TW201307287A - Cycloalkyloxy biaryl compounds - Google Patents

Abstract

The present invention is related to a compound or a pharmacologically acceptable salt thereof having excellent DGAT inhibitory effect and antifeeding activity. The compound represented by the general formula (I) or the pharmacologically acceptable salt thereof is shown as following: [wherein, R is a phenyl optionally substituted by 1 to 5 groups independently selected from the substituent group A; Q is a nitrogen atom or the group represented by -CH=; U is a nitrogen atom or the group represented by -CH=; V is a nitrogen atom or the group represented by -CH=; m is 0 or 1; n is 0 or 1; the substituent group A is halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, and the like].

Description

Cycloalkyloxybiaryl type compound

The present invention relates to a compound having a specific chemical structure having excellent thiol-coA:diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibition and excellent feeding inhibition. Or a pharmacologically acceptable salt thereof.

Obesity is a state in which the energy intake continues to be excessive compared with the energy consumed, and the fat is accumulated in the fat cells (trimethyl glycerin or triglyceride, hereinafter also referred to as TG), and the result is that the body weight is compared with the standard body weight. A state which is significantly increased (Non-Patent Document 1). Obesity can lead to hyperlipidemia, hypertriglyceridemia, diabetes, hypertension, arteriosclerosis and other lifestyle-related diseases, cerebrovascular disorders, coronary artery disease, respiratory abnormalities, low back pain, deformed knee joint disease, gout, gallbladder Stones, etc., among those who have such comorbidities in obesity, or who are likely to have such comorbidities in the future, are defined as obesity and are treated as a disease.

Animals and plant systems accumulate lipids as insoluble TGs, and if necessary, decompose TG to generate energy. The TG that is ingested by diet is decomposed into free fatty acids and monoterpene glycerol 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 in the intestinal epithelial cells, and in the small cell body, the enzymes (hereinafter referred to as ACS), 醯Kyethase A: single The new TG is synthesized by the action of thiol glycerol thiotransferase and DGAT. TG is secreted by chylomicron by a combination of phospholipids, cholesterol and apolipoprotein. In the lymphatics of the gastrointestinal tract. Furthermore, TG is secreted into the blood via the lymphatics and transported to the distal end for use. On the other hand, in adipose tissue, TG is synthesized by the action of ACS from glycerol 3-phosphate and free fatty acids, glycerol 3-phosphate thiotransferase, lysophosphatidic acid thiotransferase and DGAT. (Non-Patent Document 2). The TG which is excessively taken up in this way is accumulated in the adipose tissue, and as a result, obesity occurs.

DGAT is an enzyme that is present in the small cell bodies of cells, and is the enzyme that acts as a catalyst in the reaction of the most important final step of the TG synthesis pathway, that is, the transfer of the sulfhydryl group of Kyivase A to 1,2-dimercaptoglycerol Reaction at the 3 position (Non-Patent Documents 3 to 5). DGAT has been reported to exist in two types, isozyme DGAT1 (Non-Patent Document 6) and DGAT2 (Non-Patent Document 7). Due to the high expression of DGAT1 in the small intestine and adipose tissue, DGAT2 is highly expressed in liver and adipose tissue. It is generally believed that DGAT1 is mainly related to fat absorption in the small intestine and fat accumulation in adipose tissue. DGAT2 is associated with TG synthesis or VLDL in the liver (very low density). Secretion of very low density lipoproteins and fat accumulation in adipose tissue. The difference in the tasks of DGAT1 and DGAT2 is not clearly understood, but the relationship between DGAT and obesity, lipid metabolism, glucose metabolism, and the like has been suggested (Non-Patent Document 8). DGAT is a key enzyme for TG synthesis in epithelial cells and adipose tissue of the digestive tract. Agents that block DGAT are expected to inhibit fat accumulation in the digestive tract and fat accumulation in adipose tissue by inhibiting TG synthesis. , obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, or hyperlipemia caused by obesity Therapeutic or preventive agents for diseases such as hypertriglyceridemia, 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 system directly or indirectly regulates the appetite control system, and its mechanism of action is roughly divided into central and peripheral. The centrally acting appetite suppressing drug acts on the lower nervous system of the bed of the feeding center and the satiety center or acts on the monoamine nervous system in the brain that regulates the same nervous system, and directly suppresses appetite. On the other hand, the mechanism by which the appetite suppressing drug of the peripheral action is transmitted by sensing acts on the accumulation state of nutrient intake or residual energy via the diet, and indirectly suppresses appetite.

In recent years, with the digestion of food. Absorption of digestive tract hormones (CCK, GLP-1, PYY, etc.) secreted in close contact (Non-Patent Document 14), or leptin secreted from fat cells in response to energy accumulation (fat amount) (Non-Patent Document 15) and the like, it is clear that the mechanism of hormonal or neurogenic self-regulation of the appetite of the distal to central center. New appetite suppressants related to these peripheral signals are expected to be therapeutic drugs for obesity with fewer effective side effects.

In the case of a compound having a DGAT inhibitory action, Patent Document 1 discloses that [5-(4-{[(substituted phenyl)aminocarbamoyl]amino}phenyl)pyrimidin-2-yl]oxy group and a carboxy group The acid is an alkyl-bonded compound, [5-(4-{[(substituted phenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxyl and cyclopentanecarboxylic acid Alkyl bonded compound. Patent Document 2 describes a compound having (2,3'-bipyridin-6'-yloxy)cyclohexanecarboxylic acid. Further, Non-Patent Document 16 discloses a compound in which a 4'-[(substituted anilinocarbonyl)amino]biphenyl-4-yl group is bonded to a cyclopentanecarboxylic acid by a carbonyl group.

Prior technical literature Patent literature

Patent Document 1 WO2009/011285

Patent Document 2 WO2011/031628

Non-patent literature

Non-Patent Document 1 Ban Yingying II, "STEP Metabolism. Endocrine", Hippocampus Study, 1st Edition, 1998, p.105

Non-Patent Document 2 Coleman, R., Bell, R., J. Biol. Chem., 1976, Vol. 251, p. 4537-4543

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. 169-201

Non-Patent Document 5 R. Bell., Ann. Rev. Biochem., 1980, Vol. 49, p. 459-487

Non-Patent Document 6 Cases, S. et al., Proc. Natl. Acad. Sci. USA., 1998, Vol. 95, p. 13018-13023

Non-Patent Document 7 Cases, S. et al., J. Biol. Chem., 2001, Vol. 276, p. 38870-38876

Non-Patent Document 8 Coleman, R.A., Lee, D.P., Progress in Lipid Research, 2004, Vol. 43, p. 134-176

Non-Patent Document 9 Smith, S. J. et al., Nat. Genet., 2000, Vol. 25, p. 87-90

Non-Patent Document 10 Chen, H. C., J. Clin. Invest., 2002, Vol. 109, p. 1049-1055

Non-Patent Document 11 Buhman, K. K., J. Biol. Chem., 2002, Vol. 277, p. 25474-25479

Non-Patent Document 12 Gaziano, J., et al., Circulation, 1997, Vol. 96, p. 2520-2525

Non-Patent Document 13 Yamaguchi, K. et al., Hepatology, 2008, Vol. 47, p. 625-635

Non-Patent Document 14 Strader, A. D. et al., Gastroenterology, 2005, Vol. 128, p. 175-191

Non-Patent Document 15 Campfield, L. A. et al., Science, 1995, Vol. 269, p. 546-549

Non-Patent Document 16 Andrew J. Souers et al., Journal of Medicinal Chemistry, 2008, Vol. 51, p. 380-383

[Summary of the Invention]

As a result of intensive studies on compounds having a DGAT inhibitory action and an ingestion inhibitory effect, the present inventors have found that a compound having a specific chemical structure has an excellent DGAT inhibitory effect, and particularly has a high inhibitory effect on DGAT1. Further, the inventors have found that this compound has an excellent food suppressing action. Furthermore, the present inventors have found that this compound is useful as a complication selected from the group consisting of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance, diabetes, and diabetes. (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic omental disease, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic fatty liver disease Active ingredients for the prevention and/or treatment of diseases caused by inflammation, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease and overeating Or as hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance, diabetes, diabetes mellitus (including diabetic peripheral neuropathy, diabetic nephropathy) , diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, An active ingredient for the treatment and/or prevention of diseases of the group consisting of cerebrovascular disorders, coronary artery diseases, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout, and gallstones.

The present invention relates to:

(1) a compound represented by the formula (I) or a pharmacologically acceptable salt thereof,

Wherein R represents a phenyl group which may be substituted by 1 to 5 groups independently selected from the group of substituent A, a pyridyl group which may be substituted with 1 to 3 groups independently selected from the group of substituent A or C ₃ -C ₆ cycloalkyl, Q represents a nitrogen atom or a group represented by the formula -CH=, U represents a nitrogen atom or a group represented by the formula -CH=, V represents a nitrogen atom or a group represented by the formula -CH=, and m represents 0. Or 1, n represents 0 or 1, and the substituent group A represents a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ halogenated group. Alkoxy, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, carboxyl group, C _2- C ₇ alkylcarbonyl, C ₂ -C ₇ alkoxycarbonyl, amine, mono-C ₁ -C ₆ alkylamino, di-(C ₁ -C ₆ alkyl)amine, mono-C _a group consisting of a _2- C ₇ alkylcarbonylamino group, a mono-C ₁ -C ₆ alkylsulfonylamino group, a cyano group, a nitro group, and a hydroxyl group].

In the present invention, it is preferred that:

(2) The compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), a formula (Ib), a formula (Ic), a formula (Id), a pass Formula (Ie) or Formula (If).

(3) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is the formula (Ia).

(4) A compound or a pharmacologically acceptable salt thereof, wherein R is a phenyl group which may be substituted by 1 to 5 groups independently selected from the group of substituents A.

(5) A compound or a pharmacologically acceptable salt thereof, wherein R is independently selected from 1 to 3 (fluorine atom, chlorine atom, methyl group and methoxy group). a phenyl group substituted by a group.

The compound of any one of (1) to (3), wherein R is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, or a pharmacologically acceptable salt thereof. 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-4 -fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2,4-dimethylphenyl, 2-methoxy-5-methylphenyl or A compound of 2,4,5-trifluorophenyl or a pharmacologically acceptable salt thereof.

(7) The compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), a formula (Ib), a formula (Ic), a formula (Id), a pass Formula (Ie) or Formula (If), R is a phenyl group which may be substituted by 1 to 5 groups independently selected from the group of substituents A.

(8) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), a formula (Ib), a formula (Ic), a formula (Id), a pass Formula (Ie) or Formula (If), R is a phenyl group which may be substituted with 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group).

(9) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), a formula (Ib), a formula (Ic), a formula (Id), a pass Formula (Ie) or Formula (If), R is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4- Methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2,4-dimethylphenyl, 2-methoxy-5-methylphenyl or 2,4,5-trifluorophenyl.

(10) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), and R is a group which may be substituted by 1 to 5 groups independently selected from the group of substituents A Phenyl.

(11) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), and R is independently selected from 1 to 3 (fluorine atom, chlorine atom, A A phenyl group substituted with a methoxy group.

(12) A compound of (1) or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), and R is a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, or 4 Fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2 -Chloro-4-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2,4-dimethylphenyl, 2-methoxy-5-methylphenyl or 2,4,5 -Trifluorophenyl.

(13) A compound or a pharmacologically acceptable salt thereof, which is: (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl) Pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(4-methylphenyl))aminomethyl]amino}phenyl)pyrimidine- 2-yl]oxy}cyclohexyl)acetic acid, {cis-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid (cis-4-{[5-(4-{[(3-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis 4-(5-(4-{[(4-fluorophenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4 -{[5-(4-{[(2-methylphenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{ [5-(4-{[(3-methylphenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5 -(4-{[(2-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5- (4-{[(3-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-( 4-{[(4-methoxyphenyl)amine A (amino)phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(2,4,5-trifluorophenyl)amine) Mercapto]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(2-methoxy-5-methylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy} ring Hexyl)acetic acid, (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid , (cis-4-{[5-(4-{[(4-methylphenyl))aminomethyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid, { Cis-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyridin-2-yl)oxy]cyclohexyl}acetic acid, (cis-4-{[5-(4) -{[(2,4-dimethylphenyl)amine-carbamoyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-( 4-{[(2-chloro-4-fluorophenyl)amine-carbamoyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid, (trans-4-{[5- (4-{[(2-Fluorophenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, {trans-4-[(5-{4- [(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, (trans-4-{[5-(4-{[(4-methylphenyl)amine) Mercapto]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(2-fluoro-3-methylphenyl) Aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl) (cis-4-{[5-(4-{[(2-fluoro-4-methylphenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl Acetic acid, (cis-4-{[5-(4-{[(2,4-dimethylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy} ring Hexyl)acetic acid, {trans-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyridin-2-yl)oxy]cyclohexyl}acetic acid, (trans-4-{[5-( 4-{[(2,4-dimethylphenyl)amine-carbamoyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid, {trans-3-[(5- {4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclopentyl}acetic acid, [trans-3-{[5-(4-{[(2-fluorobenzene) Aminomethylamino]amino}phenyl)pyrimidin-2-yl]oxy}cyclopentyl]acetic acid, {cis-3-[(5-{4-[(anilinylcarbonyl)amino)] Phenyl}pyrimidin-2-yl)oxy]cyclopentyl}acetic acid, or [cis-3-{[5-(4-{[(2-fluorophenyl))aminomethyl]amino}benzene Pyrimido-2-yl]oxy}cyclopentyl]acetic acid.

(14) A compound of the compound of (13) or a pharmacologically acceptable salt thereof.

(15) A compound or a pharmacologically acceptable salt thereof, which is: (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl) Pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(4-methylphenyl))aminomethyl]amino}phenyl)pyrimidine- 2-yl]oxy}cyclohexyl)acetic acid, {cis-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid (cis-4-{[5-(4-{[(3-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis 4-{[5-(4-{[(4-Fluorophenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(2-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis -4-{[5-(4-{[(3-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis- 4-{[5-(4-{[(2-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4 -{[5-(4-{[(3-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4- {[5-(4-{[(4-Methoxyphenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{ [5-(4-{[(2,4,5-Trifluorophenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4 -{[5-(4-{[(2-methoxy-5-methylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, ( Cis-4-{[5-(4-{[(2-fluoro-3-methylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid (cis-4-{[5-(4-{[(2-fluoro-4-methylphenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl ) acetic acid, or (cis-4-{[5-(4-{[(2,4-dimethylphenyl))amine) ] Amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid.

(16) A compound of the compound of (15) or a pharmacologically acceptable salt thereof.

(17) A ketamine enzyme A: a dimercaptoglycerol hydrazinotransferase inhibitor containing the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient .

(18) An ingestion inhibitor and/or an appetite suppressant comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient.

(19) A pharmaceutical composition comprising the compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof as an active ingredient.

(20) The pharmaceutical composition according to (19), wherein the pharmaceutical composition has a hindrance effect of 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase.

(21) The pharmaceutical composition according to (19), wherein the pharmaceutical composition has an action of suppressing food intake and/or appetite suppressing.

(22) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used for the treatment of a disease which is treated and/or prevented by the action of 醯Kytozyme A: dimercaptoglycerol thiotransferase and / or prevention.

(23) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used for the treatment and/or prevention of a disease caused by an increase in the activity of the sputum enzyme A: dimercaptoglycerol thiotransferase.

(24) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used to hinder synthesis of a triglyceride by inhibiting 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase, triglyceride Absorption is inhibited, and the treatment, amelioration, alleviation and/or prevention of the symptoms are treated and/or prevented.

(25) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used to inhibit the synthesis of triglyceride by causing the sputum enzyme A: dimercaptoglyceryl thiol transferase, and the symptom Treat, improve, alleviate and/or prevent the treatment and/or prevention of the disease being achieved.

(26) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used for obesity, obesity, hyperlipidemia, high triglyceride, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, Diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, multi-cytoplasmic ovarian syndrome, atherosclerosis, porridge Treatment and/or prevention of atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating.

(27) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is for the treatment and/or prevention of obesity or obesity.

(28) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used for the treatment and/or prevention of diabetes.

(29) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is used for obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, Diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, multi-cytoplasmic ovarian syndrome, atherosclerosis, porridge Treatment and/or prevention of atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or gallstones.

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

(31) The pharmaceutical composition according to (19), wherein the pharmaceutical composition is for inhibiting fat absorption from the small intestine.

The compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof, which is used for obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism Disease, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis , treatment and/or prevention of multiple cell ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating.

(33) A compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in the treatment and/or prevention of obesity or obesity.

(34) A compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for use in the treatment and/or prevention of diabetes.

(35) Use of a compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.

(36) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for inhibiting 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase.

(37) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for inhibiting food intake and/or appetite.

(38) The use according to (35), wherein the pharmaceutical composition is used for obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes , Diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, porridge A pharmaceutical composition for the treatment and/or prevention of atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating.

(39) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prevention of obesity or obesity.

(40) The use according to (35), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prevention of diabetes.

(41) The use according to (35), wherein the pharmaceutical composition is used for hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance abnormality, diabetes caused by obesity, Diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, porridge Medical composition for the treatment and/or prevention of atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormality, low back pain, deformed knee joint disease, gout or gallstone .

(42) The use according to (35), wherein the pharmaceutical composition is for the treatment and/or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity Pharmaceutical composition.

(43) The use according to (35), wherein the pharmaceutical composition is for inhibiting fat absorption from the small intestine.

(44) A method for inhibiting 醯Kytozyme A: a dimercaptoglycerol hydrazinotransferase, which is a pharmacological method of selecting a compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof The effective amount is administered to warm-blooded animals.

(45) A method for inhibiting feeding and/or appetite suppressing, which comprises administering a pharmacologically effective amount of a compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof to warm blood. animal.

(46) A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof to warm blood. animal.

(47) The method according to (46), wherein the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism disease, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications ( Includes diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, Diabetic atherosclerosis, ischemic heart disease or overeating.

(48) The method according to (46), wherein the disease is obesity or obesity.

(49) The method according to (46), wherein the disease is diabetes.

(50) The method according to (46), wherein the disease is obesity caused by hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism disease, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including Diabetic peripheral neuropathy, diabetic nephropathy, diabetic omental disease, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, porridge Atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout or gallstones.

(51) The method according to (46), wherein the disease is hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(52) A method for inhibiting fat absorption from a small intestine, which comprises administering a pharmacologically effective amount of a compound according to any one of (1) to (16) or a pharmacologically acceptable salt thereof to warm blood. animal.

(53) The method according to any one of (44) to (52) 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. It is preferably a fluorine atom or a chlorine atom, more preferably a fluorine 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. It is preferably a linear or branched alkyl group (C ₁ -C ₄ alkyl) having 1 to 4 carbon atoms, more preferably a methyl group or an ethyl group (C ₁ -C ₂ alkyl group), and more preferably Is a methyl group.

In the present invention, the "C ₁ -C ₆ halogenated alkyl group" is a group in which one or five of the "halogen atoms" which are the same or different are bonded to the above-mentioned "C ₁ -C ₆ alkyl group". For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloro Ethyl, 2-bromoethyl or 2-fluoroethyl. Preferably, the same or different 1 to 5 of the above-mentioned "halogen atom" is bonded to the above-mentioned "C ₁ -C ₄ alkyl group" (C ₁ -C ₄ halogenated alkyl group), more preferably the same or different One to five of the above-mentioned "halogen atom" is bonded to the above-mentioned "C ₁ -C ₂ alkyl group" (C ₁ -C ₂ halogenated alkyl group), and more preferably a trifluoromethyl group.

In the present invention, the "C ₁ -C ₆ alkoxy group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. . For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy, 2-methylbutoxy Base, 3-ethylpropoxy, hexyloxy or 2,3-dimethylbutoxy. Preferred is a linear or branched alkoxy group (C ₁ -C ₄ alkoxy group) having _{1 to 4} carbon atoms, more preferably a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group) ), and more preferably methoxy.

In the present invention, the "C ₁ -C ₆ halogenated alkoxy group" is a group in which one or five of the "halogen atoms" which are the same or different are bonded to the above-mentioned "C ₁ -C ₆ alkoxy group". For example, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 2 2,2-trichloroethoxy or pentafluoroethoxy. Preferably, the same or different 1 to 5 of the above-mentioned "halogen atom" is bonded to the above-mentioned "C ₁ -C ₄ alkoxy group" (C ₁ -C ₄ halogenated alkoxy group), more preferably the same or The above-mentioned "halogen atom" which is different from the above-mentioned "C ₁ -C ₂ alkoxy group" (C ₁ -C ₂ halogenated alkoxy group) is more preferably a trifluoromethoxy group.

In the present invention, "(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group" is one of the aforementioned "C ₁ -C ₆ alkoxy groups" and the above "C ₁ -C ₆ Alkyl" bonded group. For example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, s-butoxymethyl, t-butoxymethyl, 2 -Methoxyethyl or 3-isopropoxypropyl. Preferably, one of the above-mentioned "C ₁ -C ₄ alkoxy groups" is bonded to the above-mentioned "C ₁ -C ₄ alkyl group" ((C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkane) More preferably, the above-mentioned "C ₁ -C ₂ alkoxy group" is bonded to the above-mentioned "C ₁ -C ₂ alkyl group" ((C ₁ -C ₂ alkoxy)-(C) ₁ -C ₂ alkyl) group, more preferably methoxymethyl.

In the present invention, the "C ₁ -C ₆ alkylthio group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to a sulfur atom, and is a linear or branched alkylthio group having 1 to 6 carbon atoms. . For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio or hexylthio. Preferred is a linear or branched alkanethio group (C ₁ -C ₄ alkylthio group) having 1 to 4 carbon atoms, more preferably a methylthio group or an ethylthio group (C ₁ -C ₂ alkylthio group) ), and more preferably methylthio.

In the present invention, the "C ₁ -C ₆ alkylsulfinyl group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to a sulfinyl group, and is a linear or branched carbon number of 1 to 6. A branched alkyl sulfinyl group. For example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl or hexylsulfinyl . Preferred is a linear or branched alkyl sulfinyl group (C ₁ -C ₄ alkylsulfinyl) having 1 to 4 carbon atoms, more preferably methylsulfinyl or ethyl Sulfhydryl (C ₁ -C ₂ alkylsulfinyl), more preferably methylsulfinyl.

In the present invention, the "C ₂ -C ₇ alkylcarbonyl group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded to a carbonyl group. For example, acetyl, propyl, butyl, isobutyl, pentyl, trimethylethenyl or amyl. Preferably, the above-mentioned "C ₁ -C ₄ alkyl group" is bonded to a carbonyl group (C ₂ -C ₅ alkylcarbonyl group), more preferably an ethyl hydrazino group or a propyl fluorenyl group (C ₂ -C ₃ alkyl group). More preferably, it is a carbonyl group.

In the present invention, the "C ₂ -C ₇ alkoxycarbonyl group" is a group in which one of the above-mentioned "C ₁ -C ₆ alkoxy groups" is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl. Preferably, the above-mentioned "C ₁ -C ₄ alkoxy group" is bonded to a carbonyl group (C ₂ -C ₅ alkoxycarbonyl group), more preferably a methoxycarbonyl group or an ethoxycarbonyl group (C ₂ - More preferably, C ₃ alkoxycarbonyl) is a methoxycarbonyl group.

In the present invention, the "mono-C ₁ -C ₆ alkylamino group" is a group in which one of the above-mentioned "C ₁ -C ₆ alkyl groups" is bonded to an amine group. For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, t-butylamino, pentylamino, neopentylamine Base or hexylamino group. Preferably, the above-mentioned "C ₁ -C ₄ alkyl group" is bonded to an amine group (mono-C ₁ -C ₄ alkylamino group), more preferably a methylamino group or an ethylamino group (single) -C ₁ -C ₂ alkylamino group), more preferably methylamino group.

In the present invention, the "di-(C ₁ -C ₆ alkyl)amino group" is a group in which the above-mentioned "C ₁ -C ₆ alkyl group" which is the same or different is bonded to an amine group. For example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-ethyl-N-methylamino, N-methyl- N-propylamino, N-isopropyl-N-methylamino, N-butyl-N-methylamino, N-ethyl-N-propylamino or N-ethyl-N - isoamylamino. Preferably, the same or different two of the above-mentioned "C ₁ -C ₄ alkyl group" are bonded to an amine group (di-(C ₁ -C ₄ alkyl)amino group), more preferably dimethylamine. Further, a diethylamino group or an N-ethyl-N-methylamino group (di-(C ₁ -C ₂ alkyl)amino group) is more preferably a dimethylamino group.

In the present invention, the "mono-C ₂ -C ₇ alkylcarbonylamino group" is a group in which a carbonyl group to which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded is bonded to an amine group. For example, an ethenyl group, an ethylcarbonylamino group, a propylcarbonylamino group, an isopropylcarbonylamino group, a butylcarbonylamino group or an isobutylcarbonylamino group. Preferably, one of the above-mentioned "C ₁ -C ₄ alkyl group" has a carbonyl group bonded to an amine group (mono-C ₂ -C ₅ alkylcarbonylamino group), more preferably an acetamino group or a The carbonylamino group (mono-C ₂ -C ₃ alkylcarbonylamino group) is more preferably an acetamino group.

In the present invention, the "mono-C ₁ -C ₆ alkylsulfonylamino group" is a group in which a sulfonyl group to which the above-mentioned "C ₁ -C ₆ alkyl group" is bonded is bonded to an amine group. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, t-butylsulfonyl Amino or 2-ethylbutylsulfonylamino. Preferably, one of the above-mentioned "C ₁ -C ₄ alkyl groups" is bonded to a group of a sulfonyl group bonded to an amine group (mono-C ₁ -C ₄ alkylsulfonylamino group), more preferably a methyl group. Sulfhydrylamino or ethylsulfonylamino (mono-C ₁ -C ₂ alkylsulfonylamino), more preferably methylsulfonylamino.

In the present invention, the "C ₃ -C ₆ cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, preferably a cyclohexyl group.

In the present invention, the "phenyl group which may be substituted with 1 to 5 groups independently selected from the group of the substituent group A" is a phenyl group or a phenyl group substituted with 1 to 5 groups independently selected from the group of the substituent group A. Preferred is a phenyl group which may be substituted by 1 to 3 groups independently selected from (a fluorine atom, a chlorine atom, a methyl group and a methoxy group), more preferably a phenyl group, a 2-fluorophenyl group or a 3-fluorophenyl group. , 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxybenzene Base, 2-chloro-4-fluorophenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2,4-dimethylphenyl, 2-methoxy- 5-methylphenyl or 2,4,5-trifluorophenyl.

In the present invention, the "pyridyl group which may be substituted with 1 to 3 groups independently selected from the group of the substituent group A" is a pyridyl group or a pyridyl group which is substituted with 1 to 3 groups independently selected from the group of the substituent group A. Preferred is 2-pyridyl, 3-pyridyl or 4-pyridyl.

In the present invention, a suitable formula (I) is a formula (Ia), a formula (Ib), a formula (Ic), a formula (Id), a formula (Ie) or a formula (If), which is more suitable The general formula (I) is the general formula (Ia).

In the present invention, a suitable R is a phenyl group which may be substituted by 1 to 5 groups independently selected from the group of substituents A, and more suitably R may be independently selected from 1 to 3 (fluorine atom, chlorine atom, A Further substituted phenyl groups, and more preferably R is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methyl Phenylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-fluoro-3 -methylphenyl, 2-fluoro-4-methylphenyl, 2,4-dimethylphenyl, 2-methoxy-5-methylphenyl or 2,4,5-trifluorophenyl .

In the present invention, a suitable Q is a nitrogen atom.

In the present invention, a suitable U is a nitrogen atom.

In the present invention, a suitable V is a group represented by the formula -CH=.

In the present invention, a suitable m is 1.

In the present invention, a suitable n is 1.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof contains all of the isomers (non-image, isomers, optical isomers, cyclables, etc.).

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof has various differences due to the presence of an asymmetric carbon atom in its molecule. Structure. The compounds of the present invention, such isomers and mixtures of such isomers are all represented in a single formula, i.e., in formula (I). Accordingly, the present invention should also include such isomers and mixtures of such ratios in any ratio.

The use of an optically active starting material compound, or the synthesis of a compound of the present invention using an asymmetric synthesis or asymmetric induction, or the compound of the present invention which is isolated by conventional optical separation or separation may be obtained as described above. Stereoisomers.

The compound represented by the formula (Ia) or a pharmacologically acceptable salt thereof is preferably a compound represented by the formula (Ib) to (If) or a pharmacologically acceptable salt thereof.

The compound of the present invention may contain an atomic isotope ratio of one or more of the atoms constituting such a compound. As the atomic isotope, for example, ruthenium ( ² H), ruthenium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C) may be mentioned. In addition, the compounds may be, for example, tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or carbon -14 ⁽¹⁴ C), etc. of radioisotopes for radioactivity identified. The radiolabeled compound is useful as a therapeutic or prophylactic agent, a research reagent, for example, an analytical reagent, and a diagnostic agent, for example, an in vivo imaging diagnostic agent. All isotopic variations of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"The pharmacologically acceptable salt" means that it is not significantly toxic and can be used as a medical user. The compound represented by the formula (I) of the present invention can form a salt by reacting with an acid in the case of having a basic group, and can form a salt by reacting with a base in the case of having an acidic group.

As the salt based on the basic group, for example, a hydrogen halide such as a hydrogen fluoride salt, a hydrochloride, a hydrogen bromide or a hydrogen iodide; a nitrate, a perchlorate or a sulfuric acid can be exemplified; a mineral acid salt such as a salt or a phosphate; an alkyl sulfonate such as a methanesulfonate, a trifluoromethanesulfonate or an ethanesulfonate; a besylate or a p-toluenesulfonate; An aryl sulfonate; an acid salt of an acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate or the like; And an amine acid salt such as a glycinate, an amidate, a arginine, an alanate, a glutamate or an aspartate.

On the other hand, as the salt based on the acidic group, for example, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an aluminum salt or an iron salt can be exemplified; a metal salt; an inorganic salt such as an ammonium salt; t-octylamine salt, dibenzylamine salt, Alkaloid salt, glucosamine salt, alkyl phenylglycine salt, ethylenediamine salt, N-methylglucamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine Salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine An amine salt such as an organic salt such as a salt, a tetramethylammonium salt or a hydroxy(hydroxymethyl)aminomethane salt; and a glycinate, an aminate, a arginine, an alanate, or a bran Amino acid salt such as aminate or aspartate.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof is obtained by being placed in the atmosphere or recrystallized to obtain water molecules, and in the case of becoming a hydrate, such a hydrate is also included in the present invention. Salt of the invention.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof may be a solvent which absorbs other kinds of solvents, and such a solvent is also included in the salt of the present invention.

The compound represented by the formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent DGAT inhibitory action and food suppressing action, and is useful in a warm-blooded animal (preferably a mammal, including a human). Medicine for prevention and/or treatment of diseases: selected from the group consisting of obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance, diabetes, diabetes complications (including Diabetic peripheral neuropathy, diabetic nephropathy, diabetic omental disease, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetes Diseases of the group consisting of atherosclerosis, ischemic heart disease, and overeating; or hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, and sugar tolerance caused by obesity Abnormalities, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, sugar Urinary macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, hypertension, cerebrovascular disease, coronary Diseases of the group consisting of arterial disease, fatty liver, respiratory abnormalities, low back pain, deformed knee joint disease, gout, and gallstones. Further, the novel compound represented by the formula (I) or a pharmacologically acceptable salt thereof provided by the present invention has an excellent DGAT inhibitory action, and is useful for use in a warm-blooded animal, preferably a mammal, including a human. An active ingredient of a medicine for the prevention and/or treatment of diseases. It is preferred to use a medicine for the treatment of the above-mentioned diseases.

[Formation for implementing the invention]

The compound represented by the formula (I) of the present invention can be produced according to the methods A to C described below.

The solvent to be used in the reaction of the respective steps of the following methods A to C 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 comprises hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N,N-dimethylformamide, N,N-di Indoleamines such as methyl acetamino group, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, trimethylamine hexamethylphosphate; diethyl ether, diisopropyl Ether, tetrahydrofuran, two Ethers such as alkane, dimethoxyethane, diethylene glycol dimethyl ether, cyclopentyl methyl ether; methanol, ethanol, n-propanol, i-propanol, n-butanol, 2 Alcohols such as butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexanol, and cellosolve ; anthraquinones such as dimethyl hydrazine; hydrazines such as cyclobutyl hydrazine; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate , esters such as butyl acetate and diethyl carbonate; acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone, cyclohexyl Ketones such as ketones; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, carbon tetrachloride Halogenated hydrocarbons; aromatic hydrocarbons such as benzene, toluene, xylene; N-methyl Porphyrin, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinepyridine, rind Picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline , N,N-diethylaniline, 1,5-dioxabicyclo[4.3.0]non-5-ene (DBN), 1,4-dioxabicyclo[2.2.2]octane (DABCO), 1 , 8-diindole bicyclo [5.4.0] undec-7-ene (DBU), amines such as piperidine; water; and mixed solvents thereof.

a base used in the reaction of each of the following steps A to C, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate; sodium hydrogencarbonate, potassium hydrogencarbonate or lithium hydrogencarbonate Alkali metal hydrogencarbonates; 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 , alkali metal hydroxides such as potassium hydroxide or lithium hydroxide; alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, sodium t-butoxide, t-butanol Alkali metal alkoxides such as potassium; alkali metal trialkyl sulfonium oxides such as sodium trimethyl sulfonium oxide, potassium trimethyl sulfonium oxide, lithium trimethyl sulfonium oxide; N-A base Porphyrin, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 2,6-lutidine, Colin Collidine, 4-pyrrolidinepyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline , N,N-dimethylaniline, N,N-diethylaniline, 1,5-dioxinbicyclo[4.3.0]non-5-ene (DBN), 1,4-dioxabicyclo[2.2. 2] an organic base such as octane (DABCO), 1,8-dioxinbicyclo[5.4.0]undec-7-ene (DBU); lithium diisopropyl decylamine, lithium bis(trimethyl) An organometallic base such as a decyl alkylamine; or an amino acid such as a proline.

The palladium catalyst used in the reaction of each of the following steps A to C, for example, ruthenium (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II) ), palladium black, palladium (II) bromide, 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), etidylacetone palladium(II), Palladium(II) sulfide, [1,1 ' -bis(diphenylphosphino)ferrocene]palladium(II), tris(dibenzylideneacetone)dipalladium(0), ruthenium (acetonitrile) palladium (II) A divalent palladium catalyst or a zero-valent palladium catalyst such as tetrafluoroborate or an arylplatinum dimer.

The reaction is carried out in each of the following steps A to C, and the reaction temperature varies depending on the solvent, the starting material, the reagent, and the like, and the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature, and the like.

The reaction is carried out in each step of the following methods A to C. After the reaction is completed, each compound of interest is taken from the reaction mixture according to a usual method. For example, the reaction mixture is suitably neutralized, and after being removed by filtration in the presence of insoluble matter, an organic solvent which does not mix with water and ethyl acetate is added, and the organic layer containing the objective compound is separated into water. After washing, it is dried with anhydrous magnesium sulfate, anhydrous sodium sulfate or the like, filtered, and then obtained by distilling off a solvent. If necessary, a usual method such as general recrystallization, reprecipitation, or the like, a method conventionally used for separation and purification of an organic compound, and a chromatographic method can be used to purify the obtained compound by elution with a suitable dissolving agent. The crude product obtained can be washed with a solvent to purify the objective compound which is insoluble in a solvent. Further, the objective compound of each step can be directly used in the next reaction without purification.

In the following steps from the A method to the C method, R, Q, U, V, m and n have the same meanings as described above. X represents a halogen atom (preferably a bromine atom or an iodine atom, more preferably a bromine atom), and Y represents a protecting group of a carboxyl group used in the field of organic synthetic chemistry (preferably a C ₁ -C ₆ alkyl group, more preferably A base). R ^a , which is the same as the group in the definition of R, except that the amine group, the hydroxyl group and/or the carboxyl group contained as a substituent in the group of R are a protected amino group, a hydroxyl group and/or a carboxyl group. base.

The method A is a method for producing a compound represented by the formula (I).

A-I step

This step is carried out by reacting a compound represented by the formula (II) with a compound represented by the formula (III) in the presence of a light-diffusing reagent in a solvent to produce a compound represented by the formula (IV). step.

The compound represented by the formula (II) used in the present step is a known compound, or a known compound can be easily produced as a starting material according to a known method or the like.

The compound represented by the formula (III) used in the present step is a known compound, or a known compound can be easily produced as a starting material according to a known method or the like.

The solvent used in this step is preferably an aromatic hydrocarbon or an ether, more preferably toluene or tetrahydrofuran.

The light-diffusing reagent used in this step is preferably an azodicarboxylate or a (cyanomethylene)phosphine reagent, more preferably diethyl azodicarboxylate (DEAD) or azodiamine. Diisopropyl carboxylic acid (DIAD) or (cyanomethylene) tributylphosphane (CMBP).

The reaction temperature in this step is usually -20 ° C to 180 ° C, preferably 0 ° C to 120 ° C.

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

A-II step

This step is a step of producing a compound represented by the formula (VI) by reacting the compound represented by the formula (IV) with a compound (V) in the presence of a solvent, a palladium catalyst and a base.

The solvent used in this step is preferably a mixed solvent of an ether or a guanamine and water, more preferably tetrahydrofuran or two. A mixed solvent of an alkane or N,N-dimethylacetamino group and water.

The palladium catalyst used in this step is preferably a zero-valent palladium catalyst, more preferably ruthenium (triphenylphosphine) palladium (0).

The base used in this step is preferably an alkali metal carbonate or more preferably potassium carbonate.

The reaction temperature in this step is usually from 20 ° C 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 to 24 hours.

Step A-III

This step is a step in which a compound represented by the formula (VI) is reacted with a compound represented by the formula (VII) to produce a compound represented by the formula (VIII) in a solvent.

The compound represented by the formula (VII) used in the present step is a known compound, or can be easily produced by a known method using a known compound as a starting material or the like.

The solvent used in this step is preferably an ether, more preferably tetrahydrofuran.

The reaction temperature in this step is usually -78 ° C to 180 ° C, preferably 0 ° C to 80 ° C.

The reaction time in this step is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

A-IV step

This step is represented by the general formula (VIII) according to a known method (for example, "Protective Groups in Organic Synthesis" (the method described by Theodora W. Greene, Peter GMWuts, 1999, Wiley-Interscience Publication). After the reaction of the compound, a step of producing a compound represented by the formula (I) is carried out by removing ^a protecting group of an amine group, a hydroxyl group and/or a carboxyl group in R ^a as desired. For example, the case where Y is a C ₁ -C ₆ alkyl group is shown below.

The solvent used in this step is preferably an ether or an alcohol, more preferably tetrahydrofuran or two. Alkane or methanol.

The base used in this step is preferably a quaternary ammonium salt, more preferably tetrabutylammonium hydroxide.

The reaction temperature in this step is usually from 0 ° C to 150 ° C, preferably from 20 ° C to 100 ° C.

The reaction time in the reaction is usually from 0.5 to 24 hours, preferably from 1 to 10 hours.

The B method is a method for producing a compound represented by the formula (VIII) used in the A-IV step of the above-mentioned A method.

B-I step

This step is carried out by reacting a compound represented by the formula (VI) with a compound (IX) in the presence of a base in a solvent, and in the presence of a base in a solvent, by expressing the formula (X) The compound is reacted to produce a compound represented by the formula (VIII).

The solvent used in this step is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The base used in this step is preferably an organic base, more preferably triethylamine.

The reaction temperature in this step is usually -78 ° C to 100 ° C, preferably 0 ° C to 40 ° C.

The reaction time in this step is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

The C method is a method for producing a compound represented by the formula (VIII) used in the A-IV step of the above-mentioned A method.

C-I step

This step is a step of producing a compound represented by the formula (XII) by reacting a compound represented by the formula (VI) with a compound (XI) in a solvent.

The solvent used in this step is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The reaction temperature in this step is usually -78 ° C to 120 ° C, preferably 0 ° C to 40 ° C.

The reaction time in this step is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

C-II step

This step is a step of producing a compound represented by the formula (VIII) by reacting a compound represented by the formula (XII) with a compound represented by the formula (X) in a solvent.

The solvent used in this step is preferably an ether, a nitrile, a nitro compound, a guanamine or a hydrocarbon, more preferably tetrahydrofuran, acetonitrile, nitrobenzene or N,N-dimethylacetamide. Or hexane.

The reaction temperature in this step is usually -78 ° C to 180 ° C, preferably 0 ° C to 120 ° C.

The reaction time in this step is usually from 0.1 to 72 hours, preferably from 0.5 to 24 hours.

As described above, the protective group of "protectable amine group", "protected hydroxyl group" and/or "protectable carboxyl group" in the definition of R ^a means that it can be hydrolyzed, hydrolyzed, and electrolyzed. A protecting group which is cleaved by a chemical method such as photolysis means a protecting group generally used in organic synthetic chemistry (for example, refer to TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999). year)).

The "protecting group" of the "protectable hydroxyl group" in the definition of R ^a is not particularly limited as long as it is a protecting group for a hydroxyl group used in the field of organic synthetic chemistry, for example, a thiol group, the aforementioned "C ₂ - Alkoxycarbonyl such as C ₇ alkylcarbonyl", chloroethinyl, dichloroacetinyl, trichloroethenyl, trifluoroethenyl, etc., alkoxyalkyl such as methoxyethenyl An unsaturated alkylcarbonyl group such as a carbonyl group, an acryloyl group, a propynyl group, a methacryl fluorenyl group, a crotonyl group, an isocrotonyl group, or an (E)-2-methyl-2-butenyl group "Alkylcarbonyl"; benzylidene, α-naphthylmethyl, arylcarbonyl such as β-naphthylmethyl, 2-bromobenzylidene, 4-chlorobenzyl or the like Alkoxylation of an alkylated arylcarbonyl group such as a halogenated arylcarbonyl group, a 2,4,6-trimethylbenzylidene group, a 4-toluocarbenyl group, or an 4-anisylmercapto group An alkoxycarbonyl group such as an arylcarbonyl group, a 4-nitrobenzylidene group or a 2-nitrobenzylidene group, or an alkoxycarbonyl group such as a 2-(methoxycarbonyl)benzylidene group An arylated aryl group such as an arylcarbonyl group or a 4-phenylbenzylidene group Group of "arylcarbonyl group"; the "C ₂ -C ₇ alkoxycarbonyl group", 2,2,2-trichloroethoxycarbonyl group, 2-trimethyl silicon ethoxycarbonyl group or the like halogen Or an alkoxycarbonyl group such as an alkoxycarbonyl group substituted by a trialkyldecyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydro "tetrahydropyranyl or tetrahydrothiopyranyl" such as piperazin-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran "tetrahydrofuranyl or tetrahydrothiofuranyl" such as 2-yl, tetrahydrothiofuran-2-yl; trimethyldecyl, triethyldecyl, isopropyldimethylmethyl, t- a trialkyldecylalkyl group such as butyldimethylmethylalkyl, methyldiisopropyldecyl, methyldi-t-butyldecyl, triisopropyldecyl, or diphenylmethyldecyl "Alkylalkyl" such as an alkyldiarylalkylene group or a dialkylarylalkylene group such as a diphenylbutyl decyl group, a diphenylisopropyl decyl group or a phenyl diisopropyl decyl group ; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxy Alkoxyalkyl group such as alkoxymethyl group such as isopropyloxymethyl group, butoxymethyl group or t-butoxymethyl group or alkoxy alkoxy group such as 2-methoxyethoxymethyl group "Alkoxymethyl" such as a halogenated alkoxymethyl group such as methyl, 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; 1-B a "substituted ethyl group" such as an oxyethyl group, an alkoxyethyl group such as 1-(isopropoxy)ethyl group or a halogenated ethyl group such as 2,2,2-trichloroethyl; 1 to 3 such as α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-fluorenylmethyl Alkyl-substituted alkyl; 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methyl Alkyl phenyl diphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl "Alkoxy group, alkoxy group, nitro group, halogen, aryl group substituted with 1 to 3 aryl groups of the aryl ring) substituted "alkyl group"; vinyloxycarbonyl group, allyloxycarbonyl group "Alkenyloxycarbonyl"; benzyloxycarbonyl 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc. Or an alkoxy group or a nitro group-substituted "aralkyloxycarbonyl group" of the aryl ring, preferably an alkylcarbonyl group, a decyl group or an aralkyl group.

In the above, the "protecting group" of the "protectable 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 organic synthetic chemistry, for example, the above "C ₁ - C ₆ "Alkyl";"alkenyl" such as vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl; ethynyl, 1-propynyl, 2-propynyl, 1 - "alkynyl" such as methyl-2-propynyl; the above "C ₁ -C ₆ halogenated alkyl"; hydroxyalkyl, hydroxyalkyl such as 2-hydroxyethyl; ethenylmethyl The above alkylcarbonylalkyl group; the aforementioned "aralkyl group"; or the aforementioned "decyl group" is preferably a C ₁ -C ₆ alkyl group or an aralkyl group.

In the above, the "protecting group" of the "protectable amine group" in the definition of R ^a is not particularly limited as long as it is a protecting group for the amine group used in the field of organic synthetic chemistry, and for example, "Alkylcarbonyl" in the "protecting group";"arylcarbonyl";"alkoxycarbonyl";"decylalkyl";"aralkyl";"alkenyloxycarbonyl"; or "aralkyloxy" The same group as the carbonyl group, or N,N-dimethylaminomethylene, benzylidene, 4-methoxybenzylidene, 4-nitrobenzylidene, arsenyl, 5-chloro "Forming a Schiff base substituted methylene group" such as a sulfhydryl group, a diphenylmethylene group or a (5-chloro-2-hydroxyphenyl) phenylmethylene group, preferably an alkane A carbonyl group, an arylcarbonyl group or an alkoxycarbonyl group is more preferably an alkoxycarbonyl group.

protection. The step necessary for the deprotection can be carried out according to a known method (for example, "Protective Groups in Organic Synthesis" (the method described in Theodora W. Greene, Peter G. M. Wuts, 1999, Wiley-Interscience Publication).

The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. In terms of this administration form, for example, a lozenge can be exemplified Oral administration of capsules, granules, emulsions, pills, powders, syrups (liquid preparations), or by injection (intravenous, intramuscular, subcutaneous or intraperitoneal administration), drip, suppository ( Rectal administration) and other non-oral injections. These various preparations can be generally used in the pharmaceutical preparation technology of the main drug using excipients, binding agents, disintegrating agents, lubricants, flavoring agents, dissolution aids, suspending agents, coating agents, and the like according to the conventional method. The adjuvant used was formulated.

In the case of use as a tablet, as the carrier, for example, an excipient such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, citric acid or the like; water, a combination of ethanol, propanol, monosaccharide syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; dried starch, alginic acid a disintegrant of sodium, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; a disintegration inhibitor of sugar, stearic acid, cocoa butter, hydrogenated oil, etc.; an absorption enhancer such as a fourth-order ammonium salt or sodium lauryl sulfate; a moisturizer such as glycerin or starch; starch, lactose, kaolin, soap Adsorbent for soil (bentonite), colloidal citric acid, etc.; lubricant for refining talc, stearate, boric acid powder, polyethylene glycol, etc. Further, if necessary, a tablet for administering a usual lotion such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet or a double-layer ingot, or a multilayer ingot can be prepared.

In the case of use as a pill, in terms of a carrier, for example, glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc Such excipients; agglomerates of gum arabic powder, tragacanth powder, gelatin, ethanol, etc.; disintegrators such as laminaria polysaccharide, agar, and the like.

In the case of use as a suppository, it is widely known in the art for the carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like.

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 to be used for the production of the liquid preparation, the emulsion or the suspension is not particularly limited as long as it can be used as a diluent for medical use. For example, water, ethanol, propylene glycol, and ethoxylated iso-hard can be exemplified. A fatty alcohol, a polyethoxylated isostearyl alcohol, a polyoxyethylene sorbitan fatty acid ester or the like. Further, in this case, the solution for preparing isotonicity may contain a sufficient amount of salt, glucose or glycerin in the preparation, and may contain a general dissolution aid, a buffering agent, a soothing agent and the like.

Further, the above-mentioned preparation may contain a coloring agent, a preservative, a flavor, a flavor, a sweetener, etc., if necessary, and may contain other pharmaceuticals.

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

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

[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 observation by TLC (Thin Layer Chromatography). In the observation by TLC, a silicone resin 60F ₂₅₄ manufactured by Merck Co., Ltd. as a TLC disk, and a solvent used as a solvent for elution in a column chromatography method, and a UV detector as a detection method were used. For the column, the silicone resin SK-85 (230-400 mesh) manufactured by the same Merck company or the Fuji SILYSIA chemical Chromatorex NH (200-350 mesh) was used. In addition to the general column chromatography, it is suitable to use the automatic chromatography apparatus (Purif-α2 or Purif-espoir2) of the company. The elution solvent was used at the ratio specified by the solvent specified in each example. (or change the ratio as appropriate). Further, the abbreviations used in the examples have the following types of meanings.

Mg: mg, g: gram, mL: ML, MHz: megahertz.

In the following examples, the nuclear magnetic resonance (hereinafter, ¹ H NMR) spectrum uses tetramethyl decane as a standard material, and the chemical shift value is described as a δ value (ppm). The split pattern is represented by a single line as s, a double line as d, a triple line as t, a quad line as q, a multiple line as m, and a broad line as br.

The mass analysis (hereinafter, MS) was carried out by an EI (Electron Ionization) method, an ESI (Electron Spray Ionization) method, or a FAB (Fast Atom Bombardment) method.

(Example 1)

(cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

(1a) {cis-4-[(5-bromopyrimidin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

Adding cyanamide to a solution of (trans-4-hydroxycyclohexyl)acetic acid methyl ester (WO2009119534) (2.58g) and 5-bromopyrimidin-2-ol (1.74g) in toluene (30mL) at room temperature Tributylphosphane (CMBP) (3.93 mL). The reaction mixture was heated at 120 ° C for 9 hours, cooled to room temperature, diluted with aq. The organic layer was washed with water and concentrated. The residue was purified by EtOAc EtOAcjjjjjjjj

_{^{1 H NMR (500MHz, CDCl 3}} ): δ (ppm) = 8.51 (2H, s), 5.23-5.18 (1H, m), 3.67 (3H, s), 2.28 (2H, d, J = 6.8 Hz), 2.09-1.89 (3H, m), 1.69-1.43 (6H, m).

(1b) (cis-4-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound obtained in Example (1a) (1.67 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.11 g) ), 肆 (triphenylphosphine) palladium (0) (295 mg), and potassium carbonate (1.41 g) of 1,4-two The alkane/water (7:3, 30 mL) solution was heated at 80 °C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by EtOAc EtOAcjjjjjjj

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.64 (2H, s), 7.32 (2H, d, J = 8.6Hz), 6.79 (2H, d, J = 8.2Hz), 5.29 (1H, Brs), 3.80 (2H, brs), 3.68 (3H, s), 2.29 (2H, d, J = 7.0 Hz), 2.13 - 2.09 (2H, m), 1.97-1.91 (1H, m), 1.72-1.55 (6H, m).

(1c) (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethyl)amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetate Base ester

2-Fluorophenyl isocyanate (0.088 mL) was added to a solution of the compound obtained in Example (1b). The reaction mixture was stirred for one night and concentrated. The residue was purified by column chromatography eluting elut elut elut elut eluting

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 9.28 (1H, brs), 8.88 (2H, s), 8.65 (1H, brs), 8.16 (1H, dt, J = 11.7 and 4.1Hz ), 7.67 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.29-7.23 (1H, m), 7.18-7.14 (1H, m), 7.06-7.00 (1H, m), 5.22-5.21 (1H, m), 3.60 (3H, s), 2.30 (2H, d, J = 7.0 Hz), 1.98-1.93 (2H, m), 1.89-1.83 (1H, m), 1.72 -1.63 (2H, m), 1.59-1.55 (2H, m), 1.42-1.34 (2H, m).

(1d) (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

1,4-two of the compound (251 mg) obtained in Example (1c) at room temperature Tetrabutylammonium hydroxide (1 mol/L aqueous solution, 1.1 mL) was added to the alkane (6 mL) solution. After stirring for one night, the reaction mixture was concentrated, and then neutralized with 1N aqueous hydrochloric acid (1.1 mL). Ethyl acetate and isopropyl ether were added to the mixture, stirred vigorously, and filtered. The obtained solid was dried under reduced pressure toield of 129mg (94%)

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.29 (1H, s), 8.88 (2H, s), 8.66 (1H, s), 8.16 (1H, dt , J = 11.6 and 4.2 Hz), 7.67 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.28-7.23 (1H, m), 7.16 (1H, dt, J = 10.9 and 3.9 Hz), 7.06-7.00 (1H, m), 5.22-5.20 (1H, m), 2.18 (2H, d, J = 7.0 Hz), 1.98-1.93 (2H, m), 1.87-1.80 (1H , m), 1.72-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.34 (2H, m).

MS (ESI) m / z: 465 (M+H) ⁺ .

(Example 2)

(cis-4-{[5-(4-{[(4-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

In the same manner as in the Example (1c), Compound (171 mg) and 4-methylphenylisocyanate (0.082 mL) obtained from the compound (1b) gave 198 mg (84%) of a white solid. This urea (198 mg) was hydrolyzed to give the title compound 155 mg (81%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.87 (2H, s), 8.83 (1H, s), 8.66 (1H, s), 7.64 (2H, d , J = 9.0 Hz), 7.57 (2H, d, J = 9.0 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.2 Hz), 5.22-5.20 (1H, m ), 2.25 (3H, s), 2.19 (2H, d, J = 7.1 Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.60- 1.56 (2H, m), 1.43-1.32 (2H, m).

MS (ESI) m / z: 461 (M+H) ⁺ .

(Example 3)

{cis-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (102 mg) obtained from Example (1b) and phenylisocyanate (0.042 mL) obtained 130 mg (94%) as a white solid. This urea (85 mg) was hydrolyzed to give the title compound (m.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, s), 8.87 (2H, s), 8.87 (1H, s), 8.76 (1H, s), 7.65 (2H, d , J = 8.6 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.47 (2H, d, J = 7.4 Hz), 7.30 (2H, dd, J = 8.0 and 8.0 Hz), 6.98 (1H, dd , J=7.4 and 7.4 Hz), 5.22-5.20 (1H, m), 2.20-2.18 (2H, m), 1.98-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H , m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 447 (M+H) ⁺ .

(Example 4)

(cis-4-{[5-(4-{[(3-fluorophenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained from Example (1b) and 3-fluorophenylisocyanate (0.029 mL) were obtained as a white solid, 89 mg (94%). The title compound (66 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.12 (1H, brs), 9.05 (1H, brs), 8.87 (2H, s), 7.66 (2H, d , J = 8.6 Hz), 7.59 (2H, d, J = 9.0 Hz), 7.53 - 7.49 (1H, m), 7.32 (1H, dd, J = 15.1 and 8.1 Hz), 7.16-7.14 (1H, m) , 6.80 (1H, dt, J = 12.5 and 4.2 Hz), 5.22-5.20 (1H, m), 2.18 (2H, d, J = 7.0 Hz), 1.97-1.93 (2H, m), 1.88-1.80 (1H , m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 465 (M+H) ⁺ .

(Example 5)

(cis-4-{[5-(4-{[(4-fluorophenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained in Example (1b) and 4-fluorophenylisocyanate (0.029 mL) were obtained as a white solid (yield: 85 mg (90%)). This urea (85 mg) was hydrolyzed to give the title compound (m.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.94 (1H, brs), 8.87 (2H, s), 8.86 (1H, brs), 7.65 (2H, d , J = 8.6 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.48 (2H, dd, J = 9.2 and 4.9 Hz), 7.14 (2H, dd, J = 8.8 and 8.8 Hz), 5.22-5.20 (1H,m), 2.19-2.18(2H,m),1.97-1.93(2H,m),1.87-1.80(1H,m),1.71-1.63(2H,m),1.61-1.56(2H,m) , 1.43-1.33 (2H, m).

MS (ESI) m / z: 465 (M+H) ⁺ .

(Example 6)

(cis-4-{[5-(4-{[(2-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

In the same manner as in Example (1c), Compound (68 mg) and 2-methylphenylisocyanate (0.032 mL) obtained from Example (1b) gave 83 mg (88%) as a white solid. The title compound (63 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.25 (1H, brs), 8.88 (2H, s), 8.05 (1H, brs), 7.85 (1H, d , J=8.3Hz), 7.66(2H,d,J=8.6Hz), 7.60(2H,d,J=9.0Hz), 7.20(1H,d,J=8.6Hz),7.17(1H,dd,J = 7.8 and 7.8 Hz), 6.97 (1H, dd, J = 7.6 and 7.6 Hz), 5.22-5.20 (1H, m), 2.26 (3H, s), 2.18 (2H, d, J = 7.1 Hz), 1.98 -1.93 (2H, m), 1.86-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 461 (M+H) ⁺ .

(Example 7)

(cis-4-{[5-(4-{[(3-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained in Example (1b) and 3-methylphenylisocyanate (0.032 mL) were obtained as a white solid, 90 mg (95%). This urea (90 mg) was hydrolyzed to give the title compound (yield: 88%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, brs), 8.91 (1H, brs), 8.88 (2H, s), 8.74 (1H, brs), 7.66 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.32 (1H, s), 7.25 (1H, d, J = 8.6 Hz), 7.17 (1H, dd, J = 7.8 and 7.9 Hz) , 6.81 (1H, d, J = 7.8 Hz), 5.22-5.20 (1H, m), 2.29 (3H, s), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.93 (2H, m), 1.88-1.80(1H,m),1.72-1.63(2H,m),1.61-1.56(2H,m),1.43-1.33(2H,m).

MS (ESI) m / z: 461 (M+H) ⁺ .

(Example 8)

(cis-4-{[5-(4-{[(2-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained in Example (1b) and 2-methoxyphenylisocyanate (0.035 mL) were obtained as a white solid, 51 mg (52%). . This urea (51 mg) was hydrolyzed in the same manner as in Example (1d) to give the title compound 48 mg (yield).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.48 (1H, brs), 8.87 (2H, s), 8.28 (1H, brs), 8.14 (1H, dd , J = 7.8 and 2.0 Hz), 7.66 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.04 (1H, dd, J = 7.8 and 1.6 Hz), 6.96 (1H) , dt, J = 10.8 and 3.9 Hz), 6.91 (1H, dt, J = 10.7 and 3.8 Hz), 5.22-5.20 (1H, m), 3.89 (3H, s), 2.19 (2H, d, J = 7.0) Hz), 1.98-1.93 (2H, m), 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Example 9)

(cis-4-{[5-(4-{[(3-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained in Example (1b) and 3-methoxyphenylisocyanate (0.034 mL) were obtained as a white solid, 91 mg (93%) . This urea (91 mg) was hydrolyzed to give the title compound 40 mg (45%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.19 (1H, brs), 9.09 (1H, brs), 8.87 (2H, s), 7.65 (2H, d , J=8.7Hz), 7.59 (2H, d, J=8.6Hz), 7.22 (1H, dd, J=2.4 and 2.4Hz), 7.18 (1H, dd, J=8.0 and 8.0Hz), 6.99-6.96 (1H, m), 6.57-6.54 (1H, m), 5.22-5.20 (1H, m), 3.74 (3H, s), 2.17 (2H, d, J = 7.0 Hz), 1.97-1.93 (2H, m ), 1.87-1.82 (1H, m), 1.70-1.63 (2H, m), 1.61-1.57 (2H, m), 1.42-1.34 (2H, m).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Embodiment 10)

(cis-4-{[5-(4-{[(4-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained in Example (1b) and 4-methoxyphenylisocyanate (0.034 mL) were obtained as a white solid, 86 mg (88%) as a white solid. . The title compound (68 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.87 (2H, s), 8.79 (1H, brs), 8.57 (1H, brs), 7.64 (2H, d , J = 9.0 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.37 (2H, d, J = 9.4 Hz), 6.88 (2H, d, J = 9.0 Hz), 5.21-5.20 (1H, m ), 3.72 (3H, s), 2.19 (2H, d, J = 7.1 Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.60- 1.56 (2H, m), 1.42-1.33 (2H, m).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Example 11)

(cis-4-{[5-(4-{[(2,4,5-trifluorophenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl) Acetic acid

The compound (171 mg) obtained from the compound (1b) and 2,4,5-trifluorophenylisocyanate (0.079 mL) were obtained in the same manner as in the Example (1c) to obtain a white solid (250 mg). 97%). This urea (250 mg) was hydrolyzed to give the title compound 241 mg (99%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.32 (1H, s), 8.88 (2H, s), 8.86 (1H, s), 8.24-8.17 (1H , m), 7.68 (2H, d, J = 9.0 Hz), 7.65-7.62 (1H, m), 7.58 (2H, d, J = 9.0 Hz), 5.22-5.20 (1H, m), 2.18 (2H, d, J = 7.0 Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 501 (M+H) ⁺ .

(Embodiment 12)

(cis-4-{[5-(4-{[(2-methoxy-5-methylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy} ring Hexyl)acetic acid

The compound (341 mg) obtained in Example (1b) and 2-methoxy-5-methylphenylisocyanate (424 mL) were obtained in the same manner as in Example (1) to give a white solid. 504 mg (quantitative yield). This urethane (504 mg) was hydrolyzed in the same manner as in Example (1d).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 9.48 (1H, s), 8.87 (2H, s), 8.22 (1H, s), 8.00 (1H, d, J = 2.0Hz), 7.65 (2H, d, J = 9.0 Hz), 7.57 (2H, d, J = 8.6 Hz), 6.91 (1H, d, J = 8.2 Hz), 6.76 (1H, dd, J = 8.2 and 1.5 Hz), 5.21-5.20 (1H, m), 3.85 (3H, s), 2.24 (3H, s), 2.19 (2H, d, J = 7.0 Hz), 1.97-1.93 (2H, m), 1.86-1.81 (1H, m), 1.70-1.64 (2H, m), 1.60-1.56 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 495 (M+H) ⁺ .

(Example 13)

(cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyridinium -2-yl]oxy}cyclohexyl)acetic acid

(13a){cis--4-[(5-bromopyridyl) 2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (1a), methyl (trans-4-hydroxycyclohexyl)acetate (WO2009119534) (694 mg) and 5-bromopyridinium 2-Alkyl (470 mg), cyanomethylenetributylphosphane (CMBP) (1.1 mL).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.16 (1H, d, J = 1.6 Hz), 7.99 (1H, d, J = 1.1 Hz), 5.21-5.20 (1H, m), 3.69 ( 3H, s), 2.29 (2H, d, J = 7.1 Hz), 2.03-1.99 (2H, m), 1.96-1.91 (1H, m), 1.69-1.55 (4H, m), 1.48-1.38 (2H, m).

(13b) (cis-4-{[5-(4-aminophenyl)pyridinium Methyl-2-yl]oxy}cyclohexyl)acetate

The compound (633 mg) obtained from the example (13a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride were obtained in the same manner as in the Example (1b). Pentacyclo-2-yl) aniline (421 mg) gave 324 mg (49%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.39 (1H, d, J = 1.6 Hz), 8.20 (1H, d, J = 1.6 Hz), 7.72 (2H, d, J = 8.6 Hz) , 6.78 (2H, d, J = 8.6 Hz), 5.27-5.25 (1H, m), 3.82 (2H, brs), 3.69 (3H, s), 2.31 (2H, d, J = 7.4 Hz), 2.07- 2.03 (2H, m), 1.98-1.92 (1H, m), 1.72-1.58 (4H, m), 1.53-1.46 (2H, m).

(13c) (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyridinium -2-yl]oxy}cyclohexyl)acetic acid

Obtained from the compound obtained in Example (13b) (102 mg) and 2-fluorophenylisocyanate (0.044 mL) in the same manner as 131 mg (92%) of urea in a white solid. The title compound (92 mg) (yield: 73%)

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, s), 9.28 (1H, s), 8.72 (1H, d, J = 1.2Hz), 8.64 (1H, s), 8.31 (1H, d, J = 1.2 Hz), 8.17 (1H, dt, J = 11.5 and 4.1 Hz), 7.97 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.8 and 7.8 Hz), 7.06-7.00 (1H, m), 5.25-5.21 (1H, m), 2.19 (2H, d, J = 7.1) Hz), 1.97.1.22 (2H, m), 1.86-1.80 (1H, m), 1.71-1.65 (2H, m), 1.61-1.56 (2H, m), 1.43-1.34 (2H, m).

MS (ESI) m / z: 465 (M+H) ⁺ .

(Example 14)

(cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid

(14a) {cis-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (1a), (trans-4-hydroxycyclohexyl)acetic acid methyl ester (WO2009119534) (2.58 g) and 5-bromopyridin-2-ol (1.74 g), cyania Methyl tributylphosphane (CMBP) (3.93 mL), m.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.16 (1H, d, J = 2.7 Hz), 7.62 (1H, dd, J = 8.8 and 2.5 Hz), 6.64 (1H, d, J = 8.6 Hz), 5.20-5.18 (1H, m), 3.68 (3H, s), 2.28 (2H, d, J = 7.5 Hz), 2.02-1.96 (2H, m), 1.95-1.88 (1H, m), 1.67 -1.54 (4H, m), 1.48-1.38 (2H, m).

(14b) (cis-4-{[5-(4-Aminophenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (2.76 g) obtained from the example (14a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in the Example (1b). Pentacyclo-2-yl)aniline (1.84 g) gave the title compound 2.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.30 (1H, d, J = 1.9 Hz), 7.72 (1H, dd, J = 8.4 and 2.5 Hz), 7.33 (2H, d, J = 8.7) Hz), 6.77-6.74 (1H, m), 6.76 (2H, d, J = 8.6 Hz), 5.27-5.26 (1H, m), 3.75 (2H, brs), 3.69 (3H, s), 2.30 (2H) , d, J = 7.5 Hz), 2.07-2.02 (2H, m), 1.97-1.90 (1H, m), 1.70-1.44 (6H, m).

(14c) (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid

The compound (170 mg) obtained from Example (14b) and 2-fluorophenylisocyanate (0.073 mL) obtained 221 mg (93%) as a white solid. The title compound (202 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.20 (1H, s), 8.61 (1H, d, J = 2.4Hz), 8.43 (1H, d, J =2.8 Hz), 8.17 (1H, dt, J = 11.5 and 4.1 Hz), 7.96 (1H, dd, J = 8.6 and 2.7 Hz), 7.60 (2H, d, J = 9.0 Hz), 7.55 (2H, d , J = 9.0 Hz), 7.28-7.23 (1H, m), 7.16 (1H, dd, J = 7.6 and 7.6 Hz), 7.05-6.99 (1H, m), 6.86 (1H, d, J = 8.6 Hz) , 5.23-5.22 (1H, m), 2.18 (2H, d, J = 7.4 Hz), 1.94-1.90 (2H, m), 1.85-1.79 (1H, m), 1.68-1.64 (2H, m), 1.61 -1.54(2H,m), 1.42-1.33(2H,m).

MS (ESI) m / z: 464 (M+H) ⁺ .

(Example 15)

(cis-4-{[5-(4-{[(4-methylphenyl))aminomethane]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid

The compound (413 mg) obtained from the compound (14b) and 4-methylphenylisocyanate (0.20 mL) were obtained as a white solid solid 571 mg (99%). This urea (571 mg) was hydrolyzed to give the title compound 538 mg (97%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 8.81 (1H, s), 8.66 (1H, s), 8.42 (1H, d, J = 3.1Hz), 7.96 (1H, dd, J =8.6 and 2.7 Hz), 7.59-7.52 (4H, m), 7.35 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 7.9 Hz), 6.86 (1H, d, J = 8.6 Hz) ), 5.23-5.21 (1H, m), 2.25 (3H, s), 2.18 (2H, d, J = 7.0 Hz), 1.94-1.90 (2H, m), 1.85-1.79 (1H, m), 1.67- 1.63 (2H, m), 1.60-1.54 (2H, m), 1.42-1.32 (2H, m).

MS (ESI) m / z: 460 (M+H) ⁺ .

(Embodiment 16)

{cis-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyridin-2-yl)oxy]cyclohexyl}acetic acid

The compound (383 mg) obtained from the compound (14b) and phenylisocyanate (0.179 mL) obtained 460 mg (yield: 89%) as a brown solid solid. This urea (460 mg) was hydrolyzed to give the title compound 419 mg (94%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.0 (1H, brs), 8.81 (1H, s), 8.73 (1H, s), 8.43 (1H, d, J = 2.8Hz), 7.96 (1H, dd, J = 8.6 and 2.8 Hz), 7.60-7.54 (4H, m), 7.47 (2H, d, J = 7.8 Hz), 7.30 (2H, dd, J = 7.8 and 7.8 Hz), 6.98 (1H, dd, J = 7.4 and 7.5 Hz), 6.86 (1H, d, J = 8.6 Hz), 5.23-5.23 (1H, m), 2.18 (2H, d, J = 7.1 Hz), 1.94-1.90 ( 2H, m), 1.86-1.80 (1H, m), 1.68-1.64 (2H, m), 1.61-1.54 (2H, m), 1.42-1.33 (2H, m).

MS (ESI) m / z: 446 (M+H) ⁺ .

(Example 17)

(cis-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid

The compound (170 mg) obtained from the compound (14b) and 2,4-dimethylphenylisocyanate (0.092 mL) were obtained as a pale yellow solid (m. 84%). The title compound (190 mg) (yield: 96%) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.10 (1H, s), 8.42 (1H, d, J = 3.1Hz), 7.95 (1H, dd, J =8.6 and 2.7 Hz), 7.93 (1H, s), 7.67 (1H, d, J = 8.2 Hz), 7.59-7.53 (4H, m), 7.00 (1H, s), 6.96 (1H, d, J = 8.6 Hz), 6.85 (1H, d, J = 8.6 Hz), 5.23-5.21 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 2.17 (2H, d, J = 7.1 Hz) , 1.94-1.89 (2H, m), 1.85-1.79 (1H, m), 1.67-1.63 (2H, m), 1.60-1.54 (2H, m), 1.42-1.32 (2H, m).

MS (ESI) m / z: 474 (M+H) ⁺ .

(Embodiment 18)

(cis-4-{[5-(4-{[(2-chloro-4-fluorophenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid

(18a) (cis-4-{[5-(4-{[(2-chloro-4-fluorophenyl))aminomethyl]amino}phenyl)pyridin-2-yl]oxy} ring Hexyl)methyl acetate

The compound obtained in Example (14b) (170 mg) and triethylamine (0.15 mL) in dichloromethane were added to a solution of tris (59 mg) in dichloromethane (4 mL). 4 mL) solution. A solution of 2-chloro-4-fluoroaniline (73 mg) and triethylamine (0.15 mL) in dichloromethane (4 mL) was then evaporated. The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut

¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 9.45 (1H, s), 8.43 (1H, d, J = 2.0 Hz), 8.34 (1H, s), 8.13 (1H, dd, J =9.2 and 5.7 Hz), 7.96 (1H, dd, J = 8.6 and 2.7 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.55 (2H, d, J = 9.0 Hz), 7.50 (1H, dd) , J = 8.6 and 3.1 Hz), 7.23 (1H, dt, J = 12.5 and 4.4 Hz), 6.85 (1H, d, J = 8.6 Hz), 5.23-5.22 (1H, m), 3.60 (3H, s) , 2.28 (2H, d, J = 7.0 Hz), 1.94-1.90 (2H, m), 1.87-1.82 (1H, m), 1.68-1.60 (2H, m), 1.57-1.52 (2H, m), 1.43 -1.33 (2H, m).

(18b) (cis-4-{[5-(4-{[(2-chloro-4-fluorophenyl))aminomethyl]amino}phenyl)pyridin-2-yl]oxy} ring Hexyl)acetic acid

The compound obtained in Example (18a) (193 mg).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.48 (1H, s), 8.43 (1H, d, J = 2.8Hz), 8.37 (1H, s), 8.13 (1H, dd, J = 9.4 and 5.9 Hz), 7.96 (1H, dd, J = 8.6 and 2.8 Hz), 7.61 - 7.54 (4H, m), 7.50 (1H, dd, J = 8.6 and 3.1 Hz) , 7.26-7.21(1H,m), 6.86(1H,d,J=9.0Hz),5.24-5.22(1H,m), 2.18(2H,d,J=7.0Hz),1.94-1.89(2H,m ), 1.86-1.79 (1H, m), 1.67-1.63 (2H, m), 1.60-1.54 (2H, m), 1.42-1.32 (2H, m).

MS (ESI) m / z: 498 (M + H) +.

(Embodiment 19)

(trans-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

(19a) {trans-4-[(5-bromopyrimidin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in Example (1a), methyl (cis-4-hydroxycyclohexyl)acetate (WO2009119534) (1.48 g) and 5-bromopyrimidin-2-ol (1.00 g) were obtained as colorless. The title compound was 0.62 g (33%).

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.50 (2H, s), 4.87-4.84 (1H, m), 3.68 (3H, s), 2.25-2.16 (3H, m), 1.99-1.82 (4H, m), 1.58-1.42 (2H, m), 1.18 (2H, q, J = 4.7 Hz).

MS (ESI) m/z: 330 (M+H) ⁺ .

(19b) (trans-4-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclohexylacetic acid) methyl ester

The compound (475 mg) obtained in Example (19a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in Example (1b). E The title compound 449 mg (91%) was obtained as a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.63 (2H, s), 7.32 (2H, d, J = 8.6 Hz), 6.78 (2H, d, J = 8.6 Hz), 4.99 - 4.91 ( 1H, m), 3.80 (2H, brs), 3.69 (3H, s), 2.26 (2H, d, J = 6.6 Hz), 2.23-2.20 (2H, m), 1.92-1.85 (3H, m), 1.65 -1.55 (2H, m), 1.26-1.18 (2H, m).

(19c) (trans-4-{[5-(4-{[(2-fluorophenyl))aminomethyl)amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained from the compound (19b) and 2-fluorophenylisocyanate (0.03 mL) obtained 86 mg (90%) as a white solid. The title compound (73 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.24 (1H, s), 8.89 (2H, s), 8.61 (1H, d, J = 2.4Hz), 8.19-8.14(1H,m), 7.67(2H,d,J=9.0Hz), 7.58(2H,d,J=8.6Hz), 7.28-7.23(1H,m),7.16(1H,dd,J= 7.8 and 7.8 Hz), 7.05-7.00 (1H, m), 4.95-4.87 (1H, m), 2.16-2.15 (2H, m), 2.13-2.10 (2H, m), 1.83-1.80 (1H, m) , 1.76-1.70 (2H, m), 1.52-1.42 (2H, m), 1.20-1.09 (2H, m).

MS (ESI) m / z: 465 (M+H) ⁺ .

(Embodiment 20)

{trans-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (68 mg) obtained from the compound (19b) and phenylisocyanate (0.028 mL) obtained 66 mg (72%) as a white solid. This urea (66 mg) was hydrolyzed to give the title compound (yield: 95%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.88 (1H, brs), 8.88 (2H, s), 8.78 (1H, brs), 7.65 (2H, d , J = 9.0 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.47 (2H, dd, J = 8.6 and 1.2 Hz), 7.29 (2H, dd, J = 8.0 and 8.0 Hz), 6.98 (1H) , dd, J = 7.4 and 7.5 Hz), 4.93-4.88 (1H, m), 2.15 (2H, d, J = 6.7 Hz), 2.13-2.10 (2H, m), 1.84-1.79 (2H, m), 1.75-1.70 (1H, m), 1.51-1.42 (2H, m), 1.20-1.09 (2H, m).

MS (ESI) m / z: 447 (M+H) ⁺ .

(Example 21)

(trans-4-{[5-(4-{[(4-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

The compound (68 mg) obtained from the compound (19b) and 4-methylphenylisocyanate (0.033 mL) were obtained as a white solid (yield: 68 mg, 71%). This urea (68 mg) was hydrolyzed to give the title compound (yield: 89%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.88 (2H, s), 8.81 (1H, brs), 8.64 (1H, brs), 7.64 (2H, d , J=9.0Hz), 7.57 (2H, d, J=8.7Hz), 7.35 (2H, d, J=8.2Hz), 7.10 (2H, d, J=8.2Hz), 4.95-4.87 (1H, m ), 2.25 (3H, s), 2.16 (2H, d, J = 7.0 Hz), 2.14-2.10 (2H, m), 1.84-1.79 (2H, m), 1.76-1.69 (1H, m), 1.52- 1.41 (2H, m), 1.20-1.09 (2H, m).

MS (ESI) m / z: 461 (M+H) ⁺ .

(Example 22)

(cis-4-{[5-(4-{[(2-fluoro-3-methylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl) Acetic acid

In the same manner as in Example (18a), Compound (171 mg) obtained from Example (1b) and 2-fluoro-3-methylaniline (63 mg) gave 222 mg (90%) as a white solid. ). This urea (222 mg) was hydrolyzed to give the title compound (m.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.24 (1H, brs), 8.88 (2H, s), 8.54 (1H, d, J = 2.8Hz), 7.99 (1H, dd, J = 8.0 and 8.0 Hz), 7.67 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.03 (1H, dd, J = 7.8 and 7.8 Hz) ), 6.90 (1H, dd, J = 7.1 and 7.1 Hz), 5.22-5.20 (1H, m), 2.26 (3H, d, J = 2.0 Hz), 2.19 (2H, d, J = 7.0 Hz), 1.98 -1.93(2H,m), 1.86-1.81(1H,m),1.71-1.63(2H,m),1.61-1.56(2H,m),1.43-1.33(2H,m).

MS (ESI) m / z: 495 (M+H) ⁺ .

(Example 23)

(cis-4-{[5-(4-{[(2-fluoro-4-methylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl) Acetic acid

The compound (171 mg) obtained in Example (1b) and 2-fluoro-4-methylaniline (63 mg) were obtained as a white solid 207 mg (84%). ). This urea (207 mg) was hydrolyzed to give the title compound 191 mg (95%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.16 (1H, brs), 8.87 (2H, s), 8.48 (1H, d, J = 2.4Hz), 7.99 (1H, dd, J = 8.4 and 8.4 Hz), 7, 66 (2H, d, J = 9.0 Hz), 7.57 (2H, d, J = 9.0 Hz), 7.08 (1H, dd, J = 12.1 and 1.5 Hz), 6.97 (1H, d, J = 7.8 Hz), 5.22-5.20 (1H, m), 2.27 (3H, s), 2.19 (2H, d, J = 7.0 Hz), 1.97-1.93 (2H, m), 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.42-1.33 (2H, m).

MS (ESI) m / z: 495 (M+H) ⁺ .

(Example 24)

(cis-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid

In the same manner as in Example (1c), the compound (102 mg) obtained from Example (1b) and 2,4-dimethylphenylisocyanate (0.11 mL) were obtained as a white solid 146 mg (quant. Yield). The title compound (115 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.16 (1H, brs), 8.87 (2H, s), 8.48 (1H, d, J = 2.4Hz), 7.99 (1H, dd, J = 8.4 and 8.4 Hz), 7.66 (2H, d, J = 9.0 Hz), 7.57 (2H, d, J = 9.0 Hz), 7.08 (1H, dd, J = 12.1 and 1.5 Hz) ), 6.97 (1H, d, J = 7.8 Hz), 5.22-5.20 (1H, m), 2.27 (3H, s), 2.19 (2H, d, J = 7.0 Hz), 1.97-1.93 (2H, m) , 1.87-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.42-1.33 (2H, m).

MS (ESI) m / z: 495 (M+H) ⁺ .

(Embodiment 25)

{trans-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyridin-2-yl)oxy]cyclohexyl}acetic acid

(25a){trans-4-[(5-bromopyridin-2-yl)oxy]cyclohexyl}acetic acid methyl ester

In the same manner as in the embodiment (1a), methyl (cis-4-hydroxycyclohexyl)acetate (WO2009119534) (3.43 g) and 5-bromopyridin-2-ol (2.78 g), cyania Methyl tributylphosphane (CMBP) (6.3 mL) gave the title compound 2.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.15 (1H, d, J = 3.1Hz), 7.62 (1H, dd, J = 8.8 and 2.5Hz), 6.60 (1H, d , J = 8.2 Hz), 4.93-4.85 (1H, m), 3.68 (3H, s), 2.24 (2H, d, J = 6.6 Hz), 2.16-2.12 (2H, m), 1.89-1.78 (3H, m), 1.50 -1.40 (2H, m), 1.23-1.13 (2H, m).

(25b) (trans-4-{[5-(4-aminophenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound (1.47 g) obtained from the example (25a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in the Example (1b). Pentacyclo-2-yl)aniline (980 mg) gave 897 mg (59%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.29 (1H, d, J = 2.4 Hz), 7.71 (1H, dd, J = 8.6 and 2.8 Hz), 7.33 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 6.72 (1H, d, J = 8.6 Hz), 5.01-4.94 (1H, m), 3.74 (2H, brs), 3.69 (3H, s), 2.25 (2H, d, J = 6.6 Hz), 2.21-2.17 (2H, m), 1.88-1.85 (3H, m), 1.55-1.44 (2H, m), 1.26-1.16 (2H, m).

(25c){trans-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyridin-2-yl)oxy]cyclohexyl}acetic acid

The compound (358 mg) obtained from Example (25b) and phenyl isocyanate (0.15 mL) were obtained white in the same manner as in Example (1c). Solid urea body 483 mg (quantitative yield). This urea (483 mg) was hydrolyzed to give the title compound 437 mg (94%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.79 (1H, brs), 8.71 (1H, brs), 8.43 (1H, d, J = 3.1Hz), 7.95 (1H, dd, J = 8.7 and 2.8 Hz), 7.59-7.53 (2H, m), 7.56 (2H, d, J = 7.8 Hz), 7.47 (2H, dd, J = 8.7 and 1.1 Hz), 7.29 (2H, dd, J=7.8 and 7.8 Hz), 6.98 (1H, dd, J=7.4 and 7.4 Hz), 6.82 (1H, d, J=8.7 Hz), 4.98-4.92 (1H, m), 2.15 ( 2H,d,J=7.1Hz),2.12-2.08(2H,m),1.82-1.78(1H,m),1.73-1.67(2H,m),1.46-1.36(2H,m),1.19-1.09( 2H, m).

MS (ESI) m / z: 446 (M+H) ⁺ .

(Example 26)

(trans-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl)acetic acid

The compound (170 mg) obtained in Example (25b) and 2,4-dimethylphenylisocyanate (0.092 mL) were obtained in the same manner as in the the the the The color solid urea was 244 mg (quantitative yield). This urea (244 mg) was hydrolyzed to give the title compound 224 mg (95%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.05 (1H, brs), 8.43 (1H, d, J = 2.0Hz), 7.95 (1H, dd, J =8.6 and 2.4 Hz), 7.89 (1H, brs), 7.67 (1H, d, J = 7.9 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 9.0 Hz), 7.00 (1H, s), 6.97 (1H, d, J = 8.6 Hz), 6.81 (1H, d, J = 9.0 Hz), 4.98 - 4.91 (1H, m), 2.23 (3H, s), 2.21 (3H) , s), 2.15 (2H, d, J = 6.7 Hz), 2.12 - 2.08 (2H, m), 1.82-1.78 (1H, m), 1.73-1.67 (2H, m), 1.46-1.36 (2H, m ), 1.19-1.09 (2H, m).

MS (ESI) m / z: 474 (M+H) ⁺ .

(Example 27)

{trans-3-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclopentyl}acetic acid

(27a) trans-{3-[(5-bromopyrimidin-2-yl)oxy]cyclopentyl}acetic acid methyl ester

In the same manner as in Example (1a), cis-(3-hydroxycyclopentyl)acetic acid methyl ester (WO2009119534) (1.91 g) and 5-bromopyrimidin-2-ol (1.75 g) were obtained. The title compound was 1.70 g (54%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.63 (2H, s), 7.32 (2H, d, J = 8.6 Hz), 6.78 (2H, dd, J = 6.2 and 2.0 Hz), 5.48- 5.43 (1H, m), 3.80 (2H, brs), 3.67 (3H, s), 2.71-2.63 (1H, m), 2.39 (2H, d, J = 7.1 Hz), 2.26-2.15 (2H, m) , 2.13 - 2.07 (1H, m), 1.97-1.88 (1H, m), 1.67-1.60 (1H, m), 1.35-1.25 (1H, m).

(27b) trans-(3-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclopentyl)acetic acid methyl ester

The compound obtained in Example (27a) (1.70 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in Example (1b). Pentacyclo-2-yl)aniline (1.18 g) gave the title compound 1.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.51 (2H, s), 5.39-5.36 (1H, m), 3.67 (3H, s), 2.70-2.58 (1H, m), 2.38 (2H , dd, J = 7.4 and 1.9 Hz), 2.23 - 2.06 (3H, m), 1.93-1.84 (1H, m), 1.65-1.59 (1H, m), 1.34-1.24 (1H, m).

(27c){trans-3-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclopentyl}acetic acid

The compound (144 mg) obtained from the compound (27b) and phenylisocyanate (0.062 mL) obtained 145 mg (74%) as a white solid. This urea (145 mg) was hydrolyzed to give the title compound 127 mg (91%)

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.90 (1H, brs), 8.88 (2H, s), 8.79 (1H, brs), 7.66 (1H, d , J = 9.0 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.47 (2H, dd, J = 8.8 and 1.0 Hz), 7.31 (2H, d, J = 7.4 Hz), 6.99 (2H, d , J=7.4Hz), 5.42-5.38(1H,m), 2.46-2.40(1H,m), 2.30(2H,dd,J=7.2 and 3.0Hz),2.22-2.13(1H,m),2.04- 1.93 (2H, m), 1.78-1.70 (1H, m), 1.63-1.56 (1H, m), 1.34-1.21 (1H, m).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Embodiment 28)

[trans-3-{[5-(4-{[(2-fluorophenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclopentyl]acetic acid

The compound (164 mg) obtained from the compound (27b) and 2-fluorophenylisocyanate (0.073 mL) obtained 233 mg (yield yield) as a white solid. . This urethane (233 mg) was hydrolyzed in the same manner as in Example (1d) to give the title compound 226 mg (yield).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.23 (1H, brs), 8.89 (2H, s), 8.61 (1H, d, J = 2.4Hz), 8.17(1H,m), 7.68(2H,d,J=9.0Hz), 7.58(2H,d,J=8.6Hz), 7.28-7.23(1H,m),7.16(1H,dd,J=7.8 and 7.8 Hz), 7.05-7.00 (1H, m), 5.42-5.38 (1H, m), 2.46-2.40 (1H, m), 2.30 (2H, dd, J=7.2 and 2.6 Hz), 2.22-2.13 (1H) , m), 2.03-1.93 (2H, m), 1.79-1.70 (1H, m), 1.63-1.56 (1H, m), 1.31-1.21 (1H, m).

MS (ESI) m / z: 451 (M+H) ⁺ .

(Example 29)

{cis-3-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclopentyl}acetic acid

(29a) cis-{3-[(5-bromopyrimidin-2-yl)oxy]cyclopentyl}acetic acid methyl ester

In the same manner as in the embodiment (1a), a trans-(3-hydroxycyclopentyl)acetic acid methyl ester (WO2009119534) (899 mg) and 5-bromopyrimidin-2-ol (875 mg) were obtained. The title compound was 812 mg (51%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.51 (2H, s), 5.36-5.31 (1H, m), 3.67 (3H, s), 2.49-2.33 (2H, m), 2.46 (2H , dd, J = 7.2 and 3.0 Hz), 2.00-1.88 (3H, m), 1.57-1.48 (2H, m).

(29b) cis-(3-{[5-(4-Aminophenyl)pyrimidin-2-yl]oxy}cyclopentyl)acetic acid methyl ester

The compound (812 mg) obtained by the example (29a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in the Example (1b). Pentacyclo-2-yl)aniline (564 mg) gave 624 mg (74%)

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.63 (2H, s), 7.32 (2H, d, J = 8.6 Hz), 6.78 (2H, dd, J = 6.2 and 2.0 Hz), 5.44 5.39 (1H, m), 3.80 (2H, brs), 3.67 (3H, s), 2.51-2.34 (2H, m), 2.03-1.98 (2H, m), 1.95-1.89 (3H, m), 1.59- 1.51 (2H, m).

(29c){cis-3-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclopentyl}acetic acid

The compound (122 mg) obtained from the compound (29b) and phenylisocyanate (0.052 mL) obtained 166 mg (yield yield) as a white solid. This urethane (166 mg) was hydrolyzed in the same manner as in Example (1d) to give the title compound 154 mg (yield).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.88 (2H, s), 8.84 (1H, brs), 8.74 (1H, brs), 7.66 (2H, d , J = 9.0 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.47 (2H, dd, J = 8.6 and 1.2 Hz), 7.30 (2H, dd, J = 8.0 and 8.0 Hz), 6.99 (1H) , dd, J=7, 5 and 7.5 Hz), 5.37-5.32 (1H, m), 2.41-2.33 (3H, m), 2.29-2.22 (1H, m), 2.02-1.94 (1H, m), 1.90 -1.80 (2H, m), 1.47-1.37 (2H, m).

MS (ESI) m / z: 437 (M+H) ⁺ .

(Embodiment 30)

[cis-3-{[5-(4-{[(2-fluorophenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclopentyl]acetic acid

The compound (164 mg) obtained in Example (29b) and 2-fluorophenylisocyanate (0.073 mL) obtained 231 mg (99%) as a white solid. This urea (231 mg) was hydrolyzed to give the title compound (yield: 95%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 9.23 (1H, brs), 8.89 (2H, s), 8.61 (1H, d, J = 2.7Hz), 8.19-8.14(1H,m), 7.68(2H,d,J=8.6Hz), 7.58(2H,d,J=9.0Hz), 7.28-7.23(1H,m),7.16(1H,dd,J= 7.8 and 7.8 Hz), 7.05-7.00 (1H, m), 5.37-5.32 (1H, m), 2.41-2.33 (3H, m), 2.29-2.22 (1H, m), 2.01-1.94 (1H, m) , 1.90- 1.80 (2H, m), 1.45-1.37 (2H, m).

MS (ESI) m / z: 451 (M+H) ⁺ .

(Example 31)

{cis-4-[(5-{4-[(pyridin-3-ylaminocarbamoyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

(31a) (cis-4-{[5-(4-{[(4-nitrophenoxy)carbonyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid methyl ester

The compound obtained in Example (1b) (1.36 g) and pyridine (0.34 mL) in dichloromethane (10 mL) were slowly added dropwise to 4-nitrophenylchlorocarbonate (8.06 g) at 0 °C. Methyl chloride solution (10 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour and concentrated. The residue was stirred with EtOAc EtOAc EtOAc.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 8.70 (2H, s), 8.32 (2H, d, J = 9.4Hz), 7.59 (2H, d, J = 8.6Hz), 7.53 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 9.4 Hz), 7.12 (1H, brs), 5.32-5.31 (1H, m), 3.68 (3H, s), 2.29 (2H, d, J = 7.0 Hz), 2.14 - 2.09 (2H, m), 1.99 - 1.91 (1H, m), 1.74-1.56 (6H, m).

(31b) {cis-4-[(5-{4-[(pyridin-3-ylaminocarbamoyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

A solution of the compound obtained in Example (31a) (253 mg) and 3-aminopyridine (47 mg) in acetonitrile (6 mL) The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (chromat chromatography / methylene chloride / methanol: 100:0:85:15) to afford 231 mg (yield of quantitative yield) as a white solid.

This urea (231 mg) was hydrolyzed to give the title compound 223 mg (99%)

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 9.67 (1H, brs), 9.40 (1H, brs), 8.98 (1H, d, J = 2.0Hz), 8.89 (2H, s), 8.43 (1H, d, J = 5.1 Hz), 8.25 (1H, d, J = 9.4 Hz), 7.77 (1H, dd, J = 8.4 and 5.2 Hz), 7.69 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 9.0 Hz), 5.22 - 5.21 (1H, m), 2.19 (2H, d, J = 7.0 Hz), 1.98 - 1.93 (2H, m), 1.87-1.80 (1H, m) , 1.71-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 448 (M+H) ⁺ .

(Example 32)

{cis-4-[(5-{4-[(pyridin-4-ylaminocarbamoyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (253 mg) obtained from Example (31a) and 4-aminopyridine (47 mg) were obtained as a white solid 203 mg (88%). . This urea (203 mg) was hydrolyzed to give the title compound 194 mg (99%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.0 (1H, brs), 10.9 (1H, brs), 9.89 (1H, brs), 8.90 (2H, s), 8.61 (2H, d , J = 7.1 Hz), 7.91 (2H, d, J = 7.0 Hz), 7.73 (2H, d, J = 9.0 Hz), 7.63 (2H, d, J = 8.6 Hz), 5.22 - 5.21 (1H, m ), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.93 (2H, m), 1.86-1.81 (1H, m), 1.72-1.64 (2H, m), 1.61-1.57 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 448 (M+H) ⁺ .

(Example 33)

{cis-4-[(5-{4-[(pyridin-2-ylaminocarbamoyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (253 mg) obtained from Example (31a) and 2-aminopyridine (47 mg) were obtained as a white solid 198 mg (86%). . This urea (198 mg) was hydrolyzed to give the title compound 182 mg (95%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 10.6 (1H, s), 9.5 (1H, s), 8.89 (2H, s), 8.89-8.32 (1H , m), 7.80-7.75 (1H, m), 7.70 (2H, d, J = 9.0 Hz), 7.66 (2H, d, J = 9.0 Hz), 7.52 (1H, d, J = 8.7 Hz), 7.05 -7.02 (1H, m), 5.22-5.20 (1H, m), 2.19 (2H, d, J = 7.0 Hz), 1.98-1.93 (2H, m), 1.86-1.80 (1H, m), 1.71-1.63 (2H, m), 1.61-1.56 (2H, m), 1.43-1.33 (2H, m).

MS (ESI) m / z: 448 (M+H) ⁺ .

(Example 34)

Trans-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexanecarboxylic acid

(34a) trans-4-[(5-bromopyrimidin-2-yl)oxy]cyclohexanecarboxylic acid methyl ester

In the same manner as in Example (1a), cis-4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) (1.13 g) and 5-bromopyrimidin-2-ol (1.00 g) were obtained as colorless. The title compound of the oil was 0.665 g (37%).

_{^{1 H NMR (500MHz, CDCl 3}} ): δ (ppm) = 8.50 (2H, s), 4.95-4.89 (1H, m), 3.69 (3H, s), 2.40-2.34 (1H, m), 2.23-2.19 (2H, m), 2.12-2.07 (2H, m), 1.68-1.53 (4H, m).

(34b) trans-4-{[5-(4-aminophenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

The compound (341 mg) obtained in Example (34a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in Example (1b). Pentacyclo-2-yl)aniline (240 mg) gave 273 mg (77%)

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.62 (2H, s), 7.31 (2H, d, J = 8.3 Hz), 6.78 (2H, d, J = 8.3 Hz), 5.03-4.97 ( 1H, m), 3.80 (2H, brs), 3.69 (3H, s), 2.42 - 2.36 (1H, m), 2.28-2.25 (2H, m), 2.13 - 2.09 (2H, m), 1.70-1.57 ( 4H, m).

(34c) trans-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexanecarboxylic acid

The compound (100 mg) obtained from Example (34b) and phenylisocyanate (0.046 mL) were obtained in the same manner as in Example (1c) to give 134 mg (98%) of the solid of the pale brown solid. This urea (129 mg) was hydrolyzed to give the title compound 117 mg (94%).

^{1 H NMR (500MHz, DMSO-} d 6): δ (ppm) = 12.15 (1H, brs), 8.88 (2H, s), 8.82 (1H, s), 8.71 (1H, s), 7.65 (2H, d , J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.3 Hz), 7.29 (2H, t, J = 7.9 Hz), 6.98 (1H, t, J = 7.4 Hz), 4.96-4.90 (1H, m), 2.33-2.27 (1H, m), 2.16-2.12 (2H, m), 2.01-1.97 (2H, m), 1.55-1.43 (4H, m).

(Example 35)

Trans-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid

The compound (100 mg) obtained from the compound (34b) and 2-fluorophenylisocyanate (0.048 mL) were obtained in the same manner as in the Example (1c) to obtain 144 mg of a urea compound as a pale brown solid. rate). This urea (138 mg) was hydrolyzed to give the title compound (yield: 121%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 12.14 (1H, s), 9.04 (1H, s), 8.43 (1H, s), 7.95 (1H, d, J = 8.4 Hz ), 7.88 (1H, s), 7.67 (1H, d, J = 8.3 Hz), 7.59-7.53 (3H, m), 7.00 (1H, s), 6.96 (1H, d, J = 7.5 Hz), 6.82 (1H, d, J = 8.6 Hz), 4.99-4.93 (1H, m), 2.31-2.27 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 2.16-2.10 (2H, m ), 2.00-1.95 (2H, m), 1.54-1.42 (4H, m)

(Example 36)

Trans-4-{[5-(4-{[(4-methylphenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexanecarboxylic acid

The compound (100 mg) obtained in Example (34b) and 4-methylphenylisocyanate (0.054 mL) were obtained in the same manner as in Example (1) to give 135 mg (96%) of a white solid. . The title compound (122 mg) was obtained as a white solid.

^{1 H NMR (500MHz, DMSO-} d 6): δ (ppm) = 12.14 (1H, brs), 8.88 (2H, s), 8.78 (1H, s), 8.61 (1H, s), 7.64 (2H, d , J = 8.3 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.09 (2H, d, J = 8.8 Hz), 4.96-4.90 (1H, m ), 2.33 - 2.27 (1H, m), 2.25 (3H, s), 2.16-2.12 (2H, m), 2.01-1.96 (2H, m), 1.55-1.45 (4H, m).

(Example 37)

Trans-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexanecarboxylic acid

(37a) trans-4-{[5-(4-Aminophenyl)pyridin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

In the same manner as in Example (1a), a yellow color was obtained from cis-4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) (1.00 g) and 5-bromopyridin-2-ol (1.16 g). Oil ether 889 mg (45%).

In the same manner as in the embodiment (1b), the ether (885 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were used. Aniline (617 mg) afforded 757 mg (82%)

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.29 (1H, d, J = 2.4 Hz), 7.71 (1H, dd, J = 8.1 and 2.2 Hz), 7.32 (2H, d, J = 8.3) Hz), 6.76 (2H, d, J = 8.3 Hz), 6.71 (1H, d, J = 8.8 Hz), 5.05-4.99 (1H, m), 3.74 (2H, brs), 3.69 (3H, s), 2.39-2.33 (1H, m), 2.27-2.21 (2H, m), 2.10-2.05 (2H, m), 1.71-1.63 (2H, m), 1.53-1.45 (2H, m).

(37b) trans-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl Alkanoic acid

The compound (100 mg) obtained in Example (37a) and 2,4-dimethylphenylisocyanate (0.070 mL) were obtained in the same manner as in Example (1c) to give a pale brown solid of 145 mg. (100%). This urea (143 mg) was hydrolyzed to give the title compound (yield: 76%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.29 (1H, d, J = 2.4 Hz), 7.71 (1H, dd, J = 8.1 and 2.2 Hz), 7.32 (2H, d, J = 8.3) Hz), 6.76 (2H, d, J = 8.3 Hz), 6.71 (1H, d, J = 8.8 Hz), 5.05-4.99 (1H, m), 3.74 (2H, brs), 3.69 (3H, s), 2.39-2.33 (1H, m), 2.27-2.21 (2H, m), 2.10-2.05 (2H, m), 1.71-1.63 (2H, m), 1.53-1.45 (2H, m).

(Example 38)

[cis-4-({4'-[(anilinocarbonyl)amino]biphenyl-4-yl}oxy)cyclohexyl]acetic acid

(38a) [cis-4-(4-bromophenoxy)cyclohexyl]acetic acid methyl ester

The title of pale yellow oil was obtained from (trans-4-hydroxycyclohexyl)acetic acid methyl ester (WO2009119534) (2.07 g) and 4-bromophenol (1.73 g) in the same manner as in the the the Compound 2.07 g (63%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ (ppm) = 7.36 (2H, d, J = 9.0Hz), 6.79 (2H, d, J = 9.0Hz), 4.48-4.47 (1H, m), 3.68 ( 3H, s), 2.27 (2H, d, J = 7.4 Hz), 2.01-1.97 (2H, m), 1.94-1.87 (1H, m), 1.63-1.54 (4H, m), 1.49-1.39 (2H, m).

(38b) {cis-4-[(4'-Aminobiphenyl-4-yl)oxy]cyclohexyl}acetic acid methyl ester

The compound (2.07 g) obtained from the example (38a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride in the same manner as in the Example (1b). Pentacyclo-2-yl)aniline (1.39 g) gave the title compound 1.14 g (53%).

¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 7.44 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 8.6 Hz), 6.94 (2H, d, J = 8.7 Hz) , 6.75 (2H, d, J = 8.6 Hz), 4.55 - 4.54 (1H, m), 3.71 (3H, s), 3.68 (2H, brs), 2.29 (2H, d, J = 7.5 Hz), 2.06- 2.02 (2H, m), 1.95-1.88 (1H, m), 1.65-1.45 (6H, m).

(38c) [cis-4-({4'-[(anilinocarbonyl)amino]biphenyl-4-yl}oxy)cyclohexyl]acetic acid

The compound (280 mg) obtained from Example (38b) and phenylisocyanate (0.12 mL) were obtained to give 333 mg (yield: 88%) as a white solid solid. This urea (333 mg) was hydrolyzed to give the title compound 306 mg (95%).

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.0 (1H, brs), 8.74 (1H, brs), 8.70 (1H, brs), 7.55-7.46 (8H, m), 7.29 (2H , dd, J = 7.6 and 7.6 Hz), 7.02-6.96 (3H, m), 4.61-4.60 (1H, m), 2.17 (2H, d, J = 7.0 Hz), 1.91-1.87 (2H, m), 1.84-1.78 (1H, m), 1.63-1.60 (2H, m), 1.56-1.52 (2H, m), 1.41-1.32 (2H, m).

MS (ESI) m / z: 445 (M+H) ⁺ .

(Example 39)

{cis-4-[(5-{4-[(cyclohexylaminomethyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid

The compound (253 mg) obtained from Example (31a) and the amine cyclohexane (50 mg) were obtained in the same manner as in the first half of Example (31b) to give a white solid of 220 mg (94%). ). The title compound (204 mg) was obtained as a white solid.

^{1 H NMR (400MHz, DMSO-} d 6): δ (ppm) = 12.1 (1H, brs), 8.84 (2H, s), 8.46 (1H, s), 7.59 (2H, d, J = 9.0Hz), 7.49 (2H, d, J = 8.6 Hz), 6.13 (1H, d, J = 7.4 Hz), 5.22-5.18 (1H, m), 3.50-3.44 (1H, m), 2.19 (2H, d, J = 7.0 Hz), 1.97.1.22 (2H, m), 1.83-1.79 (3H, m), 1.69-1.56 (7H, m), 1.42-1.27 (4H, m), 1.22-1.15 (3H, m).

MS (ESI) m / z: 453 (M+H) ⁺ .

(Embodiment 40)

Cis-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexanecarboxylic acid

(40a) cis-4-{[5-(4-Aminophenyl)pyridin-2-yl]oxy}cyclohexanecarboxylic acid methyl ester

In the same manner as in the embodiment (1a), a trans--4-hydroxycyclohexanecarboxylic acid methyl ester (WO2009119534) (1.00 g) and 5-bromopyridin-2-ol (1.15 g) were obtained. Yellow oil ether 1.38 g (70%).

In the same manner as in Example (1b), from ether (500 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (350 mg) gave 519 mg (yiel.

¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 8.28 (1H, d, J = 2.0 Hz), 7.71 (1H, dd, J = 8.5 and 2.8 Hz), 7.32 (2H, d, J = 8.7) Hz), 6.75 (3H, d, J = 8.3 Hz), 5.27-5.21 (1H, m), 3.74 (2H, s), 3.70 (3H, s), 2.47-2.41 (1H, m), 2.07-1.93 (4H, m), 1.82-1.76 (2H, m), 1.73-1.66 (2H, m).

(40b) cis-4-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclohexyl Alkanoic acid

The compound (110 mg) obtained in Example (40a) and 2,4-dimethylphenylisocyanate (0.080 mL) were obtained in the same manner as in Example (1). This urea (54 mg) was hydrolyzed in the same manner as in Example (1d) to give the title compound 45 mg (28%, 2 steps) as white solid.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 12.1 (1H, s), 9.08 (1H, s), 8.41 (1H, s), 7.95 (1H, d, J = 8.6 Hz ), 7.90 (1H, s), 7.67 (1H, d, J = 8.1 Hz), 7.59-7.53 (3H, m), 6.99 (1H, s), 6.95 (1H, d, J = 8.2 Hz), 6.85 (1H, d, J = 8.4 Hz), 5.21-5.15 (1H, m), 2.41-2.36 (1H, m), 2.23 (3H, s), 2.21 (3H, s), 1.92-1.60 (8H, m ).

MS (ESI) m / z: 460 (M+H) ⁺ .

(Example 41)

[cis-3-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclopentyl] Acetic acid

The compound (980 mg) obtained in Example (29b) and 2,4-dimethylphenylisocyanate (0.44 mL) were obtained in the same manner as in Example (1c) to give a white solid. (93%). This urea (1.32 g) was hydrolyzed to give the title compound 305 mg (24%).

^{1 H NMR (400MHz, DMSO-} d6): δ (ppm) = 12.1 (1H, s), 9.06 (1H, s), 8.44 (1H, d, J = 2.7Hz), 7.95 (1H, dd, J = 8.8 and 2.5 Hz), 7.89 (1H, s), 7.68 (1H, d, J = 8.2 Hz), 7.59 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 7.01 (1H, s), 6.97 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.6 Hz), 5.37-5.33 (1H, m), 2.39-2.33 (3H, m), 2.28- 2.24(1H,m), 2.24(3H,s), 2.22(3H,s),2.00-1.92(1H,m),1.86-1.76(2H,m),1.43-1.33(2H,m).

MS (ESI) m / z: 458 (MH) ⁺ .

(Example 42)

[trans-3-{[5-(4-{[(2,4-dimethylphenyl)aminemethanyl]amino}phenyl)pyridin-2-yl]oxy}cyclopentyl] Acetic acid

The compound obtained in Example (27b) (1.07 g) and 2,4-dimethylphenylisocyanate (0.48 mL) were obtained in the same manner as in Example (1c) to give a pale orange solid. 860 mg (55%). This urea (860 mg) was hydrolyzed to give the title compound (290 mg (35%)

¹ H NMR (400 MHz, DMSO-d6): δ (ppm) = 12.0 (1H, brs), 9.09 (1H, s), 8.43 (1H, d, J = 1.9 Hz), 7.95 (1H, dd, J = 8.6 and 2.4 Hz), 7.92 (1H, s), 7.67 (1H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.9 Hz), 7.55 (2H, d, J = 9.0 Hz), 7.00 (1H, s), 6.97 (1H, d, J = 8.2 Hz), 6.83 (1H, d, J = 8.3 Hz), 5.43-5.38 (1H, m), 2.46-2.38 (1H, m), 2.32 2.26(2H,m), 2.23(1H,s), 2.21(3H,s), 2.18-2.11(3H,m),1.99-1.91(1H,m),1.75-1.67(2H,m),1.61- 1.53 (1H, m), 1.61-1.53 (1H, m).

MS (ESI) m / z: 460 (M+H) ⁺ .

(Test Example 1) (1) Modulation of DGAT1 enzyme

The DGAT1 enzyme was adjusted and stored according to the method described in US2007/0249620.

(2) DGAT1 inhibitory activity test

The following composition of the reaction solution [175 mM Tris-HCl (pH 8.0), 8 mM MgCl ₂ , 1 mg / ml BSA, 0.3 mM 1,2-dioleyl-sn-glycerol (add 10% 10 times concentration EtOH solution), 10 μM [ ¹⁴ C]-oleryl-CoA (about 50 mCi/mmol), 0.5% triton X-100 (Dow Chemical), DGAT1 enzyme (10 μg) obtained in Test Example 1 (1), The test compound or vehicle (DMSO/MeOH, 7:3 solution, 5% addition), total volume 50 μl] was incubated at room temperature (23 ° C) for 30 minutes. A reaction stop solution (70 μl) composed of isopropyl alcohol/1-heptane/water (80:20:2, v/v/v) was added to the reaction mixture and stirred, and then water (30 μl) and 1-water were added thereto. Heptane (100 μl) and stirred. The 1-heptane layer (50 μl) was developed on a TLC disk and developed with a developing solvent of 1-hexane/diethyl ether/acetic acid (85:15:1, v/v/v). The radioactivity of the glyceride segment was quantified by a BAS2000 bioimage analyzer (Fuji film), and the inhibitory activity of the test compound was calculated by the following formula in comparison with the control group. Further, the radioactivity of the unreacted (0 minute culture) was used as a background.

Obstruction rate = 100 - [(radiation activity when test compound is added) - (background)] / [(radiation activity of control group) - (background)] × 100

The compounds of Examples 1-42 showed an inhibition rate of 50% or more at a test compound concentration of 1 μg/ml.

Further, the DGAT inhibitory activity test is not limited to the above method, and for example, a microsome prepared from a small intestine, an adipose tissue or a liver of an animal such as a rat or a mouse may be used as the DGAT enzyme. Further, microsomes prepared from cultured cells (3T3-L1 fat cells, primary cultured adipocytes, Caco2 cells, HepG2 cells, etc.) or cultured cells in which DGAT is highly expressed may be used as the DGAT enzyme. Further, in order to shorten the time and evaluate a large number of test compounds more efficiently, a flush plate (PerkinElmer) which omits the extraction operation can be used.

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

(Test Example 2)

The digestion and absorption of DGAT1 enzyme in neutral fat is important. When the small intestine DGAT1 is blocked, the absorption of neutral fat is inhibited. The biological activity of DGAT1 inhibition was evaluated by using neutral fat absorption inhibition after neutral fat load as an index. Male C57BL/6N mice (7-12 weeks old, body weight 17-25 g, Charles River, Japan) that were fasted for 1 night were divided into vehicle group 1, vehicle group 2, and each test compound group, and each was orally administered. And (5 mL/kg) vehicle (0.5% methylcellulose) or each test compound (1 to 10 mg/kg) suspended in the vehicle. After a certain period of time, intraperitoneal administration of (5 mL/kg) lipoprotein lipase inhibitor (Pluronic-F127: Sigma-Aldrich), 1 g/kg, at 20% weight The amount ratio was dissolved in physiological saline, and immediately, the vehicle group 1 was orally administered with distilled water, the vehicle group 2 and the compound group were orally administered (0.2 mL/mouse) with an emulsion containing 20% neutral fat ( Intralipid 20%: Terumo (shares). After a certain period of time from 1 to 4 hours after administration, blood was collected from the tail vein or the right ventricle, and the plasma was quickly separated and recovered. The neutral fat concentration in the plasma was determined using a commercially available kit (triglyceride E TEST WAKO: and light pure). Pharmaceutical industry (shares)) to measure. In this method, by the administration of a lipoprotein lipase inhibitor, the decomposition of neutral fat in the blood is inhibited, and the neutral fat accumulates in the blood, but the source is divided into two types: external factors absorbed through the digestive tract. Sexual and intrinsic to be released by the liver. The neutral fat absorption inhibitory activity of each test compound was calculated based on the following calculation formula, and the effect of the intrinsic neutral fat was removed. Further, it was confirmed that each test compound had no effect on the endogenous neutral fat concentration.

Neutral fat absorption inhibitory activity (%) = 100 - [(neutral fat concentration in each test compound group) - (median group 1 neutral fat concentration)] / [(media group 2 neutral fat concentration) - (media group 1 neutral fat concentration)] × 100

The compounds of Examples 1-30 and 34-42 showed a neutral fat absorption inhibitory activity of 60% or more in an amount of 3 mg/kg or less.

From the above results, the compound of the present invention has excellent neutral fat absorption inhibiting activity.

(Test Example 3)

Individual male C57BL/6N mice (7-12 weeks old, body weight 17-25 g, Charles River, Japan) were fed with high fat food (fat content 45 kcal%: Research diet D12451) for more than 1 week to acclimate. . Animals were equally distributed in the experimental group based on the amount of bait during the period, so that After one night of fasting, each group was orally administered (10 mL/kg) vehicle (0.5% methylcellulose) or a test compound (1 to 10 mg/kg) suspended in vehicle. After 30 minutes, the bait was fed with a high-fat diet, and the amount of the bait was measured 6 hours after the start of the feeding. The feeding inhibitory activity of each test compound was calculated based on the following calculation formula.

Ingestion inhibition activity (%) = [(the amount of the bait in the vehicle group) - (the amount of the bait in each test compound group)] / [(the amount of the bait in the vehicle group)] × 100

The compound of Example 1-2 showed an intake inhibiting activity of 25% or more in an amount of 10 mg/kg or less.

From the above results, the compound of the present invention has an excellent feeding inhibition effect.

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

Formulation Example 1: Capsule

The powder of the above formulation was mixed, sieved through a 60 mesh sieve, and the powder was placed in a 250 mg gelatin capsule to prepare a capsule.

Formulation Example 2: Lozenges

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 a tablet. This tablet can be applied to the sugar coating as necessary.

[Industry use possibility]

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

Claims (23)

a compound represented by the formula (I) or a pharmacologically acceptable salt thereof, Wherein R is a phenyl group which may be substituted by 1 to 5 groups independently selected from the group of substituents A, a pyridyl group which may be substituted with 1 to 3 groups independently selected from the group of substituent A or C ₃ -C ₆ cycloalkyl, Q represents a nitrogen atom or a group represented by the formula -CH=, U represents a nitrogen atom or a group represented by the formula -CH=, V represents a nitrogen atom or a group represented by the formula -CH=, and m represents 0. Or 1, n represents 0 or 1, and the substituent group A represents a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ halogenated group. Alkoxy, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, carboxyl group, C _2- C ₇ alkylcarbonyl, C ₂ -C ₇ alkoxycarbonyl, amine, mono-C ₁ -C ₆ alkylamino, di-(C ₁ -C ₆ alkyl)amine, mono-C _a group consisting of a _2- C ₇ alkylcarbonylamino group, a mono-C ₁ -C ₆ alkylsulfonylamino group, a cyano group, a nitro group, and a hydroxyl group]. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), a formula (Ib), a formula (Ic), a formula (Id), a pass Formula (Ie) or formula (If), The compound of claim 1 or a pharmacologically acceptable salt thereof, wherein the formula (I) is a formula (Ia), A compound or a pharmacologically acceptable salt thereof, according to any one of claims 1 to 3, wherein R is a phenyl group which may be substituted with 1 to 5 groups independently selected from the group of substituent A. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R is independently selected from 1 to 3 (fluorine atom, chlorine atom, methyl group and methoxy group). a substituted phenyl group. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein R is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- Methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-4-fluoro Phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2,4-dimethylphenyl, 2-methoxy-5-methylphenyl or 2, 4,5-trifluorophenyl. A compound or a pharmacologically acceptable salt thereof, which is: (cis-4-{[5-(4-{[(2-fluorophenyl))aminomethane]amino}phenyl)pyrimidine-2 -yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(4-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl ]oxy}cyclohexyl)acetic acid, {cis-4-[(5-{4-[(anilinocarbonyl)amino]phenyl}pyrimidin-2-yl)oxy]cyclohexyl}acetic acid, (cis 4-(5-(4-{[(3-fluorophenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5-(4-{[(4-fluorophenyl))aminomethyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis -4-{[5-(4-{[(2-methylphenyl))aminomethane]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4 -{[5-(4-{[(3-methylphenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{ [5-(4-{[(2-methoxyphenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[ 5-(4-{[(3-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5 -(4-{[(4-methoxyphenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[5- (4-{[(2,4,5-trifluorophenyl)aminemethanyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis-4-{[ 5-(4-{[(2-methoxy-5-methylphenyl)aminemethylmercapto]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis- 4-{[5-(4-{[(2-fluoro-3-methylphenyl)amine-carbamoyl]amino}phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid, (cis -4-{[5-(4-{[(2-Fluoro-4-methylphenyl)aminemethanyl]amino} Aminopyrimidin-2-yl]oxy}cyclohexyl)acetic acid, or (cis-4-{[5-(4-{[(2,4-dimethylphenyl))aminomethyl)amino) }Phenyl)pyrimidin-2-yl]oxy}cyclohexyl)acetic acid. A thiol-coenzyme A: an inhibitor of diyl glyceryl thiol transferase (Acyl-CoA: diacylglycerol acyltransferase), which comprises a compound selected from any one of claims 1 to 7 or a pharmacologically acceptable thereof Salt as an active ingredient. An ingestion inhibitor and/or an appetite suppressant comprising a compound selected from any one of claims 1 to 7 or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition containing a compound selected from any one of items 1 to 7 of the patent application or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition according to claim 10, wherein the pharmaceutical composition has a hindrance effect of 醯Kytozyme A: dimercaptoglycerol hydrazinotransferase. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition has an action of suppressing food intake and/or appetite suppressing. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is used for obstructing 醯Kystase A: dimercaptoglyceryl thiol transferase, hindering synthesis of triglyceride, absorption of triglyceride Inhibition, and treatment and/or prevention of a disease that treats, improves, reduces, and/or prevents symptoms. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is prevented from being treated and improved by hindering the synthesis of 醯Kyethase A: dimercaptoglycerol thiol transferase and triglyceride. Treatment and/or prevention of diseases that are alleviated and/or prevented. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is used for obesity, obesity, hyperlipidemia, high triglyceride, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes Diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetes) Macrovascular disease, cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating treatment and / Or prevention. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is for the treatment and/or prevention of obesity or obesity. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is for the treatment and/or prevention of diabetes. The compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof for use in the treatment and/or prevention of the following diseases: obesity, obesity, hyperlipidemia, high triglyceride blood Disease, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, Non-alcoholic steatohepatitis, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. A use of a compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition. For example, the application of the scope of the patent application is for obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, glucose tolerance, diabetes, diabetes Complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic omental disease, diabetic macroangiopathy), Treatment and/or prevention of cataracts, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovarian syndrome, atherosclerosis, atherosclerosis, diabetic atherosclerosis, ischemic heart disease or overeating. A method for the treatment and/or prevention of a disease, which comprises administering a pharmacologically effective amount of a compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof to a warm-blooded animal. For example, the method of claim 21, wherein the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, abnormal lipid metabolism, insulin resistance syndrome, abnormal glucose tolerance, diabetes, diabetes complications (including Diabetic peripheral neuropathy, diabetic nephropathy, diabetic omental disease, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, atherosclerosis, atherosclerosis, diabetes Atherosclerosis, ischemic heart disease or overeating. The method of claim 21, wherein the warm-blooded animal is a human.