WO2012134231A9 - Benzamide derivative as cannabinoid receptor (cb1) antagonist - Google Patents

Benzamide derivative as cannabinoid receptor (cb1) antagonist Download PDF

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WO2012134231A9
WO2012134231A9 PCT/KR2012/002405 KR2012002405W WO2012134231A9 WO 2012134231 A9 WO2012134231 A9 WO 2012134231A9 KR 2012002405 W KR2012002405 W KR 2012002405W WO 2012134231 A9 WO2012134231 A9 WO 2012134231A9
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phenyl
chloro
methoxy
fluoro
dichloro
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PCT/KR2012/002405
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French (fr)
Korean (ko)
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WO2012134231A2 (en
WO2012134231A3 (en
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이현규
최은복
양희철
김광록
장택수
오정택
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한국화학연구원
주식회사종근당
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Publication of WO2012134231A2 publication Critical patent/WO2012134231A2/en
Publication of WO2012134231A9 publication Critical patent/WO2012134231A9/en
Publication of WO2012134231A3 publication Critical patent/WO2012134231A3/en

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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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Definitions

  • the present invention relates to novel benzamide compounds that act as inverse agonists or antagonists of cannabinoid CB1 receptors.
  • Obesity refers to a condition in which fat, especially abdominal fat, is excessively accumulated in the human body and is medically defined as a body mass index (BMI) of 30 or more.
  • BMI body mass index
  • WHO World Health Organization
  • Obesity is caused by a number of causes, but commonly causes various adult diseases such as hypertension, diabetes, hyperlipidemia, arteriosclerosis, fatty liver, gallstones, arthritis, pulmonary dysfunction, women's disease, breast cancer, endometritis, and the like.
  • Obesity is one of the biggest causes of metabolic syndrome, including vascular diseases such as diabetes, hypertension, hyperlipidemia, and atherosclerosis. It is one of the biggest problems in modern medicine [Ref: al et al, 1999 , JAMA, 282: 1523-1529, Calle et al, 1999, N. Engl. J. Med. 341: 1097-1105.
  • Obesity is a chronic disease that is difficult to cure with short-term diet or exercise alone and requires additional medication.
  • CB1 and CB2 Two different subtypes of cannabinoid receptors (CB1 and CB2) have been isolated, all of which belong to the G protein binding receptor superfamily.
  • the cannabinoid receptor CB1R together with the CB2R and endocanabinoid ligands (endocanabinoid: ex. Anandamide, 2-AG, etc.), constitutes an endocannabinoid system that plays an important role in maintaining energy homeostasis.
  • CB1R is mainly distributed in the central nervous system, including the brain of mammals including humans, and is known to be involved in energy metabolism and appetite control.
  • CB2R is mainly distributed in peripheral tissues, especially immune cells, and is involved in various inflammation expressions including pain. [Ref .: Marzo, Nat. Rev.
  • An object of the present invention is to provide a novel benzamide compound or a pharmaceutically acceptable salt thereof, which can act as an agonist or antagonist of the cannabinoid CB1 receptor, which can be usefully used for the prevention or treatment of obesity and obesity-related metabolic diseases. will be.
  • Another object of the present invention is to provide a method for preparing the compound.
  • Another object of the present invention to provide a composition for the prevention or treatment of obesity and obesity-related metabolic diseases containing the compound as an active ingredient.
  • the present invention provides a benzamide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof and a method of preparing the same.
  • a and B are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 6 , CO 2 R 7 , CF 3 , OCF 3 , cyano or nitro group;
  • X is -O- or -S-;
  • R 1 and R 2 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, (C 2 -C 20) alkynyl,-(CH 2 ) a -Ar ,-(CH 2 ) b -HetAr, -SO 2 -R 8 , , , , or ego;
  • R One and R 2 Can form the following ring structure with N;
  • D is OR 11, SR 12 , NR 13 R 14 , CO 2 R 15 , or CN;
  • E is CH 2 , O, S, SO, SO 2 , or NR 16 ;
  • J, K are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) g -OR 21 , CO 2 R 22 , NR 23 R 24 , CONR 25 R 26 , CN, NO 2 , CF 3 , or OCF 3 ;
  • R A , R B , R C , R D are independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) h -Ar,-(CH 2 ) i -OR 27 , CO 2 R 28 , CN, NO 2 , CF 3 , or OCF 3 ;
  • R 3 is hydrogen, halogen or (C 1 -C 5) alkyl
  • R 4 , R 5 are each independently (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl,-(CH 2 ) j -Ar or-(CH 2 ) k -HetAr;
  • R 6 , R 7 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
  • R 8 is (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, or — (CH 2 ) 1 -Ar;
  • Ar is ego
  • HetAr is selected from the following structures
  • P and Q are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 31 , CO 2 R 32 , CF 3 , OCF 3 , cyano or nitro group;
  • R 11 to R 17 , R 21 to R 28 , R 31 and R 32 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
  • a to d, g to l are each an integer of 0 to 2;
  • e and f are each an integer of 0-5.
  • the substituents that may be substituted for R 1 to R 8 , R 11 to R 17 , R 21 to R 28 , R 31, and R 32 may be each independently hydrogen, halogen, (C 1 -C 10) alkyl, or halogen substituted ( C1-C10) alkyl, (C6-C30) aryl, (C3-C30) cycloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, cyano, carbazolyl, carboxyl, nitro or hydroxy It is characterized in that at least one selected from the group consisting of.
  • Substituents comprising the "alkyl” and “alkyl” moieties described in this invention include both straight and pulverized forms, and "cycloalkyl” is not only a monocyclic system, but also like adamantyl or (C7-C30) bicycloalkyl It also includes several ring hydrocarbons.
  • the invention should also be understood to include pharmaceutically acceptable salts of compounds according to the invention, and addition salts such as hydrochloride, hydrobromide or trifluoroacetic acid salts, and sodium, potassium and magnesium salts.
  • the invention should also be understood to include pharmaceutically acceptable salts of compounds according to the invention, and addition salts such as hydrochloride, hydrobromide or trifluoroacetic acid salts, and sodium, potassium and magnesium salts.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemate and optically active forms. All such compounds and enantiomers are included within the scope of the present invention.
  • compositions comprising a compound as defined above and a pharmaceutically acceptable carrier or adjuvant.
  • composition is derived from or in combination with, or in combination with, any two or more components of a product as well as a product comprising the active ingredient and an inert ingredient (pharmaceutically acceptable excipient) which constitutes the carrier. Any product resulting from dissociation of the above components or from other types of reactions or interactions of one or more components.
  • pharmaceutical compositions of the present invention include all compositions prepared by admixing a compound of formula 1, an additional active ingredient, with a pharmaceutically acceptable carrier.
  • obesity-related metabolic disease refers to a chronic disease that requires treatment to reduce excessive health risk factors associated with obesity, such as type 2 diabetes, angina, hypertension and congestive heart failure.
  • Cardiovascular diseases such as hyperlipidemia, thrombolytic disorders.
  • disease associated with the regulation of CB1 receptors refers to diseases that can be treated and prevented by the regulation of CB1 receptors. These diseases include anxiety disorders, psychosis, schizophrenia, mental disorders including depression, substance abuse disorders such as abuse or dependence of substances including alcohol dependence and nicotine dependence, memory and cognitive disorders, senile dementia, Alzheimer's disease, eating disorders , Cardiovascular diseases such as obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), angina pectoris, hypertension and congestive heart failure, hyperlipidemia, thrombolytic disorders.
  • NIDD non-insulin dependent diabetes mellitus
  • 'diseases associated with the modulation of CB1 receptors' are associated with abuse or dependence of substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), neuroinflammation, diarrhea, alcohol dependence and nicotine dependence. It is about.
  • NIDD non-insulin dependent diabetes mellitus
  • the 'disease associated with the modulation of the CB1 receptor' relates to abuse or dependence of substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), alcohol dependence and nicotine dependence, In particular obesity is most preferred.
  • substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), alcohol dependence and nicotine dependence, In particular obesity is most preferred.
  • NIDD non-insulin dependent diabetes mellitus
  • compositions of the invention can be administered orally, intramuscularly and subcutaneously.
  • Formulations for oral administration can be prepared in various forms such as syrups, tablets, capsules, creams and lozenges.
  • the syrup formulation may contain any sweetening or coloring agent, together with one or more liquid carriers selected from ethanol, peanut oil, olive oil, glycerin or water and the compounds according to the invention or salts thereof.
  • any of the pharmaceutical carriers generally used for the preparation of solid dosage forms can be used. Examples of such carriers include magnesium stearate, calcium sulfate, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • any of the general encapsulation processes may be used, for example incorporating the aforementioned carriers into the hard gelazine capsule shell.
  • any of the pharmaceutical carriers commonly used in the preparation of dispersions or suspensions may be used, such as aqueous gums, celluloses, silicates or oils. have.
  • Formulations for intramuscular or subcutaneous administration are in the form of solutions, suspensions and emulsions comprising aqueous solvents such as water, saline and Ringer's solution and lipophilic solvents such as fatty oils, sesame oil, corn oil and synthetic fatty acid esters. Can be prepared.
  • aqueous solvents such as water, saline and Ringer's solution
  • lipophilic solvents such as fatty oils, sesame oil, corn oil and synthetic fatty acid esters.
  • the pharmaceutical composition is preferably formulated in a form suitable for the patient.
  • Each unit dose of the formulation for oral administration suitably contains 0.1 to 500 mg / kg, preferably 1 to 100 mg / kg of the compound of formula 1 or a pharmaceutically acceptable salt thereof.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient may be administered 1 to 6 times in an amount of 0.01 to 40 mg / kg body weight per day, depending on the condition of the patient.
  • the compounds of formula 1 and their pharmaceutically acceptable salts can be used as medicaments, such as medicaments in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They are for example orally such as in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally for example in the form of suppositories, parenterally such as in the form of injection solutions or infusion solutions, or topically. In the form of ointments, creams or oils, for example. Oral administration is preferred.
  • the preparation of pharmaceutical preparations may be carried out by combining the compound of Formula 1 or a pharmaceutically acceptable salt thereof, optionally with other therapeutically important substances, in a preferred nontoxic inert pharmaceutically compatible solid or liquid carrier. It can be carried out in a manner familiar to those skilled in the art by making the galenose formulation dosage form in combination with the substance and, if necessary, conventional pharmaceutical auxiliaries.
  • the carrier material is acceptable as well as inorganic carrier material. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules.
  • Suitable carrier materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (which are necessary for soft capsules, although the carrier may not be necessary depending on the nature of the active ingredient).
  • Preferred carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
  • Preferred carriers for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
  • Suitable carrier materials for suppositories are, for example, natural or light oils, waxes, fats and semi-liquid or liquid polyols.
  • Preferred carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
  • Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for osmotic pressure changes, buffer materials, solubilizers, coloring and masking agents, and antioxidants are contemplated as pharmaceutical auxiliaries.
  • the dosage of the compound of formula 1 may vary within wide ranges depending on the disease, age and patient's individual condition and mode of administration, and will naturally be adjusted to the individual requirements in each particular case. For adults, a daily dosage of about 0.1 to 500 mg / kg, especially about 1 to 100 mg / kg, is contemplated. Depending on the severity of the disease and the exact pharmacokinetic profile, the compounds may be administered in one daily dosage unit or in several daily dosage units, such as one to three dosage units.
  • the pharmaceutical preparations conveniently contain about 0.1 to 500 mg / kg, preferably 1 to 100 mg / kg of the compound of formula (1).
  • Benzamide derivative (4) according to the present invention can be prepared as shown in the following scheme.
  • Compound 2 is hydrolyzed to synthesize carboxylic acid (3).
  • Carboxylic acid 3 is activated with acid chloride, active easter or mixed anhydride in a conventional manner and then reacted with HNR 1 R 2 to synthesize 4.
  • Compound 4 can also be synthesized by reacting carboxylic acid (3) with HNR 1 R 2 in the presence of binding reagents (DCC, EDC, BOP, HMPU).
  • Amide derivatives 8 according to the invention can be prepared as shown in Scheme 2 below.
  • the aniline compound (10) can be obtained by reducing the nitro compound (9) by a conventional method.
  • the amide compound (8) can be synthesized using aniline compound (10) and carboxylic acid (11) using binding reagents (DCC, EDC, BOP, HMPU).
  • the aryl urea derivative 12 according to the present invention can be prepared as shown in Scheme 3 below.
  • Isocyanate compound (13) can be synthesized from benzoic acid (3) via Curtius rearrangement. That is, compound (3) can be converted to an acid azide compound by a conventional method, and then heated to synthesize an isocyanate compound (13), which can be reacted with an amine (R 1 R 2 NH) to synthesize urea compound (12). have.
  • the urea compound (12) can also be synthesized by condensing aniline compound 10 and carbamoyl chloride compound 14 in the presence of a base, as shown in Scheme 4 below.
  • L is Cl, Br, I, OTs or OMs
  • R 1 , R 2 , R 3 , R 4 , and R 5 are the same as above, and R 'is a (C1-C20) alkyl or (C3-C20) cycloalkyl group.
  • the benzamide compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an excellent inhibitory effect on cannabinoid receptor 1 (CB1). Therefore, the pharmaceutical composition comprising as an active ingredient a benzamide compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is expected to have an excellent effect in the prevention or treatment of obesity or obesity-related metabolic diseases.
  • 1 shows a screening system of CHO-CB1- # 37 cells.
  • FIG. 2 is a diagram illustrating a 96well plate screening system.
  • 3 is a graph of the IC 50 value of the compound rimonabant used as a control agent.
  • HBTU O-benzotriazol-1-yl-N, N, N, N-tetramethyluronium hexafluorophosphate
  • NMM N-methyl morpholine
  • ether diethyl ether
  • brine means saturated aqueous NaCl solution.
  • temperatures are all in degrees Celsius. All reactions were carried out under inert atmosphere at room temperature unless otherwise noted, and all solvents were used with the highest purity unless otherwise noted.
  • Mass spectra were obtained using one of the following instruments [Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI or Agilent, 1100LC / MSD, ESI].
  • Flash column chromatography analysis was performed using Merck silica gel 60 (230-400 mesh). Most reactions are thin layer chromatography using E. Merck 0.25 mm silica gel plates (60F-254) and UV detection using 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Monitoring by graphy.
  • Step 1 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid methyl ester
  • Step 2 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid
  • step 3 It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and cyclohexyl amine. .
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-ethyl-N-propyl amine )
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 1-amino adamantane Thus synthesized.
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-amino morpholine Synthesized.
  • step 3 It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and isobutyl amine. .
  • Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-trifluoromethyl-benzyl amine It synthesize
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-amino piperidine Thus synthesized.
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxy-cyclohexyl amine )
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 1-hydroxymethyl-2-methyl-propyl amine 3, method 2).
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-sec-butyl amine Thus synthesized.
  • Example 1 (Step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-dimethylamino-1-methyl-ethyl amine 3, method 2).
  • step 3 It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiomorpholine. .
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-2-methyl-propanoic acid methylester 3, method 2).
  • Example 1 (Step 3, Method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methyl-piperazine Thus synthesized.
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxy-1,1-dimethyl-ethyl amine It synthesize
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-aminomethyl pyridine Synthesized.
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-aminomethyl pyridine Synthesized.
  • step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-aminomethyl pyridine Synthesized.
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-hydroxy-piperidine )
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-hydroxy-piperidine )
  • Example 25 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidin-4-one
  • Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-oxo-piperidine According to the synthesis.
  • Example 26 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-4-carboxylic acid methyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methoxycarbonyl-piperidine It synthesize
  • Example 27 ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl ⁇ -(1,1-dioxo-thiomorpholine- 4-day) -methanone
  • Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-dioxo-thiomorpholine )
  • Example 28 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-3-carboxylic acid ethyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-ethoxycarbonyl-piperidine It synthesize
  • Example 29 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-2-carboxylic acid ethyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-ethoxycarbonyl-piperidine It synthesize
  • Example 30 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-bis-hydro Oxymethyl-ethyl) -benzamide
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and tris (hydroxymethyl) methyl amine )
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-4-methyl-pentanoic acid tert-butyl ester It synthesize
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-methyl-butanoic acid ethyl ester 3, method 2).
  • Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-acetic acid tert-butyl ester It synthesize
  • Example 36 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to method 4).
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-propionic acid benzyl ester According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-acetic acid ethyl ester According to the synthesis.
  • Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-succinic acid 1-tert-butyl ester , According to Method 4).
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-pentanedioic acid diethyl ester Synthesis was carried out according to method 4).
  • Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-phenyl-propionic acid methyl ester , According to Method 4).
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-phenyl-propionic acid tert-butyl ester Synthesis was carried out according to step 3, method 4).
  • Example 1 (Step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-hydroxy-propionic acid methylester 3, method 4).
  • Example 45 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid tert- Butyl ester
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-hydroxy-butyl acid methyl ester Synthesis was carried out according to step 3, method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-hydroxy-pyrrolidine )
  • Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxymethyl-pyrrolidine It synthesize
  • Example 1 (Step 3, Method 4 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and pyrrolidine-2-carboxylic acid )
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-methyl-butanoic acid Synthesis was carried out according to method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-2-carboxylic acid )
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-4-carboxylic acid )
  • Example 56 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid sodium salt
  • Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and tert-butyl amine )
  • Example 57 (step from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-propazyl amine It synthesize
  • Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and morpholine Thus synthesized.
  • Example 65 ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino ⁇ -acetic acid tert-butyl ester
  • Example 57 (step from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 3-hydroxy proline It synthesize
  • Example 70 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid amide
  • Example 72 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-dimethyl-ethyl)- Benzamide
  • Example 74 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid ethyl ester
  • Example 75 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine-2-carboxylic acid isopropyl ester
  • Example 80 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N, N-bis- (2-hydroxy-ethyl) -benzamide
  • Example 81 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-3-carboxylic acid ethyl ester
  • Example 82 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ -piperidine-2-carboxylic acid ethyl ester
  • Example 84 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl ⁇ pyrrolidine-2-carboxylic acid dimethylamide
  • Example 57 (Step 2 from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-allyl amine )
  • Example 57 from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 4-chloro-benzenesulfonamide It synthesize
  • Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and methanesulfonamide According to the synthesis.
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and N- (4-trifluoromethyl-benzyl) amine Synthesis was carried out according to step 3, method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and N-amino-piperidine According to the synthesis.
  • Example 100 1- ⁇ 3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzoyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to method 4).
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 3-hydroxy-pyrrolidine )
  • Example 1 (Step 3, Method) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxymethyl-pyrrolidine It synthesize
  • Example 104 1- ⁇ 3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] benzoyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 3-hydroxy-pyrrolidine Synthesized.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxymethyl-pyrrolidine Thus synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and thiazolidine-4-carboxylic acid methyl ester According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxy-cyclohexylamine Synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 4-trifluoromethyl-benzylamine )
  • step 3 It was synthesized according to example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and isobutyl amine.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and N-aminopiperidine Synthesized.
  • Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester It synthesize
  • Example 120 ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-phenyl ⁇ -(3-hydroxy-pyrrolidin-1-yl ) -Methanone
  • Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 3-hydroxy-pyrrolidine According to the synthesis.
  • Example 1 (Step 3, Method 4 from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 2-hydroxymethyl-pyrrolidine )
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and 3-hydroxy-pyrrolidine Synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and 2-hydroxymethyl-pyrrolidine Thus synthesized.
  • Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and thiazolidine-4-carboxylic acid methyl ester According to the synthesis.
  • Example 126 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-N-piperidin-1-yl-benzamide
  • Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and N- (2-hydroxycyclohexyl) amine It synthesize
  • Example 128 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-p-tolyl-benzamide
  • Example 130 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-methoxy-benzamide
  • Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and 4-trifulormethyl-benzylamine It synthesize
  • Example 132 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-piperidin-1-yl-benzamide
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and N-amino-piperidine According to the synthesis.
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and tert-butyl amine Thus synthesized.
  • Example 136 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyll-N- (4-trifluoromethyl-benzyl) -benzamide
  • Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and 4-trifluoromethyl-benzylamine , According to Method 4).
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and isobutyl amine Synthesized.
  • Example 138 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoyl ⁇ -pyrrolidine-2-carboxylic acid Methyl ester
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester 3, method 4).
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and N- (2-hydroxy-cyclohexyl) amine It synthesize
  • Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and tert-butyl amine According to the synthesis.
  • Example 141 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N- (4-trifluoromethyl-benzyl)- Benzamide
  • Example 1 (step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and 4-trifluoromethyl-benzyl amine 3, method 4).
  • Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to step 3, method 4).
  • Example 145 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (4-trifluoromethyl-benzyl) -benzamide
  • Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-benzoic acid and 4-trifluoromethyl-benzyl amine According to the synthesis.
  • Example 150 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide
  • Example 152 4- [bis- (4-fluorophenyl) -methoxy] -3-fluoro-N- (piperidin-1-yl) benzamide
  • Example 156 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N-ethyl-N-propyl-benzamide
  • Step 3 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester
  • Step 4 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid
  • Example 158 (step 5) from 4-[(2-chloro-phenyl)-(5-chloro-pyridin-3-yl) -methoxy] -3-fluoro-benzoic acid and methyl (S) -proline Synthesized.
  • Example 160 1- ⁇ 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl ⁇ -pyrrolidine- 2-carboxylic acid methyl ester
  • Step 3 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester
  • Step 4 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid
  • Example 16 1- ⁇ 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-benzoyl ⁇ -Pyrrolidine-2-carboxylic acid methyl ester
  • Step 2 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid methyl ester
  • Step 3 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid
  • Example 1 (step 3, method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-fluoro-benzoic acid and tert-butylamine Synthesis was carried out in the same process.
  • Example 1 (Step 3, Method 4) using 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and N-amino-pyridine Synthesis was carried out in the same process as).
  • Example 1 (step 3, using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and 4-trifluoromethyl-benzylamine Synthesis was carried out in the same manner as in Method 4).
  • Example 1 (step 3, method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and tert-butylamine Synthesis was carried out in the same process.
  • Example 1 (step 3, using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and 4-trifluoromethyl-benzyl Synthesis was carried out in the same manner as in Method 4).
  • Example 1 (step 3, method using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and N-amino-piperidine It synthesize
  • Step 1 1-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-4-nitro-benzene
  • Example 176 Process of Example 176 (step 3) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline and 4-trifluoromethyl benzoyl chloride Synthesized.
  • Example 176 (step 3) process from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline and 2,2-dimethyl-propionic acid chloride Synthesized.
  • Example 180 1- ⁇ 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl ⁇ -3- (4-trifluoromethyl-benzyl ) -Urea
  • Example 180 It was synthesized according to the process of Example 180 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and t-butylamine.
  • Example 176 In the process of Example 176 (step 3) from 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-aniline and 2,2-dimethyl-propionic acid chloride Synthesized.
  • Example 184 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid N '-(2,2-dimethyl-propionyl) -hydride Zayed
  • Human CNR1 (NM016083) was cloned in human brain tumor cells (SNB-19).
  • the cloning method is briefly described by treating the human brain tumor cells with Trizol (Invitorgen) and chloroform, separating the layers by centrifugation, taking the supernatant, and then mixing the isopropyl alcohol to precipitate the mRNA.
  • CDNA is synthesized by RT-PCR (reverse transcriptional polymerase chain reaction) kit (Bioneer), amplified by polymerase chain reaction (PCR) using specific primers of cannabinoid receptor1 (CNR1), and recombined with pTarget (Invitrogen). .
  • RT-PCR reverse transcriptional polymerase chain reaction
  • CNR1 recombined with pTarget is introduced into CHO-K1 (ATCC) with a pCRE (Takara) vector and treated with 500ug / ml G418 (Gibco) for 2 weeks to select cells into which the vector is introduced.
  • CHO-CB1- # 37 cells were selected as an experiment to confirm whether luciferase increased by forskolin was inhibited by CP55940 and increased by Rimonabant (self synthesis) by simultaneously treating 2uM forskolin, 20nM CP55940 and 200nM Rimonabant.
  • the screening system of cells is shown in FIG. 1 below.
  • Selected CHO-CB1- # 37 cells are cultured in DMEM (Dulbecco's Modified Eagle Medium; Gibco), 10% FBS (fetal bovine serum; Gibco), 50ug / ml G418 medium.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • cultured CHO-CB1- # 37 cells were separated into individual cells with 0.05% trypsin EDTA (Gibco) solution, and then treated with DMEM culture medium, 20,000 cells per well were put into a 96-well plate (Corning). Incubate for 24 hours at 37 degrees in a 5% CO 2 incubator (Thermo).
  • Luminoskan (Thermo) was used to treat 50ul luciferase assay solution and measure luciferase activity for 10 seconds per well.
  • the activity of Rimonabant was measured by calculating 100% of samples treated with 2uM forkolin and 0% of wells treated with 2uM forskolin and 20nM CP55940 simultaneously. Rimonabant is used as a control antagonist for CNR1.
  • IC 50 of Rimonabant is shown in FIG. 3.
  • Human CNR2 (NM001841) was cloned in HepG2 cells.
  • CDNA is synthesized by RT-PCR (reverse transcriptional polymerase chain reaction) kit (Bioneer), amplified by PCR (polymerase chain reaction) using specific primers of CNR2, and recombined into pTarget (Invitrogen).
  • RT-PCR reverse transcriptional polymerase chain reaction
  • CNR1 recombined with pTarget is introduced into CHO-K1 (ATCC) with a pCRE (Takara) vector and treated with 500ug / ml G418 (Gibco) for 2 weeks to select cells into which the vector is introduced.
  • Compound screening methods are the same as for CHO-CB1- # 37 cells. Only CHO-CB2- # 57 cells did not increase the activity of luciferase inhibited by CP55940 by 200 nM Rimonabant.

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Abstract

The present invention relates to a novel benzamide compound functioning as an inverse agonist or an antagonist of a cannabinoid receptor (CB1), or pharmaceutically acceptable salts thereof. The compound according to the invention is useful for the prevention or treatment of obesity and obesity- related metabolic diseases. In addition, the invention provides a method for preparing the benzamide compound, a pharmaceutical compound including the same, and a method for the prevention or treatment of obesity and obesity- related metabolic diseases.

Description

카나비노이드 수용체（ＣＢ１） 길항제로서의 벤즈아미드 유도체Benzamide Derivatives as Cannabinoid Receptor (Cv1) Antagonists
본 발명은 칸나비노이드 CB1 수용체의 역효능제 또는 길항제로서 작용하는 신규한 벤즈아미드 화합물에 관한 것이다.The present invention relates to novel benzamide compounds that act as inverse agonists or antagonists of cannabinoid CB1 receptors.
비만은 인체내에 지방, 특히 복부지방이 과도하게 축척된 상태를 말하며 의학적으로는 체지방지수 (BMI: body mass index)가 30 이상인 상태로 정의된다. 최근 비만인구가 전세계적으로 급증하고 또한 이와 관련된 질병의 유병률과 사망률도 증가함에 따라 세계 보건기구 (WHO)는 비만을 세계인의 건강을 심각하게 위협하는 세계 10대 질병의 하나로 규정하고 있다 [참고문헌: Report of a WHO Consultation on Obesity: Obesity-Preventing and Managing a Global Epidemic World Health Organization: Geneva, 1997]. 비만은 여러원인에 의하여 발생하나 공통적으로 고혈압, 당뇨병, 고지혈증, 동맥경화, 지방간, 담석증, 관절염, 폐기능장애, 부인병, 유방암, 자궁내막염등과 같은 다양한 성인병의 원인이되고 있다. 특히 비만은 당뇨, 고혈압, 고지혈증, 동맥경화등의 혈관질환을 포함하는 대사증후군 (metabolic syndrome)의 가장 큰 원인질병으로 현대의학의 가장 큰 문제의 하나가 되고 있다 [참고문헌: Must et al, 1999, JAMA, 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341:1097-1105]. 비만은 만성 질환으로서 단기간의 식이요법 또는 운동만으로는 치유하기가 어렵고 부가적인 약물 치료가 필요하다. 그러나 이러한 비만의 심각성에 비하여 현재 사용되어 질 수 있는 약제는 제한적이다. 현재 장기복용이 가능한 비만치료제로 허가 받은 약제는 중추신경계에 작용하여 식욕을 감소시키는 작용을 하는 리덕틸(sibutramine)과 장관에서 지방의 흡수를 저해하는 제니칼(orlistat)의 2 약제 뿐이다. 그러나 리덕틸도 구강건조증, 두통, 변비, 불면증등의 부작용을 수반하고 있으며 부작용 때문에 한국을 포함하여 여러나라에서 사용이 금지된 상태이다. 제니칼도 지용성 비티민의 흡수방해, 지방변등의 부작용을 나타내기 때문에 최근 들어서는 판매량이 지속적으로 감소하고 있다. 그러므로 안전하고 장기적으로 사용할 수 있는 비만 치료제의 개발이 절실하게 요구되고 있다.Obesity refers to a condition in which fat, especially abdominal fat, is excessively accumulated in the human body and is medically defined as a body mass index (BMI) of 30 or more. In recent years, as the obesity population has surged worldwide and the prevalence and mortality rates of related diseases have increased, the World Health Organization (WHO) has identified obesity as one of the top 10 diseases that seriously threaten the health of people around the world. : Report of a WHO Consultation on Obesity: Obesity-Preventing and Managing a Global Epidemic World Health Organization: Geneva, 1997]. Obesity is caused by a number of causes, but commonly causes various adult diseases such as hypertension, diabetes, hyperlipidemia, arteriosclerosis, fatty liver, gallstones, arthritis, pulmonary dysfunction, women's disease, breast cancer, endometritis, and the like. Obesity is one of the biggest causes of metabolic syndrome, including vascular diseases such as diabetes, hypertension, hyperlipidemia, and atherosclerosis. It is one of the biggest problems in modern medicine [Ref: al et al, 1999 , JAMA, 282: 1523-1529, Calle et al, 1999, N. Engl. J. Med. 341: 1097-1105. Obesity is a chronic disease that is difficult to cure with short-term diet or exercise alone and requires additional medication. However, compared with the severity of obesity, currently available drugs are limited. Currently, the only two drugs that can be used for obesity treatment are reductyl, which acts on the central nervous system and reduces appetite, and two drugs, orlistat, which inhibit fat absorption in the intestine. However, reductil also has side effects such as dry mouth, headache, constipation and insomnia, and it is banned in many countries including Korea due to its side effects. Since Zenical also has side effects such as absorption of fat-soluble vitamins and fatty stools, sales volume has been continuously decreasing in recent years. Therefore, there is an urgent need for the development of safe and long-term obesity drugs.
카나비노이드 수용체의 상이한 두 아형(subtype) (CB1 및 CB2)이 단리되어 졌고, 이들 모두는 G 단백질 결합 수용체 상과 (superfamily)에 속한다. 카나비노이드 수용체 CB1R은 CB2R 및 엔도카나비노이드 리간드 (endocanabinoid: ex. anandamide, 2-AG 등)와 함께 에너지 항상성 (energy homeostasis) 유지에 중요한 역할을 하는 엔도카나비노이드 시스템 (endocanabinoid system)을 구성하고 있다. CB1R은 인간을 포함한 포유류의 뇌를 비롯한 중추신경계에 주로 분포하며 에너지대사와 식욕조절에 관여하는 것으로 알려져 있고 CB2R은 말초조직, 특히 면역 세포에 주로 분포되어 있고 통증을 포함한 여러 가지 염증발현에 관여하는 것으로 알려져 있다 [참고문헌: Marzo, Nat. Rev. Drug Discov. 2008, 7, 438-455.; Marzo et al, Trends Endocrin. Metabo. 2006, 18, 27-37]. CB1 수용체의 길항제는 많은 생체외 및 생체내 실험에 의하여 중추 및 말초 작용 메카니즘을 통하여 에너지 항상성에 영향을 미칠수 있다는 것이 알려 졌으며 선택적 CB1 수용체 길항제인 리모나반트(rimonabant, SR141716A)는 임상실험에서 비만환자의 체중을 효과적으로 감소시키며, 또한 비만과 관련된 당뇨나 심혈관질환등의 대사증후군 질병도 완화시킬 수 있다는 것이 증명된 이후 CB1 수용체는 비만 및 비만 관련 대사증후군 질환을 치료할 수 있는 유망한 표적이 되었다 [참고문헌: Pagotto et al, 2006, Endocrine Reviews, 27, 73-100; Tucci et al, 2006, Curr. Med. Chem. 13, 2669-2680; Lange and Kruse, 2004, Curr. Opinion Drug Discov. Dev., 7, 498-506]. Two different subtypes of cannabinoid receptors (CB1 and CB2) have been isolated, all of which belong to the G protein binding receptor superfamily. The cannabinoid receptor CB1R, together with the CB2R and endocanabinoid ligands (endocanabinoid: ex. Anandamide, 2-AG, etc.), constitutes an endocannabinoid system that plays an important role in maintaining energy homeostasis. CB1R is mainly distributed in the central nervous system, including the brain of mammals including humans, and is known to be involved in energy metabolism and appetite control. CB2R is mainly distributed in peripheral tissues, especially immune cells, and is involved in various inflammation expressions including pain. [Ref .: Marzo, Nat. Rev. Drug Discov. 2008, 7, 438-455 .; Marzo et al, Trends Endocrin. Metabo. 2006, 18, 27-37. It has been found that antagonists of CB1 receptors can affect energy homeostasis through central and peripheral mechanisms of action by a number of in vitro and in vivo experiments. Rimonabant (SR141716A), a selective CB1 receptor antagonist, has been used in clinical CB1 receptors have become a promising target for the treatment of obesity and obesity-related metabolic syndrome since it has been shown to effectively reduce body weight and can also alleviate metabolic syndrome diseases such as obesity-related diabetes and cardiovascular disease. Pagotto et al, 2006, Endocrine Reviews, 27, 73-100; Tucci et al, 2006, Curr. Med. Chem. 13, 2669-2680; Lange and Kruse, 2004, Curr. Opinion Drug Discov. Dev., 7, 498-506].
비만의 심각성에 비하여 현재 이를 치료하 수 있는 효과적인 약제가 부족한 상황을 고려할 때 효과적인 CB1 수용체 길항제의 개발은 비만 및 비만과 관련된 대사증후군 치료제 개발에 있어서 매우 중요한 역할을 할 것이다 [참고문헌: Adam et al., Expert Opin.Ther.Patents, 2002, 12, 1475-1489; Hertzog, Expert Opin.Ther. Patents, 2004, 14, 1435-1452; Lange et al., Drug Discov. Today, 2005, 10, 693-702; Bishop, J Med. Chem., 2006, 49, 4008-4016].Given the current lack of effective medications to treat the severity of obesity, the development of effective CB1 receptor antagonists will play a very important role in the development of obesity and obesity-related metabolic syndrome therapies [Reference: Adam et al. ., Expert Opin. Ther. Patents, 2002, 12, 1475-1489; Hertzog, Expert Opin. Ther. Patents, 2004, 14, 1435-1452; Lange et al., Drug Discov. Today, 2005, 10, 693-702; Bishop, J Med. Chem., 2006, 49, 4008-4016.
본 발명의 목적은 카나비노이드 CB1 수용체의 역효능제 또는 길항제로서 작용하여 비만 및 비만 관련 대사질환의 예방 또는 치료에 유용하게 사용될 수 있는, 신규의 벤즈아미드 화합물 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다. An object of the present invention is to provide a novel benzamide compound or a pharmaceutically acceptable salt thereof, which can act as an agonist or antagonist of the cannabinoid CB1 receptor, which can be usefully used for the prevention or treatment of obesity and obesity-related metabolic diseases. will be.
본 발명의 다른 목적은 상기 화합물의 제조방법을 제공하는 것이다. Another object of the present invention is to provide a method for preparing the compound.
본 발명의 또 다른 목적은 상기 화합물을 유효성분으로서 함유하는 비만 및 비만 관련 대사질환의 예방 또는 치료용 조성물을 제공하는 것이다.Another object of the present invention to provide a composition for the prevention or treatment of obesity and obesity-related metabolic diseases containing the compound as an active ingredient.
상기 목적에 따라 본 발명에서는 하기 화학식 1의 벤즈아미드 유도체 화합물 또는 이의 약학적으로 허용가능한 염 및 이의 제조방법을 제공한다.In accordance with the above object, the present invention provides a benzamide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof and a method of preparing the same.
[화학식 1][Formula 1]
Figure PCTKR2012002405-appb-I000001
Figure PCTKR2012002405-appb-I000001
상기 화학식에서,In the above formula,
A 및 B는 각각 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -CH2-triazole, -CH2-imidazole, OR6, CO2R7, CF3, OCF3, 시아노 또는 니트로기 이며;A and B are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 6 , CO 2 R 7 , CF 3 , OCF 3 , cyano or nitro group;
X는 -O- 또는 -S- 이고;X is -O- or -S-;
Y는 단일결합, -(C=O)- 또는 -(C=S)- 이며; Y is a single bond,-(C = O)-or-(C = S)-;
R1 및 R2는 각각 독립적으로 수소, (C1-C20)알킬, (C3-C20)시클로알킬, (C2-C20)알케닐, (C2-C20)알키닐, -(CH2)a-Ar, -(CH2)b-HetAr, -SO2-R8,
Figure PCTKR2012002405-appb-I000002
,
Figure PCTKR2012002405-appb-I000003
,
Figure PCTKR2012002405-appb-I000004
,
Figure PCTKR2012002405-appb-I000005
또는
Figure PCTKR2012002405-appb-I000006
이고;R 1 and R 2 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, (C 2 -C 20) alkynyl,-(CH 2 ) a -Ar ,-(CH 2 ) b -HetAr, -SO 2 -R 8 ,
Figure PCTKR2012002405-appb-I000002
,
Figure PCTKR2012002405-appb-I000003
,
Figure PCTKR2012002405-appb-I000004
,
Figure PCTKR2012002405-appb-I000005
or
Figure PCTKR2012002405-appb-I000006
ego;
R1과 R2 는 N과 함께 하기 링 구조를 형성할 수 있고;ROneand R2 Can form the following ring structure with N;
Figure PCTKR2012002405-appb-I000007
,
Figure PCTKR2012002405-appb-I000008
Figure PCTKR2012002405-appb-I000007
,
Figure PCTKR2012002405-appb-I000008
D는 OR11, SR12, NR13R14, CO2R15, 또는 CN 이며;D is OR 11, SR 12 , NR 13 R 14 , CO 2 R 15 , or CN;
E는 CH2, O, S, SO, SO2, 또는 NR16 이고;E is CH 2 , O, S, SO, SO 2 , or NR 16 ;
G는 CH2, -(C=0)-, O, S, SO, SO2, 또는 NR17 이며;G is CH 2 ,-(C = 0)-, O, S, SO, SO 2 , or NR 17 ;
J, K 는 각각 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -(CH2)g-OR21, CO2R22, NR23R24, CONR25R26, CN, NO2, CF3, 또는 OCF3 이고; J, K are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) g -OR 21 , CO 2 R 22 , NR 23 R 24 , CONR 25 R 26 , CN, NO 2 , CF 3 , or OCF 3 ;
RA, RB, RC, RD 는 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -(CH2)h-Ar,-(CH2)i-OR27, CO2R28, CN, NO2, CF3, 또는 OCF3 이며; R A , R B , R C , R D are independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) h -Ar,-(CH 2 ) i -OR 27 , CO 2 R 28 , CN, NO 2 , CF 3 , or OCF 3 ;
R3는 수소, 할로겐 또는 (C1-C5)알킬이며;R 3 is hydrogen, halogen or (C 1 -C 5) alkyl;
R4, R5는 각각 독립적으로 (C1-C20)알킬, (C3-C20)시클로알킬, -(CH2)j-Ar 또는 -(CH2)k-HetAr 이고;R 4 , R 5 are each independently (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl,-(CH 2 ) j -Ar or-(CH 2 ) k -HetAr;
R6, R7은 각각 독립적으로 수소, (C1-C20)알킬, (C3-C20)시클로알킬 이며;R 6 , R 7 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
R8은 (C1-C20)알킬, (C3-C20)시클로알킬, 또는 -(CH2)l-Ar 이고;R 8 is (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, or — (CH 2 ) 1 -Ar;
Ar은
Figure PCTKR2012002405-appb-I000009
이고;Ar is
Figure PCTKR2012002405-appb-I000009
ego;
HetAr은 하기 구조에서 선택되어 지며;HetAr is selected from the following structures;
P, Q는 각각 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -CH2-triazole, -CH2-imidazole, OR31, CO2R32, CF3, OCF3, 시아노 또는 니트로기 이고;P and Q are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 31 , CO 2 R 32 , CF 3 , OCF 3 , cyano or nitro group;
R11 내지 R17, R21 내지 R28, R31 및 R32 은 각각 독립적으로 수소, (C1-C20)알킬, (C3-C20)시클로알킬 이고;R 11 to R 17 , R 21 to R 28 , R 31 and R 32 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
a 내지 d, g 내지 l은 각각 0 내지 2의 정수이며;a to d, g to l are each an integer of 0 to 2;
e, f는 각각 0 내지 5의 정수이다.e and f are each an integer of 0-5.
상기 R1 내지 R8, R11 내지 R17, R21 내지 R28, R31 및 R32에 치환될 수 있는 치환기는 서로 독립적으로 수소, 할로겐, (C1-C10)알킬, 할로겐이 치환된 (C1-C10)알킬, (C6-C30)아릴, (C3-C30)시클로알킬, (C2-C10)알케닐, (C2-C10)알키닐, 시아노, 카바졸릴, 카르복실, 니트로 또는 히드록시로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 한다.The substituents that may be substituted for R 1 to R 8 , R 11 to R 17 , R 21 to R 28 , R 31, and R 32 may be each independently hydrogen, halogen, (C 1 -C 10) alkyl, or halogen substituted ( C1-C10) alkyl, (C6-C30) aryl, (C3-C30) cycloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, cyano, carbazolyl, carboxyl, nitro or hydroxy It is characterized in that at least one selected from the group consisting of.
본 발명에 기재된 「알킬」 및 「알킬」부분을 포함하는 치환체는 직쇄 또는 분쇄 형태를 모두 포함하고, 「시클로알킬」은 단일 고리계 뿐만 아니라 아다만틸 또는 (C7-C30)바이시클로알킬과 같은 여러 고리계 탄화수소도 포함한다. Substituents comprising the "alkyl" and "alkyl" moieties described in this invention include both straight and pulverized forms, and "cycloalkyl" is not only a monocyclic system, but also like adamantyl or (C7-C30) bicycloalkyl It also includes several ring hydrocarbons.
본 발명은 또한 본 발명에 따른 화합물의 약학적으로 허용가능한 염, 및 부가염, 예컨대 염산염, 브롬화수소산염 또는 트라이플루오로아세트산염, 및 나트륨, 칼륨 및 마그네슘염을 포함하는 것으로 이해되어야 한다.The invention should also be understood to include pharmaceutically acceptable salts of compounds according to the invention, and addition salts such as hydrochloride, hydrobromide or trifluoroacetic acid salts, and sodium, potassium and magnesium salts.
본 발명은 또한 본 발명에 따른 화합물의 약학적으로 허용가능한 염, 및 부가염, 예컨대 염산염, 브롬화수소산염 또는 트라이플루오로아세트산염, 및 나트륨, 칼륨 및 마그네슘염을 포함하는 것으로 이해되어야 한다.The invention should also be understood to include pharmaceutically acceptable salts of compounds according to the invention, and addition salts such as hydrochloride, hydrobromide or trifluoroacetic acid salts, and sodium, potassium and magnesium salts.
본 발명의 화합물은 하나 이상의 비대칭 탄소 원자를 함유할 수 있으며, 라세미체 및 광학적 활성 형태로 존재할 수 있다. 이러한 화합물 및 거울상 이성질체 모두는 본 발명의 범주내에 포함되는 것이다.The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemate and optically active forms. All such compounds and enantiomers are included within the scope of the present invention.
또한, 본 발명은 상기 정의된 화합물 및 약학적으로 허용가능한 담체 또는 보조제(adjuvant)를 포함하는 약학적 조성물을 제공한다. 약학적 조성물에서와 같이 "조성물"이란 용어는 활성 성분 및 담체를 구성하는 불활성 성분(약제학적으로 허용되는 부형제)를 포함하는 생성물뿐만 아니라 임의의 2개 이상의 성분들의 배합, 복합 또는 응집으로부터 또는 하나 이상의 성분의 해리로부터 또는 하나 이상의 성분의 다른 종류의 반응 또는 상호작용으로부터 초래되는 임의의 생성물을 포함한다. 따라서, 본 발명의 약제학적 조성물은 화학식 1의 화합물, 추가의 활성 성분과 약제학적으로 허용되는 담체들을 혼합하여 제조되는 모든 조성물을 포함한다.The present invention also provides a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier or adjuvant. As in pharmaceutical compositions, the term “composition” is derived from or in combination with, or in combination with, any two or more components of a product as well as a product comprising the active ingredient and an inert ingredient (pharmaceutically acceptable excipient) which constitutes the carrier. Any product resulting from dissociation of the above components or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention include all compositions prepared by admixing a compound of formula 1, an additional active ingredient, with a pharmaceutically acceptable carrier.
본원에서 사용된 용어 "비만-관련 대사질환"은 비만과 관련된 과도한 건강 위험인자를 감소시키는 치료를 필요로 하는 만성 질환을 의미하며, 그 예로는 제2형 당뇨병, 협심증, 고혈압 및 울혈성 심장마비와 같은 심혈관 질환, 고지혈증, 혈전용해장애가 포함된다.As used herein, the term “obesity-related metabolic disease” refers to a chronic disease that requires treatment to reduce excessive health risk factors associated with obesity, such as type 2 diabetes, angina, hypertension and congestive heart failure. Cardiovascular diseases, such as hyperlipidemia, thrombolytic disorders.
본원에서, 'CB1 수용체의 조절과 관련된 질병'은 CB1 수용체의 조절에 의해 치료 및 예방될 수 있는 질병을 의미한다. 이런 질병은 불안 장애, 정신병, 정신분열병, 우울증을 포함하는 정신 질환, 물질 남용 장애, 예컨대 알콜 의존증 및 니코틴 의존증을 포함하는 물질의 남용 또는 의존성, 기억 및 인지 장애, 노인성 치매, 알츠하이머병, 섭식 장애, 비만, 제Ⅱ형 당뇨병 또는 비 인슐린 의존성 당뇨병(NIDD), 협심증, 고혈압 및 울혈성 심장마비와 같은 심혈관 질환, 고지혈증, 혈전용해장애를 포함하지만 이에 한정되지는 않는다.As used herein, "disease associated with the regulation of CB1 receptors" refers to diseases that can be treated and prevented by the regulation of CB1 receptors. These diseases include anxiety disorders, psychosis, schizophrenia, mental disorders including depression, substance abuse disorders such as abuse or dependence of substances including alcohol dependence and nicotine dependence, memory and cognitive disorders, senile dementia, Alzheimer's disease, eating disorders , Cardiovascular diseases such as obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), angina pectoris, hypertension and congestive heart failure, hyperlipidemia, thrombolytic disorders.
바람직하게는 'CB1 수용체의 조절과 관련된 질병'은 섭식 장애, 비만, 제Ⅱ형형 당뇨병 또는 비 인슐린 의존성 당뇨병(NIDD), 신경염증, 설사, 알콜 의존증 및 니코틴 의존증을 포함하는 물질의 남용 또는 의존성에 관한 것이다.Preferably, 'diseases associated with the modulation of CB1 receptors' are associated with abuse or dependence of substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), neuroinflammation, diarrhea, alcohol dependence and nicotine dependence. It is about.
더욱 바람직하게는 상기 'CB1 수용체의 조절과 관련된 질병'은 섭식 장애, 비만, 제Ⅱ형 당뇨병 또는 비 인슐린 의존성 당뇨병(NIDD), 알콜 의존증 및 니코틴의존증을 포함하는 물질의 남용 또는 의존성에 관한 것이고, 특히 비만이 가장 바람직하다.More preferably the 'disease associated with the modulation of the CB1 receptor' relates to abuse or dependence of substances including eating disorders, obesity, type II diabetes or non-insulin dependent diabetes mellitus (NIDD), alcohol dependence and nicotine dependence, In particular obesity is most preferred.
본 발명의 약학 조성물은 경구, 근육내 및 피하내로 투여될 수 있다. 경구투여용 제형은 시럽, 정제, 캡슐, 크림 및 로젠지와 같은 다양한 형태로 제조될 수 있다. 시럽 제형은 에탄올, 피넛유, 올리브유, 글리세린 또는 물로부터 선택되는 하나 또는 둘이상의 액체 담체와 본 발명에 따른 화합물 또는 이의 염과 함께, 임의의 감미제 또는 착색제를 함유할 수 있다. 조성물이 정제 형태인 경우, 고형 제형의 제조에 일반적으로 사용되는 약학적 담체는 어느 것이나 사용될 수 있다. 그러한 담체의 예로는 스테아르산 마그네슘, 황산칼슘, 활석, 젤라틴, 아카시아, 스테아르산, 전분, 락토오스 및 수크로스가 포함된다. 조성물이 캡슐 형태인 경우, 일반적인 캡슐화 공정은 어느 것이나 사용될 수 있으며, 예를 들어 경질의 젤라진 캡슐 쉘에 앞서 언급된 담체를 포함시킬 수 있다. 조성물이 연질의 젤라틴 캡슐 쉘의 형태로 제형화되는 경우에는, 분산액 또는 현탁액의 제조에 일반적으로 사용되는 약학적 담체는 그 어느 것이나 사용될 수 있으며, 그러한 담체로는 수성 검, 셀룰로오스, 실리케이트 또는 오일이 있다.The pharmaceutical compositions of the invention can be administered orally, intramuscularly and subcutaneously. Formulations for oral administration can be prepared in various forms such as syrups, tablets, capsules, creams and lozenges. The syrup formulation may contain any sweetening or coloring agent, together with one or more liquid carriers selected from ethanol, peanut oil, olive oil, glycerin or water and the compounds according to the invention or salts thereof. When the composition is in tablet form, any of the pharmaceutical carriers generally used for the preparation of solid dosage forms can be used. Examples of such carriers include magnesium stearate, calcium sulfate, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. If the composition is in capsule form, any of the general encapsulation processes may be used, for example incorporating the aforementioned carriers into the hard gelazine capsule shell. When the composition is formulated in the form of soft gelatin capsule shells, any of the pharmaceutical carriers commonly used in the preparation of dispersions or suspensions may be used, such as aqueous gums, celluloses, silicates or oils. have.
근육내 또는 피하내 투여를 위한 제형은 물, 생리식염수 및 링거 용액과 같은 수성 용매 및 지방유, 참기름, 옥수수유 및 합성 지방산 에스터와 같은 친유성 용매를 포함하는 용액, 현탁액 및 에멀션과 같은 액체 형태로 제조될 수 있다.Formulations for intramuscular or subcutaneous administration are in the form of solutions, suspensions and emulsions comprising aqueous solvents such as water, saline and Ringer's solution and lipophilic solvents such as fatty oils, sesame oil, corn oil and synthetic fatty acid esters. Can be prepared.
상기 약학조성물은 해당 환자에게 적합한 형태로 제형화되는 것이 바람직하다.The pharmaceutical composition is preferably formulated in a form suitable for the patient.
경구 투여용 제형의 각 단위용량은 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 0.1 내지 500 mg/kg, 바람직하게는 1 내지 100 mg/kg으로 함유하는 것이 적합하다.Each unit dose of the formulation for oral administration suitably contains 0.1 to 500 mg / kg, preferably 1 to 100 mg / kg of the compound of formula 1 or a pharmaceutically acceptable salt thereof.
경구 투여에 있어서, 활성성분으로서 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은, 환자의 조건에 따라, 하루에 0.01 내지 40 mg/kg 체중의 양으로 1 내지 6회 투여될 수 있다.In oral administration, the compound of formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient, may be administered 1 to 6 times in an amount of 0.01 to 40 mg / kg body weight per day, depending on the condition of the patient.
화학식 1의 화합물 및 이들의 약학적으로 허용가능한 염은 약제, 예컨대 장내 투여, 비경구 투여 또는 국소 투여용 약학적 제제의 형태로 된 약제로서 사용될 수 있다. 이들은 예컨대 경구적으로 예컨대 정제, 코팅 정제, 당의정, 경질 및 연질 젤라틴 캡슐, 용액, 유제 또는 현탁액의 형태로, 직장적으로 예컨대 좌약 형태로, 비경구적으로 예컨대 주사 용액 또는 주입 용액 형태로, 또는 국소적으로 예컨대 연고, 크림 또는 오일 형태로 투여될 수 있다. 경구 투여가 바람직하다.The compounds of formula 1 and their pharmaceutically acceptable salts can be used as medicaments, such as medicaments in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They are for example orally such as in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally for example in the form of suppositories, parenterally such as in the form of injection solutions or infusion solutions, or topically. In the form of ointments, creams or oils, for example. Oral administration is preferred.
약학적 제제의 제조는 상기 화학식 1의 화합물 또는 이들의 약학적으로 허용가능한 염을, 임의적으로는 다른 치료적 으로 중요한 물질과 조합하여 바람직한 비독성 불활성 약학적으로 병존가능한(compatible) 고체 또는 액체 담체 물질 및 필요한 경우 통상의 약학적 보조제와 함께 갈레노스 제제 투여 형태로 만들어 당업자에게 익숙한 방법으로 실시될 수 있다. 상기 담체 물질은 무기 담체 물질 뿐만 아니라 유기 담체 물질도 허용된다. 예컨대 락토스, 옥수수 전분 또는 이들의 유도체, 활석, 스테아르산 또는 이것의 염이 정제, 코팅 정제, 당의정 및 경질 젤라틴 캡슐용 담체 물질로서 사용될 수 있다. 연질 젤라틴 캡슐용으로 적당한 담체 물질은 예컨대 식물성 오일, 왁스, 지방 및 반-고체 및 액체 폴리올(활성 성분의 성질에 따라 담체가 필요 없는 경우도 있지만, 연질 캡슐의 경우에는 필수적이다.)이다. 용액 및 시럽의 제조에 바람직한 담체 물질은 예컨대 물, 폴리올, 슈크로스, 전환당 등이다. 주사 용액으로 바람직한 담체는 예컨대 물, 알콜, 폴리올, 글라이세롤 및 식물성 오일이다. 좌제에 대한 적합한 담체 물질은 예컨대 천연 또는 경질 오일, 왁스, 지방 및 반-액체 또는 액체 폴리올이다. 국소 제제용으로 바람직한 담체 물질은 글라이세라이드, 반-합성 및 합성 글라이세라이드, 수소화 오일, 액체 왁스, 액체 파라핀, 액체 지방 알콜, 스테롤, 폴리에틸렌 글라이콜 및 셀룰로스 유도체이다. 통상의 안정화제, 보존제, 습윤 및 유화제, 점조도-개선제, 풍미-개선제, 삼투압 변화를 위한 염, 완충제 물질, 가용제, 착색 및 마스킹제, 및 항산화제가 약학적 보조제로서 고려된다.The preparation of pharmaceutical preparations may be carried out by combining the compound of Formula 1 or a pharmaceutically acceptable salt thereof, optionally with other therapeutically important substances, in a preferred nontoxic inert pharmaceutically compatible solid or liquid carrier. It can be carried out in a manner familiar to those skilled in the art by making the galenose formulation dosage form in combination with the substance and, if necessary, conventional pharmaceutical auxiliaries. The carrier material is acceptable as well as inorganic carrier material. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carrier materials for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (which are necessary for soft capsules, although the carrier may not be necessary depending on the nature of the active ingredient). Preferred carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Preferred carriers for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or light oils, waxes, fats and semi-liquid or liquid polyols. Preferred carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives. Conventional stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for osmotic pressure changes, buffer materials, solubilizers, coloring and masking agents, and antioxidants are contemplated as pharmaceutical auxiliaries.
화학식 1의 화합물의 투여량은 제어되는 질병, 연령 및 환자의 개별적 조건 및 투여 방식에 따라 넓은 범위 내에서 변할 수 있고, 당연히 각 특정 경우에서 개별적인 요구조건에 조정될 것이다. 성인의 경우 약 0.1 내지 500 mg/kg, 특히 약 1 내지 100 mg/kg의 하루 투여량이 고려된다. 질병의 심각성 및 정확한 약동학적 프로파일에 따라 본 화합물은 하나의 매일 투여 단위 또는 수개의 매일 투여 단위, 예컨대 1 내지 3회의 투여 단위로써 투여될 수 있다. 약학적 제제는 편리하게는 약 0.1 내지 500 mg/kg, 바람직하게는 1 내지 100 mg/kg의 화학식 1의 화합물을 함유한다.The dosage of the compound of formula 1 may vary within wide ranges depending on the disease, age and patient's individual condition and mode of administration, and will naturally be adjusted to the individual requirements in each particular case. For adults, a daily dosage of about 0.1 to 500 mg / kg, especially about 1 to 100 mg / kg, is contemplated. Depending on the severity of the disease and the exact pharmacokinetic profile, the compounds may be administered in one daily dosage unit or in several daily dosage units, such as one to three dosage units. The pharmaceutical preparations conveniently contain about 0.1 to 500 mg / kg, preferably 1 to 100 mg / kg of the compound of formula (1).
본 발명에 따른 벤즈아미드 유도체(4)는 하기 반응식에 나타난 바와 같이 제조될 수 있다.Benzamide derivative (4) according to the present invention can be prepared as shown in the following scheme.
[반응식 1] Scheme 1
Figure PCTKR2012002405-appb-I000011
Figure PCTKR2012002405-appb-I000011
화합물 2를 가수분해하여 카르복시산(3)을 합성한다. 카르복시산 3을 통상적인 방법으로 acid chloride 또는 active easter, mixed anhydride으로 활성화 시킨후 HNR1R2 와 반응시켜 4를 합성한다. 또한 카르복시산(3)과 HNR1R2를 결합시약 (DCC, EDC, BOP, HMPU )의 존재하에 반응 시켜 화합물 4를 합성할 수 있다. Compound 2 is hydrolyzed to synthesize carboxylic acid (3). Carboxylic acid 3 is activated with acid chloride, active easter or mixed anhydride in a conventional manner and then reacted with HNR 1 R 2 to synthesize 4. Compound 4 can also be synthesized by reacting carboxylic acid (3) with HNR 1 R 2 in the presence of binding reagents (DCC, EDC, BOP, HMPU).
상기 X 가 O 인 경우에 화합물 2는 하기 반응식 1a 또는 1b에 나타난 바와 같이 제조될 수 있다. When X is O, Compound 2 may be prepared as shown in Scheme 1a or 1b.
[반응식 1a]Scheme 1a
Figure PCTKR2012002405-appb-I000012
Figure PCTKR2012002405-appb-I000012
[반응식 1b]Scheme 1b
Figure PCTKR2012002405-appb-I000013
Figure PCTKR2012002405-appb-I000013
본 발명에 따른 아미드 유도체(8)는 하기 반응식 2에 나타난 바와 같이 제조될 수 있다. Amide derivatives 8 according to the invention can be prepared as shown in Scheme 2 below.
[반응식 2] Scheme 2
Figure PCTKR2012002405-appb-I000014
Figure PCTKR2012002405-appb-I000014
aniline 화합물 (10)은 니트로화합물 (9)를 통상적인 방법으로 환원시켜 얻을 수 있다. (Pd/C, Ra-Ni 등의 금속촉매하의 수소화 반응; 산 존재하에서 SnCl2 등의 금속에 의한 환원; NaBH4, LiAlH4 등의 유기금속산화제에 의한 환원등)The aniline compound (10) can be obtained by reducing the nitro compound (9) by a conventional method. (Hydrogenation reaction under metal catalyst such as Pd / C, Ra-Ni; reduction with metal such as SnCl2 in the presence of acid; reduction with organometallic oxidizer such as NaBH4, LiAlH4, etc.)
amide 화합물 (8)은 aniline 화합물 (10)과 카르복시산 (11)을 결합시약 (DCC, EDC, BOP, HMPU)을 이용하여 합성할 수 있다. The amide compound (8) can be synthesized using aniline compound (10) and carboxylic acid (11) using binding reagents (DCC, EDC, BOP, HMPU).
본 발명에 따른 아릴 우레아 유도체(12)는 하기 반응식 3에 나타난 바와 같이 제조될 수 있다.The aryl urea derivative 12 according to the present invention can be prepared as shown in Scheme 3 below.
[반응식 3] Scheme 3
Figure PCTKR2012002405-appb-I000015
Figure PCTKR2012002405-appb-I000015
이소시아네이트 화합물 (13)은 벤조산 (3)으로부터 Curtius rearrangement를 통하여 합성할 수 있다. 즉 화합물 (3)을 통상의 방법으로 acid azide 화합물로 변화시킨 후 가열하여 이소시아네이트 화합물 (13)을 합성할 수 있으며 이것을 아민 (R1R2NH)과 반응시켜 우레아 화합물 (12)를 합성할 수 있다. Isocyanate compound (13) can be synthesized from benzoic acid (3) via Curtius rearrangement. That is, compound (3) can be converted to an acid azide compound by a conventional method, and then heated to synthesize an isocyanate compound (13), which can be reacted with an amine (R 1 R 2 NH) to synthesize urea compound (12). have.
또한 urea 화합물 (12)는 하기 반응식 4에 나타낸 바와 같이 아닐린 화합물 10과 카바모일 클로라이드 화합물 14를 염기 존재하에 축합하여 합성할 수도 있다. The urea compound (12) can also be synthesized by condensing aniline compound 10 and carbamoyl chloride compound 14 in the presence of a base, as shown in Scheme 4 below.
[반응식 4] Scheme 4
Figure PCTKR2012002405-appb-I000016
Figure PCTKR2012002405-appb-I000016
상기 반응식에서,In the above scheme,
L 은 Cl, Br, I, OTs 또는 OMs 이고,L is Cl, Br, I, OTs or OMs,
A, B, R1, R2, R3, R4, R5 는 상기와 동일, R'은 (C1-C20)알킬 또는 (C3-C20)시클로알킬기이다.A, B, R 1 , R 2 , R 3 , R 4 , and R 5 are the same as above, and R 'is a (C1-C20) alkyl or (C3-C20) cycloalkyl group.
본 발명에 따른 화학식 1의 벤즈아미드 화합물 또는 이의 약학적으로 허용가능한 염은 카나비노이드 수용체 1(CB1)에 대한 우수한 억제 효과를 가진다. 따라서 본 발명에 따른 화학식 1의 벤즈아미드 화합물 또는 이의 약제학적으로 허용되는 이의 염을 유효 성분으로 포함하는 약제학적 조성물은 비만 또는 비만관련 대사질환의 예방 또는 치료에 우수한 효과를 가질 것으로 기대된다. The benzamide compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention has an excellent inhibitory effect on cannabinoid receptor 1 (CB1). Therefore, the pharmaceutical composition comprising as an active ingredient a benzamide compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is expected to have an excellent effect in the prevention or treatment of obesity or obesity-related metabolic diseases.
도 1은 CHO-CB1-#37 세포의 스크리닝 시스템을 나타낸 그림이다.1 shows a screening system of CHO-CB1- # 37 cells.
도 2는 96well plate 스크리닝 시스템을 나타낸 그림이다.2 is a diagram illustrating a 96well plate screening system.
도 3은 대조약제로 사용되는 화합물 rimonabant의 IC50값에 대한 그래프이다.3 is a graph of the IC 50 value of the compound rimonabant used as a control agent.
이하에서는 본 발명을 실시예에 의거하여 상세히 설명한다. 단, 하기 실시 예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용을 한정하는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples. However, the following examples are merely to illustrate the present invention, but not to limit the content of the present invention.
본원에서 본 발명의 공정, 반응 및 실시예를 기술하는데 사용된 기호 및 규정은 최근의 과학 문헌, 예컨대 문헌 [Journal of the American Chemical Society] 또는 [Journal of Biological Chemistry]에서 사용되는 것들과 일치한다. 본원에서 달리 언급하지 않는한, 모든 출발물질들은 상업적으로 구입한 것을 추가 정제없이 사용하였다.The symbols and conventions used herein to describe the processes, reactions and examples of the present invention are consistent with those used in recent scientific literature such as the Journal of the American Chemical Society or Journal of Biological Chemistry. Unless stated otherwise herein, all starting materials were used commercially without further purification.
Ac (아세틸)Ac (acetyl)
Bn (벤질)Bn (benzyl)
Boc (tert-부틸옥시카보닐)Boc (tert-butyloxycarbonyl)
BOP (벤조트리아졸-1-일옥시-트리스(디메틸아미노)포스포늄 헥사플루오로포스페이트)BOP (Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate)
Cbz (벤질옥시카보닐)Cbz (benzyloxycarbonyl)
(COCl)2 옥살산 디클로라이드(COCl) 2 oxalic acid dichloride
DCC (다이사이클로헥실카보다이이미드)DCC (dicyclohexylcarbodiimide)
DCM (다이클로로메탄)DCM (dichloromethane)
DMAP (4-다이메틸아미노피리딘)DMAP (4-dimethylaminopyridine)
DMF (N,N-다이메틸폼아미드)DMF (N, N-dimethylformamide)
DMSO (다이메틸설폭사이드)DMSO (dimethylsulfoxide)
DPPADPPA
EDC (1-에틸-3-[3-다이메틸아미노프로필]카보다이이미드 )EDC (1-ethyl-3- [3-dimethylaminopropyl] carbodiimide)
EDCI (1-에틸-3-[3-다이메틸아미노프로필]카보다이이미드 하이드로클로라이드)EDCI (1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride)
EtOAc (에틸 아세테이트)EtOAc (ethyl acetate)
EtOH (에탄올)EtOH (ethanol)
HBTU (O-벤조트라이아졸-1-일-N,N,N,N-테트라메틸우로늄 헥사플루오로포스페이트)HBTU (O-benzotriazol-1-yl-N, N, N, N-tetramethyluronium hexafluorophosphate)
HOAc (아세트산) HOAc (acetic acid)
HOBT (1-하이드록벤조트라이아졸)HOBT (1-hydroxybenzotriazole)
HPLC (고압 액체 크로마토그래피)HPLC (High Pressure Liquid Chromatography)
Hz (Hertz)Hz (Hertz)
i-PrOH (아이소프로판올)i-PrOH (isopropanol)
MeOH (메탄올)MeOH (Methanol)
MCPBAMCPBA
MgSO4 MgSO 4
NaOH (수산화나트륨)NaOH (Sodium Hydroxide)
NaOMe(소듐메톡사이드)NaOMe (sodium methoxide)
NMM (N-메틸 모폴린)NMM (N-methyl morpholine)
TEA (트라이에틸아민)TEA (triethylamine)
TFA (트라이플루오로아세트산)TFA (trifluoroacetic acid)
THF (테트라하이드로퓨란)THF (tetrahydrofuran)
본 명세서에서, 에테르는 다이에틸 에테르이며, 염수는 포화된 NaCl 수용액을 의미한다. 달리 언급하지 않는 한 온도는 모두 ℃ 단위이다. 모든 반응은 달리 언급하지 않는 한 실온에서 불활성 대기하에 수행하였으며, 모든 용매는 달리 언급하지 않는 한 가장 고순도의 것을 사용하였다.In the present specification, ether is diethyl ether, and brine means saturated aqueous NaCl solution. Unless otherwise noted, temperatures are all in degrees Celsius. All reactions were carried out under inert atmosphere at room temperature unless otherwise noted, and all solvents were used with the highest purity unless otherwise noted.
1H NMR은 제올(Jeol) ECX-400 또는 JNM-LA300 분광계를 이용하여 측정하였다. 화학적 이동은 "ppm(δ 단위)"으로, 결합 상수는 "Hz"로 표시하였다. 분리 패턴은 다중도를 나타내며, s(단일), d(2중), t(3중), q(4중), m(다중), br(넓음)로서 표시된다. 1 H NMR was measured using a Zeol ECX-400 or JNM-LA300 spectrometer. Chemical shifts are expressed in "ppm (δ units)" and binding constants are expressed in "Hz". The separation pattern represents multiplicity and is expressed as s (single), d (double), t (triple), q (quad), m (multiple), br (wide).
질량 스펙트럼은 하기 기기 중 하나를 이용하여 수득하였다 [Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI 또는 Agilent, 1100LC/MSD, ESI].Mass spectra were obtained using one of the following instruments [Micromass, Quattro LC Triple Quadruple Tandem Mass Spectometer, ESI or Agilent, 1100LC / MSD, ESI].
플래쉬 칼럼 크로마토그래피 분석은 머크(Merck)사의 실리카 겔 60 (230-400 메쉬)를 사용하여 수행하였다. 대부분의 반응은 이.머크(E. Merck)사의 0.25㎜ 실리카 겔 플레이트(60F-254)를 이용하고 5% 에탄올성 포스포몰리브덴산 또는 p-아니스알데하이드 용액을 사용하여 UV를 검출하는 얇은층 크로마토그래피로 모니터링하였다.Flash column chromatography analysis was performed using Merck silica gel 60 (230-400 mesh). Most reactions are thin layer chromatography using E. Merck 0.25 mm silica gel plates (60F-254) and UV detection using 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Monitoring by graphy.
실시예 1. N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드Example 1. N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide
Figure PCTKR2012002405-appb-I000017
Figure PCTKR2012002405-appb-I000017
단계 1. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산 메칠 에스테르 Step 1. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid methyl ester
Figure PCTKR2012002405-appb-I000018
Figure PCTKR2012002405-appb-I000018
3-플루오르-4-하이드록시-벤조산 메틸 에스터 (0.76g, 2.17mmol), 1-[브로모-(4-클로로-페닐)메칠]-2,4-디클로로-벤젠 (0.37g, 5.42mmol)을 DMF에 녹인후 K2CO3 (0.75g, 2.5mmol)을 가하고 62℃에서 12시간 교반한다. 반응 종료후 감압하에서 용매를 제거하고 남은 잔여물에 물과 EtOAc를 가하여 추출하였다. 분리된 유기층을 무수 황산 나트륨으로 건조시킨 후 감압 농축하여 얻어진 잔여물을 실리카겔 컬럼 크로마토그래피 (n-Hexane/EtOAc=9/1)로 정제하여 목적화합물 0.91g (수율 95%)을 수득하였다.3-Fluoro-4-hydroxy-benzoic acid methyl ester (0.76 g, 2.17 mmol), 1- [bromo- (4-chloro-phenyl) methyl] -2,4-dichloro-benzene (0.37 g, 5.42 mmol) Was dissolved in DMF, K 2 CO 3 (0.75 g, 2.5 mmol) was added, and the mixture was stirred at 62 ° C. for 12 hours. After completion of the reaction, the solvent was removed under reduced pressure, and water and EtOAc were added to the remaining residue. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-Hexane / EtOAc = 9/1) to obtain 0.91 g (yield 95%) of the title compound.
1H NMR (300Hz, CDCl3) δ 7.76-6.87(m, 10H), 6.68(s, 1H), 3.83(s, 3H) 1 H NMR (300 Hz, CDCl 3 ) δ 7.76-6.87 (m, 10H), 6.68 (s, 1H), 3.83 (s, 3H)
단계 2. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산 Step 2. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid
Figure PCTKR2012002405-appb-I000019
Figure PCTKR2012002405-appb-I000019
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-벤조산 메틸 에스터 (0.3g, 0.68 mmol) 를 THF에 녹이고, NaOH (0.07g, 1.78 mmol)을 물 (10 mL)에 녹인 용액을 첨가하여 상온에서 2시간 교반하였다. 반응 종료 후 반응액을 0℃로 냉각한 후 0.1N 염산을 천천히 가하여 반응물을 pH 2 정도로 산성화 시킨 후 EtOAc 를 가하여 추출하였다. 분리된 유기층을 무수 황산나트륨으로 건조시킨 후 감압 농축하여 얻어진 잔여물을 실리카겔 컬럼 크로마토그래피 (n-Hexane/EtOAc=2/1)로 정제하여 목적화합물 0.263g(수율 91％)을 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid methyl ester (0.3 g, 0.68 mmol) was dissolved in THF and NaOH (0.07 g , 1.78 mmol) was added to a solution of water (10 mL) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was cooled to 0 ° C., 0.1N hydrochloric acid was slowly added, the reaction was acidified to pH 2, and then extracted with EtOAc. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-Hexane / EtOAc = 2/1) to obtain 0.263 g (yield 91%) of the title compound.
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000020
7.81 (2H, t, J=11.00), 7.52~7.29 (8H, m), 6.90 (1H, t, J=8.22), 6.69 (1H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000020
7.81 (2H, t, J = 11.00), 7.52-7.29 (8H, m), 6.90 (1H, t, J = 8.22), 6.69 (1H, s)
단계 3. N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드 Step 3. N-tert-Butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide
하기 방법 1에서부터 방법 4의 공정을 통하여 합성하였다.Synthesis was carried out through the process of Method 1 to Method 4 below.
방법 1. (COCl2/DMF-cat.) Method 1. (COCl 2 / DMF-cat.)
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산을 DCM에 녹인 후 (COCl)2 (1.5당량)와 DMF (촉매량) 을 가하고 상온에서 3시간동안 교반하여 반응시킨다. 감압하에서 용매를 제거하여 카르복시산 클로라이드를 수득하였다. 수득된 카르복시산 클로라이드를 DCM에 녹인 후 TEA (2당량), tert-butyl amine (2당량), 그리고 DMAP (촉매량) 을 가하고 상온에서 5시간동안 교반한다. 반응종결후 물을 가하고 DCM으로 추출한다. 분리된 유기층을 무수 황산 나트륨으로 건조시킨 후 감압농축한 다음, 잔여물을 실리카겔 컬럼 크러마토그래피로 정제하여 벤조산 아마이드를 수득하였다.4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid was dissolved in DCM, followed by (COCl) 2 (1.5 equivalents) and DMF (catalyst amount). Was added and stirred for 3 hours at room temperature to react. The solvent was removed under reduced pressure to give carboxylic acid chloride. The obtained carboxylic acid chloride was dissolved in DCM, and then TEA (2 equivalents), tert-butyl amine (2 equivalents), and DMAP (catalyst amount) were added and stirred at room temperature for 5 hours. After completion of the reaction, water is added and extracted with DCM. The separated organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain benzoic acid amide.
방법 2. (EDC/HOBT) Method 2. (EDC / HOBT)
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산 (1당량), HOBT (1.1당량), EDC(1.1당량)을 DCM에 녹인 후 tert-butyl amine (2당량) 을 가하고 상온에서 5시간동안 교반하여 반응시킨다. 반응종료 후 물을 가하고 DCM으로 추출한다. 분리된 유기층을 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 벤조산 아마이드를 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid (1 equiv), HOBT (1.1 equiv), EDC (1.1 equiv) After dissolving in tert-butyl amine (2 equivalents), the mixture was stirred at room temperature for 5 hours to react. After the reaction was completed, water was added and extracted with DCM. The separated organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain benzoic acid amide.
방법 3. (BOP/NMM) Method 3. (BOP / NMM)
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산 (1당량), BOP (1.1당량), NMM(1.1당량)을 DCM에 녹인 후 tert-butyl amine (2당량) 을 가하고 상온에서 5시간동안 교반하여 반응시킨다. 반응종료 후 물을 가하고 DCM으 추출한다. 분리된 유기층을 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 벤조산 아마이드를 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid (1 equiv), BOP (1.1 equiv), NMM (1.1 equiv) After dissolving in tert-butyl amine (2 equivalents), the mixture was stirred at room temperature for 5 hours to react. After the reaction was completed, water was added, followed by extraction with DCM. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain benzoic acid amide.
방법 4. (HOBT ester) Method 4. (HOBT ester)
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산 (1당량), HOBT (1.1당량), EDC(1.1당량)을 DCM에 녹인 후 12시간동안 상온에서 교반하며 반응시킨다. 반응종료 후 얼음물을 가하고 DCM로 추출한다. 분리된 유기층을 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르를 수득하였다. [1H NMR (CDCl3) δ 8.10-7.00(m, 14H), 6.76(s, 1H)]4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid (1 equiv), HOBT (1.1 equiv), EDC (1.1 equiv) After dissolving in, it is reacted with stirring at room temperature for 12 hours. After completion of the reaction, ice water is added and extracted with DCM. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to give 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] 3-Fluoro-benzoic acid-benzotriazol-1-yl ester was obtained. [1H NMR (CDCl3) δ 8.10-7.00 (m, 14H), 6.76 (s, 1H)]
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르 (1당량) 과 tert-butyl amine (1.1당량)을 DCM 에 녹인후 상온에서 12시간 교반하면서 반응 시킨다. 반응종료 후 얼음물을 가하고 DCM로 추출한다. 분리된 유기층을 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 벤조산 아마이드를 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester (1 equiv) and tert-butyl amine (1.1 equiv) was dissolved in DCM and reacted with stirring at room temperature for 12 hours. After completion of the reaction, ice water is added and extracted with DCM. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain benzoic acid amide.
1H NMR (CDCl3) δ 7.55-6.77(m, 10H), 6.64(s, 1H), 5.75(bs, 1H), 1.42(s, 9H) 1 H NMR (CDCl 3) δ 7.55-6.77 (m, 10H), 6.64 (s, 1H), 5.75 (bs, 1H), 1.42 (s, 9H)
실시예 2. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-시클로헥실-3-플루오로-벤즈아미드Example 2. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-cyclohexyl-3-fluoro-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 시클로헥실 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and cyclohexyl amine. .
Figure PCTKR2012002405-appb-I000021
Figure PCTKR2012002405-appb-I000021
1H NMR (CDCl3) δ 7.54-6.83(m, 10H), 6.64(s, 1H), 5.82(m, 1H), 3.92(m, 1H), 2.00-0.85(m, 10H) 1 H NMR (CDCl 3 ) δ 7.54-6.83 (m, 10H), 6.64 (s, 1H), 5.82 (m, 1H), 3.92 (m, 1H), 2.00-0.85 (m, 10H)
실시예 3. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-에틸-N-프로필-벤즈아미드Example 3. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-ethyl-N-propyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 N-에틸-N-프로필 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-ethyl-N-propyl amine )
Figure PCTKR2012002405-appb-I000022
Figure PCTKR2012002405-appb-I000022
1H NMR (CDCl3) δ 7.54-6.81(m, 10H), 6.60(s, 1H), 3.60-3.05(m, 4H), 1.58(m, 2H), 1.30-0.70(m, 6H) 1 H NMR (CDCl 3 ) δ 7.54-6.81 (m, 10H), 6.60 (s, 1H), 3.60-3.05 (m, 4H), 1.58 (m, 2H), 1.30-0.70 (m, 6H)
실시예 4. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-아다만탄-1-일-벤즈아미드Example 4. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-adamantan-1-yl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 1-아미노 아다만탄으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 1-amino adamantane Thus synthesized.
Figure PCTKR2012002405-appb-I000023
Figure PCTKR2012002405-appb-I000023
1H NMR (CDCl3) δ 7.52-6.81(m, 10H), 6.64(s, 1H), 5.63(s, 1H), 2.10-2.07(m,. 10H), 1.70(m, 5H) 1 H NMR (CDCl 3 ) δ 7.52-6.81 (m, 10H), 6.64 (s, 1H), 5.63 (s, 1H), 2.10-2.07 (m, .10H), 1.70 (m, 5H)
실시예 5. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-모포린-4-일-벤즈아미드Example 5. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-morpholin-4-yl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 N-아미노 몰포린으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. According to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-amino morpholine Synthesized.
Figure PCTKR2012002405-appb-I000024
Figure PCTKR2012002405-appb-I000024
1H NMR (CDCl3) δ 7.52-6.83(m, 10H), 6.61(s, 1H), 3.67-3.60(m, 8H) 1 H NMR (CDCl 3 ) δ 7.52-6.83 (m, 10H), 6.61 (s, 1H), 3.67-3.60 (m, 8H)
실시예 6. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-이소부틸-벤즈아미드Example 6. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-isobutyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 이소부틸 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and isobutyl amine. .
Figure PCTKR2012002405-appb-I000025
Figure PCTKR2012002405-appb-I000025
1H NMR (CDCl3) δ 7.57-6.84(m, 10H), 6.29(s, 1H), 6.27(t, J=5.57Hz, 1H), 3.21(m, 2H), 1.89-1.80(m, 1H), 0.93(d, J=6.6Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.57-6.84 (m, 10H), 6.29 (s, 1H), 6.27 (t, J = 5.57 Hz, 1H), 3.21 (m, 2H), 1.89-1.80 (m, 1H ), 0.93 (d, J = 6.6 Hz, 6H)
실시예 7. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 7. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-트리플루오로메틸-벤질 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-trifluoromethyl-benzyl amine It synthesize | combined according to 2).
Figure PCTKR2012002405-appb-I000026
Figure PCTKR2012002405-appb-I000026
1H NMR (CDCl3) δ 7.59-6.84(m, 14H), 6.62(s, 1H), 6.62-6.58(m, 1H), 4.60(d, J=5.86Hz, 2H) 1 H NMR (CDCl 3 ) δ 7.59-6.84 (m, 14H), 6.62 (s, 1H), 6.62-6.58 (m, 1H), 4.60 (d, J = 5.86Hz, 2H)
실시예 8. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-피페리딘-1-일-벤즈아미드Example 8. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-piperidin-1-yl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 N-아미노 피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-amino piperidine Thus synthesized.
Figure PCTKR2012002405-appb-I000027
Figure PCTKR2012002405-appb-I000027
1H NMR (CDCl3) δ 7.65-6.82(m, 10H), 6.64(s, 1H), 2.83(m, 4H), 1.85(m, 4H), 1.72(m, 2H) 1 H NMR (CDCl 3 ) δ 7.65-6.82 (m, 10H), 6.64 (s, 1H), 2.83 (m, 4H), 1.85 (m, 4H), 1.72 (m, 2H)
실시예 9. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-풀루오로-N-p-톨일-벤즈아미드Example 9. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3- pullouro-N-p-tolyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 p-톨릴 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Synthesis according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and p-tolyl amine It was.
Figure PCTKR2012002405-appb-I000028
Figure PCTKR2012002405-appb-I000028
1H NMR (CDCl3) δ 8.04(m, 1H), 7.96-6.76(m, 14H), 6.63(s, 1H), 2.28(s, 3H) 1 H NMR (CDCl 3 ) δ 8.04 (m, 1H), 7.96-6.76 (m, 14H), 6.63 (s, 1H), 2.28 (s, 3H)
실시예 10. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-(2-히드록시-시클로헥실)-벤즈아미드Example 10. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-cyclohexyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-히드록시-시클로헥실 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxy-cyclohexyl amine )
Figure PCTKR2012002405-appb-I000029
Figure PCTKR2012002405-appb-I000029
1H NMR (CDCl3) δ 7.58-6.84(m, 10H), 6.65(s, 1H), 6.39(d, J=7.9Hz, 1H), 4.10-4.01(m, 2H), 2.04(bs, 1H), 1.76-0.69(m, 8H) 1 H NMR (CDCl 3 ) δ 7.58-6.84 (m, 10H), 6.65 (s, 1H), 6.39 (d, J = 7.9 Hz, 1H), 4.10-4.01 (m, 2H), 2.04 (bs, 1H ), 1.76-0.69 (m, 8H)
실시예 11. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-(1-히드록시메틸-2-메틸-프로필)-벤즈아미드Example 11. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (1-hydroxymethyl-2-methyl-propyl)- Benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 1-히드록시메틸-2-메틸-프로필 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 1-hydroxymethyl-2-methyl-propyl amine 3, method 2).
Figure PCTKR2012002405-appb-I000030
Figure PCTKR2012002405-appb-I000030
1H NMR (CDCl3) δ 7.58-6.85(m, 10H), 6.65(s, 1H), 6.19(d, J=8.2Hz, 1H), 3.92-3.86(m, 1H), 3.77-3.73(m, 2H), 2.03-1.91(m, 1H), 1.62(bs, 1H), 1.01-0.82(m, 6H) 1 H NMR (CDCl 3 ) δ 7.58-6.85 (m, 10H), 6.65 (s, 1H), 6.19 (d, J = 8.2 Hz, 1H), 3.92-3.86 (m, 1H), 3.77-3.73 (m , 2H), 2.03-1.91 (m, 1H), 1.62 (bs, 1H), 1.01-0.82 (m, 6H)
실시예 12. N-sec-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드Example 12.N-sec-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 N-sec-부틸 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-sec-butyl amine Thus synthesized.
Figure PCTKR2012002405-appb-I000031
Figure PCTKR2012002405-appb-I000031
1H NMR (CDCl3) δ7.55-6.83(m, 10H), 6.64(s, 1H), 5.70(d, J=8.1Hz, 1H), 4.11-4.02(m, 1H), 1.58-1.49(m, 2H), 1.19(d, J=6.6Hz, 3H), 0.96-0.82(m, 3H) 1 H NMR (CDCl 3 ) δ7.55-6.83 (m, 10H), 6.64 (s, 1H), 5.70 (d, J = 8.1Hz, 1H), 4.11-4.02 (m, 1H), 1.58-1.49 ( m, 2H), 1.19 (d, J = 6.6 Hz, 3H), 0.96-0.82 (m, 3H)
실시예 13. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-N-(2-다이메틸아미노-1,1-다이메틸-에틸)-3-플루오르-벤즈아마이드Example 13. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (2-dimethylamino-1, 1-dimethyl-ethyl) -3 Fluorene-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-다이메틸아미노-1,1-다이메틸-에틸아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-dimethylamino-1,1-dimethyl-ethylamine Synthesis was carried out according to 1 (Step 3, Method 2).
Figure PCTKR2012002405-appb-I000032
Figure PCTKR2012002405-appb-I000032
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000033
7.56~7.51 (2H, m) 7.42~7.25 (7H, m) 7.08 (1H, s) 6.86 (1H, t, J=8.22) 6.64 (1H, s) 2.47 (2H, s) 2.37 (6H, s) 1.44 (6H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000033
7.56 ~ 7.51 (2H, m) 7.42 ~ 7.25 (7H, m) 7.08 (1H, s) 6.86 (1H, t, J = 8.22) 6.64 (1H, s) 2.47 (2H, s) 2.37 (6H, s) 1.44 (6H, s)
실시예 14. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-N-(2-다이메틸아미노-1-메틸-에틸)-3-플루오르-벤즈아마이드Example 14. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (2-dimethylamino-1-methyl-ethyl) -3-fluoro- Benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-다이메틸아미노-1-메틸-에틸 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-dimethylamino-1-methyl-ethyl amine 3, method 2).
Figure PCTKR2012002405-appb-I000034
Figure PCTKR2012002405-appb-I000034
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000035
7.55 (2H, q, J=8.36) 7.41~7.26 (7H, m) 6.86 (1H, t, J=8.22) 6.65 (1H, s) 6.56 (1H, s) 4.03 (1H, m) 2.44 (1H, t, J=9.83) 2.26 (1H, t, J=5.43) 2.23 (6H, s) 1.26 (2H, d, J=6.16) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000035
7.55 (2H, q, J = 8.36) 7.41 to 7.26 (7H, m) 6.86 (1H, t, J = 8.22) 6.65 (1H, s) 6.56 (1H, s) 4.03 (1H, m) 2.44 (1H, t, J = 9.83) 2.26 (1H, t, J = 5.43) 2.23 (6H, s) 1.26 (2H, d, J = 6.16)
실시예 15. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-싸이오몰폴린-4-일-메타논Example 15. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -thiomorpholin-4-yl-methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 싸이오몰폴린 으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. It was synthesized according to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiomorpholine. .
Figure PCTKR2012002405-appb-I000036
Figure PCTKR2012002405-appb-I000036
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000037
7.51 (1H, d, J=8.51) 7.42~7.26 (6H, m) 7.02 (1H, m) 6.87 (1H, t, J=8.22)6.61 (1H, s) 3.82 (4H, brs) 2.63 (4H, brs) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000037
7.51 (1H, d, J = 8.51) 7.42-7.26 (6H, m) 7.02 (1H, m) 6.87 (1H, t, J = 8.22) 6.61 (1H, s) 3.82 (4H, brs) 2.63 (4H, brs)
실시예 16. 3-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-벤조일아미노}-3-메틸-부탄산 메틸 에스터Example 16. 3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-methyl-butanoic acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-2-메틸-프로판산 메틸에스테르 로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-2-methyl-propanoic acid methylester 3, method 2).
Figure PCTKR2012002405-appb-I000038
Figure PCTKR2012002405-appb-I000038
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000039
7.58~7.50 (2H, m) 7.42~7.25 (7H, m) 6.88 (1H, t, J=8.22) 6.66 (1H, s) 6.64 (1H, brs) 3.77 (3H, s) 1.65 (6H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000039
7.58 ~ 7.50 (2H, m) 7.42 ~ 7.25 (7H, m) 6.88 (1H, t, J = 8.22) 6.66 (1H, s) 6.64 (1H, brs) 3.77 (3H, s) 1.65 (6H, s)
실시예 17. {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-(4-메틸-피페라진-1-일)-메타논Example 17. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(4-methyl-piperazin-1-yl) -Metanon
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-메틸-피페라진 으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 (Step 3, Method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methyl-piperazine Thus synthesized.
Figure PCTKR2012002405-appb-I000040
Figure PCTKR2012002405-appb-I000040
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000041
7.52 (1H, d, J=8.36) 7.42~7.29 (6H, m) 7.19 (1H, dd, J=1.76, 9.24) 7.05 (1H, d, J=8.36) 6.85 (1H, t, J=8.22)6.61 (1H, s) 3.64 (4H, brs) 2.40 (4H, brs) 2.31 (3H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000041
7.52 (1H, d, J = 8.36) 7.42-7.29 (6H, m) 7.19 (1H, dd, J = 1.76, 9.24) 7.05 (1H, d, J = 8.36) 6.85 (1H, t, J = 8.22) 6.61 (1H, s) 3.64 (4H, brs) 2.40 (4H, brs) 2.31 (3H, s)
실시예 18. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(2-하이드록시-1,1-다이메틸-에틸)-벤즈아마이드Example 18. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-dimethyl-ethyl ) -Benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-하이드록시-1,1-다이메틸-에틸 아민으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxy-1,1-dimethyl-ethyl amine It synthesize | combined according to (step 3, method 2).
Figure PCTKR2012002405-appb-I000042
Figure PCTKR2012002405-appb-I000042
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000043
7.54~7.49 (2H, m) 7.41~7.31 (6H, m) 7.28~7.24 (1H, m) 6.86 (1H, t, J=8.22) 6.65 (1H, s) 6.10 (1H, brs) 4.45 (1H, t, J=6.02) 3.65 (2H, d, J=5.84) 1.37 (6H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000043
7.54 ~ 7.49 (2H, m) 7.41 ~ 7.31 (6H, m) 7.28 ~ 7.24 (1H, m) 6.86 (1H, t, J = 8.22) 6.65 (1H, s) 6.10 (1H, brs) 4.45 (1H, t, J = 6.02) 3.65 (2H, d, J = 5.84) 1.37 (6H, s)
실시예 19. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-4-일메틸)-벤즈아마이드Example 19. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-4-ylmethyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-아미노메칠 피리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다. According to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-aminomethyl pyridine Synthesized.
Figure PCTKR2012002405-appb-I000044
Figure PCTKR2012002405-appb-I000044
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000045
8.53(2H, d, J=6.03) 7.63~7.20 (11H, m) 6.89 (1H, t, J=8.22) 6.66 (1H, s) 6.60 (1H, brs) 4.61(2H, d, J=6.02) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000045
8.53 (2H, d, J = 6.03) 7.63-7.20 (11H, m) 6.89 (1H, t, J = 8.22) 6.66 (1H, s) 6.60 (1H, brs) 4.61 (2H, d, J = 6.02)
실시예 20. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(1-옥시-피리딘-4-일메틸)-벤즈아마이드Example 20. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (1-oxy-pyridin-4-ylmethyl) -benz Amide
Figure PCTKR2012002405-appb-I000046
Figure PCTKR2012002405-appb-I000046
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-4-일메틸)-벤즈아마이드 (42mg, 0.08mmol)와 MCPBA (28mg, 0.16mmol)를 DCM에 녹인후 상온에서 4시간동안 교반하여 반응시킨다. 반응종료후 물을 가하고 DCM으로 추출한다. 분리된 유기층을 무수 황산 나트륨 으로 건조시킨후 감압농축한 다음, 잔여물을 실리카겔컬럼 크러마토그래피(DCM/MeOH= 20/1)로 정제하여 목적화합물 28mg (수율 65%)을 수득하였다.4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-4-ylmethyl) -benzamide (42 mg, 0.08 mmol) MCPBA (28mg, 0.16mmol) was dissolved in DCM and reacted by stirring at room temperature for 4 hours. After completion of the reaction, water is added and extracted with DCM. The separated organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20/1) to give 28 mg (yield 65%) of the title compound.
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000047
7.98~7.92 (3H, m) 7.90~7.25 (8H, m) 7.14 (2H, d, J=6.02) 6.91(1H, t, J= 8.22) 6.66 (1H, s) 4.56(2H, d, J=5.14) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000047
7.98 ~ 7.92 (3H, m) 7.90 ~ 7.25 (8H, m) 7.14 (2H, d, J = 6.02) 6.91 (1H, t, J = 8.22) 6.66 (1H, s) 4.56 (2H, d, J = 5.14)
실시예 21. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-3-일메틸)-벤즈아마이드Example 21. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-3-ylmethyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 3-아미노메칠 피리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.According to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-aminomethyl pyridine Synthesized.
Figure PCTKR2012002405-appb-I000048
Figure PCTKR2012002405-appb-I000048
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000049
8.53(2H, d, J=6.03) 7.63~7.20 (11H, m) 6.89 (1H, t, J=8.22) 6.66 (1H, s) 6.60 (1H, brs) 4.61(2H, d, J=6.02) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000049
8.53 (2H, d, J = 6.03) 7.63-7.20 (11H, m) 6.89 (1H, t, J = 8.22) 6.66 (1H, s) 6.60 (1H, brs) 4.61 (2H, d, J = 6.02)
실시예 22. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-2-일메틸)-벤즈아마이드Example 22. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-2-ylmethyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노메칠 피리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.According to Example 1 (step 3, method 2) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-aminomethyl pyridine Synthesized.
Figure PCTKR2012002405-appb-I000050
Figure PCTKR2012002405-appb-I000050
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000051
8.53(2H, d, J=6.03) 7.63~7.20 (11H, m) 6.89 (1H, t, J=8.22) 6.66 (1H, s) 6.60 (1H, brs) 4.61(2H, d, J=6.02) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000051
8.53 (2H, d, J = 6.03) 7.63-7.20 (11H, m) 6.89 (1H, t, J = 8.22) 6.66 (1H, s) 6.60 (1H, brs) 4.61 (2H, d, J = 6.02)
실시예 23. {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐]}-(4-하이드록시-피페리딘-1-일)-메타논Example 23. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl]}-(4-hydroxy-piperidine-1 -Work) -Methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-하이드록시-피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-hydroxy-piperidine )
Figure PCTKR2012002405-appb-I000052
Figure PCTKR2012002405-appb-I000052
1H NMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000053
7.51 (1H, d, J=8.45) 7.41~7.16 (11H, m) 6.85 (1H, t, J=8.25)6.61 (1H, s) 3.98~3.94 (1H, m) 3.27 (2H, br) 2.04~1.42 (8H, m) 1 H NMR (500 Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000053
7.51 (1H, d, J = 8.45) 7.41 to 7.16 (11H, m) 6.85 (1H, t, J = 8.25) 6.61 (1H, s) 3.98 to 3.94 (1H, m) 3.27 (2H, br) 2.04 to 1.42 (8 H, m)
실시예 24. {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐]}-(3-하이드록시-피페리딘-1-일)-메타논Example 24. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl]}-(3-hydroxy-piperidine-1 -Work) -Methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 3-하이드록시-피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-hydroxy-piperidine )
Figure PCTKR2012002405-appb-I000054
Figure PCTKR2012002405-appb-I000054
1H NMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000055
7.52 (1H, d, J=8.45) 7.41~7.26 (6H, m) 7.21 (1H, d, J=10.65) 6.85 (1H, t, J=8.25)6.61 (1H, s) 3.82~3.39 (5H, m) 1.91~1.48 (4H, m) 1 H NMR (500 Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000055
7.52 (1H, d, J = 8.45) 7.41-7.26 (6H, m) 7.21 (1H, d, J = 10.65) 6.85 (1H, t, J = 8.25) 6.61 (1H, s) 3.82-3.39 (5H, m) 1.91-1.48 (4H, m)
실시예 25. 1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-벤조일}-피페리딘-4-온Example 25. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidin-4-one
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-옥소-피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, Method 2) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-oxo-piperidine According to the synthesis.
Figure PCTKR2012002405-appb-I000056
Figure PCTKR2012002405-appb-I000056
1HNMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000057
7.51 (1H, d, J=8.45) 7.43~7.25 (6H, m) 7.12 (1H, d, J=8.4) 6.89 (1H, t, J=8.20) 6.63 (1H, s) 3.85 (4H, brs) 2.49 (4H, brs) 1 HNMR (500Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000057
7.51 (1H, d, J = 8.45) 7.43 ~ 7.25 (6H, m) 7.12 (1H, d, J = 8.4) 6.89 (1H, t, J = 8.20) 6.63 (1H, s) 3.85 (4H, brs) 2.49 (4H, brs)
실시예 26. 1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-벤조일}-피페리딘-4-카복시산 메틸 에스터Example 26. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-4-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-메톡시카르보닐-피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methoxycarbonyl-piperidine It synthesize | combined according to the method 2).
Figure PCTKR2012002405-appb-I000058
Figure PCTKR2012002405-appb-I000058
1H NMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000059
7.53~7.02 (9H, m) 6.85 (1H, t, J=8.22) 6.61 (1H, s) 3.70 (3H, s) 3.07~2.99 (2H, m) 2.62~2.55 (1H, m) 1.93~1.64 (6H, m) 1 H NMR (500 Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000059
7.53 ~ 7.02 (9H, m) 6.85 (1H, t, J = 8.22) 6.61 (1H, s) 3.70 (3H, s) 3.07 ~ 2.99 (2H, m) 2.62 ~ 2.55 (1H, m) 1.93 ~ 1.64 ( 6H, m)
실시예 27. {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-(1,1-다이옥소-싸이오모폴린-4-일)-메타논Example 27. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(1,1-dioxo-thiomorpholine- 4-day) -methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-다이옥소-싸이오모폴린으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, Method 2 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-dioxo-thiomorpholine )
Figure PCTKR2012002405-appb-I000060
Figure PCTKR2012002405-appb-I000060
1H NMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000061
7.50 (1H, d, J=8.45) 7.43 (1H, d, J=2.1) 7.40~7.21 (6H, m) 7.08 (1H, d, J=8.4) 6.90 (1H, t, J=8.15) 6.63 (1H, s) 4.10 (4H, brs) 3.04 (4H, brs) 1 H NMR (500 Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000061
7.50 (1H, d, J = 8.45) 7.43 (1H, d, J = 2.1) 7.40-7.21 (6H, m) 7.08 (1H, d, J = 8.4) 6.90 (1H, t, J = 8.15) 6.63 ( 1H, s) 4.10 (4H, brs) 3.04 (4H, brs)
실시예 28. 1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-3-카르복시산 에틸 에스터Example 28. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-3-carboxylic acid ethyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 3-에톡시카르보닐-피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-ethoxycarbonyl-piperidine It synthesize | combined according to the method 2).
Figure PCTKR2012002405-appb-I000062
Figure PCTKR2012002405-appb-I000062
1H NMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000063
7.54~7.03 (9H, m) 6.85 (1H, t, J=8.22) 6.61 (1H, s) 4.12 (2H, q, J=7.04) 3.20~3.01 (2H, m) 2.12~2.09 (1H, m) 1.79~1.43 (6H, m) 1.23 (3H, t, J=7.04) 1 H NMR (500 Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000063
7.54 ~ 7.03 (9H, m) 6.85 (1H, t, J = 8.22) 6.61 (1H, s) 4.12 (2H, q, J = 7.04) 3.20 ~ 3.01 (2H, m) 2.12 ~ 2.09 (1H, m) 1.79 ~ 1.43 (6H, m) 1.23 (3H, t, J = 7.04)
실시예 29. 1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-2-카르복시산 에틸 에스터Example 29. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-2-carboxylic acid ethyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-에톡시카르보닐-피페리딘으로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-ethoxycarbonyl-piperidine It synthesize | combined according to the method 2).
Figure PCTKR2012002405-appb-I000064
Figure PCTKR2012002405-appb-I000064
1H NMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000065
7.54~7.07 (9H, m) 6.86 (1H, t, J=8.22) 6.61 (1H, s) 4.23 (2H, q, J=7.04) 3.25~3.19 (2H, m) 2.35~2.31 (1H, m) 1.77~1.36 (6H, m) 1.30 (3H, t, J=7.04) 1 H NMR (500 Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000065
7.54 ~ 7.07 (9H, m) 6.86 (1H, t, J = 8.22) 6.61 (1H, s) 4.23 (2H, q, J = 7.04) 3.25 ~ 3.19 (2H, m) 2.35 ~ 2.31 (1H, m) 1.77-1.36 (6H, m) 1.30 (3H, t, J = 7.04)
실시예 30. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-N-(2-하이드록시-1,1-비스-하이드록시메틸-에틸)-벤즈아마이드Example 30. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-bis-hydro Oxymethyl-ethyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 트리스(히드록시메칠)메틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and tris (hydroxymethyl) methyl amine )
Figure PCTKR2012002405-appb-I000066
Figure PCTKR2012002405-appb-I000066
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000067
7.60~7.28 (9H, m) 7.14 (1H, brs) 6.89 (1H, t, J=8.07) 6.67 (1H, s) 3.75 (6H, d, J=5.87) 3.56 (3H, t, J=6.02) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000067
7.60-7.28 (9H, m) 7.14 (1H, brs) 6.89 (1H, t, J = 8.07) 6.67 (1H, s) 3.75 (6H, d, J = 5.87) 3.56 (3H, t, J = 6.02)
실시예 31. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-N,N-비스-(2-하이드록시-에틸)-벤즈아마이드Example 31. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N, N-bis- (2-hydroxy-ethyl)- Benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 N,N-비스-(2-하이드록시-에틸)아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and N, N-bis- (2-hydroxy-ethyl) amine Synthesis was carried out according to 1 (Step 3, Method 4).
Figure PCTKR2012002405-appb-I000068
Figure PCTKR2012002405-appb-I000068
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000069
7.52~7.22 (10H, m) 6.85 (1H, t, J=8.22) 6.62 (1H, s) 3.98 (2H, 2H, brs) 3.76~3.45 (8H, m) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000069
7.52 ~ 7.22 (10H, m) 6.85 (1H, t, J = 8.22) 6.62 (1H, s) 3.98 (2H, 2H, brs) 3.76 ~ 3.45 (8H, m)
실시예 32. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-4-메틸-펜타논산 tert-부틸 에스터Example 32. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -4-methyl-pentanoic acid tert-butyl Ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-4-메틸-펜타논산 tert-부틸 에스테르로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-4-methyl-pentanoic acid tert-butyl ester It synthesize | combined according to (step 3, method 2).
Figure PCTKR2012002405-appb-I000070
Figure PCTKR2012002405-appb-I000070
1H NMR (CDCl3) δ 7.56-6.80(m, 10H), 6.64(s, 1H), 6.59-6.56(m, 1H), 4.71-4.63(m, 1H), 1.75-1.53(m, 3H), 1.47(s, 9H), 0.95(q, J=2.9Hz, 6.0Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.56-6.80 (m, 10H), 6.64 (s, 1H), 6.59-6.56 (m, 1H), 4.71-4.63 (m, 1H), 1.75-1.53 (m, 3H) , 1.47 (s, 9H), 0.95 (q, J = 2.9 Hz, 6.0 Hz, 6H)
실시예 33. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-메틸-부틸산 에틸 에스터Example 33. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-methyl-butyl acid ethyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-메틸-부탄산 에틸 에스테르로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-methyl-butanoic acid ethyl ester 3, method 2).
Figure PCTKR2012002405-appb-I000071
Figure PCTKR2012002405-appb-I000071
1H NMR (CDCl3) δ 7.67-6.85(m, 10H), 6.60(s, 1H), 6.52(d, 8.5Hz, 1H), 4.72-4.68(m, 1H), 4.26-4.17(q, J=6.9Hz, 14.08Hz, 2H), 2.30-2.21(m, 1H), 1.38(q, J=7.0Hz, 14.2Hz, 6H), 0.96(t, J=6.8Hz, 3H) 1 H NMR (CDCl 3 ) δ 7.67-6.85 (m, 10H), 6.60 (s, 1H), 6.52 (d, 8.5 Hz, 1H), 4.72-4.68 (m, 1H), 4.26-4.17 (q, J = 6.9 Hz, 14.08 Hz, 2H), 2.30-2.21 (m, 1H), 1.38 (q, J = 7.0 Hz, 14.2 Hz, 6H), 0.96 (t, J = 6.8 Hz, 3H)
실시예 34. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-아세트산 tert-부틸 에스터Example 34. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -acetic acid tert-butyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-아세트산 tert-부틸 에스테르로부터 실시예 1 (단계 3, 방법 2)에 따라서 합성하였다.Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-acetic acid tert-butyl ester It synthesize | combined according to 2).
Figure PCTKR2012002405-appb-I000072
Figure PCTKR2012002405-appb-I000072
1H NMR (CDCl3) δ 7.60-6.85(m, 10H), 6.65(s, 1H), 6.47(t, J=4.3Hz, 1H), 4.08(d, J=4.8, 2H), 1.49(s, 9H) 1 H NMR (CDCl 3 ) δ 7.60-6.85 (m, 10H), 6.65 (s, 1H), 6.47 (t, J = 4.3 Hz, 1H), 4.08 (d, J = 4.8, 2H), 1.49 (s , 9H)
실시예 35. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-(1H-이미다졸-4-일)-프로피온산 메틸 에스터Example 35. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3- (1H-imidazole-4 -Yl) -propionate methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-(1H-이미다졸-4-일)-프로피온산 메틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3- (1H-imidazol-4-yl) -propionic acid Synthesis was carried out according to example 1 (step 3, method 4) from methyl ester.
Figure PCTKR2012002405-appb-I000073
Figure PCTKR2012002405-appb-I000073
1H NMR (CDCl3) δ 8.21-8.19(m, 1H), 7.68-6.82(m, 13H), 6.65(s, 1H), 4.94-4.89(m, 1H), 3.67(s, 3H), 3.25-3.14(m, 2H) 1 H NMR (CDCl 3 ) δ 8.21-8.19 (m, 1H), 7.68-6.82 (m, 13H), 6.65 (s, 1H), 4.94-4.89 (m, 1H), 3.67 (s, 3H), 3.25 -3.14 (m, 2H)
실시예 36. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 36. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 피롤리딘-2-카복시산 메틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to method 4).
Figure PCTKR2012002405-appb-I000074
Figure PCTKR2012002405-appb-I000074
1H NMR (CDCl3) δ 7.53-6.82(m, 10H), 6.63(s, 1H), 4.64-4.60(m, 1H), 3.75(s, 3H), 3.67-3.51(m, 2H), 2.34-1.90(m, 4H) 1 H NMR (CDCl 3 ) δ 7.53-6.82 (m, 10H), 6.63 (s, 1H), 4.64-4.60 (m, 1H), 3.75 (s, 3H), 3.67-3.51 (m, 2H), 2.34 -1.90 (m, 4H)
실시예 37. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-프로피온산 벤질 에스터Example 37. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -propionic acid benzyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-프로피온산 벤질 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-propionic acid benzyl ester According to the synthesis.
Figure PCTKR2012002405-appb-I000075
Figure PCTKR2012002405-appb-I000075
1H NMR (CDCl3) δ 7.59-6.84(m, 15H), 6.65-6.62(m, 2H), 5.20(s, 2H), 4.80-4.76(m, 1H), 1.48(d, J=7.2Hz, 3H) 1 H NMR (CDCl 3 ) δ 7.59-6.84 (m, 15H), 6.65-6.62 (m, 2H), 5.20 (s, 2H), 4.80-4.76 (m, 1H), 1.48 (d, J = 7.2 Hz , 3H)
실시예 38. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-아세트산 에틸 에스터Example 38. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -acetic acid ethyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-아세트산 에틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-acetic acid ethyl ester According to the synthesis.
Figure PCTKR2012002405-appb-I000076
Figure PCTKR2012002405-appb-I000076
1H NMR (CDCl3) δ 7.61-6.85(m, 10H), 6.66(s, 1H), 6.54(t, J=4.6Hz, 1H), 4.25(q, J=7.2Hz, 14.4Hz, 2H), 4.18(J=4.9Hz, 2H), 1.30(t, J=7.2Hz, 3H) 1 H NMR (CDCl 3 ) δ 7.61-6.85 (m, 10H), 6.66 (s, 1H), 6.54 (t, J = 4.6 Hz, 1H), 4.25 (q, J = 7.2 Hz, 14.4 Hz, 2H) , 4.18 (J = 4.9 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H)
실시예 39. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-(4-히드록시-페닐)-프로피온산 메틸 에스터Example 39. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3- (4-hydroxy-phenyl ) -Methyl Propionate
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-(4-히드록시-페닐)-프로피온산 메틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3- (4-hydroxy-phenyl) -propionic acid methyl ester From Example 1 (step 3, method 4).
Figure PCTKR2012002405-appb-I000077
Figure PCTKR2012002405-appb-I000077
1H NMR (CDCl3) δ 7.53-6.69(m, 14H), 6.63(s, 1H), 6.51(d, J=7.8Hz, 1H), 6.03(s, 1H), 5.01-4.98(m, 1H), 3.75(s, 3H), 3.19-3.05(m, 2H) 1 H NMR (CDCl 3 ) δ 7.53-6.69 (m, 14H), 6.63 (s, 1H), 6.51 (d, J = 7.8 Hz, 1H), 6.03 (s, 1H), 5.01-4.98 (m, 1H ), 3.75 (s, 3H), 3.19-3.05 (m, 2H)
실시예 40. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-숙신산 1-tert-부틸 에스터Example 40. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -succinic acid 1-tert-butyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-숙신산 1-tert-부틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-succinic acid 1-tert-butyl ester , According to Method 4).
Figure PCTKR2012002405-appb-I000078
Figure PCTKR2012002405-appb-I000078
1H NMR (CDCl3) δ 7.60-6.68(m, 11H), 6.65(s, 1H), 4.93(m, 1H), 3.06-2.77(m, 2H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.60-6.68 (m, 11H), 6.65 (s, 1H), 4.93 (m, 1H), 3.06-2.77 (m, 2H), 1.42 (s, 9H)
실시예 41. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-펜탄디온산 디에틸 에스터Example 41. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -pentanedioic acid diethyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-펜탄디온산 디에틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-pentanedioic acid diethyl ester Synthesis was carried out according to method 4).
Figure PCTKR2012002405-appb-I000079
Figure PCTKR2012002405-appb-I000079
1H NMR (CDCl3) δ 7.62-7.26(m, 9H), 6.98(d, J=7.3. 1H), 6.91-6.85(m, 1H), 6.66(s, 1H), 4.75-4.68(m, 1H), 4.25(q, J=7.2Hz, 14.2Hz, 2H), 4.12(q, J=7.0Hz, 14.1Hz, 2H), 2.54-2.03(m, 4H), 1.31-1.19(m, 6H) 1 H NMR (CDCl 3 ) δ 7.62-7.26 (m, 9H), 6.98 (d, J = 7.3.1H), 6.91-6.85 (m, 1H), 6.66 (s, 1H), 4.75-4.68 (m, 1H), 4.25 (q, J = 7.2 Hz, 14.2 Hz, 2H), 4.12 (q, J = 7.0 Hz, 14.1 Hz, 2H), 2.54-2.03 (m, 4H), 1.31-1.19 (m, 6H)
실시예 42. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-페닐-프로피온산 메틸 에스터Example 42. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-phenyl-propionic acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-페닐-프로피온산 메틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-phenyl-propionic acid methyl ester , According to Method 4).
Figure PCTKR2012002405-appb-I000080
Figure PCTKR2012002405-appb-I000080
1H NMR (CDCl3) δ 7.52-6.82(m, 15H), 6.63(s, 1H), 6.43(d, J=7.3Hz, 1H), 5.05-4.99(m, 1H), 3.74(s, 3H), 3.28-3.14(m, 2H) 1 H NMR (CDCl 3 ) δ 7.52-6.82 (m, 15H), 6.63 (s, 1H), 6.43 (d, J = 7.3Hz, 1H), 5.05-4.99 (m, 1H), 3.74 (s, 3H ), 3.28-3.14 (m, 2H)
실시예 43. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-페닐-프로피온산 tert-부틸 에스터Example 43. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-phenyl-propionic acid tert-butyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-페닐-프로피온산 tert-부틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-phenyl-propionic acid tert-butyl ester Synthesis was carried out according to step 3, method 4).
Figure PCTKR2012002405-appb-I000081
Figure PCTKR2012002405-appb-I000081
1H NMR (CDCl3) δ 7.53-6.81(m, 15H), 6.64(s, 1H), 6.53(d, J=7.3Hz, 1H), 4.89(m, 1H), 3.18(d, J=5.9Hz, 2H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.53-6.81 (m, 15H), 6.64 (s, 1H), 6.53 (d, J = 7.3Hz, 1H), 4.89 (m, 1H), 3.18 (d, J = 5.9 Hz, 2H), 1.42 (s, 9H)
실시예 44. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-히드록시-프로피온산 메틸에스터Example 44. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-hydroxy-propionic acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-히드록시-프로피온산 메틸에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-hydroxy-propionic acid methylester 3, method 4).
Figure PCTKR2012002405-appb-I000082
Figure PCTKR2012002405-appb-I000082
1H NMR (CDCl3) δ 7.61-7.24(m, 9H), 7.05(d, J=7.3Hz, 1H), 6.87(m, 1H), 6.65(s, 1H), 4.82-4.77(m, 1H), 4.07-3.94(m, 2H), 3.78(s, 3H), 2.90(bs, 1H) 1 H NMR (CDCl 3 ) δ 7.61-7.24 (m, 9H), 7.05 (d, J = 7.3 Hz, 1H), 6.87 (m, 1H), 6.65 (s, 1H), 4.82-4.77 (m, 1H ), 4.07-3.94 (m, 2H), 3.78 (s, 3H), 2.90 (bs, 1H)
실시예 45. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 tert-부틸 에스터Example 45. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid tert- Butyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-피롤리딘-2-카복시산 tert-부틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-pyrrolidine-2-carboxylic acid tert-butyl ester Synthesis was carried out according to Example 1 (step 3, method 4).
Figure PCTKR2012002405-appb-I000083
Figure PCTKR2012002405-appb-I000083
1H NMR (CDCl3) δ7.53-6.82(m, 10H), 6.62(s, 1H), 4.52-4.47(m, 1H), 3.73-3.47(m, 2H), 2.32-1.81(m, 4H), 1.47(s, 9H) 1 H NMR (CDCl 3 ) δ7.53-6.82 (m, 10H), 6.62 (s, 1H), 4.52-4.47 (m, 1H), 3.73-3.47 (m, 2H), 2.32-1.81 (m, 4H ), 1.47 (s, 9 H)
실시예 46. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-히드록시-부틸산 메틸 에스터Example 46. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-hydroxy-butyl acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-히드록시-부틸산 메틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-hydroxy-butyl acid methyl ester Synthesis was carried out according to step 3, method 4).
Figure PCTKR2012002405-appb-I000084
Figure PCTKR2012002405-appb-I000084
1H NMR (CDCl3) δ 7.64-6.85(m, 1H), 6.65(s, 1H), 4.77-4.73(m, 1H), 4.46-4.41(m, 1H), 3.76(s, 3H), 1.24(d, J=6.4Hz, 3H) 1 H NMR (CDCl 3 ) δ 7.64-6.85 (m, 1H), 6.65 (s, 1H), 4.77-4.73 (m, 1H), 4.46-4.41 (m, 1H), 3.76 (s, 3H), 1.24 (d, J = 6.4 Hz, 3H)
실시예 47. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 47. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(3-hydroxy-pyrrolidine-1- Sun) -Methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 3-히드록시-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 3-hydroxy-pyrrolidine )
Figure PCTKR2012002405-appb-I000085
Figure PCTKR2012002405-appb-I000085
1H NMR (CDCl3) δ 7.53-6.82(m, 10H), 6.62(s, 1H), 4.55-4.44(m, 1H), 3.77-3.40(m, 4H), 2.36-1.86(m, 3H) 1 H NMR (CDCl 3 ) δ 7.53-6.82 (m, 10H), 6.62 (s, 1H), 4.55-4.44 (m, 1H), 3.77-3.40 (m, 4H), 2.36-1.86 (m, 3H)
실시예 48. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 48. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(2-hydroxymethyl-pyrrolidine-1 -Work) -Methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-히드록시메틸-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-hydroxymethyl-pyrrolidine It synthesize | combined according to 4).
Figure PCTKR2012002405-appb-I000086
Figure PCTKR2012002405-appb-I000086
1H NMR (CDCl3) δ 7.53-6.83(m, 10H), 6.63(s, 1H), 4.65(s , 1H), 4.39-4.35(m, 1H), 3.69-3.48(m,2H), 3.46-3.42(m, 2H), 2.36-1.56(m, 4H) 1 H NMR (CDCl 3 ) δ 7.53-6.83 (m, 10H), 6.63 (s, 1H), 4.65 (s, 1H), 4.39-4.35 (m, 1H), 3.69-3.48 (m, 2H), 3.46 -3.42 (m, 2H), 2.36-1.56 (m, 4H)
실시예 49. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산Example 49. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 피롤리딘-2-카복시산으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and pyrrolidine-2-carboxylic acid )
Figure PCTKR2012002405-appb-I000087
Figure PCTKR2012002405-appb-I000087
1H NMR (CDCl3) δ 7.52-6.83(m, 10H), 6.63(s, 1H), 5.29(bs,1H), 4.66(m, 1H), 3.74(m, 2H), 2.24-1.83(m, 4H), 1 H NMR (CDCl 3 ) δ 7.52-6.83 (m, 10H), 6.63 (s, 1H), 5.29 (bs, 1H), 4.66 (m, 1H), 3.74 (m, 2H), 2.24-1.83 (m , 4H),
실시예 50. 2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로벤조일아미노}-3-메틸-부탄산Example 50. 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluorobenzoylamino} -3-methyl-butanoic acid
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 2-아미노-3-메틸-부탄산으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 2-amino-3-methyl-butanoic acid Synthesis was carried out according to method 4).
Figure PCTKR2012002405-appb-I000088
Figure PCTKR2012002405-appb-I000088
1H NMR (CDCl3) δ 7.59-6.86(m, 10H), 6.66(s, 1H), 6.48(d, J=8.5Hz, 1H), 4.74-4.70(m, 1H), 2.36-2.26(m, 1H), 1.00(t, J=7.0Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.59-6.86 (m, 10H), 6.66 (s, 1H), 6.48 (d, J = 8.5 Hz, 1H), 4.74-4.70 (m, 1H), 2.36-2.26 (m , 1H), 1.00 (t, J = 7.0 Hz, 6H)
실시예 51. 3-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-2-카복시산Example 51. 3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-2-carboxylic acid
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 티아졸리딘-2-카복시산으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-2-carboxylic acid )
Figure PCTKR2012002405-appb-I000089
Figure PCTKR2012002405-appb-I000089
1H NMR (CDCl3) δ 7.51-6.86(m, 10H), 6.63(s, 1H), 5.60(m, 1H), 4.85(s, 1H), 3.89(m, 2H), 3.26-3.23(m, 2H) 1 H NMR (CDCl 3 ) δ 7.51-6.86 (m, 10H), 6.63 (s, 1H), 5.60 (m, 1H), 4.85 (s, 1H), 3.89 (m, 2H), 3.26-3.23 (m , 2H)
실시예 52. 3-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-4-카복시산Example 52. 3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-4-carboxylic acid
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 티아졸리딘-4-카복시산으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-4-carboxylic acid )
Figure PCTKR2012002405-appb-I000090
Figure PCTKR2012002405-appb-I000090
1H NMR (CDCl3) δ 7.50-6.86(m, 10H), 6.63(s, 1H), 5.18(m, 1H), 4.85(s, 1H), 4.56(m, 2H), 3.38-3.34(m, 2H) 1 H NMR (CDCl 3 ) δ 7.50-6.86 (m, 10H), 6.63 (s, 1H), 5.18 (m, 1H), 4.85 (s, 1H), 4.56 (m, 2H), 3.38-3.34 (m , 2H)
실시예 53. 3-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-2-카복시산Example 53. 3- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-2-carboxylic acid
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조산과 티아졸리딘-2-카복시산으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-2-carboxylic acid to Example 1 (step 3, method 4) Thus synthesized.
Figure PCTKR2012002405-appb-I000091
Figure PCTKR2012002405-appb-I000091
1H NMR (CDCl3) δ 7.56-6.87(m, 11H), 6.69(s, 1H), 5.60(m, 1H), 4.90(s, 1H), 3.77-3.76(m, 2H), 3.27-3.22(m, 2H) 1 H NMR (CDCl 3 ) δ 7.56-6.87 (m, 11H), 6.69 (s, 1H), 5.60 (m, 1H), 4.90 (s, 1H), 3.77-3.76 (m, 2H), 3.27-3.22 (m, 2H)
실시예 54. 3-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-4-카복시산Example 54. 3- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-4-carboxylic acid
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조산과 티아졸리딘-4-카복시산으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid and thiazolidine-4-carboxylic acid in Example 1 (step 3, method 4) Thus synthesized.
Figure PCTKR2012002405-appb-I000092
Figure PCTKR2012002405-appb-I000092
1H NMR (CDCl3) δ 7.56-6.87(m, 11H), 6.69(s, 1H), 5.20(m, 1H), 4.85(s, 1H), 4.68-4.56(m, 2H), 3.33(m, 2H) 1 H NMR (CDCl 3 ) δ 7.56-6.87 (m, 11H), 6.69 (s, 1H), 5.20 (m, 1H), 4.85 (s, 1H), 4.68-4.56 (m, 2H), 3.33 (m , 2H)
실시예 55. N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드Example 55. N- (4-Chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조산과 4-클로로아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-chloroaniline It was.
Figure PCTKR2012002405-appb-I000093
Figure PCTKR2012002405-appb-I000093
1H NMR (CDCl3) δ 8.11-7.01(m, 15H), 6.77(s, 1H) 1 H NMR (CDCl 3 ) δ 8.11-7.01 (m, 15H), 6.77 (s, 1H)
실시예 56. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 소듐염Example 56. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid sodium salt
1-{4-[(4-클로로-페닐-phenyl)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 (51mg, 0.097mmol)을 MeOH에 녹인 후 NaOMe 용액 (0.5 in methanol, 1.0eq, 0.2ml)을 가한 후 상온에서 4시간 동안 교반하고, 반응물을 증발, 농축, 건조하여 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 소듐염을 얻었다. (수율 : 20mg, 38%)1- {4-[(4-Chloro-phenyl-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid (51 mg, 0.097 mmol ) Dissolved in MeOH, NaOMe solution (0.5 in methanol, 1.0eq, 0.2ml) was added and stirred at room temperature for 4 hours, the reaction was evaporated, concentrated and dried to give 1- {4-[(4-chloro-phenyl )-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid sodium salt was obtained. (Yield 20mg, 38%)
Figure PCTKR2012002405-appb-I000094
Figure PCTKR2012002405-appb-I000094
1H NMR (CDCl3) δ 7.80-6.61(m, 10H), 6.58(s, 1H), 4.23-4.16(m, 1H), 3.64-3.48(m, 2H), 1.87-1.63(m, 4H) 1 H NMR (CDCl 3 ) δ 7.80-6.61 (m, 10H), 6.58 (s, 1H), 4.23-4.16 (m, 1H), 3.64-3.48 (m, 2H), 1.87-1.63 (m, 4H)
실시예 57. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(2-히드록시-시클로헥실)-벤즈아미드Example 57. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-cyclohexyl) -benzamide
Figure PCTKR2012002405-appb-I000095
Figure PCTKR2012002405-appb-I000095
단계 1. Step 1.
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산 (1당량), HOBT (1.1당량), EDC(1.1당량)을 DCM에 녹인 후 12시간동안 상온에서 교반하며 반응시킨다. 반응종료 후 얼음물을 가하고 DCM로 추출한다. 분리된 유기층을 무수 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조산 벤조트리아졸-1-일 에스터를 수득하였다. [1H NMR (CDCl3) δ 8.11-7.02(m, 15H), 6.83(s, 1H)]4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid (1 equiv), HOBT (1.1 equiv) and EDC (1.1 equiv) were dissolved in DCM The reaction is stirred at room temperature for 12 hours. After completion of the reaction, ice water is added and extracted with DCM. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to give 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3 -Fluoro-benzoic acid benzotriazol-1-yl ester was obtained. [ 1 H NMR (CDCl 3 ) δ 8.11-7.02 (m, 15H), 6.83 (s, 1H)]
단계 2. Step 2.
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르 (1당량) 과 아민 (1.1당량)을 DCM 에 녹인후 상온에서 12시간 교반하면서 반응 시킨다. 반응종료 후 얼음물을 가하고 DCM로 추출한다. 분리된 유기층을 무수 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 벤조산 아마이드를 수득하였다. (아민의 염산염을 사용할때는 TEA (1.5당량)을 첨가하여 반응시킨다)4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester (1 equiv) and amine (1.1 equiv) were DCM After dissolving in and reacting with stirring at room temperature for 12 hours. After completion of the reaction, ice water is added and extracted with DCM. The separated organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain benzoic acid amide. (When using amine hydrochloride, add TEA (1.5 equiv.) To react)
1H NMR (CDCl3) δ7.57-6.84(m, 11H), 6.70(s, 1H), 6.45(D, J=8.1Hz, 1H), 4.09-3.99(m, 2H), 2.05(bs, 1H), 1.80-1.25(m, 8H) 1 H NMR (CDCl 3 ) δ 7.57-6.84 (m, 11H), 6.70 (s, 1H), 6.45 (D, J = 8.1 Hz, 1H), 4.09-3.99 (m, 2H), 2.05 (bs, 1H), 1.80-1.25 (m, 8H)
실시예 58. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(1-히드록시메틸-2-메틸-프로필)-벤즈아미드)Example 58. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (1-hydroxymethyl-2-methyl-propyl) -benzamide )
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 (1-히드록시메틸)-2-메틸-프로필 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester with (1-hydroxymethyl) -2-methyl Synthesis was carried out according to Example 57 (step 2) from -propyl amine.
Figure PCTKR2012002405-appb-I000096
Figure PCTKR2012002405-appb-I000096
1H NMR (CDCl3) δ 7.58-6.86(m, 11H), 6.72(s, 1H), 6.23(d, J=8.2Hz, 1H), 3.93-3.84(m, 1H), 3.78-3.71(m, 2H), 2.02-1.90(m, 1H), 1.69(s, 1H), 1.01-0.96(m, 6H) 1 H NMR (CDCl 3 ) δ 7.58-6.86 (m, 11H), 6.72 (s, 1H), 6.23 (d, J = 8.2 Hz, 1H), 3.93-3.84 (m, 1H), 3.78-3.71 (m , 2H), 2.02-1.90 (m, 1H), 1.69 (s, 1H), 1.01-0.96 (m, 6H)
실시예 59. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 59. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 4-트리플루오로메틸-벤질 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 4-trifluoromethyl-benzyl amine Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000097
Figure PCTKR2012002405-appb-I000097
1H NMR (CDCl3) δ 7.60-6.87(m, 15H), 6.72(s, 1H), 6.33-6.29(m, 1H), 4.65(d, J=6.02Hz, 2H) 1 H NMR (CDCl 3 ) δ 7.60-6.87 (m, 15H), 6.72 (s, 1H), 6.33-6.29 (m, 1H), 4.65 (d, J = 6.02 Hz, 2H)
실시예 60. N-tert-부틸-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤즈아미드Example 60. N-tert-Butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 tert-부틸 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and tert-butyl amine )
Figure PCTKR2012002405-appb-I000098
Figure PCTKR2012002405-appb-I000098
1H NMR (CDCl3) δ 7.57-6.83(m, 11H), 6.70(s, 1H), 5.76(s, 1H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.57-6.83 (m, 11H), 6.70 (s, 1H), 5.76 (s, 1H), 1.42 (s, 9H)
실시예 61. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-프로파질-벤즈아마이드Example 61. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N-propazyl-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-프로파질 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example 57 (step from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-propazyl amine It synthesize | combined according to 2).
Figure PCTKR2012002405-appb-I000099
Figure PCTKR2012002405-appb-I000099
1H NMR (CDCl3) δ 7.58-6.86(m, 11H), 6.71(s, 1H), 6.19(d, J=8.2Hz, 1H), 3.93-3.84(m, 1H), 3.76(s, 2H), 2.45(s, 1H), 2.02-1.90(m, 1H), 1.01-0.96(m, 6H) 1 H NMR (CDCl 3 ) δ 7.58-6.86 (m, 11H), 6.71 (s, 1H), 6.19 (d, J = 8.2 Hz, 1H), 3.93-3.84 (m, 1H), 3.76 (s, 2H ), 2.45 (s, 1H), 2.02-1.90 (m, 1H), 1.01-0.96 (m, 6H)
실시예 62. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-모포린-4-일-메타논Example 62. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -morpholin-4-yl-methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 몰포린으로부터 실시예 57 (단계 2)에 따라서 합성하였다. In Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and morpholine Thus synthesized.
Figure PCTKR2012002405-appb-I000100
Figure PCTKR2012002405-appb-I000100
1H NMR (CDCl3) δ 7.58-6.72(m, 11H), 6.68(s, 1H), 3.67-3.60(m, 8H) 1 H NMR (CDCl 3 ) δ 7.58-6.72 (m, 11 H), 6.68 (s, 1 H), 3.67-3.60 (m, 8 H)
실시예 63. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 63. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피롤리딘-2-카복시산 메틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. From 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000101
Figure PCTKR2012002405-appb-I000101
1H NMR (CDCl3) δ 7.58-6.74(m, 11H), 6.69(s, 1H), 4.64-4.60(m, 1H), 3.74(s, 3H), 3.69-3.54(m, 2H), 2.33-1.84(m, 4H) 1 H NMR (CDCl 3 ) δ 7.58-6.74 (m, 11H), 6.69 (s, 1H), 4.64-4.60 (m, 1H), 3.74 (s, 3H), 3.69-3.54 (m, 2H), 2.33 -1.84 (m, 4H)
실시예 64. 2-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-메틸-부틸산 에틸 에스터Example 64. 2- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-methyl-butyl acid ethyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 2-아미노-3-메틸-부틸산 에틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 2-amino-3-methyl-butylate Synthesis was carried out according to Example 57 (step 2) from the ester.
Figure PCTKR2012002405-appb-I000102
Figure PCTKR2012002405-appb-I000102
1H NMR (CDCl3) δ 7.60-6.87(m, 11H), 6.72(s, 1H), 6.50(d, J=8.5Hz, 1H), 4.72-4.68(m, 1H), 4.27-4.18(m, 2H), 2.30-2.25(m, 1H), 1.31-1.25(m, 6H), 0.96(t, J=6.8Hz, 3H) 1 H NMR (CDCl 3 ) δ 7.60-6.87 (m, 11H), 6.72 (s, 1H), 6.50 (d, J = 8.5 Hz, 1H), 4.72-4.68 (m, 1H), 4.27-4.18 (m , 2H), 2.30-2.25 (m, 1H), 1.31-1.25 (m, 6H), 0.96 (t, J = 6.8 Hz, 3H)
실시예 65. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-아세트산 tert-부틸 에스터Example 65. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -acetic acid tert-butyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 2-아미노-아세트산 tert-부틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 2-amino-acetic acid tert-butyl ester Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000103
Figure PCTKR2012002405-appb-I000103
1H NMR (CDCl3) δ 7.60-6.85(m, 11H), 6.71(s, 1H), 6.51(t, J=4.6Hz, 1H), 4.07(d, J=4.8Hz, 2H), 1.48(s, 9H) 1 H NMR (CDCl 3 ) δ 7.60-6.85 (m, 11H), 6.71 (s, 1H), 6.51 (t, J = 4.6 Hz, 1H), 4.07 (d, J = 4.8 Hz, 2H), 1.48 ( s, 9H)
실시예 66. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 66. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(3-hydroxy-pyrrolidin-1-yl) -Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 3-히드록시 프로린으로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example 57 (step from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 3-hydroxy proline It synthesize | combined according to 2).
Figure PCTKR2012002405-appb-I000104
Figure PCTKR2012002405-appb-I000104
1H NMR (CDCl3) δ 7.58-6.83(m, 11H), 6.69(s, 1H), 4.52-4.40(m, 1H), 3.82-3.38(m, 4H), 2.55-2.46(m, 1H), 2.03-1.81(m, 3H) 1 H NMR (CDCl 3 ) δ 7.58-6.83 (m, 11H), 6.69 (s, 1H), 4.52-4.40 (m, 1H), 3.82-3.38 (m, 4H), 2.55-2.46 (m, 1H) , 2.03-1.81 (m, 3 H)
실시예 67. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2,2-디메틸-[1,3]디옥소란-4-일메틸)-3-플루오로-벤즈아미드Example 67. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2,2-dimethyl- [1,3] dioxoran-4-ylmethyl) -3-fluoro-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-(2,2-디메틸-[1,3]디옥소란-4-일)메틸 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N- (2,2-dimethyl- [1 , 3] dioxoran-4-yl) methyl amine was synthesized according to Example 57 (step 2).
Figure PCTKR2012002405-appb-I000105
Figure PCTKR2012002405-appb-I000105
1H NMR (CDCl3) δ 7.59-6.86(m, 11H), 6.71(s, 1H), 6.40(t, J = 5.3Hz, 1H), 4.36-4.26(m, 1H), 4.09-4.04(m, 1H), 3.75-3.64(m, 2H), 1.44(s, 3H), 1.34(s, 3H) 1 H NMR (CDCl 3 ) δ 7.59-6.86 (m, 11H), 6.71 (s, 1H), 6.40 (t, J = 5.3 Hz, 1H), 4.36-4.26 (m, 1H), 4.09-4.04 (m , 1H), 3.75-3.64 (m, 2H), 1.44 (s, 3H), 1.34 (s, 3H)
실시예 68. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2,3-디히드록시-프로필)-3-플루오로-벤즈아미드Example 68. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2,3-dihydroxy-propyl) -3-fluoro-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-(2,3-디히드록시-프로필) 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N- (2,3-dihydroxy- Propyl) from amines according to Example 57 (step 2).
Figure PCTKR2012002405-appb-I000106
Figure PCTKR2012002405-appb-I000106
1H NMR (CDCl3) δ 7.57-6.86(m, 11H), 6.71(s, 1H), 6.65(t, J=5.7Hz, 1H), 3.85-3.40(m, 5H), 3.38-3.13(m, 2H) 1 H NMR (CDCl 3 ) δ 7.57-6.86 (m, 11H), 6.71 (s, 1H), 6.65 (t, J = 5.7 Hz, 1H), 3.85-3.40 (m, 5H), 3.38-3.13 (m , 2H)
실시예 69. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 69. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl ) -Methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 2-히드록시메틸-피롤리딘으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 2-hydroxymethyl-pyrrolidine Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000107
Figure PCTKR2012002405-appb-I000107
1H NMR (CDCl3) δ 7.58-6.85(m, 11H), 6.69(s, 1H), 4.68(bs, 1H), 4.37-4.35(m, 1H), 3.76-3.65(m, 2H), 3.53-3.42(m, 2H), 2.36-1.55(m, 4H) 1 H NMR (CDCl 3 ) δ 7.58-6.85 (m, 11H), 6.69 (s, 1H), 4.68 (bs, 1H), 4.37-4.35 (m, 1H), 3.76-3.65 (m, 2H), 3.53 -3.42 (m, 2H), 2.36-1.55 (m, 4H)
실시예 70. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 아마이드Example 70. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid amide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피롤리딘-2-카르복시산 아마이드로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and pyrrolidine-2-carboxylic acid amide Synthesis was carried out according to 57 (Step 2).
Figure PCTKR2012002405-appb-I000108
Figure PCTKR2012002405-appb-I000108
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000109
7.95 (1H, t, J=9.24 7.44~7.32 (6H, m) 6.78~6.58 (2H, m) 6.57 (1H, s) 6.46 (1H, d, J=14.38) 1.43 (9H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000109
7.95 (1H, t, J = 9.24 7.44 ~ 7.32 (6H, m) 6.78 ~ 6.58 (2H, m) 6.57 (1H, s) 6.46 (1H, d, J = 14.38) 1.43 (9H, s)
실시예 71. 2-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-2-메틸-피로피온산 메틸 에스터Example 71. 2- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -2-methyl-pyrionic acid methyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 2-아미노-2-메틸-피로피온산 메틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 2-amino-2-methyl-pyropionic acid Synthesis was carried out according to Example 57 (step 2) from methyl ester.
Figure PCTKR2012002405-appb-I000110
Figure PCTKR2012002405-appb-I000110
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000111
7.58~7.22 (10H, m) 6.89 (1H, t, J=8.36) 6.63 (1H, brs) 3.77 (3H, s) 1.64 (6H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000111
7.58 ~ 7.22 (10H, m) 6.89 (1H, t, J = 8.36) 6.63 (1H, brs) 3.77 (3H, s) 1.64 (6H, s)
실시예 72. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(2-하이드록시-1,1-다이메틸-에틸)-벤즈아마이드Example 72. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1, 1-dimethyl-ethyl)- Benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-(2-하이드록시-1,1-다이메틸-에틸) 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N- (2-hydroxy-1,1 -Dimethyl-ethyl) amine was synthesized according to Example 57 (step 2).
Figure PCTKR2012002405-appb-I000112
Figure PCTKR2012002405-appb-I000112
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000113
7.58~7.22 (10H, m) 6.89 (1H, t, J=8.36) 6.10 (1H, brs) 4.45 (1H, t, J=6.02) 3.65 (2H, d, J=5.84) 1.37 (6H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000113
7.58 ~ 7.22 (10H, m) 6.89 (1H, t, J = 8.36) 6.10 (1H, brs) 4.45 (1H, t, J = 6.02) 3.65 (2H, d, J = 5.84) 1.37 (6H, s)
실시예 73. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(시아노-다이메틸-메틸)-3-플루오로-벤즈아마이드Example 73. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (cyano-dimethyl-methyl) -3-fluoro-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-(시아노-다이메틸-메틸) 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N- (cyano-dimethyl-methyl) Synthesis was carried out according to Example 57 (step 2) from amines.
Figure PCTKR2012002405-appb-I000114
Figure PCTKR2012002405-appb-I000114
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000115
8.11~7.96 (3H, m) 7.58~7.26 (7H, m) 7.05 (1H, t, J=8.22) 6.84 (1H, s) 1.26 (6H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000115
8.11 ~ 7.96 (3H, m) 7.58 ~ 7.26 (7H, m) 7.05 (1H, t, J = 8.22) 6.84 (1H, s) 1.26 (6H, s)
실시예 74. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 에틸 에스터Example 74. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid ethyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피롤리딘-2-카르복시산 에틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and pyrrolidine-2-carboxylic acid ethyl ester Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000116
Figure PCTKR2012002405-appb-I000116
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000117
7.56~7.16 (10H, m) 6.87 (1H, s) 5.10~5.02 (1H, m) 4.56 (1H, t, J=6.75) 3.75~3.53 (2H, m) 2.36~1.84 (6H, m) 1.26 (3H, t, J=7.04) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000117
7.56 ~ 7.16 (10H, m) 6.87 (1H, s) 5.10 ~ 5.02 (1H, m) 4.56 (1H, t, J = 6.75) 3.75 ~ 3.53 (2H, m) 2.36 ~ 1.84 (6H, m) 1.26 ( 3H, t, J = 7.04)
실시예 75. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 아이소프로필 에스터Example 75. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid isopropyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피롤리딘-2-카르복시산 아이소프로필 에스터으로부터 실시예 57 (단계 2)에 따라서 합성하였다. From 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and pyrrolidine-2-carboxylic acid isopropyl ester Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000118
Figure PCTKR2012002405-appb-I000118
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000119
7.56~7.16 (10H, m) 6.87 (1H, s) 5.10~5.02 (1H, m) 4.56 (1H, t, J=6.75) 4.12 (2H, q, J=7.04) 3.75~3.53 (2H, m) 2.36~1.84 (6H, m) 1.26 (6H, dd, J=6.16, J=7.78) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000119
7.56 ~ 7.16 (10H, m) 6.87 (1H, s) 5.10 ~ 5.02 (1H, m) 4.56 (1H, t, J = 6.75) 4.12 (2H, q, J = 7.04) 3.75 ~ 3.53 (2H, m) 2.36-1.84 (6H, m) 1.26 (6H, dd, J = 6.16, J = 7.78)
실시예 76. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-4-에틸아미노-피페리딘-4-카르복시산아마이드Example 76. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -4-ethylamino-piperidine-4-carboxylic acid Amide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 4-에틸아미노-피페리딘-4-카르복시산아마이드로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 4-ethylamino-piperidine-4- Synthesis was carried out according to Example 57 (step 2) from carboxylic acid amides.
Figure PCTKR2012002405-appb-I000120
Figure PCTKR2012002405-appb-I000120
1HNMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000121
7.53~7.02 (10H, m) 6.90 (1H, brs) 6.85 (1H, t, J=8.22) 6.61 (1H, s) 5.37(1H, brs) 3.03~2.47 (6H, m) 2.07~1.57 (4H, m) 1.11(3H, t, J=7.04) 1 HNMR (500Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000121
7.53 ~ 7.02 (10H, m) 6.90 (1H, brs) 6.85 (1H, t, J = 8.22) 6.61 (1H, s) 5.37 (1H, brs) 3.03 ~ 2.47 (6H, m) 2.07 ~ 1.57 (4H, m) 1.11 (3H, t, J = 7.04)
실시예 77. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(4-하이드록시-피페리딘-1-일)-메타논Example 77. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(4-hydroxy-piperidin-1-yl) -Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 4-하이드록시-피페리딘으로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 4-hydroxy-piperidine Synthesis was carried out according to 57 (Step 2).
Figure PCTKR2012002405-appb-I000122
Figure PCTKR2012002405-appb-I000122
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000123
7.56~7.12 (10H, m) 6.85 (1H, t, J=8.25) 6.58 (1H, s) 3.95~3.91(1H, m) 3.35 (2H, brs) 2.09~1.38 (8H, m) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000123
7.56 ~ 7.12 (10H, m) 6.85 (1H, t, J = 8.25) 6.58 (1H, s) 3.95 ~ 3.91 (1H, m) 3.35 (2H, brs) 2.09 ~ 1.38 (8H, m)
실시예 78. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(3-하이드록시-피페리딘-1-일)-메타논Example 78. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(3-hydroxy-piperidin-1-yl) -Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 3-하이드록시-피페리딘으로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 3-hydroxy-piperidine Synthesis was carried out according to 57 (Step 2).
Figure PCTKR2012002405-appb-I000124
Figure PCTKR2012002405-appb-I000124
1HNMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000125
7.58~7.23 (10H, m) 6.85 (1H, t, J=8.25) 6.63 (1H, s) 3.83~3.38 (5H, m) 1.93~1.47 (4H, m) 1 HNMR (500Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000125
7.58 ~ 7.23 (10H, m) 6.85 (1H, t, J = 8.25) 6.63 (1H, s) 3.83 ~ 3.38 (5H, m) 1.93 ~ 1.47 (4H, m)
실시예 79. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(2-하이드록시-1,1-비스-하이드록시메틸-에틸)-벤즈아마이드Example 79. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1,1-bis-hydroxymethyl- Ethyl) -benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-트리스(2-하이드록시메틸)-메틸아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-tris (2-hydroxymethyl)- Synthesis was carried out according to Example 57 (step 2) from methylamine.
Figure PCTKR2012002405-appb-I000126
Figure PCTKR2012002405-appb-I000126
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000127
7.60~7.28 (10H, m) 7.14 (1H, brs) 6.89 (1H, t, J=8.07) 6.67 (1H, s) 3.75 (6H, d, J=5.87) 3.56 (3H, t, J=6.02) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000127
7.60 ~ 7.28 (10H, m) 7.14 (1H, brs) 6.89 (1H, t, J = 8.07) 6.67 (1H, s) 3.75 (6H, d, J = 5.87) 3.56 (3H, t, J = 6.02)
실시예 80. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N,N-비스-(2-하이드록시-에틸)-벤즈아마이드Example 80. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N, N-bis- (2-hydroxy-ethyl) -benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N,N-비스-(2-하이드록시-에틸) 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester with N, N-bis- (2-hydroxy -Ethyl) from amine, according to Example 57 (step 2).
Figure PCTKR2012002405-appb-I000128
Figure PCTKR2012002405-appb-I000128
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000129
7.52~7.22 (10H, m) 6.85 (1H, t, J=8.22) 6.62 (1H, s) 3.98 (2H, 2H, brs) 3.76~3.45 (8H, m) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000129
7.52 ~ 7.22 (10H, m) 6.85 (1H, t, J = 8.22) 6.62 (1H, s) 3.98 (2H, 2H, brs) 3.76 ~ 3.45 (8H, m)
실시예 81. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-3-카르복시산 에틸 에스터Example 81. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-3-carboxylic acid ethyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피페리딘-3-카르복시산 에틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and piperidine-3-carboxylic acid ethyl ester Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000130
Figure PCTKR2012002405-appb-I000130
1HNMR (500Hz, CDCl3)
Figure PCTKR2012002405-appb-I000131
7.58~7.07 (10H, m) 6.76 (1H, t, J=8.22) 6.59 (1H, s) 4.22 (2H, q, J=7.04) 3.26~3.20 (2H, m) 2.39~2.29 (1H, m) 1.83~1.39 (6H, m) 1.28 (3H, t, J=7.04) 1 HNMR (500Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000131
7.58 ~ 7.07 (10H, m) 6.76 (1H, t, J = 8.22) 6.59 (1H, s) 4.22 (2H, q, J = 7.04) 3.26 ~ 3.20 (2H, m) 2.39 ~ 2.29 (1H, m) 1.83-1.39 (6H, m) 1.28 (3H, t, J = 7.04)
실시예 82. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-2-카르복시산 에틸 에스터Example 82. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-2-carboxylic acid ethyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피페리딘-2-카르복시산 에틸 에스터로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and piperidine-2-carboxylic acid ethyl ester Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000132
Figure PCTKR2012002405-appb-I000132
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000133
7.59~7.02 (10H, m) 6.86 (1H, t, J=8.22) 6.68 (1H, s) 4.12 (2H, q, J=7.04) 3.19~3.00 (2H, m) 2.12~2.07 (1H, m) 1.78~1.51 (6H, m) 1.23 (3H, t, J=7.04) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000133
7.59-7.02 (10H, m) 6.86 (1H, t, J = 8.22) 6.68 (1H, s) 4.12 (2H, q, J = 7.04) 3.19-3.00 (2H, m) 2.12-2.07 (1H, m) 1.78 ~ 1.51 (6H, m) 1.23 (3H, t, J = 7.04)
실시예 83. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-[2-(피롤리딘-1-카르보닐)-피롤리딘-1-일]-메타논Example 83. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-[2- (pyrrolidine-1-carbonyl)- Pyrrolidin-1-yl] -methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 2-(피롤리딘-1-카르보닐)-피롤리딘으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 2- (pyrrolidine-1-carbonyl ) Was synthesized according to Example 57 (step 2) from pyrrolidine.
Figure PCTKR2012002405-appb-I000134
Figure PCTKR2012002405-appb-I000134
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000135
7.56~7.16 (10H, m) 6.92 (1H, t, J=8.22) 6.87 (1H, s) 5.10~5.02 (1H, m) 3.75~3.17 (6H, m) 2.36~1.46 (8H, m) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000135
7.56 ~ 7.16 (10H, m) 6.92 (1H, t, J = 8.22) 6.87 (1H, s) 5.10 ~ 5.02 (1H, m) 3.75 ~ 3.17 (6H, m) 2.36 ~ 1.46 (8H, m)
실시예 84. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}피롤리딘-2-카르복시산 다이메틸아마이드Example 84. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} pyrrolidine-2-carboxylic acid dimethylamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 피롤리딘-2-카르복시산 다이메틸아마이드로부터 실시예 57 (단계 2)에 따라서 합성하였다. From 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and pyrrolidine-2-carboxylic acid dimethylamide Synthesis was carried out according to Example 57 (Step 2).
Figure PCTKR2012002405-appb-I000136
Figure PCTKR2012002405-appb-I000136
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000137
7.56~7.16 (10H, m) 6.90 (1H, t, J=8.22) 6.84 (1H, s) 5.10~5.02 (1H, m) 3.75~3.17 (6H, m) 3.02~1.65 (10H, m) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000137
7.56 ~ 7.16 (10H, m) 6.90 (1H, t, J = 8.22) 6.84 (1H, s) 5.10 ~ 5.02 (1H, m) 3.75 ~ 3.17 (6H, m) 3.02 ~ 1.65 (10H, m)
실시예 85. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-알릴-벤즈아마이드Example 85. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N-allyl-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-알릴 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example 57 (Step 2 from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N-allyl amine )
Figure PCTKR2012002405-appb-I000138
Figure PCTKR2012002405-appb-I000138
1HNMR (300Hz, CDCl3) 7.58~7.22 (10H, m) 6.89 (1H, t, J=8.4) 6.72 (1H, s) 6.02(1H, brs) 5.96~5.84 (1H, m) 5.30~5.16 (2H, m) 4.07~4.02 (2H, m) 1 HNMR (300Hz, CDCl 3 ) 7.58 ~ 7.22 (10H, m) 6.89 (1H, t, J = 8.4) 6.72 (1H, s) 6.02 (1H, brs) 5.96 ~ 5.84 (1H, m) 5.30 ~ 5.16 ( 2H, m) 4.07-4.02 (2H, m)
실시예 86. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(1,1-디메치-2-프로피닐)-벤즈아마이드Example 86. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (1,1-dimeth-2--2-pinynyl) -benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 N-(1,1-디메치-2-프로파질) 아민으로부터 실시예 57 (단계 2)에 따라서 합성하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and N- (1,1-dimeth-2) -Propazyl) amine was synthesized according to Example 57 (step 2).
Figure PCTKR2012002405-appb-I000139
Figure PCTKR2012002405-appb-I000139
1HNMR (300Hz, CDCl3) 7.57~7.22 (10H, m) 6.88 (1H, t, J=8.25) 6.72 (1H, s) 6.03(1H, brs) 2.37 (1H, s) 1.72(6H, s) 1 HNMR (300Hz, CDCl 3 ) 7.57 ~ 7.22 (10H, m) 6.88 (1H, t, J = 8.25) 6.72 (1H, s) 6.03 (1H, brs) 2.37 (1H, s) 1.72 (6H, s)
실시예 87. N-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-4-클로로-벤젠술폰아마이드Example 87. N- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -4-chloro- benzenesulfonamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 4-클로로-벤젠술폰아마이드로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example 57 from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and 4-chloro-benzenesulfonamide It synthesize | combined according to (step 2).
Figure PCTKR2012002405-appb-I000140
Figure PCTKR2012002405-appb-I000140
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000141
7.64 (1H, d, J=11.15) 7.49~7.28 (9H, m) 6.67 (1H, s), 3.37 (3H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000141
7.64 (1H, d, J = 11.15) 7.49-7.28 (9H, m) 6.67 (1H, s), 3.37 (3H, s)
실시예 88. 4-클로로-N-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-메탄술폰아마이드Example 88. 4-Chloro-N- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -methanesulfonamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플르오로-벤조산-벤조트리아졸-1-일 에스테르와 메탄술폰아마이드로부터 실시예 57 (단계 2)에 따라서 합성하였다. Example 57 (step 2) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid-benzotriazol-1-yl ester and methanesulfonamide According to the synthesis.
Figure PCTKR2012002405-appb-I000142
Figure PCTKR2012002405-appb-I000142
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000143
8.26 (2H, d, J=6.75) 7.88~7.75 (4H, m) 7.54~7.23 (9H, m) 6.77 (1H, t, J=8.36) 6.62 (1H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000143
8.26 (2H, d, J = 6.75) 7.88 ~ 7.75 (4H, m) 7.54 ~ 7.23 (9H, m) 6.77 (1H, t, J = 8.36) 6.62 (1H, s)
실시예 89. 4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오르메틸-벤질)-싸이오벤즈아마이드Example 89. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -thiobenzamide
Figure PCTKR2012002405-appb-I000144
Figure PCTKR2012002405-appb-I000144
4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오르메틸-벤질)-벤즈아마이드 (52mg, 0.10mmol)을 Toluene 10mL에 녹인 후 Lawesson's reagent (38mg. 0.10mmol)을 가하고 1시간동안 환류시킨다. 용매를 제거하고 남은 잔여물을 실리카겔 컬럼 크로마토그래피 (n-Hexane/EtOAc=5/1)로 정제하여 목적화합물 51mg(수율 96％)을 수득하였다.4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide (52 mg, 0.10 mmol) After dissolving in 10 mL of toluene, add Lawesson's reagent (38 mg. 0.10 mmol) and reflux for 1 hour. The solvent was removed and the residue was purified by silica gel column chromatography (n-Hexane / EtOAc = 5/1) to give 51 mg of the target compound (yield 96%).
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000145
7.66~7.24 (14H, m) 6.85 (1H, t, J=8.51) 5.05 (2H, d, J=5.43) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000145
7.66 ~ 7.24 (14H, m) 6.85 (1H, t, J = 8.51) 5.05 (2H, d, J = 5.43)
실시예 90. N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-싸이오벤즈아마이드Example 90. N-tert-Butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzamide
N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-벤즈아마이드 와 Lawesson's reagent로부터 실시예 89의 방법에 따라 합성하였다.It was synthesized according to the method of Example 89 from N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide and Lawesson's reagent. .
Figure PCTKR2012002405-appb-I000146
Figure PCTKR2012002405-appb-I000146
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000147
7.56~7.22 (10H, m) 6.81 (1H, t, J=8.36) 1.62 (9H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000147
7.56 ~ 7.22 (10H, m) 6.81 (1H, t, J = 8.36) 1.62 (9H, s)
실시예 91. 1-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-싸이오벤조일}-피롤리딘-2-카르복시산 메틸 에스터Example 91. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzoyl} -pyrrolidine-2-carboxylic acid methyl ester
N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-벤즈아마이드 와 Lawesson's reagent로부터 실시예 89의 방법에 따라 합성하였다.It was synthesized according to the method of Example 89 from N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide and Lawesson's reagent. .
Figure PCTKR2012002405-appb-I000148
Figure PCTKR2012002405-appb-I000148
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000149
7.59~7.07 (10H, m) 6.83 (1H, t, J=7.92) 5.07~5.05 (1H, m) 3.78 (3H, s) 3.67~3.53 (2H, m) 2.45~1.96 (4H, m) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000149
7.59 ~ 7.07 (10H, m) 6.83 (1H, t, J = 7.92) 5.07 ~ 5.05 (1H, m) 3.78 (3H, s) 3.67 ~ 3.53 (2H, m) 2.45 ~ 1.96 (4H, m)
실시예 92. 4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오르메틸-벤질)-싸이오벤즈아마이드Example 92. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -thiobenzamide
N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-벤즈아마이드 와 Lawesson's reagent로부터 실시예 89의 방법에 따라 합성하였다.It was synthesized according to the method of Example 89 from N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide and Lawesson's reagent. .
Figure PCTKR2012002405-appb-I000150
Figure PCTKR2012002405-appb-I000150
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000151
7.66~7.24 (14H, m) 6.85 (1H, t, J=8.51) 5.05 (2H, d, J=5.43) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000151
7.66 ~ 7.24 (14H, m) 6.85 (1H, t, J = 8.51) 5.05 (2H, d, J = 5.43)
실시예 93. N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-싸이오벤즈아마이드Example 93 N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzamide
N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-벤즈아마이드 와 Lawesson's reagent로부터 실시예 89의 방법에 따라 합성하였다.It was synthesized according to the method of Example 89 from N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide and Lawesson's reagent. .
Figure PCTKR2012002405-appb-I000152
Figure PCTKR2012002405-appb-I000152
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000153
7.56~7.22 (10H, m) 6.81 (1H, t, J=8.36) 1.62 (9H, s) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000153
7.56 ~ 7.22 (10H, m) 6.81 (1H, t, J = 8.36) 1.62 (9H, s)
실시예 94. 1-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-싸이오벤조일}-피롤리딘-2-카르복시산 메틸 에스터Example 94. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzoyl} -pyrrolidine-2-carboxylic acid methyl ester
N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-벤즈아마이드 와 Lawesson's reagent로부터 실시예 89의 방법에 따라 합성하였다.It was synthesized according to the method of Example 89 from N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide and Lawesson's reagent. .
Figure PCTKR2012002405-appb-I000154
Figure PCTKR2012002405-appb-I000154
1HNMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000155
7.59~7.07 (10H, m) 6.83 (1H, t, J=7.92) 5.07~5.05 (1H, m) 3.78 (3H, s) 3.67~3.53 (2H, m) 2.45~1.96 (4H, m) 1 HNMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000155
7.59 ~ 7.07 (10H, m) 6.83 (1H, t, J = 7.92) 5.07 ~ 5.05 (1H, m) 3.78 (3H, s) 3.67 ~ 3.53 (2H, m) 2.45 ~ 1.96 (4H, m)
실시예 95. N-tert-부틸-3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤즈아미드Example 95. N-tert-Butyl-3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzamide
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산 (1당량), HOBT (1.1당량), EDC(1.1당량)을 DCM에 녹인 후 tert-Butyl amine (2당량) 을 가하고 상온에서 5시간동안 교반하여 반응시킨다. 반응종료 후 물을 가하고 DCM로 추출한다. 분리된 유기층을 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 벤조산 아마이드를 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid (1 equiv), HOBT (1.1 equiv), EDC (1.1 equiv) to DCM After dissolving, tert-Butyl amine (2 equivalents) is added, followed by stirring at room temperature for 5 hours. After completion of the reaction, water was added and extracted with DCM. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain benzoic acid amide.
Figure PCTKR2012002405-appb-I000156
Figure PCTKR2012002405-appb-I000156
1H NMR (CDCl3) δ 7.76-6.79(m, 10H), 6.68(s, 1H), 5.76(bs, 1H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.76-6.79 (m, 10H), 6.68 (s, 1H), 5.76 (bs, 1H), 1.42 (s, 9H)
실시예 96. 3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-벤즈아미드Example 96. 3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-benzamide
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 이소부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and isobutyl amine. .
Figure PCTKR2012002405-appb-I000157
Figure PCTKR2012002405-appb-I000157
1H NMR (CDCl3) δ 7.80-6.82(m, 10H), 6.69(s, 1H), 5.99(m, 1H), 3.26-3.21(m, 2H), 1.90-1.81(m, 1H), 0.95(d, J=6.6Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.80-6.82 (m, 10H), 6.69 (s, 1H), 5.99 (m, 1H), 3.26-3.21 (m, 2H), 1.90-1.81 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H)
실시예 97. 3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 97. 3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 N-(4-트리플루오로메틸-벤질) 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and N- (4-trifluoromethyl-benzyl) amine Synthesis was carried out according to step 3, method 4).
Figure PCTKR2012002405-appb-I000158
Figure PCTKR2012002405-appb-I000158
1H NMR (CDCl3) δ 7.84-6.82(m, 14H), 6.69(s, 1H), 6.42-6.38(m, 1H), 4.64(d, J=5.86Hz, 2H) 1 H NMR (CDCl 3 ) δ 7.84-6.82 (m, 14H), 6.69 (s, 1H), 6.42-6.38 (m, 1H), 4.64 (d, J = 5.86 Hz, 2H)
실시예 98. 3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-피페리딘-1-일-벤즈아미드Example 98. 3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-piperidin-1-yl-benzamide
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 N-아미노-피페리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and N-amino-piperidine According to the synthesis.
Figure PCTKR2012002405-appb-I000159
Figure PCTKR2012002405-appb-I000159
1H NMR (CDCl3) δ 7.87-7.83(m, 1H), 7.55-6.72(m, 10H), 6.68(s. 1H), 2.99(m, 4H), 1.73(m, 4H), 1.44-1.42(m, 2H) 1 H NMR (CDCl 3 ) δ 7.87-7.83 (m, 1 H), 7.55-6.72 (m, 10 H), 6.68 (s. 1 H), 2.99 (m, 4H), 1.73 (m, 4H), 1.44-1.42 (m, 2H)
실시예 99. 3-클로로-N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤즈아미드Example 99. 3-Chloro-N- (4-chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzamide
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 4-클로로 아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 4-chloro aniline It was.
Figure PCTKR2012002405-appb-I000160
Figure PCTKR2012002405-appb-I000160
1H NMR (CDCl3) δ 7.91-6.88(m, 14H), 6.72(s, 1H) 1 H NMR (CDCl 3 ) δ 7.91-6.88 (m, 14H), 6.72 (s, 1H)
실시예 100. 1-{3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 100. 1- {3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzoyl} -pyrrolidine-2-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 피롤리딘-2-카복시산 메틸 에스터로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to method 4).
Figure PCTKR2012002405-appb-I000161
Figure PCTKR2012002405-appb-I000161
1H NMR (CDCl3) δ 7.67-6.71(m, 10H), 6.68(s, 1H), 4.64-4.60(m, 1H), 3.75(s, 3H), 3.69-3.51(m, 2H), 2.34-1.85(m, 4H) 1 H NMR (CDCl 3 ) δ 7.67-6.71 (m, 10H), 6.68 (s, 1H), 4.64-4.60 (m, 1H), 3.75 (s, 3H), 3.69-3.51 (m, 2H), 2.34 -1.85 (m, 4H)
실시예 101. {3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 101. {3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -phenyl}-(3-hydroxy-pyrrolidin-1-yl ) -Methanone
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 3-히드록시-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 3-hydroxy-pyrrolidine )
Figure PCTKR2012002405-appb-I000162
Figure PCTKR2012002405-appb-I000162
1H NMR (CDCl3) δ 7.59-6.81(m, 10H), 6.67(s, 1H), 4.60(s, 1H), 4.38-4.36(m, 1H), 3.77-3.43(m, 4H), 2.34-1.86(m, 3H) 1 H NMR (CDCl 3 ) δ 7.59-6.81 (m, 10H), 6.67 (s, 1H), 4.60 (s, 1H), 4.38-4.36 (m, 1H), 3.77-3.43 (m, 4H), 2.34 -1.86 (m, 3H)
실시예 102. {3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 102. {3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -phenyl}-(2-hydroxymethyl-pyrrolidine-1- Sun) -Methanone
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 2-히드록시메틸-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxymethyl-pyrrolidine It synthesize | combined according to 4).
Figure PCTKR2012002405-appb-I000163
Figure PCTKR2012002405-appb-I000163
1H NMR (CDCl3) δ 7.70-6.79(m, 10H), 4.55-4.43(m, 1H), 3.77-3.39(m, 4H), 2.14-1.95(m, 4H) 1 H NMR (CDCl 3 ) δ 7.70-6.79 (m, 10H), 4.55-4.43 (m, 1H), 3.77-3.39 (m, 4H), 2.14-1.95 (m, 4H)
실시예 103. 3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-p-톨일-벤즈아미드Example 103. 3-Chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-p-tolyl-benzamide
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-클로로-벤조산과 4-메틸아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-chloro-benzoic acid and 4-methylaniline It was.
Figure PCTKR2012002405-appb-I000164
Figure PCTKR2012002405-appb-I000164
1H NMR (CDCl3) δ 7.64-6.80(m, 15H), 6.72(s, 1H), 2.33(s, 3H) 1 H NMR (CDCl 3 ) δ 7.64-6.80 (m, 15H), 6.72 (s, 1H), 2.33 (s, 3H)
실시예 104. 1-{3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 104. 1- {3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] benzoyl} -pyrrolidine-2-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 피롤리딘-2-카복시산 메틸 에스터으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester According to the synthesis.
Figure PCTKR2012002405-appb-I000165
Figure PCTKR2012002405-appb-I000165
1H NMR (CDCl3) δ 8.09-6.78(m, 11H), 6.74(s, 1H), 4.62-4.61(m, 1H), 3.75(s, 3H), 3.66-3.54(m, 2H), 2.03-1.87(m, 4H) 1 H NMR (CDCl 3 ) δ 8.09-6.78 (m, 11H), 6.74 (s, 1H), 4.62-4.61 (m, 1H), 3.75 (s, 3H), 3.66-3.54 (m, 2H), 2.03 -1.87 (m, 4H)
실시예 105. {3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 105. {3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -phenyl}-(3-hydroxy-pyrrolidin-1-yl)- Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 3-히드록시-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.According to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 3-hydroxy-pyrrolidine Synthesized.
Figure PCTKR2012002405-appb-I000166
Figure PCTKR2012002405-appb-I000166
1H NMR (CDCl3) δ 7.61-6.82(m, 11H), 6.73(s,1H), 4.56-4.44(m, 1H), 3.77-3.40(m, 4H), 2.16-1.67(m, 3H) 1 H NMR (CDCl 3 ) δ 7.61-6.82 (m, 11H), 6.73 (s, 1H), 4.56-4.44 (m, 1H), 3.77-3.40 (m, 4H), 2.16-1.67 (m, 3H)
실시예 106. {3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 106. {3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 2-히드록시메틸-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxymethyl-pyrrolidine Thus synthesized.
Figure PCTKR2012002405-appb-I000167
Figure PCTKR2012002405-appb-I000167
1H NMR (CDCl3) δ 7.59-6.83(m, 11H), 6.74(s, 1H), 4.36-4.35(m, 1H), 3.76-3.46(m, 4H), 2.14-1.61(m, 3H) 1 H NMR (CDCl 3 ) δ 7.59-6.83 (m, 11H), 6.74 (s, 1H), 4.36-4.35 (m, 1H), 3.76-3.46 (m, 4H), 2.14-1.61 (m, 3H)
실시예 107. 3-{3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-벤조일}-티아졸리딘-4-카복시산 메틸 에스터Example 107. 3- {3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -benzoyl} -thiazolidine-4-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 티아졸리딘-4-카복시산 메틸 에스터으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and thiazolidine-4-carboxylic acid methyl ester According to the synthesis.
Figure PCTKR2012002405-appb-I000168
Figure PCTKR2012002405-appb-I000168
1H NMR (CDCl3) δ 7.60-6.71(m, 11H), 6.36(s, 1H), 5.34-5.30(m, 1H), 4.23(m, 2H), 3.78(s, 3H), 3.28-3.24(m, 2H) 1 H NMR (CDCl 3 ) δ 7.60-6.71 (m, 11H), 6.36 (s, 1H), 5.34-5.30 (m, 1H), 4.23 (m, 2H), 3.78 (s, 3H), 3.28-3.24 (m, 2H)
실시예 108. {3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-페닐}-모포린-4-일-메타논Example 108. {3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -phenyl} -morpholin-4-yl-methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 몰포린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and morpholine.
Figure PCTKR2012002405-appb-I000169
Figure PCTKR2012002405-appb-I000169
1H NMR (CDCl3) δ 7.59-6.73(m, 11H), 6.68(s, 1H), 3.75-3.42(m, 8H) 1 H NMR (CDCl 3 ) δ 7.59-6.73 (m, 11 H), 6.68 (s, 1 H), 3.75-3.42 (m, 8 H)
실시예 109. 3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-피페리딘-1-일-벤즈아미드Example 109. 3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N-piperidin-1-yl-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 N-아미노-피페리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and N-amino-piperidine It was.
Figure PCTKR2012002405-appb-I000170
Figure PCTKR2012002405-appb-I000170
1H NMR (CDCl3) δ 7.50-6.83(m, 11H), 6.75(s, 1H), 2.85(m, 4H), 1.73(m, 4H), 1.73(m, 2H) 1 H NMR (CDCl 3 ) δ 7.50-6.83 (m, 11H), 6.75 (s, 1H), 2.85 (m, 4H), 1.73 (m, 4H), 1.73 (m, 2H)
실시예 110. 3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2-히드록시-시클로헥실)-벤즈아미드Example 110. 3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2-hydroxy-cyclohexyl) -benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-클로로-벤조산과 2-히드록시-시클로헥실아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.According to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-chloro-benzoic acid and 2-hydroxy-cyclohexylamine Synthesized.
Figure PCTKR2012002405-appb-I000171
Figure PCTKR2012002405-appb-I000171
1H NMR (CDCl3) δ 7.59-6.83(m, 11H), 6.76(s, 1H), 6.39-6.36(m, 1H), 4.09-4.01(m, 1H), 3.76-3.72(m, 1H), 1.90-1.42(m, 8H) 1 H NMR (CDCl 3 ) δ 7.59-6.83 (m, 11H), 6.76 (s, 1H), 6.39-6.36 (m, 1H), 4.09-4.01 (m, 1H), 3.76-3.72 (m, 1H) , 1.90-1.42 (m, 8H)
실시예 111. N-(4-클로로페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤즈아미드Example 111. N- (4-Chlorophenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 4-클로로아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 4-chloroaniline. .
Figure PCTKR2012002405-appb-I000172
Figure PCTKR2012002405-appb-I000172
1H NMR (CDCl3) δ 8.10-6.82(m, 15H), 6.72(s, 1H), 2.42(s, 3H) 1 H NMR (CDCl 3 ) δ 8.10-6.82 (m, 15H), 6.72 (s, 1H), 2.42 (s, 3H)
실시예 112. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 112. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 4-트리플루오로메틸-벤질아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 4-trifluoromethyl-benzylamine )
Figure PCTKR2012002405-appb-I000173
Figure PCTKR2012002405-appb-I000173
1H NMR (CDCl3) δ 7.63(m, 1H), 7.52-6.64(m, 14H), 6.60(s, 1H), 4.53(d, J=5.7Hz, 2H), 2.28(s, 3H) 1 H NMR (CDCl 3 ) δ 7.63 (m, 1H), 7.52-6.64 (m, 14H), 6.60 (s, 1H), 4.53 (d, J = 5.7Hz, 2H), 2.28 (s, 3H)
실시예 113. N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤즈아미드Example 113. N-tert-Butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 tert-부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and tert-butyl amine. .
Figure PCTKR2012002405-appb-I000174
Figure PCTKR2012002405-appb-I000174
1H NMR (CDCl3) δ 7.56-6.63(m, 10H), 6.60(s, 1H), 5.83(s, 1H), 2.33(s, 3H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.56-6.63 (m, 10H), 6.60 (s, 1H), 5.83 (s, 1H), 2.33 (s, 3H), 1.42 (s, 9H)
실시예 114. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-3-메틸-벤즈아미드Example 114. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-methyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 이소부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and isobutyl amine.
Figure PCTKR2012002405-appb-I000175
Figure PCTKR2012002405-appb-I000175
1H NMR (CDCl3) δ 7.60(m, 1H), 7.46-6.65(m, 10H), 6.61(s, 1H), 6.06(m, 1H), 3.25-3.21(m, 3H), 2.34(s, 3H), 1.89-1.80(m, 1H), 0.94(d, J=6.6Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.60 (m, 1H), 7.46-6.65 (m, 10H), 6.61 (s, 1H), 6.06 (m, 1H), 3.25-3.21 (m, 3H), 2.34 (s , 3H), 1.89-1.80 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H)
실시예 115. 4-[(4-클로로-페닐)-(2,4-디크로로-페닐)-메톡시]-3-메틸-N-피페리딘-1-일-벤즈아미드Example 115. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N-piperidin-1-yl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 N-아미노피페리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.According to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and N-aminopiperidine Synthesized.
Figure PCTKR2012002405-appb-I000176
Figure PCTKR2012002405-appb-I000176
1H NMR (CDCl3) δ 7.57(s, 1H), 7.42-6.64(m, 10H), 6.61(s. 1H), 2.81(m, 4H), 2.34(s, 3H), 1.74-1.73(m, 4H), 1.43(m, 2H) 1 H NMR (CDCl 3 ) δ 7.57 (s, 1H), 7.42-6.64 (m, 10H), 6.61 (s. 1H), 2.81 (m, 4H), 2.34 (s, 3H), 1.74-1.73 (m , 4H), 1.43 (m, 2H)
실시예 116. N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤즈아미드Example 116 N- (4-Chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 4-클로로아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 4-chloroaniline. .
Figure PCTKR2012002405-appb-I000177
Figure PCTKR2012002405-appb-I000177
1H NMR (CDCl3) δ 8.10-6.82(m, 15H), 6.72(s, 1H), 2.42(s, 3H) 1 H NMR (CDCl 3 ) δ 8.10-6.82 (m, 15H), 6.72 (s, 1H), 2.42 (s, 3H)
실시예 117. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-N-벤즈아미드Example 117. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis was carried out according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and aniline.
Figure PCTKR2012002405-appb-I000178
Figure PCTKR2012002405-appb-I000178
1H NMR (CDCl3) δ 8.11-7.01(m, 16H), 6.77(s, 1H), 2.33(s, 3H) 1 H NMR (CDCl 3 ) δ 8.11-7.01 (m, 16H), 6.77 (s, 1H), 2.33 (s, 3H)
실시예 118. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-N-p-톨일-벤즈아미드Example 118. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N-p-tolyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 4-메틸아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 4-methylaniline. .
Figure PCTKR2012002405-appb-I000179
Figure PCTKR2012002405-appb-I000179
1H NMR (CDCl3) δ 8.11-7.01(m, 15H), 6.77(s, 1H), 2.33(s, 3H), 2.22(s, 3H) 1 H NMR (CDCl 3 ) δ 8.11-7.01 (m, 15H), 6.77 (s, 1H), 2.33 (s, 3H), 2.22 (s, 3H)
실시예 119. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 119. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 피롤리딘-2-카복시산 메틸 에스터으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester It synthesize | combined according to 4).
Figure PCTKR2012002405-appb-I000180
Figure PCTKR2012002405-appb-I000180
1H NMR (CDCl3) δ 7.44-6.63(m, 10H), 6.59(s, 1H), 4.65-4.61(m, 1H), 3.75(s, 3H), 3.70-3.56(m, 2H), 2.32(s, 3H), 2.17-1.83(m, 4H), 1 H NMR (CDCl 3 ) δ 7.44-6.63 (m, 10H), 6.59 (s, 1H), 4.65-4.61 (m, 1H), 3.75 (s, 3H), 3.70-3.56 (m, 2H), 2.32 (s, 3H), 2.17-1.83 (m, 4H),
실시예 120. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 120. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-phenyl}-(3-hydroxy-pyrrolidin-1-yl ) -Methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 3-히드록시-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 3-hydroxy-pyrrolidine According to the synthesis.
Figure PCTKR2012002405-appb-I000181
Figure PCTKR2012002405-appb-I000181
1H NMR (CDCl3) δ 7.43-6.62(m, 10H), 6.58(s, 1H), 4.48-4.37(m, 1H), 3.74-3.40(m, 4H), 2.32(s, 3H), 2.09-1.90(m, 3H) 1 H NMR (CDCl 3 ) δ 7.43-6.62 (m, 10H), 6.58 (s, 1H), 4.48-4.37 (m, 1H), 3.74-3.40 (m, 4H), 2.32 (s, 3H), 2.09 -1.90 (m, 3H)
실시예 121. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 121. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-phenyl}-(2-hydroxymethyl-pyrrolidine-1- Sun) -Methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조산과 2-히드록시메틸-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4 from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoic acid and 2-hydroxymethyl-pyrrolidine )
Figure PCTKR2012002405-appb-I000182
Figure PCTKR2012002405-appb-I000182
1H NMR (CDCl3) δ 7.43-6.64(m, 10H), 6.60(s, 1H), 4.96(s, 1H), 4.39-4.36(m, 1H), 3.76-3.43(m, 4H), 2.32(s, 3H), 2.16-1.84(m, 4H) 1 H NMR (CDCl 3 ) δ 7.43-6.64 (m, 10H), 6.60 (s, 1H), 4.96 (s, 1H), 4.39-4.36 (m, 1H), 3.76-3.43 (m, 4H), 2.32 (s, 3H), 2.16-1.84 (m, 4H)
실시예 122. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 122. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-phenyl}-(3-hydroxy-pyrrolidin-1-yl)- Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산과 3-히드록시-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.According to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and 3-hydroxy-pyrrolidine Synthesized.
Figure PCTKR2012002405-appb-I000183
Figure PCTKR2012002405-appb-I000183
1H NMR (CDCl3) δ 7.49-6.70(m, 11H), 6.66(s, 1H), 4.39- 4.34(m, 1H), 3.79-3.42(m, 4H), 2.34(s, 3H), 2.17-2.10(m, 1H), 1.82-1.63(m, 2H) 1 H NMR (CDCl 3 ) δ 7.49-6.70 (m, 11H), 6.66 (s, 1H), 4.39-4.34 (m, 1H), 3.79-3.42 (m, 4H), 2.34 (s, 3H), 2.17 -2.10 (m, 1H), 1.82-1.63 (m, 2H)
실시예 123. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 123. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -Metanon
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산과 2-히드록시메틸-피롤리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and 2-hydroxymethyl-pyrrolidine Thus synthesized.
Figure PCTKR2012002405-appb-I000184
Figure PCTKR2012002405-appb-I000184
1H NMR (CDCl3) δ 7.50-6.67(m, 11H), 6.65(s, 1H), 4.48-4.36(m, 1H), 3.76-3.39(m, 4H), 2.32(s, 3H), 2.04-1.90(m, 3H) 1 H NMR (CDCl 3 ) δ 7.50-6.67 (m, 11H), 6.65 (s, 1H), 4.48-4.36 (m, 1H), 3.76-3.39 (m, 4H), 2.32 (s, 3H), 2.04 -1.90 (m, 3H)
실시예 124. 3-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조일}-티아졸리딘-4-카복시산 메틸에스터Example 124. 3- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoyl} -thiazolidine-4-carboxylic acid methyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산과 티아졸리딘-4-카복시산 메틸에스터으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and thiazolidine-4-carboxylic acid methyl ester According to the synthesis.
Figure PCTKR2012002405-appb-I000185
Figure PCTKR2012002405-appb-I000185
1H NMR (CDCl3) δ 7.48-6.64(m, 11H), 6.66(s, 1H), 5.36-5.34(m, 1H), 4.62(m, 2H), 3.77(s, 3H), 3.30-3.22(m, 2H), 2.34(s, 3H) 1 H NMR (CDCl 3 ) δ 7.48-6.64 (m, 11H), 6.66 (s, 1H), 5.36-5.34 (m, 1H), 4.62 (m, 2H), 3.77 (s, 3H), 3.30-3.22 (m, 2 H), 2.34 (s, 3 H)
실시예 125. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-페닐}-모포린-4-일-메타논Example 125. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-phenyl} -morpholin-4-yl-methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산과 몰포린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and morpholine.
Figure PCTKR2012002405-appb-I000186
Figure PCTKR2012002405-appb-I000186
1H NMR (CDCl3) δ 7.49-6.69(m, 11H), 6.65(s, 1H), 3.75-3.42(m, 8H), 2.34(s, 3H) 1 H NMR (CDCl 3 ) δ 7.49-6.69 (m, 11H), 6.65 (s, 1H), 3.75-3.42 (m, 8H), 2.34 (s, 3H)
실시예 126. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-N-피페리딘-1-일-벤즈아미드Example 126. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-N-piperidin-1-yl-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산과 N-아미노피페리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and N-aminopiperidine. .
Figure PCTKR2012002405-appb-I000187
Figure PCTKR2012002405-appb-I000187
1H NMR (CDCl3) δ 7.57-7.05(m, 10H), 6.78-6.64(m, 2H), 2.83(m, 4H), 2.35(s, 3H), 1.74-1.42(m, 6H) 1 H NMR (CDCl 3 ) δ 7.57-7.05 (m, 10H), 6.78-6.64 (m, 2H), 2.83 (m, 4H), 2.35 (s, 3H), 1.74-1.42 (m, 6H)
실시예 127. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2-히드록시-시클로헥실)-3-메틸-벤즈아미드Example 127. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2-hydroxy-cyclohexyl) -3-methyl-benzamide
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산과 N-(2-히드록시-시클로헥실) 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid and N- (2-hydroxycyclohexyl) amine It synthesize | combined according to 4).
Figure PCTKR2012002405-appb-I000188
Figure PCTKR2012002405-appb-I000188
1H NMR (CDCl3) δ 7.61-7.20(m, 11H), 6.68(s, 1H), 6.47-6.44(m, 1H), 4.06(m, 1H), 4.04(s, 1H), 2.35(s, 3H), 1.75-1.42(m, 8H) 1 H NMR (CDCl 3 ) δ 7.61-7.20 (m, 11H), 6.68 (s, 1H), 6.47-6.44 (m, 1H), 4.06 (m, 1H), 4.04 (s, 1H), 2.35 (s , 3H), 1.75-1.42 (m, 8H)
실시예 128. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-N-p-톨일-벤즈아미드Example 128. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-p-tolyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 4-메틸아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and 4-methylaniline It was.
Figure PCTKR2012002405-appb-I000189
Figure PCTKR2012002405-appb-I000189
1H NMR (CDCl3) δ 7.63-6.76(m, 10H), 6.65(s, 1H), 3.94(s, 3H), 2.33(s, 3H) 1 H NMR (CDCl 3 ) δ 7.63-6.76 (m, 10H), 6.65 (s, 1H), 3.94 (s, 3H), 2.33 (s, 3H)
실시예 129. N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤즈아미드Example 129. N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 tert-부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and tert-butyl amine It was.
Figure PCTKR2012002405-appb-I000190
Figure PCTKR2012002405-appb-I000190
1H NMR (CDCl3) δ 7.57-6.68(m, 10H), 6.62(s, 1H), 5.83(s, 1H), 3.91(s, 3H), 1.43(s, 9H) 1 H NMR (CDCl 3 ) δ 7.57-6.68 (m, 10H), 6.62 (s, 1H), 5.83 (s, 1H), 3.91 (s, 3H), 1.43 (s, 9H)
실시예 130. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-3-메톡시-벤즈아미드Example 130. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-methoxy-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 이소부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and isobutyl amine. .
Figure PCTKR2012002405-appb-I000191
Figure PCTKR2012002405-appb-I000191
1H NMR (CDCl3) δ 7.57-6.71(m, 10H), 6.62(s, 1H), 6.05-6.01(m, 1H), 3.92(s, 3H), 3.26-3.22(m, 2H), 1.90-1.83(m, 1H), 0.95(d, J=6.6Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.57-6.71 (m, 10H), 6.62 (s, 1H), 6.05-6.01 (m, 1H), 3.92 (s, 3H), 3.26-3.22 (m, 2H), 1.90 -1.83 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H)
실시예 131. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-N-(4-트리풀루오르메틸-벤질)-벤즈아미드Example 131. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N- (4-trifulormethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 4-트리풀루오르메틸-벤질아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and 4-trifulormethyl-benzylamine It synthesize | combined according to 4).
Figure PCTKR2012002405-appb-I000192
Figure PCTKR2012002405-appb-I000192
1H NMR (CDCl3) δ 7.60-6.72(m, 14H), 6.69(s, 1H), 6.38-6.34(m, 1H), 4.66(d, J = 5.7Hz, 2H), 3.92(s, 3H) 1 H NMR (CDCl 3 ) δ 7.60-6.72 (m, 14H), 6.69 (s, 1H), 6.38-6.34 (m, 1H), 4.66 (d, J = 5.7 Hz, 2H), 3.92 (s, 3H )
실시예 132. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-N-피페리딘-1-일-벤즈아미드Example 132. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-piperidin-1-yl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 N-아미노-피페리딘으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and N-amino-piperidine According to the synthesis.
Figure PCTKR2012002405-appb-I000193
Figure PCTKR2012002405-appb-I000193
1H NMR (CDCl3) δ 7.56-6.69(m, 10H), 6.62(s, 1H), 3.91(s, 3H), 2.82(m, 4H), 1.73(m, 4H), 1.42(m, 2H) 1 H NMR (CDCl 3 ) δ 7.56-6.69 (m, 10H), 6.62 (s, 1H), 3.91 (s, 3H), 2.82 (m, 4H), 1.73 (m, 4H), 1.42 (m, 2H )
실시예 133. {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-페닐}-모포린-4-일-메타논Example 133. {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-phenyl} -morpholin-4-yl-methanone
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 몰포린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and morpholine.
Figure PCTKR2012002405-appb-I000194
Figure PCTKR2012002405-appb-I000194
1H NMR (CDCl3) δ 7.57-6.71(m, 10H), 6.59(s, 1H), 3.88(s, 3H), 3.67(m, 8H) 1 H NMR (CDCl 3 ) δ 7.57-6.71 (m, 10H), 6.59 (s, 1H), 3.88 (s, 3H), 3.67 (m, 8H)
실시예 134. N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤즈아미드Example 134. N- (4-Chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤조산과 4-클로로아닐린으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Synthesis according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzoic acid and 4-chloroaniline It was.
Figure PCTKR2012002405-appb-I000195
Figure PCTKR2012002405-appb-I000195
1H NMR (CDCl3) δ 7.71-6.80(m, 15H), 6.74(s, 1H), 3.97(s, 3H) 1 H NMR (CDCl 3 ) δ 7.71-6.80 (m, 15H), 6.74 (s, 1H), 3.97 (s, 3H)
실시예 135. N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤즈아미드Example 135. N-tert-Butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조산과 tert-부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.In Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and tert-butyl amine Thus synthesized.
Figure PCTKR2012002405-appb-I000196
Figure PCTKR2012002405-appb-I000196
1H NMR (CDCl3) δ 7.97-6.87(m, 10H), 6.76(s, 1H), 5.79(s, 1H), 1.44(s, 9H) 1 H NMR (CDCl 3 ) δ 7.97-6.87 (m, 10H), 6.76 (s, 1H), 5.79 (s, 1H), 1.44 (s, 9H)
실시예 136. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸l-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 136. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyll-N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조산과 4-트리플루오로메틸-벤질아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and 4-trifluoromethyl-benzylamine , According to Method 4).
Figure PCTKR2012002405-appb-I000197
Figure PCTKR2012002405-appb-I000197
1H NMR (CDCl3) δ 8.05-6.90(m, 14H), 6.76(s, 1H), 6.62(t, J=5.8Hz, 1H), 4.62(d, J=5.8Hz, 2H) 1 H NMR (CDCl 3 ) δ 8.05-6.90 (m, 14H), 6.76 (s, 1H), 6.62 (t, J = 5.8 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H)
실시예 137. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-3-트리플루오로메틸-벤즈아미드Example 137. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-trifluoromethyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조산과 이소부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.According to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and isobutyl amine Synthesized.
Figure PCTKR2012002405-appb-I000198
Figure PCTKR2012002405-appb-I000198
1H NMR (CDCl3) δ 8.02-6.89(m, 10H), 6.76(s, 1H), 6.18(t, J= 5.5Hz, 1H), 3.26-3.22(m, 2H), 1.90-1.81(m, 1H), 0.94(d, J=6.3Hz, 6H) 1 H NMR (CDCl 3 ) δ 8.02-6.89 (m, 10H), 6.76 (s, 1H), 6.18 (t, J = 5.5 Hz, 1H), 3.26-3.22 (m, 2H), 1.90-1.81 (m , 1H), 0.94 (d, J = 6.3 Hz, 6H)
실시예 138. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 138. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoyl} -pyrrolidine-2-carboxylic acid Methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조산과 피롤리딘-2-카복시산 메틸 에스터으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester 3, method 4).
Figure PCTKR2012002405-appb-I000199
Figure PCTKR2012002405-appb-I000199
1H NMR (CDCl3) δ 7.89-6.83(m, 10H), 6.75(s, 1H), 4.66-4.61(m, 1H), 3.76(s, 3H), 3.17-3.47(m, 2H), 2.35-1.86(m, 4H) 1 H NMR (CDCl 3 ) δ 7.89-6.83 (m, 10H), 6.75 (s, 1H), 4.66-4.61 (m, 1H), 3.76 (s, 3H), 3.17-3.47 (m, 2H), 2.35 -1.86 (m, 4H)
실시예 139. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-(2-히드록시-시클로헥실)-3-트리플루오로메틸-벤즈아미드Example 139. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (2-hydroxy-cyclohexyl) -3-trifluoromethyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조산과 N-(2-히드록시-시클로헥실) 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoic acid and N- (2-hydroxy-cyclohexyl) amine It synthesize | combined according to (step 3, method 4).
Figure PCTKR2012002405-appb-I000200
Figure PCTKR2012002405-appb-I000200
1H NMR (CDCl3) δ 8.03-6.89(m, 10H), 6.76(s, 1H), 6.46-6.43(m, 1H), 4.11-4.07(m, 1H), 4.06-4.02(m, 1H), 1.78-1.39(m, 8H) 1 H NMR (CDCl 3 ) δ 8.03-6.89 (m, 10H), 6.76 (s, 1H), 6.46-6.43 (m, 1H), 4.11-4.07 (m, 1H), 4.06-4.02 (m, 1H) , 1.78-1.39 (m, 8H)
실시예 140. N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤즈아미드Example 140 N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조산과 tert-부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and tert-butyl amine According to the synthesis.
Figure PCTKR2012002405-appb-I000201
Figure PCTKR2012002405-appb-I000201
1H NMR (CDCl3) δ 7.68-6.70(m, 9H), 6.66(s, 1H), 6.36(m, 1H), 1.43(s, 9H) 1 H NMR (CDCl 3 ) δ 7.68-6.70 (m, 9H), 6.66 (s, 1H), 6.36 (m, 1H), 1.43 (s, 9H)
실시예 141. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 141. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N- (4-trifluoromethyl-benzyl)- Benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조산과 4-트리플루오로메틸-벤질 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다. Example 1 (step from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and 4-trifluoromethyl-benzyl amine 3, method 4).
Figure PCTKR2012002405-appb-I000202
Figure PCTKR2012002405-appb-I000202
1H NMR (CDCl3) δ 7.74-6.89(m, 13H), 6.79-6.73(m, 1H), 6.67(s, 1H), 4.69(d, J=5.7Hz, 2H) 1 H NMR (CDCl 3 ) δ 7.74-6.89 (m, 13H), 6.79-6.73 (m, 1H), 6.67 (s, 1H), 4.69 (d, J = 5.7 Hz, 2H)
실시예 142. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-N-이소부틸-벤즈아미드Example 142. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N-isobutyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조산과 이소부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and isobutyl amine to Example 1 (step 3, method 4) Thus synthesized.
Figure PCTKR2012002405-appb-I000203
Figure PCTKR2012002405-appb-I000203
1H NMR (CDCl3) δ 7.74-6.71(m, 9H), 6.66(s, 1H), 6.59-6.54(m, 1H), 3.30-3.26(m, 2H), 1.92-1.71(m, 1H), 0.96(d, J=6.6Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.74-6.71 (m, 9H), 6.66 (s, 1H), 6.59-6.54 (m, 1H), 3.30-3.26 (m, 2H), 1.92-1.71 (m, 1H) , 0.96 (d, J = 6.6 Hz, 6H)
실시예 143. 1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 143. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoyl} -pyrrolidine-2-carboxy Acid methyl ester
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조산과 피롤리딘-2-카복시산 메틸 에스터으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and pyrrolidine-2-carboxylic acid methyl ester Synthesis was carried out according to step 3, method 4).
Figure PCTKR2012002405-appb-I000204
Figure PCTKR2012002405-appb-I000204
1H NMR (CDCl3) δ 7.51-6.62(m, 9H), 6.61(s, 1H), 4.64(m, 1H), 3.76(s, 3H), 3.55-3.38(m, 2H), 2.35-1.85(m, 4H), 1 H NMR (CDCl 3 ) δ 7.51-6.62 (m, 9H), 6.61 (s, 1H), 4.64 (m, 1H), 3.76 (s, 3H), 3.55-3.38 (m, 2H), 2.35-1.85 (m, 4H),
실시예 144. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로--N-(2-히드록시-시클로헥실)-벤즈아미드Example 144. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N- (2-hydroxy-cyclohexyl)- Benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조산과 N-(2-히드록시-시클로헥실) 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoic acid and N- (2-hydroxy-cyclohexyl) amine Synthesis was carried out according to 1 (Step 3, Method 4).
Figure PCTKR2012002405-appb-I000205
Figure PCTKR2012002405-appb-I000205
1H NMR (CDCl3) δ 7.72-6.83(m, 9H), 6.76-6.70(m, 1H), 6.66(s, 1H), 4.14(s, 1H), 4.01(s, 1H), 1.78-1.30(m, 8H) 1 H NMR (CDCl 3 ) δ 7.72-6.83 (m, 9H), 6.76-6.70 (m, 1H), 6.66 (s, 1H), 4.14 (s, 1H), 4.01 (s, 1H), 1.78-1.30 (m, 8 H)
실시예 145. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-N-(4-트라이플루오르메틸-벤질)-벤즈아마이드Example 145. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤조산과 4-트라이플루오르메틸-벤질 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzoic acid and 4-trifluoromethyl-benzyl amine. .
Figure PCTKR2012002405-appb-I000206
Figure PCTKR2012002405-appb-I000206
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000207
7.71 (2H, d, J=8.95Hz) 7.57 (2H, d, J=8.07) 7.43~7.21 (8H, m) 6.91 (2H, d, J=8.95) 6.60 (1H, s) 6.50 (1H, t, J=5.87) 4.64 (2H, d, J=5.87) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000207
7.71 (2H, d, J = 8.95 Hz) 7.57 (2H, d, J = 8.07) 7.43 ~ 7.21 (8H, m) 6.91 (2H, d, J = 8.95) 6.60 (1H, s) 6.50 (1H, t , J = 5.87) 4.64 (2H, d, J = 5.87)
실시예 146. N-tert-뷰틸-4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-벤즈아마이드Example 146. N-tert-Butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤조산과 tert-부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzoic acid and tert-butyl amine.
Figure PCTKR2012002405-appb-I000208
Figure PCTKR2012002405-appb-I000208
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000209
7.62 (2H, d, J=8.51Hz) 7.43~7.21 (7H, m) 6.59 (1H, s) 5.80 (1H, brs) 1.43 (9H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000209
7.62 (2H, d, J = 8.51 Hz) 7.43 ~ 7.21 (7H, m) 6.59 (1H, s) 5.80 (1H, brs) 1.43 (9H, s)
실시예 147. 4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-2-플루오르-N-(4-트라이플루오르메틸-벤질)-벤즈아마이드Example 147. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2-플루오르-벤조산과 4-트라이플루오르메틸-벤질 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.Example 1 (Step 3, Method 4) from 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-benzoic acid and 4-trifluoromethyl-benzyl amine According to the synthesis.
Figure PCTKR2012002405-appb-I000210
Figure PCTKR2012002405-appb-I000210
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000211
8.04 (1H, t, J=9.10) 7.58 (2H, d, J=8.22) 7.45~7.35 (8H, m) 7.27~7.23 (1H, m) 7.04~6.96 (1H, m) 6.82~6.61 (2H, m) 6.58 (1H, s) 4.69 (2H, d, J=5.72) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000211
8.04 (1H, t, J = 9.10) 7.58 (2H, d, J = 8.22) 7.45 ~ 7.35 (8H, m) 7.27 ~ 7.23 (1H, m) 7.04 ~ 6.96 (1H, m) 6.82 ~ 6.61 (2H, m) 6.58 (1H, s) 4.69 (2H, d, J = 5.72)
실시예 148. N-tert-뷰틸-4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-2-프루오르-벤즈아마이드Example 148. N-tert-Butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2-플루오르-벤조산과 tert-부틸 아민으로부터 실시예 1 (단계 3, 방법 4)에 따라서 합성하였다.It was synthesized according to Example 1 (step 3, method 4) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-benzoic acid and tert-butyl amine. .
Figure PCTKR2012002405-appb-I000212
Figure PCTKR2012002405-appb-I000212
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000213
7.95 (1H, t, J=9.24 7.44~7.32 (6H, m) 6.78~6.58 (2H, m) 6.57 (1H, s) 6.46 (1H, d, J=14.38) 1.43 (9H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000213
7.95 (1H, t, J = 9.24 7.44 ~ 7.32 (6H, m) 6.78 ~ 6.58 (2H, m) 6.57 (1H, s) 6.46 (1H, d, J = 14.38) 1.43 (9H, s)
실시예 149. 4-[비스-(4-플루오로페닐)-메톡시]-N-tert-부틸-3-플루오로-벤즈아미드Example 149. 4- [bis- (4-fluorophenyl) -methoxy] -N-tert-butyl-3-fluoro-benzamide
Figure PCTKR2012002405-appb-I000214
Figure PCTKR2012002405-appb-I000214
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산 (1당량), HOBT (1.1당량), EDC(1.1당량)을 DCM에 녹인 후 tert-Butyl amine (2당량) 을 가하고 상온에서 12시간동안 교반하여 반응시킨다. 반응종료 후 물을 가하고 DCM로 추출한다. 분리된 유기층을 황산 나트륨으로 건조시킨 후 감압 농축한 다음, 잔여물을 실리카겔 컬럼 크로마토그래피로 정제하여 벤조산 아마이드를 수득하였다.4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid (1 equiv), HOBT (1.1 equiv) and EDC (1.1 equiv) were dissolved in DCM and then tert-Butyl amine ( 2 equivalents) is added and reacted by stirring at room temperature for 12 hours. After completion of the reaction, water was added and extracted with DCM. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain benzoic acid amide.
1H NMR (CDCl3) δ 7.50-6.84(m, 11H), 6.25(s, 1H), 5.17(bs, 1H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.50-6.84 (m, 11H), 6.25 (s, 1H), 5.17 (bs, 1H), 1.42 (s, 9H)
실시예 150. 4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 150. 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 4-트리플루오로메틸-벤질아민으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-trifluoromethyl-benzylamine.
Figure PCTKR2012002405-appb-I000215
Figure PCTKR2012002405-appb-I000215
1H NMR (CDCl3) δ 7.59-6.87(m, 15H), 6.35(t, J=5.2Hz, 1H), 6.27(s, 1H), 4.64(d, 5.8Hz, 2H) 1 H NMR (CDCl 3 ) δ 7.59-6.87 (m, 15 H), 6.35 (t, J = 5.2 Hz, 1 H), 6.27 (s, 1 H), 4.64 (d, 5.8 Hz, 2H)
실시예 151. 4-[비스-(4-플루오로페닐)-메톡시]-3-플루오로-N-p-톨일벤즈아미드Example 151. 4- [bis- (4-fluorophenyl) -methoxy] -3-fluoro-N-p-tolylbenzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 4-메틸-아닐린으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and 4-methyl-aniline.
Figure PCTKR2012002405-appb-I000216
Figure PCTKR2012002405-appb-I000216
1H NMR (CDCl3) δ 7.65-6.90(m, 16H), 6.29(s, 1H), 2.32(s, 3H) 1 H NMR (CDCl 3 ) δ 7.65-6.90 (m, 16H), 6.29 (s, 1H), 2.32 (s, 3H)
실시예 152. 4-[비스-(4-플루오로페닐)-메톡시]-3-플루오로-N-(피페리딘-1-일)벤즈아미드Example 152. 4- [bis- (4-fluorophenyl) -methoxy] -3-fluoro-N- (piperidin-1-yl) benzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 N-아미노피페리딘으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-aminopiperidine.
Figure PCTKR2012002405-appb-I000217
Figure PCTKR2012002405-appb-I000217
1H NMR (CDCl3) δ 7.52-6.85(m, 11H), 6.63(bs, 1H), 6.26(s, 1H), 2.81(m, 4H), 1.74(m, 4H), 1.42(m, 2H) 1 H NMR (CDCl 3 ) δ 7.52-6.85 (m, 11H), 6.63 (bs, 1H), 6.26 (s, 1H), 2.81 (m, 4H), 1.74 (m, 4H), 1.42 (m, 2H )
실시예 153. 4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-N-이소부틸-벤즈아미드Example 153. 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N-isobutyl-benzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 이소부틸아민으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and isobutylamine.
Figure PCTKR2012002405-appb-I000218
Figure PCTKR2012002405-appb-I000218
1H NMR (CDCl3) δ 7.54-6.86(m, 11H), 6.26(s, 1H), 5.99(s, 1H), 3.24(m, 2H), 1.90-1.81(m, 1H), 0.96(d, J=6.7Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.54-6.86 (m, 11H), 6.26 (s, 1H), 5.99 (s, 1H), 3.24 (m, 2H), 1.90-1.81 (m, 1H), 0.96 (d , J = 6.7 Hz, 6H)
실시예 154. {4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-페닐}-모포린-4-일-메탄온Example 154. {4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-phenyl} -morpholin-4-yl-methanone
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 몰포린으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and morpholine.
Figure PCTKR2012002405-appb-I000219
Figure PCTKR2012002405-appb-I000219
1H NMR (CDCl3) δ 7.42-6.86(m, 11H), 6.23(s, 1H), 3.67-3.60(m, 8H) 1 H NMR (CDCl 3 ) δ 7.42-6.86 (m, 11 H), 6.23 (s, 1 H), 3.67-3.60 (m, 8 H)
실시예 155. 4-[비스-(4-플루오로-페닐)-메톡시]-N-시클로헥실-3-플루오로-벤즈아미드Example 155. 4- [bis- (4-fluoro-phenyl) -methoxy] -N-cyclohexyl-3-fluoro-benzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 N-시클로헥실아민으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-cyclohexylamine.
Figure PCTKR2012002405-appb-I000220
Figure PCTKR2012002405-appb-I000220
1H NMR (CDCl3) δ 7.53-6.85(m, 1H), 6.26(s, 1H), 5.77(d, J=7.6Hz, 1H), 3.93-3.87(m, 1H), 2.35-1.12(m, 10H) 1 H NMR (CDCl 3 ) δ 7.53-6.85 (m, 1H), 6.26 (s, 1H), 5.77 (d, J = 7.6 Hz, 1H), 3.93-3.87 (m, 1H), 2.35-1.12 (m , 10H)
실시예 156. 4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-N-에틸-N-프로필-벤즈아미드Example 156. 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N-ethyl-N-propyl-benzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 N-에틸-N-프로필아민으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and N-ethyl-N-propylamine.
Figure PCTKR2012002405-appb-I000221
Figure PCTKR2012002405-appb-I000221
1H NMR (CDCl3) δ 7.40-6.83(m, 11H), 6.21(s, 1H), 3.60-3.05(m, 4H), 1.65-1.45(m, 2H), 1.30-0.70(m, 6H) 1 H NMR (CDCl 3 ) δ 7.40-6.83 (m, 11H), 6.21 (s, 1H), 3.60-3.05 (m, 4H), 1.65-1.45 (m, 2H), 1.30-0.70 (m, 6H)
실시예 157. 4-[비스(4-플루오로페닐)-메톡시]-3-플루오로-N-[2-히드록시-시클로헥실]-벤즈아미드Example 157. 4- [bis (4-fluorophenyl) -methoxy] -3-fluoro-N- [2-hydroxycyclohexyl] -benzamide
4-[비스-(4-플루오로-페닐)-메톡시]-3-플르오로-벤조산과 N-(2-히드록시-시클로헥실)아민으로부터 실시예 149 에 따라서 합성하였다. It was synthesized according to Example 149 from 4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-benzoic acid and N- (2-hydroxycyclohexyl) amine.
Figure PCTKR2012002405-appb-I000222
Figure PCTKR2012002405-appb-I000222
1H NMR (CDCl3) δ 7.57-6.86(m, 10H), 6.37(d, J=7.9Hz, 1H), 6.26(s, 1H), 4.09-4.01(m, 2H), 1.76-1.38(m, 8H,) 1 H NMR (CDCl 3 ) δ 7.57-6.86 (m, 10H), 6.37 (d, J = 7.9 Hz, 1H), 6.26 (s, 1H), 4.09-4.01 (m, 2H), 1.76-1.38 (m , 8H,)
실시예 158. (R)-1-{4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 158. (R) -1- {4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine- 2-carboxylic acid methyl ester
Figure PCTKR2012002405-appb-I000223
Figure PCTKR2012002405-appb-I000223
단계 1. (2-클로로-페닐)-(5-클로로-피리딘-2-일)-메탄올 Step 1. (2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methanol
2-클로로페닐마그네슘브로마이드(5.8g, 26.8mmol)의 THF 용액에 5-클로로-피리딘-2-카르보알데히드(1eq, 3.8g)을 THF 녹여서 천천히 가한다. 반응혼합물을 5시간 동안 환류하에 반응시킨다. 반응이 종결된 후 반응용액을 얼음물에 붓고 EtOAc로 2회 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 1.3g, 19%)To a THF solution of 2-chlorophenylmagnesium bromide (5.8 g, 26.8 mmol), 5-chloro-pyridine-2-carboaldehyde (1 eq, 3.8 g) was slowly added to THF. The reaction mixture is reacted under reflux for 5 hours. After completion of the reaction, the reaction solution was poured into iced water, extracted twice with EtOAc, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 1.3g, 19%)
1H NMR (300MHz, CDCl3) δ 8.52-8.51(m, 1H), 7.61-7.18(m, 6H), 6.25(s, 1H), 5.09(s, 1H) 1 H NMR (300MHz, CDCl 3 ) δ 8.52-8.51 (m, 1H), 7.61-7.18 (m, 6H), 6.25 (s, 1H), 5.09 (s, 1H)
단계 2. 2-[브로모-(2-클로로-페닐)-메틸]-5-클로로-피리딘 Step 2. 2- [Bromo- (2-chloro-phenyl) -methyl] -5-chloro-pyridine
(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메탄올(1.3g, 5.1mmol)를 CCl4에 녹인후 PBr3(0.4eq, 0.55g)을 첨가하고 반응혼합물을 3시간 동안 환류하에 반응시켰다. 반응종료후 반응혼합물을 얼음물에 붓고 DCM으로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.44g, 27%)Dissolve (2-chloro-phenyl)-(5-chloro-pyridin-2-yl) -methanol (1.3 g, 5.1 mmol) in CCl 4 , add PBr 3 (0.4eq, 0.55 g), and add the reaction mixture to 3 Reaction was carried out at reflux for hours. After completion of the reaction, the reaction mixture was poured into iced water, extracted with DCM, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.44g, 27%)
1H NMR (300MHz, CDCl3) 8.45-8.42(m, 1H), 7.40-6.94(m, 6H), 6.71(s, 1H) 1 H NMR (300 MHz, CDCl 3 ) 8.45-8.42 (m, 1 H), 7.40-6.94 (m, 6 H), 6.71 (s, 1 H)
단계 3. 4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산 메틸 에스터 Step 3. 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester
2-[브로모-(2-클로로-페닐)-메틸]-5-클로로-피리딘 (0.44g, 1.1mmol)과 K2CO3 (3eq, 0.47g)을 DMF에서 교반하면서 녹인 후, 3-플루오로-4-히드록시-벤조산 메틸 에스터(1eq, 0.19g)을 가하였다. 반응물을 상온에서 24시간 교반한 후 얼음물에 붓고 물층을 EtOAc로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.5g, 90%)2- [bromo- (2-chloro-phenyl) -methyl] -5-chloro-pyridine (0.44 g, 1.1 mmol) and K 2 CO 3 (3 eq, 0.47 g) were dissolved in DMF with stirring, then 3- Fluoro-4-hydroxy-benzoic acid methyl ester (1eq, 0.19 g) was added. The reaction was stirred at room temperature for 24 hours, poured into iced water, extracted with EtOAc, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.5g, 90%)
1H NMR (300MHz, CDCl3) 8.58-8.42(m,1H), 7.69-6.87(m, 6H), 6.34(s, 1H), 3.88(s, 3H) 1 H NMR (300MHz, CDCl 3 ) 8.58-8.42 (m, 1H), 7.69-6.87 (m, 6H), 6.34 (s, 1H), 3.88 (s, 3H)
단계4. 4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산 Step 4. 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid
4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산 메틸 에스터(0.5g, 1.2mmol)을 CH3CN과 물(1:1용액)에 넣고 교반 하면서 NaOH(3eq, 0.15g)을 가한 후, 반응물을 50℃로 가열하면서 24시간 동안 교반 하였다. 반응물을 감압 증류하여 CH3CN을 제거하고 남은 수용액을 냉각시킨후 1N-염산수용액으로 pH 5~6으로 산성화한 후 EtOAc로 추출 하고 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.45g, 93%) 4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester (0.5 g, 1.2 mmol) was purified by CH 3 CN and water (1 (1 solution) was added with NaOH (3eq, 0.15g) while stirring, and the reaction was stirred for 24 hours while heating to 50 ℃. The reaction mixture was distilled under reduced pressure to remove CH 3 CN, the remaining aqueous solution was cooled, acidified to pH 5-6 with 1N hydrochloric acid solution, extracted with EtOAc, the combined organic layers were washed with water, dried over anhydrous MgSO 4 , evaporated and concentrated. Then purified by column chromatography. (Yield 0.45g, 93%)
1H NMR (300MHz, CDCl3) 8.53-8.41(m,1H), 7.83-6.83(m, 7H), 6.32(s, 1H) 1 H NMR (300MHz, CDCl 3 ) 8.53-8.41 (m, 1H), 7.83-6.83 (m, 7H), 6.32 (s, 1H)
단계 5. Step 5.
4-[(2-클로로-페닐)-(5-클로로-피리딘-3-일)-메톡시]-3-플루오로-벤조산(0.1g, 0.26mmol)과 (2R)-피롤리딘-2-카복시산 메틸 에스테르 히드로클로라이드(2eq, 84.5mg), NMM (2.5eq, 65mg)를 건조된 DCM에 녹인 후, BOP (1eq, 0.11g) 을 가하고 상온에서 24시간 동안 교반하였다. 반응종료후 반응혼합물을 얼음물에 붓고 DCM으로 추출한 후 무수 MgSO4로 건조하고, 증발 농축 한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 32mg, 25%)4-[(2-Chloro-phenyl)-(5-chloro-pyridin-3-yl) -methoxy] -3-fluoro-benzoic acid (0.1 g, 0.26 mmol) and (2R) -pyrrolidine-2 Carboxylic acid methyl ester hydrochloride (2eq, 84.5mg), NMM (2.5eq, 65mg) was dissolved in dried DCM, BOP (1eq, 0.11g) was added and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was poured into iced water, extracted with DCM, dried over anhydrous MgSO 4 , concentrated by evaporation, and purified by column chromatography. (Yield 32mg, 25%)
1H NMR (300MHz, CDCl3) δ 7.62-6.52(m, 11H), 4.62-4.60(m, 1H), 3.76(s, 3H), 3.62-3.55(m, 2H), 2.23-1.85(m, 4H) 1 H NMR (300 MHz, CDCl 3 ) δ 7.62-6.52 (m, 11H), 4.62-4.60 (m, 1H), 3.76 (s, 3H), 3.62-3.55 (m, 2H), 2.23-1.85 (m, 4H)
실시예 159. (S)-1-{4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 159. (S) -1- {4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine- 2-carboxylic acid methyl ester
4-[(2-클로로-페닐)-(5-클로로-피리딘-3-일)-메톡시]-3-플루오로-벤조산과 메틸 (S)-프로린으로부터 실시예 158 (단계 5)에 따라서 합성하였다. According to Example 158 (step 5) from 4-[(2-chloro-phenyl)-(5-chloro-pyridin-3-yl) -methoxy] -3-fluoro-benzoic acid and methyl (S) -proline Synthesized.
Figure PCTKR2012002405-appb-I000224
Figure PCTKR2012002405-appb-I000224
1H NMR (CDCl3) δ 7.62-6.52(m, 11H), 4.62-4.60(m, 1H), 3.76(s, 3H), 3.62-3.55(m, 2H), 2.23-1.85(m, 4H) 1 H NMR (CDCl 3 ) δ 7.62-6.52 (m, 11H), 4.62-4.60 (m, 1H), 3.76 (s, 3H), 3.62-3.55 (m, 2H), 2.23-1.85 (m, 4H)
실시예 160. 1-{4-[(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 160. 1- {4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine- 2-carboxylic acid methyl ester
Figure PCTKR2012002405-appb-I000225
Figure PCTKR2012002405-appb-I000225
단계 1. (5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메탄올 Step 1. (5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methanol
2-브로모-3-크로로-피리딘(1.96g, 10.2mmol)을 건조된 에테르에 넣고 질소하에서 -60℃를 유지하면서 n-부틸 리튬 (1.6mol 헥산 용액, 1.5eq, 9.6ml)를 천천히 가하고 30분간 교반한다. 5-클로로-피리딘-2-카브알데히드 (1eq,1.4g)을 건조 된 에테르에 녹여서 천천히 가한다. 반응혼합물을 천천히 상온으로 올린후 상온에서 3시간 교반한 후 얼음물에 붓고 EtOAc로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.43g, 17%)2-bromo-3-chloro-pyridine (1.96 g, 10.2 mmol) was added to the dried ether and slowly n-butyl lithium (1.6 mol hexane solution, 1.5eq, 9.6 ml) was maintained at -60 ° C under nitrogen. Add and stir for 30 minutes. 5-chloro-pyridine-2-carbaldehyde (1eq, 1.4 g) is dissolved in dried ether and slowly added. The reaction mixture was slowly raised to room temperature, stirred at room temperature for 3 hours, poured into iced water, extracted with EtOAc, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.43g, 17%)
1H NMR (300MHz, CDCl3) δ 8.57-7.20(m, 6H), 6.14-6.12(m, 1H), 5.42-5.40(m, 1H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.57-7.20 (m, 6H), 6.14-6.12 (m, 1H), 5.42-5.40 (m, 1H)
단계 2. (5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-브로모 메탄 Step 2. (5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -bromo methane
(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메탄올(0.45g, 18mmol)를 CCl4에 녹인후 PBr3(0.4eq, 0.19g)을 첨가하고 반응혼합물을 3시간 동안 환류하에 반응시켰다. 반응종료후 반응혼합물을 얼음물에 붓고 DCM으로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.15g, 27%)Dissolve (5-chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methanol (0.45 g, 18 mmol) in CCl 4 , and then add PBr 3 (0.4 eq, 0.19 g) and react. The mixture was reacted under reflux for 3 hours. After completion of the reaction, the reaction mixture was poured into iced water, extracted with DCM, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.15g, 27%)
1H NMR (300MHz, CDCl3) δ 8.56-7.19(m, 6H), 6.74(s, 1H) 1 H NMR (300 MHz, CDCl 3 ) δ 8.56-7.19 (m, 6H), 6.74 (s, 1H)
단계 3. 4-[(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산 메틸 에스터 Step 3. 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester
(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-브로모 메탄 (0.15g, 0.47mmol)과 K2CO3 (3eq, 0.2g)을 DMF에서 교반하면서 녹인 후, 3-플루오로-4-히드록시-벤조산 메틸 에스터(1eq, 0.08g)을 가하였다. 반응물을 상온에서 24시간 교반한 후 얼음물에 붓고 물층을 EtOAc로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.17g, 86%)(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -bromo methane (0.15 g, 0.47 mmol) and K 2 CO 3 (3eq, 0.2 g) were stirred in DMF with After melting, 3-fluoro-4-hydroxy-benzoic acid methyl ester (1eq, 0.08 g) was added. The reaction was stirred at room temperature for 24 hours, poured into iced water, the water layer was extracted with EtOAc, the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.17g, 86%)
1H NMR (300MHz, CDCl3) δ 8.53-6.99(m, 9H), 6.95(s, 1H), 3.87(s, 3H) 1 H NMR (300MHz, CDCl 3 ) δ 8.53-6.99 (m, 9H), 6.95 (s, 1H), 3.87 (s, 3H)
단계 4. 4-[(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산 Step 4. 4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid
4-[(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산 메틸 에스터 (0.16g, 0.4mmol)을 CH3CN과 물(1:1용액)에 넣고 교반 하면서 NaOH(3eq, 0.047g)을 가한 후, 반응물을 50℃로 가열하면서 24시간 동안 교반 하였다. 반응물을 감압 증류하여 CH3CN을 제거하고 남은 수용액을 냉각시킨후 1N-염산수용액으로 pH 5~6으로 산성화한 후 EtOAc로 추출 하고 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (yield ; 0.15g, 98%)4-[(5-chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid methyl ester (0.16 g, 0.4 mmol) was CH 3 CN And NaOH (3eq, 0.047g) was added to the water (1: 1 solution) with stirring, and the reaction was stirred for 24 hours while heating to 50 ℃. The reaction mixture was distilled under reduced pressure to remove CH 3 CN, the remaining aqueous solution was cooled, acidified to pH 5-6 with 1N hydrochloric acid solution, extracted with EtOAc, the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated and concentrated. Then purified by column chromatography. (yield; 0.15g, 98%)
1H NMR (300MHz, CDCl3) δ 8.54-7.02(m, 10H), 6.96(s, 1H) 1 H NMR (300MHz, CDCl 3 ) δ 8.54-7.02 (m, 10H), 6.96 (s, 1H)
단계 5. Step 5.
4-[(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조산(57mg, 0.15mmol)과 피롤리딘-2-카복시산 메틸 에스테르 히드로클로라이드(2eq, 48mg), NMM (2.5eq, 32mg)를 건조된 DCM에 녹인 후, BOP (1eq, 64mg) 을 가하고 상온에서 24시간 동안 교반하였다. 반응종료후 반응혼합물을 얼음물에 붓고 DCM으로 추출한 후 무수 MgSO4로 건조하고, 증발 농축 한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 59mg, 80%)4-[(5-Chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoic acid (57 mg, 0.15 mmol) and pyrrolidine-2- Carboxylic acid methyl ester hydrochloride (2eq, 48mg) and NMM (2.5eq, 32mg) were dissolved in dried DCM, BOP (1eq, 64mg) was added and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was poured into iced water, extracted with DCM, dried over anhydrous MgSO 4 , concentrated by evaporation, and purified by column chromatography. (Yield 59mg, 80%)
1H NMR (300MHz, CDCl3) δ 8.52-6.97(m, 9H), 6.90(s, 1H), 4.64-4.60(m, 1H), 3.75(s, 3H), 3.65-3.57(m, 2H), 2.34-1.88(m, 4H) 1 H NMR (300MHz, CDCl 3 ) δ 8.52-6.97 (m, 9H), 6.90 (s, 1H), 4.64-4.60 (m, 1H), 3.75 (s, 3H), 3.65-3.57 (m, 2H) , 2.34-1.88 (m, 4H)
실시예 161. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(1,2,4-트리아졸-1-일)메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 161. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-benzoyl} -Pyrrolidine-2-carboxylic acid methyl ester
Figure PCTKR2012002405-appb-I000226
Figure PCTKR2012002405-appb-I000226
단계 1. Step 1.
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조산 메틸 에스터(0.5g, 1.25mmol)를 CCl4에 녹이고 NBS (1eq, 0.22g)과 촉매량의 AIBN을 가하였다. 반응혼합물을 3시간 동안 환류 교반 시킨 후 얼음물에 붓고 EtOAc로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.34g, 56%)4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoic acid methyl ester (0.5 g, 1.25 mmol) was dissolved in CCl 4 , followed by NBS (1eq, 0.22 g). A catalytic amount of AIBN was added. The reaction mixture was stirred under reflux for 3 hours, poured into iced water, extracted with EtOAc, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.34g, 56%)
1H NMR (300MHz, CDCl3) δ 8.03-6.73(m, 12H), 4.62(q, J=9.6Hz, 17.7Hz, 2H), 3.85(s, 3H) 1 H NMR (300MHz, CDCl 3 ) δ 8.03-6.73 (m, 12H), 4.62 (q, J = 9.6Hz, 17.7Hz, 2H), 3.85 (s, 3H)
단계 2. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-[1,2,4]트리아졸-1-일메틸-벤조산 메틸 에스터 Step 2. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid methyl ester
3-브로모-메틸-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-벤조산 메틸 에스터 (0.34g, 0.7mmol)과 K2CO3 (3eq, 0.29g)을 DMF에 교반하면서 녹인 후, 1H-[1,2,4]트리아졸 (1.2eq, 58mg)을 가하였다. 반응혼합물을 상온에서 24시간 교반한 후 얼음물에 붓고 EtOAc로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.23g, 70.4%)3-Bromo-methyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -benzoic acid methyl ester (0.34 g, 0.7 mmol) with K 2 CO 3 (3 eq, 0.29 g ) Was dissolved in DMF with stirring, and then 1H- [1,2,4] triazole (1.2eq, 58 mg) was added. The reaction mixture was stirred at room temperature for 24 hours, poured into iced water, extracted with EtOAc, and the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 0.23g, 70.4%)
1H NMR (300MHz, CDCl3) δ 8.00-6.74(m, 13H), 6.67(s, 1H), 5.47-5.35(m, 2H), 3.86(s, 3H) 1 H NMR (300MHz, CDCl 3 ) δ 8.00-6.74 (m, 13H), 6.67 (s, 1H), 5.47-5.35 (m, 2H), 3.86 (s, 3H)
단계 3. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-[1,2,4]트리아졸-1-일메틸-벤조산 Step 3. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-[1,2,4]트리아졸-1-일메틸-벤조산 메틸 에스터 (0.29g, 0.62mmol) 을 CH3CN과 물(1:1용액)에 넣고 교반 하면서 NaOH (3eq, 74mg)을 가한 후, 반응혼합물을 50℃로 가열하면서 24시간 동안 교반 하였다. 반응혼합물을 감압 증발 하여 CH3CN을 제거하고 1N-염산수용액으로 pH 5~6으로 한 후 EtOAc로 추출 하고 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 0.17g, 61%) 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-ylmethyl-benzoic acid methyl ester (0.29 g, 0.62 mmol) Was added to CH 3 CN and water (1: 1 solution), followed by adding NaOH (3eq, 74mg) while stirring, and the reaction mixture was stirred for 24 hours while heating to 50 ℃. The reaction mixture was evaporated under reduced pressure to remove CH 3 CN, pH 5-6 with 1N hydrochloric acid, extracted with EtOAc, and the organic layers were collected and washed with water, dried over anhydrous MgSO 4 , evaporated and concentrated, followed by column chromatography. Isolate and purify. (Yield 0.17g, 61%)
1H NMR (300MHz, CDCl3) δ 8.09-6.75(m, 14H), 6.68(s, 1H), 5.48-5.37(m, 2H) 1 H NMR (300MHz, CDCl 3 ) δ 8.09-6.75 (m, 14H), 6.68 (s, 1H), 5.48-5.37 (m, 2H)
단계 4. Step 4.
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-[1,2,4]트리아졸-1-일-메틸-벤조산 (40mg, 0.088mmol)과 피롤리딘-2-카복시산 메틸 에스테르 히드로클로라이드(2eq, 29mg), NMM (2.2eq, 19.6mg)를 건조된 DCM에 녹인 후, BOP (1eq, 39mg) 을 가하고 상온에서 24시간 동안 교반하였다. 반응종료후 반응혼합물을 얼음물에 붓고 DCM으로 추출한 후 무수 MgSO4로 건조하고, 증발 농축 한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 38mg, 76%)4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-yl-methyl-benzoic acid (40 mg, 0.088 mmol) Lolidine-2-carboxylic acid methyl ester hydrochloride (2eq, 29mg) and NMM (2.2eq, 19.6mg) were dissolved in dried DCM, and then BOP (1eq, 39mg) was added and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was poured into iced water, extracted with DCM, dried over anhydrous MgSO 4 , concentrated by evaporation, and purified by column chromatography. (Yield 38mg, 76%)
1H NMR (300MHz, CDCl3) δ 8.23-6.71(m, 13H), 6.64(s, 1H), 5.49-5.40(m, 2H), 4.63-4.59(m, 1H), 3.75(s, 3H), 3.68-3.54(m, 2H), 2.33-1.84(m, 4H) 1 H NMR (300MHz, CDCl 3 ) δ 8.23-6.71 (m, 13H), 6.64 (s, 1H), 5.49-5.40 (m, 2H), 4.63-4.59 (m, 1H), 3.75 (s, 3H) , 3.68-3.54 (m, 2H), 2.33-1.84 (m, 4H)
실시예 162. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(1,2,4-트리아졸-1-일)메틸-페닐}-(3-히드록시-피롤리딘-1-일)-메타논Example 162. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-phenyl}-( 3-hydroxy-pyrrolidin-1-yl) -methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-[1,2,4]트리아졸-1-일-메틸-벤조산과 3-히드록시-피롤리딘으로부터 실시예 161 (단계 4)에 따라 합성하였다.4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-yl-methyl-benzoic acid and 3-hydroxy-pyrroli Synthesis was carried out according to Example 161 (step 4) from Dean.
Figure PCTKR2012002405-appb-I000227
Figure PCTKR2012002405-appb-I000227
1H NMR (CDCl3) δ 8.14-6.71(m, 13H), 6.64(s, 1H), 5.47-5.34(m, 2H), 4.55-4.42(m, 1H), 3.76-3.38(m, 4H), 2.17-1.94(m, 3H) 1 H NMR (CDCl 3 ) δ 8.14-6.71 (m, 13H), 6.64 (s, 1H), 5.47-5.34 (m, 2H), 4.55-4.42 (m, 1H), 3.76-3.38 (m, 4H) , 2.17-1.94 (m, 3 H)
실시예 163. {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(1,2,4-트리아졸-1-일)메틸-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논Example 163. {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-phenyl}-( 2-hydroxymethyl-pyrrolidin-1-yl) -methanone
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-[1,2,4]트리아졸-1-일-메틸-벤조산과 3-히드록시-피롤리딘으로부터 실시예 161 (단계 4)에 따라 합성하였다.4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- [1,2,4] triazol-1-yl-methyl-benzoic acid and 3-hydroxy-pyrroli Synthesis was carried out according to Example 161 (step 4) from Dean.
Figure PCTKR2012002405-appb-I000228
Figure PCTKR2012002405-appb-I000228
1H NMR (CDCl3) δ 7.95-6.72(m, 13H), 6.65(s, 1H), 5.47-5.34(m, 2H), 4.86(s, 1H), 4.37-4.35(m, 1H), 3.75-3.66(m, 2H), 3.52-3.41(m 2H), 2.17-1.59(m, 4H) 1 H NMR (CDCl 3 ) δ 7.95-6.72 (m, 13H), 6.65 (s, 1H), 5.47-5.34 (m, 2H), 4.86 (s, 1H), 4.37-4.35 (m, 1H), 3.75 -3.66 (m, 2H), 3.52-3.41 (m 2H), 2.17-1.59 (m, 4H)
실시예 164. 1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(이미다졸-1-일)메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터Example 164. 1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (imidazol-1-yl) methyl-benzoyl} -pyrrolidine-2 Carboxylic Acid Methyl Ester
Triazole 대신 Imidazole을 사용한 것을 제외하고는 실시예 161 (단계 4)과 동일한 공정으로 합성하였다. Synthesis was carried out in the same manner as in Example 161 (Step 4), except that Imidazole was used instead of Triazole.
Figure PCTKR2012002405-appb-I000229
Figure PCTKR2012002405-appb-I000229
1H NMR (CDCl3) δ 7.64-6.70(m, 14H), 6.64(s, 1H), 5.17-5.14(m, 2H), 4.59-4.63(m, 1H), 3.75(s, 3H), 3.68-3.43(m, 2H), 2.36-1.85(m, 4H) 1 H NMR (CDCl 3 ) δ 7.64-6.70 (m, 14H), 6.64 (s, 1H), 5.17-5.14 (m, 2H), 4.59-4.63 (m, 1H), 3.75 (s, 3H), 3.68 -3.43 (m, 2H), 2.36-1.85 (m, 4H)
실시예 165. N-tert-부틸-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-플루오로-벤즈아미드Example 165. N-tert-butyl-3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-fluoro-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-플루오로-벤조산과 tert-부틸아민을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Example 1 (step 3, method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-fluoro-benzoic acid and tert-butylamine Synthesis was carried out in the same process.
Figure PCTKR2012002405-appb-I000230
Figure PCTKR2012002405-appb-I000230
1H NMR (CDCl3) δ 7.57-7.04(m, 10H), 6.68(s, 1H), 5.73(s, 1H), 1.43(s, 9H) 1 H NMR (CDCl 3 ) δ 7.57-7.04 (m, 10H), 6.68 (s, 1H), 5.73 (s, 1H), 1.43 (s, 9H)
실시예 166. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-N-피페리딘-1-일-벤즈아미드Example 166. 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-N-piperidin-1-yl-benzamide
Figure PCTKR2012002405-appb-I000231
Figure PCTKR2012002405-appb-I000231
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤조산과 N-아미노-피테리딘을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Example 1 (Step 3, Method 4) using 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and N-amino-pyridine Synthesis was carried out in the same process as).
1H NMR (CDCl3) δ 7.46-7.12(m, 10H), 6.72(bs, 1H), 6.65(s, 1H), 2.80(m, 4H), 2.33(s, 3H), 1.71(m, 4H), 1.42(m, 2H) 1 H NMR (CDCl 3 ) δ 7.46-7.12 (m, 10H), 6.72 (bs, 1H), 6.65 (s, 1H), 2.80 (m, 4H), 2.33 (s, 3H), 1.71 (m, 4H ), 1.42 (m, 2H)
실시예 167. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 167. 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-N- (4-trifluoromethyl-benzyl) -benzamide
Figure PCTKR2012002405-appb-I000232
Figure PCTKR2012002405-appb-I000232
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤조산과 4-트리플루오로메틸-벤질아민을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Example 1 (step 3, using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and 4-trifluoromethyl-benzylamine Synthesis was carried out in the same manner as in Method 4).
1H NMR (CDCl3) δ 7.61-7.16(m, 14H), 6.65(s, 1H), 6.37(t, J=5.42Hz, 1H), 4.63(d, J=5.86Hz, 2H), 2.35(s, 3H) 1 H NMR (CDCl 3 ) δ 7.61-7.16 (m, 14H), 6.65 (s, 1H), 6.37 (t, J = 5.42 Hz, 1H), 4.63 (d, J = 5.86 Hz, 2H), 2.35 ( s, 3 H)
실시예 168. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-4-메틸-벤즈아미드 Example 168. 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-4-methyl-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤조산과 이소부틸아민을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Same process as in Example 1 (Step 3, Method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and isobutylamine Synthesized.
Figure PCTKR2012002405-appb-I000233
Figure PCTKR2012002405-appb-I000233
1H NMR (CDCl3) δ 7.46-7.18(m, 10H), 6.66(s, 1H), 5.98(s, 1H), 3.23-3.20(m, 2H), 2.34(s, 3H), 1.90-1.81(m, 1H), 0.95(d, J=6.6Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.46-7.18 (m, 10H), 6.66 (s, 1H), 5.98 (s, 1H), 3.23-3.20 (m, 2H), 2.34 (s, 3H), 1.90-1.81 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H)
실시예 169. N-tert-부틸-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤즈아미드Example 169. N-tert-butyl-3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤조산과 tert-부틸아민을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Same as Example 1 (Step 3, Method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and tert-butylamine Synthesis by process.
Figure PCTKR2012002405-appb-I000234
Figure PCTKR2012002405-appb-I000234
1H NMR (CDCl3) δ 7.47-7.15(m, 10H), 6.66(s, 1H), 5.76(bs, 1H), 2.33(s, 3H), 1.43(s, 9H) 1 H NMR (CDCl 3 ) δ 7.47-7.15 (m, 10H), 6.66 (s, 1H), 5.76 (bs, 1H), 2.33 (s, 3H), 1.43 (s, 9H)
실시예 170. N-(4-클로로-페닐)-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤즈아미드Example 170. N- (4-Chloro-phenyl) -3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤조산과 4-클로로아닐린을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Same as Example 1 (Step 3, Method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and 4-chloroaniline Synthesis by process.
Figure PCTKR2012002405-appb-I000235
Figure PCTKR2012002405-appb-I000235
1H NMR (CDCl3) δ 7.57-7.24(m, 15H), 6.69(s, 1H), 2.46(s, 3H) 1 H NMR (CDCl 3 ) δ 7.57-7.24 (m, 15H), 6.69 (s, 1H), 2.46 (s, 3H)
실시예 171. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-N-p-톨일-벤즈아미드Example 171. 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-N-p-tolyl-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤조산과 4-메틸아닐린을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Same as Example 1 (Step 3, Method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and 4-methylaniline Synthesis by process.
Figure PCTKR2012002405-appb-I000236
Figure PCTKR2012002405-appb-I000236
1H NMR (CDCl3) δ 7.55-7.15(m, 15H), 6.70(s, 1H), 2.38(s, 3H), 2.34(s, 3H) 1 H NMR (CDCl 3 ) δ 7.55-7.15 (m, 15H), 6.70 (s, 1H), 2.38 (s, 3H), 2.34 (s, 3H)
실시예 172. N-tert-부틸-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-벤즈아미드Example 172. N-tert-butyl-3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-벤조산과 tert-부틸아민을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Example 1 (step 3, method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and tert-butylamine Synthesis was carried out in the same process.
Figure PCTKR2012002405-appb-I000237
Figure PCTKR2012002405-appb-I000237
1H NMR (CDCl3) δ 7.62-6.84(m, 10H), 6.65(s, 1H), 5.69(s, 1H), 3.89(s, 3H), 1.42(s, 9H) 1 H NMR (CDCl 3 ) δ 7.62-6.84 (m, 10H), 6.65 (s, 1H), 5.69 (s, 1H), 3.89 (s, 3H), 1.42 (s, 9H)
실시예 173. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-N-(4-트리플루오로메틸-벤질)-벤즈아미드Example 173. 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-N- (4-trifluoromethyl-benzyl) -benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-벤조산과 4-트리플루오로메틸-벤질을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Example 1 (step 3, using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and 4-trifluoromethyl-benzyl Synthesis was carried out in the same manner as in Method 4).
Figure PCTKR2012002405-appb-I000238
Figure PCTKR2012002405-appb-I000238
1H NMR (CDCl3) δ 7.62-7.24(m, 13H), 6.89-6.87(m, 1H), 6.65(s, 1H), 6.24(m, 1H), 4.64(d, J=5.87Hz, 2H), 3.90(s, 3H) 1 H NMR (CDCl 3 ) δ 7.62-7.24 (m, 13H), 6.89-6.87 (m, 1H), 6.65 (s, 1H), 6.24 (m, 1H), 4.64 (d, J = 5.87Hz, 2H ), 3.90 (s, 3 H)
실시예 174. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-4-메톡시-벤즈아미드Example 174 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-4-methoxy-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-벤조산과 이소부틸아민을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Same as Example 1 (Step 3, Method 4) using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and isobutylamine Synthesis by process.
Figure PCTKR2012002405-appb-I000239
Figure PCTKR2012002405-appb-I000239
1H NMR (CDCl3) δ 7.61-6.87(m, 10H), 6.65(s, 1H), 5.91(m, 1H), 3.90(s, 3H), 3.25-3.20(m, 2H), 1.90-1.81(m, 1H), 0.96(d, J=6.7Hz, 6H) 1 H NMR (CDCl 3 ) δ 7.61-6.87 (m, 10H), 6.65 (s, 1H), 5.91 (m, 1H), 3.90 (s, 3H), 3.25-3.20 (m, 2H), 1.90-1.81 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H)
실시예 175. 3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-N-피페리딘-1-일-벤즈아미드Example 175. 3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-N-piperidin-1-yl-benzamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-벤조산과 N-아미노-피페리딘을 사용하여 실시예 1 (단계 3, 방법 4)와 동일한 공정으로 합성하였다. Example 1 (step 3, method using 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzoic acid and N-amino-piperidine It synthesize | combined by the same process as 4).
Figure PCTKR2012002405-appb-I000240
Figure PCTKR2012002405-appb-I000240
1H NMR (CDCl3) δ 7.62-6.84(m, 10H), 6.63(s, 1H), 6.50(bs, 1H), 3.89(s, 3H), 2.80(m, 4H), 1.73(m, 4H), 1.42(m, 2H) 1 H NMR (CDCl 3 ) δ 7.62-6.84 (m, 10H), 6.63 (s, 1H), 6.50 (bs, 1H), 3.89 (s, 3H), 2.80 (m, 4H), 1.73 (m, 4H ), 1.42 (m, 2H)
실시예 176. 시클로헥산카복시산 {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-아미드Example 176. Cyclohexanecarboxylic acid {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -amide
Figure PCTKR2012002405-appb-I000241
Figure PCTKR2012002405-appb-I000241
단계 1. 1-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2-플루오로-4-니트로-벤젠 Step 1. 1-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-4-nitro-benzene
1-[브로모-(4-클로로-페닐)-메틸]-2,4-디클로로-벤젠 (1.2g, 3.4mmol)과 K2CO3 (3eq, 0.94g)을 DMF에서 교반하면서 녹인 후, 2-플루오로-4-니트로-페놀(1eq, 0.54g)을 가하였다. 반응물을 상온에서 24시간 교반한 후 얼음물에 붓고 물층을 EtOAc로 추출한 후 유기층을 모아 물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 1.3g, 89%)1- [bromo- (4-chloro-phenyl) -methyl] -2,4-dichloro-benzene (1.2 g, 3.4 mmol) and K 2 CO 3 (3 eq, 0.94 g) were dissolved in DMF with stirring, 2-fluoro-4-nitro-phenol (1eq, 0.54 g) was added. The reaction was stirred at room temperature for 24 hours, poured into iced water, the water layer was extracted with EtOAc, the organic layers were collected, washed with water, dried over anhydrous MgSO 4 , evaporated, concentrated and separated and purified by column chromatography. (Yield 1.3g, 89%)
1H NMR (300MHz, CDCl3) δ 8.02-6.91(m, 10H), 6.71(s, 1H) 1 H NMR (300MHz, CDCl 3 ) δ 8.02-6.91 (m, 10H), 6.71 (s, 1H)
단계 2. 4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-아닐린 Step 2. 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline
1-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2-플루오로-4-니트로-벤젠(1.3g, 3mmol)을 MeOH에 녹인 후 Raney Nikel (0.5g)을 넣은 후, 수소화장치에서 50psi를 유지하며 상온에서 24시간 교반 하였다. 반응물을 셀라이트에서 여과하고 증발 농축하고 얻어진 결과물을 다음 반응에 바로 사용하였다.Dissolve 1-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-4-nitro-benzene (1.3 g, 3 mmol) in MeOH and then Raney Nikel (0.5 After the g) was added, it was stirred at room temperature for 24 hours while maintaining 50psi in a hydrogenation apparatus. The reaction was filtered through celite, concentrated by evaporation and the resultant used directly for the next reaction.
단계 3. 시클로헥산카복시산 {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-아미드 Step 3. Cyclohexanecarboxylic acid {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -amide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-아닐린 (70mg, 0.18mmol)을 DMF 에 녹인 후 K2CO3 (2eq, 49mg)를 넣고 교반하면서 시클로헥산카보닐클로라이드 (1.2eq, 30.8mg)을 가하였다. 반응물을 상온에서 24시간 교반한 후, 얼음물에 붓고 EtOAc로 추출하였다. 유기층을 소금물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. (수율 : 15mg, 17%)4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline (70 mg, 0.18 mmol) was dissolved in DMF and K 2 CO 3 (2eq, 49 mg ) And cyclohexanecarbonyl chloride (1.2eq, 30.8mg) was added while stirring. The reaction was stirred at room temperature for 24 hours, then poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO 4 , evaporated and concentrated, and then purified by column chromatography. (Yield 15mg, 17%)
1H NMR (300MHz, CDCl3) δ7.59-6.75(m, 11H), 6.52(s, 1H), 2.21-2.12(m, 1H), 1.93-1.25(m, 10H) 1 H NMR (300 MHz, CDCl 3 ) δ7.59-6.75 (m, 11H), 6.52 (s, 1H), 2.21-2.12 (m, 1H), 1.93-1.25 (m, 10H)
실시예 177. N-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-4-트리플루오로메틸-벤즈아미드Example 177. N- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -4-trifluoromethyl-benzamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-아닐린과 4-트리플루오로메틸 벤조일 클로라이드로부터 실시예 176 (단계 3)의 공정으로 합성하였다. Process of Example 176 (step 3) from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline and 4-trifluoromethyl benzoyl chloride Synthesized.
1H NMR (CDCl3) δ 7.94-6.83(m, 15H), 6.57(s, 1H) 1 H NMR (CDCl 3 ) δ 7.94-6.83 (m, 15 H), 6.57 (s, 1 H)
실시예 178. N-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-2,2-디메틸-프로피온아미드Example 178. N- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -2,2-dimethyl-propionamide
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-아닐린과 2,2-디메틸-프로피온산 클로라이드로부터 실시예 176 (단계 3)의 공정으로 합성하였다. Example 176 (step 3) process from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline and 2,2-dimethyl-propionic acid chloride Synthesized.
Figure PCTKR2012002405-appb-I000243
Figure PCTKR2012002405-appb-I000243
1H NMR (CDCl3) δ 7.59-6.76(m, 11H), 6.53(s, 1H), 1.27(s, 9H) 1 H NMR (CDCl 3 ) δ 7.59-6.76 (m, 11 H), 6.53 (s, 1 H), 1.27 (s, 9 H)
실시예 179. 3-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-1,1-디메틸-우레아Example 179. 3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -1,1-dimethyl-urea
4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-아닐린 (70mg, 0.18mmol)을 DMF 에 녹인 후 K2CO3 (2eq, 49mg)를 넣고 교반하면서 N,N-디메틸-카보닐클로라이드 (1.2eq, 31.4mg)을 가하였다. 반응물을 상온에서 24시간 교반한 후, 얼음물에 붓고 EtOAc로 추출하였다. 유기층을 소금물로 씻은 후 무수 MgSO4로 건조하고, 증발, 농축한 후 컬럼크로마토그라피로 분리 정제 하였다. 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-aniline (70 mg, 0.18 mmol) was dissolved in DMF and K 2 CO 3 (2eq, 49 mg N, N-dimethyl-carbonylchloride (1.2eq, 31.4 mg) was added while stirring. The reaction was stirred at room temperature for 24 hours, then poured into ice water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO 4 , evaporated and concentrated, and then purified by column chromatography.
Figure PCTKR2012002405-appb-I000244
Figure PCTKR2012002405-appb-I000244
1H NMR (CDCl3) δ 7.61-6.75(m, 10H), 6.50(s, 1H), 6.16(s, 1H), 2.99(s, 6H) 1 H NMR (CDCl 3 ) δ 7.61-6.75 (m, 10H), 6.50 (s, 1H), 6.16 (s, 1H), 2.99 (s, 6H)
실시예 180. 1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-3-(4-트리플루오르메틸-벤질)-유레아 Example 180. 1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -3- (4-trifluoromethyl-benzyl ) -Urea
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산(50mg, 0.12mmol), 다이페닐포릴아자이드 (DPPA, 39mg, 0.14mmol) 및 TEA (14mg, 0.14mmol)을 Toluene 에 녹인후 상온에서 10시간 교반하여반응시킨 후, 4-트리플루오르메틸 벤질아민 (20mg, 0.14mmol)을 가하고 80oC로 올린 후 12시간 더 교반하여 반응시킨후, 감압하여 용매를 제거하였다. 남은 잔여물에 물과 EtOAc를 가하고 추출하였다. 분리된 유기층을 무수 황산 나트륨으로 건조시킨 후 감압농축한 다음, 잔여물을 실리카겔 컬럼 크러마토그래피 (n-Hexane/EtOAc=2/1)로 정제하여 목적화합물 48mg (수율 68%)을 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid (50 mg, 0.12 mmol), diphenylporyl azide (DPPA, 39 mg, 0.14 mmol) and TEA (14mg, 0.14mmol) were dissolved in Toluene and stirred at room temperature for 10 hours to react, then 4-trifluoromethyl benzylamine (20mg, 0.14mmol) was added to 80 ° C., followed by further stirring for 12 hours. After the reaction was carried out under reduced pressure, the solvent was removed under reduced pressure. To the remaining residue was added water and EtOAc and extracted. The separated organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-Hexane / EtOAc = 2/1) to obtain 48 mg (yield 68%) of the title compound.
Figure PCTKR2012002405-appb-I000245
Figure PCTKR2012002405-appb-I000245
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000246
7.59~7.55 (3H, m) 7.41~7.18 (9H, m) 6.80~6.78(2H, m) 6.52 (1H, s) 6.22 (1H, brs) 4.99(1H, brs) 4.47 (2H, d, J=5.87) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000246
7.59 ~ 7.55 (3H, m) 7.41 ~ 7.18 (9H, m) 6.80 ~ 6.78 (2H, m) 6.52 (1H, s) 6.22 (1H, brs) 4.99 (1H, brs) 4.47 (2H, d, J = 5.87)
실시예 181. 1-tert-뷰틸-3-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-유레아Example 181. 1-tert-Butyl-3- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -urea
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산과 t-부틸아민으로부터 실시예 180 의 공정에 따라 합성하였다.It was synthesized according to the process of Example 180 from 4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid and t-butylamine.
Figure PCTKR2012002405-appb-I000247
Figure PCTKR2012002405-appb-I000247
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000248
7.59 (1H, d, J= 8.51 7.38~7.23 (9H, m) 6.76(2H, t, J=2.35) 6.51 (1H, s) 5.92 (1H, s) 4.39(1H, s) 1.35 (9H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000248
7.59 (1H, d, J = 8.51 7.38 ~ 7.23 (9H, m) 6.76 (2H, t, J = 2.35) 6.51 (1H, s) 5.92 (1H, s) 4.39 (1H, s) 1.35 (9H, s )
실시예 182. N-{3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-페닐}-2,2-디메틸-프로피온아미드Example 182. N- {3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-phenyl} -2,2-dimethyl-propionamide
3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-아닐린과 2,2-디메틸-프로피온산 클로라이드로부터 실시예 176 (단계 3)의 공정으로 합성하였다. In the process of Example 176 (step 3) from 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-aniline and 2,2-dimethyl-propionic acid chloride Synthesized.
Figure PCTKR2012002405-appb-I000249
Figure PCTKR2012002405-appb-I000249
1H NMR (CDCl3) δ 7.51-6.87(m, 11H), 6.60(s, 1H), 2.24(s, 3H), 1.28(s, 9H) 1 H NMR (CDCl 3 ) δ 7.51-6.87 (m, 11H), 6.60 (s, 1H), 2.24 (s, 3H), 1.28 (s, 9H)
실시예 183. 1-tert-부틸-3-{3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-페닐}-우레아Example 183. 1-tert-Butyl-3- {3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-phenyl} -urea
3-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-4-메틸-벤조산과 t-부틸아민으로부터 실시예 180 의 공정에 따라 합성하였다.It was synthesized according to the process of Example 180 from 3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzoic acid and t-butylamine.
Figure PCTKR2012002405-appb-I000250
Figure PCTKR2012002405-appb-I000250
1H NMR (CDCl3) δ 7.48-6.52(m, 10H), 6.50(s, 1H), 5.84(s, 1H), 4.46(s, 1H), 1.29(s, 9H) 1 H NMR (CDCl 3 ) δ 7.48-6.52 (m, 10H), 6.50 (s, 1H), 5.84 (s, 1H), 4.46 (s, 1H), 1.29 (s, 9H)
실시예 184. 4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조산 N'-(2,2-다이메틸-프로피오닐)-하이드라이자이드Example 184. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid N '-(2,2-dimethyl-propionyl) -hydride Zayed
4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플르오로-벤조산 (100mg, 0.20mmol), HOBT (54mg, 0.40mmol), EDC (77mg,0.4mmol)을 CH2Cl2에 녹인 후 2,2-다이메틸-프로피오닐)-하이드라이자이드 (0.04 mmol)를 가하고 상온에서 5시간동안 교반하여 반응시킨다. 반응종료 후 물을 가하고 CH2Cl2 로 추출한다. 분리된 유기층을 무수 황산 나트륨으로 건조시킨 후 감압 농축하여 얻어진 잔여물을 실리카겔 컬럼 크로마토그래피 (n-Hexane/EtOAc=2/1)로 정제하여 목적화합물 92mg(수율 96％)을 수득하였다.4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoic acid (100 mg, 0.20 mmol), HOBT (54 mg, 0.40 mmol), EDC (77 mg , 0.4 mmol) was dissolved in CH 2 Cl 2 , and then 2,2-dimethyl-propionyl) -hydrazide (0.04 mmol) was added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, water was added, followed by extraction with CH 2 Cl 2 . The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-Hexane / EtOAc = 2/1) to give 92 mg (yield 96%) of the title compound.
Figure PCTKR2012002405-appb-I000251
Figure PCTKR2012002405-appb-I000251
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000252
8.94(1H, d, J=6.60) 8.56(1H, d, J=6.31) 7.61~7.29(10H, m) 6.89(1H, t, J=8.36) 6.60 (1H, s) 1.28 (9H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000252
8.94 (1H, d, J = 6.60) 8.56 (1H, d, J = 6.31) 7.61-7.29 (10H, m) 6.89 (1H, t, J = 8.36) 6.60 (1H, s) 1.28 (9H, s)
실시예 185. N-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-페닐}-옥살산 에틸 에스터Example 185. N- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -oxalic acid ethyl ester
4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐아민 (37mg, 0.1mmol) 을 DCM에 녹이고, 에틸 클로로옥소아세테이트 (14㎕, 0.12mmol) 를 가하고 TEA을 (17㎕, 0.12mmol) 가한 후 상온에서 12시간 교반한다. 반응종료 후 물을 가하고 DCM으로 추출하여 분리된 유기층을 무수 황산나트륨으로 건조시킨 후 감압 농축하여 얻어진 잔여물을 실리카겔 컬럼 크로마토그래피 (용출액: 헥산/에틸아세테이트=3/1)로 정제하여 목적화합물 42mg(수율 89％)을 수득하였다. 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenylamine (37 mg, 0.1 mmol) was dissolved in DCM and ethyl chlorooxoacetate (14 μl, 0.12 mmol) is added and TEA (17 μl, 0.12 mmol) is added and stirred at room temperature for 12 hours. After completion of the reaction, water was added, extraction was performed with DCM, and the separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluate: hexane / ethyl acetate = 3/1) to give the title compound (42 mg). Yield 89%) was obtained.
Figure PCTKR2012002405-appb-I000253
Figure PCTKR2012002405-appb-I000253
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000254
8.75 (1H, brs) 7.63~7.57 (2H, m) 7.43~7.22 (7H, m) 7.11(1H, d, J=8.80) 6.86 (1H, d, J=8.80) 6.63 (1H, s) 4.41 (2H, q, J=7.19) 1.42 (3H, t, J=7.19) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000254
8.75 (1H, brs) 7.63 to 7.57 (2H, m) 7.43 to 7.72 (7H, m) 7.11 (1H, d, J = 8.80) 6.86 (1H, d, J = 8.80) 6.63 (1H, s) 4.41 ( 2H, q, J = 7.19) 1.42 (3H, t, J = 7.19)
실시예 186. N-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-페닐}-옥살산 Example 186. N- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -oxalic acid
N-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-페닐}-옥살산 에틸 에스터 (39mg, 0.08 mmol) 를 1,4-다이옥산 (5mL)에 녹이고 LiOHH2O(5.3mg, 0.13 mmol)을 물 (5 mL)에 녹인 후 첨가하여 상온에서 2시간 교반하면서 반응 시킨다. 반응 종료후 0.1N 염산으로 산성화 시킨 후 EtOAc 로 추출하였다. 이를 무수 황산나트륨으로 건조시킨 후 감압 농축한 다음, 남은 잔여물을 실리카겔 컬럼 크로마토그래피 (용출액: 헥산/에틸아세테이트=1/1)로 정제하여 목적화합물 18mg(수율 50％)을 수득하였다.N- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -oxalic acid ethyl ester (39 mg, 0.08 mmol) in 1,4-dioxane After dissolving in (5mL), LiOHH 2 O (5.3mg, 0.13 mmol) was dissolved in water (5mL) and added and reacted with stirring at room temperature for 2 hours. After the reaction was acidified with 0.1N hydrochloric acid and extracted with EtOAc. It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to obtain 18 mg (yield 50%) of the title compound.
Figure PCTKR2012002405-appb-I000255
Figure PCTKR2012002405-appb-I000255
1H NMR (300Hz, CDCl3)
Figure PCTKR2012002405-appb-I000256
9.01 (1H, brs) 7.58~7.22 (10H, m) 6.89 (1H, t, J=8.36) 6.86 (1H, s) 1 H NMR (300Hz, CDCl 3 )
Figure PCTKR2012002405-appb-I000256
9.01 (1H, brs) 7.58-7.22 (10H, m) 6.89 (1H, t, J = 8.36) 6.86 (1H, s)
[시험예 1] Cannabinoid receptor 1 (CNR1) 발현 세포 확립Test Example 1 Establishment of Cannabinoid Receptor 1 (CNR1) Expression Cells
인간 CNR1 (NM016083)을 인간뇌종양세포 (SNB-19)에서 클로닝했다.Human CNR1 (NM016083) was cloned in human brain tumor cells (SNB-19).
클로닝 방법을 간단히 설명하면 인간뇌종양세포에 Trizol (Invitorgen)과 클로로포름을 처리하여 원심분리기로 층을 분리하고 상층액을 취한 다음 isopropyl alcohol을 섞어 mRNA를 침강시킨다. 분리한 mRNA를 RT-PCR(reverse transcriptional polymerase chain reaction) kit(Bioneer)로 cDNA를 합성하고 cannabinoid receptor1(CNR1)의 특정 primer를 사용하여 PCR(polymerase chain reaction)로 증폭하여 pTarget(Invitrogen)에 재조합한다.The cloning method is briefly described by treating the human brain tumor cells with Trizol (Invitorgen) and chloroform, separating the layers by centrifugation, taking the supernatant, and then mixing the isopropyl alcohol to precipitate the mRNA. CDNA is synthesized by RT-PCR (reverse transcriptional polymerase chain reaction) kit (Bioneer), amplified by polymerase chain reaction (PCR) using specific primers of cannabinoid receptor1 (CNR1), and recombined with pTarget (Invitrogen). .
pTarget에 재조합된 CNR1을 CHO-K1 (ATCC)에 pCRE(Takara)벡터와 같이 도입하여 500ug/ml G418(Gibco)로 2주간 처리하여 벡터가 도입된 세포를 선별한다.CNR1 recombined with pTarget is introduced into CHO-K1 (ATCC) with a pCRE (Takara) vector and treated with 500ug / ml G418 (Gibco) for 2 weeks to select cells into which the vector is introduced.
G418에 내성을 가진 세포 중에서 2uM forskolin(Sigma)을 처리하여 luciferase가 증가하는지 확인하고 다른 한편으로는 2uM forskolin과 20nM CP55940(Sigma)를 동시에 처리하여 forskolin에 의해 증가하는 luciferase가 CP55940에 의해 억제 되는지를 확인한다.Treatment with 2uM forskolin (Sigma) to increase luciferase among cells resistant to G418, and on the other hand, treatment with 2uM forskolin and 20nM CP55940 (Sigma) simultaneously inhibited luciferase increased by forskolin by CP55940 Check it.
최종적으로 2uM forskolin, 20nM CP55940 그리고 200nM Rimonabant를 동시에 처리하여 forskolin에 의해 증가한 luciferase가 CP55940에 의해 억제되고 다시 Rimonabant (자체 합성)에 의해 증가하는지를 확인하는 실험으로 CHO-CB1-#37세포를 선별하였다.Finally, CHO-CB1- # 37 cells were selected as an experiment to confirm whether luciferase increased by forskolin was inhibited by CP55940 and increased by Rimonabant (self synthesis) by simultaneously treating 2uM forskolin, 20nM CP55940 and 200nM Rimonabant.
세포의 스크리닝 시스템을 하기 도 1에 제시하였다.The screening system of cells is shown in FIG. 1 below.
선별된 CHO-CB1-#37세포는 DMEM (Dulbecco's Modified Eagle Medium; Gibco), 10% FBS(fetal bovine serum; Gibco), 50ug/ml G418배지에서 배양한다.Selected CHO-CB1- # 37 cells are cultured in DMEM (Dulbecco's Modified Eagle Medium; Gibco), 10% FBS (fetal bovine serum; Gibco), 50ug / ml G418 medium.
[시험예 2] CNR1 antagonist 스크리닝[Test Example 2] CNR1 antagonist screening
우선 배양된 CHO-CB1-#37세포를 0.05% trypsin EDTA(Gibco)용액으로 낱개의 세포로 떼어낸 다음 DMEM배양배지를 처리하여 96-well plate(Corning)에 한 well 당 20,000개의 세포를 넣은 다음 24시간 37도 5% CO2배양기(Thermo)에서 배양한다.First, cultured CHO-CB1- # 37 cells were separated into individual cells with 0.05% trypsin EDTA (Gibco) solution, and then treated with DMEM culture medium, 20,000 cells per well were put into a 96-well plate (Corning). Incubate for 24 hours at 37 degrees in a 5% CO 2 incubator (Thermo).
배양한 96-well plate에 화합물을 처리하여 4시간 동안 CO2배양기에서 반응한 다음 배지를 버리고 50ul 1X reporter lysis buffer(Promega)를 처리하여 실온에서 10분간 반응한다. 96-well plate 스크리닝 시스템을 간략하게 도 2에 나타내었다. Luminoskan(Thermo)을 이용하여 50ul luciferase assay solution을 처리하고 한 well당 10초간 luciferase의 활성을 측정한다. 2uM forkolin을 처리한 샘플을 100%로 계산하고 2uM forskolin, 20nM CP55940을 동시에 처리한 well을 0%로 계산하여 Rimonabant의 활성을 측정한다. Rimonabant는 CNR1의 대조 antagonist로 사용한다.After treating the compound in the cultured 96-well plate for 4 hours in a CO 2 incubator, the medium was discarded and treated with 50ul 1X reporter lysis buffer (Promega) for 10 minutes at room temperature. The 96-well plate screening system is briefly shown in FIG. 2. Luminoskan (Thermo) was used to treat 50ul luciferase assay solution and measure luciferase activity for 10 seconds per well. The activity of Rimonabant was measured by calculating 100% of samples treated with 2uM forkolin and 0% of wells treated with 2uM forskolin and 20nM CP55940 simultaneously. Rimonabant is used as a control antagonist for CNR1.
Rimonabant의 IC50은 도 3과 같다.IC 50 of Rimonabant is shown in FIG. 3.
[시험예 3] Cannabinoid receptor 2 (CNR2) 발현세포 확립Test Example 3 Establishment of Cannabinoid Receptor 2 (CNR2) Expressing Cells
인간 CNR2 (NM001841)을 HepG2세포에서 클로닝했다.Human CNR2 (NM001841) was cloned in HepG2 cells.
클로닝 방법을 간단히 설명하면 HepG2에 Trizol (Invitorgen)과 클로로포름을 처리하여 원심분리기로 층을 분리하고 상층액을 취한 다음 isopropyl alcohol을 섞어 mRNA를 침강시킨다. 분리한 mRNA를 RT-PCR(reverse transcriptional polymerase chain reaction) kit(Bioneer)로 cDNA를 합성하고 CNR2의 특정 primer를 사용하여 PCR(polymerase chain reaction)로 증폭하여 pTarget(Invitrogen)에 재조합한다.Briefly describing the cloning method, HepG2 was treated with Trizol (Invitorgen) and chloroform, the layers were separated by centrifugation, the supernatant was taken, and the isopropyl alcohol was mixed to precipitate the mRNA. CDNA is synthesized by RT-PCR (reverse transcriptional polymerase chain reaction) kit (Bioneer), amplified by PCR (polymerase chain reaction) using specific primers of CNR2, and recombined into pTarget (Invitrogen).
pTarget에 재조합된 CNR1을 CHO-K1 (ATCC)에 pCRE(Takara)벡터와 같이 도입하여 500ug/ml G418(Gibco)로 2주간 처리하여 벡터가 도입된 세포를 선별한다.CNR1 recombined with pTarget is introduced into CHO-K1 (ATCC) with a pCRE (Takara) vector and treated with 500ug / ml G418 (Gibco) for 2 weeks to select cells into which the vector is introduced.
G418에 내성을 가진 세포 중에서 2uM forskolin(Sigma)을 처리하여 luciferase가 증가하는지 확인하고 다른 한편으로는 2uM forskolin과 20nM CP55940(Sigma)를 동시에 처리하여 forskolin에 의해 증가하는 luciferase가 CP55940에 의해 억제 되는지를 확인한다.Treatment with 2uM forskolin (Sigma) to increase luciferase among cells resistant to G418, and on the other hand, treatment with 2uM forskolin and 20nM CP55940 (Sigma) simultaneously inhibited luciferase increased by forskolin by CP55940 Check it.
여기서 CHO-CB2-#59세포를 선별하였다.Here CHO-CB2- # 59 cells were selected.
화합물 스크리닝 방법은 CHO-CB1-#37세포와 동일하다. 단지 CHO-CB2-#57세포는 CP55940에 의해 억제된 luciferase의 활성이 200nM Rimonabant에 의해 증가하지 않는다.Compound screening methods are the same as for CHO-CB1- # 37 cells. Only CHO-CB2- # 57 cells did not increase the activity of luciferase inhibited by CP55940 by 200 nM Rimonabant.
상기 실시예에서 제조된 화합물의 활성 결과를 하기 표 1에 나타내었다.The activity results of the compounds prepared in the above examples are shown in Table 1 below.
[표 1]TABLE 1
Figure PCTKR2012002405-appb-I000257
Figure PCTKR2012002405-appb-I000257
Figure PCTKR2012002405-appb-I000258
Figure PCTKR2012002405-appb-I000258
Figure PCTKR2012002405-appb-I000259
Figure PCTKR2012002405-appb-I000259
Figure PCTKR2012002405-appb-I000260
Figure PCTKR2012002405-appb-I000260
Figure PCTKR2012002405-appb-I000261
Figure PCTKR2012002405-appb-I000261
Figure PCTKR2012002405-appb-I000262
Figure PCTKR2012002405-appb-I000262
Figure PCTKR2012002405-appb-I000263
Figure PCTKR2012002405-appb-I000263
Figure PCTKR2012002405-appb-I000264
Figure PCTKR2012002405-appb-I000264

Claims (6)

  1. 하기 화학식 1의 벤즈아미드 유도체 화합물 또는 이의 약제학적으로 허용되는 이의 염:Benzamide derivative compounds of Formula 1 or their pharmaceutically acceptable salts thereof
    [화학식 1][Formula 1]
    Figure PCTKR2012002405-appb-I000265
    Figure PCTKR2012002405-appb-I000265
    상기 화학식에서,In the above formula,
    A 및 B는 각각 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -CH2-triazole, -CH2-imidazole, OR6, CO2R7, CF3, OCF3, 시아노 또는 니트로기 이며;A and B are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 6 , CO 2 R 7 , CF 3 , OCF 3 , cyano or nitro group;
    X는 -O- 또는 -S- 이고;X is -O- or -S-;
    Y는 단일결합, -(C=O)- 또는 -(C=S)- 이며; Y is a single bond,-(C = O)-or-(C = S)-;
    R1 및 R2는 각각 독립적으로 수소, (C1-C20)알킬, (C3-C20)시클로알킬, (C2-C20)알케닐, (C2-C20)알키닐, -(CH2)a-Ar, -(CH2)b-HetAr, -SO2-R8,
    Figure PCTKR2012002405-appb-I000266
    ,
    Figure PCTKR2012002405-appb-I000267
    ,
    Figure PCTKR2012002405-appb-I000268
    ,
    Figure PCTKR2012002405-appb-I000269
    또는
    Figure PCTKR2012002405-appb-I000270
    이고;    R 1 and R 2 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, (C 2 -C 20) alkenyl, (C 2 -C 20) alkynyl,-(CH 2 ) a -Ar ,-(CH 2 ) b -HetAr, -SO 2 -R 8 ,
    Figure PCTKR2012002405-appb-I000266
    ,
    Figure PCTKR2012002405-appb-I000267
    ,
    Figure PCTKR2012002405-appb-I000268
    ,
    Figure PCTKR2012002405-appb-I000269
    or
    Figure PCTKR2012002405-appb-I000270
    ego;
    R1과 R2 는 N과 함께 하기 링 구조를 형성할 수 있고;ROneand R2 Can form the following ring structure with N;
    Figure PCTKR2012002405-appb-I000271
    ,
    Figure PCTKR2012002405-appb-I000272
    Figure PCTKR2012002405-appb-I000271
    ,
    Figure PCTKR2012002405-appb-I000272
    D는 OR11, SR12, NR13R14, CO2R15, 또는 CN 이며;D is OR 11, SR 12 , NR 13 R 14 , CO 2 R 15 , or CN;
    E는 CH2, O, S, SO, SO2, 또는 NR16 이고;E is CH 2 , O, S, SO, SO 2 , or NR 16 ;
    G는 CH2, -(C=0)-, O, S, SO, SO2, 또는 NR17 이며;G is CH 2 ,-(C = 0)-, O, S, SO, SO 2 , or NR 17 ;
    J, K 는 각각 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -(CH2)g-OR21, CO2R22, NR23R24, CONR25R26, CN, NO2, CF3, 또는 OCF3 이고; J, K are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) g -OR 21 , CO 2 R 22 , NR 23 R 24 , CONR 25 R 26 , CN, NO 2 , CF 3 , or OCF 3 ;
    RA, RB, RC, RD 는 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -(CH2)h-Ar,-(CH2)i-OR27, CO2R28, CN, NO2, CF3, 또는 OCF3 이며; R A , R B , R C , R D are independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl,-(CH 2 ) h -Ar,-(CH 2 ) i -OR 27 , CO 2 R 28 , CN, NO 2 , CF 3 , or OCF 3 ;
    R3는 수소, 할로겐 또는 (C1-C5)알킬이며;R 3 is hydrogen, halogen or (C 1 -C 5) alkyl;
    R4, R5는 각각 독립적으로 (C1-C20)알킬, (C3-C20)시클로알킬, -(CH2)j-Ar 또는 -(CH2)k-HetAr 이고;R 4 , R 5 are each independently (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl,-(CH 2 ) j -Ar or-(CH 2 ) k -HetAr;
    R6, R7은 각각 독립적으로 수소, (C1-C20)알킬, (C3-C20)시클로알킬 이며;R 6 , R 7 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
    R8은 (C1-C20)알킬, (C3-C20)시클로알킬, 또는 -(CH2)l-Ar 이고;R 8 is (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl, or — (CH 2 ) 1 -Ar;
    Ar은
    Figure PCTKR2012002405-appb-I000273
    이고;    Ar is
    Figure PCTKR2012002405-appb-I000273
    ego;
    HetAr은 하기 구조에서 선택되어 지며;HetAr is selected from the following structures;
    Figure PCTKR2012002405-appb-I000274
    Figure PCTKR2012002405-appb-I000274
    P, Q는 각각 독립적으로 수소, 할로겐, (C1-C20)알킬, (C3-C20)시클로알킬, -CH2-triazole, -CH2-imidazole, OR31, CO2R32, CF3, OCF3, 시아노 또는 니트로기 이고;P and Q are each independently hydrogen, halogen, (C1-C20) alkyl, (C3-C20) cycloalkyl, -CH 2 -triazole, -CH 2 -imidazole, OR 31 , CO 2 R 32 , CF 3 , OCF 3 , cyano or nitro group;
    R11 내지 R17, R21 내지 R28, R31 및 R32 은 각각 독립적으로 수소, (C1-C20)알킬, (C3-C20)시클로알킬 이고;R 11 to R 17 , R 21 to R 28 , R 31 and R 32 are each independently hydrogen, (C 1 -C 20) alkyl, (C 3 -C 20) cycloalkyl;
    a 내지 d, g 내지 l은 각각 0 내지 2의 정수 이며;a to d, g to l are each an integer of 0 to 2;
    e, f는 각각 0 내지 5의 정수이다.e and f are each an integer of 0-5.
  2. 제 1항에 있어서,The method of claim 1,
    상기 R1 내지 R8, R11 내지 R17, R21 내지 R28, R31 및 R32에 치환될 수 있는 치환기는 서로 독립적으로 수소, 할로겐, (C1-C10)알킬, 할로겐이 치환된 (C1-C10)알킬, (C6-C30)아릴, (C3-C30)시클로알킬, (C2-C10)알케닐, (C2-C10)알키닐, 시아노, 카바졸릴, 카르복실, 니트로 또는 히드록시로 이루어진 군으로부터 선택되는 하나 이상인 것을 특징으로 하는 벤즈아미드 유도체 화합물 또는 이의 약제학적으로 허용되는 이의 염.Substituents which may be substituted on R 1 to R 8 , R 11 to R 17 , R 21 to R 28 , R 31 and R 32 may be each independently hydrogen, halogen, (C 1 -C 10) alkyl, or halogen substituted ( C1-C10) alkyl, (C6-C30) aryl, (C3-C30) cycloalkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, cyano, carbazolyl, carboxyl, nitro or hydroxy Benzamide derivative compound or a pharmaceutically acceptable salt thereof, characterized in that at least one selected from the group consisting of.
  3. 하기 화합물로부터 선택되는 것을 특징으로 하는 벤즈아미드 유도체 화합물 또는 이의 약제학적으로 허용되는 이의 염:Benzamide derivative compounds or their pharmaceutically acceptable salts thereof, characterized in that they are selected from the following compounds:
    N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드;N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-시클로헥실-3-플루오로-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-cyclohexyl-3-fluoro-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-에틸-N-프로필-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-ethyl-N-propyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-아다만탄-1-일-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-adamantan-1-yl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-모포린-4-일-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-morpholin-4-yl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-이소부틸-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-isobutyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-피페리딘-1-일-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N-piperidin-1-yl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-풀루오로-N-p-톨일-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3- pullouro-N-p-tolyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-(2-히드록시-시클로헥실)-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-cyclohexyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-N-(1-히드록시메틸-2-메틸-프로필)-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (1-hydroxymethyl-2-methyl-propyl) -benzamide;
    N-sec-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드; N-sec-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-N-(2-다이메틸아미노-1,1-다이메틸-에틸)-3-플루오르-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (2-dimethylamino-1, 1-dimethyl-ethyl) -3-fluoro-benz Amides;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-N-(2-다이메틸아미노-1-메틸-에틸)-3-플루오르-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (2-dimethylamino-1-methyl-ethyl) -3- fluor-benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-싸이오몰폴린-4-일-메타논;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -thiomorpholin-4-yl-methanone;
    3-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-벤조일아미노}-3-메틸-부탄산 메틸 에스터;3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-methyl-butanoic acid methyl ester;
    {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-(4-메틸-피페라진-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(4-methyl-piperazin-1-yl) -methanone;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(2-하이드록시-1,1-다이메틸-에틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1,1-dimethyl-ethyl) -benzamide ;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-4-일메틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-4-ylmethyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(1-옥시-피리딘-4-일메틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (1-oxy-pyridin-4-ylmethyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-3-일메틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-3-ylmethyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-N-(피리딘-2-일메틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (pyridin-2-ylmethyl) -benzamide;
    {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐]}-(4-하이드록시-피페리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl]}-(4-hydroxy-piperidin-1-yl)- Metanon;
    {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐]}-(3-하이드록시-피페리딘-1-일)-메타논; {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl]}-(3-hydroxy-piperidin-1-yl)- Metanon;
    1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-벤조일}-피페리딘-4-온; 1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidin-4-one;
    1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-벤조일}-피페리딘-4-카복시산 메틸 에스터; 1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-4-carboxylic acid methyl ester;
    {4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-(1,1-다이옥소-싸이오모폴린-4-일)-메타논;  {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(1,1-dioxo-thiomorpholin-4-yl) -Methanone;
    1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-3-카르복시산 에틸 에스터; 1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-3-carboxylic acid ethyl ester;
    1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-2-카르복시산 에틸 에스터; 1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-2-carboxylic acid ethyl ester;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-N-(2-하이드록시-1,1-비스-하이드록시메틸-에틸)-벤즈아마이드;  4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1,1-bis-hydroxymethyl-ethyl ) -Benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오로-N,N-비스-(2-하이드록시-에틸)-벤즈아마이드;  4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-N, N-bis- (2-hydroxy-ethyl) -benzamide;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-4-메틸-펜타논산 tert-부틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -4-methyl-pentanoic acid tert-butyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-메틸-부틸산 에틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-methyl-butyl acid ethyl ester;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-아세트산 tert-부틸 에스터; {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -acetic acid tert-butyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-(1H-이미다졸-4-일)-프로피온산 메틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3- (1H-imidazol-4-yl)- Propionic acid methyl ester;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터;  1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-프로피온산 벤질 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -propionic acid benzyl ester;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-아세트산 에틸 에스터;{4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -acetic acid ethyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-(4-히드록시-페닐)-프로피온산 메틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3- (4-hydroxy-phenyl) -methyl propionate Ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-숙신산 1-tert-부틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -succinic acid 1-tert-butyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-펜탄디온산 디에틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -pentanedioic acid diethyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-페닐-프로피온산 메틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-phenyl-propionic acid methyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-페닐-프로피온산 tert-부틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-phenyl-propionic acid tert-butyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-히드록시-프로피온산 메틸에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-hydroxy-propionic acid methyl ester;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 tert-부틸 에스터; 1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid tert-butyl ester;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-히드록시-부틸산 메틸 에스터; 2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-hydroxy-butyl acid methyl ester;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-(3-히드록시-피롤리딘-1-일)-메타논; {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(3-hydroxy-pyrrolidin-1-yl) -meta Paddy fields;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논; {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl)- Metanon;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산; 1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid;
    2-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로벤조일아미노}-3-메틸-부탄산;2- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluorobenzoylamino} -3-methyl-butanoic acid;
    3-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-2-카복시산;3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-2-carboxylic acid;
    3-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-4-카복시산;3- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-4-carboxylic acid;
    3-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-2-카복시산;3- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-2-carboxylic acid;
    3-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-티아졸리딘-4-카복시산;3- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -thiazolidine-4-carboxylic acid;
    N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤즈아미드;N- (4-Chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzamide;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 소듐염;1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid sodium salt;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(2-히드록시-시클로헥실)-벤즈아미드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-cyclohexyl) -benzamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(1-히드록시메틸-2-메틸-프로필)-벤즈아미드);4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (1-hydroxymethyl-2-methyl-propyl) -benzamide);
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide;
    N-tert-부틸-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤즈아미드;N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-프로파질-벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N-propazyl-benzamide;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-모포린-4-일-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -morpholin-4-yl-methanone;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    2-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-3-메틸-부틸산 에틸 에스터;2- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -3-methyl-butyl acid ethyl ester;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-아세트산 tert-부틸 에스터;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -acetic acid tert-butyl ester;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(3-히드록시-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(3-hydroxy-pyrrolidin-1-yl) -methanone;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2,2-디메틸-[1,3]디옥소란-4-일메틸)-3-플루오로-벤즈아미드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2,2-dimethyl- [1,3] dioxoran-4-ylmethyl) -3-fluoro Rho-benzamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2,3-디히드록시-프로필)-3-플루오로-벤즈아미드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2,3-dihydroxy-propyl) -3-fluoro-benzamide;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -methanone ;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 아마이드;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid amide;
    2-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일아미노}-2-메틸-피로피온산 메틸 에스터;2- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoylamino} -2-methyl-pyrionic acid methyl ester;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(2-하이드록시-1,1-다이메틸-에틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-l, 1-dimethyl-ethyl) -benzamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(시아노-다이메틸-메틸)-3-플루오로-벤즈아마이드; 4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (cyano-dimethyl-methyl) -3-fluoro-benzamide;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 에틸 에스터;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid ethyl ester;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카르복시산 아이소프로필 에스터; 1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid isopropyl ester;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-4-에틸아미노-피페리딘-4-카르복시산아마이드;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -4-ethylamino-piperidine-4-carboxylic acid amide;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(4-하이드록시-피페리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(4-hydroxy-piperidin-1-yl) -methanone;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-(3-하이드록시-피페리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-(3-hydroxy-piperidin-1-yl) -methanone;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(2-하이드록시-1,1-비스-하이드록시메틸-에틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (2-hydroxy-1,1-bis-hydroxymethyl-ethyl) -benz Amides;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N,N-비스-(2-하이드록시-에틸)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N, N-bis- (2-hydroxy-ethyl) -benzamide;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-3-카르복시산 에틸 에스터;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-3-carboxylic acid ethyl ester;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-피페리딘-2-카르복시산 에틸 에스터;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -piperidine-2-carboxylic acid ethyl ester;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-페닐}-[2-(피롤리딘-1-카르보닐)-피롤리딘-1-일]-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl}-[2- (pyrrolidine-1-carbonyl) -pyrrolidine- 1-yl] -methanone;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}피롤리딘-2-카르복시산 다이메틸아마이드;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} pyrrolidine-2-carboxylic acid dimethylamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-알릴-벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N-allyl-benzamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-N-(1,1-디메치-2-프로피닐)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (1,1-dimeth-2-propynyl) -benzamide;
    N-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-4-클로로-벤젠술폰아마이드;N- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -4-chloro- benzenesulfonamide;
    4-클로로-N-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조일}-메탄술폰아마이드;4-chloro-N- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoyl} -methanesulfonamide;
    4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오르메틸-벤질)-싸이오벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -thiobenzamide;
    N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-싸이오벤즈아마이드;N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzamide;
    1-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-싸이오벤조일}-피롤리딘-2-카르복시산 메틸 에스터;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오르메틸-벤질)-싸이오벤즈아마이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -thiobenzamide;
    N-tert-부틸-4-[(4-크로로-페닐)-(2크로로-페닐)-메톡시]-3-플루오로-싸이오벤즈아마이드;N-tert-butyl-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzamide;
    1-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-싸이오벤조일}-피롤리딘-2-카르복시산 메틸 에스터;1- {4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-thiobenzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    N-tert-부틸-3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤즈아미드;N-tert-butyl-3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzamide;
    3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-벤즈아미드;3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-benzamide;
    3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-(4-트리플루오로메틸-벤질)-벤즈아미드;3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (4-trifluoromethyl-benzyl) -benzamide;
    3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-피페리딘-1-일-벤즈아미드;3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-piperidin-1-yl-benzamide;
    3-클로로-N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤즈아미드;3-chloro-N- (4-chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzamide;
    1-{3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    {3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-페닐}-(3-히드록시-피롤리딘-1-일)-메타논;{3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -phenyl}-(3-hydroxy-pyrrolidin-1-yl) -methanone ;
    {3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논;{3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -meta Paddy fields;
    3-클로로-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-p-톨일-벤즈아미드;3-chloro-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-p-tolyl-benzamide;
    1-{3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {3-chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    {3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-페닐}-(3-히드록시-피롤리딘-1-일)-메타논;{3-chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -phenyl}-(3-hydroxy-pyrrolidin-1-yl) -methanone;
    {3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논;{3-chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -methanone;
    3-{3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-벤조일}-티아졸리딘-4-카복시산 메틸 에스터;3- {3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -benzoyl} -thiazolidine-4-carboxylic acid methyl ester;
    {3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-페닐}-모포린-4-일-메타논;{3-Chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -phenyl} -morpholin-4-yl-methanone;
    3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-피페리딘-1-일-벤즈아미드;3-chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N-piperidin-1-yl-benzamide;
    3-클로로-4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2-히드록시-시클로헥실)-벤즈아미드;3-chloro-4-[(4-chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2-hydroxy-cyclohexyl) -benzamide;
    N-(4-클로로페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤즈아미드;N- (4-Chlorophenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-N-(4-트리플루오로메틸-벤질)-벤즈아미드; 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N- (4-trifluoromethyl-benzyl) -benzamide;
    N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤즈아미드;N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-3-메틸-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-methyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디크로로-페닐)-메톡시]-3-메틸-N-피페리딘-1-일-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N-piperidin-1-yl-benzamide;
    N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤즈아미드;N- (4-Chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-N-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-N-p-톨일-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-N-p-tolyl-benzamide;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-페닐}-(3-히드록시-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-phenyl}-(3-hydroxy-pyrrolidin-1-yl) -methanone ;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메틸-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methyl-phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -meta Paddy fields;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-페닐}-(3-히드록시-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-phenyl}-(3-hydroxy-pyrrolidin-1-yl) -methanone;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-phenyl}-(2-hydroxymethyl-pyrrolidin-1-yl) -methanone;
    3-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-벤조일}-티아졸리딘-4-카복시산 메틸에스터;3- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-benzoyl} -thiazolidine-4-carboxylic acid methyl ester;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-페닐}-모포린-4-일-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-phenyl} -morpholin-4-yl-methanone;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-메틸-N-피페리딘-1-일-벤즈아미드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-methyl-N-piperidin-1-yl-benzamide;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-N-(2-히드록시-시클로헥실)-3-메틸-벤즈아미드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -N- (2-hydroxy-cyclohexyl) -3-methyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-N-p-톨일-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-p-tolyl-benzamide;
    N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤즈아미드;N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-3-메톡시-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-methoxy-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-N-(4-트리풀루오르메틸-벤질)-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N- (4-trifulormethyl-benzyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-N-피페리딘-1-일-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-N-piperidin-1-yl-benzamide;
    {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-페닐}-모포린-4-일-메타논;{4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-phenyl} -morpholin-4-yl-methanone;
    N-(4-클로로-페닐)-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-메톡시-벤즈아미드;N- (4-Chloro-phenyl) -4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-methoxy-benzamide;
    N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤즈아미드;N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸l-N-(4-트리플루오로메틸-벤질)-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyll-N- (4-trifluoromethyl-benzyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-3-트리플루오로메틸-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-3-trifluoromethyl-benzamide;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-트리플루오로메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-trifluoromethyl-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-(2-히드록시-시클로헥실)-3-트리플루오로메틸-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (2-hydroxy-cyclohexyl) -3-trifluoromethyl-benzamide;
    N-tert-부틸-4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤즈아미드;N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드; 4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N- (4-trifluoromethyl-benzyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-N-이소부틸-벤즈아미드;4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N-isobutyl-benzamide;
    1-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-benzoyl} -pyrrolidine-2-carboxylic acid methyl ester;
    4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-2,3-디플루오로--N-(2-히드록시-시클로헥실)-벤즈아미드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2,3-difluoro-N- (2-hydroxy-cyclohexyl) -benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-N-(4-트라이플루오르메틸-벤질)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N- (4-trifluoromethyl-benzyl) -benzamide;
    N-tert-뷰틸-4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-벤즈아마이드; N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -benzamide;
    4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-2-플루오르-N-(4-트라이플루오르메틸-벤질)-벤즈아마이드;4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide;
    N-tert-뷰틸-4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-2-프루오르-벤즈아마이드;N-tert-butyl-4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -2-fluoro-benzamide;
    4-[비스-(4-플루오로페닐)-메톡시]-N-tert-부틸-3-플루오로-벤즈아미드;4- [bis- (4-fluorophenyl) -methoxy] -N-tert-butyl-3-fluoro-benzamide;
    4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-N-(4-트리플루오로메틸-벤질)-벤즈아미드;4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N- (4-trifluoromethyl-benzyl) -benzamide;
    4-[비스-(4-플루오로페닐)-메톡시]-3-플루오로-N-p-톨일벤즈아미드;4- [bis- (4-fluorophenyl) -methoxy] -3-fluoro-N-p-tolylbenzamide;
    4-[비스-(4-플루오로페닐)-메톡시]-3-플루오로-N-(피페리딘-1-일)벤즈아미드;4- [bis- (4-fluorophenyl) -methoxy] -3-fluoro-N- (piperidin-1-yl) benzamide;
    4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-N-이소부틸-벤즈아미드;4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N-isobutyl-benzamide;
    {4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-페닐}-모포린-4-일-메탄온;{4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-phenyl} -morpholin-4-yl-methanone;
    4-[비스-(4-플루오로-페닐)-메톡시]-N-시클로헥실-3-플루오로-벤즈아미드;4- [bis- (4-fluoro-phenyl) -methoxy] -N-cyclohexyl-3-fluoro-benzamide;
    4-[비스-(4-플루오로-페닐)-메톡시]-3-플루오로-N-에틸-N-프로필-벤즈아미드;4- [bis- (4-fluoro-phenyl) -methoxy] -3-fluoro-N-ethyl-N-propyl-benzamide;
    4-[비스(4-플루오로페닐)-메톡시]-3-플루오로-N-[2-히드록시-시클로헥실]-벤즈아미드;4- [bis (4-fluorophenyl) -methoxy] -3-fluoro-N- [2-hydroxycyclohexyl] -benzamide;
    (R)-1-{4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터;(R) -1- {4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid Methyl ester;
    (S)-1-{4-[(2-클로로-페닐)-(5-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터;(S) -1- {4-[(2-Chloro-phenyl)-(5-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid Methyl ester;
    1-{4-[(5-클로로-피리딘-2-일)-(3-클로로-피리딘-2-일)-메톡시]-3-플루오로-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(5-chloro-pyridin-2-yl)-(3-chloro-pyridin-2-yl) -methoxy] -3-fluoro-benzoyl} -pyrrolidine-2-carboxylic acid Methyl ester;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(1,2,4-트리아졸-1-일)메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-benzoyl} -pyrrolidine -2-carboxylic acid methyl ester;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(1,2,4-트리아졸-1-일)메틸-페닐}-(3-히드록시-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-phenyl}-(3-hydroxy -Pyrrolidin-1-yl) -methanone;
    {4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(1,2,4-트리아졸-1-일)메틸-페닐}-(2-히드록시메틸-피롤리딘-1-일)-메타논;{4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (1,2,4-triazol-1-yl) methyl-phenyl}-(2-hydroxy Methyl-pyrrolidin-1-yl) -methanone;
    1-{4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-(이미다졸-1-일)메틸-벤조일}-피롤리딘-2-카복시산 메틸 에스터;1- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3- (imidazol-1-yl) methyl-benzoyl} -pyrrolidine-2-carboxylic acid methyl Ester;
    N-tert-부틸-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-플루오로-벤즈아미드;N-tert-butyl-3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-fluoro-benzamide;
    3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-N-피페리딘-1-일-벤즈아미드;3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-N-piperidin-1-yl-benzamide;
    3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-N-(4-트리플루오로메틸-벤질)-벤즈아미드;3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-N- (4-trifluoromethyl-benzyl) -benzamide;
    3-[(4-클로로-페닐)-(2.4-디클로로-페닐) 메톡시]-N-이소부틸-4-메틸-벤즈아미드; 3-[(4-chloro-phenyl)-(2.4-dichloro-phenyl) methoxy] -N-isobutyl-4-methyl-benzamide;
    N-tert-부틸-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤즈아미드;N-tert-butyl-3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzamide;
    N-(4-클로로-페닐)-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-벤즈아미드;N- (4-Chloro-phenyl) -3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-benzamide;
    3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-N-p-톨일-벤즈아미드;3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-N-p-tolyl-benzamide;
    N-tert-부틸-3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-벤즈아미드;N-tert-butyl-3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-benzamide;
    3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-N-(4-트리플루오로메틸-벤질)-벤즈아미드;3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-N- (4-trifluoromethyl-benzyl) -benzamide;
    3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-N-이소부틸-4-메톡시-벤즈아미드;3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -N-isobutyl-4-methoxy-benzamide;
    3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메톡시-N-피페리딘-1-일-벤즈아미드;3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methoxy-N-piperidin-1-yl-benzamide;
    시클로헥산카복시산 {4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-아미드;Cyclohexanecarboxylic acid {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -amide;
    N-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-4-트리플루오로메틸-벤즈아미드;N- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -4-trifluoromethyl-benzamide;
    N-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-2,2-디메틸-프로피온아미드;N- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -2,2-dimethyl-propionamide;
    3-{4-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-3-플루오로-페닐}-1,1-디메틸-우레아;3- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -1,1-dimethyl-urea;
    1-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-3-(4-트리플루오르메틸-벤질)-유레아;1- {4-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -3- (4-trifluoromethyl-benzyl) -urea;
    1-tert-뷰틸-3-{4-[(4-클로로-페닐)-(2,4-다이클로로-페닐)-메톡시]-3-플루오르-페닐}-유레아;1-tert-butyl-3- {4-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -3-fluoro-phenyl} -urea;
    N-{3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-페닐}-2,2-디메틸-프로피온아미드;N- {3-[(4-Chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-phenyl} -2,2-dimethyl-propionamide;
    1-tert-부틸-3-{3-[(4-클로로-페닐)-(2,4-디클로로-페닐)-메톡시]-4-메틸-페닐}-우레아;1-tert-butyl-3- {3-[(4-chloro-phenyl)-(2,4-dichloro-phenyl) -methoxy] -4-methyl-phenyl} -urea;
    4-[(4-클로로-페닐)-(2-클로로-페닐)-메톡시]-3-플루오로-벤조산 N'-(2,2-다이메틸-프로피오닐)-하이드라이자이드;4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-benzoic acid N '-(2,2-dimethyl-propionyl) -hydrazide;
    N-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-페닐}-옥살산 에틸 에스터;N- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -oxalic acid ethyl ester;
    N-{4-[(4-클로로-페닐)-(2-크로로-페닐)-메톡시]-3-플루오로-페닐}-옥살산.N- {4-[(4-Chloro-phenyl)-(2-chloro-phenyl) -methoxy] -3-fluoro-phenyl} -oxalic acid.
  4. (a) 하기 화학식 4와 5의 화합물로부터 하기 화학식 2의 벤조산 에스테르 화합물을 제조하는 단계; 및(a) preparing a benzoic acid ester compound of Formula 2 from compounds of Formulas 4 and 5; And
    (b) 하기 화학식 2의 벤조산 에스테르 화합물의 가수분해로부터 제조된 하기 화학식 3의 벤조산 화합물에 하기 화학식 6의 화합물을 HNR1R2와 반응시켜 하기 화학식 7의 화합물을 제조하는 단계; 를 포함하는 벤즈아미드 유도체 화합물의 제조방법:(b) reacting a compound of formula 6 with HNR 1 R 2 to a benzoic acid compound of formula 3 prepared from hydrolysis of a benzoic acid ester compound of formula 2 to prepare a compound of formula 7; Method for producing a benzamide derivative compound comprising:
    [화학식 2][Formula 2]
    Figure PCTKR2012002405-appb-I000275
    Figure PCTKR2012002405-appb-I000275
    [화학식 3][Formula 3]
    Figure PCTKR2012002405-appb-I000276
    Figure PCTKR2012002405-appb-I000276
    [화학식 4][Formula 4]
    Figure PCTKR2012002405-appb-I000277
    Figure PCTKR2012002405-appb-I000277
    [화학식 5][Formula 5]
    Figure PCTKR2012002405-appb-I000278
    Figure PCTKR2012002405-appb-I000278
    [화학식 6][Formula 6]
    Figure PCTKR2012002405-appb-I000279
    Figure PCTKR2012002405-appb-I000279
    [화학식 7][Formula 7]
    Figure PCTKR2012002405-appb-I000280
    Figure PCTKR2012002405-appb-I000280
    상기 화학식에서 A, B, 및 R1 내지 R5에 대한 정의는 청구항 제 1항에서의 정의와 동일하며; In the above formula, the definitions for A, B, and R 1 to R 5 are the same as those in claim 1;
    R'은 (C1-C20)알킬 또는 (C3-C20)시클로알킬이고; R 'is (C1-C20) alkyl or (C3-C20) cycloalkyl;
    L 은 Cl, Br, I, OTs 또는 OMs이다.L is Cl, Br, I, OTs or OMs.
  5. 제 3항의 벤즈아미드 유도체 화합물 또는 약제학적으로 허용되는 이의 염을 유효성분으로 포함하는 비만 또는 비만관련 대사질환의 치료 또는 예방용 약제학적 조성물.A pharmaceutical composition for the treatment or prevention of obesity or obesity-related metabolic diseases comprising the benzamide derivative compound of claim 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
  6. 제 5항에 있어서,The method of claim 5,
    상기 비만관련 대사질환은 제 2형 당뇨병, 협심증, 고혈압, 울혈성 심장마비, 고지혈증 또는 혈전용해장애인 것을 특징으로 하는 비만 또는 비만관련 대사질환의 치료 또는 예방용 약제학적 조성물.The obesity-related metabolic diseases are type 2 diabetes, angina pectoris, hypertension, congestive heart failure, hyperlipidemia or thrombolytic disorders, characterized in that the pharmaceutical composition for the treatment or prevention of obesity or obesity-related metabolic diseases.
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