WO2011078102A1

WO2011078102A1 - Novel phenoxypyrimidine derivative

Info

Publication number: WO2011078102A1
Application number: PCT/JP2010/072848
Authority: WO
Inventors: 芳一宇都
Original assignee: 第一三共株式会社
Priority date: 2009-12-22
Filing date: 2010-12-20
Publication date: 2011-06-30
Also published as: TW201124401A

Abstract

Disclosed is a compound having an excellent DGAT-inhibiting activity and an excellent anti-feeding activity, or a pharmacologically acceptable salt thereof. Specifically disclosed is a compound represented by general formula (I) [wherein R represents a phenyl group that may be substituted by 1 to 3 groups independently selected from a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ halogenated alkyl group, a hydroxymethyl group, a cyano group, a carboxyl group, a carboxymethyl group, a C₂-C₇ alkoxycarbonyl group and a C₂-C₇ hydroxyalkoxycarbonyl group] or a pharmacologically acceptable salt thereof.

Description

New phenoxypyrimidine derivatives

The present invention relates to a compound having a specific chemical structure having an excellent acyl coenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibitory action and an excellent antifeedant action, or a pharmacologically Relates to acceptable salts.

In obesity, triglyceride (triacylglycerol or triglyceride, hereinafter also referred to as TG) accumulates in adipocytes due to the persistence of excess energy compared to energy consumption, resulting in standard weight gain. It is in a state of significantly increasing compared to body weight (Non-Patent Document 1). Obesity is hyperlipidemia, hyperTGemia, diabetes, hypertension, lifestyle-related diseases such as arteriosclerosis, cerebrovascular disorder, coronary artery disease, respiratory abnormalities, low back pain, knee osteoarthritis, gout, cholelithiasis, etc. Any obesity that has these complications or that may cause these complications in the future is defined as obesity and is treated as a disease.

Animals and plants store lipid as insoluble TG, and decompose TG as necessary to produce energy. TG ingested by the meal is broken down into free fatty acids and monoacylglycerol by the action of bile acids and pancreatic lipase in the lumen of the small intestine. Micelles composed of free fatty acid, monoacylglycerol and bile acid are absorbed into small intestinal epithelial cells, and in the endoplasmic reticulum by the action of acylcoenzyme A synthase (hereinafter referred to as ACS), acylcoenzyme A: monoacylglycerol acyltransferase and DGAT. TG is newly synthesized. TG, in combination with phospholipids, cholesterol and apolipoprotein, is secreted into the gastrointestinal lymphatic vessels as kilomicrons. Furthermore, TG is secreted into the blood via the lymph main duct and transported to the periphery for use. On the other hand, in adipose tissue, TG is synthesized from glycerol 3-phosphate and free fatty acids by the action of ACS, glycerol 3-phosphate acyltransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-patent Document 2). Thus, TG ingested excessively accumulates in adipose tissue, resulting in obesity.

DGAT is an enzyme that is present in the endoplasmic reticulum in the cell and catalyzes the most important final step reaction in the TG synthesis pathway, that is, the reaction of transferring the acyl group of acylcoenzyme A to the 3-position of 1,2-diacylglycerol. (Non-Patent Documents 3 to 5). It has been reported that DGAT has two types of isozymes DGAT1 (Non-patent document 6) and DGAT2 (Non-patent document 7). Since DGAT1 is highly expressed in the small intestine and adipose tissue, and DGAT2 is highly expressed in the liver and adipose tissue, DGAT1 is mainly used for fat absorption from the small intestine and fat accumulation in the adipose tissue, and DGAT2 is used for TG synthesis or VLDL in the liver. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue. Although the difference in the roles of DGAT1 and DGAT2 has not yet been clarified in detail, the relationship between DGAT and obesity, lipid metabolism, sugar metabolism, etc. has been suggested (Non-patent Document 8). DGAT is a key enzyme for TG synthesis in gastrointestinal epithelial cells and adipose tissue, and a drug that inhibits DGAT suppresses fat absorption in the gastrointestinal tract and fat accumulation in adipose tissue by suppressing TG synthesis, and obesity , Obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, diabetes, non-alcoholic steatohepatitis, or obesity-induced hyperlipidemia, hypertriglyceridemia, lipid metabolism It is expected to be useful as a therapeutic or prophylactic agent for abnormal diseases, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, hypertension, arteriosclerosis, cerebrovascular disorder, coronary artery disease, etc. 9 to 13).

An appetite suppressant directly or indirectly regulates the appetite control system, but its mechanism of action is roughly divided into central and peripheral. An appetite suppressant acting centrally acts on the hypothalamic nervous system where the feeding center and satiety center exist and the monoamine nervous system in the brain that regulates the nervous system, thereby directly suppressing appetite. On the other hand, an appetite suppressant that acts on the periphery acts on a mechanism that senses and transmits the intake of nutrients and the accumulation of surplus energy, and indirectly suppresses appetite.

In recent years, gastrointestinal hormones (CCK, GLP-1, PYY, etc.) secreted in close association with the digestion and absorption of food (Non-Patent Document 14) and from fat cells according to the energy accumulation (fat mass) The mechanism by which secreted leptin (Non-patent Document 15) or the like transmits a signal that regulates appetite from the periphery to the center in a hormonal or neurological manner has been clarified. These new appetite suppressants associated with peripheral signals are expected to be more effective and less effective for the treatment of obesity.

As a compound having a structure similar to the compound of the present invention, Patent Document 1 discloses cyclohexyl having a substituent on (1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group. A compound in which a carbonylamino group is bonded via an ethylene bond (Example E150) etc. and their use as DGAT inhibitors are described. On the other hand, in the compound of the present invention, a phenyl group having a substituent is directly bonded to the (1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group. In Patent Document 2, a phenyl group is substituted on the pyrazole ring side of the 3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group, and a carboxyl group is formed on the amino group side through two aromatic rings. Bound compounds (compound no. 70) etc. and their use as DGAT inhibitors are described. On the other hand, in the compound of the present invention, a pyridyl group is substituted on the pyrazole ring side of the 3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group, and two amino rings and phenoxy ether are introduced on the amino group side. And a substituent such as a carboxyl group is bonded. Patent Document 2 discloses a compound having a substituted piperidine ring at the 4-position of the benzene ring of [(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] phenyl group ( Compound No. 75) etc. and their use as DGAT inhibitors are described. On the other hand, the compound of the present invention has a substituted pyrimidine ring at the 4-position of the benzene ring of the [(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] phenyl group. Yes. In Patent Document 3, a cycloalkylmethyl group having a carboxyl group is substituted on the oxygen atom side of the 5- [4- (carbonylamino) phenyl] pyrimidin-2-yloxy group, and the carbonyl group side has a substituent. Compounds with substituted phenyl groups (Compound No. 405) and their use as DGAT inhibitors are described. On the other hand, in the compound of the present invention, a phenyl group having a substituent on the oxygen atom side of the 5- [4- (carbonylamino) phenyl] pyrimidin-2-yloxy group is substituted, and 1-pyridine-2- The yl-3-trifluoromethyl-1H-pyrazole group is substituted.

WO2008 / 011130 WO2008 / 141976 WO2009 / 011285

As a result of intensive studies on compounds having a DGAT inhibitory action and an antifeedant action, the inventors have found that a compound having a specific chemical structure has an excellent DGAT inhibitory action, particularly high for DGAT1. It was found to have an inhibitory effect. The present inventors have also found that this compound has an excellent antifeeding action. Furthermore, the present inventors have found that this compound is obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral Neuropathy, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic Hyperlipidemia, hypertriglyceridemia, lipid metabolism resulting from obesity or as an active ingredient of a medicament for the prevention and / or treatment of a disease selected from the group consisting of arteriosclerosis, ischemic heart disease and bulimia Abnormal diseases, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, Gynecologic diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformity It was found useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of knee arthropathy, gout, and cholelithiasis.

The present invention comprises (1) general formula (I)

[Where:
R represents a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a hydroxymethyl group, a cyano group, a carboxyl group, a carboxymethyl group, a C ₂ -C ₇ alkoxycarbonyl group and a C _2- group. A phenyl group which may be independently substituted with 1 to 3 groups independently selected from a C ₇ hydroxyalkoxycarbonyl group. Or a pharmacologically acceptable salt thereof.

In the present invention, preferably,
(2) In (1),
A compound in which R is a phenyl group independently substituted with one or two groups selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a carboxyl group, and a carboxymethyl group, or a pharmacologically acceptable salt thereof. Salt.

(3) In (1),
R is 4-carboxylphenyl group, 4-carboxyl-2-fluorophenyl group, 4-carboxyl-2-chlorophenyl group, 4-carboxyl-2-methylphenyl group, 4-carboxyl-2-trifluoromethylphenyl group or A compound having a 4-carboxymethyl-2-chlorophenyl group or a pharmacologically acceptable salt thereof.

(4) A compound having the general formula (I)
[3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) phenyl] acetic acid ,
3-chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
3-fluoro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
3-methyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid, or ,
4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid Or a pharmacologically acceptable salt thereof.

(5) A compound having the general formula (I)
[3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) phenyl] acetic acid ,
3-chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
3-fluoro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
3-methyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid, or ,
4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid A compound that is

(6) An acyl coenzyme A: diacylglycerol acyltransferase inhibitor containing the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof as an active ingredient.

(7) An eating inhibitor and / or an appetite suppressant containing 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 as an active ingredient the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof.

(9) The pharmaceutical composition according to (8), wherein the pharmaceutical composition has an acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.

(10) The pharmaceutical composition according to (8), wherein the pharmaceutical composition has an antifeedant action and / or an appetite suppressive action.

(11) The pharmaceutical composition according to (8), for treating and / or preventing a disease wherein the pharmaceutical composition is treated and / or prevented by acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.

(12) The pharmaceutical composition according to (8), wherein the pharmaceutical composition is used for treatment and / or prevention of a disease caused by an increase in acylcoenzyme A: diacylglycerol acyltransferase activity.

(13) The pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby treating, improving, reducing and / or preventing symptoms. (8) The pharmaceutical composition for treatment and / or prevention of a disease.

(14) The pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase and inhibits the synthesis of triglyceride, thereby treating and / or treating diseases in which symptoms are treated, ameliorated, reduced and / or prevented. The pharmaceutical composition according to (8) for prevention.

(15) The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceride disease, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The pharmaceutical composition according to (8) for the treatment and / or prevention of blood heart disease or bulimia.

(16) The pharmaceutical composition according to (8), wherein the pharmaceutical composition is for the treatment and / or prevention of obesity or obesity.

(17) The pharmaceutical composition according to (8), wherein the pharmaceutical composition is for the treatment and / or prevention of diabetes.

(18) When the pharmaceutical composition is obesity-induced hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension (8) The pharmaceutical composition for treatment and / or prevention of symptom, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormality, low back pain, knee osteoarthritis, gout or cholelithiasis.

(19) The pharmaceutical composition according to (8), wherein the pharmaceutical composition is for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(20) The pharmaceutical composition according to (8), wherein the pharmaceutical composition suppresses fat absorption from the small intestine.

(21) Use of the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.

(22) The use according to (21), wherein the pharmaceutical composition is a composition for inhibiting acylcoenzyme A: diacylglycerol acyltransferase.

(23) The use according to (21), wherein the pharmaceutical composition is a composition for suppressing eating and / or appetite.

(24) The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The use according to (21), which is a composition for the treatment and / or prevention of blood heart disease or bulimia.

(25) The use according to (21), wherein the pharmaceutical composition is a composition for the treatment and / or prevention of obesity or obesity.

(26) The use according to (21), wherein the pharmaceutical composition is a composition for treating and / or preventing diabetes.

(27) Hyperlipidemia, hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic kidney) , Including diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension The use according to (21), which is a composition for the treatment and / or prevention of cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis.

(28) The use according to (21), wherein the pharmaceutical composition is a composition for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(29) The use according to (21), wherein the pharmaceutical composition is a composition for suppressing fat absorption from the small intestine.

(30) Acyl coenzyme A: diacylglycerol for administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof Acyltransferase inhibition method.

(31) Inhibition of feeding and / or administration of a pharmacologically effective amount of the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof to a warm-blooded animal Appetite suppression method.

(32) Treatment of diseases and / or diseases in which a pharmacologically effective amount of the compound described in any one of (1) to (5) or a pharmaceutically acceptable salt thereof is administered to a warm-blooded animal Prevention method.

(33) The disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy) , Including diabetic retinopathy, diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart The method according to (32), which is a disease or bulimia.

(34) The method according to (32), wherein the disease is obesity or obesity.

(35) The method according to (32), wherein the disease is diabetes.

(36) Hyperlipidemia caused by obesity, hypertriglyceridemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, brain (32) The method according to (32), which is vascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis.

(37) The method according to (32), wherein the disease is hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(38) Absorption of fat from the small intestine in which a pharmacologically effective amount of the compound described in any one of (1) to (5) or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal. How to suppress.

(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 an iodine atom. Preferable is a fluorine atom or a chlorine atom.

In the present invention, the “C ₁ -C ₆ alkyl 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 group, suitable Is a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ -C ₄ alkyl group), more preferably a methyl group or an ethyl group (C ₁ -C ₂ alkyl group). And even more preferred is a methyl group.

In the present invention, the “C ₁ -C ₆ halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₆ alkyl group”. For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl or 2- A fluoroethyl group, and preferably a group (C ₁ -C ₄ halogenated alkyl group) in which the same or different 1 to 5 “halogen atoms” are bonded to the “C ₁ -C ₄ alkyl group”. More preferably, the same or different 1 to 5 “halogen atoms” are groups (C ₁ -C ₂ halogenated alkyl groups) bonded to the “C ₁ -C ₂ alkyl group”, More preferably, it is a trifluoromethyl group.

In the present invention, the “C ₂ -C ₇ alkoxycarbonyl group” is a group in which one oxygen atom bonded to the “C ₁ -C ₆ alkyl group” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group, preferably one of the above-mentioned “C ₁ -C ₄ alkyl” A group (C ₂ -C ₅ alkoxycarbonyl group) in which an oxygen atom to which a group is bonded is bonded to a carbonyl group, and more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C ₂ -C ₃ alkoxycarbonyl group) And even more preferred is a methoxycarbonyl group.

In the present invention, the “C ₂ -C ₇ hydroxyalkoxycarbonyl group” is a group in which one hydroxy group is bonded to the “C ₁ -C ₆ alkyl group” of the “C ₂ -C ₇ alkoxycarbonyl group”. . For example, 1-hydroxymethoxycarbonyl, 2-hydroxyethoxycarbonyl, 1-hydroxyethoxycarbonyl or 3-hydroxypropoxycarbonyl group, preferably “C ₁ -C ₃ ” of the above “C ₂ -C ₃ alkoxycarbonyl group” ₂ alkyl group ”is a group in which one hydroxy group is bonded (C ₂ -C ₃ hydroxyalkoxycarbonyl group), more preferably a 2-hydroxyethoxycarbonyl group.

In the present invention, “halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenated alkyl group, hydroxymethyl group, cyano group, carboxyl group, carboxymethyl group, C ₂ -C ₇ alkoxycarbonyl group and C _A phenyl group which may be independently substituted with 1 to 3 groups independently selected from a group selected from _2- C ₇ hydroxyalkoxycarbonyl groups ”means 1 to 3 halogen atoms, C ₁ -C ₆ alkyl groups, C ₁ —; Groups independently selected from C ₆ halogenated alkyl groups, hydroxymethyl groups, cyano groups, carboxyl groups, carboxymethyl groups, C ₂ -C ₇ alkoxycarbonyl groups and C ₂ -C ₇ hydroxyalkoxycarbonyl groups are independently substituted. A phenyl group, preferably a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, A phenyl group independently substituted with one or two groups selected from a ruboxyl group and a carboxymethyl group, more preferably a 4-carboxylphenyl group, a 4-carboxyl-2-fluorophenyl group, 4- A carboxyl-2-chlorophenyl group, a 4-carboxyl-2-methylphenyl group, a 4-carboxyl-2-trifluoromethylphenyl group or a 4-carboxymethyl-2-chlorophenyl group;

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (diastereoisomers, optical isomers, rotational isomers, etc.).

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of the atomic isotope include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. The compound can also be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

“The pharmacologically acceptable salt” refers to a salt that has no significant toxicity and can be used as a medicine. When the compound having the general formula (I) of the present invention has a basic group, it is reacted with an acid, and when it has an acidic group, it is reacted with a base to form a salt. Can do.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C ₁ -C ₆ alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.

On the other hand, examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.

When the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is left in the air or recrystallized to take in water molecules to become a hydrate. Such hydrates are also included in the salts of the present invention.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also a solvate of the present invention. Included in the salt.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and feeding inhibitory action, and is a warm-blooded animal (preferably a mammal, Diseases (including humans): obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis , A disease selected from the group consisting of ischemic heart disease and bulimia, or hyperlipidemia, hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, sugar caused by obesity Urinary disease, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis Disease selected from the group consisting of infectious disease, atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout, and cholelithiasis It is useful as a medicament for the prevention and / or treatment. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action, and is a warm-blooded animal (preferably a mammalian animal). And is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases (including humans). Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.

The compound having the general formula (I) of the present invention can be produced according to Method A described below.

The inert solvent used in the reaction of each step of Method A below is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, Alcohols such as methyl cellosolve; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; acetic acid, formic acid, propionic acid, Carboxylic acids such as tyryl acid and trifluoroacetic acid; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine , Picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5 -Diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7 -Amine (DBU), amines such as piperidine; water; and a mixed solvent thereof.

The base used in the reaction of each step of the following method A is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, etc. Alkali metal bicarbonates; alkali metal acetates such as sodium acetate, potassium acetate, lithium acetate, cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, water Alkali metal hydroxides such as potassium oxide, barium hydroxide and lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium-t-butoxide, potassium-t -Alkali metal alkoxides such as butoxide; Alkali metal trialkylsiloxides such as methylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine 2,6-lutidine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethyl Aniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8 -Diazabicyclo [5.4.0] undec-7-ene (D Organic bases such as U); organometallic bases such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide; or an amino acid such as proline.

In the reaction of each step of Method A below, the reaction temperature varies depending on the solvent, starting material, reagent, and the like, and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.

In the reaction of each step of Method A below, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.

Method A is a method for producing a compound having the general formula (I).

In the present invention, R represents the same meaning as described above, and R ^a represents a hydroxy group and / or carboxyl group in which a hydroxy group and / or carboxyl group contained as a substituent in the R group may be protected. In addition to these, the same groups as those in the definition of the R group are shown.

Step A1 This step is a step of producing a compound having the general formula (IV).

This step is performed by reacting the compound having the general formula (II) with the compound (III) in the presence of a base in a solvent.

The compound having the general formula (II) is a known compound (for example, WO2006 / 004200, J. Med. Chem. 1987, 30, 1887, etc.) or a known method using a known compound as a starting material (for example, , WO2006 / 004200, J. Med. Chem. 1987, 30, 1887, etc.) or similar methods.

The solvent used in this step is preferably an amide, and more preferably N, N-dimethylacetamide.

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 0 ° C. to 180 ° C., preferably 60 ° C. to 120 ° C.

The reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.

Step A2 This step is a step of producing a compound having the general formula (I).

In this step, a compound having the general formula (IV) is reacted with the compound (V) in a solvent in the presence of a palladium catalyst and a base, and then, optionally, ^a protective group for ^a hydroxy group and / or a carboxyl group in ^Ra . This is done by removing.

The solvent used in this step is preferably a mixed solvent of amides and water, and more preferably a mixed solvent of N, N-dimethylacetamide and water.

The palladium catalyst used in this step is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II), palladium black, palladium bromide (II ), Palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (acetonitrile) palladium (II), dichlorobis (Benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium sulfide (II), [1,1'-bis (diphenylphosphino) ferrocene] Palladium (II) dichroic A divalent palladium catalyst such as Lido, tris (dibenzylideneacetone) dipalladium (0), tetrakis (acetonitrile) palladium (II) tetrafluoroborate or arylpalladium chloride dimer, preferably a zerovalent palladium catalyst, , A zero-valent palladium catalyst, and more preferably tetrakis (triphenylphosphine) palladium (0).

The reaction temperature in this step is usually 20 ° C. to 180 ° C., preferably 60 ° C. to 120 ° C.

In the above, the protecting group of “optionally protected hydroxy group” and “optionally protected carboxyl group” in the definition of R ^a is a chemical group such as hydrogenolysis, hydrolysis, electrolysis or photolysis. This refers to a protecting group that can be cleaved by a method, and shows a protecting group commonly used in organic synthetic chemistry (for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)). reference).

In the above, the “protecting group” of the “hydroxy group that may be protected” in the definition of R ^a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of synthetic organic chemistry. Groups, C ₂ -C ₇ alkylcarbonyl groups such as acetyl, propionyl, butyryl, pentanoyl, valeryl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, alkoxy such as methoxyacetyl “Alkylcarbonyl groups” such as alkylcarbonyl groups, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, α-naphthoyl, β-naphthoyl Arylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl halide arylcarbonyl group such as yl, 2,4,6-trimethylbenzoyl, _4-C 1 -C ₆ alkylated ants such as toluoyl - ylcarbonyl Groups, C ₁ -C ₆ alkoxylated arylcarbonyl groups such as 4-anisoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, C _2- such as 2- (methoxycarbonyl) benzoyl An “arylcarbonyl group” such as a C ₇ alkoxycarbonylated arylcarbonyl group, an arylated arylcarbonyl group such as 4-phenylbenzoyl; the aforementioned “C ₂ -C ₇ alkoxycarbonyl group”, 2,2,2-trichloroethoxycarbonyl , 2-Trimethylsilylethoxycal An “alkoxycarbonyl group” such as a C ₂ -C ₇ alkoxycarbonyl group substituted with a halogen such as bornyl or a tri- (C ₁ -C ₆ alkyl) silyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran "Tetrahydropyranyl or tetrahydrothiopyranyl group" such as 2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran- “Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as 2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl Birds such as triisopropylsilyl - (C ₁ -C ₆ alkyl) silyl group, diphenylmethyl silyl, diphenyl butylsilyl, diphenyl isopropylsilyl, such as phenyl diisopropylsilyl (C ₁ -C ₆ alkyl) diarylsilyl or di - A “silyl group” such as (C ₁ -C ₆ alkyl) arylsilyl group; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl; (C ₁ -C ₆ alkoxy) methyl groups such as, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy) methyl groups such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl (C ₁ -C, such as bis (2-chloroethoxy) methyl, “Alkoxymethyl groups” such as _6- halogenated alkoxy) methyl; 1-ethoxyethyl, (C ₁ -C ₆ alkoxy) ethyl groups such as 1- (isopropoxy) ethyl, 2,2,2-trichloroethyl and the like “Substituted ethyl groups” such as ethyl halide groups; 1 to 3 such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl C ₁ -C ₆ alkyl group substituted with allyl group, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenyl Methyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanoben _C 1 -C ₆ alkyl, such as _Gilles, C 1 -C ₆ alkoxy, nitro, halogen, a cyano group - Le ring of 1 to 3 substituted ants - _C 1 -C substituted with Le group “Aralkyl groups” such as ₆ alkyl groups; “alkenyloxycarbonyl groups” such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitro An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with one or two C ₁ -C ₆ alkoxy or nitro groups, such as benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; Is an alkylcarbonyl group, a silyl group or an aralkyl group.

In the above, the “protecting group” of the “optionally protected carboxyl group” in the definition of R ^a is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of synthetic organic chemistry. “C ₁ -C ₆ alkyl group”; “C ₂ -C ₆ alkenyl group” such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl; ethynyl, 1-propynyl, 2-propynyl, “C ₂ -C ₆ alkynyl group” such as 1-methyl-2-propynyl; the aforementioned “C ₁ -C ₆ halogenated alkyl group”; C ₁ -C ₆ hydroxyalkyl such as hydroxymethyl and 2-hydroxyethyl A group; such as acetylmethyl (C ₂ -C ₇ alkylcarbonyl)-(C ₁ -C ₆ alkyl group); said “aralkyl group”; or “silyl group” And preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

Processes that require protection / deprotection are described in known methods (for example, “Protective Groups in Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, 1999, published by Wiley-Interscience Publication)). Method).

The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration). These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. It can be formulated with the resulting adjuvant.

When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Use of lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can do. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.

When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.

When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be included in the preparation, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be included. You may go out.

In addition, the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.

The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.

The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck Co., Ltd. or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) was used. In addition to ordinary column chromatography, an automated chromatography apparatus (SP-1) manufactured by Biotage was used as appropriate. As the elution solvent, the solvent specified in each example was used at the specified ratio. (Or, the ratio was changed as necessary.) The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H NMR) spectra are described with chemical shift values as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, m for multiple lines and br for broad lines.

Mass spectrometry (hereinafter referred to as MS) was performed by EI (Electron Ionization) method, ESI (Electron Spray Ionization) method, or FAB (Fast Atom Bombardment) method.

(Example 1)
[3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) phenyl] acetic acid

(1a) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane-2 -Yl) phenyl] amide 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (WO2008011130 A2) (2.17 g), 4- (4,4,5,5-tetramethyl -[1,3,2] dioxaborolan-2-yl) -phenylamine (1.85 g), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) (4.13 g), and triethylamine ( 1.4 mL) of the mixture in dimethylacetamide (20 mL) was stirred for 7 days. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (dichloromethane / ethyl acetate) and the resulting oil was stirred vigorously in methanol. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 3.00 g (78%) of the title compound as a white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.67 (1H, s), 9.67-8.64 (1H, m), 8.17-8.11 (1H, m), 8.04 ( 1H, d, J = 8.2Hz), 7.79 (2H, d, J = 8.6Hz), 7.68 (2H, d, J = 8.7Hz), 7.59-7.56 (1H, m), 1.30 (12H, s).
(1b) [4- (5-Bromopyrimidin-2-yloxy) -3-chlorophenyl] acetic acid methyl ester (3-chloro-4-hydroxyphenyl) acetic acid methyl ester (WO2006004200A1) (3.69 g), 5-bromo-2 A suspension of chloropyrimidine (3.58 g) and 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, washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (dichloromethane / ethyl acetate) to give 5.90 g (90%) of the title compound as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.58 (2H, s), 7.45 (1H, d, J = 2.0 Hz), 7.29-7.21 (2H, m), 3.73 (3H, s), 3.64 (2H, s)
MS (ESI) m / z: 358 (M + H) ^<+> .

(1c) [3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) -amino] -phenyl} -pyrimidine-2 -Iloxy) -phenyl] -acetic acid methyl ester Methyl [4- (5-bromopyrimidin-2-yloxy) -3-chlorophenyl] acetate obtained in Example (1a) (516 mg), (1b) A suspension of ester (401 mg), tetrakis (triphenylphosphine) palladium (0) (65 mg), and potassium carbonate (319 mg) in dimethylacetamide / water (20: 1, 10 mL) at 80 ° C. Heated for hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography (dichloromethane / ethyl acetate) to obtain 289 mg (42%) of the title compound as a colorless transparent amorphous.
MS (ESI) m / z: 609 (M + H) ⁺ .
(1d) [3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) [Phenyl] acetic acid [3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) -amino] obtained in Example (1c) ] -Phenyl} -pyrimidin-2-yloxy) -phenyl] -acetic acid methyl ester (289 mg) in 1,4-dioxane (5 mL) and tetrabutylammonium hydroxide (1 mol / L aqueous solution, 1 mL) Was added at room temperature. After 19 hours, the reaction mixture was concentrated, acidified with 1 N aqueous hydrochloric acid (10 mL), diluted with ethyl acetate, and stirred vigorously for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 277 mg (98%) of the title compound as a white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.5 (1H, brs), 10.5 (1H, s), 9.67 (1H, s), 9.01 (2H, s), 8.64 (1H, d, J = 5.9Hz), 8.15 (1H, dd, J = 7.8 and 7.8Hz), 8.05 (1H, d, J = 8.2Hz), 7.90 (2H, d, J = 9.0Hz), 7.77 (2H, d, J = 8.6Hz), 7.60-7.54 (2H, m), 7.40-7.33 (2H, m), 3.68 (2H, s)
MS (ES) m / z: 595 (M + H) ^<+> .

(Example 2)
[4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) phenyl] acetic acid

(2a) [4- (5-Bromopyrimidin-2-yloxy) phenyl] acetic acid methyl ester In the same manner as in Example (1b), (4-hydroxyphenyl) acetic acid methyl ester (3.08 g) and 5-bromo- From 2-chloropyrimidine (3.59 g), 4.84 g (81%) of the title compound was obtained as a light beige solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.57 (2H, 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-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) phenyl] acetic acid In the same manner as in Example (1c), [4- (5-bromopyrimidin-2-yloxy) phenyl] acetic acid methyl ester (171 mg) obtained in Example (2a) and the compound obtained in Example (1a) (244 mg) gave 197 mg (64%) of a biaryl compound as a white solid. From this biaryl compound (197 mg), 120 mg (62%) of the title compound was obtained as a white solid in the same manner as in Example (1d).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.3 (1H, brs), 10.5 (1H, s), 9.66 (1H, s), 8.98 (2H, s), 8.65-8.63 (1H, m), 8.16-8.12 (1H, m), 8.06-8.03 (1H, m), 7.89 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 9.0Hz), 7.59-7.56 (1H , m), 7.35 (2H, 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-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

(3a) 4- (5-Bromo-pyrimidin-2-yloxy) -3-chlorobenzoic acid methyl ester In the same manner as in Example (1b), 3-chloro-4-hydroxy-benzoic acid methyl ester (J. Med. Chem. 1987, 30, 1887) (3.09 g) and 5-bromo-2-chloropyrimidine (3.21 g) gave 4.35 g (76%) of the title compound as a pale yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.59 (2H, s), 8.19 (1H, d, J = 1.9Hz), 8.04 (1H, dd, J = 8.6 and 2.0Hz), 7.33 ( 1H, d, J = 8.6Hz), 3.95 (3H, s).
(3b) 3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid Acid In the same manner as in Example (1c), 4- (5-bromo-pyrimidin-2-yloxy) -3-chlorobenzoic acid methyl ester (349 mg) obtained in Example (3a) and Example (1a) ) From the compound (458 mg) obtained in), a biaryl compound (468 mg, 79%) was obtained as a white solid. In the same manner as in Example (1d), 385 mg (84%) of the title compound was obtained as a white solid from this biaryl compound (468 mg).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.4 (1H, 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), 7.80 (2H, d, J = 8.6Hz), 7.62-7.56 (2H, m).
MS (ESI) m / z: 581 (M + H) ^<+> .

Example 4
4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

In the same manner as in Example (1c), 4- (5-bromopyrimidin-2-yloxy) benzoic acid methyl ester (Org. Lett., 2009, 11, 2511.) (311 mg) and Example (1a) From the compound (462 mg) obtained in 1 above, 385 mg (68%) of a biaryl compound was obtained as a white solid. In the same manner as in Example (1d), 210 mg (56%) of the title compound was obtained as a white solid from this biaryl compound (385 mg).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.0 (1H, 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), 8.06-8.03 (1H, m), 7.90 (2H, d, J = 8.6Hz), 7.80 ( 2H, d, J = 8.6Hz), 7.60-7.57 (1H, m), 7.38 (2H, d, J = 8.6Hz).
MS (ESI) m / z: 547 (M + H) ^<+> .

(Example 5)
3- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

In the same manner as in Example (1c), methyl 3- (5-bromopyrimidin-2-yloxy) benzoate (Org. Lett., 2009, 11, 2511.) (148 mg) and Example (1a) From the compound obtained in (220 mg), 222 mg (83%) of a biaryl compound was obtained as a white solid. From this biaryl compound (222 mg), 99 mg (45%) of the title compound was obtained as a white solid in the same manner as in Example (1d).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.2 (1H, brs), 10.5 (1H, s), 9.66 (1H, s), 9.01 (2H, s), 8.64 (1H, d, J = 6.6Hz), 8.16-8.12 (1H, m), 8.04 (1H, d, J = 8.2Hz), 7.89 (2H, d, J = 8.6Hz), 7.89-7.85 (1H, m), 7.79 ( 2H, d, J = 9.0Hz), 7.75-7.73 (1H, m), 7.62-7.51 (3H, m).
MS (FAB) m / z: 547 (M + H) ⁺ ; m / z 585 (M + K) ⁺ .

(Example 6)
3-Fluoro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

(6a) 4- (5-Bromopyrimidin-2-yloxy) -3-fluorobenzoic acid methyl ester In the same manner as in Example (1b), 3-fluoro-4-hydroxy-benzoic acid methyl ester (J. Org Chem. 1952, 17, 1425.) (984 mg) and 5-bromo-2-chloropyrimidine (1.12 g) gave 1.83 g (97%) of the title compound as a white solid.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 8.88 (2H, s), 7.90 (2H, dd, J = 9.0 and 9.0Hz), 7.61 (1H, dd, J = 8.2 and 8.2Hz) , 3.89 (3H, s).
(6b) 3-Fluoro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid Acid In the same manner as in Example (1c), 4- (5-bromopyrimidin-2-yloxy) -3-fluorobenzoic acid methyl ester (230 mg) obtained in Example (6a) and Example (1a) From the compound obtained in (323 mg), 321 mg of a biaryl compound was obtained as a pale yellow solid. In the same manner as in Example (1d), 221 mg (56%) of the title compound was obtained as a light beige solid from this biaryl compound (321 mg).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.3 (1H, brs), 10.5 (1H, s), 9.66 (1H, s), 9.03 (2H, s), 8.64 (1H, d, J = 3.1Hz), 8.16-8.12 (1H, m), 8.04 (1H, d, J = 8.2Hz), 7.91-7.87 (4H, m), 7.80 (2H, d, J = 8.6Hz), 7.63- 7.56 (2H, m).
MS (FAB) m / z: 565 (M + H) ⁺ ; m / z 587 (M + K) ⁺ .
HRMS m / z calcd for C ₂₇ H ₁₇ F ₄ N ₆ O ₄ 565.1247, found 565.1250.

(Example 7)
3-Methyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

(7a) 4- (5-Bromo-pyrimidin-2-yloxy) -3-methylbenzoic acid methyl ester In the same manner as in Example (1b), 4-hydroxy-3-methylbenzoic acid methyl ester (Organic & Biomolecular Chemistry 2005, 3, 2271.) (5.63 g) and 5-bromo-2-chloropyrimidine (6.56 g) gave 8.63 g (79%) of the title compound as a white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 8.83 (2H, s), 7.96 (1H, s), 7.86 (1H, d, J = 9.0 Hz), 7.31 (1H, d, J = 8.6Hz), 3.86 (3H, s), 2.16 (3H, s).
(7b) 3-Methyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid Acid In the same manner as in Example (1c), 4- (5-bromo-pyrimidin-2-yloxy) -3-methylbenzoic acid methyl ester (162 mg) obtained in Example (7a) and Example (1a) ), 264 mg (91%) of a biaryl compound was obtained as a colorless amorphous form from the compound (234 mg) obtained in (1). From this biaryl compound (264 mg), 173 mg (67%) of the title compound was obtained as a white solid in the same manner as in Example (1d).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.9 (1H, brs), 10.5 (1H, s), 9.66 (1H, s), 9.00 (2H, s), 8.63 (1H, d, J = 5.5Hz), 8.16-8.12 (1H, m), 8.04 (1H, d, J = 8.2Hz), 7.95-7.85 (2H, m), 7.89 (2H, d, J = 9.0Hz), 7.78 ( 2H, d, J = 9.0Hz), 7.59-7.56 (1H, m), 7.29 (1H, d, J = 8.2Hz), 2.18 (3H, s)
MS (FAB) m / z: 561 (M + H) ⁺ .
HRMS m / z calcd for C ₂₈ H ₁₉ F ₃ N ₆ O ₄ 561.1498, found 561.1499.

(Example 8)
1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (2-phenoxypyrimidin-5-yl) phenyl] amide

In the same manner as in Example (1c), 5-bromo-2-phenoxypyrimidine (Org. Lett., 2009, 11, 2511) (127 mg) and the compound (231 mg) obtained in Example (1a) were used. 191 mg (75%) of the title compound were obtained as a white solid.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.66 (1H, s), 8.98 (2H, s), 8.64 (1H, d, J = 4.0Hz), 8.14 (1H, dd, J = 7.8 and 7.8Hz), 8.04 (1H, d, J = 7.8Hz), 7.89 (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), 7.30 (1H, d, J = 7.5Hz), 7.26 (2H, d, J = 8.6Hz) .
MS (FAB) m / z: 503 (M + H) ⁺ ; m / z: 541 (M + K) ⁺ .

Example 9
4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid

(9a) 4- (5-Bromopyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid methyl ester In the same manner as in Example (1b), 4-hydroxy-3-trifluoromethylbenzoic acid methyl ester ( Tetrahedron Letters 1991, 32, 7525.) (970 mg) and 5-bromo-2-chloropyrimidine (853 mg) gave 639 mg (38%) of the title compound as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.60 (2H, s), 8.44 (1H, s), 8.31 (1H, d, J = 8.6Hz), 7.36 (1H, d, J = 8.3 Hz), 3.97 (3H, s).
(9b) 4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) -3-trifluoro Methylbenzoic acid Performed in the same manner as in Example (1c), with 4- (5-bromopyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid methyl ester (215 mg) obtained in Example (9a) From the compound (265 mg) obtained in Example (1a), 205 mg (56%) of a biaryl compound was obtained as an off-white amorphous substance. In the same manner as in Example (1d), 144 mg (72%) of the title compound was obtained as a pale yellow solid from this biaryl compound (205 mg).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 13.5 (1H, brs), 10.5 (1H, s), 9.66 (1H, s), 9.05 (2H, s), 8.64 (1H, d, J = 4.0Hz), 8.33-8.23 (1H, m), 8.30 (1H, s), 8.17-8.12 (1H, m), 8.05 (1H, d, J = 8.2Hz), 7.91 (2H, d, J = 9.0Hz), 7.81 (2H, d, J = 9.0Hz), 7.68 (1H, d, J = 8.6Hz), 7.60-7.56 (1H, m).
MS (FAB) m / z: 615 (M + H) ^<+> .

(Example 10)
2- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid methyl ester

In the same manner as in Example (1c), 2- (5-bromopyrimidin-2-yloxy) benzoic acid methyl ester (Org. Lett., 2009, 11, 2511) (260 mg) and Example (1a) From the obtained compound (383 mg), 489 mg (quantitative yield) of the title compound was obtained as a light brown solid.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.66 (1H, s), 8.95 (2H, s), 8.64 (1H, 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 4.3Hz), 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: 561 (M + H) ⁺ ; m / z: 599 (M + K) ⁺ .

Example 11
2- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

2- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid obtained in Example 10 In the same manner as in Example (1d), 144 mg (39%) of the title compound was obtained as a light gray solid from the methyl ester (382 mg).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.9 (1H, 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 = 9.0Hz), 7.70 (1H, dd, J = 8.6 and 7.0Hz), 7.58 (1H, dd, J = 7.8 and 5.5Hz), 7.42 (1H, dd, J = 8.0 and 7.2Hz), 7.35 (1H, d, J = 9.0Hz).
MS (FAB) m / z: 547 (M + H) ⁺ ; m / z: 585 (M + K) ⁺ .

(Example 12)
1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {4- [2- (4-hydroxymethylphenoxy) pyrimidin-5-yl] phenyl} amide

(12a) [4- (5-Bromopyrimidin-2-yloxy) phenyl] methanol
In the same manner as in Example (1b), 665 mg (23%) of the title compound was obtained as a pale yellow solid from 4-hydroxybenzyl alcohol (1.25 g) and 5-bromo-2-chloropyrimidine (1.95 g). .
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 8.80 (2H, s), 7.38 (2H, d, J = 8.2Hz), 7.17 (2H, d, J = 8.6Hz), 5.21 (1H , t, J = 5.7Hz), 4.51 (2H, d, J = 5.8Hz).
(12b) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {4- [2- (4-hydroxymethylphenoxy) pyrimidin-5-yl] phenyl} amide Example ( In the same manner as in 1c), [4- (5-bromopyrimidin-2-yloxy) phenyl] methanol (141 mg) obtained in Example (12a) and the compound (227 mg) obtained in Example (1a) This afforded 254 mg (96%) of the title compound as a white solid.
H NMR (400MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.66 (1H, s), 8.97 (2H, s), 8.64 (1H, d, J = 6.6Hz), 8.14 ( 1H, 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 = 8.6Hz), 5.23 (1H, t, J = 5.6Hz), 4.53 ( (2H, d, J = 5.5Hz)
MS (FAB) m / z: 533 (M + H) ⁺ ; m / z: 571 (M + K) ⁺ .

(Example 13)
1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (2-p-tolyloxypyrimidin-5-yl) phenyl] amide

(13a) 5-Bromo-2-p-tolyloxypyrimidine
In the same manner as in Example (1b), 2.49 g (94%) of the title compound was obtained as a white solid from p-cresol (1.1 mL) and 5-bromo-2-chloropyrimidine (1.93 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ (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-tolyloxypyrimidin-5-yl) phenyl] amide Example (1c) and In the same manner, from the 5-bromo-2-p-tolyloxypyrimidine (136 mg) obtained in Example (13a) and the compound (235 mg) obtained in Example (1a), 170 mg (64 mg %) Was obtained as an off-white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.66 (1H, s), 8.97 (2H, s), 8.64 (1H, d, J = 4.7 Hz), 8.14 (1H, dd, J = 9.4 and 7.8Hz), 8.04 (1H, d, J = 8.2Hz), 7.89 (2H, d, J = 8.6Hz), 7.77 (2H, d, J = 8.7Hz), 7.58 (1H, dd, J = 8.0 and 5.3Hz), 7.26 (2H, d, J = 8.2Hz), 7.12 (2H, d, J = 8.6Hz), 2.34 (3H, s).
MS (FAB) m / z: 517 (M + H) ^<+> .

(Example 14)
1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (2-m-tolyloxypyrimidin-5-yl) phenyl] amide

(14a) 5-Bromo-2-m-tolyloxypyrimidine In the same manner as in Example (1b), from m-cresol (1.1 mL) and 5-bromo-2-chloropyrimidine (1.93 g), the title compound 2.50 g (94%) was obtained as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.58 (2H, s), 7.33 (1H, t, J = 7.6 Hz), 7.10 (1H, d, J = 7.5 Hz), 7.00 (1H, s), 6.99 (1H, d, J = 8.6Hz), 2.39 (3H, s).
(14b) 1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (2-m-tolyloxypyrimidin-5-yl) phenyl] amide Example (1c) and In the same manner, from the 5-bromo-2-m-tolyloxypyrimidine (137 mg) obtained in Example (14a) and the compound (237 mg) obtained in Example (1a), 195 mg (73 %) Was obtained as a white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.67 (1H, s), 8.98 (2H, s), 8.64 (1H, d, J = 4.7 Hz), 8.15 (1H, 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), 7.58 (1H, dd, J = 7.2 and 4.9Hz), 7.35 (1H, dd, J = 7.7 and 7.7Hz), 7.11-7.03 (3H, m), 2.35 (3H, s).
MS (FAB) m / z: 517 (M + H) ^<+> .

(Example 15)
1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (2-o-tolyloxypyrimidin-5-yl) phenyl] amide

(15a) 5-Bromo-2-o-tolyloxypyrimidine In the same manner as in Example (1b), from o-cresol (1.1 mL) and 5-bromo-2-chloropyrimidine (1.93 g), the title compound 2.56 g (97%) was obtained as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.56 (2H, s), 7.31-7.19 (3H, m), 7.10 (1H, d, J = 7.9 Hz), 2.18 (3H, s).
(15b) 1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [4- (2-o-tolyloxypyrimidin-5-yl) phenyl] amide Example (1c) and In the same manner, from the 5-bromo-2-o-tolyloxypyrimidine (134 mg) obtained in Example (15a) and the compound (232 mg) obtained in Example (1a), the title compound 104 mg (40 mg %) Was obtained as a white solid.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.66 (1H, s), 8.97 (2H, s), 8.64 (1H, d, J = 5.8Hz), 8.15 (1H, dd, J = 8.2 and 7.4Hz), 8.04 (1H, d, J = 8.2Hz), 7.89 (2H, d, J = 8.6Hz), 7.77 (2H, d, J = 9.0Hz), 7.58 (1H, dd, J = 7.6 and 5.3Hz), 7.35 (1H, d, J = 6.6Hz), 7.29 (1H, dd, J = 9.0 and 7.5Hz), 7.23-7.15 (2H, m), 2.12 ( 3H, s).
MS (FAB) m / z: 517 (M + H) ^<+> .

(Example 16)
3,5-dimethyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid

(16a) 4- (5-Bromo-pyrimidin-2-yloxy) -3,5-dimethylbenzoic acid methyl ester In the same manner as in Example (1b), 4-hydroxy-3,5-dimethylbenzoic acid methyl ester (J. Med. Chem. 2008, 51, 183.) (1.81 g) and 5-bromo-2-chloropyrimidine (1.92 g) gave 3.11 g (93%) of the title compound as an off-white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.56 (2H, s), 7.84 (2H, s), 3.91 (3H, s), 2.17 (6H, s).
MS (FAB) m / z: 337 (M + H) ⁺ ; m / z: 375 (M + K) ⁺ .
(16b) 3,5-Dimethyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy ) Benzoic acid In the same manner as in Example (1c), 4- (5-bromo-pyrimidin-2-yloxy) -3,5-dimethylbenzoic acid methyl ester (167 mg) obtained in Example (16a) and From the compound (229 mg) obtained in Example (1a), 256 mg (88%) of a biaryl compound was obtained as a colorless amorphous. In the same manner as in Example (1d), 172 mg (69%) of the title compound was obtained as a white solid from this biaryl compound (256 mg).
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.9 (1H, brs), 10.5 (1H, s), 9.66 (1H, s), 8.98 (2H, s), 8.64 (1H, d, J = 3.9Hz), 8.14 (1H, dd, J = 8.8 and 6.8Hz), 8.04 (1H, d, J = 8.2Hz), 7.89 (2H, d, J = 8.6Hz), 7.78 (2H, d, J = 7.1Hz), 7.77 (2H, s), 7.58 (1H, dd, J = 7.4 and 4.7Hz), 2.13 (6H, s).
MS (FAB) m / z: 575 (M + H) ⁺ ; m / z: 613 (M + K) ⁺ .

(Example 17)
1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {4- [2- (4-cyanophenoxy) -pyrimidin-5-yl] phenyl} amide

In the same manner as in Example (1c), obtained in 4- (5-bromo-pyrimidin-2-yloxy) benzonitrile (Org. Lett., 2009, 11, 2511) (139 mg) and Example (1a). The title compound (150 mg, 57%) was obtained as a light brown solid from the obtained compound (229 mg).
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.66 (1H, s), 9.04 (2H, s), 8.64 (1H, d, J = 5.4Hz), 8.14 (1H, dd, J = 8.8 and 6.8Hz), 8.04 (1H, d, J = 8.2Hz), 7.97 (2H, d, J = 9.0Hz), 7.90 (2H, d, J = 9.0Hz), 7.80 (2H, d, J = 8.6Hz), 7.58 (1H, dd, J = 8.2 and 4.7Hz), 7.51 (2H, d, J = 9.0Hz).
MS (FAB) m / z: 528 (M + H) ⁺ ; m / z: 566 (M + K) ⁺ .

(Example 18)
2-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid methyl ester

(18a) 4- (5-Bromo-pyrimidin-2-yloxy) -2-chlorobenzoic acid methyl ester In the same manner as in Example (1b), 2-chloro-4-hydroxybenzoic acid methyl ester (WO 2006004200) (4.29 g) and 5-bromo-2-chloropyrimidine (4.46 g) afforded 7.94 g (quantitative yield) of the title compound as a light beige solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.60 (2H, s), 7.95 (2H, d, J = 8.6Hz), 7.33 (1H, d, J = 2.0Hz), 7.16 (1H, dd, J = 8.6 and 2.4Hz), 3.94 (3H, s).
(18b) 2-chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid Acid methyl ester In the same manner as in Example (1c), from the compound (172 mg) obtained in Example (18a) and the compound (229 mg) obtained in Example (1a), 174 mg (58% ) Was obtained as a white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.67 (1H, s), 9.05 (2H, s), 8.64 (1H, d, J = 4.7 Hz), 8.15 (1H, dd, J = 8.6 and 7.0Hz), 8.05 (1H, d, J = 8.6Hz), 7.96 (1H, d, J = 8.6Hz), 7.91 (2H, d, J = 8.6Hz), 7.81 (2H, d, J = 8.6Hz), 7.64 (1H, d, J = 2.4Hz), 7.59 (1H, dd, J = 4.9 and 3.3Hz), 7.41 (1H, dd, J = 8.6 and 2.4Hz) , 3.89 (3H, s).
MS (FAB) m / z: 595 (M + H) ⁺ ; m / z: 617 (M + Na) ⁺ ; m / z: 633 (M + K) ⁺ .

(Example 19)
4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid 2-hydroxyethyl ester

(19a) 4- (5-Bromo-pyrimidin-2-yloxy) benzoic acid 2-hydroxyethyl ester In the same manner as in Example (1b), 4-hydroxybenzoic acid 2-hydroxyethyl ester (1.82 g) and 5 From bromo-2-chloropyrimidine (1.93 g), 965 mg (29%) of the title compound was obtained as a white solid.
¹ H NMR (400MHz, DMSO-d6): δ (ppm) = 8.86 (2H, s), 8.08 (2H, d, J = 8.6Hz), 7.40 (2H, d, J = 9.0Hz), 4.94 (1H , 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-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid 2-hydroxy Ethyl ester In the same manner as in Example (1c), from the compound (169 mg) obtained in Example (19a) and the compound (228 mg) obtained in Example (1a), the title compound 191 mg (65%) Was obtained as a white solid.
¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 10.5 (1H, s), 9.67 (1H, s), 9.04 (2H, s), 8.64 (1H, d, J = 6.7 Hz), 8.17 -8.04 (1H, m), 8.11 (2H, d, J = 8.6Hz), 7.91 (2H, d, J = 9.0Hz), 7.80 (2H, d, J = 8.6Hz), 7.66-7.54 (2H, m), 7.42 (2H, 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 the method described in US2007 / 0249620, DGAT1 enzyme was prepared and stored.
(2) DGAT1 inhibitory activity test Reaction solution [175 mM Tris-HCl (pH 8.0), 8 mM MgCl ₂ , 1 mg / ml BSA, 0.3 mM 1,2-dioleoyl-sn-glycerol (10-fold concentration) 10% EtOH solution), 10 μM [ ¹⁴ C] -oleoyl-CoA (about 50 mCi / mmol), 0.5% triton X-100, DGAT1 enzyme (10 μg) obtained in Test Example 1 (1), test compound Or a vehicle (DMSO / MeOH, 7: 3 solution, 5% added), total volume 50 μl] was incubated at room temperature (23 ° C.) for 30 minutes. To the reaction mixture was added a reaction stop solution (70 μl) consisting of isopropanol / 1-heptane / water (80: 20: 2, v / v / v) and stirred, then water (30 μl) and 1-heptane (100 μl) Was added and stirred. A 1-heptane layer (50 μl) was spotted on a TLC plate and developed with a developing solvent consisting of 1-hexane / diethyl ether / acetic acid (85: 15: 1, v / v / v). The radioactivity of the triglyceride fraction was quantified with a BAS2000 bioimage analyzer (Fuji Film), and the inhibitory activity of the test compound was calculated by the following formula by comparing with the control. The unreacted (0 minute incubation) radioactivity was used as the background.

Inhibition rate = 100 − [(radioactivity at the time of addition of test compound) − (background)] / [(radioactivity of control) − (background)] × 100
The compounds of Examples 1 to 10 and 12 to 18 showed an inhibition rate of 50% or more at a test compound concentration of 1 μg / ml.

The DGAT inhibitory activity test is not limited to the above method. For example, microsomes prepared from the small intestine, adipose tissue, or liver of animals such as rats and mice may be used as the DGAT enzyme. Alternatively, microsomes prepared from cultured cells (3T3-L1 adipocytes, primary cultured adipocytes, Caco2 cells, HepG2 cells, etc.) or cultured cells highly expressing DGAT can also be used as the DGAT enzyme. Furthermore, in order to efficiently evaluate a large number of test compounds in a short time, a flash plate (PerkinElmer) in which the extraction operation is omitted can be used.

From the above results, the compound of the present invention has excellent DGAT1 inhibitory biological activity.

(Test Example 2)
The DGAT1 enzyme is important for digestion and absorption of neutral fat, and when small intestine DGAT1 is inhibited, the absorption of neutral fat is suppressed. The biological activity of the DGAT1 inhibitory action was evaluated using as an index the suppression of neutral fat absorption after loading with neutral fat. Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) fasted overnight were assigned to Vehicle Group 1, Vehicle Group 2 and each test compound group, respectively vehicle (0.5% Methylcellulose) Alternatively, each test compound (1 to 10 mg / kg) suspended in the vehicle was orally administered (5 mL / kg). Lipoprotein lipase inhibitor (Pluronic-F127: Sigma-Aldrich Co., Ltd., 1 g / kg, dissolved in physiological saline at 20% by weight) was intraperitoneally administered (5 mL / kg) Distilled water was orally administered to Vehicle Group 1 and 20% neutral fat-containing emulsion (Intralipid 20%: Terumo Corporation) was orally administered (0.2 mL / mouse) to Vehicle Group 2 and Compound Group. After 1 to 4 hours after administration, blood is collected from the tail vein or right ventricle, and plasma is promptly separated and collected, and then the neutral fat concentration in the plasma is measured using a commercially available kit (Triglyceride E Test Wako: Wako Pure Chemical Industries, Ltd.) (Industry Co., Ltd.). In this method, the administration of lipoprotein lipase inhibitor suppresses the degradation of neutral fat flowing into the blood, and neutral fat accumulates in the blood, but its origin is exogenous absorbed in the digestive tract And it is divided into endogenous ones released from the liver. The neutral fat absorption inhibitory activity of each test compound was calculated based on the following formula, excluding the influence of endogenous neutral fat. It has been separately confirmed that each test compound does not affect the endogenous triglyceride concentration.

Neutral fat absorption inhibitory activity (%) = 100-[(Neutral fat concentration of each test compound group)-(Neutral fat concentration of Vehicle group 1)] / [(Neutral fat concentration of Vehicle group 2)-( Vehicle group 1 neutral fat concentration)] × 100
The compounds of Examples 1, 3, 4, 6, 7, 9, and 18 exhibited a neutral fat absorption inhibitory activity of 60% or more at a dose of 3 mg / kg or less.

(Test Example 3)
Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) are reared individually and fed with a high fat diet (fat content 45 kcal%: Research Diet D12451) for over a week. I got used to it. Allocate animals evenly to the experimental groups based on the amount of food consumed during the period, fast overnight, and then add vehicle (0.5% Methylcellulose) or test compound suspended in vehicle (10 mg / kg) to each group. Oral administration (10 mL / kg) was performed. A high fat diet was fed 30 minutes after the administration, and the amount of food intake was measured 6 hours after the start of feeding. The feeding inhibitory activity of each test compound was calculated based on the following formula.

Feeding inhibitory activity (%) = [(food consumption of vehicle group) − (food consumption of each test compound group)] / [(food consumption of vehicle group)] × 100
The compound of Example 1 showed an antifeedant activity of 25% or more at a dose of 10 mg / kg.

From the above results, the compound of the present invention has an excellent antifeedant action.

Note that the high-fat diet used for the feed is not limited to the above-mentioned high-fat diet, and for example, a rodent feed containing 45 to 60% neutral fat as calories can be used.

Formulation Example 1: Capsule 50 mg of the compound of Example 1 or 2
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
------- 250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.

Formulation Example 2: Tablet Example 1 or 2 compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
ーーーーーーーーーーーーーー 200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent DGAT inhibitory action and antifeeding action, and is useful as a medicine.

Claims

Formula (I)

[Where:
R is a halogen atom, C 1 -C 6 alkyl group, C 1 -C 6 halogenated alkyl group, hydroxymethyl group, cyano group, carboxyl group, carboxymethyl group, C 2 -C 7 alkoxycarbonyl group and C 2-. A phenyl group which may be independently substituted with 1 to 3 groups independently selected from a C 7 hydroxyalkoxycarbonyl group; Or a pharmacologically acceptable salt thereof.
The compound according to claim 1, wherein R is a phenyl group independently substituted with one or two groups selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a carboxyl group, and a carboxymethyl group, or Its pharmacologically acceptable salt.
In Claim 1, R is 4-carboxylphenyl group, 4-carboxyl-2-fluorophenyl group, 4-carboxyl-2-chlorophenyl group, 4-carboxyl-2-methylphenyl group, 4-carboxyl-2-triphenyl A compound which is a fluoromethylphenyl group or a 4-carboxymethyl-2-chlorophenyl group or a pharmacologically acceptable salt thereof.
A compound having the general formula (I)
[3-Chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) phenyl] acetic acid ,
3-chloro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
3-fluoro-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid,
3-methyl-4- (5- {4-[(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) benzoic acid, or ,
4- (5- {4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl} pyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid Or a pharmacologically acceptable salt thereof.
An acyl coenzyme A: diacylglycerol acyltransferase inhibitor containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
An antifeedant and / or an appetite suppressant containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 7, which has an acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.
The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition has an anti-feeding action and / or an appetite-suppressing action.
The pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby preventing the treatment, amelioration, reduction and / or prevention of symptoms. 8. A pharmaceutical composition according to claim 7 for treatment and / or prevention.
For the treatment and / or prevention of a disease in which the pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase and the synthesis of triglyceride is inhibited, thereby treating, ameliorating, reducing and / or preventing symptoms. The pharmaceutical composition according to claim 7.
The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceride disease, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease Or the pharmaceutical composition of Claim 7 for the treatment and / or prevention of bulimia.
The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is for the treatment and / or prevention of obesity or obesity.
The pharmaceutical composition according to claim 7, which is used for the treatment and / or prevention of diabetes.
Use of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
If the pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease Or use of Claim 15 which is a composition for the treatment and / or prevention of bulimia.
A method for treating and / or preventing a disease, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof.
Diseases are obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic Retinopathy, including diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or binge eating The method of claim 17, wherein the disease is
The method according to claim 17 or 18, wherein the warm-blooded animal is a human.