TW201124401A - New phenoxypyrimidine derivatives - Google Patents

Abstract

The subject of present invention is related to a compound having excellent DGAT inhibition and ingestion inhibition or a pharmacologically acceptable salt thereof. The solution is to provide a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, (wherein R is a phenyl optionally substituted by 1 to 3 substituents independently selected from halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, hydroxymethyl, cyano, carboxyl, carboxylmethyl, C2-C7 alkoxycarbonyl and C2-C7 hydroxyalkoxycarbonyl).

Description

201124401 VI. Description of the Invention: [Technical Field] The present invention relates to a compound having a specific chemical structure or a pharmacologically acceptable salt thereof, which is excellent in Kjungsky enzyme A: dimercapto glycerolase-based transfer The enzyme (Acyl-CoA: diacylglycerol acyltransferase; hereinafter also referred to as DGAT) inhibits and has excellent feeding inhibition. [Prior Art] Obesity is a state in which excess energy is continuously in excess of consumption energy, and fat cells accumulate neutral fat (triacylglycerol or triglyceride; hereinafter referred to as TG) As a result, the body weight is significantly increased compared with the standard body weight (Non-Patent Document 1). Obesity leads to hyperlipidemia, hypertriglyceridemia, diabetes, hypertension, arteriosclerosis and other lifestyle-related diseases, cerebrovascular disorders, coronary artery disease, respiratory abnormalities, low back pain, degenerative knee arthritis, gout, cholelithiasis Those who have a sputum such as Ιΐί in obesity, or who may develop such convulsions in the future are defined as obesity and are treated as a disease. Animals and plants 'accumulate lipids with insoluble TG, and TG is decomposed as necessary to generate energy. By ingesting the TG, it is decomposed into free fatty acids and monoacylglyCer〇l by the action of bile acids and pancreatic lipase in the lumen of the small intestine. The micelles composed of free fatty acids, monoterpene glycerol and bile acids are absorbed by intestinal epithelial cells and are synthesized in the endoplasmic reticulum by 醯Kytozyme A synthetase (hereinafter referred to as ACS), 醯Kyethase A : The role of monoterpene glycerol thiotransferase and d GAT, heavy -4- 201124401 was newly synthesized into TG. TG is secreted in the lymphatic vessels of the gastrointestinal tract after being combined with phospholipids, cholesterol and apolipoprotein as chylomicron. Further, TG is secreted into the blood via the main lymphatic vessel and transported to the distal end for utilization. On the other hand, TG is also synthesized from glycerol 3-phosphate and free fatty acids in adipose tissue by ACS, glycerol 3-phosphate thiotransferase, lysophosphatidic acid thiol transferase and DGAT. Non-patent document 2). Thus, the excessively ingested TG is accumulated in the adipose tissue, and as a result, obesity is produced. DG AT is an enzyme present in the endoplasmic reticulum of cells and is the most important final reaction step in catalyzing the TG synthesis pathway, ie, 醯Kymase A transfers thiol to the third position of 1,2-dimercaptoglycerol The enzyme of the reaction (Non-Patent Documents 3 to 5). It has been reported that DGAT has two isoenzymes (isoenzyme) - DGAT1 (Non-Patent Document 6) and DGAT2 (Non-Patent Document 7). Since DGAT1 is abundantly expressed in the small intestine and adipose tissue, and DGAT2 is abundantly expressed in hepatic sputum and adipose tissue, DG AT 1 is considered to be mainly involved in fat absorption from the small intestine and fat accumulation in adipose tissue, while DGAT2 is involved in TG in liver sputum. Secretion of synthetic or very low density lipoproteins (VLDL), and accumulation of fat in adipose tissue. Although the functions of DGAT1 and DGAT2 are different, they are not described in detail, but suggest that DG AT is related to obesity, lipid metabolism, and glucose metabolism (Non-Patent Document 8). DG AT is a key enzyme for TG synthesis in digestive tract epithelial cells and adipose tissue, so it inhibits TG AT, inhibits TG synthesis, inhibits fat absorption in the digestive tract and fat accumulation in fat tissue, and is expected to be used in 201124401. Obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis; or hyperlipidemia, hypertriglyceridemia due to obesity Therapeutic or prophylactic agents for diseases such as diseases of abnormal lipid metabolism, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, hypertension, arteriosclerosis, cerebrovascular disease or coronary artery disease (Non-Patent Documents 9 to 13) ). The appetite suppressing drug directly or indirectly regulates the appetite regulating system, but its mechanism of action is roughly divided into central and peripheral. Centrally active appetite The inhibitory drug acts directly on the nervous system of the ventricle in the presence of the feeding center and the satiety center or regulates the nervous system monoamine (m 〇 m 〇 a m i n e ) in the nervous system to directly suppress appetite. Conversely, a peripherally acting appetite suppressant acts indirectly on a mechanism that senses and conveys the accumulation of nutrients or residual energy through the diet to suppress appetite. In recent years, digestive tract hormones (CCK, GLP-1, PYY, etc.) secreted in close contact with food digestion and absorption (Non-Patent Document 14), or thin cells derived from fat cells in response to energy accumulation (fat amount) Leptin (Non-Patent Document 15), etc., hormonal or neurogenic appetite regulation signal transmission mechanism from the distal to the central has been gradually elucidated. The novel appetite suppressant associated with these peripheral signals is expected as an effective treatment for obesity with fewer side effects. A compound having a structure similar to the compound of the present invention, and a (1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino group and a substituent are described in Patent Document 1. The cyclohexylcarbonylamine group is bonded to the ethyl group-bonded group-6-201124401 (Example E150) and the like and used as a DGAT inhibitor. On the other hand, the compound of the present invention is directly bonded to a phenyl group having a substituent on a (1-pyridine-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amine group. Further, in Patent Document 2, a pyrazole ring terminal of a (3-trifluoromethyl-1H-pyrazole-4-decyl) amine group is substituted with a phenyl group, and an amine group is bonded via two aromatic rings and a residue. The phase-bonded compound (Compound Wig 70) and the like and the use thereof as a DGAT inhibitor. On the other hand, the compound of the present invention is substituted with a pyridyl ring at the pyrazole ring of the (3-trifluoromethyl-1 Η-pyrazole-4-carbonyl)amine group, and the amine terminal is substituted with two aromatic rings. And the phenoxy ether is bonded to a substituent such as a carboxyl group. Further, in Patent Document 2, the fourth position of the benzene ring of [(1 -pyridin-2-yl-3-trifluoromethyl-1 fluorene-4-oxo-4-carbonyl)amino]phenyl has a substituted The compound of the piperidine ring (Compound No. 7 5 ) and the like and the use thereof as a d G AT inhibitor. On the other hand, the compound of the present invention is the fourth position of the benzene ring of [(1 _pyridine-2-yl-3-trifluoromethyl-1H-indenyl-4-ylamino)amino]phenyl] There is a substituted pyrimidine ring. Further, in Patent Document 3, the oxygen atom terminal of 5-[4-(carbonylamino)phenyl]pyrimidin-2-yloxy group is substituted with a cycloalkylmethyl group having a carboxyl group, and the terminal has a substituent. The phenyl substituted compound (Compound No. 405) and the like and the use thereof as a DG AT inhibitor. In another aspect, the compound of the present invention is substituted at the oxygen atom of the 5-[4-(carbonylamino)phenyl]pyrimidin-2-yloxy group via a substituted phenyl group, and the carbonyl end is via pyridine_2_ Substituted by 3-trifluoromethyl-1 Η-pyrazolyl. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Non-Patent Document Non-Patent Document 1 垣 垣英二 "STEP Metabolism. Endocrinology", Hippocampus, 1st edition, 1 998, p.105; Non-Patent Document 2 Coleman, R., Bell, R., J. Biol. Chem . , 1976, Vol. 25, p. 453 7-4543; Non-Patent Document 3 Coleman, R., Methods in Enzymology, 1992, Vol. 209, p. 98-104; Non-Patent Document 4 Lehner, R., Kuksis, A., Prog. Lipid Res., 1996, Vol. 35, p.1 69-20 1 ; Non-Patent Document 5 R. Bell., Ann. Rev. Biochem., 1980, 49, p_459-487; Non-Patent Document 6 Cases, S. et al., Proc. Natl. Acad. Sci. USA·, 1998, Vol. 95, ρ·13018-13023; Non-Patent Document 7 Cases, S Et al., J. Biol. Chem., 2001, Vol. 276, p. 38870-38876; Non-Patent Document 8 Coleman, RA, Lee, DP, Progress in Lipid Research, 2004, Vol. 43, p .134-176 ; Non-Patent Document 9 Smith, SJ et al., Nat. Genet, 2000, Vol. 25, p. 87-90; -8- 201124401 Non-Patent Document 10 Chen, Η·C·, J. Clin. Invest·, 2002, 109th, p. 1049-1055; Non-Patent Document 11 Buhman, Κ·Κ·, J. Biol. Chem., 2002, Vol. 2 7.7, ρ·2 5 474-2 5 4 79 ; Non-Patent Document 12 Gaziano, J. , et al., Circulation, 1997, Vol. 96, ρ·2520-2525; Non-Patent Document 13 Yamaguchi, K. et al., Hepatology, 2008, Vol. 47, p. 625-63 5; Non-patent Literature 14 Strader, AD et al., Gastroenterology, 205, vol. 128, p. 175-191; Non-Patent Document 15 Campfield, LA et al., Science, 1995, Vol. 269, p. 546- 549. DISCLOSURE OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION The present inventors have found that a compound having a specific chemical structure has an excellent DGAT inhibitory effect on a compound having a DGAT inhibitory action and a food suppressing action, and is particularly high for DGAT1. Inhibition. Further, the present inventors have found that this compound has an excellent food suppressing action. Further, the present inventors have found that the compound can be used as an animal selected from the group consisting of obesity, obesity, hyperlipemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance, diabetes, and diabetes mellitus. (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes-9- 201124401 disease, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis Active ingredient of a drug for the prevention and/or treatment of diseases caused by a group consisting of atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease and overeating; or hyperlipidemia attributed to obesity 'high triglycerideemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetes) Macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary Group, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, degenerative knee arthritis, gout and cholelithiasis An active ingredient of a pharmaceutical product for the treatment and/or prevention of diseases of the group formed. Means for Solving the Problems The present invention relates to (1) a compound of the general formula (I) or a pharmaceutically acceptable salt thereof,

N

R Ο Ν

(I) 201124401 (wherein R represents 1 to 3 independently selected from a halogen atom, C, -C6, a Ci-C6 halide, a methyl group, a cyano group, a residue, a carboxymethyl group, a C2-C7 alkoxycarbonyl group and a C2-C7 hydroxyalkyloxycarbonyl group-substituted phenyl group). The compound of (1) or a pharmacologically acceptable salt thereof, wherein R is 1 or 2 independently selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, or a pharmacologically acceptable salt thereof. a phenyl group substituted with a carboxyl group and a carboxymethyl group. (3) A compound of (1) or a pharmacologically acceptable salt thereof, wherein R is 4_residylphenyl, 4-resin-2-phenylene, 4-residyl-2-chlorophenyl, 4 - Residue-2 -tolyl, 4-mercapto-2-trifluoromethylphenyl or 4-resin methyl 2 -chlorophenyl. (4) A compound of the general formula (I) or a pharmacologically acceptable salt thereof, wherein the compound is [3·chloro-4-(5-{4_[(l - shame steep_2_yl_3_3) Fluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidine-2-yloxy)phenyl]acetic acid, 3-chloro-4-(5-{4-[(1-Π ratio) Π定-2-yl-3-trifluoromethyl_1H_D ratio π sit-4·carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, 4-(5-{4-[( 1-Ethyl U-l-yl-3-difluoromethyl_ιη_|]pyridin-4-reyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, 3-fluoro-4 -(5-{4-[(1-Pyridin-2-yl-3-trifluoromethyl·1Η•pyrazole_4·carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, 3-methyl-4-(5-{4-[(1-ladox-2-yl-3-trifluoromethyl-p--4-indenyl)amino]phenyl}-butyl D-butyl-2- Benzyl)benzoic acid, or 4-(5-{4-[(1-indole-dept-2-yl-3-difluoromethyl-1H•indolyl)amino]phenyl}pyrimidine- 2-yloxy)-3-trifluoromethylbenzoic acid. 201124401 (5) - A compound of the general formula (I), which is [3_chloro-4 -(5 - { 4 - [( 1 -pyridin-2-yl-3-trifluoromethyl-1 Η - Pyrazole-4 carbonyl)amino]phenyl}pyrimidin-2-yloxy)phenyl]acetic acid, 3-chloro-4-(5-{4-[(1-acridin-2-yl-3-) Trifluoromethyl_ιη·pyridin-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, 4-(5-{4-[(1-pyridin-2-yl)3 -trifluoromethyl-1Η-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, 3-air-4-(5-{4-[(1-la steep) · 2 -yl-3-dimethylmethyl-1Η-indole 哩-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, 3-methyl· 4 - ( 5 - { 4-[(1-pyridin-2-yl-3-trifluoromethyl-1 η-pyrazolecarbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, or 4-(5-{ 4-[(pyridin-2-yl-3-trifluoromethyl-1Η-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)_ 3 _trifluoromethylbenzoic acid . (6) - 醯 Α Α Α Α Α 醯 醯 Α Α Α Α Α Α Α Α Α ' ' ' ' ' ' ' ' ' ' ' 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯ingredient. (7) An ingestion inhibitor and/or an appetite suppressant, which comprises the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof as an active ingredient. (8) A pharmaceutical composition comprising a compound selected from any one of (1) to (5) or a pharmacologically acceptable salt thereof as an active ingredient. (9) The pharmaceutical composition as described in (8), which has a 醯Kymase enzyme: dimercaptoglycerol hydrazinotransferase inhibitory action. -12-201124401 (10) The pharmaceutical composition according to (8), which has an action of suppressing food intake and/or appetite suppressing. (1) The pharmaceutical composition described in (8), which is used for the treatment of a disease to be treated and/or prevented by the inhibition of 醯Kytozyme A: dimercaptoglycerol thiotransferase / or prevention. (1) The pharmaceutical composition as described in (8), which is used for the treatment and/or prevention of a disease attributed to the activity of 醯Kytozyme A: dimercaptoglycerol thiotransferase. (1) The pharmaceutical composition according to (8), which is used for inhibiting the synthesis of trimethyl glyceryl thiol transferase, inhibiting the synthesis of triglyceride, and inhibiting triglyceride by inhibiting 醯K. Absorption, treatment and/or prevention of symptoms that are treated, ameliorated, alleviated and/or prevented. (1) The pharmaceutical composition described in (8), which is used for treating a symptom by inhibiting the synthesis of 醯Kystase A: dimercaptoglyceryl thiol transferase and inhibiting triglyceride. Treatment, and/or prevention of diseases that improve, alleviate and/or prevent. (1) The pharmaceutical composition described in (8), which is used for obesity, obesity, hyperlipidemia, triglyceride, abnormal lipid metabolism disease, insulin resistance syndrome, abnormal glucose tolerance, diabetes Diabetes mellitus (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis Treatment and/or prevention of disease, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. -13- 201124401 (1) The pharmaceutical composition described in (8), which is used for the treatment and/or prevention of obesity or obesity. (1) The pharmaceutical composition described in (8), which is used for the treatment and/or prevention of diabetes. (1) The pharmaceutical composition according to (8), which is used for hyperlipemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and anti-sugar tolerance abnormality attributed to obesity Diabetes, diabetes mellitus (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome, arteries Sclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, degenerative knee arthritis, gout or cholelithiasis and/or Or prevention. (1) The pharmaceutical composition described in (8), which is used for the treatment of hyperlipemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension attributed to obesity and/or prevention. (20) The pharmaceutical composition as described in (8), which is for inhibiting fat absorption from the small intestine. (2 1 ) The use of the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition. (22) The use as described in (21), wherein the pharmaceutical composition is for inhibiting 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase. (2 3) The use as described in (2 1 ), wherein the pharmaceutical composition is for inhibiting feeding and/or eating. -14- 201124401 (24) The use as described in (2 1 ), wherein the pharmaceutical composition is used for obesity, obesity, hyperlipemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and sugar tolerance Abnormal, diabetes, diabetes mellitus (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary Treatment and/or prevention of syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. (2 5) The use as described in (2 1 ), wherein the pharmaceutical composition is for the treatment and/or prevention of obesity or obesity. (2 6) The use as described in (2 1 ), wherein the pharmaceutical composition is for the treatment and/or prevention of diabetes. (2 7) The use as described in (2 1 ), wherein the pharmaceutical composition is used for hyperlipemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, Diabetes, diabetes mellitus (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome, arteries Sclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, degenerative knee arthritis, gout or cholelithiasis and/or Or prevention. (2) The use as described in (2 1 ), wherein the pharmaceutical composition is used for the treatment of hyperlipemia, hypertriglyceridemia, diabetes, atherosclerosis or hypertension due to obesity and/or prevention. -15- 201124401 (29) The use as described in (21), wherein the pharmaceutical composition is used to inhibit fat absorption from the small intestine. (30) A method for inhibiting 醯Kystase a: dimercaptoglycerol thiotransferase, which is a pharmacologically effective amount of a compound selected from any one of (!) to (5) for a warm-blooded animal. Or a pharmaceutically acceptable salt thereof. (3 1 ) A method for inhibiting ingestion and/or suppressing appetite, which is a pharmacologically effective amount of a compound selected from any one of (1) to (5) or pharmacologically acceptable thereto. Salt. (3 2 ) A method for treating and/or preventing a disease, which is a pharmacologically effective amount selected from the group consisting of any one of (1) to (5) or a pharmacologically acceptable amount thereof. salt. (3 3 ) The method described in (3 2 ), the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance, diabetes, diabetes Symptoms (including diabetic neurological disorders, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, arteries Atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. (3 4) The method described in (3 2), wherein the disease is obesity or obesity. (35) The method according to (32), wherein the disease is diabetes. (3 6 ) The method described in (3 2 ), the disease is hyperlipemia due to obesity, hypertriglyceridemia, abnormal lipid metabolism disease, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes 倂Hair disease (including 16-201124401 with diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, Atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, degenerative knee arthritis, gout or cholelithiasis. (37) The method according to (32), wherein the disease is hyperlipemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension which is attributed to obesity. (3 8 ) A method for inhibiting fat absorption from a small intestine, which comprises administering to a warm-blooded animal a pharmacologically effective amount of a compound selected from any one of (1) to (5) or a pharmacologically acceptable one thereof salt. (39) The method according to any one of (30) to (38) wherein the warm-blooded animal is a human. In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or a ya atom. Preferred are fluorine atoms or chlorine atoms. In the present invention, "Ci-C: 6-yard group" is a linear or branched alkyl group having 1 to 6 carbon atoms. For example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl or 4-methylpentyl, preferably a linear or branched alkyl group having 1 to 4 carbon atoms (C^C: 4 alkyl), more preferably It is a methyl group or an ethyl group (Ci-Cz alkyl group), and even more preferably a methyl group. -17- 201124401 In the present invention, "Cl_C6 halogenated alkyl group" is one or five identical or different "halogen atoms" bonded to the above "C^-C: 6 alkyl group". For example: trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloro Ethyl, 2-bromoethyl '2-chloroethyl or 2-fluoroethyl' is preferably one to five identical or different "halogen atoms" bonded to the aforementioned "C^C:4 alkyl group". The basis of the "Cl_C4 toothed sulfhydryl group" is preferably 1 to 5 identical or different "halogen atoms" bonded to the base of the "Ci-C2 hospital base" (C1-C2 halogenated base) Further, further preferred is trifluoromethyl. In the present invention, the "c2_c7 alkoxycarbonyl group" is a group in which an oxygen atom bonded to one of the aforementioned "Cl-C6 alkyl groups" is bonded to a carbonyl group. For example: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy, S-butoxycarbonyl or t-butoxycarbonyl, preferably with one of the foregoing The Cl_c4 alkyl group-bonded oxygen atom is bonded to a carbonyl group (c2-c5 alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (c2-c3 alkoxycarbonyl group), and even more preferably Methoxycarbonyl. In the present invention, the "c2-c7 hydroxyalkoxycarbonyl group" is a group having one hydroxyl group bonded to the "alkyl group" of the above "c2-c7 alkoxycarbonyl group". For example, 1-hydroxymethoxycarbonyl, 2-hydroxyethoxycarbonyl, 1-hydroxyethoxycarbonyl or 3-hydroxypropoxycarbonyl, preferably the above-mentioned "C2-C3 alkoxycarbonyl" alkyl bond There is one hydroxyl group (C2-C3 hydroxyalkyloxycarbonyl group), more preferably 2-hydroxyethoxycarbonyl group. -18- 201124401 In the present invention, "" may be selected from 1 to 3 independently selected from a halogen atom, a Cl-C6 alkyl group, a Ci-C6 dentate, a methyl group, a cyano group, a decyl group, a fluorenyl group, a c2 group. a -C7 alkoxycarbonyl group and a C2_C:7 hydroxyalkyloxycarbonyl group-substituted phenyl group", which may be independently selected from the group consisting of a halogen atom, a C"C6 alkyl group, a C1-alkyl group, a C1-C6 alkyl group, a hydroxymethyl group. a phenyl group substituted by a cyano group, a carboxy group, a carboxymethyl group, a Cz-C7 alkoxycarbonyl group and a c2-C7 hydroxyalkyloxyalkyl group, preferably one or two independently selected from a fluorine atom and a chlorine atom. More preferably, the phenyl group substituted with a methyl group, a trifluoromethyl group, a carboxyl group or a carboxymethyl group is a 4-carboxyphenyl group, a 4-carboxy-2-fluorophenyl group, a 4-hydroxy-2-chlorophenyl group. , 4-hydroxy-2-methylphenyl, 4-mercapto-2-trifluoromethylphenyl or 4-resylmethyl-2-chlorophenyl. The compound of the invention having the general formula (I) or pharmacologically thereof Acceptable salts have all of the isomers (diastereomers, optical isomers, rotational isomers, etc.), and have the general formula of the present invention. a compound of (I) or a pharmaceutically acceptable salt thereof There are various isomers in the molecule, and thus various isomers. In the compounds of the present invention, 'these isomers and mixtures of such isomers are represented by a single chemical formula', that is, the general formula (I). The invention also encompasses all such isomers and mixtures of such isomers in any ratio. The stereoisomers as described above may be obtained by using optically active starting compounds; or using asymmetric or asymmetric induction ( A method of reacting induces a compound of the present invention; or a synthetically related compound of the present invention is obtained by separating according to a general optical resolution or separation method. -19- 201124401 The compound of the present invention is also An atomic isotope having an unnatural ratio may be contained in one or more atoms constituting such a compound, and examples thereof include ruthenium (2H), ruthenium (3H), iodine 125 (1251), or carbon 14 (14C) as atomic isotopes. Further, the aforementioned compound may be radioactively labeled with a radioisotope such as hydrazine (3H), iodine 1 2 5 (12 5 1 ) or carbon 14 (14C). The compound of the sex marker can be used as a therapeutic or prophylactic agent, a test drug (for example, an analytical reagent), and a diagnostic agent (for example, an in vivo diagnostic agent). All isotopic variations of the compound of the present invention, whether radioactive or not, It is included in the scope of the present invention. The "pharmaceutically acceptable salt" means a salt which can be used as a pharmaceutical product without significant toxicity. The compound of the present invention having a general formula (I) can be reacted with an acid when it has a basic group; and it can be converted into a salt by reacting with a base when it has an acidic group. The salt derived from the basic group may, for example, be a hydrofluoride, a hydrochloride, a hydrobromide, a hydroiodide hydrohalide, a nitrate, a perchlorate, a sulfate, a phosphate, or the like. Inorganic acid salts; such as methanesulfonate, triflate, ethanesulfonate, C?-Ce alkyl sulfonate, arylsulfonic acid such as besylate or P-toluenesulfonate Salts, acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates, and the like; and, for example, glycinates, Amino acid salt of aminate, arginine, alanate, glutamate, aspartate. On the other hand, examples of the salt derived from an acidic group include, for example, a sodium salt, a potassium salt, an alkali metal salt of a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an aluminum salt, and an iron salt of -20-201124401. a metal salt; an inorganic salt such as an ammonium salt, such as t-octylamine salt, benzhydrylamine salt, wortrine salt, glucosamine salt, alkyl phenylglycine salt, ethylenediamine salt, N -Methyl-reduced glucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine An amine salt of a salt, a procaine salt, a diethanolamine salt, a N-benzylphenethylamine salt, a piperazine salt, a tetramethylammonium salt, an organic salt of a tris(hydroxymethyl)aminomethane salt, and the like; Amino acid salts such as glycinate, lysinate, arginine, alanate, glutamate, aspartate. The compound of the present invention having a general formula (I) or a pharmacologically acceptable salt thereof may absorb water molecules to form a hydrate due to being placed in the atmosphere or recrystallized, and such a hydrate is also included in the salt of the present invention. The compound of the present invention having the general formula (I) or a pharmacologically acceptable salt thereof may absorb other solvents to form a solvent, and such a solvent is also included in the salt of the present invention. EFFECT OF THE INVENTION The compound represented by the general formula (I) or a pharmacologically acceptable salt thereof has excellent D GAT inhibitory action and food suppressing action, and can be used as a warm-blooded animal (preferably a mammal, including Human diseases: from obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus (including diabetes) Slightly neurological disorders, diabetic nephropathy 'diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome-2 1- 201124401 group, arteriosclerosis, arterial porridge a disease caused by a group consisting of sclerosis, diabetic atherosclerosis, ischemic heart disease, and overeating; or a hyperlipidemia due to obesity, hypertriglyceridemia, abnormal lipid metabolism, Insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes mellitus (including diabetic neuropathy, diabetes) Kidney disease, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension Medicines for the prevention and/or treatment of diseases caused by diseases, cerebrovascular disorders, coronary artery diseases, fatty liver, respiratory abnormalities, low back pain, degenerative knee arthritis, gout and cholelithiasis. Further, the novel compound represented by the general formula (I) or a pharmacologically acceptable salt thereof according to the present invention has excellent DG AT inhibitory action and can be used as a warm-blooded animal (preferably a mammal, including a human) An active ingredient of a pharmaceutical for the prevention and/or treatment of the above diseases. Preferably, it is a therapeutic drug which can be used as the above-mentioned disease. [Embodiment] EMBODIMENT OF THE INVENTION The compound of the general formula (I) of the present invention can be produced according to the A method described below. The inactive solvent used in the reaction of each step of the following A method is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and is, for example, selected from the following solvent groups. The solvent group is a hydrocarbon such as pentane, hexane, xinyuan, petroleum ether, ligr〇ine, and cyclohexyl; for example, -22- 201124401 methotrexate, N,N-dimethyl group Indoleamine, N,N-dimethylacetamide, Ν·methyl-2-indole, pyrrolidone, Ν-methyl-2-d pyrrolidinone, hexamethyl phosphate Amidoxime; such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, ether of cyclopentyl methyl ether Such as methanol, ethanol, n-propanol, i-propanol, η-butanol, 2-butanol, 2-methyl-1·propanol, t-butanol, isoamyl alcohol, two Diethylene glycol, glycerol, octanol, cyclohexanol, methylcellosolve alcohols; such as dimethyl sulfoxide, hydrazines; such as sulfolane; Such as acetonitrile, propionitrile, butyronitrile, nitrile nitrile; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate ester; such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone a ketone of cyclohexanone; such as a nitro compound of nitrous oxide or nitrobenzene; such as dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, tetrachloroethylene (carbon) Tetrachloride); aromatic hydrocarbons such as benzene, toluene, and xylene; carboxylic acids such as acetic acid, formic acid, propionic acid, butyric acid, and trifluoroacetic acid; such as N-methylofofolin, triethyl Amines 'tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, piperidine, piperazine D, 2,6-lutidine , 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4- Pyridine, quinoline, N,N-dimethylaniline' Ν, Ν-diethylamine, 1,5-ditibicyclo[4.3.0] 壬-5-ene (〇8>^) , 1,4-dioxinebicyclo[2_2.2] 辛院-23- 201124401 (DABCO), 1,8-dioxinbicyclo[5.4.0]~i--7-ene (DBU), piperidine Amines; water; and these mixed solvents. The base used in the reaction of each step of the following A method is, for example, sodium carbonate, potassium carbonate, lithium carbonate, alkali metal carbonate of carbonic acid; for example, alkali metal such as sodium hydrogencarbonate, potassium hydrogencarbonate or lithium hydrogencarbonate Bicarbonate; such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetate of acetic acid; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; such as sodium hydroxide, potassium hydroxide, hydrogen An alkali metal hydroxide such as cerium oxide or lithium hydroxide; an inorganic base such as sodium fluoride or an alkali metal fluoride of potassium fluoride; an alkali metal such as sodium t-butoxide or potassium t-butoxide Alkoxide (aik〇xide); such as sodium trimethyl sulfonium oxide, potassium trimethyl sulfonium oxide, lithium trimethyl sulfonium oxide alkali metal trialkyl sulfonium oxide (siloxide); such as N -methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-dimethylpyridine, 4 - Pyrrolidone, methylpyridine, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-pyridinium, benzopyridine, N,N-dimethylaniline , N,N-diethylamine, anthracene, 5-dioxabicyclo[43〇]壬-5_ene (DBN), 1,4 -dibicyclo[2_2,2]octane (DABCO), 1,8 - An organic base such as lithium diisopropylamine or lithium bis(trimethylammonium) decylamine; or a proline such as lysine; (proline) amino acid. In the reaction of each step of the following A method, the reaction temperature varies depending on the solvent, the starting material, the reagent, and the like; the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like. -24- 201124401 In the reaction of each step of the following A method, after the reaction is completed, each compound of interest is extracted from the reaction mixture according to a usual method. For example, the reaction mixture is moderately neutralized, and when insoluble matter is present, it is removed by filtration, and an organic solvent such as water and ethyl acetate is not added, and the organic layer containing the objective compound is separated and water is used. After washing, it is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate or the like, filtered, and then obtained by distilling off a solvent. The obtained target compound may be appropriately combined with a usual method, for example, recrystallization, reprecipitation, or the like, which is generally used for separation and purification of an organic compound, by column chromatography and by dissolution with a suitable dissolving agent. (elution), separation and purification. The compound which is insoluble in the solvent can be washed and purified by using the obtained crude solid product as a solvent. Further, the objective compound of each step can be directly used in the next reaction without purification. Method A is for the production of a compound having the general formula (Π25-201124401 A method)

Br

Cl Λ N (HI) Step A1 N^V^Br

(I) In the present invention, 'R represents the same meaning as the above; Ra is a hydroxy group and/or a carboxyl group which is contained in the substituent as a substituent, and is a protected thiol group and/or a thiol group. The same base in the definition. Step A 1 This step is a step of producing a compound of the general formula (IV). This step is carried out by reacting a compound of the general formula (11) with a compound (III) in the presence of a solvent in a solvent. The compound having the general formula (II) is a conventional compound (for example, WO2006/004200, J. Med. Chem., 1 98 7, 30, 1887-26-201124401, etc.) or is easy to start with a conventional compound. Starting materials are produced according to a conventional method (for example, WO2006/004200, j. Med_Chem., 1987, 30, 1887, etc.) or a method similar thereto. The solvent used in this step is preferably guanamine, and more preferably ruthenium, osmium-dimethylacetamide. The base used in this step is preferably an alkali metal carbonate, more preferably potassium carbonate. The reaction temperature in this step is usually from 〇 ° C to 180 ° C, preferably from 60 ° C to 120 ° C. The reaction time in this step is usually from 5 hours to 72 hours, preferably from 2 hours to 24 hours. Step A2 This step is a step of producing a compound of the general formula (I). This step is carried out by reacting a compound of the general formula (IV) with a compound (V) in the presence of a solvent, a palladium catalyst and a base, and removing the protecting group of the hydroxyl group and/or the carboxyl group in Ra according to the expectation. And proceed. The solvent used in this step is preferably a mixed solvent of guanamine and water. The more preferred one is ruthenium, a mixed solvent of ruthenium dimethylacetamide and water. The palladium catalyst used in this step, for example, tetrakis(triphenylphosphine)palladium(0), palladium-activated carbon, palladium(II) acetate, palladium(II) trifluoroacetate, Palladium black , palladium (II) bromide, palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium oxide (11), palladium (II) sulfate, dichlorobis (acetonitrile) palladium (II), dichlorobis(benzonitrile)palladium(11), dichloro(1,5-cyclooctadiene)palladium-27- 201124401 (II), acetamacetone palladium (ruthenium), vulcanization Palladium (II), dichloro[1,1'-bis(diphenylphosphine) ruthenium]palladium (palladium), tris(dibenzylideneacetone) dipalladium(0) a tetravalent palladium catalyst of tetrakis (acetonitrile) palladium (II) tetrafluoroborate or an aryl palladium chloride dimer or a zero-valent palladium catalyst, preferably The ruthenium palladium catalyst is more preferably tetrakis(triphenylphosphine)palladium (ruthenium). The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate. The reaction temperature in this step is usually from 20 t to 180 ° C, preferably from 60 ° C to 120 ° C. The reaction time in this step is usually from 0.5 to 72 hours, preferably from 2 hours to 24 hours. In the above, the term "protective hydroxyl group" and "protectable carboxyl group" as used in the definition of Ra means protection by chemical decomposition such as hydrogenolysis, hydrolysis, electrolysis or photolysis. The group represents a protecting group generally used in organic synthetic chemistry (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)). In the above, Ra2 The "protecting group" in the definition of "protectable hydroxyl group" is only a protecting group for a hydroxyl group used in the field of organic synthetic chemistry, and is not particularly limited, but is, for example, a methyl group, an ethyl group, a propyl group. C2-C7 Institute of butyl, butyl ketone, pentanoyl, valeryl -28- 201124401 carbonyl; such as chloroethinyl, dichloroacetamidine, trichloroethane, trifluoroacetamidine a halogenated alkylcarbonyl group; an alkoxycarbonyl group such as a methoxyethyl group; such as an acryloyl group, a propynyl group, a methacryl fluorenyl group, a crotonoyl group, an isocrotonyl group, (E)- 2-methyl-2-butyzanyl (butenoyl) unsaturated plant An "alkylcarbonyl group" such as a fluorenyl group; an arylcarbonyl group such as a benzamidine group, a naphthylmethyl group or a non-naphthylmethyl group; a halogenated arylcarbonyl group such as a 2-bromobenzylidene group or a 4-chlorobenzylidene group; Such as 2,4,6-trimethylbenzyl, 4 toluoyl 2 C^-Ce alkylated arylcarbonyl; such as 4-p-methoxybenzoyl (aniSOyi) Cl-C6 alkoxylated arylcarbonyl; such as 4-nitrobenzhydryl, 2-nitrobenzylidene nitroalkyloxy; such as 2-(methoxycarbonyl)benzhydryl C2_C7 An alkoxycarbonylated arylcarbonyl group; an "arylcarbonyl group" such as an aryllated arylcarbonyl group of a 4-phenylbenzylidene group; such as the aforementioned "CrC7 alkoxycarbonyl group", 2,2,2-trichloroethoxycarbonyl group An alkoxycarbonyl group such as a Cz-C7 alkoxycarbonyl group substituted with a halogen or a tris-(Ci-C^alkyl)silyl group; Hydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydrofuran-4-yl, tetrahydrothiopyran-2-yl, "tetrahydrofuranyl or tetrahydropyranyl" of 4-methoxytetrahydrothiopyran-4-yl; "four tetrahydrofuran-2-yl, tetrathiathiophen-2-yl" "Phenyl or tetrahydrothiophenyl"; such as trimethyl decyl, triethyl decyl, isopropyl dimethyl sulfonyl, t-butyl dimethyl sulfoxide, methyl isopropyl sand, methyl two -t-Bingsole base, triisopropenyl-tris-(C^C6 alkyl)decyl, diphenylcarbazide, diphenylbutane, diphenylisopropenyl , phenyl diisopropyl sand-based (Ci-C: 6-base) diaryl sand yard base or di-(Ci-Ce fluorene) aryl sand yard base, etc. -29- 201124401 "矽 alkyl" Such as methoxymethyl, hydrazine,. Dimethyl-1.methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 1-butoxymethyl (C!-C6 alkoxy) A a group such as 2-methoxyethoxymethyl (Ci-Ce) alkoxymethyl), such as 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy) Methyl (Ci-C6 halogenated alkoxy) methyl or the like "house oxygen methyl"; such as 1-ethoxyethyl, 1-(isopropoxy)ethyl (Ci_C6-oxime) ethyl "Substituted ethyl group" such as a halogenated ethyl group of 2,2,2-trichloroethyl; such as benzyl, α-naphthylmethyl, /3-naphthylmethyl, diphenylmethyl, trityl a C?-Ce alkyl group substituted with 1 to 3 aryl groups, such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, with naphthyldiphenylmethyl and 9-onionylmethyl. ,3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4- a bromobenzyl group, a 4-cyanobenzyl group having 1 to 3 aryl groups, which is an alkyl group substituted by a C^-Ce alkyl group, an alkoxy group, a nitro group, a halogen group, a cyano group, or the like. "Aralkyl"; such as ethylene oxycarbonyl, allylic oxycarbonyl As the benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 3,4-dimethoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, the aromatic ring can be The "aralkyloxycarbonyl group" substituted by 1 or 2 C^C6 alkoxy groups or a nitro group is preferably an alkyl fluorenyl group, a decyl group or an aralkyl group. The "protecting group" of the "protectable carboxyl group" in the definition of 'R 8 above" is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of organic synthetic chemistry. "ethenyl", 1-propenyl, 2-propenyl, fluorenyl-methyl-2-propenyl "c2-C6 alkenyl"; such as ethynyl, 丨-propynyl , 2-propynyl, 1-methyl-30- 201124401-2-propynyl-based "CrC6 alkynyl"; as described above, r Cl-C6 halogenated alkyl"; hydroxymethyl, 2-hydroxyethyl hydroxy An alkyl group; such as an ethyl hydrazine methyl group (C2-C7 alkylcarbonylalkyl group); the aforementioned "aralkyl group"; or the aforementioned "alkylene group", preferably a C丨-C6 alkyl group or an aralkyl group. Protection and deprotection are necessary steps according to conventional methods (eg: Protective Groups in Organic Synthesis) (Theodora W. Greene, Peeter G. M · Wu ts, 1989, Wi 1 ey -1 The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the administration form include a tablet, a capsule, and a capsule. Oral administration of an agent, emulsion, nine doses, powder, syrup (liquid), or by injection (intravenous, intramuscular, subcutaneous or intraperitoneal administration), drip, and suppository (rectal administration) Oral administration, etc. These various preparations can be used as an auxiliary agent in the main drug according to the usual method, which is an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, a solubilizing agent. In the technical field of pharmaceutical preparations such as suspending agents and film coating agents, it is generally available for users to formulate. When used as a tablet, for example, lactose, white sugar, sodium chloride, glucose, urea, starch can be used. Excipients of calcium carbonate, kaolin, crystalline cellulose, citric acid, etc.; water, ethanol, propanol, monosaccharide, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, Adhesives such as potassium phosphate and polyvinylpyrrolidone; dry powder, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, carbonate-3 1- 201124401 calcium, polyoxyethylene sorbitan a disintegrant of fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; disintegration of white sugar, stearin, cocoa butter (coc 〇abu 11 er ), hydrogenated oil, etc. Inhibitor; fourth-grade ammonium salt, sodium lauryl sulfate and the like; humectant such as glycerin' starch; adsorbent for starch, lactose, kaolin, bentonite, colloidal tannic acid, etc. a lubricant such as refined talc, stearate, boric acid powder, polyethylene glycol, etc., and, if necessary, a tablet which is applied to a general film coat, such as a sugar-coated tablet, a gelatin capsule, or an enteric-coated tablet. Film coat or Double-layer ingots, multi-layer ingots. When used as a nine-agent, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc, etc.; gum arabic powder, jaundice can be used. A carrier such as a tragacanth powder, a gelatin or an ethanol; a disintegrator such as a kelp polysaccharide or agar; and the like, as a carrier, a conventionally used person as a carrier in the field can be widely used. Ethylene glycol, cocoa butter, high alcohol, high alcohol esters, gelatin, semi-synthetic glycerides, etc. When used as an injection, it can be used as a liquid, emulsion or suspension. Such liquids, emulsions or suspensions are preferably sterilized and are isotonic with blood. The solvent for producing such a liquid preparation, emulsion or suspending agent is not particularly limited as long as it can be used as a diluent for medical use, and examples thereof include water, ethanol, propylene glycol, and ethoxylated isostearyl alcohol. Polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Further, in this case, a sufficient amount of salt, glucose or glycerin may be contained in the preparation to prepare an isotonic -32-201124401 solution, or a general solubilizer, a buffering agent, a pain-relieving agent or the like may be contained. Further, the above preparation may contain a coloring agent, a preservative, a flavor, a flavor, a sweetener, and the like as necessary, and may further contain other pharmaceuticals. The amount of the active ingredient compound contained in the above-mentioned preparation is not particularly limited, but is appropriately selected from a wide range, and is usually from 0.5 to 70% by weight, preferably from 1 to 30% by weight, based on the total composition. . Although the amount of use varies depending on the symptoms, age, etc. of the patient (warm-blooded animals, especially humans), when administered orally, the upper limit for adults is 2000 mg (preferably 100 mg), and the lower limit is O. Lmg (preferably 1 mg, further preferably l〇mg), preferably 1 to 6 times per day in response to symptoms. EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples and test examples, but the scope of the invention is not limited thereto. The elution in the column chromatography of the examples was carried out by observing TLC (Thin Layer Chromatography). In the TLC observation, a silicone resin 60F254 manufactured by Merck Co., Ltd. was used as a TLC sheet; a solvent used as a solvent for elution in a column chromatography method was used as a developing solvent; and a UV detector was used as a detection method. For the column, the silicone resin SK-85 (230~4〇0 mesh) or Fuji Silysia Chemical Ltd. Chromatorex NH (200-350 mesh) was also used. In addition to the general column chromatography method, Biotage's automatic chromatography unit (SP-1) is also suitably used. -33- 201124401 Solvent Dissolving Medium The solvent specified in each example was used at a specified ratio (or the ratio was changed as necessary). Further, the abbreviations used in the examples have the following meanings. Mg: mg, g: gram 'mL: ml 'MHz: megahertz. In the following examples, the 'nuclear magnetic resonance (hereinafter referred to as 1 H NMR ) spectrum uses tetramethyl decane as a standard substance, and the chemical shift 値 is described as (5 値 (ppm). The single line (singlet) in the split pattern is s, double line (doublet ) is represented by d, triplet (trip I et ) by t, quartet by q, multiplet by m, and broad by br. Mass spectrometry (hereinafter referred to as MS) It is carried out by Electron Ionization (EI) method, Electron Spray Ionization (ESI) method, or Fast Atom Bombardment (FAB) method. (Example 1) [3-Chloro- 4- ( 5-{4-[(l-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)phenyl]acetic acid

(la) 1-pyridin-2-yl-3-trifluoromethyl s_1H-pyrazole-4 -carboxylic acid [4-(4,4,5,5-tetramethyl-[1,3,2]dioxin Azylcyclopentaneborane-2_yl)phenyl]decylamine-34- 201124401 1-Pyridine-2-yl-3-trifluoromethyl-1 Η-pyrazole-4 -carboxylic acid (W02008011130 Α2) ( 2.17g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxazolylcyclopentan-2-yl)-phenylamine (1.85g), benzene And triazol-1-yloxy-tris(dimethylamino)scale hexafluorophosphate (BOP reagent) (4.13g), and triethylamine (1.4mL) of dimethylacetamide (20mL) The mixture in the mixture was stirred for 7 days. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography (dichloromethane / ethyl acetate). The precipitated solid was filtered, dried and evaporated to dryness crystals crystals crystals crystalsssssssssssssssssssssssssssssss , 9.67(1H, s), 9.6 7- 8.64( 1 H, m), 8 . 1 7 - 8 . 1 1 (1 H,m), 8.04(1H, d, J = 8,2Hz), 7.79( 2H, d, J = 8.6Hz), 7.68(2H, d, J = 8.7Hz), 7.5 9 -7.5 6 (lH, m), 1.30(12H, s). (lb) [4-(5-bromo) Methyl (3-chloro-4-hydroxyphenyl)acetate (W02006004200A1) (3.69g), 5·bromo-2-chloropyrimidine (Methylpyrimidin-2-yloxy)-3.chlorophenyl]acetate 3.58 g), a suspension of potassium carbonate (5.10 g) in dimethylacetamide (30 mL) was heated at 80 ° C for 10 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography EtOAcjjjjjjjj 1 H NMR (400 MHz, CDC13): δ (ppm) = 8. 5 8 (2 Η , s), 7.45 (1 Η, d, J = 2.0 Hz), 7.2 9 - 7.2 1 (2 Η , m), 3.73 (3Η, s), 3 · 64(2Η, s). -35- 201124401 MS(ESI) m/z:3 5 8 (M + H) + . (lc) [3-Chloro 4-(5- {4-[(l-Pyridin-2-yl-3-trifluoromethyl-1H-pyridin-4-yl)-amino]-phenylpyranyl)-benzyl]-acetate The compound (5 16 mg) obtained in the example (1a) and the methyl [4-(5-bromopyrimidin-2-yloxy)-3-chlorophenyl]acetate obtained in (1b) were aw. a suspension of 401 mg), tetrakis(triphenylphosphine)palladium (ruthenium) (65 mg), and potassium carbonate (319 mg) in dimethylacetamide/water (20:1, 1 〇m L) at 80 Heat at °C for 8 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was purified by chromatography (methylene chloride / ethyl acetate) toiel MS (ESI) m / z: 609 (M + H) + . (ld) [3 - chloro-4-(5-{4-[(l-pyridin-2-yl-3-trifluoromethyl-1H) -(pyridazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)phenyl]acetic acid [3 -chloro-4 - ( 5 - { 4 - [( 1 ) -pyridine-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)-amino]-phenylpyrimidin-2-yloxy)-phenyl]-acetic acid methyl ester (289mg) To a solution of 1,4-dioxane (5 mL), tetrabutylammonium hydroxide (1 mol/L aqueous solution, 1 mL) was added at room temperature. After 19 hours, the reaction mixture was concentrated and evaporated with EtOAc EtOAc. The precipitated solid was taken-~~~~~~~~~~~~~~~~~~~ -36- 201124401 Η NMR ( 4 Ο 0 Μ Η z, DMS Ο - d 6 ) : δ (ppm ) = 1 2.5 ( 1 Η , brs ), 10.5 (1H, s), 9.67 (1H, s), 9.01 (2H, s), 8.64 (1H, d, J = 5.9 Hz), 8.15 (1H, dd, J = 7.8 and 7.8 Hz), 8.05 (1H, d, J = 8.2 Hz), 7.90 (2H, d, J = 9.0 Hz), 7.77 (2H, d, J = 8.6 Hz), 7.6 0 - 7.5 4 ( 2 H , m), 7.40-7.3 3 (2H, m), 3.68 (2H, s). MS (ES) m/z: 5 95 (M + H) + . (Example 2) [4-(5-{4-[(l-pyridin-2-yl-3-trifluoromethyl-1H-pyridinium-) 4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)phenyl]acetic acid

(2a) Methyl [4-(5-bromopyrimidin-2-yloxy)phenyl]acetate (Methyl (4-hydroxyphenyl)acetate (3.08 g)) - bromo-2-chloropyrimidine (3.59 g), mp. 'H NMR (400MHz, CDC13): 5 (ppm) = 8. 5 7 (2 H , s), 7.37 (2H, d, J = 8.6Hz), 7.15 (2H, d, J = 8.6Hz), 3.72 (3H, s), 3.66(2H, s). (2b) [4-(5-{4-[(l-tl is more than 2-yl-3-dimethyl-lH-H) 4- 4-(5-bromopyrimidine) obtained from the compound (2a) in the same manner as in Example (1c) Methyl 2-methyloxy)phenyl]acetate (I71 mg) Compound (244 mg) obtained from Example (1) (yield: bis- </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ br> ). From the above, the bisaryl compound (197 mg) was obtained from the titled compound (1d) (yield: EtOAc (d) 1 Η , brs), 10.5(1Η, s), 9.66(1Η, s), 8.98(2Η, s), 8.6 5 - 8.6 3 ( 1 Η , m), 8 . 1 6-8 · 1 2( 1 Η, m), 8.0 6 - 8.0 3 ( 1 Η , m), 7.89 (2Η, d, J = 8.6Hz), 7.76(2Η, d, J = 9.0Hz), 7.5 9-7.5 6 ( 1 Η, m), 7.3 5 (2Η, d, J = 8,6Hz), 7.19(2H, d, J = 8.6Hz), 3.32(2H, s). MS(FAB) m/z:561 (M + H) (Example 3) 3 -Chloro-4 -( 5 - { 4 - [(1 -pyridin-2-yl-3-trifluoromethyl-1 H-pyrazole-4-carbonyl)amino]benzene Pyrimidine-2-yloxy)benzoic acid

(3a) 4-(5-Bromo-pyrimidin-2-yloxy)-3-chlorobenzoic acid methyl ester according to the same procedure as in Example (lb), from 3-chloro-4-hydroxy-benzoic acid methyl acetate (J Med. Chem., 1987, 30, 1887) ( 3.09 g) and 5-bromo-2-chloropyrimidine (3.21 g). 1H NMR (400MHz, CDC13): δ (ppm) = 8 . 5 9 ( 2 Η , s), 8 . 1 9 ( 1 Η, d, J = 1.9 Hz), 8.04 ( 1 Η, dd, J-8.6 And 2.0Hz), 7.33(1H, d, J = 8.6Hz), 3,95(3H, s)., -38- 201124401 (3b) 3 -chloro-4- (5-{4-[(1- Lath-2-yl-3-trifluoromethyl-1H-portyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid according to the same procedure as in Example (1c) Methyl 4-(5-bromo-pyrimidin-2-yloxy)-3.chlorobenzoate (349 mg) obtained from Example (3a) and compound obtained in Example (1a) (4 5 8 mg ) ' 468 mg (79%) of the bisaryl compound as a white solid. From the bis-aryl compound (468 mg), m. 1 Η NMR (4 0 0 Μ H z, DMS Ο - d 6): &lt;5 (ppm) = 1 3.4 ( 1 H , brs) 10.5 (1H, s), 9.67 (1H, s), 9.04 (2H , s), 8.64 (1H, d, J = 5.5Hz) 8.17-8.00(4H, m), 7.90(2H, d, J = 8.6Hz), 7.8〇(2H, d J = 8.6Hz), 7.62- 7.5 6(2H, m). MS(ES I) m/z : 5 8 1 (M + H) + . (Example 4) 4-(5-{4-[(lD ratio steep-2-yl-) 3-dimethylmethyl-1Η-Π比哩_4_yl) Amino]phenyl}pyrimidin-2-yloxy)benzoic acid

Methyl 4-(5-bromopyrimidin-2-yloxy)benzoate (Org. Lett., 2009, 11, 2511) (311 mg) and Example (la) according to the same procedure as in Example (1c) The obtained compound (462 mg) gave 385 mg (yield: 68%) of bis. From the above, the bisaryl compound (385 mg) was obtained from the titled compound (yield: 21%) (yield: 56%). *H NMR (4 〇〇 MHz, DMSO-d6): &lt;5 (ppm) = 1 3.0 (1 Η , brs), 10.5 (1H, s), 9.67 (1H, s), 9.03 (2H, s) , 8.64 (1H, d, J = 5.5Hz), 8.17-8.13(1H, m), 8.05(2H, d, J = 9.0Hz), 8.0 6 - 8.0 3 ( 1 H , m), 7.90 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 7.6 0 - 7.5 7 ( 1 H , m), 7.38 (2H, d, J = 8.6 Hz). MS (ESI) m/ z: 547 (M + H) + . (Example 5) 3-(5-{4-[(l-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amine Phenyl]}pyrimidin-2-yloxy)benzoic acid

Methyl 3-(5-bromopyrimidin-2-yloxy)benzoate (Org. Lett., 2009, 11, 2511) (148 mg) and Example (la) according to the same procedure as in Example (1c) The obtained compound (22 O mg) gave 222 mg (yield: 83%) as a white solid. From the bis-aryl compound (22 2 mg), m. *H NMR (400MHz, DMSO-d6): δ (ρ ρ m) = 1 3.2 ( 1 Η , brs), 1〇.5(1Η, s), 9.66(1Η, s), 9.01(2Η, s) , 8.64 (1Η, d, J = 6.6Hz), 8. 1 6-8 . 1 2( 1 Η, m), 8.04(1Η, d, J = 8.2Hz), 7.89(2Η, d, -40- 201124401 J = 8.6Hz), 7.8 9-7.8 5 (lH, m), 7.79(2H, d, J = 9.0Hz), 7.7 5 -7.7 3 (lH, m), 7.6 2 - 7.5 1 ( 3 H , m). MS(FAB) m/z: 5 47 (M + H) + ; m/z 5 8 5 (M + K) + . (Example 6) 3 - gas-4-(5-{4- [(lU than steep-2-yl-3-dimethylmethyl-1Η-indole Π -4-4_ carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid'

(6a) Methyl 4-(5-bromopyrimidin-2-yloxy)-3-fluorobenzoate according to the same procedure as in Example (lb), from 3-fluoro-4-hydroxy-benzoic acid methylacetic acid (J. Org. Chem., 1952, 17, 1 42 5 ) ( 984 mg), m. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.8 8 ( 2 Η , s), 7.90 (2H, dd, J = 9.0 and 9.0 Hz), 7.61 (1H, dd, J = 8.2 and 8.2 Hz), 3.89(3H, s). (6b) 3-Fluoro-4-(5-{4-[(pyridin-2-yl-3-trifluoromethyl-iH-pyrazole-4-carbonyl) Amino]phenyl}pyrimidin-2-yloxy)benzoic acid 4-(5-bromo-n-decyloxy)-3-win from Example (6a) according to the same procedure as in Example (1c) Methyl benzoate (23 mg) and the compound obtained from Example (1a) (3 2 3 mg) were obtained as a pale yellow solid bis aryl compound 3 2 1 mg. From the above, the bisaryl compound (3 2 ! m g ) was obtained from the titled compound 221 mg (56%). -4 1- 201124401 1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 1 3 .3 (1 Η, brs), 10.5 (1 Η, s), 9.66 (1 Η, s), 9.03 (2 Η, s), 8.64( 1 Η, d, J = 3. 1 Hz), 8.16-8.12(1H, m), 8.04(1H, d, J = 8.2Hz), 7.9 1 - 7.8 7 ( 4 H , m) , 7.80(2H, d, J = 8.6Hz), 7.6 3 - 7.5 6 (2 H , m). MS(FAB) m/z:565 (M + H)+; m/z 5 8 7 (M + K)+. HRMS m/z calcd for C27H17F4N604 5 6 5.1 2 47, found 5 6 5.1 2 5 0. (Example 7) 3 -Methyl-4-(5-{4-[(l-pyridine-2) -yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid

(7a) Methyl 4-(5-bromo-pyrimidin-2-yloxy)-3-methylbenzoate The same procedure as in Example (lb), from 4-hydroxy-3-methylbenzoic acid Organic &amp; Biomolecular Chemistry 2005, 3, 2271) (5.63 g), mp. *H NMR (400MHz, DMSO-d6): δ (p pm) = 8.8 3 (2 Η , s), 7.96 (1 Η, s), 7. 86 ( 1 Η, d, J = 9.0 Hz), 7.3 1(1Η, d, J = 8.6Hz), 3.86(3H, s), 2.16(3H, s). (7b) 3-Methyl 4-(5-{4-[(l-pyridine-2- Benzyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid-42- 201124401 According to the same method of the embodiment (1 〇), self-implementation Methyl 4-(5-bromo-pyrimidin-2-yloxy)-3-methylbenzoate (1 62 mg) obtained in Example (7a), and the compound obtained in Example (1a) (2 3 4 mg), There was obtained 264 mg (91%) of a colorless amorphous bisaryl compound. From the above, the bis aryl compound ( 264 mg), m. NMR (400MHz, DMSO-d6): δ (Ρ Ρ m) = l 2.9 (1 Η brs) 10·5(1Η, s), 9·66(1Η, s), 9.00(2Η, s),8· 63(1Η, d, J = 5.5Hz), 8. 1 6 - 8 . 1 2 (1 Η , m), 8.04(1Η, d, J = 8.2Hz), 7.9 5 - 7.8 5 ( 2 Η , m ), 7.89 (2Η, d, J = 9.0Hz), 7.78(2Η, d, J-9.0Hz), 7.5 9 - 7.5 6 ( 1 Η , m), 7.29(1 Η, d, J = 8.2Hz) , 2.18(3Η, s). MS(FAB) m/z:561 (M + H) + . HRMS m/z cal cd for C28 Hi 9F3N6〇4 56 1.1 498,found 5 6 1 .1 4 99. ( Example 8) [pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(2-phenoxypyrimidin-5-yl)phenyl]decylamine

The compound obtained from the 5-bromo-2-phenoxypyrimidine (Org. Lett., 2009, 11, 2 5 1 1 ) (1 27 mg) and the compound of the formula (la) according to the same procedure of Example (lc) The title compound I91 mg (75%) was obtained as a white solid. -43- 201124401 'H NMR (400MHz, DMSO-d6): δ (ppm) = 1 0.5 ( 1 Η , s), 9·66 (1Η, s), 8·98 (2Η, s), 8.64 (1Η ,d, J = 4.0Hz),8·14(1Η,dd, J = 7.8 and 7.8Hz), 8.04( 1 H, d, J = 7.8Hz), 7.8 9(2H , d, J = 8,6Hz ), 7.78(2H, d, J = 8.6Hz), 7.58(1H, dd, J = 7.2 and 4.9Hz), 7.48(2H, dd, J = 7.9 and 7.8Hz), 7.3 0( 1 H, d, J = 7.5 Hz), 7.26 (2H, d, J = 8.6 Hz). MS (FAB) m/z: 5 03 (M + H) + ; m/z: 541 (M + K) +, (Example 9) 4-(5-{4-[(l-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid

(9a) 4-(5-Bromopyrimidin-2-yloxy)-3-trifluoromethylbenzoic acid methyl ester according to the same procedure as in Example (lb), from 4-hydroxy-3-trifluoromethylbenzoic acid Methyl ester (Tetrahedron Letters 1 99 1, 3 2, 7525 ) ( 970 mg ) and 5-bromo-2-chloropyrimidine ( 853 mg) NMR (400MHz, CDC13): δ (ppm) = 8 · 6 0 (2 Η, s), 8.44 ( 1 Η, s), 8. 3 1 (1 Η, d, J-8.6Hz), 7.36(1 Η, d, J = 8 .3 Hz), 3.97(3H, s). -44- 201124401 (9b) 4·(5-{4-[(1-pyridin-2-yl-3-trifluoromethyl) -1H-pyrazole-4-hydroxy)amino]phenyl}pyrimidin-2-yloxy)-3·trifluoromethylbenzoic acid The same procedure as in Example (1c) was used to yield from Example (9a) Methyl 4-(5-bromopyrimidin-2-yloxy)-3-trifluoromethylbenzoate (215 mg) and the compound obtained in Example (1a) (2 6 5 mg) were pale gray ( 〇ff _ wh丨te ) Amorphous bisaryl compound 205 mg (56%). From the above, the bisaryl compound (250 g) was obtained. 1 Η NMR ( 4 0 0 Μ H z, DMS Ο - d 6 ): 6 ( ppm ) = 1 3 · 5 ( 1 Η, brs ), 10.5 (1H, s), 9.66 (1H, s), 9.05 ( 2H, s), 8.64 (1H, d, J = 4.0Hz), 8.3 3 - 8.2 3 (lH, m), 8.30(1H, s), 8. 1 7 - 8 . 1 2 (1 H , m) , 8.05(1H, d, J = 8.2Hz), 7.91(2H, d, J = 9.0Hz), 7.8l(2H, d, J = 9.0Hz), 7.68(1H, d, J = 8.6Hz), 7.6 0 - 7.5 6 ( 1 H , m). MS (FAB) m/z: 615 (M + H) + . (Example 1 〇) 2 - ( 5 - { 4 - [ (1 -pyridine· 2 - Methyl 3-trifluoromethyl·ih-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoate

F

Methyl 2·(5-bromopyrimidin-2-yloxy)benzoate (〇rg. Lett., 2009, 11, 2511) (260 mg) and the examples (in the same manner as in Example (1C) The title compound ( 489 mg (quantitative amount)) was obtained as a pale brown solid. -45- 201124401 1 Η NMR (4 0 0 Μ Η z , DMS Ο - d 6): (5 (ppm) = 1 0.5 (1 Η , s), 9.66 (1 H, s), 8.95 (2H, s ), 8.64( 1 H, d, J = 3,9Hz), 8.17-8.12(1H, m), 8.04(1H, d, J = 8.2Hz), 7.98(1H, dd, J = 7.8 and 1.9Hz) , 7.89(2H, d, J = 9.0Hz), 7.77(2H, d, J = 9.0Hz), 7.73(1H, dd, J = 7.4 and 2.0Hz), 7.58(1H, dd, J = 7.8 and 4.3 Hz), 7.45(1H, dd, J = 8.2 and 7.0Hz), 7.46(1H, d, J = 7.4Hz), 3.62(3H, s). MS(FAB) m/z:56 1 (M + H + ; m / z : 5 9 9 ( M + K) + (Example 11) 2 - ( 5 - { 4 - [ (1 -pyridine-2-yl-3-trifluoromethyl-1 H-pyridyl) Azole-4 -carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid

2 - ( 5 - { 4 - [(1 _pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidine 2 obtained from Example 1 Methyl benzoate benzoate ( 382 mg) ield: 1 Η NMR (4 0 0 Μ H z, DMS Ο - d 6 ): (5 (ppm) = 1 2.9 (1 Η, brs), 10.5 (1H, s), 9.66 (1H, s), 8.94 (2H , S), 8.64 (1H, d, J = 4.7Hz), 8.16-8.12(1H, m), 8.04(1H, d, J = 8,2Hz), 7.97(1H, dd, J = 7.8 and 1.9Hz ), 7.88 (2H, d, J - 8.6 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.70 (1H, dd, J - 8.6 and 7.0 Hz), 7.58 (1H, dd, J = 7.8 and -46- 201124401 5·5Ηζ), 7 · 42 (1 Η , dd, J = 8 · 0 and 7 · 2 Hz), 7.3 5 ( 1 Η, d, J = 9.0 Hz). MS(FAB) m/ z:5 47 (M + H) + ; m/z: 5 8 5 (M + K) + . (Example 1 2 ) 1-pyridin-2-yl-3-tris-methyl-1H-pyrazole -4-residual acid {4-[2-(4-tetramethyloxy)pyrimidin-5(yl)phenyl}decylamine

(12a) [4-(5-Bromopyrimidin-2-yloxy)phenyl]methanol according to the same procedure as in Example (lb), from 4-hydroxybenzyl alcohol (1.25 g) and 5-bromo-2-chloro Pyrimidine (1 · 9.5 g), mp EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) , d, J = 8.2Hz), 7.17(2Η, d, J = 8.6Hz), 5.21(1Η, t, J = 5.7Hz), 4.5 1 (2H, d, J = 5.8Hz). (12b) 1 -pyridine-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {4-[2-(4-hydroxymethylphenyloxy)pyrimidin-5-yl]phenyl}decylamine according to implementation Example (1c) In the same manner, [4-(5-bromopyrimidin-2-yloxy)phenyl]methanol (141 mg) obtained from Example (1 2 a) and the compound obtained in Example (1) The title compound 254 mg (96%) 〇-47-201124401 1 H NMR (400 MHz, DMSO-d6): δ (ρ ρ m) = 1 0.5 (1 Η, s), 9.66 (1 Η, s), 8.97(2Η, s), 8.64(1Η, d, J = 6.6Hz), 8.14(1Η, dd, J = 8.8 and 6.8Hz), 8.04(1H, d, J = 8.2Hz), 7.89( 2H, d, J = 8.6Hz), 7.77(2H, d, J = 8.6Hz), 7.58(1H, dd, J = 7.4 and 4.7Hz), 7.40(2H, d, J = 8.3Hz), 7.19( 2H, d, J = 8.6 Hz), 5.23 (1 H, t, J = 5.6 Hz), 4.53 (2H, d, J = 5.5 Hz). MS (FAB) m/z: 5 3 3 (M + H) + m/z: 571 (M + K) + . (Example 1 3 ) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(2'- P-tolylpyrimidine _5-yl)phenyl]decylamine

(13a) 5-bromo-2-P-tolylpyrimidine according to the same procedure as in Example (lb), from p-cresol (1.1 mL) and 5-bromo-2-chloropyrimidine (1.93 g) The title compound was obtained as a white solid, 2.49 g (94%). 'H NMR (400MHz, CDCl3): 5 (ppm) = 8.57 (2H, s), 7.24 (2H, d, J = 7.8 Hz), 7.07 (2H, d, J = 8,6 Hz), 2.38 (3H, s). (13b) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(2-p-tolylpyrimidin-5-yl)phenyl] The guanamine was obtained in the same manner as in Example (1c), from 5-bromo-2-P-tolylpyrimidine (136 mg) obtained from Example (1 3 a ) The title compound 170 mg (64%) was obtained as pale white. -48- 201124401 Η Ν Μ R (4 0 0 Μ Η ζ , D Μ S Ο - d 6 ): δ (ρ ρ m ) = 1 0 · 5 ( 1 Η, s ), 9.66(1Η, s), 8.97(2Η, s), 8.64(1Η, d, J = 4.7Hz), 8.14(1Η, dd, J = 9.4 and 7.8Hz), 8.04(1H, d, J = 8.2Hz), 7.89(2H, d , J = 8.6 Hz), 7.77 (2H, d, J = 8.7 Hz), 7.5 8 (1 H, dd, J = 8.0 and 5.3 Hz), 7.2 6 (2H, d, J = 8.2 Hz), 7. 1 2 (2H, d, J = 8.6 Hz), 2.34 (3H, s). MS (FAB) m/z: 5 1 7 (M + H) + . (Example 1 4 ) 1-pyridine-2- 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-(2-m-tolylpyrimidin-5-yl)phenyl]decylamine

(1 4 a ) 5-bromo-2- m-tolyloxypyrimidine according to the same procedure as in Example (lb), from m-cresol (1.lmL) and 5-bromo-2-chloropyrimidine (1.93 g), The title compound was 2.50 g (94%). lK NMR (400MHz, CDC13): ¢5 ( ρ pm ) = 8 . 5 8 ( 2 Η , s), 7.33 (1Η, t, J-7.6Hz), 7. 1 0(1 Η, d, J- 7.5 Hz), 7.00(1Η, s), 6.99( 1 Η, d, J = 8,6Hz), 2.39(3Η, s). (14b ) 1-pyridin-2-yl-3-trifluoromethyl- 1Η-pyrazole-4-carboxylic acid [4-(2-m-tolylpyrimidin-5-yl)phenyl]decylamine-49- 201124401 The same procedure as in Example (1 c), from Example (14a) The obtained 5-bromo-2-m-tolylpyrimidine (137 mg) was obtained from the title compound (237 mg) 1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 1 0.5 (1 Η, s), 9.67 (1 Η, s), 8.98 (2 Η, s), 8.64 (1 Η, d, J = 4.7 Hz) , 8.15 (1Η, dd, J = 7.8 and 7.8Hz), 8.05(2H, d, J = 7.8Hz), 7.90(2H, d, J = 9.0Hz), 7.78(1H, d, J = 8,6Hz ), 7.5 8 ( 1 H, dd, J = 7.2 and 4.9 Hz), 7.35 (1H, dd, J = 7.7 and 7.7 Hz), 7.1 1 - 7.0 3 (3 H, m), 2.35 (3H, s) MS(FAB) m/z: 517 (M + H) +, (Example 1 5 ) pyridine-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4-( 2-0-tolylpyrimidin-5-yl)phenyl]decylamine

(15a) 5-bromo-2-0-tolylpyrimidine according to the same procedure as in Example (lb), from hydrazine-cresol (1.lmL) and 5-bromo-2-chloropyrimidine (1.93 g) The title compound of the solid 2.56g (97%) 〇1H NMR (400MHz, CDC13): δ (ρ ρ m) = 8 . 5 6 (2 Η , s), 7.3 1-7.1 9(3Η, m), 7.10 (1Η, d, J = 7.9Hz), 2.18(3Η, s). -50- 201124401 (15b ) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [ 4-(2-indole-tolylpyrimidin-5-yl)phenyl]decylamine 5-bromo-2-0-toluene obtained from Example (15 a) according to the same procedure of Example (1c) The title compound (104 mg (40%)) 1 H NMR (400 MHz, DMSO-d6): δ (ppm) = l 0.5 (1H, s), 9.66 (1 H, s), 8.97 (2 Η, s), 8.64 (1 Η, d, J = 5 8 Η ζ ),8 · 1 5 ( 1 Η, dd , J-8.2 and 7.4 Hz), 8.04 (1H, d, J = 8.2 Hz), 7.89 (2H, d, J = 8.6 Hz), 7.77 (2H , d, J = 9.0Hz), 7.5 8 (1 H, dd, J = 7.6 and 5.3Hz), 7.3 5 (1 H, d, J-6.6Hz), 7.29 ( 1 H, dd, J = 9.0 and 7.5 Hz), 7.23-7. 1 5(2H, m), 2.12(3H, s). MS(FAB) m/z: 517 (M + H) + . (Example 1 6 ) 3,5- Methyl-4-(5-{4-[(1-pyridin-2-yl-3-trifluoromethyl-111-pyrazole-4-ylcarbonyl)amino]phenyl}pyrimidin-2-yloxy )benzoic acid

(16a) 4-(5-Bromo-pyrimidin-2-yloxy)-3,5-dimethylbenzoic acid methyl ester The same procedure as in Example (lb), from 4-hydroxy-3,5-dimethyl Methyl benzoate (J. Med. Chem., 2 008, 51, 183) (1.81 g) and 5-201124401 bromo-2-chloropyrimidine (1.92 g) gave the title compound as a pale yellow solid. 3. llg (93%). 'H NMR (400MHz, CDC13): δ (ppm) = 8.5 6 (2 Η , s), 7.84 (2H, s), 3.91 (3H, s), 2.17 (6H, s). MS(FAB) m/ z:3 3 7 (M + H) + ; m/z: 3 7 5 (M + K) + . (16b) 3,5-dimethyl-4-(5-{4-[(1-pyridine) 2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid The same procedure as in Example (1c), from Example (1 6 a ) The obtained methyl 4-(5-bromo-pyrimidin-2-yloxy)-3,5-dimethylbenzoate (167 mg) and the compound obtained in Example (1 a ) (2 2 ) 9 mg ) gave 256 mg (88%) of a colorless amorphous bisaryl compound. From the above, the bisaryl compound (256 mg) was obtained from the titled compound (yield: EtOAc (d): (1 Η , brs), 1 Ο . 5 (1 Η , s), 9.66 (1Η, s), 8.98 (2Η, s), 8.64 (1Η, d, J-3.9Hz), 8. 1 4 ( 1 Η, dd, J = 8 . 8 and 6.8 Hz), 8.04 ( 1 H, d, J = 8, 2 Hz), 7.89 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 7. 1 Hz), 7.77(2H, s), 7.58(1H, dd, J = 7.4 and 4.7Hz), 2. 1 3(6H, s). MS(FAB) m/z:5 7 5 (M + H + ; m / z: 613 (M + K) + . (Example 1 7 ) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {4-[2 -(4-cyanophenoxy)-pyrimidin-5-yl]phenyl}decylamine-52- 201124401

According to the same procedure as in Example (1c), from 4-(5-bromo-pyrimidin-2-yloxy)benzonitrile (Org. Lett., 2009, 11, 2511) (139 mg) and Example (la) The title compound (22 9 mg) wasield 1 H NMR (400 MHz, DMSO-d6): δ ( ρ ρ m ) = 1 0.5 ( 1 Η , s), 9.66 ( 1 Η , s), 9.04 (2 Η, s), 8.64 ( 1 Η, d, J = 5 · 4 Η ζ ), 8 · 1 4 ( 1 Η, dd, J = 8.8 and 6.8 Hz), 8.04 (1 H, d, J = 8, 2 Hz), 7,97 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz), 7.8 0 (2H, d, J = 8, 6 Hz), 7.58 (1 H, dd, J = 8. 2 and 4.7 Hz), 7.51 (2H) , d, J = 9.0 Hz). MS (FAB) m/z: 5 2 8 (M + H) + ; m/z: 5 6 6 (M + K) +. (Example 1 8) 2-chloro -4-(5-{4-[(l-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole- 4-

Methyl carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoate F

(18a) Methyl 4-(5-bromo-pyrimidin-2-yloxy)-2-chlorobenzoate. Methyl 2-chloro-4-hydroxybenzoate according to the same procedure as in Example (lb) (W0 2006004200 (4_29g) and 5-bromo-2-chloropyrimidine (4.46g) were obtained as the title compound (yield: quantitatively). -53- 201124401 H NMR (400MHz, CDCl3): δ (ppm) = 8.60(2H, s), 7.95(2H,d,J = 8.6Hz),7·33(1Η,d,J = 2.0Hz), 7. 1 6 (1 H, dd, J = 8.6 and 2.4 H z ), 3.9 4 ( 3 H , s ). (18b) 2 -chloro- 4- (5-{4-[(l-pyridine-2) -methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid methyl ester according to the same procedure as in Example (1c), from Example (1 8 a ) Compound ( 172 mg) Compound Compound Compound Compound Compound Compound 1 H NMR (400 MHz, DMSO-d6): δ (ppm) = 1 0.5 (1 Η, s), 9.67 (1 Η, s), 9.05 (2 Η, s), 8 · 6 4 (1 Η, d, J = 4 · 7 Η ζ ), 8. 1 5 (1 Η, dd, J = 8.6 and 7.0 Hz), 8.05 ( 1 H, d, J = 8.6 Hz), 7.96 (1 H, d, J = 8.6 Hz), 7.91(2H, d, J-8.6Hz), 7.81(2H, d, J = 8.6Hz), 7.64(1H, d, J = 2.4Hz), 7.59(1 H, dd, J = 4.9 and 3,3 Hz), 7.4 1 (1 H, dd, J = 8.6 and 2, 4 Hz), 3 .89 (3H, s). MS (FAB) m/z: 5 9 5 (M + H) + ; m /z: 617 (M + Na) + ; m/z: 633 (M + K) + . (Example 1 9 ) 4_(5_{4-[(l-pyridin-2-yl-3-trifluoromethyl) 2-H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid 2-hydroxyethyl ester

54-201124401 (19a) 2-Hydroxyethyl 4-(5-bromo-pyrimidin-2-yloxy)benzoate 2-hydroxyethyl 4-hydroxybenzoate (1.82) g), 5-bromo-2-chloropyrimidine (1.93 g). 1 H NMR (400 MHz, DMSO-d6): δ (ρ ρ m) = 8.8 6 (2 Η , s), 8.08 (2 Η, d, J = 8.6 Hz), 7.40 (2 Η, d, J = 9.0 Hz) , 4.94 (1Η, t, J = 5.9Hz), 4.30(2H, t, J = 4.9Hz), 3.71(2H, dt, J = 5.2 and 5.1Hz). (19b) ( 4-(5-{4 -[(l-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole•4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid 2-hydroxyethyl ester according to implementation Example (1c) The title compound (191 mg (65%) Compound Compound Compound Compound Compound Compound Compound H NMR (400MHz, DMSO-d6): δ (ρ pm) = 1 〇. 5 (1 Η , s), 9· 67( 1 Η, s), 9.04(2Η , s), 8.64( 1 Η, d , J = 6.7Hz), 8.17-8.04(1Η, m), 8.11(2Η, d, J = 8.6Hz), 7.91(2Η, d, J = 9.0Hz), 7.80(2Η, d, J = 8.6Hz ), 7.6 6 - 7.5 4 (2 Η , m), 7.42 (2Η, d, J = 9.0Hz), 4.96(1H, t, J = 5.6Hz), 4.31(2H, t, J = 4.9Hz), 3.73 (2H, dt, J = 5.2 and 5.0 Hz). MS (FAB) m/z: 591 (M + H) + . (Test Example 1) (1) Preparation of DGAT1 enzyme according to US 2 007/0249620 Prepare and save DGA in the method described in the bulletin T1 enzyme. -55- 201124401 (2) DGAT1 inhibitory activity test The following composition of the reaction solution (175 mM tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl) (pH 8.0), 8 mM magnesium dichloride (MgCl2) , lmg/ml bovine serum albumin (BSA), 0.3 mM 1,2-dioleoyl-sn-glycerol (add 10% 10 times ethanol) (EtOH) solution), lO/zMfMC] - oleoyl-coenzyme A ([14C]-oleoyl-CoA) (about 50 mCi/mmol), 0.5% triton X-100, DGAT1 enzyme obtained in Test Example 1 (1) (10 // g), test compound or vehicle (dimethyl sulfoxide (DMSO) / methanol (MeOH), 7:3 solution, 5% Addition □); total volume 50 //1) Incubate for 30 minutes at room temperature (23 ° C). The reaction solution was added with isopropanol / 1-heptane / water (80:20:2 (v / v / v)) to stop the reaction solution (70 Μ Ο and stirred. Second, add water (30 &quot; 1 And 1-heptane (100 //1) and stirred. The 1-heptane layer (50^/1) was added to the TLC plate and was taken in 1-hexane/diethyl ether/acetic acid (85:15) : 1 ( ν / ν / ν )) is developed in the developing solvent. The radiation of the triglyceride fraction is performed by the BAS2000 Bio-imaging analyzer (Fujifilm). The activity was quantified, and the inhibitory activity of the test compound was calculated according to the following formula by comparison with the control group. The radioactivity of the unreacted (cultured for 0 minutes) was used as the background . Inhibition rate = 1 0 0 — [(radioactive activity when test compound is added)_ (background 値)] / [(radiation activity of control group) - (background 値)] x 1 〇〇-56- 201124401 Examples 1 to 1 〇 and 1 2 to 1 The compound of 8 showed an inhibition rate of 50% or more at a concentration of the test compound of 1 // g/ml. The 'DG AT inhibitory activity test is not limited to the above method, and may be adjusted. The small intestine, adipose tissue or hepatic microsomes of animals such as rats, mice, etc. are used as DGAT enzymes. Alternatively, they can be formulated from cultured cells (3T3-L1 fat cells, primary cultured adipocytes, Caeo2 cells). Microparticles of cultured cells with high expression of DGAT, etc., are used as DG AT enzymes. Further, in order to evaluate a large number of test compounds with good efficiency in a short time, a flat-plate filter plate with an extraction operation may be used ( Flush plate) (3⁄4 perkinElmer). According to the above results, the compound of the present invention has excellent DGAT 1 inhibitory biological activity. (Test Example 2) DGAT 1 enzyme is important for the digestion and absorption of neutral fat. If the small intestine DG AT 1 is inhibited, the absorption of neutral fat will be inhibited. The neutral fat absorption inhibition after neutral fat loading is used as an indicator to evaluate the biological activity of DGAT 1 inhibition. 5 7 BL/ 6 N male mice (7 - 12 weeks old, body weight 17-25 g, Japan Charles River) were divided into carrier group 1, carrier group 2 and each test compound group. And each of the test compounds (1% to 1 〇mg/kg) was orally administered (5 mL/kg) carrier (0.5% methylcellulose (Methylcellulose)) or suspended in the carrier, and administered intraperitoneally after a fixed time ( 5mL/kg) lipoprotein iipase inhibitor (Pluronic-F127: Sikma Erdish-57-201124401 (Sigma-Aldrich Corporation), lg/kg, dissolved in physiological weight at 20% by weight Saline solution), then immediately administered to vehicle group 1 orally (〇.2m L/mouse) distilled water; carrier group 2 and compound group were administered orally (〇.2mL/mouse) containing 20% neutral fat Emulsion (emu 1 si ο η ) (intralipid 20%: Terumo). After a fixed time of 1 to 4 hours after administration, blood was collected from the tail vein or the right ventricle, and plasma was quickly separated and recovered, and a commercially available kit (Triglyceride E-Test Wako) was used. Wako Pure Chemical Industries, Ltd.) measures the concentration of neutral fat in plasma. In this method, due to the administration of lipoprotein lipase inhibitors, the decomposition of neutral fat into the blood is inhibited. Although the neutral fat accumulates in the blood, the source is divided into two in the digestive tract. An intrinsic person released from the liver. The neutral fat absorption inhibitory activity of each test compound was calculated by removing the influence of the endogenous neutral fat according to the following formula. Further, it was confirmed that each test compound did not affect the endogenous neutral fat concentration. Neutral fat absorption inhibitory activity (%) = 1 00 - [(neutral fat concentration in each test compound group) 1 (carrier group 1 neutral fat concentration)] / [(carrier group 2 neutral fat concentration) - (Carbide group 1 neutral fat concentration)] X100 The compounds of Examples 1, 3, 4, 6, 7, 9, and 18 showed an inhibition of neutral fat absorption of 60% or more at a dose of 3 mg/kg or less. active. -58- 201124401 (Test Example 3) C57BL/6N male mice (7-12 weeks old, body weight i7_25 g, Japan Charles River) were individually raised 'with fat diet (fat content 45 kcal%: 硏Research Diets, Inc. 〇1 245 1 ) Domesticated for more than 1 week. According to the amount of food during the period, the animals were evenly distributed to the experimental group 'after one night of fasting', the carrier (〇. 5 % methylcellulose) or the test compound suspended in the carrier (1 〇mg/kg) was orally administered. Pre (丨0mL/kg) each group. After 30 minutes, the high-fat diet was fed and the amount of food consumed 6 hours after the start of feeding was measured. The feeding inhibitory activity of each test compound was calculated according to the following formula. Ingestion-inhibiting activity (%) = [(the amount of the food in the carrier group) - (the amount of the food in each test compound group)] / [(the amount of the food in the carrier group)] X 1 0 0 The compound of Example 1 in l〇mg At a dose of /kg, it showed more than 25% of the food suppressing activity. According to the above results, the compound of the present invention has an excellent food suppressing action. Further, the high fat feed used for the feed is not limited to the above high fat feed, and for example, a rodent feed containing 45 to 60% of calories of neutral fat can be used. -59- 201124401 Formulation Example 1: Capsules Compound of Example 1 or 2 5 0 mg Lactose 1 2 8 mg Corn starch 70 mg Magnesium stearate _ — — ~ — — — _ _ — _ _ — — _ — — _ 2mg 2 5 0 mg The powder of the above formulation was mixed and sieved through a mesh of 60 mesh. This powder was placed in a 25 Omg gelatin capsule to make a capsule. Formulation Example 2: Lozenge Compound of Example 1 or 2 5 0 Lactose 1 2 6 mg Corn starch 2 3 mg Magnesium stearate*^ _ _ — _ — — _ _ _ _ _ 1 mg 2 0 0 mg The powder of the above prescription was mixed, granulated with corn starch paste, dried, and then tableted by a tableting machine to prepare a tablet of 200 mg in one tablet. This tablet can be applied to the sugar coating as necessary. INDUSTRIAL APPLICABILITY The compound of the present invention having a general formula ( Ϊ) or a pharmacologically acceptable salt thereof has excellent DGAT inhibition and food intake inhibition, and can be used as a pharmaceutical product - 60-201124401 [Simple diagram Description] 〇【Main component symbol description】 〇/\w -6 1

Claims (1)

201124401 VII. Scope of application for patents: A compound having the following general formula (a compound of hydrazine or a pharmaceutically acceptable salt thereof, R, (wherein R represents 1 to 3 independently selected from a halogen atom, a Cl-C6 alkyl group, a C^-C:6 halogenated alkyl group, a hydroxymethyl group, a cyano group, a carboxyl group, or a carboxymethyl group. , ere? alkoxycarbonyl and a phenyl group substituted by a c2-C7 hydroxyalkyloxycarbonyl group. 2) A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R is 1 or 2 a phenyl group independently substituted with a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a carboxyl group, and a carboxymethyl group. 3. A compound according to claim 1 or a pharmacologically acceptable salt thereof R is 4-carboxyphenyl, 4-carboxy-2-fluorophenyl, 4-carboxy-2-chlorophenyl, 4-carboxy-2-tolyl, 4-carboxy-2-trifluoromethylphenyl or 4- Carboxymethyl-2-chlorophenyl 4. A compound of the general formula (I) or a pharmacologically acceptable salt thereof, which is [3-chloro-4-(5-{4-[(l- Pyridine-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)phenyl]acetic acid, 3-chloro-4 - (5- { 4 - [( 1 -Pyridin-2-yl-3-trifluoromethyl-1 Η-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzoic acid, -62-201124401 4-(5-{4-[(l-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2-yloxy)benzene Formic acid, 3-fluoro-4-(5-{4-[(l-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl)amino]phenyl}pyrimidin-2- Benido)benzoic acid, 3-methyl-4-(5-{4-[(l-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-decyl)amino] Phenyl}Il·Ment-2-yloxy)benzoic acid, or 4-(5-{4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4) -carbonyl)amino]phenyl}pyrimidin-2-yloxy)-3-trifluoromethylbenzoic acid. 5.--Kryptomase A: inhibition of diacylglycerol acyltransferase An agent comprising a compound selected from any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, as an active ingredient. 6. Ingestion inhibitor and/or appetite suppressant, which comprises A compound selected from any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, as an active ingredient. 7. A pharmaceutical composition comprising a component selected from the first to fourth aspects of the patent application. Any one The compound or a pharmacologically acceptable salt thereof is used as an effective ingredient. 8 A pharmaceutical composition according to claim 7 of the patent application, which has an inhibitory effect of 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase. 9. A pharmaceutical composition as claimed in claim 7 which has a food suppressing action and/or an appetite suppressing action. -63- 201124401 1 〇. The pharmaceutical composition according to claim 7 of the patent application, which is used for inhibiting the synthesis of 醯Kystase A: dimercaptoglycerol thiol transferase, inhibiting the synthesis of triglyceride, Inhibition of the absorption of triglycerides, the treatment and/or prevention of conditions in which the symptoms are treated, ameliorated, alleviated and/or prevented. 1 1. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition is used for treating symptoms by inhibiting the synthesis of 醯Kystase A: dimercaptoglycerol thiol transferase and inhibiting the synthesis of triglyceride Treatment, and/or prevention of diseases that improve, alleviate and/or prevent. 1 2 · The pharmaceutical composition of claim 7 is for use in obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and abnormal glucose tolerance , diabetes, diabetes mellitus (including diabetic neuropathic disorders, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, Treatment and/or prevention of atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease and overeating. A pharmaceutical composition according to claim 7 for use in the treatment and/or prevention of obesity or obesity. I4. The pharmaceutical composition of claim 7, which is for use in the treatment and/or prevention of diabetes. The use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition. -64- 201124401 1 6 . For the use of Article 15 of the patent application, the pharmaceutical composition is used for obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome , abnormal sugar tolerance, diabetes, diabetes mellitus (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy) 'cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic Treatment and/or prevention of ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease and overeating. A method for treating and/or preventing a disease, which comprises administering to a warm-blooded animal a pharmacologically effective amount of a compound selected from any one of claims 1 to 4 or a pharmacologically acceptable salt thereof. . 1 8 · The method of claim 17th, wherein the diseases are obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes Autism (including diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, Atherosclerosis, diabetic atherosclerosis, ischemic heart disease, and overeating. 1 9. The method of claim 17 or claim 18, wherein the warm-blooded animal is a human. -65- 201124401 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None 0. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R (I)