
72 55.9 720.1 　 - -
73 71.2 322.2 　 3.9(0.4 c %@1uM) 0.0(0.6 c %@1uM)
74 61.8 593.2 33.8 - -
75 84.6 260.5 　 - -
76 64.1 171 40.3 24.2(4.7c%@1uM) 3.7(5.3 c %@1uM)
77 97.3 100.5 43.5 4.8(1.2 c %@1uM) 3.1(2.3 c %@1uM)
78 98.9 70.1 65b(10 uM) - -
a. Evaluation result of 0.3μM, b. Evaluation result of 10μM, c. Evaluation result of 1μM

Claims (16)

  1. A compound represented by the following Chemical Formula 1 and its pharmaceutically approved salt.
    <Chemical Formula 1>
    Figure PCTKR2011002115-appb-I000025
    Wherein,
    R1 and R2, which may be the same or different, are hydrogen, halogen, or halogen-substituted or non-substituted lower alkyl of C1~C6,
    R3 is
    Figure PCTKR2011002115-appb-I000026
    ,
    Figure PCTKR2011002115-appb-I000027
    ,
    Figure PCTKR2011002115-appb-I000028
    , or
    Figure PCTKR2011002115-appb-I000029
    ;
    wherein R6 is hydrogen, hydroxy, a hydroxy-substituted or non-substituted lower alkoxy of C1~C6, -OC(O)-R13, or -OSO2-R13 wherein R13 is a lower alkyl of C1~C6; R7 is a lower alkyl of C1~C6 having a lower cycloalkyl of C3~C7 as a substituent, or no substitutents; R8 and R9, which may be the same or different, are hydrogen, halogen, a halogen-substituted or non-substituted lower alkyl of C1~C6, or a lower alkylthio of C1~C6; X and Y, which may be the same or different, are carbon or nitrogen; R10 is hydrogen, aldehyde, oxime, or -C(O)O-R14 with the proviso that X is carbon, wherein R14 is a lower alkyl of C1~C6; R11 and R12, which may be the same or different, are hydrogen, halogen, cyano, nitro, a lower alkyl of C1~C6, or a lower alkoxy of C1~C6;
    R4 is hydrogen, hydroxy, amino, a lower alkyl of C1~C6, a lower cycloalkyl of C3~C7, phenyl, or -(CH(R15))n-R16, wherein the phenyl may be substituted at one or more positions with halogen or a halogen-substituted or non-substituted lower alkyl or alkoxy of C1~C6; n is an integer of 0 to 5; R15 is a lower alkyl of C1~C6; R16 is a lower alkylamino or heteroaryl of C1~C6, with the proviso that when R16 is a heteroaryl, this heteroaryl may be substituted at one or more positions with a heteroaryl having a lower alkyl of C1~C6, a lower alkoxy of C1~C6, or a lower alkyl of C1~C6 as a substituent; and
    A and B, which may be the same or different, are carbon or nitrogen, with the proviso that when B is carbon, R5 is a hydrogen, hydroxy, amino or a halogen-substituted or non-substituted lower alkyl of C1~C6.
  2. The compound represented by Chemical Formula 1 according to Claim 1, wherein R3 is
    Figure PCTKR2011002115-appb-I000030
    ; or its pharmaceutically approved salt.
  3. The compound represented by Chemical Formula 1 according to Claim 1, wherein R3 is
    Figure PCTKR2011002115-appb-I000031
    ; or its pharmaceutically approved salt.
  4. The compound represented by Chemical Formula 1 according to Claim 1, wherein R3 is
    Figure PCTKR2011002115-appb-I000032
    ; or its pharmaceutically approved salt.
  5. The compound represented by Chemical Formula 1 according to Claim 1, wherein R3 is
    Figure PCTKR2011002115-appb-I000033
    ; or its pharmaceutically approved salt.
  6. The compound selected from the group consisting of;
    (1) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (2) 5-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (3) 5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (4) 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
    (5) 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (6) 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (7) 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (8) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (9) 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (10) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (11) 1-(5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
    (12) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate;
    (13) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate;
    (14) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate;
    (15) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (16) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
    (17) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (18) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
    (19) 5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (20) 5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (21) 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
    (22) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-imidizol-2-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (23) 5-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (24) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
    (25) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate;
    (26) 5-(3-(4-amino-5-trifluoromethyl)-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
    (27) 5-(6,7-dichloro-3-(4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (28) 5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
    (29) 5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (30) 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1,3,4-oxathiazole;
    (31) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (32) 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl) quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (33) 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (34) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (35) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (36) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (37) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline;
    (38) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (39) 6,7-dichloro-2-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-3-(2-(methylthio)-1H-imidazole-1-yl)quinoxaline;
    (40) 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (41) 6,7-dichloro-2-(2-methyl-4-(trifluoromethyl)-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (42) 6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (43) 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (44) 6,7-dichloro-2-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline;
    (45) 2-(5-(6,7-dichloro-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (46) 6-chloro-1-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
    (47) 6-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
    (48) methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate;
    (49) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (50) 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (51) 6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (52) (E)-6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde oxime;
    (53) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde;
    (54) 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde;
    (55) 6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (56) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (57) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde;
    (58) 5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (59) 1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile;
    (60) 6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (61) 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (62) 1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (63) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (64) 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (65) 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (66) 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (67) 6,7-dichloro-2-(6-chloro-5-fluoro-1H-benzo[d]imidazole-1-yl)-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline;
    (68) 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (69) 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (70) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
    (71) 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
    (72) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
    (73) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
    (74) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
    (75) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-7-trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (76) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
    (77) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (78) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol.
  7. The compound represented by Chemical Formula 1, wherein the compound represented by Chemical Formula 2 below is reacted with the thiol compound represented by Chemical Formula 3; or its pharmaceutically approved salt.
    <Chemical Formula 1>
    Figure PCTKR2011002115-appb-I000034
    <Chemical Formula 2>
    Figure PCTKR2011002115-appb-I000035
    <Chemical Formula 3>
    Figure PCTKR2011002115-appb-I000036
    Wherein, R1, R2, R3, R4, R5, A, and B are as defined in Chemical Formula 1; and R3a is a halogen element.
  8. The compound represented by Chemical Formula 1 according to Claim 7, wherein the compound of Chemical Formula 2 is prepared by Suzuki coupling reaction, Stille coupling reaction, or nucleophilic substitution with the compounds of chemical Formula 4 and 5; and the process for preparing its pharmaceutically approved salt.
    <Chemical Formula 4>
    Figure PCTKR2011002115-appb-I000037
    Wherein, R1 and R2 are as defined in Chemical Formula 1; R3c is halogen or hydroxyl; and R3b is halogen.
    <Chemical Formula 5>
    Figure PCTKR2011002115-appb-I000038
    Wherein, RA is hydrogen or Me3Sn-, Bu3Sn-, B(OH)2-, and R3 protector of
    Figure PCTKR2011002115-appb-I000039
    . Further, R3 is as defined in Chemical Formula 1 of Claim 1.
  9. The process according to Claim 8, wherein R6 and R10 as the substituent of R3 represented by Chemical Formula 5 are selected from alkoxy and aldehyde respectively.
  10. The process for preparing the compound represented by Chemical Formula 1 and its pharmaceutically approved salt, wherein R3 of chemical Formula 1 is
    Figure PCTKR2011002115-appb-I000040
    ; and the compound represented by Chemical Formula 1 is reacted with thiol compound of chemical Formula 3 after manufacturing the compound of Chemical Formula 2 by the condensation reaction of the compounds of Chemical Formula 6 and 7.
    <Chemical Formula 1>
    Figure PCTKR2011002115-appb-I000041
    <Chemical Formula 2>
    Figure PCTKR2011002115-appb-I000042
    <Chemical Formula 3>
    Figure PCTKR2011002115-appb-I000043
    <Chemical Formula 6>
    Figure PCTKR2011002115-appb-I000044
    <Chemical Formula 7>
    Figure PCTKR2011002115-appb-I000045
    Wherein, R3 is
    Figure PCTKR2011002115-appb-I000046
    ; R1, R2, R4, R5, A, and B are as defined in Chemical Formula 1 of Claim 1; R3a is halogen; and RB is hydroxyl or the lower alcohol of C1~C6.
  11. The process for preparing the compound represented by Chemical Formula 1 and its pharmaceutically approved salt according to Claim 10, wherein R3 of Chemical Formula 1 is
    Figure PCTKR2011002115-appb-I000047
    ; and the compound of chemical Formula 2 which R3a is halogen manufactured by adding oxalyl halogen in case that the 3- position of the compound prepared by condensation reaction is hydroxyl.
  12. The process preparing the compound represented by Chemical Formula 1, wherein R3 is
    Figure PCTKR2011002115-appb-I000048
    and its pharmaceutically approved salt comprising;
    i) A step for preparing the compound of Chemical Formula 9 by reacting with hydrazine hydrate after condensation reaction of the compounds of Chemical Formula 6 and 8;
    ii) a step for preparing the compound of Chemical Formula 2 by reacting the compound of Chemical Formula 9 with the one of Chemical Formula 10; and
    iii) a step for reacting the compound of Chemical Formula 2 with thiol compound of Chemical Formula 3.
    <Chemical Formula 1>
    Figure PCTKR2011002115-appb-I000049
    <Chemical Formula 2>
    Figure PCTKR2011002115-appb-I000050
    <Chemical Formula 3>
    Figure PCTKR2011002115-appb-I000051
    <Chemical Formula 6>
    Figure PCTKR2011002115-appb-I000052
    <Chemical Formula 8>
    Figure PCTKR2011002115-appb-I000053
    <Chemical Formula 9>
    Figure PCTKR2011002115-appb-I000054
    <Chemical Formula 10>
    Figure PCTKR2011002115-appb-I000055
    Wherein, R3 is
    Figure PCTKR2011002115-appb-I000056
    ; R1, R2, R4, R5, R7, A, and B are as defined in Chemical Formula 1 of Claim 1; R3a is halogen; RB is hydroxyl or the lower alcohol of C1~C6; and RC is the lower alcohol of C1~C6.
  13. The pharmaceutical composition for declining of blood sugar and improving of insulin resistance comprising the compound of Chemical Formula 1 in Claim 1 or its pharmaceutically approved salt as the active ingredients.
  14. The pharmaceutical composition for declining of blood sugar and improving of insulin resistance comprising the compound as an active ingredient selected from the group consisting of;
    (1) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (2) 5-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (3) 5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (4) 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
    (5) 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (6) 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (7) 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (8) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (9) 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (10) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (11) 1-(5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
    (12) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate;
    (13) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate;
    (14) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate;
    (15) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (16) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
    (17) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (18) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
    (19) 5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (20) 5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (21) 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
    (22) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-imidizol-2-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (23) 5-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (24) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
    (25) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate;
    (26) 5-(3-(4-amino-5-trifluoromethyl)-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
    (27) 5-(6,7-dichloro-3-(4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (28) 5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
    (29) 5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (30) 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1,3,4-oxathiazole;
    (31) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (32) 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl) quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (33) 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (34) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (35) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (36) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (37) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline;
    (38) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (39) 6,7-dichloro-2-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-3-(2-(methylthio)-1H-imidazole-1-yl)quinoxaline;
    (40) 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (41) 6,7-dichloro-2-(2-methyl-4-(trifluoromethyl)-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (42) 6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (43) 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (44) 6,7-dichloro-2-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline;
    (45) 2-(5-(6,7-dichloro-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (46) 6-chloro-1-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
    (47) 6-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
    (48) methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate;
    (49) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (50) 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (51) 6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (52) (E)-6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde oxime;
    (53) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde;
    (54) 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde;
    (55) 6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (56) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (57) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde;
    (58) 5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (59) 1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile;
    (60) 6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (61) 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (62) 1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (63) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (64) 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (65) 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (66) 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (67) 6,7-dichloro-2-(6-chloro-5-fluoro-1H-benzo[d]imidazole-1-yl)-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline;
    (68) 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (69) 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (70) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
    (71) 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
    (72) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
    (73) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
    (74) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
    (75) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-7-trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (76) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
    (77) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (78) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol.
  15. The pharmaceutical composition for preventing or treating diabetes and obesity comprising the compound of Chemical Formula 1 in Claim 1 or its pharmaceutically approved salt as the active ingredients.
  16. The pharmaceutical composition for preventing treating of diabetes and obesity comprising the compound as an active ingredient selected from the group consisting of;
    (1) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (2) 5-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (3) 5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (4) 1-(5-(6,7-dichloro-3-(1-methyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
    (5) 5-(6,7-dichloro-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (6) 5-(6,7-dichloro-3-(1-(2-(4-methylpiperazine-1-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (7) 5-(6,7-dichloro-3-(1-(4-(4-methylpiperazine-1-yl)-tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (8) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (9) 5-(6,7-dichloro-3-(1-((3S,4S)-4-methoxy-1-methylpyrrolidine-3-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (10) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (11) 1-(5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yloxy)propane-2-ol;
    (12) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl acetate;
    (13) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl pentanoate;
    (14) 5-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-yl isobutyrate;
    (15) 5-(6,7-dichloro-3-(1-(1-ethylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (16) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
    (17) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (18) 5-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-2-methoxythiazole;
    (19) 5-(6,7-dichloro-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (20) 5-(6,7-dichloro-3-(1-((1-methylpiperidine-4-yl)methyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (21) 5-(3-(1-amino-1H-tetrazole-5-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
    (22) 5-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-imidizol-2-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (23) 5-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (24) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
    (25) 5-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-yl propane-1-sulfonate;
    (26) 5-(3-(4-amino-5-trifluoromethyl)-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)thiazole-2-ol;
    (27) 5-(6,7-dichloro-3-(4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (28) 5-(6,7-dichloro-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazole-3-ylthio) quinoxaline-2-yl)thiazole-2-ol;
    (29) 5-(6,7-dichloro-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (30) 2-(cyclopentylmethyl)-5-(6,7-dichloro-3-(1-cycloprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1,3,4-oxathiazole;
    (31) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (32) 2-(5-(6,7-dichloro-3-(2-ethyl-4-methyl-1H-imidazole-1-yl) quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (33) 6,7-dichloro-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (34) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (35) 6,7-dichloro-2-(2-ethyl-1H-imidazole-1-yl)-3-(1-prophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (36) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (37) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(1-(1-methylpiperidine-4-yl)ethyl)-1H-tetrazole-5-ylthiazole)quinoxaline;
    (38) 6,7-dichloro-2-(2-isoprophyl-1H-imidazole-1-yl)-3-(1-(4-(4-methylpiperazine-1-yl)tetrahydrofuran-3-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (39) 6,7-dichloro-2-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-3-(2-(methylthio)-1H-imidazole-1-yl)quinoxaline;
    (40) 6,7-dichloro-2-(2-(isoprophylthio)-1H-imidazole-1-yl)-3-(1-(1-methylpipiridine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (41) 6,7-dichloro-2-(2-methyl-4-(trifluoromethyl)-1H-imidazole-1-yl)-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline;
    (42) 6,7-dichloro-2-(2-chloro-1H-imidazole-1-yl)-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline;
    (43) 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (44) 6,7-dichloro-2-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline;
    (45) 2-(5-(6,7-dichloro-3-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine;
    (46) 6-chloro-1-(6,7-dichloro-3-(5-hydroxy-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
    (47) 6-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde;
    (48) methyl 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carboxylate;
    (49) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (50) 6-bromo-1-(6,7-dichloro-3-(5-hydroxy-4-(1-(1-methylpiperidine-4-yl)ethyl)-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (51) 6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (52) (E)-6-bromo-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde oxime;
    (53) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-5-fluoro-1H-indole-3-carbaldehyde;
    (54) 1-(3-(4-amino-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-bromo-1H-indole-3-carbaldehyde;
    (55) 6-bromo-1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (56) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (57) 1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-nitro-1H-indole-3-carbaldehyde;
    (58) 5-chloro-1-(6,7-dichloro-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (59) 1-(6,7-dichloro-3-(4-(isoprophyl-4H-1,2,4-triazole-3-thiol)quinoxaline-2-yl)-3-formyl-1H-indole-5-carbonitrile;
    (60) 6-bromo-1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-1H-indole-3-carbaldehyde;
    (61) 1-(6,7-dichloro-3-(1-isoprophyl-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (62) 1-(3-(5-amino-4-isoprophyl-4H-1,2,4-triazole-3-ylthio)-6,7-dichloroquinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (63) 1-(6,7-dichloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (64) 1-(6,7-dichloro-3-(1-(3-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (65) 1-(6,7-dichloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (66) 1-(6,7-dichloro-3-(4-(2-(dimethylamino)ethyl)-5-hydroxy-4H-1,2,4-triazole-3-ylthio)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (67) 6,7-dichloro-2-(6-chloro-5-fluoro-1H-benzo[d]imidazole-1-yl)-3-(4-isoprophyl-4H-1,2,4-triazole-3-ylthio)quinoxaline;
    (68) 5-(6-chloro-3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (69) 5-(6-chloro-3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)quinoxaline-2-yl)thiazole-2-ol;
    (70) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
    (71) 5-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol;
    (72) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
    (73) 6-fluoro-1-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl))-1H-indole-3-carbaldehyde;
    (74) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-6-(trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
    (75) 1-(3-(1-(2-(dimethylamino)ethyl)-1H-tetrazole-5-ylthio)-7-trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (76) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-6-trifluoromethyl)quinoxaline-2-yl))-6-fluoro-1H-indole-3-carbaldehyde;
    (77) 1-(3-(1-(2-(dimethylamino)prophyl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)-6-fluoro-1H-indole-3-carbaldehyde;
    (78) 5-(3-(1-(1-methylpiperidine-4-yl)-1H-tetrazole-5-ylthio)-7-(trifluoromethyl)quinoxaline-2-yl)thiazole-2-ol.
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