WO2010093191A2 - Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same - Google Patents

Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same Download PDF

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WO2010093191A2
WO2010093191A2 PCT/KR2010/000893 KR2010000893W WO2010093191A2 WO 2010093191 A2 WO2010093191 A2 WO 2010093191A2 KR 2010000893 W KR2010000893 W KR 2010000893W WO 2010093191 A2 WO2010093191 A2 WO 2010093191A2
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methyl
thiazole
carboxylic acid
indol
cyano
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PCT/KR2010/000893
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French (fr)
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WO2010093191A3 (en
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Sung Pil Choi
Geun Tae Kim
Jeong Uk Song
Tae Hun Kim
Dong Chul Lim
Seung Wan Kang
Hyung Jin Kim
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Lg Life Sciences Ltd.
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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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds of formula (1):
  • A, D, E, G, Y, Q, Wi, W 2 , W 3 and W 4 are as defined below, which are effective as an inhibitor for xanthine oxidase, a process for preparing the same, and a pharmaceutical composition comprising a therapeutically effective amount of the same.
  • Xanthine oxidase is known as an enzyme which converts hypozanthine to xanthine and further converts thus-formed zanthine to uric acid. Although most mammals have uricase, humans and chimpanzees do not, thereby uric acid is known to be the final product of purine metabolism (S. P. Bruce, Ann. Pharm., 2006, 40, 2187-2194). Sustained elevation of blood concentration of uric acid can cause various diseases, representatively including gout.
  • gout is caused by an elevated level of uric acid in the body, indicating the condition in which uric acid crystals accumulated in cartilage, ligament and surrounding tissue induce severe inflammation and pain. Gout is a kind of inflammatory articular disease, and its incidence rate has steadily increased during past 40 years (N. L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587-2590).
  • gout patients in the West exhibited an astonishing increase of about 200-300%, mainly in males.
  • the increased rate of gout patients can be traced to obesity, aging, kidney function decline, hypertension, etc.
  • the incidence rate of gout appears to be a level of about 1.4/1,000 persons, but it also depends on the uric acid level. That is, while the incidence rate of gout is 0.5% in a patient group with a blood uric acid level of 7.0 mg/dl or more, the incidence rate of gout is 5.5% in a patient group with a uric acid level of 9.0 mg/dl or more (G. Nuki, Medicine, 2006, 34, 417-423).
  • Allopurinol was a unique drug for the treatment of gout for 40 years, until febuxostat was approved as an arthrifuge in Europe in 2008 (Brain Tomlinson, Current Opin. Invest. Drugs, 2005, 6, 1168-1178). Allopurinol is known to be a non-specific inhibitor for various enzymes that are involved in purine and pyrimidine metabolism, and it has a Ki of 700 nM for xanthine oxidase (Y. Takano et al., Life Sciences, 2005, 76, 1835-1847). Allopurinol is immediately oxidized to oxypurinol by xanthine oxidase, and this metabolite is known to act as a potent inhibitor for xanthine oxidase.
  • One object of the present invention is to provide novel compounds of formula (1) which exhibit very excellent inhibitory effect against xanthine oxidase.
  • Another object of the present invention is to provide a novel process for the preparation of the compounds of formula (1).
  • Still another object of the present invention is to provide a pharmaceutical composition for the inhibition of xanthine oxidase, which comprises a therapeutically effective amount of the compounds of formula (1) as an active ingredient.
  • Still another object of the present invention is to provide a method for the treatment and/or prevention of the diseases associated with xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and articular disease, and inflammatory bowel disease, which comprises using the compounds of formula (1) as an active ingredient.
  • diseases associated with xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and articular disease, and inflammatory bowel disease
  • Wi, W 2 , W 3 and W 4 represent N or C, provided that only one is N when Wi, W 2 , W 3 or W 4 represents N,
  • A represents the following A-i or A-ii: [35] (A-i)
  • J represents hydrogen; halogen; d-C 6 -alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted d-C 6 -alkoxy, and X represents O or S
  • A is linked to only C when A is linked to Wi, W 2 , W 3 or W 4 ,
  • E represents hydrogen; halogen; nitro; cyano; amino; substituted or unsubstituted Ci -
  • D represents hydrogen; halogen; cyano; nitro; Ci-C 6 -alkyl which is unsubstituted or substituted by halogen; or-CHO,
  • Q is selected form the following Q-i, Q-ii, Q-iii-1 to Q-iii-14:
  • RlO and RI l independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1-3
  • R12 represents substituted or unsubstituted lower alkyl or aryl, and n denotes an integer of 0-3)
  • Rl 3 and R14 independently of one another represent substituted or unsubstituted lower alkyl, or together with the nitrogen atom to which they are attached may form a 3-7 membered heterocycle containing N as the hetero atom, and n denotes an integer of 0-3)
  • N R15 0 (wherein R15 represents substituted or unsubstituted lower alkyl, and m denotes an integer of 1-3), [60] [61] (Q-iii-8)
  • Rl 6 and R17 independently of one another represent hydrogen or substituted or unsubstituted lower alkyl, or together with the atoms to which they are attached may form a 3-7 membered heterocycle containing N as the hetero atom, and m denotes an integer of 1-3
  • Wi, W 2 , W 3 , W 4 and W 5 represent N or C, provided that only one is N when Wi, W 2 , W 3 , W 4 or W 5 represents N, R24 and R25 independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1 ⁇ 3),
  • Y represents hydrogen; halogen; substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl; substituted or unsubstituted Ci - C 6 -alkoxy; C 6 -Ci 0 -aryl; substituted or unsubstituted 3-7 membered heteroaryl which contains N as the hetero atom; substituted or unsubstituted 3-7 membered heterocycle which contains N as the hetero atom, or
  • G represents hydrogen; or substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl, pharmaceutically acceptable salts, or isomers thereof.
  • the compounds of formula (1) as an active in- gredient of the therapeutic agent include all their pharmaceutically acceptable salts and isomers, and they should be instrued to fall under the scope of the present invention.
  • they are simply referred to as 'compounds of formula (I)' in the present specification.
  • the above compounds of formula (1) according to the present invention have a quite different chemical structure from the earlier known xanthine oxidase inhibitors. As shown in the following experiments, they exhibit an excellent inhibitory effect against xanthine oxidase associated with gout. Thus, they can be used for the prevention and treatment of diseases associated with xanthine oxidase, such as, for example, hyperuricemia, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, articular disease, etc.
  • diseases associated with xanthine oxidase such as, for example, hyperuricemia, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, articular disease, etc.
  • substituted or un- substituted means to include both the cases of being substituted and unsubstituted.
  • the radical may be substituted by one or more groups individually and independently selected from alkyl, cycloalkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, carbonyl, thiocarbonyl, sulfonyl, nitro, aryl and their protective derivatives. If appropriate, these groups may be furthermore substituted.
  • pharmaceutically acceptable salts means the salt forms of a compound, which neither give any serious irritation to the organism to which the compound is administered nor damage the biological activities and properties of the compound.
  • a pharmaceutically acceptable salt includes a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-to
  • the compounds of formula (1) can also form a pharmaceutically acceptable base addition salt, for example, a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.
  • the compounds of formula (1) of the present invention may be converted to their salts according to any of the conventional methods.
  • “isomer” means those having the same chemical or molecular formula as, but optically or sterically different from, the compounds of formula (1), or salts thereof.
  • the compounds of formula (1) of the present invention may have an oxime structure, and so may exist in the form of geometrical isomers, trans and cis. All the isomers, their salts, and their mixtures (including racemic mixture) are also covered by the present invention.
  • aryl means a carbocyclic group (e.g., phenyl) having a covalent ⁇ electronic system and at least one ring. This term also includes monocyclic or fused- ring polycyclic (i.e., rings share the adjacent carbon pairs) groups.
  • heteroaryl means a heterocyclic aryl group having a covalent ⁇ electronic system and at least one ring. It includes but is not limited to furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.
  • alkyl means an aliphatic hydrocarbon group.
  • the alkyl group may be "a saturated alkyl” not containing alkene or alkine moiety at all, or "an unsaturated alkyl” containing at least one alkene or alkine moiety.
  • alkene means a group having at least one carbon-carbon double bond
  • alkine means a group having at least one carbon-carbon triple bond. Regardless of being saturated or unsaturated, the alkyl group may be branched, linear or cyclic.
  • the alkyl group may contain 1 to 20 carbon atoms, and the lower alkyl group may contain 1 to 7 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • heterocycle means a group wherein the ring carbon atom is replaced by oxygen, nitrogen, sulfur, etc. It may optionally include a double bond.
  • the typical examples thereof may include but are not limited to pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, etc.
  • halogen means F (or-F), Cl (or-Cl), Br (or-Br) and I (or-I).
  • W 1 , W 2 , W 3 and W 4 represent N or C, provided that only one is N when W 1 , W 2 , W 3 or W 4 represents N,
  • A represents the following A-i or A-ii:
  • J represents hydrogen; Q-Ce-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted Q-Ce-alkoxy, and X represents O or S
  • A is linked to only C when A is linked to W 1 , W 2 , W 3 or W 4 ,
  • E represents hydrogen; halogen; nitro; cyano; amino; or Q-Ce-alkyl, provided that E is linked to only C when E is linked to W 1 , W 2 , W 3 or W 4 ,
  • D represents hydrogen; halogen; cyano; or nitro
  • Q is selected form the following Q-i, Q-ii, Q-iii- 1 to Q-iii- 14:
  • %S-R12 0 (wherein R 12 represents lower alkyl, and n denotes an integer of 0-3)
  • Rl 6 and R17 independently of one another represent hydrogen or lower alkyl, or together with the atoms to which they are attached may form a 5-6 membered heterocycle containing one (1) N as the hetero atom, and m denotes an integer of 1-3
  • Wi, W 2 , W 3 , W 4 and W 5 represent N or C, provided that only one is N when Wi, W 2 , W 3 , W 4 or W 5 represents N, R24 and R25 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1-3),
  • Y represents hydrogen; saturated or unsaturated and straight-chain, branched or cyclic alkyl which is unsubstituted or substituted by lower alkoxy or C 3 -C 6 -cycloalkyl; C 6 -Ci 0 - aryl; 5-6 membered heteroaryl which contains 1-2 N as the hetero atom and which is unsubstituted or substituted by lower alkyl; 5-6 membered heterocycle which contains 1-2 N as the hetero atom and which is unsubstituted or substituted by lower alkoxycarbonyl, lower alkyl or lower alkylsulfonyl, or [153] [154] Q and Y together with the atoms to which they are attached may form a 5-6 membered heterocycle which contains 1 N as the hetero atom, and [155] [156] G represents hydrogen; or saturated or unsaturated and straight-chain, branched or cyclic lower alkyl. [157] [158] Particularly preferred compounds among the preferred compounds are: are
  • A represents
  • J represents hydrogen; d-C 6 -alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted d-C 6 -alkoxy, preferably represents Ci-C 4 - alkyl which is unsubstituted or substituted by halogen).
  • D represents halogen, cyano or nitro.
  • the present invention also provides processes for preparing the compounds of formula (1).
  • One of ordinary skill in the art to which the present invention pertains (“a skilled artisan") may prepare the compounds of formula (1) via various routes according to their structures, and such processes should be construed to fall under the scope of the present invention.
  • the compounds of formula (1) may be prepared by optionally combining various synthetic methods which are described in the present specification or disclosed in the prior arts.
  • the processes for preparing the compounds of formula (1) cover even such processes and are not limited to those explained below.
  • the compounds of formula (1) wherein Q is not hydrogen may be prepared by reacting compounds of formula (2) with compounds of formula (3) in the presence of a base, as depicted in the following Reaction Scheme (1):
  • L 1 is a leaving group in the substitution reaction, for example, halogen, methanesul- fonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy, etc.
  • the above reaction may be carried out in an organic solvent such as dimethyl- formamide, dimethylacetamide, acetonitrile, etc., and in some cases a mixture of two or more organic solvents may be used.
  • organic solvent such as dimethyl- formamide, dimethylacetamide, acetonitrile, etc.
  • Typical examples for the base used in the reaction include sodium hydride, sodium hydroxide, potassium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium bis(trimethylsilyl)amide, etc., and in some cases a mixture of two or more bases may be used.
  • W 1 , W 2 , W 3 , W 4 , A, D, E, G and Y are as defined in formula (1), provided that D is not hydrogen.
  • Compound (4) and N-chlorosuccinimide may be reacted in an organic solvent such as methanol, ethanol, dimethylformamide, dimethylacetamide, acetonitrile, etc. to give the desired Compound (2). If appropriate, a mixture of two or more organic solvents may be used.
  • the substituent Q may be first introduced to Compound (4) in the same manner as the above Reaction Scheme (1), and the chloro group may be introduced later as explained above.
  • [317] a is NaSH, MgCl 2 , DMF,
  • [318] b is pyridine, ethanol,
  • W 1 , W 2 , W 3 , W 4 , A, E, G and Y are as defined in formula (1), and
  • Rn is lower alkyl
  • the present invention further provides a pharmaceutical composition for the in- hibition of xanthine oxidase, which comprises (a) a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof and (b) pharmaceutically acceptable carriers, diluents, excipients or their combinations.
  • pharmaceutical composition means compositions comprising the compounds of the present invention and other chemical components such as carriers, diluents, excipients, etc.
  • a pharmaceutical composition facilitates the administration of the compound into a living organism.
  • techniques to administer the compound include but are not limited to oral, injectable, aerosol, parenteral and topical administration.
  • the therapeutically active ingredients to be contained in the pharmaceutical composition may be converted to their salts by reacting acid compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. with the compounds of formula (1).
  • therapeutically effective amount means the amount of active ingredient effective to alleviate or remove one or more symptoms of the disorder to be treated, or to delay clinical markers or the initiation of symptoms of the disease to be prevented.
  • therapeutically effective amount means the amount having the effect of (1) reversing the rate of progress of the disease, (2) prohibiting further progress of the disease and/or (3) alleviating (preferably, removing) one or more symptoms associated with the disease.
  • the therapeutically effective amount can be determined on the basis of experience by testing compounds in the in vivo and invitro model systems known for the disease to be treated.
  • carrier means a substance that facilitates the incorporation of the compound into cells or tissues.
  • DMSO dimethylsulfoxide
  • carrier facilitates the introduction of various organic compounds into cells or tissues of living organisms.
  • diluent is defined as a substance that is diluted in water which dissolves the compound, as well as stabilizes the biologically active form of the subject compound.
  • the salts dissolved in a buffer solution are utilized as diluents in the art.
  • a typically used buffer solution is phosphate-buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
  • the compound used herein may be administered as the compound per se or as a pharmaceutical composition comprising the compound with other active ingredients in the combination therapy or with other suitable carriers or excipients, to the human patient.
  • Techniques for formulations and administrations of a compound can be found in "Remington's Pharmaceutical Sciences” (Mack Publishing Co., Easton, PA, 18 th edition, 1990).
  • composition of the present invention may be prepared by known methods, such as, for example, conventional mixing, dissolving, granulating, dragee- preparing, powdering, emulsifying, capsulating, trapping or freeze-drying, etc.
  • the pharmaceutical composition of the present invention may be prepared by the conventional methods of using one or more pharmaceutically acceptable carriers.
  • the carriers include excipients or adjuvants by which the active compound can be easily converted to pharmaceutically acceptable formulations. Suitable formulations may depend on the selected administration route. Techniques, carriers and excipients, and means known in the art, for example, in "Remington's Pharmaceutical Sciences,” as explained above may be appropriately selected.
  • the compounds of formula (1) of the present invention can be formulated as an injectable preparation, oral preparation, etc., depending on the purpose intended.
  • the active compounds of the present invention can be formulated to a liquid preparation by using pharmaceutically suitable buffers, preferably Hank solution, Ringer solution, physiological saline, etc.
  • pharmaceutically suitable buffers preferably Hank solution, Ringer solution, physiological saline, etc.
  • penetration promoters suitable for the barrier to be penetrated are used for the formulation. Such penetration promoters are conventionally known in the art.
  • the active compounds of the present invention can be easily formulated as solid dosage forms for oral administration by combining the compounds with pharmaceutically acceptable carriers known in the art. With the use of such carriers, the compounds of the present invention can be formulated to tablets, pills, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. Capsules, tablets, pills, powders and granules are advantageous, and capsules and tablets are particularly advantageous. Preferably, tablets and pills are prepared as enteric coated forms.
  • the solid dosage forms for oral administration can be obtained as follows. [349]
  • One or more compounds of the present invention are mixed with one or more ex- cipients, and the mixture is pulverized, if appropriate. Suitable adjuvants are added if necessary, and tablets or dragee cores can be obtained from the granule mixtures.
  • suitable excipients fillers such as lactose, sucrose, mannitol or sorbitol; cellulose substances such as corn starch, wheat, starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP); etc. can be mentioned.
  • disintegrating agents such as cross-linked polyvinylpyrrolidone, agar-agar, alginic acid or its salts like sodium alginate, lubricating agents such as magnesium stearate and binding agents may be added as a carrier.
  • the oral preparations may include sealed soft capsules that are made from gelatin and plastic agents such as glycol or sorbitol, and hard gelatin capsules that are made from gelatin.
  • the hard gelatin capsules may contain the active compound as a mixture with fillers such as lactose, binding agents such as starch, and/or lubricating agents such as talc or magnesium stearate.
  • the active compound may be dissolved or dispersed in a suitable medium such as fatty acid, liquid paraffin or liquid polyethyleneglycol.
  • a stabilizing agent may be included. All formulations for oral administration may contain a suitable amount of the active compound for such administration.
  • the active compound can also be formulated as an injection preparation, such as, for example, a large pill-type injection or continuous -type injection, for parenteral administration.
  • the injection preparation may be provided in the form of an ampoule having a preservative or a unit dosage form charged in a multi-dose container.
  • the compositions may take such forms as suspensions in oily or liquefied vehicles, solutions or emulsions and may contain such components for formulations as suspending agents, stabilizing agents and/or dispersing agents.
  • the active ingredient can be a form of dry powder which is intended to be reconstructed by dissolving in sterile, pyrogen-free water prior to use.
  • the compounds of the present invention can also be formulated into suppository forms utilizing typical suppository bases such as cocoa butter or other glycerides.
  • compositions according to the present invention contain the active ingredient in an amount effective to achieve its intended purpose. More specifically, the therapeutically effective amount means the amount of the active compound effective to prolong the survival of the subject to be treated, or to prevent, alleviate or ameliorate the symptoms of the disease. A skilled artisan would be able to determine the therapeutically effective amount, particularly in light of the detailed description provided herein.
  • the active compounds of formula (1) are preferably contained in an amount of about 0.1 to 1,000 mg per unit dosage.
  • the dosage of the compounds of formula (1) depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 1 to 1,000 mg per day, depending on the intensity and frequency of the administration. When administered to an adult via intramuscular or intravenous routes, total dosage typically from about 1 to 500 mg per day will be sufficient when separately administered in a single dosage, but for some patients a higher daily dosage may be desirable.
  • the present invention further provides a method for the prevention or treatment of diseases associated with human xanthine oxidase, using a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof.
  • diseases associated with human xanthine oxidase mean such diseases that can be treated or prevented by inhibiting human xanthine oxidase, and they include but are not limited to hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, complications of diabetes, kidney disease, inflammation and articular disease, inflammatory bowel disease, etc.
  • hyperlipidemia, atherosclerosis, obesity, hypertension, retinosis, renal failure, etc. may be mentioned.
  • treatment means the interruption or delay of the progress of the disease when applied to a subject showing the onset of disease symptoms
  • prevention means the interruption or delay of the sign of the onset of disease when applied to a subject who does not show, but is at risk of, the onset of disease symptoms.
  • Figure 1 is a graph showing the result of measuring the uric acid concentration (mg/dl) in the plasma according to the procedure of Experiment 2 ( ** P ⁇ 0.01, *** P ⁇ 0.001: ANOVA and post Dunnet's test).
  • Figure 2 is a graph showing the result of measuring the inhibitory rate (%) for uric acid in the plasma according to the procedure of Experiment 2.
  • Figure 3 is a graph showing the result of measuring the inhibitory ability for uric acid in the liver according to the procedure of Experiment 2 (LC-MS/MS peak area).
  • Step (1) (1.23g, 3.9mmol) obtained in Step (1) was dissolved in 2OmL of pyridine, hydroxyam- moniumchloride (406mg, 5.85mmol) was added, and the mixture was stirred while being heated to reflux for 5 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and ethyl acetate was added thereto. The mixture was washed with lN-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was washed with ethyl acetate, and dried to give 1.15g (3.51mmol, Yield 90%) of the title compound.
  • Step (1) (202mg, 0.59mmol) obtained in Step (1) was reacted according to the same procedures as Steps (1), (2), (3) of Preparation 18 to give the title compound (177mg, Yield 82%).
  • N,N-dimethylformamide, magnesium chloride 6 hydrate 14.03g, 69mmol was added, and the mixture was stirred for 10 min at room temperature.
  • reaction solution was poured to 0.1 N hydrochloric acid, which was then controlled to basic using aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was collected, and distilled under reduced pressure. The remaining substance was purified by column chromatography to give 2.06g (8mmol, Yield 94%) of the title compound.
  • Preparation 108 was added 7OmL of dichloromethane, and the mixture was cooled to O 0 C. 3-chloroperoxybenzoic acid (70%, 3.94g, l ⁇ mmol) was slowly added, and the mixture was warmed to room temperature and stirred for 48 h. After completion of the reaction, dichloromethane was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was distilled under reduced pressure, and the remaining substance was purified by column chromatography to give 1.98g (7.22mmol, Yield 90%) of the title compound.

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Abstract

The present invention relates to novel compounds which are effective as an inhibitor for xanthine oxidase, a process for preparing the same, and a pharmaceutical composition comprising a therapeutically effective amount of the same.

Description

NOVEL COMPOUNDS EFFECTIVE AS XANTHINE OXIDASE INHIBITORS, METHOD FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
The present invention relates to novel compounds of formula (1):
Figure PCTKR2010000893-appb-I000001
in which
A, D, E, G, Y, Q, W1, W2, W3 and W4 are as defined below, which are effective as an inhibitor for xanthine oxidase, a process for preparing the same, and a pharmaceutical composition comprising a therapeutically effective amount of the same.
Xanthine oxidase is known as an enzyme which converts hypozanthine to xanthine and further converts thus-formed zanthine to uric acid. Although most mammals have uricase, humans and chimpanzees do not, thereby uric acid is known to be the final product of purine metabolism (S. P. Bruce, Ann. Pharm., 2006, 40, 2187~2194). Sustained elevation of blood concentration of uric acid can cause various diseases, representatively including gout.
As described above, gout is caused by an elevated level of uric acid in the body, indicating the condition in which uric acid crystals accumulated in cartilage, ligament and surrounding tissue induce severe inflammation and pain. Gout is a kind of inflammatory articular disease, and its incidence rate has steadily increased during past 40 years (N. L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587~2590).
From the 1960s to the mid-1990s, gout patients in the West exhibited an astonishing increase of about 200~300%, mainly in males. The increased rate of gout patients can be traced to obesity, aging, kidney function decline, hypertension, etc. The incidence rate of gout appears to be a level of about 1.4/1,000 persons, but it also depends on the uric acid level. That is, while the incidence rate of gout is 0.5% in a patient group with a blood uric acid level of 7.0 mg/dl or more, the incidence rate of gout is 5.5% in a patient group with a uric acid level of 9.0 mg/dl or more (G. Nuki, Medicine, 2006, 34, 417~423). Considering the incidence rate as described above, blood uric acid level is found to be an important causative factor for gout. In addition, dietary habits, alcohol, lipid and obesity can serve as important inducing factors of gout. Recently, the correlation of uric acid with heart failure, hypertension, diabetes and cardiovascular diseases has been extensively investigated by many researchers, and the importance of uric acid control has been increased (D. I. Feig et al., N. Eng. J. Med, 2008, 23, 1811~1821). In addition, as an inhibitor of xanthine oxidase, allopurinol is known to have an effect on ulcerative colitis (Aliment. Pharmacol. Ther. 2000, 14, 1159~1162 ; WO 2007/043457).
Allopurinol was a unique drug for the treatment of gout for 40 years, until febuxostat was approved as an arthrifuge in Europe in 2008 (Brain Tomlinson, Current Opin. Invest. Drugs, 2005, 6, 1168~1178). Allopurinol is known to be a non-specific inhibitor for various enzymes that are involved in purine and pyrimidine metabolism, and it has a Ki of 700 nM for xanthine oxidase (Y. Takano et al., Life Sciences, 2005, 76, 1835~1847). Allopurinol is immediately oxidized to oxypurinol by xanthine oxidase, and this metabolite is known to act as a potent inhibitor for xanthine oxidase.
However, it is known that allopurinol causes gastrointestinal side effects and skin rash and exhibits poor compliance in the case of long-term administration. Especially among patients receiving allopurinol, the side effect of Stevens-Johnson syndrome is reported, at a low rate but it is unpredictable and lethal (Felix Arellano et al., Ann. Pharm., 1993, 27, 337~43). This serious side effect is known to accompany necrocytosis in the skin and mouth mucosa, and without proper treatment about 25% of patients may die as a result.
Thus, in order to develop novel xanthine oxidase inhibitors various researches have been conducted resulting in numerous patent publications (for example, WO 1992/009279, WO 1998/018765, WO 2007/004688, WO 2008/126770, WO 2008/126898, WO 2008/126899).
Among these, WO 1992/009279 describes the inhibitory effect of thiazoles and phenyl derivatives against xanthine oxidase, and WO 2008/126898 reports that indole compounds exhibit an inhibitory effect against xanthine oxidase.
One object of the present invention is to provide novel compounds of formula (1) which exhibit very excellent inhibitory effect against xanthine oxidase.
Another object of the present invention is to provide a novel process for the preparation of the compounds of formula (1).
Still another object of the present invention is to provide a pharmaceutical composition for the inhibition of xanthine oxidase, which comprises a therapeutically effective amount of the compounds of formula (1) as an active ingredient.
Still another object of the present invention is to provide a method for the treatment and/or prevention of the diseases associated with xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and articular disease, and inflammatory bowel disease, which comprises using the compounds of formula (1) as an active ingredient.
In order to solve the above stated technical subject, the present invention provides the compounds of the following formula (1):
Figure PCTKR2010000893-appb-I000002
in the above formula (1),
W1, W2, W3 and W4 represent N or C, provided that only one is N when W1, W2, W3 or W4 represents N,
A represents the following A-i or A-ii:
(A-i)
Figure PCTKR2010000893-appb-I000003
(A-ii)
Figure PCTKR2010000893-appb-I000004
(wherein, J represents hydrogen; halogen; C1-C6-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted C1-C6-alkoxy, and X represents O or S), provided that A is linked to only C when A is linked to W1, W2, W3 or W4,
E represents hydrogen; halogen; nitro; cyano; amino; substituted or unsubstituted C1-C6-alkyl; or substituted or unsubstituted C1-C6-alkoxy, provided that E is linked to only C when E is linked to W1, W2, W3 or W4,
D represents hydrogen; halogen; cyano; nitro; C1-C6-alkyl which is unsubstituted or substituted by halogen; or-CHO,
Q is selected form the following Q-i, Q-ii, Q-iii-1 to Q-iii-14:
(Q-i) hydrogen,
(Q-ii) substituted or unsubstituted, saturated or unsaturated, or straight-chain, branched or cyclic alkyl,
(Q-iii-1)
Figure PCTKR2010000893-appb-I000005
(wherein W represents O or S, R7 represents hydrogen or substituted or unsubstituted lower alkyl, and n denotes an integer of 0~3),
(Q-iii-2)
Figure PCTKR2010000893-appb-I000006
(wherein W represents O or S, R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
(Q-iii-3)
Figure PCTKR2010000893-appb-I000007
(wherein R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
(Q-iii-4)
Figure PCTKR2010000893-appb-I000008
(wherein R10 and R11 independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1~3),
(Q-iii-5)
Figure PCTKR2010000893-appb-I000009
(wherein R12 represents substituted or unsubstituted lower alkyl or aryl, and n denotes an integer of 0~3),
(Q-iii-6)
Figure PCTKR2010000893-appb-I000010
(wherein R13 and R14 independently of one another represent substituted or unsubstituted lower alkyl, or together with the nitrogen atom to which they are attached may form a 3~7 membered heterocycle containing N as the hetero atom, and n denotes an integer of 0~3),
(Q-iii-7)
Figure PCTKR2010000893-appb-I000011
(wherein R15 represents substituted or unsubstituted lower alkyl, and m denotes an integer of 1~3),
(Q-iii-8)
Figure PCTKR2010000893-appb-I000012
(wherein m denotes an integer of 1~3),
(Q-iii-9)
Figure PCTKR2010000893-appb-I000013
(wherein R16 and R17 independently of one another represent hydrogen or substituted or unsubstituted lower alkyl, or together with the atoms to which they are attached may form a 3~7 membered heterocycle containing N as the hetero atom, and m denotes an integer of 1~3),
(Q-iii-10)
Figure PCTKR2010000893-appb-I000014
(wherein R18 represents hydrogen; substituted or unsubstituted lower alkyl; alkoxy; or aryl, and m denotes an integer of 1~3),
(Q-iii-11)
Figure PCTKR2010000893-appb-I000015
(wherein R19 represents hydrogen or substituted or unsubstituted lower alkyl, R20 represents substituted or unsubstituted lower alkyl or alkoxy, and n denotes an integer of 0~3),
(Q-iii-12)
Figure PCTKR2010000893-appb-I000016
(wherein W represents O or S, R21 represents hydrogen or substituted or unsubstituted lower alkyl, and n denotes an integer of 0~3),
(Q-iii-13)
Figure PCTKR2010000893-appb-I000017
(wherein R22 and R23 independently of one another represent substituted or unsubstituted lower alkyl, and n denotes an integer of 0~3),
(Q-iii-14)
Figure PCTKR2010000893-appb-I000018
(wherein W1, W2, W3, W4 and W5 represent N or C, provided that only one is N when W1, W2, W3, W4 or W5 represents N, R24 and R25 independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1~3),
Y represents hydrogen; halogen; substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl; substituted or unsubstituted C1-C6-alkoxy; C6-C10-aryl; substituted or unsubstituted 3~7 membered heteroaryl which contains N as the hetero atom; substituted or unsubstituted 3~7 membered heterocycle which contains N as the hetero atom, or
Q and Y together with the atoms to which they are attached may form a 3~7 membered heterocycle which contains N as the hetero atom, and
G represents hydrogen; or substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl, pharmaceutically acceptable salts, or isomers thereof.
Hereinafter, unless specially restricted, the compounds of formula (1) as an active ingredient of the therapeutic agent include all their pharmaceutically acceptable salts and isomers, and they should be instrued to fall under the scope of the present invention. For the convenience of explanation only, they are simply referred to as ‘compounds of formula (1)’ in the present specification.
The above compounds of formula (1) according to the present invention have a quite different chemical structure from the earlier known xanthine oxidase inhibitors. As shown in the following experiments, they exhibit an excellent inhibitory effect against xanthine oxidase associated with gout. Thus, they can be used for the prevention and treatment of diseases associated with xanthine oxidase, such as, for example, hyperuricemia, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, articular disease, etc.
The terms as used herein will be briefly explained below.
If there is no special mention in the present specification, the term “substituted or unsubstituted” means to include both the cases of being substituted and unsubstituted. In the case of “substituted,” the radical may be substituted by one or more groups individually and independently selected from alkyl, cycloalkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, carbonyl, thiocarbonyl, sulfonyl, nitro, aryl and their protective derivatives. If appropriate, these groups may be furthermore substituted.
As used herein, “pharmaceutically acceptable salts” means the salt forms of a compound, which neither give any serious irritation to the organism to which the compound is administered nor damage the biological activities and properties of the compound. Such a “pharmaceutically acceptable salt” includes a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. The compounds of formula (1) can also form a pharmaceutically acceptable base addition salt, for example, a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compounds of formula (1) of the present invention may be converted to their salts according to any of the conventional methods.
As used herein, “isomer” means those having the same chemical or molecular formula as, but optically or sterically different from, the compounds of formula (1), or salts thereof. The compounds of formula (1) of the present invention may have an oxime structure, and so may exist in the form of geometrical isomers, trans and cis. All the isomers, their salts, and their mixtures (including racemic mixture) are also covered by the present invention.
As used herein, “aryl” means a carbocyclic group (e.g., phenyl) having a covalent π electronic system and at least one ring. This term also includes monocyclic or fused-ring polycyclic (i.e., rings share the adjacent carbon pairs) groups.
As used herein, “heteroaryl” means a heterocyclic aryl group having a covalent π electronic system and at least one ring. It includes but is not limited to furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.
As used herein, “alkyl” means an aliphatic hydrocarbon group. The alkyl group may be “a saturated alkyl” not containing alkene or alkine moiety at all, or “an unsaturated alkyl” containing at least one alkene or alkine moiety. The term “alkene” means a group having at least one carbon-carbon double bond, and “alkine” means a group having at least one carbon-carbon triple bond. Regardless of being saturated or unsaturated, the alkyl group may be branched, linear or cyclic.
Unless otherwise stated, the alkyl group may contain 1 to 20 carbon atoms, and the lower alkyl group may contain 1 to 7 carbon atoms. As typical examples thereof, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, ethinyl, propinyl, butinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. can be mentioned. The alkyl group may be substituted or unsubstituted.
As used herein, “heterocycle” means a group wherein the ring carbon atom is replaced by oxygen, nitrogen, sulfur, etc. It may optionally include a double bond. The typical examples thereof may include but are not limited to pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, etc.
As used herein, “halogen (or halo)” means F (or-F), Cl (or-Cl), Br (or-Br) and I (or-I).
Other terms in the present specification may be construed to have the meaning conventionally understood in this field by a skilled artisan, unless otherwise defined.
Preferred compounds among the compounds of formula (1) above are those wherein
W1, W2, W3 and W4 represent N or C, provided that only one is N when W1, W2, W3 or W4 represents N,
A represents the following A-i or A-ii:
(A-i)
Figure PCTKR2010000893-appb-I000019
(A-ii)
Figure PCTKR2010000893-appb-I000020
(wherein, J represents hydrogen; C1-C6-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted C1-C6-alkoxy, and X represents O or S), provided that A is linked to only C when A is linked to W1, W2, W3 or W4,
E represents hydrogen; halogen; nitro; cyano; amino; or C1-C6-alkyl, provided that E is linked to only C when E is linked to W1, W2, W3 or W4,
D represents hydrogen; halogen; cyano; or nitro,
Q is selected form the following Q-i, Q-ii, Q-iii-1 to Q-iii-14:
(Q-i) hydrogen,
(Q-ii) saturated or unsaturated and straight-chain, branched or cyclic alkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen; lower alkoxy; hydroxy; C3-C6-cycloalkyl; 5~6 membered heteroaryl which is unsubstituted or substituted by lower alkyl and contains 1~3 hetero atoms selected from N, S and O; and 5~6 membered heterocycle which is saturated or unsaturated and contains 1~3 hetero atoms selected from N, S and O,
(Q-iii-1)
Figure PCTKR2010000893-appb-I000021
(wherein W represents O or S, R7 represents hydrogen or lower alkyl, and n denotes an integer of 0~3),
(Q-iii-2)
Figure PCTKR2010000893-appb-I000022
(wherein W represents O or S, R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
(Q-iii-3)
Figure PCTKR2010000893-appb-I000023
(wherein R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
(Q-iii-4) (wherein R10 and R11 independently of one another represent hydrogen; halogen; or lower alkoxy, and m denotes an integer of 1~3),
(Q-iii-5)
Figure PCTKR2010000893-appb-I000025
(wherein R12 represents lower alkyl, and n denotes an integer of 0~3),
(Q-iii-6)
Figure PCTKR2010000893-appb-I000026
(wherein R13 and R14 independently of one another represent lower alkyl, and n denotes an integer of 0~3),
(Q-iii-7)
Figure PCTKR2010000893-appb-I000027
(wherein R15 represents lower alkyl, and m denotes an integer of 1~3),
(Q-iii-8)
Figure PCTKR2010000893-appb-I000028
(wherein m denotes an integer of 1~3),
(Q-iii-9)
Figure PCTKR2010000893-appb-I000029
(wherein R16 and R17 independently of one another represent hydrogen or lower alkyl, or together with the atoms to which they are attached may form a 5~6 membered heterocycle containing one (1) N as the hetero atom, and m denotes an integer of 1~3),
(Q-iii-10)
Figure PCTKR2010000893-appb-I000030
(wherein R18 represents hydrogen; or lower alkyl unsubstitued or substituted by lower alkoxy or phenyl, and m denotes an integer of 1~3),
(Q-iii-11)
Figure PCTKR2010000893-appb-I000031
(wherein R19 represents hydrogen or lower alkyl, R20 represents lower alkyl or lower alkoxy, and n denotes an integer of 0~3),
(Q-iii-12)
Figure PCTKR2010000893-appb-I000032
(wherein W represents O or S, R21 represents hydrogen or lower alkyl, and n denotes an integer of 0~3),
(Q-iii-13)
Figure PCTKR2010000893-appb-I000033
(wherein R22 and R23 independently of one another represent lower alkyl, and n denotes an integer of 0~3),
(Q-iii-14)
Figure PCTKR2010000893-appb-I000034
(wherein W1, W2, W3, W4 and W5 represent N or C, provided that only one is N when W1, W2, W3, W4 or W5 represents N, R24 and R25 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
Y represents hydrogen; saturated or unsaturated and straight-chain, branched or cyclic alkyl which is unsubstituted or substituted by lower alkoxy or C3-C6-cycloalkyl; C6-C10-aryl; 5~6 membered heteroaryl which contains 1~2 N as the hetero atom and which is unsubstituted or substituted by lower alkyl; 5~6 membered heterocycle which contains 1~2 N as the hetero atom and which is unsubstituted or substituted by lower alkoxycarbonyl, lower alkyl or lower alkylsulfonyl, or
Q and Y together with the atoms to which they are attached may form a 5~6 membered heterocycle which contains 1 N as the hetero atom, and
G represents hydrogen; or saturated or unsaturated and straight-chain, branched or cyclic lower alkyl.
Particularly preferred compounds among the preferred compounds are those wherein A represents
Figure PCTKR2010000893-appb-I000035
(wherein J represents hydrogen; C1-C6-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted C1-C6-alkoxy, preferably represents C1-C4-alkyl which is unsubstituted or substituted by halogen).
Also particularly preferred compounds are those wherein D represents halogen, cyano or nitro.
Also particularly preferred compounds are those wherein G represents hydrogen.
The representative compounds of formula (1) according to the present invention include the following listed compounds:
2-(1-Isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Chloro-1-isobutyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Chloro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Chloro-1-cyclohexyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-{3-Chloro-1-[2-(diethylamino)-2-oxoethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Chloro-1-(3-methoxybenzyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Chloro-1-cyclopentyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Chloro-1-(tetrahydrofuran-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Chloro-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-morpholin-4-ylethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2,2-dimethylpropyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-{3-Cyano-1-[2-(methylsulfonyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(tetrahydrofuran-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(3-methylbutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-{3-Cyano-1-[(3,5-dimethylisoxazol-4-yl)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-{2-[(methylsulfonyl)amino]ethyl}-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(cyclopentylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(isobutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(cyclopentyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-{3-Cyano-1-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(1,3-thiazol-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-methoxyethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-{1-[2-(Acetylamino)ethyl]-3-cyano-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-propyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-cyclopropyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(oxazol-4-ylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(3,3,3-trifluoropropyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-sec-butyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-[(2,4-difluorophenyl)methyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Allyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-prop-2-inyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-pyridylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-methoxy-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-[2-(2-methoxyethoxy)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Benzyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-cyclobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-[2-(2-oxopyrrolidin-1-yl)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-ethyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-methoxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-fluoroethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Butyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-{3-Cyano-1-[(4-fluorophenyl)-methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-ethoxyethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-hydroxy-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(2-fluoro-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[1-(2-Benzyloxyethyl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid;
2-{3-Cyano-1-[2-fluoro-1-(fluoromethyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[1-(1-Acetylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(1-methoxycarbonylpyrrolidin-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(1-cyano-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-sec-Butyl-3-cyano-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-ethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-cyclopropylmethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-cyclopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-methyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-ethyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-sec-butyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isobutyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-tetrahydrofuran-3-yl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-cyclopentyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Chloro-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-4-carboxylic acid;
2-(1-Isopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[1-(Cyclopropylmethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Cyclopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[1-(2-Methoxyethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Nitro-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-sec-Butyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Isobutyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Ethyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid;
2-(1-Isopropyl-7-methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(1-Isopropyl-3-nitro-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-4-fluoro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-7-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[3-Cyano-1-(cyclopropylmethyl)-7-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid;
2-[2-(1-t-Butoxycarbonyl-pyrrolidin-2-yl)-7-chloro-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid hydrochloride;
2-[7-Chloro-2-(1-isopropyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[7-Chloro-2-(1-methanesulfonyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Chloro-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Chloro-2-isobutyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Chloro-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Chloro-2-cyclopentylmethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Chloro-2-cyclopentylmethyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Bromo-2-pyridin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[7-Bromo-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(5-Bromo-2,3-dihydro-1H-pyrrolo[1,2a]indol-7-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Bromo-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
2-(7-Bromo-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Cyano-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Cyano-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Cyano-2-pyridin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-[7-Cyano-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Cyano-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(7-Cyano-2-phenyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
2-(2-Benzyl-7-cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
4-Methyl-2-(7-nitro-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
2-(2-Isobutyl-7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
4-Methyl-2-(7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid; and
2-(7-Amino-2-phenyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid.
The present invention also provides processes for preparing the compounds of formula (1). One of ordinary skill in the art to which the present invention pertains (“a skilled artisan”) may prepare the compounds of formula (1) via various routes according to their structures, and such processes should be construed to fall under the scope of the present invention. In other words, the compounds of formula (1) may be prepared by optionally combining various synthetic methods which are described in the present specification or disclosed in the prior arts. The processes for preparing the compounds of formula (1) cover even such processes and are not limited to those explained below.
As one typical process, the compounds of formula (1) wherein Q is not hydrogen may be prepared by reacting compounds of formula (2) with compounds of formula (3) in the presence of a base, as depicted in the following Reaction Scheme (1):
Reaction Scheme 1
Figure PCTKR2010000893-appb-I000036
in the above Reaction Scheme (1)
W1, W2, W3, W4, A, D, E, G, Y and Q are as defined in formula (1), provided that Q is not hydrogen, and
L1 is a leaving group in the substitution reaction, for example, halogen, methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy, etc.
The above reaction may be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, acetonitrile, etc., and in some cases a mixture of two or more organic solvents may be used. Typical examples for the base used in the reaction include sodium hydride, sodium hydroxide, potassium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium bis(trimethylsilyl)amide, etc., and in some cases a mixture of two or more bases may be used.
If necessary, when G is not hydrogen, the compounds obtained by the above Reaction Scheme (1) may be hydrolyzed to give the compounds of formula (1) wherein G is hydrogen.
As another typical process, the compounds of formula (1) wherein D is not hydrogen and Q is hydrogen may be prepared by introducing the substituent D according to the following Reaction Scheme (2):
Reaction Scheme 2
Figure PCTKR2010000893-appb-I000037
in the above Reaction Scheme (2), W1, W2, W3, W4, A, D, E, G and Y are as defined in formula (1), provided that D is not hydrogen.
In the above Reaction Scheme (2), the case wherein D is chloro is explained first as follows.
Compound (4) and N-chlorosuccinimide may be reacted in an organic solvent such as methanol, ethanol, dimethylformamide, dimethylacetamide, acetonitrile, etc. to give the desired Compound (2). If appropriate, a mixture of two or more organic solvents may be used.
If necessary, the substituent Q may be first introduced to Compound (4) in the same manner as the above Reaction Scheme (1), and the chloro group may be introduced later as explained above.
In the above Reaction Scheme (2), the case wherein D is cyano is explained as follows.
The indole Compound (4) is reacted with oxalyl chloride in dichloromethane, tetrahydrofuran and ammonium acetate are added in drops thereto, and the mixture is heated to give an aldehyde compound [Compound (2) wherein D is-CHO]. The aldehyde compound is reacted with hydroxylamine in pyridine solvent to give an oxime compound. The oxime compound is reacted with 2-chloro-1-methyl-pyridinium iodide and triethylamine or with 1,1’-thiocarbonyldiimidazole in tetrahydrofuran to give Compound (2) wherein D is-CN. This reaction may be carried out by referring to J. Ludwig et al., J. Med. Chem., 2006, 49, 2611.
If necessary, the substituent Q may be first introduced to Compound (4) in the same manner as the above Reaction Scheme (1), and the cyano group may be introduced later as explained above.
Compound (4) used as a starting material in the above Reaction Scheme (2) may be prepared according to the following Reaction Scheme (3):
Reaction Scheme 3
Figure PCTKR2010000893-appb-I000038
in the above Reaction Scheme (3)
a is NaSH, MgCl2, DMF,
b is pyridine, ethanol,
W1, W2, W3, W4, A, E, G and Y are as defined in formula (1), and
Rn is lower alkyl.
Specifically, Compound (5) is converted to a thioamide Compound (6) using sodium sulfide and magnesium chloride in N,N-dimethylformamide. In order to cyclize Compound (6) to the desired Compound (4), Compound (6) is reacted with Compound (7) in the presence of pyridine in ethanol.
A skilled artisan might also prepare the above reacting compounds by various processes on the basis of their chemical structures under the scope of the present invention.
A skilled artisan could confirm the specific reaction conditions, etc. for the preparation of the compounds according to the present invention through preparations and examples below, and thus their detailed explanations are omitted here.
The present invention further provides a pharmaceutical composition for the inhibition of xanthine oxidase, which comprises (a) a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof and (b) pharmaceutically acceptable carriers, diluents, excipients or their combinations.
As used herein, “pharmaceutical composition” means compositions comprising the compounds of the present invention and other chemical components such as carriers, diluents, excipients, etc. A pharmaceutical composition facilitates the administration of the compound into a living organism. There are a number of techniques to administer the compound, and they include but are not limited to oral, injectable, aerosol, parenteral and topical administration. The therapeutically active ingredients to be contained in the pharmaceutical composition may be converted to their salts by reacting acid compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. with the compounds of formula (1).
As used herein, “therapeutically effective amount” means the amount of active ingredient effective to alleviate or remove one or more symptoms of the disorder to be treated, or to delay clinical markers or the initiation of symptoms of the disease to be prevented. Thus, the therapeutically effective amount means the amount having the effect of (1) reversing the rate of progress of the disease, (2) prohibiting further progress of the disease and/or (3) alleviating (preferably, removing) one or more symptoms associated with the disease. The therapeutically effective amount can be determined on the basis of experience by testing compounds in the in vivo and in vitro model systems known for the disease to be treated.
As used herein, “carrier” means a substance that facilitates the incorporation of the compound into cells or tissues. For example, dimethylsulfoxide (DMSO) is a typical carrier that facilitates the introduction of various organic compounds into cells or tissues of living organisms.
As used herein, “diluent” is defined as a substance that is diluted in water which dissolves the compound, as well as stabilizes the biologically active form of the subject compound. The salts dissolved in a buffer solution are utilized as diluents in the art. A typically used buffer solution is phosphate-buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
The compound used herein may be administered as the compound per se or as a pharmaceutical composition comprising the compound with other active ingredients in the combination therapy or with other suitable carriers or excipients, to the human patient. Techniques for formulations and administrations of a compound can be found in “Remington’s Pharmaceutical Sciences” (Mack Publishing Co., Easton, PA, 18th edition, 1990).
The pharmaceutical composition of the present invention may be prepared by known methods, such as, for example, conventional mixing, dissolving, granulating, dragee-preparing, powdering, emulsifying, capsulating, trapping or freeze-drying, etc.
Thus, the pharmaceutical composition of the present invention may be prepared by the conventional methods of using one or more pharmaceutically acceptable carriers. The carriers include excipients or adjuvants by which the active compound can be easily converted to pharmaceutically acceptable formulations. Suitable formulations may depend on the selected administration route. Techniques, carriers and excipients, and means known in the art, for example, in “Remington’s Pharmaceutical Sciences,” as explained above may be appropriately selected.
For example, the compounds of formula (1) of the present invention can be formulated as an injectable preparation, oral preparation, etc., depending on the purpose intended.
As for the injection preparation, the active compounds of the present invention can be formulated to a liquid preparation by using pharmaceutically suitable buffers, preferably Hank solution, Ringer solution, physiological saline, etc. For the purpose of administration through mucous membranes, penetration promoters suitable for the barrier to be penetrated are used for the formulation. Such penetration promoters are conventionally known in the art.
The active compounds of the present invention can be easily formulated as solid dosage forms for oral administration by combining the compounds with pharmaceutically acceptable carriers known in the art. With the use of such carriers, the compounds of the present invention can be formulated to tablets, pills, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. Capsules, tablets, pills, powders and granules are advantageous, and capsules and tablets are particularly advantageous. Preferably, tablets and pills are prepared as enteric coated forms. For example, the solid dosage forms for oral administration can be obtained as follows.
One or more compounds of the present invention are mixed with one or more excipients, and the mixture is pulverized, if appropriate. Suitable adjuvants are added if necessary, and tablets or dragee cores can be obtained from the granule mixtures. As suitable excipients, fillers such as lactose, sucrose, mannitol or sorbitol; cellulose substances such as corn starch, wheat, starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP); etc. can be mentioned. If necessary, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar-agar, alginic acid or its salts like sodium alginate, lubricating agents such as magnesium stearate and binding agents may be added as a carrier.
The oral preparations may include sealed soft capsules that are made from gelatin and plastic agents such as glycol or sorbitol, and hard gelatin capsules that are made from gelatin. The hard gelatin capsules may contain the active compound as a mixture with fillers such as lactose, binding agents such as starch, and/or lubricating agents such as talc or magnesium stearate. In a soft capsule, the active compound may be dissolved or dispersed in a suitable medium such as fatty acid, liquid paraffin or liquid polyethyleneglycol. Furthermore, a stabilizing agent may be included. All formulations for oral administration may contain a suitable amount of the active compound for such administration.
The active compound can also be formulated as an injection preparation, such as, for example, a large pill-type injection or continuous-type injection, for parenteral administration. The injection preparation may be provided in the form of an ampoule having a preservative or a unit dosage form charged in a multi-dose container. The compositions may take such forms as suspensions in oily or liquefied vehicles, solutions or emulsions and may contain such components for formulations as suspending agents, stabilizing agents and/or dispersing agents.
Furthermore, the active ingredient can be a form of dry powder which is intended to be reconstructed by dissolving in sterile, pyrogen-free water prior to use.
The compounds of the present invention can also be formulated into suppository forms utilizing typical suppository bases such as cocoa butter or other glycerides.
The pharmaceutical compositions according to the present invention contain the active ingredient in an amount effective to achieve its intended purpose. More specifically, the therapeutically effective amount means the amount of the active compound effective to prolong the survival of the subject to be treated, or to prevent, alleviate or ameliorate the symptoms of the disease. A skilled artisan would be able to determine the therapeutically effective amount, particularly in light of the detailed description provided herein.
When the compound is formulated to a unit dosage form, the active compounds of formula (1) are preferably contained in an amount of about 0.1 to 1,000 mg per unit dosage. The dosage of the compounds of formula (1) depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 1 to 1,000 mg per day, depending on the intensity and frequency of the administration. When administered to an adult via intramuscular or intravenous routes, total dosage typically from about 1 to 500 mg per day will be sufficient when separately administered in a single dosage, but for some patients a higher daily dosage may be desirable.
The present invention further provides a method for the prevention or treatment of diseases associated with human xanthine oxidase, using a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof. The “diseases associated with human xanthine oxidase” mean such diseases that can be treated or prevented by inhibiting human xanthine oxidase, and they include but are not limited to hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, complications of diabetes, kidney disease, inflammation and articular disease, inflammatory bowel disease, etc. As examples of said complications of diabetes, hyperlipidemia, atherosclerosis, obesity, hypertension, retinosis, renal failure, etc. may be mentioned.
As used herein, “treatment” means the interruption or delay of the progress of the disease when applied to a subject showing the onset of disease symptoms, and “prevention” means the interruption or delay of the sign of the onset of disease when applied to a subject who does not show, but is at risk of, the onset of disease symptoms.
Figure 1 is a graph showing the result of measuring the uric acid concentration (mg/dl) in the plasma according to the procedure of Experiment 2 (**P<0.01, ***P<0.001: ANOVA and post Dunnet’s test).
Figure 2 is a graph showing the result of measuring the inhibitory rate (%) for uric acid in the plasma according to the procedure of Experiment 2.
Figure 3 is a graph showing the result of measuring the inhibitory ability for uric acid in the liver according to the procedure of Experiment 2 (LC-MS/MS peak area).
Hereinafter, the present invention will be more specifically explained by preparations, examples and experiments. However, it should be understood that the scope of the present invention is not confined thereto.
Preparation 1: 1H-indole-5-carboxamide
Figure PCTKR2010000893-appb-I000039
1H-indole-5-carboxylic acid (0.5g, 3.1mmol) was dissolved in N,N-dimethylformamide (30mL). HBTU (O-Benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate)(1.76g, 4.6mmol), ammonium chloride (0.83g, 15.5mmol) and triethylamine (2.1mL, 15.5mmol) were added at 0℃, and the mixture was stirred for 15 h at room temperature. The solvent was distilled off, ethyl acetate (50mL) was added, and the mixture was washed with sodium bicarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.36g (Yield 74%) of the title compound.
NMR: 1H-NMR (CDCl3) δ 8.19(1H, s), 7.74(1H, d), 7.49(1H, d), 7.34(1H, m), 6.68(1H, s)
Mass(EI): 161(M++1)
Preparation 2: 1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000040
1H-indole-5-carboxamide (0.36g, 2.25mmol) obtained in Preparation 1 was dissolved in tetrahydrofuran (30ml). Lawesson's Reagent (0.9g, 2.25mmol) was added, and the mixture was refluxed for 3 h. The solvent was distilled off, ethyl acetate (50mL) was added, and the mixture was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.33g (Yield 91%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.31(1H, s), 7.88(1H, d), 7.44(1H, d), 7.34(1H, m), 6.69(1H, s)
Mass(EI): 177(M++1)
Preparation 3: 2-(1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000041
1H-indole-5-carbothioamide (0.33g, 1.87mmol) obtained in Preparation 2 was dissolved in ethanol (30ml). Ethyl-2-chloroacetoacetate (0.05g, 3.1mmol) and pyridine (25mg, 0.31mmol) were added, and the mixture was refluxed for 15 h. The solvent was distilled off, and ethyl acetate (50mL) was added to the residue. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.38g (Yield 72%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.38(1H, s), 8.34(1H, s), 7.88(1H, d), 7.48(1H, d), 7.32(1H, m), 6.67(1H, s), 4.40(2H, q), 2.83(3H, s), 1.43(3H, t)
Mass(EI): 287(M++1)
Preparation 4: 2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) 1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000042
Sodium hydrosulfide (70%, 2.4g, 30mmol) and magnesium chloride (3.13g, 15.4mmol) were dissolved in 30mL of N,N-dimethylformamide. 5-Cyanoindole (2g, 14mmol) was added, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was poured into 60mL of water. The mixture was stirred, and the resulting solid was filtered. This solid compound was added to aqueous 1N-hydrochloric acid solution, which was then stirred for 30 min, filtered, washed with water and dried to give 2.29g (13mmol, Yield 92.8%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.31(1H, s), 7.88(1H, d), 7.44(1H, d), 7.34(1H, m), 6.69(1H, s)
Mass(EI): 177(M++1)
(2) 2-(1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000043
1H-indole-5-carbothioamide (2.29g, 13mmol) obtained in Step (1) was reacted according to the same procedure as Preparation 3 to give 3.1g (10.8mmol, Yield 83.3%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 11.45(1H, s), 8.26(1H, s), 7.76(1H, d), 7.52(1H, d), 7.47(1H, s), 6.59(1H, s), 4.33(2H, q), 2.70(3H, s), 1.34(3H, t)
Mass(EI): 287(M++1)
(3) 2-(3-chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000044
To 2-(1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (1g, 3.5mmol) obtained in Step (2) was added 30mL of methanol and N-chlorosuccinimide (513mg, 3.8mmol). The mixture was stirred for 1 h at room temperature. After completion of the reaction, the solvent was removed, and ethylacetate was added to the residue. The mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethylacetate=3:1) to give 842mg (2.63mmol, Yield 75%) of the title compound.
NMR: 1H-NMR(DMSOd6) δ 11.7(1H, s), 8.09(1H, s), 7.79(1H, d), 7.63(1H, s), 7.52(1H, d), 4.27(2H, q), 2.67(3H, s), 1.29(3H, t)
Mass(EI) : 321(M++1)
Preparation 5: 2-(1-Isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000045
2-(1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.38g, 1.32 mmol) obtained in Preparation 3 was dissolved in 10mL of N,N-dimethylformamide. Sodium hydride (0.08g, 2.0mmol) was added at 0℃, and the mixture was stirred for 10 min at room temperature. 1-Bromo-2-methylpropane (0.2g, 1.46mmol) was added, and the mixture was stirred for 15 h at room temperature. The solvent was distilled off, and ethyl acetate (50mL) was added. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give the title compound (0.33g, Yield 73%).
Mass(EI) :343(M++1)
Preparation 6: 2-(3-Chloro-1-isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000046
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.16g, 0.5mmol) obtained in Preparation 4, sodium hydride (0.03g, 0.75mmol), 1-bromo-2-methylpropane (0.08mL, 0.75mmol) and N,N-dimethylformamide were reacted according to the same procedure as Preparation 5 to give 0.18g (Yield 95%) of the title compound.
Mass(EI) :377(M++1)
Preparation 7: 2-Methyl-1H-indole-5-carboxamide
Figure PCTKR2010000893-appb-I000047
2-Methyl-1H-indole-5-carboxylic acid [prepared by referring to Tetrahedron Letter: 2007, 48, 7721-25] (0.31g, 1.77mmol) was dissolved in N,N-dimethylformamide (30mL). HBTU (1.0g, 2.65mmol), ammonium chloride (0.47g, 8.85mmol) and triethylamine (1.2mL, 8.85mmol) were added at 0℃, and the mixture was stirred for 15 h at room temperature. The solvent was distilled off, and ethyl acetate (50mL) was added to the residue. The mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.3g (Yield 97%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.23(1H, s), 8.04(1H, s), 7.64(1H, d), 7.30(1H, d), 6.33(1H, s), 2.51(3H, s)
Mass(EI): 175(M++1)
Preparation 8: 2-Methyl-1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000048
2-Methyl-1H-indole-5-carboxamide (0.3g, 1.72mmol) obtained in Preparation 7 was dissolved in tetrahydrofuran (30mL). Lawesson’s Reagent (0.7g, 1.72mmol) was added, and the mixture was refluxed for 3 h. The solvent was distilled off, and ethyl acetate (50mL) was added to the residue. The mixture was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.32g (Yield 97%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 9.30(2H, S), 8.15(1H, s), 8.11(1H, s), 7.77(1H, d), 7.31(1H, d), 6.33(1H, s), 2.50(3H, s)
Mass(EI): 191(M++1)
Preparation 9: 4-Methyl-2-(2-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000049
2-Methyl-1H-indole-5-carbothioamide (0.51g, 2.68mmol) obtained in Preparation 8 was dissolved in ethanol (30mL). Ethyl-2-chloroacetoacetate (0.49g, 2.95mmol) and pyridine (0.23g, 2.95mmol) were added, and the mixture was refluxed for 15 h. The solvent was distilled off, and ethyl acetate (50mL) was added to the residue. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.13g (Yield 16%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.19(1H, s), 8.07(1H, s), 7.78(1H, d), 7.38(1H, d), 6.33(1H, s), 4.40(2H, q), 2.82(2H, s), 2.50(3H, s), 1.41(3H, t)
Mass(EI) :301(M++1)
Preparation 10: 2-(3-Chloro-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000050
4-Methyl-2-(2-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (130mg, 0.43mmol) obtained in Preparation 9, N-chlorosuccinimide (64mg, 0.47mmol) and methanol were reacted according to the same procedure as Step (3) of Preparation 4 to give 143mg (Yield 99%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.19(1H, s), 8.09(1H, s), 7.86(1H, d), 7.36(1H, d), 4.41(2H, q), 2.84(2H, s), 2.50(3H, s), 1.44(3H, t)
Mass(EI) :335 (M++1)
Preparation 11: 2-(3-Chloro-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000051
2-(3-Chloro-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (190mg, 0.56mmol) obtained in Preparation 10, sodium hydride (34mg, 0.85mmol) and 1-bromo-2-methylpropane (0.09mL, 0.85mmol) were reacted according to the same procedure as Preparation 5 to give 120mg (Yield 54%) of the title compound.
Mass(EI) :391 (M++1)
Preparation 12: 2-(3-Chloro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000052
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 4 and 2-iodopropane (79mg, 0.47mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (75mg, Yield 67%).
Mass(EI): 363(M++1)
Preparation 13: 2-(3-Chloro-1-cyclohexyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000053
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 4 and cyclohexyl iodide (98.7mg, 0.47mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (30mg, Yield 24%).
Mass(EI): 403(M++1)
Preparation 14: 2-(3-Chloro-1-[2-(diethylamino)-2-oxoethyl]-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000054
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 4 and 2-chloro-N,N-diethylacetamide (70mg, 0.47mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (85mg, Yield 63%).
Mass(EI): 434(M++1)
Preparation 15: 2-[3-Chloro-1-(3-methoxybenzyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000055
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 4 and 3-methoxybenzyl bromide (94.5mg, 0.47mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (80mg, Yield 59%).
Mass(EI) : 441(M++1)
Preparation 16: 2-(3-Chloro-1-cyclopentyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000056
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 4 and cyclopentyl bromide (70mg, 0.47mmol) were reacted according to the same procedure as Preparation 5 to give 76mg (0.195mmol, Yield 63%) of the title compound.
Mass(EI): 389(M++1)
Preparation 17: 2-[3-Chloro-1-(tetrahydrofuran-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) Tetrahydrofuran-3-yl-methane sulfonate
3-Hydroxytetrahydrofuran (500mg, 5.67mmol) was dissolved in 30mL of dichloromethane, triethylamine (1.15g, 11.34mmol) was added, and methanesulfonylchloride (780mg, 6.81mmol) was slowly added in drops at 0℃. After stirring for 1 h, completion of the reaction was confirmed. The reaction solution was concentrated under reduced pressure, aqueous 1N-hydrochloric acid solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethylacetate = 1:1) to give 754mg (4.54mmol, Yield 80%) of the title compound.
(2) 2-[3-Chloro-1-(tetrahydrofuran-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000057
2-(3-Chloro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 4 and tetrahydrofuran-3-yl-methane sulfonate (78mg, 0.47mmol) obtained in Step (1) were reacted according to the same procedure as Preparation 5 to give 85mg (0.22mmol, Yield 71%) of the title compound.
Mass(EI): 391(M++1)
Preparation 18: 2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) 2-(3-Formyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000058
To 30mL of anhydrous dichloromethane was added oxalyl chloride (533mg, 4.2mmol). N,N-dimethylformamide (307mg, 4.2mmol) was added thereto at 0℃, and the mixture was stirred for 30 min at 0℃. To this reaction solution was added 2-(1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (1g, 3.5mmol) obtained in Preparation 3, and the mixture was stirred for 1 h at room temperature. The solvent was removed, and to the residue were added 40mL of tetrahydrofuran and 50mL of 20% aqueous ammonium acetate solution. The mixture was stirred while being heated to reflux for 30 min. The reaction solution was cooled, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid compound was filtered, washed with ethyl acetate, and dried to give 1.23g (3.9mmol, Yield 93%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 9.99(1H, s), 8.76(1H, s), 8.42(1H, s), 7.92(1H, d), 7.65(1H, d), 4.34(2H, q), 2.71(3H, s), 1.34(3H, t)
Mass(EI): 315(M++1)
(2) 2-{3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000059
2-(3-Formyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (1.23g, 3.9mmol) obtained in Step (1) was dissolved in 20mL of pyridine, hydroxyammoniumchloride (406mg, 5.85mmol) was added, and the mixture was stirred while being heated to reflux for 5 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and ethyl acetate was added thereto. The mixture was washed with 1N-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was washed with ethyl acetate, and dried to give 1.15g (3.51mmol, Yield 90%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ (mixture of E and Z): 11.89(0.3H, s), 11.73(0.7H, s), 8.74(1H, m), 8.32(1H, m), 7.86-7.80(1H, m), 7.57-7.52(1H, m), 4.33-4.27(2H, m), 2.70(1H, s), 2.70(2H, s), 1.34-1.30(3H, m)
Mass(EI): 330(M++1)
(3) 2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000060
2-{3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (1.15g, 3.51mmol) obtained in Step (2) was dissolved in 30mL of anhydrous tetrahydrofuran and 20mL of anhydrous dichloromethane, 2-chloro-1-methylpyridinium iodide (1.17g, 4.56mmol) was added, and the mixture was stirred for 10 min at room temperature. To this reaction solution was slowly added in drops triethylamine (461mg, 4.56mmol) for 15 min, which was then stirred for 20 h at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with 0.5N-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was washed with ethyl acetate, and dried to give 1g (3.23mmol, Yield 92%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 12.52(1H, s), 8.39(1H, s), 8.26(1H, s), 7.94(1H, d), 7.69(1H, d), 4.34(2H, q), 2.72(3H, s), 1.34(3H, t)
Mass(EI): 312(M++1)
Preparation 19: 2-(3-Formyl-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000061
2-(1-Isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (50mg, 0.15mmol), oxalyl chloride (0.02mL, 0.18mmol), N,N-dimethylformamide (0.02mL, 0.18mmol) and dichloromethane were reacted according to the same procedure as Step (1) of Preparation 18 to give 54mg (Yield 99%) of the title compound.
NMR: 1H-NMR (CDCl3) δ 10.09(1H, s), 8.91(1H, s), 8.09(1H, d), 7.94(1H, s), 7.52(1H, d), 4.80(1H, m), 4.42(2H, m), 2.84(3H, s), 1.67(6H, d), 1.44(3H, t)
Mass(EI): 357 (M++1)
Preparation 20: 2-{3-[(E,Z)-(hydroxyimino)methyl]-1-isopropyl-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000062
2-(3-Formyl-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (50mg, 0.14mmol) obtained in Preparation 19, hydroxyammonium chloride (12mg, 0.16mmol) and pyridine were reacted according to the same procedure as Step (2) of Preparation 18 to give 52mg (Yield 99%) of the title compound.
NMR: 1H-NMR(CD3OD) δ 8.74(1H, s), 8.53(1H, s), 8.49(1H, s), 8.26(1H, s), 8.03(1H, s), 7.86(2H, m), 7.70(1H, s), 7.66(1H, d), 7.56(1H, d), 4.76(1H, m), 4.34(4H, m), 4.12(1H, m), 2.73(6H, s), 1.61(6H, d), 1.55(6H, d), 1.40(6H, t)
Mass(EI): 372 (M++1)
Preparation 21: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000063
2-{3-[(E,Z)-(hydroxyimino)methyl]-1-isopropyl-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.16mmol) obtained in Preparation 20, 2-chloro-1-methylpyridinium iodide (50mg, 0.2mmol) and triethylamine (0.09mL, 0.64mmol) were reacted according to the same procedure as Step (3) of Preparation 18 to give 55mg (Yield 97%) of the title compound.
NMR: 1H-NMR (CDCl3) δ 8.42(1H, s), 8.04(1H, d), 7.83(1H, s), 7.55(1H, d), 4.79(1H, m), 4.42(2H, m), 2.84(3H, s), 1.65(6H, d), 1.44(3H, t)
Mass(EI): 354 (M++1)
Preparation 22: 2-[1-(Cyclopropylmethyl)-3-formyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000064
2-[1-(Cyclopropylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.26mmol), oxalyl chloride (0.03mL, 0.32mmol), N,N-dimethylformamide (0.03mL, 0.32mmol) and dichloromethane were reacted according to the same procedure as Step (1) of Preparation 18 to give 90mg (Yield 92%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 10.14(1H, s), 8.92(1H, s), 8.10(1H, d), 7.99(1H, s), 7.50(1H, d), 4.41(2H, q), 4.16(2H, d), 2.84(3H, s), 1.41(3H, t), 1.30(1H, m), 0.83(2H, m), 0.51(2H, m)
Mass(EI): 369 (M++1)
Preparation 23: 2-{1-(Cyclopropylmethyl)-3-[(E,Z)-(hydroxyimino)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000065
2-[1-(Cyclopropylmethyl)-3-formyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.24mmol) obtained in Preparation 22, hydroxyammonium chloride (20mg, 0.29mmol) and pyridine were reacted according to the same procedure as Step (2) of Preparation 18 to give 93mg (Yield 99%) of the title compound.
Mass(EI): 384 (M++1)
Preparation 24: 2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000066
2-{1-(Cyclopropylmethyl)-3-[(E,Z)-(hydroxyimino)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (110mg, 0.28mmol) obtained in Preparation 23, 2-chloro-1-methylpyridinium iodide (88mg, 0.34mmol) and triethylamine (0.16mL, 1.15mmol) were reacted according to the same procedure as Step (3) of Preparation 18 to give 100mg (Yield 96%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.42(1H, s), 8.04(1H, d), 7.85(1H, s), 7.50(1H, d), 4.41(2H, q), 4.16(2H, d), 2.84(3H, s), 1.41(3H, t), 1.30(1H, m), 0.83(2H, m), 0.51(2H, m)
Mass(EI): 366 (M++1)
Preparation 25: 2-[3-Cyano-1-(2-morpholin-4-ylethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000067
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (15mg, 0.05mmol) obtained in Preparation 18, sodium hydride (30mg, 0.07mmol) and 4-(2-chloroethyl)morpholine (10mg, 0.06mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (12mg, Yield 60%).
Mass(EI): 425(M++1)
Preparation 26: 2-[3-Cyano-1-(2,2-dimethylpropyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000068
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (15mg, 0.05mmol) obtained in Preparation 18, sodium hydride (10mg, 0.06mmol) and 1-bromo-2,2-dimethylpropane (30mg, 0.07mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (7mg, Yield 38%).
Mass(EI): 382 (M++1)
Preparation 27: 2-{3-Cyano-1-[2-(methylsulfonyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000069
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.19mmol) obtained in Preparation 18, sodium hydride (10mg, 0.25mmol) and 2-(methylsulfonyl)ethyl methanesulfonate (50mg, 0.23mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (46mg, Yield 58%).
Mass(EI): 418 (M++1)
Preparation 28: 2-[3-Cyano-1-(tetrahydrofuran-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000070
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (20mg, 0.48mmol) and 2-(chloromethyl)tetrahydrofuran (40mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (60mg, Yield 48%).
Mass(EI): 396 (M++1)
Preparation 29: 2-[3-Cyano-1-(3-methylbutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000071
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (20mg, 0.48mmol) and 1-bromo-3-methylbutane (58mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (90mg, Yield 74%).
Mass(EI): 382 (M++1)
Preparation 30: 2-{3-Cyano-1-[(3,5-dimethylisoxazol-4-yl)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000072
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (20mg, 0.48mmol) and 4-(chloromethyl)-3,5-dimethylisoxazole (60mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (89mg, Yield 66%).
Mass(EI): 421 (M++1)
Preparation 31: 2-(3-Cyano-1-{2-[(methylsulfonyl)amino]ethyl}-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000073
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (20mg, 0.48mmol) and 2-[(methylsulfonyl)amino]ethyl methanesulfonate (86mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give 83mg (Yield 60%) of the title compound.
Mass(EI): 433 (M++1)
Preparation 32: 2-[3-Cyano-1-(cyclopentylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000074
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.05mmol) obtained in Preparation 18, sodium hydride (20mg, 0.48mmol) and cyclopentylmethyl methanesulfonate (60mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give 96mg (Yield 76%) of the title compound.
Mass(EI): 394 (M++1)
Preparation 33: 2-[3-Cyano-1-(isobutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000075
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.29mmol) obtained in Preparation 18 and 1-bromo-2-methylpropane (60mg, 0.435mmol) were reacted according to the same procedure as Preparation 5 to give 70mg (0.19mmol, Yield 66%) of the title compound.
Mass(EI): 368(M++1)
Preparation 34: 2-[3-Cyano-1-(cyclopentyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000076
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.29mmol) obtained in Preparation 18 and cyclopentylbromide (65mg, 0.435mmol) were reacted according to the same procedure as Preparation 5 to give 41mg (0.108mmol, Yield 37%) of the title compound.
Mass(EI): 380(M++1)
Preparation 35: 2-{3-Cyano-1-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000077
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.29mmol) obtained in Preparation 18 and 2-(2-methyl-1,3-oxazol-4-yl)ethyl 4-methylbenzosulfonate (122mg, 0.435mmol) synthesized by the method of JP08-151386 were reacted according to the same procedure as Preparation 5 to give 20mg (0.048mmol, Yield 17%) of the title compound.
Mass(EI): 421(M++1)
Preparation 36: 2-[3-Cyano-1-(1,3-thiazol-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000078
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.29mmol) obtained in Preparation 18 and 2-chloromethylthiazole hydrochloride (74mg, 0.435mmol) were reacted according to the same procedure as Preparation 5 to give 22mg (0.054mmol, Yield 18.6%) of the title compound.
Mass(EI): 409(M++1)
Preparation 37: 2-[3-Cyano-1-(2-methoxyethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000079
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.29mmol) obtained in Preparation 18 and 2-bromoethylmethylether (60mg, 0.435mmol) were reacted according to the same procedure as Preparation 5 to give 73mg (0.198mmol, Yield 68%) of the title compound.
Mass(EI): 370(M++1)
Preparation 38: 2-{1-[2-(Acetylamino)ethyl]-3-cyano-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000080
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.29mmol) obtained in Preparation 18 and 2-acetylaminoethyl methanesulfonate (78.8mg, 0.435mmol) were reacted according to the same procedure as Preparation 5 to give 25mg (0.063mmol, Yield 22%) of the title compound.
Mass(EI): 397(M++1)
Preparation 39: 2-(3-Cyano-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000081
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (150mg, 0.48mmol) obtained in Preparation 18, sodium hydride (23mg, 0.96mmol) and iodomethane (0.045mL, 0.72 mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (104mg, Yield 67%).
NMR: 1H-NMR(DMSO-d6) δ 8.39(1H, s), 8.26(1H, s), 7.97(1H, d), 7.79(1H, d), 4.31(2H, q), 4.01(3H, s), 2.72(3H, s), 1.32(3H, t)
Mass(EI): 326 (M++1)
Preparation 40: 2-(3-Cyano-1-propyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000082
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (15mg, 0.64mmol) and 1-bromopropane (0.04mL, 0.48mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (90mg, Yield 79%).
NMR: 1H-NMR(DMSO-d6) δ 8.44(1H, s), 8.24(1H, s), 7.93(1H, d), 7.85(1H, d), 4.35(2H, q), 4.27(2H, t), 2.69(3H, s), 1.87-1.78(2H, m), 1.32(3H, t), 0.85(3H, t)
Mass(EI): 354 (M++1)
Preparation 41: 2-(3-Cyano-1-cyclopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000083
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (200mg, 0.64mmol) obtained in Preparation 18 was dissolved in toluene (3mL). Cyclopropylboronic acid (110mg, 1.28mmol), N,N-diethylaminopyridine (235mg, 1.93mmol), cupper acetate (116mg, 0.64mmol) and potassium bis(trimethylsilyl)amide (128mg, 0.64mmol) were added, and the mixture was refluxed for 15 h. Ethyl acetate (15mL) was added, and the mixture was washed with 1N-aqueous hydrochloric acid solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give the title compound (130mg, Yield 58%).
NMR: 1H-NMR(DMSO-d6) δ 8.43(1H, s), 8.25(1H, s), 7.99(1H, dd), 7.85(1H, d), 4.31(2H, q), 3.67-3.66(1H, m), 2.72(3H, s), 1.32(3H, t), 1.17-1.14(2H, m), 1.13-1.08(2H, m)
Mass(EI): 352 (M++1)
Preparation 42: 2-(1-Benzyl-3-cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000084
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (200mg, 0.64mmol) obtained in Preparation 18 and benzyl bromide (0.1mL, 0.83mmol) were reacted according to the same procedure as Preparation 5 to give 0.25g (0.62mmol, Yield 97%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.40(1H, d), 7.95(1H, dd), 7.65(1H, s), 7.40(4H, m), 7.17(2H, m), 5.37(2H, s), 4.36(2H, q), 2.80(3H, s), 1.40(3H, t)
Mass(EI): 402 (M++1)
Preparation 43: 2-[3-Cyano-1-(oxazol-4-ylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000085
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (20mg, 0.064mmol) obtained in Preparation 18, sodium hydride (4mg, 0.096mmol) and oxazol-4-ylmethyl methanesulfonate (14mg, 0.077mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (20mg, Yield 80%).
Mass(EI): 393(M++1)
Preparation 44: 2-[3-Cyano-1-(3,3,3-trifluoropropyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000086
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and 3-bromo-1,1,1-trifluoro-propane (85mg, 0.48mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (8mg, Yield 6%).
Mass(EI): 408(M++1)
Preparation 45: 2-(3-Cyano-1-sec-butyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000087
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and 2-iodobutane (70mg, 0.38mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (110mg, Yield 94%).
Mass(EI): 368(M++1)
Preparation 46: 2-[3-Cyano-1-[(2,4-difluorophenyl)methyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000088
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and 2,4-difluorobenzylbromide (80mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (124mg, Yield 89%).
Mass(EI): 438(M++1)
Preparation 47: 2-(1-Allyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000089
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and 3-bromo-1-propene (47mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (102mg, Yield 91%).
Mass(EI): 352(M++1)
Preparation 48: 2-(3-Cyano-1-prop-2-inyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000090
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and propargyl bromide (45mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (100mg, Yield 89%).
Mass(EI): 350(M++1)
Preparation 49: 2-[3-Cyano-1-(2-pyridylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000091
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and 3-chloromethylpyridine hydrochloride (64mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (113mg, Yield 88%).
Mass(EI): 403(M++1)
Preparation 50: 2-[3-Cyano-1-(2-methoxy-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000092
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and (2-methoxy-1-methyl-ethyl) methanesulfonate (60mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (93mg, Yield 76%).
Mass(EI): 384(M++1)
Preparation 51: 2-[3-Cyano-1-[2-(2-methoxyethoxy)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000093
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, sodium hydride (19mg, 0.48mmol) and 2-(2-methoxyethoxy)ethyl methanesulfonate (77mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (94mg, Yield 71%).
Mass(EI): 414(M++1)
Preparation 52: 2-[3-Cyano-1-[2-(2-oxopyrrolidin-1-yl)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000094
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (146.5mg, 0.47mmol) obtained in Preparation 18 was dissolved in 4.7mL of N,N-dimethylformamide. Sodium hydride (55%, 41.0mg, 0.94mmol) was added at 0℃, and the mixture was stirred for 10 min at room temperature. 2-(2-Oxopyrrolidin-1-yl)ethyl methanesulfonate (146.3mg, 0.71mmol) was added, and the mixture was stirred for 15 h at room temperature. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 99.8mg (0.24mmol, Yield 50%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.39(1H, d, J= 1.2Hz), 8.01(1H, dd, J= 1.8, 8.6Hz), 7.66(1H, s), 7.52(1H, d, J= 8.4Hz), 4.44(2H, t), 4.37(2H, q), 3.68(2H, t), 2.86(2H, t), 2.81(3H, s), 2.31(2H, t), 1.81(2H, quint), 1.41(3H, t)
Mass(EI): 423(M++1)
Preparation 53: 2-(3-Cyano-1-ethyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000095
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (108.5mg, 0.35mmol) obtained in Preparation 18, sodium hydride (55%, 22.8mg, 0.52mmol) and iodoethane (0.04mL, 0.50mmol) were reacted according to the same procedure as Preparation 5 to give 43.1mg (0.127mmol, Yield 36%) of the title compound.
Mass(EI): 340(M++1)
Preparation 54: 2-(3-Cyano-1-cyclobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000096
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (50mg, 0.16mmol) obtained in Preparation 18 and cyclobutyl bromide (0.024mL, 0.24mmol) were reacted according to the same procedure as Preparation 5 to give 28mg (0.077mmol, Yield 48%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.38(1H, d), 7.99(1H, dd), 7.83(1H, s), 7.48(1H, d), 4.36(2H, q), 4.04(1H, d), 2.80(3H, s), 2.67(1H, m), 2.46(1H, m), 1.40(3H, t), 1.30(H, m), 0.76(1H, m), 0.44(1H, m)
Mass(EI):366 (M++1)
Preparation 55: 2-[3-Cyano-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000097
To sodium hydride (56mg, 1.26mmol) was added 10mL of anhydrous tetrahydrofuran. 2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.2g, 0.64mmol) obtained in Preparation 18 was added, and the mixture was stirred for 30 min at room temperature. Anhydrous lithium perchlorate (0.34g, 3.21mmol) and 2,2-dimethyloxirane (51mg, 0.71mmol) were added, and the mixture was stirred while being refluxed for 15 h. The mixture was cooled to room temperature, ethyl acetate was added, and the organic layer was washed with 1N hydrochloric acid. The organic solvent was distilled under reduced pressure, and the remaining compound was washed with methanol and dried to give 82mg (0.21mmol, Yield 33%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 8.27(1H, s), 8.25(1H, s), 7.94(1H, d), 7.92(1H, d), 4.82(1H, s), 4.31(2H, q), 4.22(2H, s), 2.71(3H, s), 1.32(3H, t), 1.11(6H, s)
Mass(EI): 384(M++1)
Preparation 56: 2-[3-Cyano-1-(2-fluoroethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000098
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, 60% sodium hydride (20mg, 0.48mmol) and 1-bromo-2-fluoroethane (50mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (80mg, Yield 70%).
Mass(EI): 358(M++1)
Preparation 57: 2-(1-Butyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000099
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, 60% sodium hydride (20mg, 0.48mmol) and 1-bromobutane (53mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (91.7mg, Yield 78%).
Mass(EI): 368(M++1)
Preparation 58: 2-{3-Cyano-1-[(4-fluorophenyl)methyl]indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000100
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, 60% sodium hydride (20mg, 0.48mmol) and 4-fluorobenzylbromide (73mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (111mg, Yield 80%).
Mass(EI): 420(M++1)
Preparation 59: 2-[3-Cyano-1-(2-ethoxyethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000101
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, 60% sodium hydride (20mg, 0.48mmol) and 2-bromoethyl ethyl ether (60mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (98mg, Yield 80%).
Mass(EI): 384(M++1)
Preparation 60: 2-{3-Cyano-1-[1-methyl-2-(methyl-acryloyloxy)ethyl]indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) 2-Methyl-acrylic acid-2-methanesulfonyloxy-propyl ester
2-Hydroxypropylmethacrylate (2g, 13.87mmol) was dissolved in 50mL of dichloromethane, triethylamine (3.04g, 30mmol) was added, and methanesulfonyl chloride (1.9g, 16.64mmol) was slowly added in drops at 0℃. After stirring for 1 h, completion of the reaction was confirmed. The reaction solution was concentrated under reduced pressure, 1N-aqueous hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethylacetate = 1:1) to give 2.62g (11.79mmol, Yield 85%) of the title compound.
Mass(EI): 223(M++1)
(2) 2-{3-Cyano-1-[1-methyl-2-(methyl-acryloyloxy)ethyl]indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000102
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (500mg, 1.6mmol) obtained in Preparation 18 was dissolved in DMF, 60% sodium hydride (100mg, 2.4mmol) and 2-methyl-acrylic acid-2-methanesulfonyloxy-propyl ester (53.3mg, 2.4mmol) obtained in Step (1) were added, and the mixture was stirred for 48 h at 50℃. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and 1N-HCl, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethylacetate = 1:1) to give the title compound (371mg, Yield 53%).
Mass(EI): 438(M++1)
Preparation 61: 2-[1-(2-Benzyloxyethyl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000103
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 18, 60% sodium hydride (20mg, 0.48mmol) and benzyl-2-bromoethyl ether (84mg, 0.39mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (93mg, Yield 65%).
Mass(EI): 446(M++1)
Preparation 62: 2-(3-Cyano-1H-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) 2-(1H-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000104
1H-indole-5-carbothioamide (500mg, 2.83mmol) obtained in Preparation 2 was dissolved in ethanol (30mL). Ethyl-2-chloro-4,4,4-trifluoroacetoacetate (928mg, 4.24mmol) and pyridine (224mg, 2.83mmol) were added, and the mixture was refluxed for 15 h. The solvent was distilled off, and ethyl acetate (100mL) was added to the residue. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 202mg (Yield 21%) of the title compound.
Mass(EI): 341(M++1)
(2) 2-(3-Cyano-1H-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000105
2-(1H-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester (202mg, 0.59mmol) obtained in Step (1) was reacted according to the same procedures as Steps (1), (2), (3) of Preparation 18 to give the title compound (177mg, Yield 82%).
Mass(EI): 366(M++1)
Preparation 63: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000106
2-(3-Cyano-1H-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester (177mg, 0.48mmol) obtained in Preparation 62, 60% sodium hydride (29mg, 0.72mmol) and 2-iodopropane (122mg, 0.72mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (133mg, Yield 68%).
Mass(EI): 408(M++1)
Preparation 64: 2-{3-Cyano-1-[2-fluoro-1-(fluoromethyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
(1) 2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
Figure PCTKR2010000893-appb-I000107
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester obtained in Preparation 18 was hydrolyzed by 1N-sodium hydroxide to give 2-(3-cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid (200mg, 0.77mmol), which was then dissolved in 5mL of DMF. HBTU (O-Benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate)(350mg, 0.92mmol), diisopropylethylamine (198mg, 1.54mmol) and allyl alcohol (53mg, 0.92mmol) were added, and the mixture was stirred for 1 h at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate and 1N-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate to give the title compound (224mg, Yield 90%).
Mass(EI): 324(M++1)
(2) [2-Fluoro-1-(fluoromethyl)ethyl]trifluoromethane-sulfonate
1,3-Difluoro-2-propanol (1g, 10.4mmol) and trifluoromethane-sulfonyl anhydride ) were reacted according to the same procedure as Step (1) of Preparation 17 to give the title compound (1.78g, Yield 75%).
NMR: 1H-NMR(CDCl3) δ 5.25-5.13(1H, m), 4.82-4.75(2H, m), 4.70-4.63(2H, m)
Mass(EI): 229(M++1)
(3) 2-{3-Cyano-1-[2-fluoro-1-(fluoromethyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
Figure PCTKR2010000893-appb-I000108
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (250mg, 0.77mmol) obtained in Step (1) and [2-fluoro-1-(fluoromethyl)ethyl]trifluoromethanesulfonate (350mg, 1.54mmol) obtained in Step (2) were reacted according to the same procedure as Preparation 5 to give the title compound (139mg, Yield 45%).
Mass(EI): 402(M++1)
Preparation 65: 2-(3-Cyano-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) Tetrahydropyran-4-yl-trifluoromethanesulfonate
4-Hydroxytetrahydropyran (1g, 9.8mmol) was reacted according to the same procedure as Step (2) of Preparation 64 to give the title compound (1.83g, Yield 80%).
Mass(EI): 235(M++1)
(2) 2-(3-Cyano-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000109
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (250mg, 0.8mmol) obtained in Preparation 18 was dissolved in DMF, 60% sodium hydride (50mg, 1.2mmol) and tetrahydropyran-4-yl-trifluoromethanesulfonate (950mg, 2.4mmol) obtained in Step (1) were added, and the mixture was stirred for 24 h at 50℃. The reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate and 1N-HCl, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (hexane:ethylacetate = 1:1) to give the title compound (117mg, Yield 37%).
Mass(EI): 396(M++1)
Preparation 66: 2-[1-(1-Acetylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
(1) t-Butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate
1-t-Butoxycarbonyl-3-hydroxypyrrolidine was reacted according to the same procedure as Step (1) of Preparation 17 to give the title compound (Yield 83%).
Mass(EI): 266(M++1)
(2) 2-[1-(1-t-Butoxycarbonylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000110
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (200mg, 0.64mmol) obtained in Preparation 18, 60% sodium hydride (40mg, 0.96mmol) and t-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate obtained in Step (1) (510mg, 1.92mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (160mg, Yield 52%).
Mass(EI): 481(M++1)
(3) 2-[1-(1-Acetylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000111
2-[1-(1-t-Butoxycarbonylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (160mg, 0.33mmol) obtained in Step (2) was dissolved in 3mL of dichloromethane. 4N-hydrochloric acid (1,4-dioxane solution) was added, and the mixture was stirred for 1 h at room temperature. The solvent was concentrated under reduced pressure, and 10mL of dichloromethane was added to the residue. Triethylamine (100mg, 0.99mmol) was added, acetic anhydride (51mg, 0.5mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (118mg, Yield 85%).
Mass(EI): 423(M++1)
Preparation 67: 2-[3-Cyano-1-(1-methoxycarbonylpyrrolidin-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000112
2-[1-(1-t-Butoxycarbonylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (160mg, 0.33mmol) obtained in Step (2) of Preparation 66 was dissolved in 3mL of dichloromethane. 4N-hydrochloric acid (1,4-dioxane solution) was added, and the mixture was stirred for 1 h at room temperature. The solvent was concentrated under reduced pressure, and 10mL of dichloromethane was added to the residue. Triethylamine (100mg, 0.99mmol) was added, methylchloroformate (51mg, 0.5mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (107mg, Yield 73%).
Mass(EI): 439(M++1)
Preparation 68: 2-[3-Cyano-1-(1-cyano-1-methyl-ethyl)indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
(1) 2-[3-Cyano-1-(1-cyanoethyl)indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
Figure PCTKR2010000893-appb-I000113
2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (200mg, 0.62mmol) obtained in Step (1) of Preparation 64, 60% sodium hydride (50mg, 1.24mmol) and 2-bromopropionitrile (166mg, 1.24mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (175mg, Yield 75%).
Mass(EI): 377(M++1)
(2) 2-[3-Cyano-1-(1-cyano-1-methyl-ethyl)indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
Figure PCTKR2010000893-appb-I000114
2-[3-Cyano-1-(1-cyanoethyl)indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (175mg, 0.46mmol) obtained in Step (1) was dissolved in 5mL of anhydrous tetrahydrofuran, 0.5mL of 1M-lithium bistrimethylsilylamide tetrahydrofuran solution was added, and the mixture was stirred for 5 min at 0℃. Iodomethane (78mg, 0.55mmol) was added thereto, and the mixture was stirred for 1 h. After completion of the reaction, saturated aqueous ammonium chloride solution was added at 0℃. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and purified by column chromatography (hexane:ethylacetate= 1:1) to give the title compound (111mg, Yield 61%).
Mass(EI): 391(M++1)
Preparation 69: 1-(Benzenesulfonyl)indole-5-carbonitrile
Figure PCTKR2010000893-appb-I000115
To 300mL of anhydrous tetrahydrofuran was dissolved sodium hydride (23.4g, 537mmol) at 0℃. 1H-indole-5-carbonitrile (25.43g, 179mmol) was dissolved in 100mL of anhydrous tetrahydrofuran, which was then slowly added in drops at 0℃. The mixture was stirred for 30 min. Benzenesulfonyl chloride (63.2g, 358mmol) was dissolved in 100mL of anhydrous tetrahydrofuran, which was then slowly added in drops at 0℃. The mixture was slowly warmed to room temperature while stirring for 15 h. After completion of the reaction, ethyl acetate was added. The mixture was washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure, and the resulting solid was washed with ethanol and dried to give 45.84g (157mmol, Yield 86%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.09(1H, d), 7.90(3H, m), 7.70(1H, d), 7.55-7.62(2H, m), 7.49(2H, t), 6.73(1H, d)
Mass(EI): 283(M++1)
Preparation 70: 1-(Benzenesulfonyl)-2-methyl-indole-5-carbonitrile
Figure PCTKR2010000893-appb-I000116
Lithium diisopropylamide tetrahydrofuran solution (170mmol) was cooled to -78℃ under nitrogen, and stirred. 1-(Benzenesulfonyl)indole-5-carbonitrile (43.69g, 155mmol) obtained in Preparation 69 was diluted with 100mL of tetrahydrofuran, and slowly added in drops. After 30 min, the temperature of the solution was raised to -40℃ and after 30 min, lowered again to -78℃. Iodomethane (44g, 310mmol) was diluted with tetrahydrofuran, and slowly added in drops. The reaction solution was stirred for 15 h while slowly warming it to room temperature. After completion of the reaction, ethyl acetate was added. The mixture was washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure, and the resulting solid was washed with ethanol and dried to give 41.33g (139mmol, Yield 90%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.26(1H, d), 7.79(2H, m), 7.74(1H, d), 7.59(1H, m), 7.52(1H, dd), 7.48(2H, t), 6.41(1H, s), 2.62(3H, s)
Mass(EI): 297(M++1)
Preparation 71: 2-Methyl-1H-indole-5-carbonitrile
Figure PCTKR2010000893-appb-I000117
1-(Benzenesulfonyl)-2-methyl-indole-5-carbonitrile (41.33g, 139mmol) obtained in Preparation 70 was dissolved in 250mL of tetrahydrofuran and 250mL of methanol, and the mixture was cooled to 0℃. 140mL of 10N sodium hydroxide was slowly added in drops, and the mixture was stirred for 30 min at 0℃. The mixture was slowly warmed to room temperature over 15 h while stirring. After completion of the reaction, water was added. The solid compound was filtered, washed with water, and dried to give 20.39g (131mmol, Yield 93%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.23(1H, br), 7.84(1H, s), 7,34(2H, m), 6.29(1H, s), 2.48(3H, s)
Mass(EI): 157(M++1)
Preparation 72: 2-Methyl-1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000118
Sodium hydrosulfide (70%, 16.6g, 207mmol) was dissolved in 100mL of N,N-dimethylformamide, magnesium chloride 6 hydrate (14.03g, 69mmol) was added, and the mixture was stirred for 10 min at room temperature. 2-Methyl-1H-indole-5-carbonitrile (10.78g, 69mmol) obtained in Preparation 71 was added, and the mixture was stirred for 15 h. The reaction solution was poured to 2.5L of water. The solid compound was collected, and poured to 500mL of 1N hydrochloric acid. The mixture was stirred for 1 h. The solid compound was filtered, washed with water, and dried to give 12.77g (67mmol, Yield 97%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 11.17(1H, s), 9.49(1H, br), 9.25(1H, br), 8.10(1H, s), 7.72(1H, d), 7.23(1H, d), 6.22(1H, s), 2.39(3H, s)
Mass(EI): 191(M++1)
Preparation 73: 4-Methyl-2-(2-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000119
To 2-methyl-1H-indole-5-carbothioamide (12.77g, 67mmol) obtained in Preparation 72 were added 100mL of ethanol and pyridine (5.8g, 73mmol). Ethyl 2-chloro-3-oxo-butanoate (12g, 73mmol) was added, and the mixture was stirred under reflux for 2 h. After completion of the reaction, ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure, and methanol was added thereto. The resulting solid precipitate was separated, washed with methanol and hexane, and dried to give 18.02g (60mmol, Yield 89%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.15(1H, s), 8.04(1H, br), 7.73(1H, d), 7.30(1H, d), 6.29(1H, s), 4.34(2H, q), 2.78(3H, s), 2.46(3H, s), 1.39(3H, t)
Mass(EI): 301(M++1)
Preparation 74: 2-(3-Formyl-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000120
4-Methyl-2-(2-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (10.02g, 33mmol) obtained in Preparation 73, oxalyl chloride (6.3g, 50mmol), N,N-dimethylformamide (41mL, 53mmol) and dichloromethane were reacted according to the same procedure as Step (1) of Preparation 18 to give 10.85g (33mmol, Yield 99%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 12.28(1H, s), 10.10(1H, s), 8.71(1H, s), 7.82(1H, d), 7.50(1H, d), 4.30(2H, q), 2.72(3H, s), 2.71(3H, s), 1.32(3H, t)
Mass(EI): 329(M++1)
Preparation 75: 2-[3-[(E,Z)-hydroxyiminomethyl]-2-methyl-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000121
2-(3-Formyl-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (10.85g, 33mmol) obtained in Preparation 74, hydroxyammonium chloride (2.87g, 41mmol) and pyridine were reacted according to the same procedure as Step (2) of Preparation 18 to give 10.89g (32mmol, Yield 96%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 11.66(1H, s), 10.71(1H, br), 8.63(1H, s), 8.35(1H, s), 7.74(1H, d), 7.41 (1H, d), 4.29(2H, q), 2.69(2H, s), 2.48(1H, s), 1.31(3H, t)
Mass(EI): 344(M++1)
Preparation 76: 2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000122
2-[3-[(E,Z)-hydroxyiminomethyl]-2-methyl-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (10.89g, 32mmol) obtained in Preparation 75 was dissolved in 500mL of anhydrous tetrahydrofuran, 1,1’-thiocarbonyldiimidazole (14.3g, 80mmol) was added at 0℃, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and 1N-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and the resulting solid was washed with methanol to give 9.58g (29.4mmol, Yield 92%) of the title compound.
Preparation 77: 2-(3-Cyano-1-isopropyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000123
2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 76, sodium hydride (18mg, 0.46mmol) and 2-iodopropane (62mg, 0.37mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (92mg, Yield 82%).
Mass(EI): 368(M++1)
Preparation 78: 2-(1-sec-Butyl-3-cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000124
2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 76 and 2-iodobutane (0.05mL, 0.40mmol) were reacted according to the same procedure as Preparation 5 to give 24mg (0.062mmol, Yield 20%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.29(1H, d), 7.85(1H, dd), 7.53(1H, d), 4.40(1H, m), 4.36(2H, q), 2.80(3H, s), 2.62(3H, s), 2.15(1H, m), 2.00(1H, m), 1.66(3H, d), 1.40(3H, t), 0.80(3H, t)
Mass(EI): 382 (M++1)
Preparation 79: 2-[3-Cyano-1-ethyl-2-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000125
2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (120mg, 0.37mmol) obtained in Preparation 76, sodium hydride (18mg, 0.74mmol) and bromoethane (0.04mL, 0.55mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (110mg, Yield 85%).
Mass(EI): 354 (M++1)
Preparation 80: 2-(3-Cyano-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000126
2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 76, 60% sodium hydride (25mg, 0.62mmol) and 1-bromo-2-methylpropane (85mg, 0.62mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (98mg, Yield 83%).
Mass(EI): 382(M++1)
Preparation 81: 2-(3-Cyano-1-cyclopentyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000127
2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.31mmol) obtained in Preparation 76, 60% sodium hydride (25mg, 0.62mmol) and cyclopentylbromide (92mg, 0.62mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (90mg, Yield 74%).
Mass(EI): 394(M++1)
Preparation 82: 2-(1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
(1) (E)-2-chloro-3-hydroxy-acrylic acid ethyl ester
Figure PCTKR2010000893-appb-I000128
Potassium t-butoxide (7.6g, 67.49mmol) was suspended in 100mL of diethylether. Ethyl formate (5.0g, 67.49mmol) and ethyl chloroacetate (8.27g, 67.49mmol) were dissolved in diethylether, and this solution was slowly added in drops to the above potassium t-butoxide suspension at 0℃. The mixture was stirred for 18 h at room temperature. After completion of the reaction, water was slowly added at 0℃. The mixture was extracted three times with diethylether, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate to give 6.5g (43.17mmol, Yield 65%) of the title compound.
1H NMR (400 MHz, CDCl3); δ 7.82(s, 1H), 4.36(q, 2H), 1.36(t, 3H)
Mass(EI): 151(M++1)
(2) 2-(1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000129
1H-indole-5-carbothioamide (3.3g, 18.7mmol) obtained in Preparation 2 and (E)-2-chloro-3-hydroxy-acrylic acid ethyl ester (4.2g, 28.05mmol) obtained in Step (1) were reacted according to the same procedure as Preparation 3 to give the title compound (3.3g, Yield 65%).
Mass(EI): 273(M++1)
Preparation 83: 2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000130
2-(1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (3.3g, 12.1mmol) obtained in Preparation 82 was reacted according to the same procedures as Steps (1), (2), (3) of Preparation 18 to give the title compound (2.98g, Yield 83%).
Mass(EI): 298(M++1)
Preparation 84: 2-[3-Cyano-1-cyclopropyl-indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000131
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.34mmol) obtained in Preparation 83 was reacted according to the same procedure as Preparation 41 to give the title compound (70mg, Yield 61%).
Mass(EI): 338 (M++1)
Preparation 85: 2-[3-Cyano-1-methyl-indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000132
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (50mg, 0.17mmol) obtained in Preparation 83, sodium hydride (8mg, 0.34mmol) and iodomethane (0.02mL, 0.25mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (40mg, Yield 77%).
Mass(EI): 312 (M++1)
Preparation 86: 2-[3-Cyano-1-ethyl-indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000133
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (50mg, 0.17mmol) obtained in Preparation 83, sodium hydride (8mg, 0.34mmol) and bromoethane (0.02mL, 0.25mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (45mg, Yield 82%).
Mass(EI): 326 (M++1)
Preparation 87: 2-[3-Cyano-1-sec-butyl-indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000134
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.20mmol) obtained in Preparation 83, sodium hydride (7mg, 0.30mmol) and 2-bromobutane (0.05mL, 0.40mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (60mg, Yield 85%).
Mass(EI): 354 (M++1)
Preparation 88: 2-[3-Cyano-1-isobutyl-indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000135
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.20mmol) obtained in Preparation 83, sodium hydride (7mg, 0.30mmol) and 1-bromo-2-methyl-propane (0.05mL, 0.40mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (68mg, Yield 96%).
Mass(EI): 354 (M++1)
Preparation 89: 2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000136
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.34mmol) obtained in Preparation 83, 60% sodium hydride (27.2mg, 0.68mmol) and 2-iodopropane (116mg, 0.68mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (86mg, Yield 75%).
Mass(EI): 340(M++1)
Preparation 90: 2-[3-Cyano-1-(cyclopropylmethyl)indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000137
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.34mmol) obtained in Preparation 83, 60% sodium hydride (27.2mg, 0.68mmol) and bromomethylcyclopropane (92mg, 0.68mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (99mg, Yield 83%).
Mass(EI): 352(M++1)
Preparation 91: 2-(3-Cyano-1-tetrahydrofuran-3-yl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000138
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.34mmol) obtained in Preparation 83, 60% sodium hydride (27.2mg, 0.68mmol) and tetrahydrofuran-3-yl-methanesulfonate (113mg, 0.68mmol) obtained in Step (1) of Preparation 17 were reacted according to the same procedure as Preparation 5 to give the title compound (57mg, Yield 46%).
Mass(EI): 368(M++1)
Preparation 92: 2-(3-Cyano-1-cyclopentyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid cyclopentyl ester
Figure PCTKR2010000893-appb-I000139
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.33mmol) obtained in Preparation 83 and bromocyclopentane (0.11mL, 1mmol) were reacted according to the same procedure as Preparation 5 to give 75mg (0.18mmol, Yield 54%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.39(1H, s), 8.37(1H, d), 8.01(1H, dd), 7.75(1H, s), 7.54(1H, d), 5.42(1H, m), 4.85(1H, m), 2.31(2H, m), 1.90(14H, m), 1.68(2H, m)
Mass(EI): 406 (M++1)
Preparation 93: 2-(3-Chloro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000140
2-(1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (500mg, 1.84mmol) obtained in Preparation 82 and N-chlorosuccinimide (248mg, 1.84mmol) were reacted according to the same procedure as Step (3) of Preparation 4 to give the title compound (463mg, Yield 82%).
Mass(EI): 307(M++1)
Preparation 94: 2-(3-Chloro-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000141
2-(3-Chloro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.33mmol) obtained in Preparation 93, 60% sodium hydride (26.4mg, 0.66mmol) and 2-iodopropane (113mg, 0.66mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (96mg, Yield 84%).
Mass(EI): 349(M++1)
Preparation 95: 2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester
(1) 2-(1H-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000142
1H-indole-5-carbothioamide (1.3g, 7.4mmol) obtained in Preparation 2 and ethylbromopyruvate (2.16g, 11.1mmol) were reacted according to the same procedure as Preparation 3 to give the title compound (1.4g, Yield 70%).
Mass(EI): 273(M++1)
(2) 2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000143
2-(1H-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester (1.4g, 5.1mmol) obtained in Step (1) was reacted according to the same procedures as Steps (1), (2), (3) of Preparation 18 to give the title compound (1.26g, Yield 83%).
Mass(EI): 298(M++1)
Preparation 96: 2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000144
2-(3-Cyano-1H-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester (100mg, 0.37mmol) obtained in Preparation 95, 60% sodium hydride (27.2mg, 0.74mmol) and 2-iodopropane (126mg, 0.74mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (99mg, Yield 79%).
Mass(EI): 340(M++1)
Preparation 97: 4-Methyl-2-(3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000145
Cupper(II) nitrate (0.2g, 0.84mmol) was dissolved in acetic anhydride (10mL) at 0℃, and stirred for 10 min. 2-(1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.2g, 7.0mmol) was dissolved in acetic anhydride (10mL), which was then slowly added to the above mixed solution. The mixture was stirred for 2 h at 0℃. Water (20mL) was added, and the mixture was stirred. Ethyl acetate (30mL) was added, and the mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.105g (Yield 46%) of the title compound.
NMR: 1H-NMR(CD3OD) δ 8.82(1H, s), 8.48(1H, s), 7.99(1H, d), 7.66(1H, d), 4.39(q, 2H), 2.78(3H, s), 1.41(3H, t)
Mass(EI): 332(M++1)
Preparation 98: 2-(1-Isopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000146
4-Methyl-2-(3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (120mg, 0.36mmol) obtained in Preparation 97, sodium hydride (21mg, 0.54mmol) and 2-iodopropane (74mg, 0.43mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (104mg, Yield 77%).
Mass(EI): 374(M++1)
Preparation 99: 2-[1-(Cyclopropylmethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000147
4-Methyl-2-(3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (200mg, 0.6mmol) obtained in Preparation 97, sodium hydride (36mg, 0.90mmol) and bromomethyl-cyclopropane (120mg, 0.72mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (134mg, Yield 58%).
Mass(EI): 386(M++1)
Preparation 100: 2-(1-Cyclopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000148
4-Methyl-2-(3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.16g, 0.48mmol) obtained in Preparation 97, cyclopropylboronic acid (83mg, 0.96mmol), cupper(II) acetate (0.17g, 0.09mmol), potassium hexamethyldisilazide (0.1g, 0.48mmol) and N,N-dimethyl-4-aminopyridine (0.18g, 1.44mmol) were dissolved in toluene (50mL), and the mixture was stirred for 15 h at 95℃. Ethyl acetate (50mL) was added, and the mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give the title compound (68mg, Yield 38%).
Mass(EI): 372(M++1)
Preparation 101: 2-[1-(2-Methoxyethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000149
4-Methyl-2-(3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.3mmol) obtained in Preparation 97, sodium hydride (18mg, 0.45mmol) and 1-bromo-2-methoxyethane (50mg, 0.36mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (69mg, Yield 59%).
Mass(EI): 390(M++1)
Preparation 102: 2-(1-sec-Butyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000150
2-(3-Nitro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 97 and 2-iodobutane were reacted according to the same procedure as Preparation 5 to give 50mg (0.13mmol, Yield 43%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.87(1H, s), 8.22(1H, s), 8.06(1H,d), 7.51(1H, d), 4.38(2H, q), 2.81(3H, s), 1.98(2H, m), 1.62(3H, d), 1.41(3H, t), 0.90(3H, t)
Mass(EI): 388 (M++1)
Preparation 103: 2-(1-Isobutyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000151
2-(3-Nitro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 97 and 1-iodo-2-methylpropane were reacted according to the same procedure as Preparation 5 to give 40mg (0.10mmol, Yield 33%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.87(1H, d), 8.12(1H, s), 8.07(1H, dd), 7.45(1H, d), 4.37(2H, q), 4.01(2H, d), 2.81(3H, s), 2.26(1H, m), 1.41(3H, t), 1.00(6H, d)
Mass(EI): 388 (M++1)
Preparation 104: 2-(1-Methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000152
2-(3-Nitro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 97 and iodomethane were reacted according to the same procedure as Preparation 5 to give 20mg (0.058mmol, Yield 20%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.85(1H, d), 8.11(1H, s), 8.10(1H, dd), 7.44(1H, d), 4.34(2H, q), 4.11(3H, s), 2.81(3H, s), 1.41(3H, t)
Mass(EI): 346 (M++1)
Preparation 105: 2-(1-Ethyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000153
2-(3-Nitro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 97 and iodoethane were reacted according to the same procedure as Preparation 5 to give 24mg (0.067mmol, Yield 22%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.86(1H, d), 8.19(1H, s), 8.09(1H, dd), 7.48(1H, d), 4.28(2H, q), 4.21(2H, q), 2.81(3H, s), 1.61(3H, t), 1.40(3H, t)
Mass(EI): 360 (M++1)
Preparation 106: 2-(3-Nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000154
2-(1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (500mg, 1.84mmol) obtained in Preparation 82 was dissolved in 9mL of acetic anhydride and stirred at -78℃, during which 90% nitric acid solution (0.23mL, 5.5mmol) was added thereto. The mixture was stirred for 3 h, and the solvent was distilled off. Ethyl acetate was added to the residue, and the mixture was washed with cold water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give the title compound (248mg, Yield 42%).
Mass(EI): 318(M++1)
Preparation 107: 2-(3-Nitro-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000155
2-(3-Nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.32mmol) obtained in Preparation 106, 60% sodium hydride (25.6mg, 0.64mmol) and 2-iodopropane (126mg, 0.74mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (92mg, Yield 80%).
Mass(EI): 360(M++1)
Preparation 108: 1-(Benzenesulfonyl)pyrrolo[3,2-b]pyridine
Figure PCTKR2010000893-appb-I000156
Sodium hydride (0.74g, 16.9mmol) was dissolved in 30mL of anhydrous tetrahydrofuran. 1H-pyrrolo[3,2-b]pyridine (1g, 8.46mmol) dissolved in 10mL of anhydrous tetrahydrofuran was slowly added in drops, and the mixture was stirred for 30 min. Benzenesulfonyl chloride (3g, 16.9mmol) dissolved in 10mL of anhydrous tetrahydrofuran was slowly added in drops, and the mixture was stirred for 15 h at room temperature. The reaction solution was poured to 0.1N hydrochloric acid, which was then controlled to basic using aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was collected, and distilled under reduced pressure. The remaining substance was purified by column chromatography to give 2.06g (8mmol, Yield 94%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.54(1H, d), 8.27(1H, d), 7.87(2H, d), 7.80(1H, d), 7.57(1H, t), 7.47(2H, t), 7.24(1H, dd), 6.88(1H, d)
Mass(EI): 259(M++1)
Preparation 109: 1-(Benzenesulfonyl)-4-oxido-pyrrolo[3,2-b]pyridin-4-ium
Figure PCTKR2010000893-appb-I000157
To 1-(benzenesulfonyl)pyrrolo[3,2-b]pyridine (2.06g, 8mmol) obtained in Preparation 108 was added 70mL of dichloromethane, and the mixture was cooled to 0℃. 3-chloroperoxybenzoic acid (70%, 3.94g, 16mmol) was slowly added, and the mixture was warmed to room temperature and stirred for 48 h. After completion of the reaction, dichloromethane was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was distilled under reduced pressure, and the remaining substance was purified by column chromatography to give 1.98g (7.22mmol, Yield 90%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.19(1H, d), 7.92-7.87 (3H, m), 7.71(1H, d), 7.63(1H, t), 7.51(2H, t), 7.18(1H, dd), 7.15(1H, d)
Mass(EI): 275(M++1)
Preparation 110: 1-(Benzenesulfonyl)pyrrolo[3,2-b]pyridine-5-carbonitrile
Figure PCTKR2010000893-appb-I000158
To 1-(benzenesulfonyl)-4-oxido-pyrrolo[3,2-b]pyridin-4-ium (1.98g, 7.22mmol) obtained in Preparation 109 were added 20mL of triethylamine, 20mL of 1,2-dichloroethane and trimethylsilylformonitrile (6.3mL, 50.5mmol), and the mixture was stirred under reflux for 15 h. After completion of the reaction, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was distilled under reduced pressure, and the remaining substance was washed with a solvent mixture of ethyl acetate and hexane and dried to give 1.57g (5.54mmol, Yield 77%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.38(1H, d), 7.96(1H, d), 7.90(2H, d), 7.66-7.62(2H, m), 7.52(2H, t), 6.94(1H, d)
Mass(EI): 284(M++1)
Preparation 111: 1-(Benzenesulfonyl)pyrrolo[3,2-b]pyridine-5-carbothioamide
Figure PCTKR2010000893-appb-I000159
To 1-(benzenesulfonyl)pyrrolo[3,2-b]pyridine-5-carbonitrile (1.57g, 5.54mmol) obtained in Preparation 110 were added 40mL of methanol, 20mL of tetrahydrofuran and ammonium sulfide (40%, 1mL, 6mmol), and the mixture was stirred for 15 h at room temperature. After completion of the reaction, 40mL of water was added, and the resulting solid compound was separated. This solid compound was washed with a solvent mixture of methanol and water, and dried to give 1.44g (4.54mmol, Yield 82%) of the title compound.
NMR 1H-NMR(CDCl3) δ 9.42(1H, br), 8.76(1H, d), 8.35(1H, d), 7.91-7.87(3H, m), 7.62?7.58(2H, m), 7.49(2H, t), 6.85(1H, d)
Mass(EI): 318(M++1)
Preparation 112: 2-[1-(Benzenesulfonyl)pyrrolo[3,2-b]pyridin-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000160
To 1-(benzenesulfonyl)pyrrolo[3,2-b]pyridine-5-carbothioamide (2.04g, 6.43mmol) obtained in Preparation 111 were added 40mL of ethanol and pyridine (0.61g, 7.7mmol). Ethyl 2-chloro-3-oxo-butanoate (1.27g, 7.7mmol) was added, and the mixture was stirred under reflux for 15 h. After completion of the reaction, water was added, and the resulting solid compound was separated. This solid compound was washed with a solvent mixture of ethanol and water, and dried to give 2.40g (5.6mmol, Yield 87%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.36(1H, d), 8.21(1H, d), 7.89(2H, d), 7.84(1H, d), 7.59(1H, t), 7.48(2H, t), 6.92(1H, d), 4.34 (2H, q), 2.79(3H, s), 1.38(3H, t)
Mass(EI): 428(M++1)
Preparation 113: 2-(1H-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000161
To 2-[1-(Benzenesulfonyl)pyrrolo[3,2-b]pyridin-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.17mmol) obtained in Preparation 112 were added 20mL each of tetrahydrofuran, methyl alcohol and distilled water, and the compound was dissolved. The solid sodium hydroxide (1g, 23.4mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure. 1N-aqueous hydrochloric acid solution was slowly added to the residue. The resulting solid was filtered and washed with distilled water to give 0.3g (1.16mmol, Yield 98%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 11.61(1H, s), 7.98(1H, d), 7.91(1H, d), 7.78(1H, t), 6.67(1H, s), 2.68(3H, s)
Mass(EI): 260 (M++1)
Preparation 114: 2-(1-Isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester
Figure PCTKR2010000893-appb-I000162
2-(1H-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.3g, 1.16mmol) obtained in Preparation 113 and 2-iodopropane were reacted according to the same procedure as Preparation 5 to give 0.38g (1.13mmol, Yield 98%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.10(1H, d), 7.74(1H, d), 7.51(1H, d), 6.78(1H, d), 5.20(1H, m), 4.68(1H, m), 2.80(3H, s), 1.57(6H, d), 1.36(6H, d)
Mass(EI): 344 (M++1)
Preparation 115: 2-(3-Formyl-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester
Figure PCTKR2010000893-appb-I000163
2-(1-Isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester (0.38g, 1.16mmol) obtained in Preparation 114 was reacted according to the same procedure as Step (1) of Preparation 18 to give 0.33g (0.88mmol, Yield 76%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 10.53(1H, s), 8.26(1H, d), 8.25(1H, s), 7.87(1H, d), 5.27(1H, m), 4.76(1H, m), 2.85(3H, s), 1.67(6H, d), 1.43(6H, d)
Mass(EI): 372 (M++1)
Preparation 116: 2-{3-[(E,Z)-hydroxyiminomethyl]-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester
Figure PCTKR2010000893-appb-I000164
2-(3-Formyl-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester (0.33mg, 0.88mmol) obtained in Preparation 115, hydroxyammonium chloride (74mg, 1.06mmol) and pyridine were reacted according to the same procedure as Step (2) of Preparation 18 to give 0.32g (0.82mmol, Yield 93%) of the title compound.
NMR: 1H-NMR(CD3OD) δ 8.70(1H, s), 8.15(1H, d), 8.09(1H, d), 7.99(1H, s), 5.22(1H, m), 4.80(1H, m), 2.77(3H, s), 1.63(6H, d), 1.41(6H, d)
Mass(EI): 387 (M++1)
Preparation 117: 2-(3-Cyano-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester
Figure PCTKR2010000893-appb-I000165
2-{3-[(E,Z)-hydroxyiminomethyl]-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester (0.32g, 0.82mmol) obtained in Preparation 116 and 1,1’-thiocarbonyldiimidazole (0.4g, 2.24mmol) were dissolved in 20mL of tetrahydrofuran, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, ethyl acetate was added to the reaction solution, which was then washed with aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.13g (0.35mmol, Yield 43%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.23(1H, d), 7.95(1H, s), 7.83(1H, d), 5.20(1H, m), 4.70(1H, m), 2.80(3H, s), 1.62(6H, d), 1.38(6H, d)
Mass(EI): 369 (M++1)
Preparation 118: 4-Amino-3-bromo-5-methyl-benzonitrile
Figure PCTKR2010000893-appb-I000166
To 4-amino-3-methyl-benzonitrile (5.35g, 40.5mmol) was added 100mL of dichloromethane, and the mixture was cooled to -15℃. Bromine (6.47g, 40.5mmol) dissolved in dichloromethane was slowly added in drops, and the mixture was stirred for 30 min at -15℃. After completion of the reaction, dichloromethane was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was distilled under reduced pressure, and the residue was washed with ethanol and hexane, and dried to give 7.48g (35.4mmol, Yield 87%) of the title compound.
NMR 1H-NMR(CDCl3) δ 7.59(1H, d), 7.27(1H, d), 4.58(2H, br), 2.22(3H, s)
Mass(EI): 211, 213(M++1)
Preparation 119: 4-Amino-3-methyl-5-(2-trimethylsilylethinyl)benzonitrile
Figure PCTKR2010000893-appb-I000167
To 4-amino-3-bromo-5-methyl-benzonitrile (5.36g, 25.4mmol) obtained in Preparation 118 were added ethinyl-trimethyl-silane (2.75g, 27.9mmol), tris(dibenzylideneacetone)dipalladium (0.58g, 0.64mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxantene (0.73g, 1.27mmol), cupper iodide (0.24g, 1.27mmol) and 50mL of anhydrous N,N,N’,N’-tetramethyl-ethane-1,2-diamine. The temperature was raised to 100℃ under nitrogen, and the mixture was stirred for 15 h. The mixture was cooled to room temperature. Ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid solution. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 5.49g (24.0mmol, Yield 95%) of the title compound.
NMR 1H-NMR(CDCl3) δ 7.48(1H, d), 7.24(1H, d), 4.70(2H, br), 2.16(3H, s), 0.27(9H, s)
Mass(EI): 229(M++1)
Preparation 120: 4-Amino-3-ethinyl-5-methyl-benzonitrile
Figure PCTKR2010000893-appb-I000168
To 4-amino-3-methyl-5-(2-trimethylsilylethinyl)benzonitrile (6.45g, 28.24mmol) obtained in Preparation 119 were added potassium carbonate (11.71g, 84.72mmol) and 200mL of methanol, and the mixture was stirred for 3 h at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic solvent was distilled off under reduced pressure, and the remaining solid compound was washed with a solvent mixture of ethyl acetate and hexane, and dried to give 4.00g (25.61mmol, Yield 91%) of the title compound.
NMR 1H-NMR(CDCl3) δ 7.50(1H, d), 7.28(1H, d), 4.73(2H, br), 3.44(1H, s), 2.17(3H, s)
Mass(EI): 157(M++1)
Preparation 121: 7-Methyl-1H-indole-5-carbonitrile
Figure PCTKR2010000893-appb-I000169
To 4-amino-3-ethinyl-5-methyl-benzonitrile (4.00g, 25.61mmol) obtained in Preparation 120 were added 50mL of 1-methyl-2-pyrrolidone and potassium 2-methylpropan-2-olate (8.62g, 76.83mmol), and the mixture was stirred for 15 h at room temperature. Ethyl acetate was added, and the mixture was washed with 1N hydrochloric acid solution. The organic solvent was distilled off under reduced pressure, and purified by column chromatography to give 3.62g (23.2mmol, Yield 90%) of the title compound.
NMR 1H-NMR(CDCl3) δ 8.39(1H, br), 7.86(1H, s), 7.33(1H, t), 7.23(1H, s), 6.64(1H, dd), 2.53(3H, s)
Mass(EI): 157(M++1)
Preparation 122: 4-Methyl-2-(7-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
(1) 7-Methyl-1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000170
7-Methyl-1H-indole-5-carbonitrile (2.0g 12.8mmol) obtained in Preparation 121, sodium hydrosulfide (70%, 3.1g, 38.4mmol), 20mL of N,N-dimethylformamide and magnesium chloride 6 hydrate (2.6g, 12.8mmol) were reacted according to the same procedure as Preparation 111 to give 2.14g (Yield 88%) of the title compound.
Mass(EI): 191(M++1)
(2) 4-Methyl-2-(7-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000171
7-Methyl-1H-indole-5-carbothioamide obtained in Step (1), 30mL of ethanol, pyridine (1.22g, 15.4mmol) and ethyl 2-chloro-3-oxo-butanoate (2.53g, 15.4mmol) were reacted according to the same procedure as Preparation 112 to give 3.32g (11.1mmol, Yield 86%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 11.42(1H, s), 8.08(1H, s), 7.55(1H, s), 7.44(1H, t), 6.57(1H, dd), 4.29(2H, q), 2.68(3H, s), 2.53(3H, s), 1.31(3H, t)
Mass(EI): 301(M++1)
Preparation 123: 2-(3-Formyl-7-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000172
4-Methyl-2-(7-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (1.32g, 4.4mmol) obtained in Preparation 122, oxalyl chloride (0.84g, 6.6mmol), N,N-dimethylformamide (0.55mL, 7mmol) and dichloromethane were reacted according to the same procedure as Step (1) of Preparation 18 to give 1.33g (4.05mmol, Yield 92%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 12.45(1H, s), 9.98(1H, s), 8.58(1H, d), 8.42(1H, s), 7.71(1H, s), 4.29(2H, q), 2.70(3H, s), 2.57(3H, s), 1.31(3H, t)
Mass(EI): 329(M++1)
Preparation 124: 2-[3-[(E,Z)-hydroxyiminomethyl]-7-methyl-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
2-(3-Formyl-7-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (1.33g, 4.05mmol) obtained in Preparation 123, hydroxyammonium chloride (0.35g, 1.25mmol) and pyridine were reacted according to the same procedure as Step (2) of Preparation 18 to give 1.38g (4.02mmol, Yield 99%) of the title compound.
Mass(EI): 344(M++1)
Preparation 125: 2-(3-Cyano-7-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000174
2-[3-[(E,Z)-hydroxyiminomethyl]-7-methyl-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (1.38g, 4.02mmol) obtained in Preparation 124, 2-chloro-1-methylpyridinium iodide (1.03g, 4.05mmol), triethylamine (0.41g, 4.05mmol) and 25mL of N,N-dimethylformamide were reacted according to the same procedure as Step (3) of Preparation 18 to give 1.06g (3.26mmol, Yield 81%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 12.54(1H, s), 8.38(1H, s), 8.09(1H, s), 7.73(1H, s), 4.30(2H, q), 2.70(3H, s), 2.57(3H, s), 1.31(3H, t)
Mass(EI): 326(M++1)
Preparation 126: 2-(3-Cyano-1-isopropyl-7-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000175
2-(3-Cyano-7-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (150mg, 0.46mmol) obtained in Preparation 125 and 2-iodopropane were reacted according to the same procedure as Preparation 5 to give 130mg (0.35mmol, Yield 76%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.18(1H, s), 7.78(1H, s), 7.73(1H, s), 5.17(1H, m), 4.35(2H, q), 2.80(3H, s), 2.79(3H, s), 1.58(6H, d), 1.40(6H, d)
Mass(EI): 368 (M++1)
Preparation 127: 2-[3-Cyano-1-(cyclopropylmethyl)-7-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000176
2-(3-Cyano-7-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (150mg, 0.46mmol) obtained in Preparation 125 and 2-iodomethyl-cyclopropane were reacted according to the same procedure as Preparation 5 to give 130mg (0.34mmol, Yield 74%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.18(1H, d), 7.77(1H, s), 7.72(1H, d), 4.36(2H, q), 4.29(2H, d), 2.81(3H, s), 2.80(3H, s), 1.40(3H, t), 1.29(1H, m), 0.75(2H, m), 0.41(2H, m)
Mass(EI): 380 (M++1)
Preparation 128: 4-Methyl-2-(7-methyl-3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000177
Cupper(II) nitrate (0.48g, 1.99mmol) was dissolved in acetic anhydride (10mL) at 0℃, and stirred for 10 min. 4-Methyl-2-(7-methyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.66mmol) obtained in Preparation 122 dissolved in acetic anhydride (10mL) was added, and the mixture was stirred for 2 h at 0℃. Water (20mL) was added, and the mixture was stirred. Ethyl acetate (30mL) was added, and the mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.19g (Yield 36%) of the title compound.
NMR: 1H-NMR(CD3OD) δ 8.61(1H, s), 8.56(1H, s), 7.73(1H, s), 4.37(2H, q), 2.74(3H, s), 2.59(3H, s), 1.41(3H, t)
Mass(EI): 346(M++1)
Preparation 129: 2-(1-Isopropyl-7-methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000178
4-Methyl-2-(7-methyl-3-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.49mmol) obtained in Preparation 128, cesium carbonate (240mg, 0.74mmol) and 2-iodopropane (100mg, 0.59mmol) were dissolved in acetonitrile (30mL), and refluxed for 5 h. Ethyl acetate (50mL) was added, and the mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.123g (Yield 64%) of the title compound.
Mass(EI): 388(M++1)
Preparation 130: (4-Fluoro-indol-1-yl)-triisopropylsilane
Figure PCTKR2010000893-appb-I000179
Butyl lithium (2.5M hexane solution, 9mL, 22.38mmol) was added to 50mL of anhydrous tetrahydrofuran at -15℃, and 4-fluoroindole (2.52g, 18.65mmol) dissolved in 10mL of anhydrous tetrahydrofuran was slowly added thereto. The mixture was stirred for 1 h at -15℃, and chlorotri(isopropyl)silane (4.32g, 22.38mmol) dissolved in 10mL of anhydrous tetrahydrofuran was slowly added. The mixture was stirred for 12 h at room temperature. After completion of the reaction, ethyl acetate and water were added. The mixture was dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 5.43g (18.6mmol, Yield 99%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 7.27(1H, d), 7.21(1H, d), 7.04(1H, m), 6.77(1H, dd), 6.71(1H, d), 1.69(3H, m), 1.14(18H, d)
Mass(EI): 292(M++1)
Preparation 131: (4-Fluoro-5-iodo-indol-1-yl)-triisopropylsilane
Figure PCTKR2010000893-appb-I000180
To 100mL of anhydrous tetrahydrofuran and tetramethylethylenediamine (3.9mL, 25.73mmol) which were cooled to -78℃ was slowly added s-butyl lithium (1.4M cyclohexane solution, 18.4mL, 25.73mmol). (4-Fluoro-indol-1-yl)-triisopropylsilane obtained in Preparation 130 was dissolved in 50mL of anhydrous tetrahydrofuran, and slowly added to the above mixture. The resulting mixture was stirred for 7 h at -78℃. Diiodoethane (7.25g, 25.73mmol) dissolved in 50mL of anhydrous tetrahydrofuran was slowly added, and the mixture was stirred for 12 h at room temperature. After completion of the reaction, ethyl acetate and aqueous sodium thiosulfite solution were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and passed through SiO2 to give 4.92g (11.8mmol, Yield 55%) of the title compound.
NMR: 1H-NMR (CDCl3) δ 7.37(1H, dd), 7.17(1H, d), 7.08(1H, d), 6.68(1H, d), 1.69(3H, m), 1.14(18H, d)
Mass(EI): 418(M++1)
Preparation 132: 4-Fluoro-5-iodo-1H-indole
Figure PCTKR2010000893-appb-I000181
(4-Fluoro-5-iodo-indol-1-yl)-triisopropylsilane (4.92g, 11.8mmol) obtained in Preparation 131 was dissolved in 100mL of anhydrous tetrahydrofuran. Then, tetrabutylammonium fluoride (1M tetrahydrofuran solution, 24.1mL, 24.1mmol) was added, and the mixture was stirred for 1 h at room temperature. After completion of the reaction, ethyl acetate and water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 2.74g (10.5mmol, Yield 89%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.28(1H, bs), 7.42(1H, dd), 7.14(1H, t), 6.99(1H, dd), 6.61(1H, m)
Mass(EI): 262(M++1)
Preparation 133: 4-Fluoro-1H-indole-5-carbonitrile
Figure PCTKR2010000893-appb-I000182
4-Fluoro-5-iodo-1H-indole (1.88g, 7.2mmol) obtained in Preparation 132 and zinc cyanide (0.51g, 4.32mmol) were dissolved in 25mL of N,N-dimethylformamide. Tetrakis(triphenylphosphine)palladium (0.5g, 0.432mmol) was added, and the reaction vessel was filled with nitrogen. The mixture was stirred under reflux for 12 h at 90℃. After completion of the reaction, ethyl acetate and water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 1.07g (6.68mmol, Yield 93%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.67(1H, bs), 7.34-7.30(2H, m), 7.26(1H, d), 6.73(1H, m)
Mass(EI): 161(M++1)
Preparation 134: 2-(4-Fluoro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000183
4-Fluoro-1H-indole-5-carbonitrile (1.07g, 6.68mmol) obtained in Preparation 133 was reacted according to the same procedures as Preparation 111 and 112 to give 1.66g (5.48mmol, Yield 82%) of the title compound.
Mass(EI): 305(M++1)
Preparation 135: 2-(3-Cyano-4-fluoro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000184
2-(4-Fluoro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (610mg, 2.0mmol) obtained in Preparation 134 was reacted according to the same procedure as Preparation 18 to give 132mg (0.39mmol, Yield 20%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.42(1H, s), 8.13(1H, dd), 7.53(1H, d), 4.32(2H, q), 2.72(3H, s), 1.33(3H, t)
Mass(EI): 329 (M++1)
Preparation 136: 2-(3-Cyano-4-fluoro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000185
2-(3-Cyano-4-fluoro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (70mg, 0.21mmol) obtained in Preparation 135 was reacted according to the same procedure as Preparation 5 to give 78mg (0.21mmol, Yield 99%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.28(1H, dd), 7.74(1H, s), 7.31(1H, d), 4.73(1H, m), 4.37(2H, q), 2.81(3H, s), 1.60(6H, d), 1.40(6H, d)
Mass(EI): 372 (M++1)
Preparation 137: 1-Isopropylindole-5-carbothioamide
Figure PCTKR2010000893-appb-I000186
Sodium hydrosulfide (70%, 4.54g, 80.9mmol) and magnesium chloride (5.48g, 26.9mmol) were dissolved in 100mL of N,N-dimethylformamide, 1-isopropylindole-5-carbonitrile (4.97g, 26.9mmol) was added, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, this solution was poured to 100mL of water, and stirred. The resulting solid was filtered, and added to 1N-aqueous hydrochloric acid solution. The mixture was stirred for 30 min, filtered, washed with water, and dried to give the title compound (5.35g, Yield 91%).
NMR: 1H-NMR(CDCl3) δ 8.28(1H, s), 7.89(1H, d), 7.41(1H, s), 7.33(1H, d), 6.65(1H, d), 4.75(1H, m), 1.60(6H, d)
Mass(EI): 219(M++1)
Preparation 138: 4-Hydroxy-2-(1-isopropylindol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000187
1-Isopropylindole-5-carbothioamide (2.0g, 9.16mmol) obtained in Preparation 137, diethyl bromomalonate (2.63g, 11.0mmol) and pyridine (0.73g, 9.16mmol) were dissolved in ethanol (100mL), and refluxed for 3 h. After distillation under reduced pressure, ethyl acetate (50mL) was added to the residue. The mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.74g (Yield 25%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 10.03(1H, s), 8.44(1H, s), 7.91(1H, d), 7.46(1H, d), 7.39(1H, d), 6.65(1H, d), 4.74(1H, m), 4.41(2H, q), 1.62(6H, d), 1.42(3H, t)
Mass(EI): 331(M++1)
Preparation 139: 2-(1-Isopropylindol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000188
4-Hydroxy-2-(1-isopropylindol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.5mmol) obtained in Preparation 138, diisopropylethylamine (0.4mL, 2.3mmol) and iodomethane (0.32g, 2.3mmol) were dissolved in dichloromethane (30mL), and refluxed for 3 h. Dichloromethane (30mL) was added, and the mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give 0.42g (Yield 80%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.31(1H, s), 7.85(1H, d), 7.46(1H, d), 7.32(1H, d), 6.64(1H, d), 4.74(1H, m), 4.41(2H, q),4.29(3H, s), 1.62(6H, d), 1.42(3H, t)
Mass(EI): 345(M++1)
Preparation 140: 2-(3-Formyl-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000189
To 30mL of anhydrous dichloromethane was added oxalyl chloride (0.12mL, 1.35mmol). N,N-dimethylformamide (0.12mL, 1.35mmol) was added at 0℃, and the mixture was stirred for 30 min at 0℃. To this reaction solution was added 2-(1-isopropylindol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester (0.42g, 1.12mmol) obtained in Preparation 139, and the mixture was stirred for 1 h at room temperature. The solvent was removed, 30mL of tetrahydrofuran and 30mL of 20% aqueous ammonium acetate solution were added, and the mixture was heated for 30 min while being refluxed and stirred. The reaction solution was cooled, and ethyl acetate was added. The mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was filtered, washed with ethyl acetate, and dried to give the title compound (0.41g, Yield 98%).
NMR: 1H-NMR(CDCl3) δ 10.09(1H, s), 8.94(1H, s), 8.04(2H, m), 7.52(1H, d), 4.79(1H, m), 4.43(2H, q),4.31(3H, s), 1.66(6H, d), 1.43(3H, t)
Mass(EI): 373(M++1)
Preparation 141: 2-{3-[(E,Z)-hydroxyiminomethyl]-1-isopropyl-indol-5-yl}-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000190
2-(3-Formyl-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester (0.41g, 1.1mmol) obtained in Preparation 140 was dissolved in 30mL of pyridine, hydroxyammonium chloride (0.1g, 1.32mmol) was added, and the mixture was heated for 5 h while being stirred and refluxed. After completion of the reaction, the solvent was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with 1N-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was washed with ethyl acetate and dried to give 0.35g (Yield 83%) of the title compound.
NMR: 1H-NMR(CD3OD) δ 8.79(1H, m), 8.30(1H, m), 7.90(1H, d), 7.72(1H, m), 7.54(1H, m), 4.23(2H, q), 4.18(3H, s), 1.61(6H, d), 1.38(3H, t)
Mass(EI): 388(M++1)
Preparation 142: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000191
2-[3-[(E,Z)-hydroxyiminomethyl]-1-isopropyl-indol-5-yl]-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester (0.35g, 0.9mmol) obtained in Preparation 141 was dissolved in 30mL of anhydrous tetrahydrofuran, 1,1’-thiocarbonyldiimidazole (0.4g, 2.3mmol) was added, and the mixture was stirred for 13 h at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with 0.5N-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was washed with ethyl acetate and dried to give 0.25g (Yield 76%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.44(1H, s), 7.97(1H, d), 7.82(2H, s), 7.54(1H, d), 4.79(1H, m), 4.39(2H, q), 4.31(3H, s), 1.65(6H, d), 1.43(3H, t)
Mass(EI): 370(M++1)
Preparation 143: 1H-indole-5-carboxylic acid-1-ethoxycarbonyl-2-oxo-propyl ester
Figure PCTKR2010000893-appb-I000192
1H-indole-5-carboxylic acid (1g, 6.21mmol) was dissolved in 21mL of N,N-dimethylformamide, ethyl 2-chloroacetoacetate (0.95mL, 6.83mmol) and potassium carbonate (1.72g, 12.42mmol) were added, and the mixture was stirred for 3 h at 50℃. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give the title compound (1.2g, Yield 67%).
NMR: 1H-NMR(MeOD-d4) 8.50(1H, d), 7.88(1H, dd), 7.48(1H, d), 7.36(1H, d), 6.62(1H, dd), 4.32(2H, q), 2.47(3H, s), 1.32(3H, t)
Preparation 144: 2-(1H-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000193
1H-indole-5-carboxylic acid-1-ethoxycarbonyl-2-oxo-propyl ester (1.2g, 3.46mmol) obtained in Preparation 143 was dissolved in 17mL of acetic acid, ammonium acetate (320mg, 4.15mmol) was added, and the mixture was refluxed for 30 h. After the mixture was cooled to room temperature, the solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with 1N aqueous sodium hydroxide solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and purified by column chromatography to give the title compound (655g, Yield 70%).
Mass(EI): 271 (M++1)
Preparation 145: 2-(3-Formyl-1H-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000194
2-(1H-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester (386mg, 1.43mmol) obtained in Preparation 144 was reacted according to the same procedure as Step (1) of Preparation 18 to give the title compound (270mg, Yield 63%).
Mass(EI): 299 (M++1)
Preparation 146: 2-{3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl}-4-methyl-oxazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000195
2-(3-Formyl-1H-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester (250mg, 0.84mmol) obtained in Preparation 145 was reacted according to the same procedure as Step (2) of Preparation 18 to give the title compound (230mg, Yield 87%).
Mass(EI): 314 (M++1)
Preparation 147: 2-(3-Cyano-1H-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000196
2-{3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl}-4-methyl-oxazole-5-carboxylic acid ethyl ester (230mg, 0.73mmol) obtained in Preparation 146 was reacted according to the same procedure as Step (3) of Preparation 18 to give the title compound (180mg, Yield 84%).
NMR: 1H-NMR(DMSO-d6) 8.38(1H, s), 8.22(1H, s), 7.95(1H, dd), 7.73(1H, dd), 4.35(2H, q), 2.47(3H, s), 1.35(3H, t)
Mass(EI): 296 (M++1)
Preparation 148: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000197
2-(3-Cyano-1H-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester (140mg, 0.47mmol) obtained in Preparation 147, sodium hydride (17mg, 0.71mmol) and 2-iodopropane (0.09mL, 0.94mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (100mg, Yield 63%).
Mass(EI): 338 (M++1)
Preparation 149: 4-Amino-3-chloro-5-iodo-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000198
4-Amino-3-chloro-benzoic acid methyl ester, iodine (21g, 82.7mmol) and silver nitrate (14g, 82.7mmol) were added to 10mL of ethanol and reacted for 12 h at room temperature. After reaction, the solution was filtered through celite using ethanol. After filtration, 20mL of sodium thiosulfate solution was added, and 20mL of ethyl acetate was added. The organic layer was separated and dried over anhydrous magnesium sulfate. Ethyl acetate was thoroughly evaporated under reduced pressure. The product was solidified from hexane and dichloromethane, filtered and dried under nitrogen gas to give the title compound (8g, Yield 47%).
NMR: 1H-NMR(CDCl3) δ 8.28(1H, d), 7.97(1H, d), 5.12(2H, s), 3.91 (3H, s)
Mass(EI): 312(M++1)
Preparation 150: 4-Amino-3-chloro-5-(4-methyl-pent-1-inyl)-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000199
4-Amino-3-chloro-5-iodo-benzoic acid methyl ester (2g, 6.4mmol) obtained in Preparation 149, dichlorobis(triphenylphosphine)palladium (225mg, 0.3mmol), cupper iodide (61mg, 0.3mmol), 4-methyl-1-pentine (632mg, 6.4mmol) and triethylamine (4.47mL, 30mmol) were added to 5mL of tetrahydrofuran and reacted for 3 h at room temperature. After reaction, the solution was filtered through celite using ethyl acetate. After filtration, 10mL of 1N-hydrochloric acid solution was added, and 10mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (1.8g, Yield 90%).
NMR: 1H-NMR(CDCl3) δ 7.86(2H, s), 4.97(2H, s), 3.85(2H, s), 2.37(2H, d), 1.93(1H, m), 1.05(6H, d)
Mass(EI): 266(M++1)
Preparation 151: 7-Chloro-2-isobutyl-1H-indole-5-carboxylic acid methyl ester
Figure PCTKR2010000893-appb-I000200
4-Amino-3-chloro-5-(4-methyl-pent-1-inyl)-benzoic acid methyl ester (1.8g, 6.7mmol) obtained in Preparation 150 was dissolved in 5mL of N,N-dimethylformamide, sodium hydride (443mg, 10mmol) was added, and the mixture was reacted for 12 h. After reaction, 10mL of ethyl acetate and 10mL of water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (1.5g, Yield 83%).
NMR: 1H-NMR(CDCl3) δ 8.29(1H, s), 8.18(1H, s), 7.83(1H, s), 6.36(1H, s), 4.91(3H, s), 2.65(2H, d), 2.03(1H, m), 0.99(6H, d)
Mass(EI): 266(M++1)
Preparation 152: 7-Chloro-2-isobutyl-1H-indole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000201
7-Chloro-2-isobutyl-1H-indole-5-carboxylic acid methyl ester (0.4g, 1.5mmol) obtained in Preparation 151 was added to 5.0mL of tetrahydrofuran, 5.0L of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed, and the residue was purified by column chromatography to give the title compound (0.35g, Yield 92%).
Preparation 153: 7-Chloro-2-isobutyl-1H-indole-5-carboxylic acid amide
Figure PCTKR2010000893-appb-I000202
7-Chloro-2-isobutyl-1H-indole-5-carboxylic acid (0.4g, 1.5mmol) obtained in Preparation 152 was dissolved in 30mL of N,N-dimethylformamide. HBTU (0.9g, 2.2mmol), ammonium chloride (0.42g, 7.9mmol) and triethylamine (1.1mL, 7.9mmol) were added at 0℃, and stirred for 15 h at room temperature. The solvent was distilled off, and 50mL of ethyl acetate was added. The mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.4g, Yield 92%).
Preparation 154: 7-Chloro-2-isobutyl-1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000203
7-Chloro-2-isobutyl-1H-indole-5-carboxylic acid amide (0.4g, 1.5mmol) obtained in Preparation 153 was dissolved in 20mL of tetrahydrofuran. Lawesson’s Reagent (0.6g, 1.5mmol) was added, and the mixture was refluxed for 3 h. The solvent was distilled off, and 50mL of ethyl acetate was added. The mixture was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.13g, Yield 30%).
Preparation 155: 2-(7-Chloro-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000204
7-Chloro-2-isobutyl-1H-indole-5-carbothioamide (0.3g, 1.0mmol) obtained in Preparation 154 was dissolved in 20mL of ethanol. Ethyl-2-chloroacetoacetate (155ul, 1.1mmol) and pyridine (90ul, 1.1mmol) were added, and the mixture was refluxed for 12 h. The solvent was distilled off, and 50mL of ethyl acetate was added. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.3g, Yield 70%).
NMR: 1H-NMR(CDCl3) δ 8.22(1H, s), 8.01(1H, s), 7.79(1H, s), 6.32(1H, s), 4.33(2H, q), 2.77(3H, s), 2.64(2H, d), 2.01(1H, m), 1.38(3H, t), 0.99(6H, d)
Mass(EI): 377(M++1)
Preparation 156: 2-(7-Chloro-2-isobutyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000205
2-(7-Chloro-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.08g, 0.19mmol) obtained in Preparation 155 was dissolved in 5mL of tetrahydrofuran, sodium hydride (0.01, 0.19mmol) and methyl iodide (15ul, 0.19mmol) were added, and the mixture was reacted for 1 h at room temperature. After reaction, 10mL of ethyl acetate and 10mL of water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.07g, Yield 83%).
NMR: 1H-NMR(CDCl3) δ 7.98(1H, s), 7.73(1H, s), 6.30(1H, s), 4.35(2H, q), 4.03(3H, s), 2.77(3H, s), 2.58(2H, d), 1.97(1H, m), 1.38(3H, t), 1.00(6H, d)
Mass(EI): 391(M++1)
Preparation 157: 4-Amino-3-chloro-5-(3-cyclopentyl-prop-1-inyl)-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000206
4-Amino-3-chloro-5-iodo-benzoic acid methyl ester (2g, 6.4mmol) obtained in Preparation 149, dichlorobis(triphenylphosphine)palladium (225mg, 0.3mmol), cupper iodide (61mg, 0.3mmol), 3-cyclopentyl-1-propine (833mg, 7.7mmol) and triethylamine (4.47mL, 30mmol) were added to 5mL of tetrahydrofuran, and reacted for 3 h at room temperature. After reaction, the solution was filtered through celite using ethyl acetate. After filtration, 10mL of 1N-hydrochloric acid solution was added, and 10mL of ethyl acetate was added. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (1.9g, Yield 99%).
NMR: 1H-NMR(CDCl3) δ 7.86(2H, s), 4.97(2H, s), 3.84(2H, s), 2.37(2H, d), 2.15(1H, m), 1.84(2H, m), 1.65(2H, m), 1.58(2H, m), 1.33(2H, m)
Mass(EI): 292(M++1)
Preparation 158: 2-(7-Chloro-2-cyclopentylmethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000207
4-Amino-3-chloro-5-(3-cyclopentyl-prop-1-inyl)-benzoic acid methyl ester (1.9g, 6.4mmol) obtained in Preparation 157 was reacted according to the same procedures as Preparation 151, Preparation 152, Preparation 153, Preparation 154 and Preparation 155 to give the title compound (0.05g, 0.1mmol).
NMR: 1H-NMR(CDCl3) δ 8.26(1H, s), 8.00(1H, s), 7.78(1H, s), 6.32(1H, d), 4.34(2H, q), 2.77(3H, s), 2.76(2H, d), 2.24(1H, m), 1.81(2H, m), 1.66(2H, m), 1.56(2H, m), 1.38(3H, t), 1.25(2H, m)
Mass(EI): 403(M++1)
Preparation 159: 2-(7-Chloro-2-cyclopentylmethyl-1-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000208
2-(7-Chloro-2-cyclopentylmethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.08g, 0.19mmol) obtained in Preparation 158 was dissolved in 5mL of tetrahydrofuran, sodium hydride (0.01, 0.19mmol) and methyl iodide (15ul, 0.19mmol) were added, and the mixture was reacted for 1 h at room temperature. After reaction, 10mL of ethyl acetate and 10mL of water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.07g, Yield 83%).
NMR: 1H-NMR(CDCl3) δ 7.97(1H, d), 7.73(1H, d), 6.31(1H, s), 4.33(2H, q), 4.05(3H, s), 2.77(3H, s), 2.70(2H, d), 2.23(2H, d), 2.23(1H, m), 1.83(2H, m), 1.67(2H, m), 1.57(2H, m), 1.36(3H, t), 1.26(2H, m)
Mass(EI): 417(M++1)
Preparation 160: 7-Bromo-5-methyl-1H-indole-2-carboxylic acid methyl ester
Figure PCTKR2010000893-appb-I000209
To 2-[(2-bromo-4-methyl-phenyl)-hydrazono]-propionic acid methyl ester was added 20mL of trifluoroacetic acid, which was then reacted for 12 h at room temperature. After reaction, the solvent was removed, and the residue was adjusted to neutral pH using 30mL of sodium bicarbonate solution. Then, 30mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (0.52g, Yield 55%).
Preparation 161: 7-Bromo-5-methyl-1H-indole-2-carboxylic acid
Figure PCTKR2010000893-appb-I000210
7-Bromo-5-methyl-1H-indole-2-carboxylic acid methyl ester (1.0 g, 3.7mmol) obtained in Preparation 160 was added to a mixture of 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed, and the residue was purified by column chromatography to give the title compound (0.86g, Yield 90%).
Preparation 162: 7-Bromo-5-methyl-1H-indole-2-carboxylic acid amide
Figure PCTKR2010000893-appb-I000211
7-Bromo-5-methyl-1H-indole-2-carboxylic acid (0.86g, 3.2mmol) obtained in Preparation 161 was dissolved in N,N-dimethylformamide (30mL). HBTU (1.8g, 4.8mmol), ammonium chloride (0.85g, 16mmol) and triethylamine (2.23mL, 16mmol) were added at 0℃, and the mixture was stirred for 15 h at room temperature. The solvent was distilled off, and 50mL of ethyl acetate was added to the residue. The mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.43g, Yield 50%).
NMR: 1H-NMR(DMSO) δ 11.1(1H, s), 7.98(1H, s), 7.43(1H, s), 7.38(1H, s), 7.07(1H, s), 2.34(3H, s)
Mass(EI): 254(M++1)
Preparation 163: 7-Bromo-5-methyl-1H-indole-2-carbothioamide
Figure PCTKR2010000893-appb-I000212
7-Bromo-5-methyl-1H-indole-2-carboxylic acid amide (0.22g, 0.86mmol) obtained in Preparation 162 was dissolved in 10mL of tetrahydrofuran. Lawesson’s Reagent (0.35g, 0.86mmol) was added, and the mixture was refluxed for 12 h. The solvent was distilled off, and 50mL of ethyl acetate was added to the residue. The mixture was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.18g, Yield 84%).
Preparation 164: 2-(7-Bromo-5-methyl-1H-indol-2-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000213
7-Bromo-5-methyl-1H-indole-2-carbothioamide (0.18g, 0.66mmol) obtained in Preparation 163 was dissolved in 10mL of ethanol. Ethyl-2-chloroacetoacetate (101ul, 0.66mmol) and pyridine (64ul, 0.66mmol) were added, and the mixture was refluxed for 12 h. The solvent was distilled off, and 50mL of ethyl acetate was added to the residue. The mixture was washed with aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.07g, Yield 27%).
NMR: 1H-NMR(CDCl3) δ 9.37(1H, s), 7.33(1H, s), 7.26(1H, s), 7.01(1H, s), 4.34(2H, q), 2.76(3H, s), 2.41(3H, s), 1.38(3H, t)
Mass(EI): 340(M++1)
Preparation 165: 2-(7-Cyano-5-methyl-1H-indol-2-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000214
To 2-(7-bromo-5-methyl-1H-indol-2-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.07g, 0.66mmol) obtained in Preparation 164 were added zinc cyanide (0.02mg, 0.18mmol), tri(dibenzylideneacetone)palladium (0.009mg, 0.009mmol) and Xantphos (0.01mg, 0.06mmol), which was then dissolved in 10mL of N,N-dimethylformamide and 2mL of N-methylmorpholine and reacted for 3 day at 100℃. After reaction, the solution was filtered through celite using 30mL of ethyl acetate. 20mL of sodium bicarbonate solution was added, and the mixture was extracted. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (0.03g, Yield 49%).
NMR: 1H-NMR(DMSO) δ 9.55(1H, s), 7.64(1H, s), 7.41(1H, s), 7.01(1H, s), 4.35(2H, q), 2.76(3H, s), 2.45(3H, s), 1.39(3H, t)
Mass(EI): 326(M++1)
Preparation 166: 4-Amino-3-bromo-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000215
4-Amino-benzoic acid methyl ester (17g, 0.1mol) was dissolved in chloroform (250mL). N-bromosuccinimide (20g, 0.1mol) was added at 0℃, and at the same temperature the mixture was stirred for 3 h. The solvent was distilled off, and ethyl acetate (100mL) was added to the residue. The mixture was washed with aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified from hexane to give the title compound (24.3g, Yield 93%).
NMR: 1H-NMR(CDCl3) δ 8.11(1H, d), 7.79-7.77(1H, m), 6.72(1H, d), 4.51(2H, br s), 3.85(3H, s)
Preparation 167: 4-Amino-3-bromo-5-iodo-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000216
4-Amino-3-bromo-benzoic acid methyl ester (24g, 0.1mol) obtained in Preparation 166 was reacted according to the same procedure as Preparation 149 to give the title compound (25.8g, Yield 70%).
NMR: 1H-NMR(CDCl3) δ 8.28(1H, d), 8.10(1H, d), 5.03(2H, br s), 3.87(3H, s)
Preparation 168: 4-Amino-3-bromo-5-iodo-benzoic acid
Figure PCTKR2010000893-appb-I000217
4-Amino-3-bromo-5-iodo-benzoic acid methyl ester (10g, 0.028mol) obtained in Preparation 167 was reacted according to the same procedure as Preparation 152 to give the title compound (9.4g, Yield 98%).
NMR: 1H-NMR(DMSO-d6) δ 12.73(1H, br s), 8.07(1H, d), 7.86(1H, d), 5.89(2H, s)
Preparation 169: 4-Amino-3-bromo-5-iodo-benzamide
Figure PCTKR2010000893-appb-I000218
4-Amino-3-bromo-5-iodo-benzoic acid (9.23g, 0.027mol) obtained in Preparation 168 was reacted according to the same procedure as Preparation 153 to give the title compound (8.1g, Yield 85%).
NMR: 1H-NMR(DMSO-d6) δ 8.16(1H, d), 7.98(1H, d), 7.89(1H, br s), 7.17(1H, br s), 5.67(2H, s)
Preparation 170: 4-Amino-3-bromo-5-iodo-thiobenzamide
Figure PCTKR2010000893-appb-I000219
4-Amino-3-bromo-5-iodo-benzamide (8.05g, 0.024mol) obtained in Preparation 169 was reacted according to the same procedure as Preparation 154 to give the title compound (6.67g, Yield 79%).
NMR: 1H-NMR(DMSO-d6) δ 9.58(1H, br s), 9.27(1H, br s), 8.33(1H, d), 8.15(1H, d), 5.82(2H, s)
Preparation 171: 2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000220
4-Amino-3-bromo-5-iodo-thiobenzamide (8.05g, 0.019mol) obtained in Preparation 170 was reacted according to the same procedure as Preparation 155 to give the title compound (7.34g, Yield 89%).
NMR: 1H-NMR(DMSO-d6) δ 8.15(1H, d), 7.98(1H, d), 5.85(2H, s), 4.25-4.23(1H, q), 2.60(3H, s), 1.25(3H, t)
Preparation 172: 2-(4-Amino-3-bromo-5-pyrazin-2-ylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000221
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1mmol) obtained in Preparation 171, dichlorobis(triphenylphosphine)palladium (37mg, 0.05mmol), cupper iodide (10mg, 0.05mmol), 2-ethinylpyrazine (220mg, 2.0mmol) and triethylamine (4.47mL, 5mmol) were added to 5mL of tetrahydrofuran, and the mixture was reacted for 12 h at room temperature. After reaction, the solution was filtered through celite using 30mL of ethyl acetate. After filtration, 20mL of sodium bicarbonate solution was added, and 10mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.5g, Yield 52%).
NMR: 1H-NMR(DMSO) δ 8.78(1H, s), 8.59(1H, s), 8.53(1H, s), 8.12(1H, s), 8.00(1H, s), 5.19(2H, s), 4.34(2H, q), 2.74(3H, s), 1.36(3H, t)
Mass(EI): 444(M++1)
Preparation 173: 2-(7-Bromo-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000222
2-(4-Amino-3-bromo-5-pyrazin-2-ylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.1mmol) obtained in Preparation 172 was dissolved in 3mL of 1-methyl-2-pyrrolidinone (NMP). Potsssium t-butoxide (0.14g, 1.65mmol) was added at room temperature, and the mixture was stirred for 1 h. After reaction, 30mL of ethyl acetate was added, and the mixture was washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.24g, Yield 48%).
Preparation 174: 2-(7-Cyano-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000223
2-(7-Bromo-2-pyrazin-2-yl-1H?indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.2g, 0.45mmol) obtained in Preparation 173 was reacted according to the same procedure as Preparation 165 to give the title compound (0.04g, Yield 23%).
Preparation 175: 2-(4-Amino-3-bromo-5-(6-methyl-pyridin-2-ylethinyl)-phenyl-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000224
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1mmol) obtained in Preparation 171 and 2-ethinyl-6-methyl-pyridine were reacted according to the same procedure as Preparation 172 to give the title compound (0.5g, Yield 50%).
Preparation 176: 2-[7-Bromo-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000225
2-(4-Amino-3-bromo-5-(6-methyl-pyridin-2-ylethinyl)-phenyl-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.48g, 1.05mmol) obtained in Preparation 175 was reacted according to the same procedure as Preparation 173 to give the title compound (0.2g, Yield 45%).
NMR: 1H-NMR(CDCl3) δ 9.71(1H, s), 8.17(1H, s), 7.62(2H, m), 7.07(2H, m), 4.35(2H, q), 2.78(3H, s), 2.62(3H, s), 1.39(3H, t)
Mass(EI): 457(M++1)
Preparation 177: 2-[7-Cyano-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000226
2-[7-Bromo-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.16g, 0.35mmol) obtained in Preparation 176 was reacted according to the same procedure as Preparation 165 to give the title compound (0.04g, Yield 25%).
NMR: 1H-NMR(CDCl3) δ　10.11(1H, s), 8.42(1H, s), 8.16(1H, s), 7.64(2H, m), 7.11(2H, m), 4.36(1H, q), 2.79(3H, s), 2.67(3H, s), 1.38(3H, t)
Mass(EI): 403(M++1)
Preparation 178: 4-Amino-3-iodo-5-nitro-benzoic acid
Figure PCTKR2010000893-appb-I000227
4-Amino-3-iodo-5-nitro-benzoic acid ethyl ester (15g, 0.044mol) was reacted according to the same procedure as Preparation 152 to give the title compound (13g, Yield 85%).
Preparation 179: 4-Amino-3-iodo-5-nitro-benzamide
Figure PCTKR2010000893-appb-I000228
4-Amino-3-iodo-5-nitro-benzoic acid (13g, 0.042mol) obtained in Preparation 178 was reacted according to the same procedure as Preparation 153 to give the title compound (10g, Yield 76%).
Preparation 180: 4-Amino-3-iodo-5-nitro-benzene-carbothioamide
Figure PCTKR2010000893-appb-I000229
4-Amino-3-iodo-5-nitro-benzamide (3.4g, 11mmol) obtained in Preparation 179 was reacted according to the same procedure as Preparation 154 to give the title compound (2g, Yield 77%).
Preparation 181: 2-(4-Amino-3-iodo-5-nitro-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000230
4-Amino-3-iodo-5-nitro-benzene-carbothioamide (0.8g, 2.4mmol) obtained in Preparation 180 was reacted according to the same procedure as Preparation 155 to give the title compound (0.8g, Yield 74%).
NMR: 1H-NMR(DMSO-d6) δ 8.54(1H, d), 8.47(1H, d), 7.45(2H, s), 4.23(2H, q), 2.62(3H, s), 1.27(3H, t)
Preparation 182: 2-(4-Amino-3-nitro-5-trimethylsilanylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000231
2-(4-Amino-3-iodo-5-nitro-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.8g, 1.8mmol) obtained in Preparation 181 and trimethylsilanylacetylene (306uL, 1.9mmol) were reacted according to the same procedure as Preparation 172 to give the title compound (0.5g, Yield 40%).
NMR: 1H-NMR(CDCl3) δ 8.69(1H, s), 8.18(1H, s), 4.34(2H, q), 2.75(2H, s), 1.37(3H, t), 0.31(9H, s)
Mass(EI): 406(M++1)
Preparation 183: 2-(4-Amino-3-ethinyl-5-nitro-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000232
2-(4-Amino-3-nitro-5-trimethylsilanylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.18g, 0.4mmol) obtained in Preparation 182 was dissolved in 10mL of methanol, potassium carbonate (5mg, 0.2mmol) was added, and the mixture was reacted for 2 h at room temperature. After reaction, 20mL of water and 20mL of ethyl acetate were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.13g, Yield 85%).
NMR: 1H-NMR(CDCl3) δ 8.73(1H, s), 8.22(1H, s), 4.35(2H, q), 3.88(2H, s), 3.66(1H, s), 2.75(3H, s), 1.37(3H, t)
Preparation 184: 4-Methyl-2-(7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000233
2-(4-Amino-3-ethinyl-5-nitro-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.2g, 0.49mmol) obtained in Preparation 183 was reacted according to the same procedure as Preparation 173 to give the title compound (0.010g, Yield 5%).
NMR: 1H-NMR(CDCl3) δ 8.72(1H, s), 8.56(1H, s), 7.43(1H, s), 6.76(1H, s), 4.33(2H, q), 2.76(3H, s), 1.38(3H, t)
Preparation 185: 2-[4-Amino-3-bromo-5-(3-methoxy-prop-1-inyl)-phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000234
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.3g, 0.64mmol) obtained in Preparation 171 and 3-methoxy-propine (0.07mL, 0.83mmol) were reacted according to the same procedure as Preparation 172 to give the title compound (0.25g, Yield 94%).
NMR: 1H-NMR(CDCl3) δ 8.07(1H, d), 7.86(1H, d), 4.99(2H, br s), 4.39(2H, s), 4.37-4.31(2H, q), 3.47(3H, s), 2.74(3H, s), 1.38(3H, t)
Preparation 186: 2-(7-Bromo-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000235
2-[4-Amino-3-bromo-5-(3-methoxy-prop-1-inyl)-phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.25g, 0.61mmol) obtained in Preparation 185 was reacted according to the same procedure as Preparation 173 to give the title compound (0.11g, Yield 42%).
NMR: 1H-NMR(CDCl3) δ 8.57(1H, br s), 8.12(1H, s), 8.00(1H, s), 6.55(1H, d), 4.63(2H, s), 4.37-4.33(2H, q), 3.43(3H, s), 2.78(3H, s), 1.39(3H, t)
Preparation 187: 2-(7-Cyano-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000236
2-(7-Bromo-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.1g, 0.24mmol) obtained in Preparation 186 was reacted according to the same procedure as Preparation 165 to give the title compound (0.01g, Yield 8.7%).
NMR: 1H-NMR(CDCl3) δ 9.07(1H, br s), 8.38(1H, s), 8.15(1H, s), 6.64(1H, s), 4.69(2H, s), 4.39-4.34(2H, q), 3.47(3H, s), 2.79(3H, s), 1.40(3H, t)
Preparation 188: 2-(4-Amino-3-bromo-5-pyridin-2-ylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000237
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.19g, 0.41mmol) obtained in Preparation 171 and 2-ethinyl-pyridine (0.05mL, 0.49mmol) were reacted according to the same procedure as Preparation 172 to give the title compound (0.15g, Yield 80%).
NMR: 1H-NMR(CDCl3) δ 8.64(1H, d), 8.10(1H, d), 7.98(1H, d), 7.72-7.71(1H, m), 7.55-7.54(1H, m), 7.30-7.29(1H, m), 5.18(2H, s), 4.35-4.31(2H, q), 2.75(3H, s), 1.38(3H, t)
Preparation 189: 2-(4-Amino-3-bromo-5-phenylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000238
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.07mmol) obtained in Preparation 171 and ethinyl-benzene (0.15mL, 1.39mmol) were reacted according to the same procedure as Preparation 172 to give the title compound (0.4g, Yield 85%).
NMR: 1H-NMR(DMSO-d6) δ 8.01(1H, d), 7.89(1H, d), 7.67-7.40(5H, m), 6.22(2H, s), 4.26-4.23(2H, q), 2.62(3H, s), 1.27(3H, t)
Preparation 190: 2-[4-Amino-3-bromo-5-(3-phenyl-prop-1-inyl)-phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000239
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.07mmol) obtained in Preparation 171 and prop-2-inyl-benzene (0.16mL, 1.28mmol) were reacted according to the same procedure as Preparation 172 to give the title compound (0.4g, Yield 81%).
NMR: 1H-NMR(DMSO-d6) δ 7.99(1H, d), 7.78(1H, d), 7.46-7.25(5H, m), 6.07(2H, s), 4.30-4.25(2H, q), 3.99(2H, s), 2.63(3H, s), 1.27(3H, t)
Preparation 191: 2-[4-Amino-3-bromo-5-(5-chloro-pent-1-inyl)-phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000240
2-(4-Amino-3-bromo-5-iodo-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.5g, 1.07mmol) obtained in Preparation 171 and 5-chloro-1-pentine (0.16mL, 1.28mmol) were reacted according to the same procedure as Preparation 172 to give the title compound (0.44g, Yield 85%).
NMR: 1H-NMR((CDCl3) δ 8.03(1H, d), 7.80(1H, d), 4.95(2H, s), 4.36-4.31(2H, q), 3.73(2H, t), 2.79(3H, s), 2.74-2.70(2H, m), 2.13-2.04(2H, m), 1.38(3H, t)
Preparation 192: 2-(5-Bromo-2,3-dihydro-1H-pyrrolo[1,2a]indol-7-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000241
2-[4-Amino-3-bromo-5-(5-chloro-pent-1-inyl)-phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.38g, 0.86mmol) obtained in Preparation 191 was reacted according to the same procedure as Preparation 186 to give the title compound (0.097g, Yield 28%).
NMR: 1H-NMR((CDCl3) δ 8.04(1H, s), 7.88(1H, s), 6.24(1H, s), 4.52(2H, t), 4.36-4.32(2H, q), 2.98(2H, t), 2.61-2.57(2H, m), 1.38(3H, t)
Preparation 193: 4-Amino-3-bromo-5-(4-methyl-pent-1-inyl)-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000242
4-Amino-3-bromo-5-iodo-benzoic acid methyl ester (1.0g, 2.81mmol) obtained in Preparation 167 and 4-methyl-1-pentine (0.28g, 3.37mmol) were reacted according to the same procedure as Preparation 150 to give the title compound (0.66g, Yield 76%).
NMR: 1H-NMR(CDCl3) δ 8.04(1H, d), 7.90(1H, d), 5.04(2H, br s), 3.86(3H, s), 2.39(2H, d), 1.98-1.88(1H, m), 1.05(6H, d)
Preparation 194: 2-(7-Bromo-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000243
4-Amino-3-bromo-5-(4-methyl-pent-1-inyl)-benzoic acid methyl ester (0.66g, 2.13mmol) obtained in Preparation 193 was reacted according to the same procedures as Preparation 151, Preparation 152, Preparation 153, Preparation 154, Preparation 155 in the order to give the title compound (0.34g).
NMR: 1H-NMR(DMSO-d6) δ 11.42(1H, s), 8.08(1H, s), 7.81(1H, s), 6.37(1H, d), 4.27-4.23(2H, q), 2.64(3H, s), 2.60(2H, d), 2.01-1.95(1H, m), 1.27(3H, t), 0.89(6H, d)
Preparation 195: 2-(2-Amino-3-chloro-5-methoxycarbonyl-phenylethinyl)-pyrrolidine-1-carboxylic acid t-butyl ester
Figure PCTKR2010000893-appb-I000244
4-Amino-3-chloro-5-iodo-benzoic acid methyl ester (1.5g, 4.82mmol) obtained in Preparation 149 and 2-ethinyl-pyrrolidine-1-carboxylic acid t-butyl ester (1.13g, 5.78mmol) were reacted according to the same procedure as Preparation 150 to give the title compound (1.52g, Yield 83%).
NMR: 1H-NMR(CDCl3) δ 7.88(1H, s), 7.81(1H, s), 5.49(1H, br s), 5.30(1H, br s), 4.71-4.68(1H, m), 3.86(1H, s), 3.48(1H, br s), 3.38(1H, br s), 2.26-2.04(4H, m), 1.49(9H, s)
Preparation 196: 2-[2-(1-t-Butoxycarbonyl-pyrrolidin-2-yl)-7-chloro-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000245
2-(2-Amino-3-chloro-5-methoxycarbonyl-phenylethinyl)-pyrrolidine-1-carboxylic acid t-butyl ester (1.42g, 3.75mmol) obtained in Preparation 195 was reacted according to the same procedures as Preparation 151, Preparation 152, Preparation 153, Preparation 154, Preparation 155 in the order to give the title compound (1.52g, Yield 3%).
NMR: 1H-NMR(DMSO-d6) δ 11.70(1H, d), 8.11(1H, s), 7.74(1H, s), 6.37(1H, d), 5.03-4.96(1H, m), 4.33-4.27(2H, q), 3.57(1H, br s), 3.43-3.38(1H, m), 2.68(3H, s), 2.25-1.88(4H, m), 1.41(4H, s), 1.31(3H, t), 1.16(5H, s)
Preparation 197: 2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester hydrochloride
Figure PCTKR2010000893-appb-I000246
2-[2-(1-t-Butoxycarbonyl-pyrrolidin-2-yl)-7-chloro-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.38g, 0.78mmol) obtained in Preparation 196 was dissolved in 1,4-dioxane. 4-N-hydrochloride 1,4-dioxane solution (0.8mL, 3.10mmol) was added at room temperature, and the mixture was stirred for 20 h at the same temperature. The solvent was distilled off. The residue was solidified by ether, filtered and dried using nitrogen gas to give the title compound (0.3g).
NMR(DMSO-d6) δ 12.04(1H, s), 9.74(1H, br s), 9.12(1H, br s), 8.22(1H, s), 7.83(1H, s), 6.85(1H, s), 4.84-4.81(1H, m), 4.28-4.24(2H, q), 3.32(2H, m), 2.66(3H, s), 2.41-2.02(4H, m), 1.28(3H, t)
Preparation 198: 2-[7-Chloro-2-(1-isopropyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000247
2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester hydrochloride (0.05g, 0.13mmol) obtained in Preparation 197 was dissolved in 1,2-dichloroethane. Acetone (0.015g, 0.26mmol) and sodium triacetoxyborohydride (0.082g, 0.38mmol) were added at room temperature, and the mixture was stirred for 16 h. The solvent was distilled off, and 30mL of ethyl acetate was added to the residue. The mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.042g, Yield 75%).
NMR(CDCl3) δ 8.94(1H, br s), 8.02(1H, d), 7.81(1H, d), 6.38(1H, s), 4.36-4.32(2H, q), 4.00(1H, m), 3.15(1H, m), 2.83(1H, m), 2.77(3H, s), 2.61(1H, m), 2.19(1H, m), 1.87(3H, m), 1.38(3H, t), 1.05(3H, d), 0.99(3H, d)
Preparation 199: 2-[7-Chloro-2-(1-methanesulfonyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000248
2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester hydrochloride (0.05g, 0.13mmol) obtained in Preparation 197 was dissolved in dichloromethane. Triethylamine (0.02mL, 0.14mmol) and methanesulfonyl chloride (0.01mL, 0.14mmol) were added at room temperature, and the mixture was stirred for 1 h. The solvent was distilled off, and 30mL of ethyl acetate was added to the residue. The mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.055g, Yield 91%).
NMR(CDCl3) δ 9.39(1H, s), 8.06(1H, s), 7.85(1H, s), 6.45(1H, s), 5.05-5.02(1H, m), 4.38-4.33(2H, q), 3.59-3.45(2H, m), 2.89(3H, s), 2.78(3H, s), 2.38-2.10(4H, m), 1.39(3H, t)
Preparation 200: 4-Amino-3-chloro-5-(3-methoxy-prop-1-inyl)-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000249
4-Amino-3-chloro-5-iodo-benzoic acid methyl ester (1.0g, 3.21mmol) obtained in Preparation 149 and 3-methoxy-propine (0.33mL, 3.85mmol) were reacted according to the same procedure as Preparation 150 to give the title compound (0.75g, Yield 92%).
NMR: 1H-NMR(CDCl3) δ 7.92(2H, s), 5.03(2H, br s), 4.38(2H, s), 3.86(3H, s), 3.46(3H, s)
Preparation 201: 4-Amino-3-bromo-5-(3-methoxy-prop-1-inyl)-benzoic acid methyl ester
Figure PCTKR2010000893-appb-I000250
4-Amino-3-chloro-5-iodo-benzoic acid methyl ester (1.0g, 3.21mmol) obtained in Preparation 149 and 4-methyl-1-pentine (0.33mL, 3.85mmol) were reacted according to the same procedure as Preparation 150 to give the title compound (0.75g, Yield 92%).
NMR: 1H-NMR(CDCl3) δ 7.92(2H, s), 5.03(2H, br s), 4.38(2H, s), 3.86(3H, s), 3.46(3H, s)
Preparation 202: 7-Nitro-2-phenyl-1H-indole-5-carboxylic acid amide
Figure PCTKR2010000893-appb-I000251
7-Nitro-2-phenyl-1H-indole-5-carboxylic acid (1g, 3.54mmol) was dissolved in 50mL of dichloromethane. Thionyl chloride (1.26g, 10.63mmol) and 1mL of anhydrous N,N-dimethylformamide were added at room temperature, and the mixture was refluxed for 3 h. The solvent was distilled off, and the resulting solid compound was dissolved in 30mL of tetrahydrofuran without purification. This solution was slowly added to 15mL of the aqueous ammonia solution which was prepared in advance while maintaining the temperature at 0℃, and the mixture was stirred for 1 h. The resulting solid was filtered, washed with water and ether and dried under nitrogen gas to give the title compound (0.8g, Yield 80%).
NMR: 1H-NMR(DMSO-d6) δ 11.83(1H, br s), 8.65(1H, s), 8.61(1H, s), 8.27(1H, br s), 8.05(2H, d), 7.52-7.44(3H, m), 7.44(1H, br s)
Preparation 203: 7-Nitro-2-phenyl-1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000252
7-Nitro-2-phenyl-1H-indole-5-carboxylic acid amide (0.8g, 2.84mmol) obtained in Preparation 202 was reacted according to the same procedure as Preparation 154 to give the title compound (0.5g, Yield 59%).
NMR: 1H-NMR(DMSO-d6) δ 11.91(1H, s), 10.00(1H, br s), 9.76(1H, br s), 8.81(1H, d), 8.66(1H, d), 8.06(2H, s), 7.55-7.43(3H, m), 7.30(1H, s)
Preparation 204: 4-Methyl-2-(7-nitro-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000253
7-Nitro-2-phenyl-1H-indole-5-carbothioamide (0.2g, 0.67mmol) obtained in Preparation 203 was dissolved in 10mL of N,N-dimethylformamide and reacted according to the same procedure as Preparation 155 to give the title compound (0.19g, Yield 70%).
NMR: 1H-NMR(DMSO-d6) δ 8.67(1H, s), 8.64(1H, s), 8.04(2H, d), 7.56-7.45(3H, m), 7.28(1H, s), 4.36-4.31(2H, q), 2.74(3H, s), 1.35(3H, t)
Preparation 205: 4-Methyl-2-(7-amino-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000254
4-Methyl-2-(7-nitro-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.087g, 0.21mmol) obtained in Preparation 204 was dissolved in 3mL of tetrahydrofuran, 3mL of methanol and 3mL of water. Iron (0.12g, 2.1mmol) and ammonium chloride (0.14g, 2.1mmol) were added at room temperature, and the mixture was refluxed for 3 h. The reaction solution was filtered through celite using tetrahydrofuran. After filtration, the solvent was distilled off. 30mL of ethyl acetate was added to the residue. The mixture was washed with water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.04g, Yield 50%).
NMR: 1H-NMR(DMSO-d6) δ 11.25(1H, s), 7.85(1H, s), 7.83(1H, s), 7.52-7.35(4H, m), 7.05(1H, d), 6.92(1H, d), 5.50(2H, s), 4.32-4.26(2H, q), 2.67(3H, s), 1.31(3H, t)
Preparation 206: 4-Amino-3-(4-methyl-1-pentinyl)-5-nitro-benzoic acid ethyl ester
Figure PCTKR2010000893-appb-I000255
4-Amino-3-iodo-5-nitro-benzoic acid ethyl ester (3g, 8.93mmol) was reacted according to the same procedure as Preparation 150 to give the title compound (2g, Yield 77%).
Preparation 207: 2-Isobutyl-7-nitro-1H-indole-5-carbothioamide
Figure PCTKR2010000893-appb-I000256
4-Amino-3-(4-methyl-1-pentinyl)-5-nitro-benzoic acid ethyl ester (0.7g, 2.41mmol) obtained in Preparation 206 was reacted according to the same procedures as Preparation 151, Preparation 152, Preparation 153, Preparation 154 in the order to give the title compound (0.18g).
Preparation 208: 2-(2-Isobutyl-7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000257
2-Isobutyl-7-nitro-1H-indole-5-carbothioamide (0.18g, 0.65mmol) obtained in Preparation 207 and 2-chloro-3-oxo-propionic acid ethyl ester (0.2g, 1.3mmol) were reacted according to the same procedure as Preparation 155 to give the title compound (0.1g, Yield 41%).
NMR: 1H-NMR(CDCl3) δ 9.71(1H, br s), 8.69(1H, s), 8.46(1H, s), 8.42(1H, s), 6.47(1H, d), 4.41-4.37(2H, q), 2.72(2H, d), 2.09-2.06(1H, m), 1.41(3H, t), 1.03(6H, d)
Example 1: 2-(1-Isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000258
2-(1-Isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.33g, 0.10mmol) obtained in Preparation 5 was added to 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (0.23g, Yield 76%).
NMR: 1H-NMR(CD3OD) δ 8.22(1H, s), 7.76(1H, d), 7.61(1H, d), 7.45(1H, d), 6.60(1H, d), 4.02(2H, d), 2.66(3H, s), 2.14(1H, m), 0.86(6H, d)
Mass(EI): 315 (M++1)
Example 2: 2-(3-Chloro-1-isobutyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000259
2-(3-Chloro-1-isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (180mg, 0.48mmol) obtained in Preparation 6 was added to 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (130mg, Yield 78%).
NMR: 1H-NMR(CD3OD) δ 8.12(1H, s), 7.84(1H, d), 7.73(1H, s), 7.71(1H, d), 4.05(2H, d), 2.69(3H, s), 2.16(1H, m), 0.87(6H, d)
Mass(EI): 349 (M++1)
Example 3: 2-(3-Chloro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000260
2-(3-Chloro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (75mg, 0.2mmol) obtained in Preparation 12 was reacted according to the same procedure as Example 1 to give the title compound (66mg, Yield 95%).
NMR: 1H-NMR(DMSO-d6) δ 8.11(1H, s), 7.86(1H, s), 7.84(1H, d), 7.75(1H, d), 4.88-4.81(1H, m), 2.69(3H, s), 1.48(6H, d)
Mass(EI): 335(M++1)
Example 4: 2-(3-Chloro-1-cyclohexyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000261
2-(3-Chloro-1-cyclohexyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (30mg, 0.074mmol) obtained in Preparation 13 was reacted according to the same procedure as Example 1 to give the title compound (27mg, Yield 98%).
NMR: 1H-NMR(DMSO-d6) δ 8.10(1H, s), 7.84(1H, d), 7.82(1H, s), 7.75(1H, d), 5.01-4.95(1H, m), 2.69(3H, s), 2.24-2.11(4H, m), 1.90-1.80(4H, m), 1.77-1.67(2H, m)
Mass(EI): 375(M++1)
Example 5: 2-{3-Chloro-1-[2-(diethylamino)-2-oxoethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000262
2-{3-Chloro-1-[2-(diethylamino)-2-oxoethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (80mg, 0.18mmol) obtained in Preparation 14 was reacted according to the same procedure as Example 1 to give the title compound (71mg, Yield 95%).
NMR: 1H-NMR(DMSO-d6) δ 8.12(1H, s), 7.84(1H, d), 7.62(1H, s), 7.55(1H, d), 5.23(2H, s), 3.50(2H, q), 3.32(2H, q), 2.71(3H, s), 1.28(3H, t), 1.07(3H, t)
Mass(EI): 406(M++1)
Example 6: 2-[3-Chloro-1-(3-methoxybenzyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000263
2-[3-Chloro-1-(3-methoxybenzyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (80mg, 0.18mmol) obtained in Preparation 15 was reacted according to the same procedure as Example 1 to give the title compound (72mg, Yield 96%).
NMR: 1H-NMR(DMSO-d6) δ 8.14(1H, s), 7.88(1H, s), 7.84(1H, d), 7.73(1H, d), 7.25(1H, t), 6.89-6.85(2H, m), 6.81(1H, d), 5.44(2H, s), 3.73(3H, s), 2.70(3H, s)
Mass(EI): 413(M++1)
Example 7: 2-(3-Chloro-1-cyclopentyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000264
2-(3-Chloro-1-cyclopentyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (76mg, 0.195mmol) obtained in Preparation 16 was reacted according to the same procedure as Example 1 to give the title compound (67mg, Yield 95%).
NMR: 1H-NMR(DMSO-d6) δ 8.09(1H, s), 7.83(1H, d), 7.81(1H, s), 7.74(1H, d), 4.99-4.93(1H, m), 2.68(3H, s), 2.22-2.12(2H, m), 1.89-1.81(4H, m), 1.77-1.67(2H, m)
Mass(EI): 361(M++1)
Example 8: 2-[3-Chloro-1-(tetrahydrofuran-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000265
2-[3-Chloro-1-(tetrahydrofuran-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (85mg, 0.22mmol) obtained in Preparation 17 was reacted according to the same procedure as Example 1 to give the title compound (73mg, Yield 92%).
NMR: 1H-NMR(DMSO-d6) δ 8.14(1H, s), 7.86(1H, d), 7.81(1H, d), 7.74(1H, s), 5.35(1H, m), 4.15-4.10(1H, m), 4.15-3.83(m, 4H), 2.71(3H, s), 2.16(2H, m)
Mass(EI): 363(M++1)
Example 9: 2-(3-Chloro-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000266
2-(3-Chloro-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (120mg, 0.3mmol) obtained in Preparation 11 was reacted according to the same procedure as Example 1 to give the title compound (20mg, Yield 18%).
NMR: 1H-NMR(CD3OD) δ 8.09(1H, s), 7.79(1H, d), 7.51(1H, d), 4.03(2H, d), 2.75(3H, s), 2.47(3H, s), 2.20(1H, m), 0.96(6H, d)
Mass(EI): 363 (M++1)
Example 10: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000267
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.16mmol) obtained in Preparation 21 was added to 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (40 mg, Yield 53%).
NMR: 1H-NMR(CD3OD) δ 8.29(1H, s), 8.25(1H, s), 7.96(1H, d), 7.77(1H, d), 4.94(1H, m), 2.76(3H, s), 1.60(6H, d)
Mass(EI): 326 (M++1)
Example 11: 2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000268
2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (110mg, 0.28mmol) obtained in Preparation 24 was added to 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (60mg, Yield 63%).
NMR: 1H-NMR(CD3OD) δ 8.27(1H, s), 8.17(1H, s), 7.92(1H, d), 7.73(1H, d), 4.15(2H, d), 2.72(3H, s), 1.34(1H, m), 0.64(2H, m), 0.46(2H, m)
Mass(EI): 338 (M++1)
Example 12: 2-[3-Cyano-1-(2-morpholin-4-ylethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000269
2-[3-Cyano-1-(2-morpholin-4-ylethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (12mg, 0.03mmol) obtained in Preparation 25 was reacted according to the same procedure as Example 1 to give the title compound (10mg, Yield 89%).
NMR: 1H-NMR(CD3OD) δ 8.21(1H, s), 8.13(1H, s), 7.91(1H, d), 7.71(1H, d), 4.42(2H, t), 3.66(4H, t), 2.81(2H, t), 2.75(3H, s), 2.51(4H, t)
Mass(EI): 397 (M++1)
Example 13: 2-[3-Cyano-1-(2,2-dimethylpropyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000270
2-[3-Cyano-1-(2,2-dimethylpropyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (7mg, 0.02mmol) obtained in Preparation 26 was reacted according to the same procedure as Example 1 to give the title compound (2mg, Yield 31%).
NMR: 1H-NMR(CD3OD) δ 8.25(1H, s), 8.06(1H, s), 7.91(1H, d), 7.73(1H, d), 4.13(2H, s), 2.76(3H, s), 1.05(9H, s)
Mass(EI): 354 (M++1)
Example 14: 2-{3-Cyano-1-[2-(methylsulfonyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000271
2-{3-Cyano-1-[2-(methylsulfonyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (46mg, 0.11mmol) obtained in Preparation 27 was reacted according to the same procedure as Example 1 to give the title compound (40mg, Yield 97%).
NMR: 1H-NMR(CD3OD) δ 8.27(1H, s), 8.16(1H, s), 7.98(1H, d), 7.79(1H, d), 4.82(2H, t), 3.77(2H, t), 2.91(3H, s), 2.75(3H, s)
Mass(EI): 390 (M++1)
Example 15: 2-[3-Cyano-1-(tetrahydrofuran-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000272
2-[3-Cyano-1-(tetrahydrofuran-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.15mmol) obtained in Preparation 28 was reacted according to the same procedure as Example 1 to give the title compound (30mg, Yield 53%).
NMR: 1H-NMR(CD3OD) δ 8.29(1H, s), 8.11(1H, s), 7.94(1H, d), 7.78(1H, d), 4.46(2H, d), 4.29(1H, m), 3.88-3.72(2H, m), 2.76(3H, s), 2.10(1H, m), 1.92-1.80(2H, m), 1.67(1H, m)
Mass(EI): 368 (M++1)
Example 16: 2-[3-Cyano-1-(3-methylbutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000273
2-[3-Cyano-1-(3-methylbutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.05mmol) obtained in Preparation 29 was reacted according to the same procedure as Example 1 to give the title compound (60mg, Yield 72%).
NMR: 1H-NMR(CD3OD) δ 8.24(1H, s), 8.09(1H, s), 7.92(1H, d), 7.67(1H, d), 4.30(2H, t), 2.72(3H, s), 1.77(2H, m), 1.60(1H, m), 0.98(6H, d)
Mass(EI): 354 (M++1)
Example 17: 2-{3-Cyano-1-[(3,5-dimethylisoxazol-4-yl)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000274
2-{3-Cyano-1-[(3,5-dimethylisoxazol-4-yl)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (89mg, 0.21mmol) obtained in Preparation 30 was reacted according to the same procedure as Example 1 to give the title compound (80mg, Yield 96%).
NMR: 1H-NMR(CD3OD) δ 8.33(1H, s), 8.07(1H, s), 7.99(1H, d), 7.71(1H, d), 5.36(2H, s), 2.76(3H, s), 2.42(3H, s), 2.06(3H, s)
Mass(EI): 393 (M++1)
Example 18: 2-(3-Cyano-1-{2-[(methylsulfonyl)amino]ethyl}-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000275
2-(3-Cyano-1-{2-[(methylsulfonyl)amino]ethyl}-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (83mg, 0.19mmol) obtained in Preparation 31 was reacted according to the same procedure as Example 1 to give the title compound (52mg, Yield 67%).
NMR: 1H-NMR(CD3OD) δ 8.32(1H, s), 8.13(1H, s), 7.98(1H, d), 7.80(1H, d), 4.47(2H, t), 3.53(2H, t), 2.86(3H, s), 2.77(3H, s)
Mass(EI): 405 (M++1)
Example 19: 2-[3-Cyano-1-(cyclopentylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000276
2-[3-Cyano-1-(cyclopentylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (96mg, 0.24mmol) obtained in Preparation 32 was reacted according to the same procedure as Example 1 to give the title compound (70mg, Yield 79%).
NMR: 1H-NMR(CD3OD) δ 8.29(1H, s), 8.13(1H, s), 7.95(1H, d), 7.74(1H, d), 4.25(2H, d), 2.76(3H, s), 2.51(1H, m), 1.74(4H, m), 1.62(2H, m), 1.35(2H, m)
Mass(EI): 366 (M++1)
Example 20: 2-[3-Cyano-1-(isobutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000277
2-[3-Cyano-1-(isobutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (70mg, 0.19mmol) obtained in Preparation 33 was reacted according to the same procedure as Example 1 to give the title compound (63mg, Yield 97%).
NMR: 1H-NMR(DMSO-d6) δ 8.43(1H, s), 8.25(1H, s), 7.95(1H, d), 7.88(1H, d), 4.14(2H, d), 2.70(3H, s), 2.19-2.15(1H, m), 0.88(d, 6H)
Mass(EI): 340(M++1)
Example 21: 2-[3-Cyano-1-(cyclopentyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000278
2-[3-Cyano-1-(cyclopentyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (41mg, 0.108mmol) obtained in Preparation 34 was reacted according to the same procedure as Example 1 to give the title compound (37mg, Yield 98%).
NMR: 1H-NMR(DMSO-d6) δ 8.56(1H, s), 8.25(1H, s), 7.96(1H, d), 7.90(1H, d), 5.06-5.03(1H, m), 2.71(3H, s), 2.12-2.22(2H, m), 1.89-1.81(4H, m), 1.77-1.67(2H, m)
Mass(EI): 352(M++1)
Example 22: 2-{3-Cyano-1-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000279
2-{3-Cyano-1-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (20mg, 0.048mmol) obtained in Preparation 35 was reacted according to the same procedure as Example 1 to give the title compound (18.5mg, Yield 98%).
NMR: 1H-NMR(DMSO-d6) δ 8.36(1H, s), 8.22(1H, s), 7.94(1H, d), 7.79(1H, d), 7.62(1H, s), 4.55(2H, t), 2.98(2H, t), 2.70(3H, s), 2.36(3H, s)
Mass(EI): 393(M++1)
Example 23: 2-[3-Cyano-1-(1,3-thiazol-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000280
2-[3-Cyano-1-(1,3-thiazol-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (22mg, 0.054mmol) obtained in Preparation 36 was reacted according to the same procedure as Example 1 to give the title compound (20mg, Yield 98%).
NMR: 1H-NMR(DMSO-d6) δ 9.07(1H, s), 8.53(1H, s), 8.23(1H, s), 7.94-7.86(2H, m), 7.76(1H, s), 5.70(2H, s), 2.69(3H, s)
Mass(EI): 381(M++1)
Example 24: 2-[3-Cyano-1-(2-methoxyethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000281
2-[3-Cyano-1-(2-methoxyethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (73mg, 0.198mmol) obtained in Preparation 37 was reacted according to the same procedure as Example 1 to give the title compound (65mg, Yield 97%).
NMR: 1H-NMR(DMSO-d6) δ 8.39(1H, s), 8.24(1H, s), 7.95(1H, d), 7.87(1H, d), 4.49(2H, t), 3.71(2H, t), 3.23(3H, s), 2.71(3H, s)
Mass(EI): 342(M++1)
Example 25: 2-{1-[2-(Acetylamino)ethyl]-3-cyano-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000282
2-{1-[2-(Acetylamino)ethyl]-3-cyano-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (25mg, 0.063mmol) obtained in Preparation 38 was reacted according to the same procedure as Example 1 to give the title compound (20mg, Yield 86%).
NMR: 1H-NMR(DMSO-d6) δ 8.38(1H, s), 8.25(1H, s), 7.96(1H, d), 7.81(d, 1H), 4.36(2H, t), 3.45(2H, t), 2.71(3H, s), 1.73(3H, s)
Mass(EI): 369(M++1)
Example 26: 2-[3-Cyano-1-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000283
2-(3-Cyano-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester obtained in Preparation 39 was reacted according to the same procedure as Example 1 to give the title compound (88mg, Yield 92%).
NMR: 1H-NMR(DMSO-d6) δ 8.37(1H, s), 8.24(1H, s), 7.96(1H, d), 7.78(1H, d), 3.89(1H, s), 2.69(3H, s)
Mass(EI): 298 (M+1)
Example 27: 2-[3-Cyano-1-propyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000284
2-(3-Cyano-1-propyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.28mmol) obtained in Preparation 40 was reacted according to the same procedure as Example 1 to give the title compound (72mg, Yield 87%).
NMR: 1H-NMR(DMSO-d6) δ 8.44(1H, s), 8.24(1H, s), 7.93(1H, d), 7.85(1H, d), 4.27(2H, t), 2.69(3H, s), 1.87-1.78(2H, m), 0.85(3H, t)
Mass(EI): 326 (M++1)
Example 28: 2-[3-Cyano-1-cyclopropyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000285
2-(3-Cyano-1-cyclopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (130mg, 0.37mmol) obtained in Preparation 41 was reacted according to the same procedure as Example 1 to give the title compound (80mg, Yield 67%).
NMR: 1H-NMR(DMSO-d6) δ 8.41(1H, s), 8.22(1H, s), 7.97(1H, dd), 7.84(1H, d), 3.68-3.64(1H, m), 2.69(3H, s), 1.15-1.11(2H, m), 1.10-1.08(2H, m)
Mass(EI): 324 (M++1)
Example 29: 2-[3-Cyano-1-(oxazol-4-ylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000286
2-[3-Cyano-1-(oxazol-4-ylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (20mg, 0.05mmol) obtained in Preparation 43 was reacted according to the same procedure as Example 1 to give the title compound (3mg, Yield 16%).
NMR: 1H-NMR(CD3OD) δ 8.27(1H, s), 8.16(1H, s), 8.06(1H, s), 7.91(1H, d), 7.79(d, 1H), 7.63(1H, d), 5.46(2H, s), 2.74(3H, s)
Mass(EI): 365(M++1)
Example 30: 2-[3-Cyano-1-(3,3,3-trifluoropropyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000287
2-[3-Cyano-1-(3,3,3-trifluoropropyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (8mg, 0.02mmol) obtained in Preparation 44 was reacted according to the same procedure as Example 1 to give the title compound (4mg, Yield 54%).
NMR: 1H-NMR(CD3OD) δ 8.31(1H, s), 8.16(1H, s), 8.01(1H, d), 7.76(1H, d), 4.65(2H, t), 2.91(2H, m), 2.78(3H, s)
Mass(EI): 378(M++1)
Example 31: 2-(3-Cyano-1-sec-butyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000288
2-(3-Cyano-1-sec-butyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (110mg, 0.3mmol) obtained in Preparation 45 was reacted according to the same procedure as Example 1 to give the title compound (56mg, Yield 56%).
NMR: 1H-NMR(CD3OD) δ 8.32(1H, s), 8.25(1H, s), 7.97(1H, d), 7.79(1H, d), 4.68(1H, m), 2.77(3H, s), 2.00(2H, m), 1.60(3H, d), 0.86(3H, t),
Mass(EI): 340(M++1)
Example 32: 2-[3-Cyano-1-[(2,4-difluorophenyl)methyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000289
2-[3-Cyano-1-[(2,4-difluorophenyl)methyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (124mg, 0.28mmol) obtained in Preparation 46 was reacted according to the same procedure as Example 1 to give the title compound (84mg, Yield 72%).
NMR: 1H-NMR(CD3OD) δ 8.32(1H, s), 8.19(1H, s), 7.94(1H, d), 7.72(1H, d), 7.34(1H, m), 7.08(1H, m), 7.03(1H, m), 5.57(2H, s), 2.76(3H, s)
Mass(EI): 410(M++1)
Example 33: 2-(1-Allyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000290
2-(1-Allyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (102mg, 0.29mmol) obtained in Preparation 47 was reacted according to the same procedure as Example 1 to give the title compound (75mg, Yield 73%).
NMR: 1H-NMR(CD3OD) δ 8.32(1H, s), 8.10(1H, s), 7.97(1H, d), 7.69(1H, d), 6.08(1H, m), 5.29(2H, d), 4.97(2H, d), 2.77(3H, s)
Mass(EI): 324(M++1)
Example 34: 2-(3-Cyano-1-prop-2-inyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000291
2-(3-Cyano-1-prop-2-inyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.29mmol) obtained in Preparation 48 was reacted according to the same procedure as Example 1 to give the title compound (68mg, Yield 68%).
NMR: 1H-NMR(CD3OD) δ 8.30(1H, s), 8.18(1H, s), 7.99(1H, d), 7.94(1H, d), 7.56(1H, t), 5.83(2H, d),(2H, d), 2.77(3H, s)
Mass(EI): 322(M++1)
Example 35: 2-[3-Cyano-1-(2-pyridylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000292
2-[3-Cyano-1-(2-pyridylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (113mg, 0.28mmol) obtained in Preparation 49 was reacted according to the same procedure as Example 1 to give the title compound (92mg, Yield 87%).
NMR: 1H-NMR(CD3OD) δ 8.56(1H, d), 8.30(1H, s), 8.24(1H, s), 7.90(1H, d), 7.81(1H, t), 7.62(1H, d), 7.36(1H, m), 7.26(1H, m), 5.64(2H, s), 2.74(3H, s)
Mass(EI): 375(M++1)
Example 36: 2-[3-Cyano-1-(2-methoxy-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000293
2-[3-Cyano-1-(2-methoxy-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (93mg, 0.24mmol) obtained in Preparation 50 was reacted according to the same procedure as Example 1 to give the title compound (20mg, Yield 23%).
NMR: 1H-NMR(CD3OD) δ 8.29(1H, s), 8.24(1H, s), 7.94(1H, d),7.77(1H, d), 4.95(1H, m), 3.75 (2H, m), 3.33(3H, s), 2.76(3H, s), 1.61(3H, d)
Mass(EI): 356(M++1)
Example 37: 2-[3-Cyano-1-[2-(2-methoxyethoxy)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000294
2-[3-Cyano-1-[2-(2-methoxyethoxy)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (94mg, 0.22mmol) obtained in Preparation 51 was reacted according to the same procedure as Example 1 to give the title compound (68mg, Yield 78%).
NMR: 1H-NMR(CD3OD) δ 8.29(1H, s), 8.14(1H, s), 7.96(1H, d), 7.77(1H, d), 4.49(2H, t), 3.87 (2H, m), 3.58(2H, t), 3.47(2H, t), 3.29(3H, s), 2.77(3H, s)
Mass(EI): 386(M++1)
Example 38: 2-(1-Benzyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000295
2-(1-Benzyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.25g, 0.62mmol) obtained in Preparation 42 was reacted according to the same procedure as Example 1 to give 54mg (0.14mmol, Yield 23%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.59(1H, s), 8.25(1H, d), 7.89(1H, dd), 7.79(1H, d), 7.32(5H, m), 5.57(2H, s), 2.68(3H, s)
Mass(EI): 374 (M++1)
Example 39: 2-(3-Cyano-1-cyclobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000296
2-(3-Cyano-1-cyclobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (28mg, 0.077mmol) obtained in Preparation 54 was reacted according to the same procedure as Example 1 to give 16mg (0.047mmol, Yield 61%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.50(1H, s), 8.24(1H, s), 7.90(2H, m), 4.17(1H, d), 2.69(3H, s), 2.47(2H, m), 1,31(2H, m), 0.56(1H, m), 0.44(1H, m)
Mass(EI): 338 (M++1)
Example 40: 2-[3-Cyano-1-[2-(2-oxopyrrolidin-1-yl)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000297
2-[3-Cyano-1-[2-(2-oxopyrrolidin-1-yl)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (67.3mg, 0.16mmol) obtained in Preparation 52 was added to 10mL of tetrahydrofuran, 20mL of methanol and 5mL of 6N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, the organic solvent was removed under reduced pressure. The remaining aqueous layer was washed with ethyl acetate. The aqueous solution was acidfied to pH=1 using 6N hydrochloric acid, and the precipitated solid compound was filtered, washed with distilled water and dried to give 24.5mg (0.06mmol, Yield 39%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.41(1H, s), 8.24(1H, d, J= 1.6Hz), 7.97(1H, d, J= 1.8Hz), 7.85(1H, d, J= 8.8Hz), 4.47(2H, t), 3.61(2H, t), 3.22(2H, t), 2.71(3H, s), 2.07(2H, t)
Mass(EI): 395(M++1)
Example 41: 2-(3-Cyano-1-ethyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000298
2-(3-Cyano-1-ethyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (43.1mg, 0.127mmol) obtained in Preparation 53, 10mL of tetrahydrofuran, 20mL of methanol and 5mL of 6N sodium hydroxide solution were reacted according to the same procedure as Example 1 to give 21.2mg (0.068mmol, Yield 54%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.85(1H, s), 8.48(1H, s), 7.96(1H, d), 7.86(1H, d), 4.36(2H, q), 2.71(3H, s), 1.44(3H, t)
Mass(EI): 312(M++1)
Example 42: 2-[3-Cyano-1-(2-methoxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
(1) 2-[3-Cyano-1-(2-methoxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester
Figure PCTKR2010000893-appb-I000299
2-[3-Cyano-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (79.8mg, 0.21mmol) obtained in Preparation 55, sodium hydride (55%, 13.6mg, 0.52mmol) and iodomethane (0.04mL, 0.50mmol) were reacted according to the same procedure as Preparation 5 to give the title compound (72mg, Yield 86%).
Mass(EI): 398(M++1)
(2) 2-[3-Cyano-1-(2-methoxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000300
2-[3-Cyano-1-(2-methoxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester obtained in Step (1) was added to 2mL of tetrahydrofuran, 2mL of methanol and 1mL of 6N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, the organic solvent was removed under reduced pressure. The remaining aqueous layer was washed with ethyl acetate and acidified to pH=1 using 6N hydrochloric acid. The precipitated solid was filtered and purified by column chromatography to give 25.1mg (0.068mmol, Yield 33%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.23(2H, s), 7.91(2H, s), 4.33(2H, s), 3.16(3H, s), 3.25(3H, s), 1.10(6H, s)
Mass(EI): 370(M++1)
Example 43: 2-[3-Cyano-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000301
To sodium hydride (56mg, 1.26mmol) was added 10mL of anhydrous tetrahydrofuran. 2-(3-Cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.2g, 0.64mmol) obtained in Preparation 18 was added, and stirred for 30 min at room temperature. Anhydrous lithium perchlorate (0.34g, 3.21mmol) and 2,2-dimethyloxirane (51mg, 0.71mmol) were added, and the mixture was stirred under reflux for 15 h. The reaction solution was cooled to room temperature, and ethyl acetate was added thereto. The organic layer was washed with 1N hydrochloric acid solution. The organic solvent was distilled off under reduced pressure, and the remaining compound was washed with methanol and dried to give 134mg (0.38mmol, Yield 59%) of the title compound.
NMR 1H-NMR(DMSO-d6) δ 8.23(1H, s), 8.11(1H, s), 7.84(1H, d), 7.82(1H, d), 4.82(1H, s), 4.20(2H, s), 2.65(3H, s), 1.10(6H, s)
Mass(EI): 356(M++1)
Example 44: 2-[3-Cyano-1-(2-fluoroethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000302
2-[3-Cyano-1-(2-fluoroethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (85mg, 0.24mmol) obtained in Preparation 56 was reacted according to the same procedure as Example 1 to give the title compound (65mg, Yield 83%).
NMR: 1H-NMR(DMSO-d6) δ 8.45(1H, s), 8.27(1H, s), 7.98(1H, d), 7.88(1H, d), 4.87(1H, t), 4.76-4.71(2H, m), 4.66(1H, t), 2.71(3H. s)
Mass(EI): 330(M++1)
Example 45: 2-(1-Butyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000303
2-(1-Butyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.25mmol) obtained in Preparation 57 was reacted according to the same procedure as Example 1 to give the title compound (70mg, Yield 85%).
NMR: 1H-NMR(DMSO-d6) δ 8.45(1H, s), 8.24(1H, s), 7.93(1H, d), 7.85(1H, d), 4.31(2H, t), 2.70(3H, s), 1.82-1.75(2H, m), 1.29-1.21(2H, m), 0.89(3H, t)
Mass(EI): 340(M++1)
Example 46: 2-{3-Cyano-1-[(4-fluorophenyl)-methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000304
2-{3-Cyano-1-[(4-fluorophenyl)methyl]indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (78mg, 0.19mmol) obtained in Preparation 58 was reacted according to the same procedure as Example 1 to give the title compound (64mg, Yield 89%).
NMR: 1H-NMR(DMSO-d6) δ 8.60(1H, s), 8.27(1H, s), 7.92(1H, d), 7.82(1H, d), 7.42-7.36(2H, m), 7.23-7.17(2H, m), 5.58(2H, s), 2.70(3H, s)
Mass(EI): 392(M++1)
Example 47: 2-[3-Cyano-1-(2-ethoxyethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000305
2-[3-Cyano-1-(2-ethoxyethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (82mg, 0.21mmol) obtained in Preparation 59 was reacted according to the same procedure as Example 1 to give the title compound (68mg, Yield 90%).
NMR: 1H-NMR(DMSO-d6) δ 8.40(1H, s), 8.25(1H, s), 7.95(1H, d), 7.87(1H, d), 4.49(2H, t), 3.75(2H, t), 3.42(2H, q), 2.71(3H, s), 1.03(3H, t)
Mass(EI): 356(M++1)
Example 48: 2-[3-Cyano-1-(2-hydroxy-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000306
2-{3-Cyano-1-[1-methyl-2-(methyl-acryloyloxy)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (90mg, 0.20mmol) obtained in Preparation 60 was reacted according to the same procedure as Example 1 to give the title compound (62mg, Yield 88%).
NMR: 1H-NMR(DMSO-d6) δ 8.34(1H, s), 8.23(1H, s), 7.92(1H, d), 7.85(1H, d), 5.10-4.95(1H, m), 4.32(1H, dd), 4.16-4.11(1H, m), 4.05-3.92(1H, m), 2.70(3H, s), 1.12(3H, d)
Mass(EI): 342(M++1)
Example 49: 2-[3-Cyano-1-(2-fluoro-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
(1) 2-[3-Cyano-1-(2-hydroxy-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
Figure PCTKR2010000893-appb-I000307
2-[3-Cyano-1-(2-hydroxy-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid (200mg, 0.59mmol) obtained in Example 48 was reacted according to the same procedure as Step (1) of Preparation 64 to give the title compound (187mg, Yield 83%).
Mass(EI): 382(M++1)
(2) 2-[3-Cyano-1-(2-fluoro-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester
Figure PCTKR2010000893-appb-I000308
2-[3-Cyano-1-(2-hydroxy-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (187mg, 0.49mmol) obtained in Step (1) was dissolved in 5mL of dichloromethane, diethylaminosulfur trifluoride (95mg, 0.59mmol) was added at 0℃, and the mixture was stirred for 10 min and stirred for 1 h at room temperature. After completion of the reaction, the solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and purified by column chromatography to give the title compound (128mg, Yield 68%).
Mass(EI): 384(M++1)
(3) 2-[3-Cyano-1-(2-fluoro-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000309
2-[3-Cyano-1-(2-fluoro-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (128mg, 0.33mmol) obtained in Step (2) was dissolved in 5mL of ethanol. 12mg of palladium/carbon and ammonium formate (42mg, 0.66mmol) were added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solid was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the title compound (90mg, Yield 80%).
NMR: 1H-NMR(DMSO-d6) δ 8.40(1H, s), 8.25(1H, s), 7.94(1H, d), 7.89(1H, d), 5.18-4.95(1H, m), 4.72-4.42(2H, m), 2.70(3H, s), 1.47-1.27(3H, m)
Mass(EI): 344(M++1)
Example 50: 2-[1-(2-Benzyloxyethyl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000310
2-[1-(2-Benzyloxyethyl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (80mg, 0.18mmol) obtained in Preparation 61 was reacted according to the same procedure as Example 1 to give the title compound (62mg, Yield 82%).
NMR: 1H-NMR(DMSO-d6) δ 8.40(1H, s), 8.24(1H, s), 7.91(1H, d), 7.85(1H, d), 7.28-7.21(3H, m), 7.14(2H, d), 4.53(2H, t), 4.46(2H, s), 3.80(2H, t), 2.70(3H, s)
Mass(EI): 418(M++1)
Example 51: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000311
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid ethyl ester (85mg, 0.20mmol) obtained in Preparation 63 was reacted according to the same procedure as Example 1 to give the title compound (66mg, Yield 83%).
NMR: 1H-NMR(DMSO-d6) δ 8.63(1H, s), 8.29(1H, s), 7.98(1H, d), 7.93(1H, d), 4.96-4.91(1H, m), 1.51(6H, d)
Mass(EI): 380(M++1)
Example 52: 2-{3-Cyano-1-[2-fluoro-1-(fluoromethyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000312
2-{3-Cyano-1-[2-fluoro-1-(fluoromethyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (91mg, 0.23mmol) obtained in Preparation 64 was reacted according to the same procedure as Step (3) of Example 49 to give the title compound (70mg, Yield 85%).
NMR: 1H-NMR(DMSO-d6) δ 8.60(1H, s), 8.21(1H, s), 7.93(2H, s), 5.58-5.38(1H, m), 5.12-4.82(4H, m), 2.66(3H, s)
Mass(EI): 362(M++1)
Example 53: 2-(3-Cyano-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000313
2-(3-Cyano-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (85mg, 0.22mmol) obtained in Preparation 65 was reacted according to the same procedure as Example 1 to give the title compound (73mg, Yield 92%).
NMR: 1H-NMR(DMSO-d6) δ 8.64(1H, s), 8.26(1H, s), 8.00-7.95(2H, m), 4.92-4.80(1H, m), 4.10-4.00(2H, m), 3.65-3.52(2H, m), 2.71(3H, s), 2.13-1.95(4H, m)
Mass(EI): 368(M++1)
Example 54: 2-[1-(1-Acetylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000314
2-[1-(1-Acetylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (87mg, 0.20mmol) obtained in Preparation 66 was reacted according to the same procedure as Example 1 to give the title compound (71.5mg, Yield 88%).
NMR: 1H-NMR(DMSO-d6) δ 8.57(0.47H, s), 8.49(0.53H, s), 8.27(1H, s), 7.98-7.91(2H, m), 5.48-5.40(0.47H, m), 5.40-5.32(0.53H, m), 4.13-4.05(1H, m), 3.94-3.84(1H, m), 3.80-3.43(4H, m), 2.71(3H, s), 2.03(1.59H, s), 2.00(1.41H,s)
Mass(EI): 395(M++1)
Example 55: 2-[3-Cyano-1-(1-methoxycarbonylpyrrolidin-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000315
2-[3-Cyano-1-(1-methoxycarbonylpyrrolidin-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (86mg, 0.20mmol) obtained in Preparation 67 was reacted according to the same procedure as Example 1 to give the title compound (70mg, Yield 87%).
Mass(EI): 411(M++1)
Example 56: 2-[3-Cyano-1-(1-cyano-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000316
2-[3-Cyano-1-(1-cyano-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid allyl ester (78mg, 0.20mmol) obtained in Preparation 68 was reacted according to the same procedure as Step (3) of Example 49 to give the title compound (57mg, Yield 82%).
NMR: 1H-NMR(DMSO-d6) δ 8.57(1H, s), 8.25(1H, s), 8.06-7.96(2H, m), 2.67(3H, s), 2.14(6H, s)
Mass(EI): 351(M++1)
Example 57: 2-(3-Cyano-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000317
2-(3-Cyano-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (77mg, 0.20mmol) obtained in Preparation 80 was reacted according to the same procedure as Example 1 to give the title compound (61mg, Yield 86%).
Mass(EI): 354(M++1)
Example 58: 2-(1-sec-Butyl-3-cyano-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000318
2-(1-sec-Butyl-3-cyano-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (24mg, 0.06mmol) obtained in Preparation 78 was reacted according to the same procedure as Example 1 to give 18mg (0.05mmol, Yield 83%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.14(1H, d), 7.88(1H, d), 7.81(1H, dd), 4.57(1H, m), 2.69(3H, s), 2.62(3H, s), 2.09(1H, m), 1.96(1H, m), 1.59(3H, d), 0.70(3H, t)
Mass(EI): 354 (M++1)
Example 59: 2-(3-Cyano-1-ethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000319
2-(3-Cyano-1-ethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (110mg, 0.31mmol) obtained in Preparation 79 was reacted according to the same procedure as Example 1 to give the title compound (70mg, Yield 69%).
NMR: 1H-NMR(DMSO-d6) δ 8.15(1H, d), 7.88(1H, dd), 7.77(1H, d), 4.31(2H, q), 2.69(3H, s), 2.62(3H, s), 1.30(3H, t)
Mass(EI): 326 (M++1)
Example 60: 2-(3-Cyano-1-isopropyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000320
2-(3-Cyano-1-isopropyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (92mg, 0.25mmol) obtained in Preparation 77 was reacted according to the same procedure as Example 1 to give the title compound (56mg, Yield 66%).
NMR: 1H-NMR(CD3OD) δ 8.17(1H, s), 7.86(1H, d), 7.82(1H, d), 4.93(1H, m), 2.73 (3H, s), 2.67(3H, s), 1.68(6H, d)
Mass(EI): 340(M++1)
Example 61: 2-(3-Cyano-1-cyclopropylmethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000321
2-(3-Cyano-2-methyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (95.5mg, 0.29mmol) obtained in Preparation 76 was dissolved in 3.0mL of N,N-dimethylformamide. Sodium hydride (55%, 19.2mg, 0.44mmol) was added at 0℃, and the mixture was stirred for 10 min at room temperature. Bromomethylcyclopropane (0.04mL, 0.41mmol) was added, and the mixture was stirred for 15 h at room temperature. 2mL of 6N sodium hydroxide solution was added to the reaction solution, and the mixture was reacted for 1 h at room temperature. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give 25.1mg (0.071mmol, Yield 28%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.15(1H, s), 7.88(1H, d), 7.82(1H, d), 4.22(2H, d), 2.71(3H, s), 2.67(3H, s), 1.29-1.22(1H, m), 0.52(2H, m), 0.46(2H, m)
Mass(EI): 352(M++1)
Example 62: 2-(3-Cyano-1-cyclopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000322
2-(3-Cyano-1-cyclopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (70mg, 0.21mmol) obtained in Preparation 84 was reacted according to the same procedure as Example 1 to give the title compound (43mg, Yield 66%).
NMR: 1H-NMR(DMSO-d6) δ 8.45(1H, s), 8.43(1H, s), 8.27(1H, s), 8.04(1H, dd), 7.88(1H, d), 3.70-3.66(1H, m), 1.18-1.15(2H, m), 1.11-1.09(2H, m)
Mass(EI): 310 (M++1)
Example 63: 2-(3-Cyano-1-methyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000323
2-(3-Cyano-1-methyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (40mg, 0.13mmol) obtained in Preparation 85 was reacted according to the same procedure as Example 1 to give the title compound (21mg, Yield 68%).
NMR: 1H-NMR(MeOH-d4) δ 8.41(1H, s), 8.35(1H, d), 8.08(1H, s), 8.03(1H, dd), 7.73(1H, d), 3.97(3H, s)
Mass(EI): 284 (M++1)
Example 64: 2-(3-Cyano-1-ethyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000324
2-(3-Cyano-1-ethyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (45mg, 0.14mmol) obtained in Preparation 86 was reacted according to the same procedure as Example 1 to give the title compound (32mg, Yield 77%).
NMR: 1H-NMR(DMSO-d6) δ 8.47(1H, s), 8.31(1H, s), 8.25(1H, s), 7.97(1H, dd), 7.86(1H, d), 4.34(2H, q), 1.42(3H, t)
Mass(EI): 298 (M++1)
Example 65: 2-(3-Cyano-1-sec-butyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000325
2-(3-Cyano-1-sec-butyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (60mg, 0.17mmol) obtained in Preparation 87 was reacted according to the same procedure as Example 1 to give the title compound (28mg, Yield 51%).
NMR: 1H-NMR(MeOD-d4) δ 8.41(1H, s), 8.33(1H, d), 8.25(1H, s), 7.99(1H, dd), 7.78(1H, d), 4.71-4.64(1H, m), 1.97-1.94(2H, m), 1.60(3H, d), 0.86(3H, t)
Mass(EI): 326 (M++1)
Example 66: 2-(3-Cyano-1-isobutyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000326
2-(3-Cyano-1-isobutyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (68mg, 0.19mmol) obtained in Preparation 88 was reacted according to the same procedure as Example 1 to give the title compound (35mg, Yield 57%).
NMR: 1H-NMR(DMSO-d6) δ 8.44(1H, s), 8.40(1H, s), 8.23(1H, s), 7.97(1H, d), 7.89(1H, d), 4.14(2H, d), 2.17(1H, m), 0.86(6H, d)
Mass(EI): 326 (M++1)
Example 67: 2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000327
2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (83mg, 0.24mmol) obtained in Preparation 89 was reacted according to the same procedure as Example 1 to give the title compound (69mg, Yield 91%).
NMR: 1H-NMR(DMSO-d6) δ 8.60(1H, s), 8.41(1H, s), 8.27(1H, d), 7.98(1H, d), 7.91(1H, d), 4.96-4.90(1H, m), 1.51(6H, d)
Mass(EI): 312(M++1)
Example 68: 2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000328
2-[3-Cyano-1-(cyclopropylmethyl)indol-5-yl]-1,3-thiazole-5-carboxylic acid ethyl ester (84mg, 0.24mmol) obtained in Preparation 90 was reacted according to the same procedure as Example 1 to give the title compound (63mg, Yield 82%).
NMR: 1H-NMR(DMSO-d6) δ 8.52(1H, s), 8.42(1H, s), 8.29(1H, d), 8.00(1H, d), 7.92(1H, d), 4.20(2H, d), 1.40-1.30(1H, m), 0.58-0.55(1H, m), 0.48-0.45(1H, m)
Mass(EI): 324(M++1)
Example 69: 2-(3-Cyano-1-tetrahydrofuran-3-yl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000329
2-(3-Cyano-1-tetrahydrofuran-3-yl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (85mg, 0.23mmol) obtained in Preparation 91 was reacted according to the same procedure as Example 1 to give the title compound (65mg, Yield 83%).
NMR: 1H-NMR(DMSO-d6) δ 8.45(1H, s), 8.40(1H, s), 8.26(1H, s), 8.00(1H, d), 7.93(1H, d), 5.40(1H, m), 4.13(1H, m), 3.97(2H, d), 3.84(1H, m), 2.57(1H, m), 2.20(1H, m)
Mass(EI): 340 (M++1)
Example 70: 2-(3-Cyano-1-cyclopentyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000330
2-(3-Cyano-1-cyclopentyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid cyclopentyl ester (75mg, 0.18mmol) obtained in Preparation 92 was reacted according to the same procedure as Example 1 to give 56mg (0.16mmol, Yield 89%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 7.55(1H, s), 7.52(1H, d), 7.44(1H, s), 7.20(1H, dd), 6.99(1H, d), 4.22(1H, m), 1.54(2H, m), 1.19(4H, m), 1.07(2H, m)
Mass(EI): 338 (M++1)
Example 71: 2-(3-Chloro-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000331
2-(3-Chloro-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (87mg, 0.25mmol) obtained in Preparation 94 was reacted according to the same procedure as Example 1 to give the title compound (73mg, Yield 91%).
NMR: 1H-NMR(DMSO-d6) δ 8.38(1H, s), 8.13(1H, s), 7.87(1H, d), 7.76(1H, d), 4.92-4.82(1H, m), 1.47(6H, d)
Mass(EI): 321(M++1)
Example 72: 2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-4-carboxylic acid
Figure PCTKR2010000893-appb-I000332
2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-4-carboxylic acid ethyl ester (78mg, 0.23mmol) obtained in Preparation 96 was reacted according to the same procedure as Example 1 to give the title compound (62mg, Yield 86%).
NMR: 1H-NMR(DMSO-d6) δ 8.59(1H, s), 8.49(1H, s), 8.22(1H, s), 7.96-7.89(2H, m), 4.96-4.90(1H, m), 1.51(6H, d)
Mass(EI): 312(M++1)
Example 73: 2-(1-Isopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000333
2-(1-Isopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (104mg, 0.28mmol) obtained in Preparation 98 was reacted according to the same procedure as Example 1 to give the title compound (30mg, Yield 31%).
NMR: 1H-NMR(DMSO-d6) δ 8.96(1H, s), 8.75(1H, s), 7.99(2H, m), 4.99(1H, m), 2.72(3H, s), 1.58(6H, d)
Mass(EI): 346(M++1)
Example 74: 2-[1-(Cyclopropylmethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000334
2-[1-(Cyclopropylmethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (134mg, 0.34mmol) obtained in Preparation 99 was reacted according to the same procedure as Example 1 to give the title compound (72mg, Yield 58%).
NMR: 1H-NMR(CD3OD) δ 8.81(1H, s), 8.63(1H, s), 8.02(1H, d), 7.79(1H, d), 4.22(2H, d), 2.78 (3H, s), 1.43(1H, m), 0.74(2H, m), 0.54(2H, m)
Mass(EI): 358(M++1)
Example 75: 2-(1-Cyclopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000335
2-(1-Cyclopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (68mg, 0.18mmol) obtained in Preparation 100 was reacted according to the same procedure as Example 1 to give the title compound (25mg, Yield 36%).
NMR: 1H-NMR(CD3OD) δ 8.80(1H, s), 8.52(1H, s), 8.03(1H, d), 7.91(1H, d), 3.67(1H, m), 2.78(3H, s), 1.18(2H, m), 0.91(2H, m)
Mass(EI): 344(M++1)
Example 76: 2-[1-(2-Methoxyethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000336
2-[1-(2-Methoxyethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (69mg, 0.17mmol) obtained in Preparation 101 was reacted according to the same procedure as Example 1 to give the title compound (35mg, Yield 54%).
NMR: 1H-NMR(CD3OD) δ 8.80(1H, s), 8.51(1H, s), 8.01(1H, d), 7.78(1H, d), 4.52(2H, t), 3.80(2H, t), 3.35(3H, s), 2.77(3H, s)
Mass(EI): 362(M++1)
Example 77: 2-(3-Nitro-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000337
2-(3-Nitro-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 97 and tetrahydropyran-4-yl methanesulfonate (200mg, 1.1mmol) were reacted according to the same procedure as Preparation 5 and then according to the same procedure as Example 1 to give 2mg (0.005mmol, Yield 1%) of the title compound.
NMR: 1H-NMR(CDCl3) δ 8.78(1H, d), 8.78(1H, s), 7.99(1H, dd), 7.86(1H, d), 5.34(1H, m), 4.13(2H, m), 3.71(2H, m), 2.76(3H, s), 2.18(2H, m), 2.01(2H, m)
Mass(EI): 416 (M++1)
Example 78: 2-(1-sec-Butyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000338
2-(1-sec-Butyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (50mg, 0.13mmol) obtained in Preparation 102 was reacted according to the same procedure as Example 1 to give the title compound 19mg (0.053mmol, Yield 40%).
NMR: 1H-NMR(DMSO-d6) δ 8.97(1H, s), 8.74(1H, s), 7.98(2H, s), 4.76(1H, m), 2.81(3H, s), 1.97(1H, m), 1.91(1H, m), 1.55(3H, d), 0.77(3H, t)
Mass(EI): 360 (M++1)
Example 79: 2-(1-Isobutyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000339
2-(1-Isobutyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (40mg, 0.10mmol) obtained in Preparation 103 was reacted according to the same procedure as Example 1 to give 15mg (0.042mmol, Yield 0.42%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.87(1H, s), 8.73(1H, d), 7.96(1H, dd), 7.93(1H, d), 4.19(2H, d), 2.71(3H, s), 2.21(1H, m) 0.88(6H, d)
Mass(EI): 360 (M++1)
Example 80: 2-(1-Methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000340
2-(1-Methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (20mg, 0.058mmol) obtained in Preparation 104 was reacted according to the same procedure as Example 1 to give 2.2mg (0.007mmol, Yield 12%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ8.79(1H, d), 8.49(1H, s), 8.01(1H, dd), 7.71(1H, d), 4.29(1H, m), 3.98(3H, s), 2.75(3H, s)
Mass(EI): 318 (M++1)
Example 81: 2-(1-Ethyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000341
2-(1-Ethyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (24mg, 0.067mmol) obtained in Preparation 105 was reacted according to the same procedure as Example 1 to give 1mg (0.003mmol, Yield 45%) of the title compound.
NMR: 1H-NMR(CD3OD) δ 8.77(1H, d), 8.53(1H, s), 7.97(1H, dd), 7.73(1H, d), 4.35(2H, q), 2.73(3H, s), 1.51(3H, t)
Mass(EI): 332 (M++1)
Example 82: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000342
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid ethyl ester (250mg, 0.67mmol) obtained in Preparation 142 was reacted according to the same procedure as Example 1 to give the title compound (110mg, Yield 47%).
NMR: 1H-NMR(CD3OD) δ 8.33(1H, s), 8.27(1H, s), 7.97(1H, d), 7.78(1H, d), 4.69(1H, m), 4.24(3H, s), 1.62(6H, d)
Mass(EI): 342(M++1)
Example 83: 2-(1-Isopropyl-7-methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000343
2-(1-Isopropyl-7-methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (123mg, 0.31mmol) obtained in Preparation 129 was reacted according to the same procedure as Example 1 to give the title compound (75mg, Yield 65%).
NMR: 1H-NMR(CD3OD) δ 8.70(1H, s), 8.65(1H, s), 7.76(1H, d), 5.33(1H, m), 2.87(3H,s), 2.76(3H, s), 1.66(6H, d)
Mass(EI): 360(M++1)
Example 84: 2-(1-Isopropyl-3-nitro-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000344
2-(1-Isopropyl-3-nitro-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (75mg, 0.23mmol) obtained in Preparation 107 was reacted according to the same procedure as Example 1 to give the title compound (60mg, Yield 87%).
NMR: 1H-NMR(DMSO-d6) δ 8.95(1H, s), 8.78(1H, s), 8.57(1H, s), 8.05-7.98(2H, m), 5.03-4.92(1H, m), 1.56(6H, d)
Mass(EI): 332(M++1)
Example 85: 2-(3-Cyano-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000345
2-(3-Cyano-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid isopropyl ester (130mg, 0.35mmol) obtained in Preparation 117 was reacted according to the same procedure as Example 1 to give 100mg (0.30mmol, Yield 85%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.86(1H, s), 8.38(1H, d), 8.16(1H, d), 4.95(1H, m), 2.71(3H, s), 1.52(6H, d)
Mass(EI): 327 (M++1)
Example 86: 2-(3-Cyano-4-fluoro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000346
2-(3-Cyano-4-fluoro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (70mg, 0.21mmol) obtained in Preparation 136 was reacted according to the same procedure as Example 1 to give 61mg (0.17mmol, Yield 80%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.64(1H, s), 8.16(1H, dd), 7.76(1H, d), 4.92(1H, m), 2.71(3H, s), 1.51(6H, d)
Mass(EI): 344 (M++1)
Example 87: 2-(3-Cyano-1-isopropyl-7-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000347
2-(3-Cyano-1-isopropyl-7-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (130mg, 0.35mmol) obtained in Preparation 126 was reacted according to the same procedure as Example 1 to give 115mg (0.34mmol, Yield 95%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.58(1H, s), 8.06(1H, d), 7.70(1H, d), 5.20(1H, m), 2.80(3H, s), 2.69(3H, s), 1.51(6H, d)
Mass(EI): 340 (M++1)
Example 88: 2-[3-Cyano-1-(cyclopropylmethyl)-7-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000348
2-[3-Cyano-1-(cyclopropylmethyl)-7-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (130mg, 0.34mmol) obtained in Preparation 127 was reacted according to the same procedure as Example 1 to give 120mg (0.34mmol, Yield 99%) of the title compound.
NMR: 1H-NMR(DMSO-d6) δ 8.43(1H, s), 8.06(1H, d), 7.69(1H, d), 4.34(2H, d), 2.82(3H, s), 2.69(3H, s), 1.30(1H, m), 0.58(2H, m), 0.45(2H, m)
Mass(EI): 352 (M++1)
Example 89: 2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000349
2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid ethyl ester (100mg, 0.30mmol) obtained in Preparation 148 was reacted according to the same procedure as Example 1 to give the title compound (70mg, Yield 75%).
NMR: 1H-NMR(DMSO-d6) δ 8.62(1H, s), 8.24(1H, s), 7.98(1H, d), 7.93(1H, d), 4.92(1H, m), 2.47(3H, s), 1.51(6H, d)
Mass(EI): 310 (M++1)
Example 90: 2-[2-(1-t-Butoxycarbonyl-pyrrolidin-2-yl)-7-chloro-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000350
2-[2-(1-t-Butoxycarbonyl-pyrrolidin-2-yl)-7-chloro-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.07g, 0.18mmol) obtained in Preparation 196 was added to 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (0.06g, Yield 71%).
NMR: 1H-NMR(DMSO-d6) δ 11.64(1H, d), 8.05(1H, s), 7.69(1H, s), 6.32(1H, d), 5.01-4.92(1H, m), 3.54(1H, m), 3.38-3.34(1H, m), 2.63(3H, s), 2.23(1H, m), 1.88-1.83(3H, m), 1.38(4H, s), 1.10(5H, s)
Mass(EI): 462(M++1)
Example 91: 2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid hydrochloride
Figure PCTKR2010000893-appb-I000351
2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester hydrochloride (0.055g, 0.12mmol) obtained in Preparation 197 was reacted according to the same procedure as Example 90 to give the title compound (0.038g, Yield 80%).
NMR: 1H-NMR(DMSO-d6) δ 12.09(1H, s), 10.03(1H, s), 9.26(1H, s), 8.18(1H, s), 7.81(1H, s), 6.85(1H, s), 4.84-4.81(1H, m), 3.34-3.30(2H, m), 2.64(3H, s), 2.41-2.38(1H, m), 2.23-2.02(3H, m)
Mass(EI): 362(M++1)
Example 92: 2-[7-Chloro-2-(1-isopropyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000352
2-[7-Chloro-2-(1-isopropyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.043g, 0.01mmol) obtained in Preparation 198 was reacted according to the same procedure as Example 90 to give the title compound (0.034g, Yield 85%).
NMR: 1H-NMR(DMSO-d6) δ 12.08(1H, s), 8.18(1H, s), 7.81(1H, s), 6.98(1H, s), 4.73(1H, br s), 4.08(1H, d), 3.47(1H, br s), 3.13(2H, d), 2.64(3H, s), 2.41-2.05(4H, m), 1.18(6H, t)
Mass(EI): 404(M++1)
Example 93: 2-[7-Chloro-2-(1-methanesulfonyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000353
2-[7-Chloro-2-(1-methanesulfonyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.055g, 0.12mmol) obtained in Preparation 199 was reacted according to the same procedure as Example 90 to give the title compound (0.047g, Yield 92%).
NMR: 1H-NMR(DMSO-d6) δ 11.59(1H, s), 8.10(1H, s), 7.75(1H, s), 6.57(1H, s), 5.02-4.99(1H, m), 3.58-3.42(2H, m), 2.97(3H, s), 2.66(3H, s), 2.33-2.28(1H, m), 2.07-2.06(1H, m), 1.95-1.91(2H, m)
Mass(EI): 440(M++1)
Example 94: 2-(7-Chloro-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000354
2-(7-Chloro-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.05g, 0.13mmol) obtained in Preparation 155 was reacted according to the same procedure as Example 90 to give the title compound (0.05g, Yield 95%).
Mass(EI): 349(M++1)
Example 95: 2-(7-Chloro-2-isobutyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000355
2-(7-Chloro-2-isobutyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.07g, 0.13mmol) obtained in Preparation 156 was added to 5.0mL of tetrahydrofuran, 5.0mL of methanol and 1mL of 1N sodium hydroxide solution, and reacted for 1 h at room temperature. After reaction, 5mL of saturated ammonium chloride solution was added, and 20mL of ethyl acetate was added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The solvent was removed and the residue was purified by column chromatography to give the title compound (0.07g, Yield 95%).
Mass(EI): 363(M++1)
Example 96: 2-(7-Chloro-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000356
4-Amino-3-chloro-5-(3-methoxy-prop-1-inyl)-benzoic acid methyl ester (0.75g, 2.96mmol) obtained in Preparation 200 was reacted according to the same procedures as Preparation 151, Preparation 152, Preparation 153, Preparation 154, Preparation 155 and Example 90 in the order to give the title compound (0.12g).
NMR: 1H-NMR(DMSO-d6) δ 13.32(1H, br s), 11.89(1H, s), 8.16(1H, s), 7.77(1H, s), 6.65(1H, d), 4.56(2H, s), 2.67(3H, s)
Mass(EI): 337(M++1)
Example 97: 2-(7-Chloro-2-cyclopentylmethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000357
2-(7-Chloro-2-cyclopentylmethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.05g, 0.13mmol) obtained in Preparation 158 was reacted according to the same procedure as Example 90 to give the title compound (0.04g, Yield 85%).
Mass(EI): 375(M++1)
Example 98: 2-(7-Chloro-2-cyclopentylmethyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000358
2-(7-Chloro-2-cyclopentylmethyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.07g, 0.13mmol) obtained in Preparation 159 was reacted according to the same procedure as Example 90 to give the title compound (0.07g, Yield 95%).
Mass(EI): 389(M++1)
Example 99: 2-(7-Bromo-2-pyridin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000359
2-(4-Amino-3-bromo-5-pyridin-2-ylethinyl-phenyl)-4-methyl-1,3-thiazole-carboxylic acid ethyl ester (0.12g, 0.26mmol) obtained in Preparation 188 was reacted according to the same procedures as Preparation 173 and Example 90 in the order to give the title compound (0.04g).
NMR: 1H-NMR(DMSO-d6) δ 13.30(1H, br s), 11.61(1H, s), 8.66(1H, d), 8.25(1H, s), 8.15(1H, d), 7.95(1H, d), 7.90(1H, m), 7.39(1H, d), 7.36-7.35(1H, m), 2.65(3H, s)
Mass(EI): 415(M++1)
Example 100: 2-[7-Bromo-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000360
2-[7-Bromo-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.04g, 0.08mmol) obtained in Preparation 176 was reacted according to the same procedure as Example 90 to give the title compound (0.02g, Yield 50%).
Mass(EI): 429(M++1)
Example 101: 2-(5-Bromo-2,3-dihydro-1H-pyrrolo[1,2a]indol-7-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000361
2-(5-Bromo-2,3-dihydro-1H-pyrrolo[1,2a]indol-7-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.04g, 0.099mmol) obtained in Preparation 192 was reacted according to the same procedure as Example 90 to give the title compound (0.03g, Yield 80%).
NMR: 1H-NMR(DMSO-d6) δ 13.27(1H, br s), 8.10(1H, d), 7.81(1H, d), 6.38(1H, s), 4.48(2H, t), 2.97(2H, t), 2.66(3H, s), 2.56(2H, t)
Mass(EI): 378(M++1)
Example 102: 2-(7-Bromo-2-pyrazin-2-yl-1H?indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000362
2-(7-Bromo-2-pyrazin-2-yl-1H?indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.1g, 0.2mmol) obtained in Preparation 173 was reacted according to the same procedure as Example 90 to give the title compound (0.07g, Yield 75%).
Mass(EI): 362(M++1)
Example 103: 2-(7-Bromo-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000363
2-(7-Bromo-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.03g, 0.07mmol) obtained in Preparation 194 was reacted according to the same procedure as Example 90 to give the title compound (0.022g, Yield 79%).
NMR: 1H-NMR(DMSO-d6) δ 11.39(1H, s), 8.04(1H, s), 7.80(1H, s), 6.38(1H, s), 2.63(3H, s), 2.60(2H, d), 2.02-1.98(1H, m), 0.89(6H, d)
Mass(EI): 394 (M++1)
Example 104: 2-(7-Cyano-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000364
2-(7-Cyano-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.01g, 0.028mmol) obtained in Preparation 187 was reacted according to the same procedure as Example 90 to give the title compound (0.006g, Yield 61%).
NMR: 1H-NMR(DMSO-d6) δ 12.43(1H, s), 8.49(1H, s), 8.15(1H, s), 6.73(1H, s), 4.57(2H, s), 2.67(3H, s)
Mass(EI): 328(M++1)
Example 105: 2-(7-Cyano-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000365
2-(7-Bromo-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.24g, 0.57mmol) obtained in Preparation 194 was reacted according to the same procedures as Preparation 165 and Example 90 in the order to give the title compound (0.15g, Yield 76%).
NMR: 1H-NMR(DMSO-d6) δ 13.30(1H, br s), 12.11(1H, s), 8.37(1H, s), 8.04(1H, s), 6.44(1H, s), 2.64(3H, s), 2.61(2H, d), 2.01-1.99(1H, m), 0.89(6H, d)
Mass(EI): 340 (M++1)
Example 106: 2-(7-Cyano-2-pyridin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000366
2-(4-Amino-3-bromo-5-pyridin-2-ylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.39g, 0.88mmol) obtained in Preparation 188 was reacted according to the same procedures as Preparation 173, Preparation 165 and Example 90 in the order to give the title compound (0.02g).
NMR: 1H-NMR(DMSO-d6) δ 10.11(1H, s), 8.65(1H, d), 8.46(1H, d), 8.19(1H, d), 7.85-7.75(2H, m), 7.33-7.27(1H, m), 7.13(1H, s), 2.80(3H, s)
Mass(EI): 361(M++1)
Example 107: 2-[7-Cyano-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000367
2-[7-Cyano-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.03g, 0.09mmol) obtained in Preparation 177 was reacted according to the same procedure as Example 90 to give the title compound (0.02g, Yield 80%).
NMR: 1H-NMR(DMSO) δ 12.91(1H, s), 9.38(1H, s), 8.71(1H, s), 8.59(1H, s), 8.54(1H, s), 8.19(1H, s), 2.64(3H, s), 1.8(2H, s)
Mass(EI): 362(M++1)
Example 108: 2-(7-Cyano-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000368
2-(7-Cyano-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.03g, 0.09mmol) obtained in Preparation 174 was reacted according to the same procedure as Example 90 to give the title compound (0.02g, Yield 80%).
NMR: 1H-NMR(DMSO) δ 12.91(1H, s), 9.38(1H, s), 8.71(1H, s), 8.59(1H, s), 8.54(1H, s), 8.19(1H, s), 2.64(3H, S), 1.8(2H, s)
Mass(EI): 362(M++1)
Example 109: 2-(7-Cyano-2-phenyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000369
2-(4-Amino-3-bromo-5-phenylethinyl-phenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.4g, 0.91mmol) obtained in Preparation 189 was reacted according to the same procedures as Preparation 173, Preparation 165 and Example 90 in the order to give the title compound (0.07g).
NMR: 1H-NMR(CDCl3+CD3OD) δ 8.41(1H, d), 8.11(1H, d), 7.89(1H, s), 7.87(1H, s), 7.52-7.38(3H, m), 6.99(1H, s), 2.78(3H, s)
Mass(EI): 340(M++1)
Example 110: 2-(2-Benzyl-7-cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000370
2-[4-Amino-3-bromo-5-(3-phenyl-prop-1-inyl)-phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester (0.42g, 0.92mmol) obtained in Preparation 190 was reacted according to the same procedures as Preparation 173, Preparation 165 and Example 90 in the order to give the title compound (0.03g).
NMR: 1H-NMR(CDCl3+CD3OD) δ 8.29(1H, d), 8.04(1H, d), 7.35-7.23(5H, m), 6.37(1H, s), 4.18(2H, s), 2.76(3H, s)
Mass(EI): 374(M++1)
Example 111: 4-Methyl-2-(7-nitro-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000371
4-Methyl-2-(7-nitro-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.1g, 0.25mmol) obtained in Preparation 204 was reacted according to the same procedure as Example 90 to give the title compound (0.065g, Yield 70%).
NMR: 1H-NMR(DMSO-d6) δ 13.40(1H, br s), 11.93(1H, s), 8.59(2H, s), 7.99-7.41(5H, m), 7.23(1H, s), 2.67(3H, s)
Mass(EI): 380(M++1)
Example 112: 2-(2-Isobutyl-7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000372
2-(2-Isobutyl-7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.1g, 0.27mmol) obtained in Preparation 208 was reacted according to the same procedure as Example 90 to give the title compound (0.08g, Yield 86%).
NMR: 1H-NMR(DMSO-d6) δ 11.96(1H, s), 8.57(1H, s), 8.54(1H, s), 8.30(1H, s), 6.58(1H, d), 2.73(2H, d), 2.10-2.01(1H, m), 0.95(6H, d)
Mass(EI): 346(M++1)
Example 113: 4-Methyl-2-(7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000373
4-Methyl-2-(7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.01g, 0.03mmol) obtained in Preparation 184 was reacted according to the same procedure as Example 90 to give the title compound (0.007g, Yield 80%).
NMR: 1H-NMR(CD3OD) δ 11.7(1H, s), 8.72(1H, s), 8.58(1H, s), 7.55(1H, m), 6.82(1H, m), 2.74(3H, s)
Mass(EI): 306(M++1)
Example 114: 2-(7-Amino-2-phenyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
Figure PCTKR2010000893-appb-I000374
4-Methyl-2-(7-amino-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid ethyl ester (0.04g, 0.11mmol) obtained in Preparation 205 was reacted according to the same procedure as Example 90 to give the title compound (0.029g, Yield 80%).
NMR: 1H-NMR(DMSO-d6) δ 11.23(1H, s), 7.85(1H, s), 7.84(1H, s), 7.52-7.03(5H, m), 6.92(1H, d), 3.26(3H, s)
Mass(EI): 350(M++1)
Experiment 1: Xanthine oxidase inhibition activity
Xanthine oxidase originated from butter milk (Sigma) was adjusted to 0.05U/mL by using 50 mM phosphate buffer, and then added to 96-well plate at 20 ㎕/well. 50 mM phosphate buffer was added at 140 ㎕/well, and test compounds of various concentrations (10% DMSO phosphate buffer) were added at 20 ㎕/well, and pre-incubated for 3 min at room temperature. Immediately after 200 μM xanthine solution was added at 20 ㎕/well, the initial velocity of uric acid formation was determined at 293 nm using microplate reader SpectraMax spectrophotometer. Linear Vmax during 5 min for each test compound concentration was determined as initial velocity. Ki value was calculated utilizing Dixon plot equation (Affinity for xanthine, the substrate of xanthine oxidase, Km=9.2 μM).
In addition, the initial velocity of test compound at each concentration was converted to % inhibition rate on the basis of the initial velocity under the absence of the inhibitor, thereby the inhibitor concentration needed for 50% inhibition was calculated as IC50 values. According to the present invention, some compounds which show IC50 values at similar levels to febuxostat were discovered. Table 1 represents the inhibitory activities against xanthine oxidase of the test compounds.
Table 1
Figure PCTKR2010000893-appb-T000001
Figure PCTKR2010000893-appb-I000375
Figure PCTKR2010000893-appb-I000376
Experiment 2: In vivo xanthine oxidase assay - Uric acid-lowering activity in plasma and liver (oxonic acid-induced high-uric acid model in rat)
In order to estimate the plasma uric acid-lowering ability of the compounds according to the present invention, experiments were carried out using oxonic acid-induced high-uric acid model.
300 mg/kg of potassium oxonate suspended in 0.8% carboxymethylcellulose solution was intraperitoneally administered to male SD rats of body weight 200 g (control group, compound administration group). 1 h after the oxonic acid administration, test compounds dissolved in polyethyleneglycol 400 : ethanol (2 : 1) solution were orally administered (compound administration group), and after the time period of 1 h blood was sampled. Plasma was separated from thus-obtained blood, and the uric acid concentration in the plasma was quantified utilizing LC-MS/MS. Figure 1 and 2 represent the results of plasma uric acid concentration and inhibition rate of plasma uric acid, respectively.
Through the present experiment, excellent plasma uric acid-lowering activity of the compounds according to the present invention was verified. For example, the uric acid inhibition rate of the compound of Example 10 (10 mg/kg) at 1 h after oral administration (putting the plasma uric acid level of normal group as 100% inhibition, and plasma uric acid level of control group as 0% inhibition) was 60%, indicating a suppression rate similar to the earlier reported xanthine oxidase inhibitor febuxostat (10 mg/kg) treated group. In addition, in an experiment wherein excised liver tissue was pulverized and the uric acid level in the liver was compared through the peak area of LC-MS/MS, a potent efficacy was observed which accomplish the suppression below the level of normal group. Figure 3 represents the results from the comparison of the liver uric acid suppression ability.
As revealed by the above experiments, the compounds of formula (1) according to the present invention exert an excellent inhibitory effect on xanthine oxidase. Therefore, the compounds according to the present invention can be used as an agent for the treatment and prevention of the diseases associated with human xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, articular disease, and inflammatory bowel disease.
Those skilled in the art will be able to make various applications and modifications on the basis of above disclosure within the scope of the present invention.

Claims (14)

  1. Compounds of the following formula (1):
    Figure PCTKR2010000893-appb-I000377
    in the above formula (1),
    W1, W2, W3 and W4 represent N or C, provided that only one is N when W1, W2, W3 or W4 represents N,
    A represents the following A-i or A-ii:
    (A-i)
    Figure PCTKR2010000893-appb-I000378
    (A-ii)
    Figure PCTKR2010000893-appb-I000379
    (wherein, J represents hydrogen; halogen; C1-C6-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted C1-C6-alkoxy, and X represents O or S), provided that A is linked to only C when A is linked to W1, W2, W3 or W4,
    E represents hydrogen; halogen; nitro; cyano; amino; substituted or unsubstituted C1-C6-alkyl; or substituted or unsubstituted C1-C6-alkoxy, provided that E is linked to only C when E is linked to W1, W2, W3 or W4,
    D represents hydrogen; halogen; cyano; nitro; C1-C6-alkyl which is unsubstituted or substituted by halogen; or-CHO,
    Q is selected form the following Q-i, Q-ii, Q-iii-1 to Q-iii-14:
    (Q-i) hydrogen,
    (Q-ii) substituted or unsubstituted, saturated or unsaturated, or straight-chain, branched or cyclic alkyl,
    (Q-iii-1)
    Figure PCTKR2010000893-appb-I000380
    (wherein W represents O or S, R7 represents hydrogen or substituted or unsubstituted lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-2)
    Figure PCTKR2010000893-appb-I000381
    (wherein W represents O or S, R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-3)
    Figure PCTKR2010000893-appb-I000382
    (wherein R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-4)
    Figure PCTKR2010000893-appb-I000383
    (wherein R10 and R11 independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-5)
    Figure PCTKR2010000893-appb-I000384
    (wherein R12 represents substituted or unsubstituted lower alkyl or aryl, and n denotes an integer of 0~3),
    (Q-iii-6)
    Figure PCTKR2010000893-appb-I000385
    (wherein R13 and R14 independently of one another represent substituted or unsubstituted lower alkyl, or together with the nitrogen atom to which they are attached may form a 3~7 membered heterocycle containing N as the hetero atom, and n denotes an integer of 0~3),
    (Q-iii-7)
    Figure PCTKR2010000893-appb-I000386
    (wherein R15 represents substituted or unsubstituted lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-8)
    Figure PCTKR2010000893-appb-I000387
    (wherein m denotes an integer of 1~3),
    (Q-iii-9)
    Figure PCTKR2010000893-appb-I000388
    (wherein R16 and R17 independently of one another represent hydrogen or substituted or unsubstituted lower alkyl, or together with the atoms to which they are attached may form a 3~7 membered heterocycle containing N as the hetero atom, and m denotes an integer of 1~3),
    (Q-iii-10)
    Figure PCTKR2010000893-appb-I000389
    (wherein R18 represents hydrogen; substituted or unsubstituted lower alkyl; alkoxy; or aryl, and m denotes an integer of 1~3),
    (Q-iii-11)
    Figure PCTKR2010000893-appb-I000390
    (wherein R19 represents hydrogen or substituted or unsubstituted lower alkyl, R20 represents substituted or unsubstituted lower alkyl or alkoxy, and n denotes an integer of 0~3),
    (Q-iii-12)
    Figure PCTKR2010000893-appb-I000391
    (wherein W represents O or S, R21 represents hydrogen or substituted or unsubstituted lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-13)
    Figure PCTKR2010000893-appb-I000392
    (wherein R22 and R23 independently of one another represent substituted or unsubstituted lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-14)
    Figure PCTKR2010000893-appb-I000393
    (wherein W1, W2, W3, W4 and W5 represent N or C, provided that only one is N when W1, W2, W3, W4 or W5 represents N, R24 and R25 independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1~3),
    Y represents hydrogen; halogen; substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl; substituted or unsubstituted C1-C6-alkoxy; C6-C10-aryl; substituted or unsubstituted 3~7 membered heteroaryl which contains N as the hetero atom; substituted or unsubstituted 3~7 membered heterocycle which contains N as the hetero atom, or
    Q and Y together with the atoms to which they are attached may form a 3~7 membered heterocycle which contains N as the hetero atom, and
    G represents hydrogen; or substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl, pharmaceutically acceptable salts, or isomers thereof.
  2. The compounds of Claim 1 wherein
    W1, W2, W3 and W4 represent N or C, provided that only one is N when W1, W2, W3 or W4 represents N,
    A represents the following A-i or A-ii:
    (A-i)
    Figure PCTKR2010000893-appb-I000394
    (A-ii)
    Figure PCTKR2010000893-appb-I000395
    (wherein, J represents hydrogen; C1-C6-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted C1-C6-alkoxy, and X represents O or S), provided that A is linked to only C when A is linked to W1, W2, W3 or W4,
    E represents hydrogen; halogen; nitro; cyano; amino; or C1-C6-alkyl, provided that E is linked to only C when E is linked to W1, W2, W3 or W4,
    D represents hydrogen; halogen; cyano; or nitro,
    Q is selected form the following Q-i, Q-ii, Q-iii-1 to Q-iii-14:
    (Q-i) hydrogen,
    (Q-ii) saturated or unsaturated and straight-chain, branched or cyclic alkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen; lower alkoxy; hydroxy; C3-C6-cycloalkyl; 5~6 membered heteroaryl which is unsubstituted or substituted by lower alkyl and contains 1~3 hetero atoms selected from N, S and O; and 5~6 membered heterocycle which is saturated or unsaturated and contains 1~3 hetero atoms selected from N, S and O,
    (Q-iii-1)
    Figure PCTKR2010000893-appb-I000396
    (wherein W represents O or S, R7 represents hydrogen or lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-2)
    Figure PCTKR2010000893-appb-I000397
    (wherein W represents O or S, R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-3)
    Figure PCTKR2010000893-appb-I000398
    (wherein R8 and R9 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-4)
    Figure PCTKR2010000893-appb-I000399
    (wherein R10 and R11 independently of one another represent hydrogen; halogen; or lower alkoxy, and m denotes an integer of 1~3),
    (Q-iii-5)
    Figure PCTKR2010000893-appb-I000400
    (wherein R12 represents lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-6)
    Figure PCTKR2010000893-appb-I000401
    (wherein R13 and R14 independently of one another represent lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-7)
    Figure PCTKR2010000893-appb-I000402
    (wherein R15 represents lower alkyl, and m denotes an integer of 1~3),
    (Q-iii-8)
    Figure PCTKR2010000893-appb-I000403
    (wherein m denotes an integer of 1~3),
    (Q-iii-9)
    Figure PCTKR2010000893-appb-I000404
    (wherein R16 and R17 independently of one another represent hydrogen or lower alkyl, or together with the atoms to which they are attached may form a 5~6 membered heterocycle containing one (1) N as the hetero atom, and m denotes an integer of 1~3),
    (Q-iii-10)
    Figure PCTKR2010000893-appb-I000405
    (wherein R18 represents hydrogen; or lower alkyl unsubstitued or substituted by lower alkoxy or phenyl, and m denotes an integer of 1~3),
    (Q-iii-11)
    Figure PCTKR2010000893-appb-I000406
    (wherein R19 represents hydrogen or lower alkyl, R20 represents lower alkyl or lower alkoxy, and n denotes an integer of 0~3),
    (Q-iii-12)
    Figure PCTKR2010000893-appb-I000407
    (wherein W represents O or S, R21 represents hydrogen or lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-13)
    Figure PCTKR2010000893-appb-I000408
    (wherein R22 and R23 independently of one another represent lower alkyl, and n denotes an integer of 0~3),
    (Q-iii-14)
    Figure PCTKR2010000893-appb-I000409
    (wherein W1, W2, W3, W4 and W5 represent N or C, provided that only one is N when W1, W2, W3, W4 or W5 represents N, R24 and R25 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1~3),
    Y represents hydrogen; saturated or unsaturated and straight-chain, branched or cyclic alkyl which is unsubstituted or substituted by lower alkoxy or C3-C6-cycloalkyl; C6-C10-aryl; 5~6 membered heteroaryl which contains 1~2 N as the hetero atom and which is unsubstituted or substituted by lower alkyl; 5~6 membered heterocycle which contains 1~2 N as the hetero atom and which is unsubstituted or substituted by lower alkoxycarbonyl, lower alkyl or lower alkylsulfonyl, or
    Q and Y together with the atoms to which they are attached may form a 5~6 membered heterocycle which contains 1 N as the hetero atom, and
    G represents hydrogen; or saturated or unsaturated and straight-chain, branched or cyclic lower alkyl.
  3. The compounds of Claim 2 wherein A represents
    Figure PCTKR2010000893-appb-I000410
    (wherein J represents hydrogen; C1-C6-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted C1-C6-alkoxy).
  4. The compounds of Claim 3 wherein J represents C1-C4-alkyl which is unsubstituted or substituted by halogen.
  5. The compounds of Claim 2 wherein D represents halogen, cyano or nitro.
  6. The compounds of Claim 2 wherein G represents hydrogen.
  7. The compounds of Claim 1 which are selected from the following group:
    2-(1-Isobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Chloro-1-isobutyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Chloro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Chloro-1-cyclohexyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-{3-Chloro-1-[2-(diethylamino)-2-oxoethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Chloro-1-(3-methoxybenzyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Chloro-1-cyclopentyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Chloro-1-(tetrahydrofuran-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Chloro-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-morpholin-4-ylethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2,2-dimethylpropyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-{3-Cyano-1-[2-(methylsulfonyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(tetrahydrofuran-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(3-methylbutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-{3-Cyano-1-[(3,5-dimethylisoxazol-4-yl)methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-{2-[(methylsulfonyl)amino]ethyl}-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(cyclopentylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(isobutyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(cyclopentyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-{3-Cyano-1-[2-(2-methyl-1,3-oxazol-4-yl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(1,3-thiazol-2-ylmethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-methoxyethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-{1-[2-(Acetylamino)ethyl]-3-cyano-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-propyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-cyclopropyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(oxazol-4-ylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(3,3,3-trifluoropropyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-sec-butyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-[(2,4-difluorophenyl)methyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Allyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-prop-2-inyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-pyridylmethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-methoxy-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-[2-(2-methoxyethoxy)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Benzyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-cyclobutyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-[2-(2-oxopyrrolidin-1-yl)ethyl]indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-ethyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-methoxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-hydroxy-2-methyl-propyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-fluoroethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Butyl-3-cyano-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-{3-Cyano-1-[(4-fluorophenyl)-methyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-ethoxyethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-hydroxy-1-methyl-ethyl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(2-fluoro-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[1-(2-Benzyloxyethyl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-indol-5-yl)-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid;
    2-{3-Cyano-1-[2-fluoro-1-(fluoromethyl)ethyl]-indol-5-yl}-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[1-(1-Acetylpyrrolidin-3-yl)-3-cyano-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(1-methoxycarbonylpyrrolidin-3-yl)-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(1-cyano-1-methyl-ethyl)indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isobutyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-sec-Butyl-3-cyano-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-ethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-cyclopropylmethyl-2-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-cyclopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-methyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-ethyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-sec-butyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isobutyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(cyclopropylmethyl)-indol-5-yl]-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-tetrahydrofuran-3-yl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-cyclopentyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Chloro-1-isopropyl-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-indol-5-yl)-1,3-thiazole-4-carboxylic acid;
    2-(1-Isopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[1-(Cyclopropylmethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Cyclopropyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[1-(2-Methoxyethyl)-3-nitro-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Nitro-1-tetrahydropyran-4-yl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-sec-Butyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Isobutyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Ethyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methoxy-1,3-thiazole-5-carboxylic acid;
    2-(1-Isopropyl-7-methyl-3-nitro-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(1-Isopropyl-3-nitro-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-pyrrolo[3,2-b]pyridin-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-4-fluoro-1-isopropyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-7-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[3-Cyano-1-(cyclopropylmethyl)-7-methyl-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(3-Cyano-1-isopropyl-indol-5-yl)-4-methyl-oxazole-5-carboxylic acid;
    2-[2-(1-t-Butoxycarbonyl-pyrrolidin-2-yl)-7-chloro-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Chloro-2-pyrrolidin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid hydrochloride;
    2-[7-Chloro-2-(1-isopropyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[7-Chloro-2-(1-methanesulfonyl-pyrrolidin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Chloro-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Chloro-2-isobutyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Chloro-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Chloro-2-cyclopentylmethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Chloro-2-cyclopentylmethyl-1-methyl-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Bromo-2-pyridin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[7-Bromo-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(5-Bromo-2,3-dihydro-1H-pyrrolo[1,2a]indol-7-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Bromo-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid
    2-(7-Bromo-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Cyano-2-methoxymethyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Cyano-2-isobutyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Cyano-2-pyridin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-[7-Cyano-2-(6-methyl-pyridin-2-yl)-1H-indol-5-yl]-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Cyano-2-pyrazin-2-yl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(7-Cyano-2-phenyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    2-(2-Benzyl-7-cyano-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid;
    4-Methyl-2-(7-nitro-2-phenyl-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    2-(2-Isobutyl-7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid;
    4-Methyl-2-(7-nitro-1H-indol-5-yl)-1,3-thiazole-5-carboxylic acid; and
    2-(7-Amino-2-phenyl-1H-indol-5-yl)-4-methyl-1,3-thiazole-5-carboxylic acid.
  8. A process for preparing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof according to Claim 1 characterized by the following Reaction Scheme (1):
    Reaction Scheme 1
    Figure PCTKR2010000893-appb-I000411
    in the above Reaction Scheme (1)
    W1, W2, W3, W4, A, D, E, G, Y and Q are as defined in Claim 1, provided that Q is not hydrogen, and
    L1 is a leaving group in the substitution reaction.
  9. The process of Claim 8 wherein L1 is halogen, methanesulfonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy.
  10. A process for preparing the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof according to Claim 1 characterized by the following Reaction Scheme (2):
    Reaction Scheme 2
    Figure PCTKR2010000893-appb-I000412
    in the above Reaction Scheme (2), W1, W2, W3, W4, A, D, E, G and Y are as defined in Claim 1, provided that D is not hydrogen.
  11. A pharmaceutical composition for the inhibition of xanthine oxidase, which comprises (a) a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof according to Claim 1 and (b) pharmaceutically acceptable carriers, diluents, excipients or their combinations.
  12. The pharmaceutical composition for the inhibition of xanthine oxidase, which is used for the prevention or treatment of diseases associated with human xanthine oxidase.
  13. The composition of Claim 12 wherein the diseases associated with human xanthine oxidase is selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, complications of diabetes, kidney disease, inflammation, articular disease and inflammatory bowel disease.
  14. The composition of Claim 13 wherein the complications of diabetes is selected from the group consisting of hyperlipidemia, atherosclerosis, obesity, hypertension, retinosis and renal failure.
PCT/KR2010/000893 2009-02-13 2010-02-12 Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same WO2010093191A2 (en)

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